Annals of Human Genetics via MedWorm.com

Association of Genetic Variants, Ethnicity and Preterm Birth with Amniotic Fluid Cytokine Concentrations

Annals of Human Genetics — Wed, 10 Mar 2010 00:00:00 +0100

We examined the association of 166 single nucleotide polymorphisms (SNPs) in cytokines and cytokine related genes with cytokine concentrations (IL-1[beta], IL-8, and IL-10) in the amniotic fluid (AF). These cytokines have been associated with spontaneous preterm birth (PTB) and their genetic regulation may play a role in disease risk. These associations were studied in both PTB and term births in African Americans and Caucasians; maternal and fetal genotypes were studied separately. Analyses modeled genotype, pregnancy status, and marker by pregnancy status (case/control) interaction with cytokine concentration as outcome. Our results indicate that AF cytokines (IL-1[beta] and IL-10) were associated with interactions between pregnancy status and both maternal and fetal SNPs, with the most ...

Population-Specific Susceptibility to Crohn's Disease and Ulcerative Colitis; Dominant and Recessive Relative Risks in the Japanese Population

Annals of Human Genetics — Wed, 10 Mar 2010 00:00:00 +0100

Crohn's disease (CD), a type of chronic inflammatory bowel disease (IBD), is commonly found in European and East Asian countries. The calculated heritability of CD appears to be higher than that of ulcerative colitis (UC), another type of IBD. Recent genome-wide association studies (GWAS) have identified more than thirty CD-associated genes/regions in the European population. In the East Asian population, however, a clear association between CD and an associated gene has only been detected with TNFSF15. In order to determine if CD susceptibility differs geographically, nine SNPs from seven of the European CD-associated genomic regions were selected for analysis. The genotype frequencies for these SNPs were compared among the 380 collected Japanese samples, which consisted of 212 IBD cases ...

Common Susceptibility Variants Examined for Association with Dilated Cardiomyopathy

Annals of Human Genetics — Tue, 02 Mar 2010 00:00:00 +0100

Rare mutations in more than 20 genes have been suggested to cause dilated cardiomyopathy (DCM), but explain only a small percentage of cases, mainly in familial forms. We hypothesised that more common variants may also play a role in increasing genetic susceptibility to DCM, similar to that observed in other common complex disorders. To test this hypothesis, we performed case-control analyses on all DNA polymorphic variation identified in a resequencing study of six candidate DCM genes (CSRP3, LDB3, MYH7, SCN5A, TCAP, and TNNT2) conducted in 289 unrelated white probands with DCM of unknown cause and 188 unrelated white controls. In univariate analyses, we identified associated common variants at LDB3 site 10779, LDB3 site 57877, MYH7 sites 16384 and 17404, and TCAP sites 140 and 1735. Mult...

Limited Distribution of a Cardiomyopathy-Associated Variant in India

Annals of Human Genetics — Mon, 01 Mar 2010 00:00:00 +0100

Heart failure is a leading cause of death of people in South Asia, and cardiomyopathy is a major cause of heart failure. Myosin binding protein C (MYBPC3) is expressed in the heart muscle, where it regulates the cardiac response to adrenergic stimulation and is important for the structural integrity of the sarcomere. Mutations in the MYBPC3 gene are associated with hypertrophic or dilated cardiomyopathies. A 25-base-pair deletion in intron 32 causes skipping of the downstream exon and is associated with familial cardiomyopathy. To date, this deletion is found primarily in India and South Asia, although it is also found at low frequency in Southeast Asia. In order to better characterise the distribution of this variant, we determined its frequency in 447 individuals from 19 populations, inc...

Heritability of Obesity-related Phenotypes and Association with Adiponectin Gene Polymorphisms in the Chinese National Twin Registry

Annals of Human Genetics — Mon, 01 Mar 2010 00:00:00 +0100

The purpose of this study was to estimate the heritability of obesity-related phenotypes and investigate the association of adiponectin gene polymorphisms +45T>G and +276G>T with these measures in Chinese twins. 1260 twin pairs were recruited from two cities through the Chinese National Twin Registry System from 2001 to 2005. Two SNPs at the adiponectin locus (+45T>G and +276G>T) were genotyped. Structural equation modeling (SEM) was used to estimate heritability and the best-fitting variance component model. The regular association among all twins was analysed with generalised estimating equations (GEE). Sib-transmission/disequilibrium test (TDT) within dizygotic (DZ) twin pairs discordant for their genotype was performed using SEM. Additive genetic, common and unique environmental (ACE) ...

GJB2 Mutations in Mongolia: Complex Alleles, Low Frequency, and Reduced Fitness of the Deaf

Annals of Human Genetics — Mon, 01 Mar 2010 00:00:00 +0100

We screened the GJB2 gene for mutations in 534 (108 multiplex and 426 simplex) probands with non-syndromic sensorineural deafness, who were ascertained through the only residential school for the deaf in Mongolia, and in 217 hearing controls. Twenty different alleles, including four novel changes, were identified. Biallelic GJB2 mutations were found in 4.5% of the deaf probands (8.3% in multiplex, 3.5% in simplex). The most common mutations were c.IVS1 + 1G > A (c.-3201G > A) and c.235delC with allele frequencies of 3.5% and 1.5%, respectively. The c.IVS1 + 1G > A mutation appears to have diverse origins based on associated multiple haplotypes. The p.V27I and p.E114G variants were frequently detected in both deaf probands and hearing controls. The p.E114G variant was always in cis with the...

Linkage Disequilibrium Pattern in Asthma Candidate Genes from 5q31-q33 in the Singapore Chinese Population

Annals of Human Genetics — Wed, 13 Jan 2010 00:00:00 +0100

In this study, we investigated 20 asthma candidate genes from this region for all possible informative polymorphisms within our population, linkage disequilibrium (LD) structure and tagging SNP transferability from HapMap populations. We re-sequenced these genes and identified 267 polymorphisms including 26 insertion-deletions, four microsatellite markers and 237 single nucleotide polymorphisms. The region contained 17 distinct LD blocks with the largest within the serine peptidase inhibitor kazal type 5 (SPINK5) gene spanning 23 kb. Of the 267 polymorphisms identified, 40% are represented in HapMap Han Chinese from Beijing and 29% in Han Chinese from Denver. 72% of the polymorphisms can be represented by tagged SNPs from the HapMap Beijing Han Chinese population and are highly correlated ...

Founder Mutation(s) in the RSPH9 Gene Leading to Primary Ciliary Dyskinesia in Two Inbred Bedouin Families

Annals of Human Genetics — Wed, 13 Jan 2010 00:00:00 +0100

A rare mutation in the RSPH9 gene leading to primary ciliary dyskinesia was previously identified in two Bedouin families, one from Israel and one from the United Arab Emirates (UAE). Herein we analyse mutation segregation in the Israeli family, present the clinical disease spectrum, and estimate mutation age in the two families. Mutation segregation was studied by restriction fragment length analysis. Mutation ages were estimated using a model of the decrease in the length of ancestral haplotypes. The mutations in each of the two families had a common ancestor less than 95 and less than 17 generations in the past. If the mutations in the two families are descended from a common ancestor, that mutation would have to have arisen at least 150 generations ago. If the Bedouin population has be...

Genome-Wide Association Study Confirms SNPs in SNCA and the MAPT Region as Common Risk Factors for Parkinson Disease

Annals of Human Genetics — Wed, 13 Jan 2010 00:00:00 +0100

This study confirms that SNCA and the MAPT region are major genes whose common variants are influencing risk of PD. (Source: Annals of Human Genetics)

Interaction between Fibrinogen and IL-6 Genetic Variants and Associations with Cardiovascular Disease Risk in the Cardiovascular Health Study

Annals of Human Genetics — Wed, 16 Dec 2009 15:31:25 +0100

The inflammatory cytokine interleukin-6 (IL-6) is a main regulator of fibrinogen synthesis, though its interaction with fibrinogen genes (FGA, FGB, FGG) and subsequent impact on cardiovascular disease (CVD) risk is not well-studied. We investigated joint associations of fibrinogen and IL6 tagSNPs with fibrinogen concentrations, carotid intima-media thickness, and myocardial infarction or ischemic stroke in 3900 European-American Cardiovascular Health Study participants. To identify combinations of genetic main effects and interactions associated with outcomes, we used logic regression. We also evaluated whether the relationship between fibrinogen SNPs and fibrinogen level varied by IL-6 level using linear regression models with multiplicative interaction terms. Combinations of fibrinogen a...

Inferring Continental Ancestry of Argentineans from Autosomal, Y-Chromosomal and Mitochondrial DNA

Annals of Human Genetics — Tue, 15 Dec 2009 00:00:00 +0100

We investigated the bio-geographic ancestry of Argentineans, and quantified their genetic admixture, analyzing 246 unrelated male individuals from eight provinces of three Argentinean regions using ancestry-sensitive DNA markers (ASDM) from autosomal, Y and mitochondrial chromosomes. Our results demonstrate that European, Native American and African ancestry components were detectable in the contemporary Argentineans, the amounts depending on the genetic system applied, exhibiting large inter-individual heterogeneity. Argentineans carried a large fraction of European genetic heritage in their Y-chromosomal (94.1%) and autosomal (78.5%) DNA, but their mitochondrial gene pool is mostly of Native American ancestry (53.7%); instead, African heritage was small in all three genetic systems ( (So...

Frequency of the AGT Pro11Leu Polymorphism in Humans: does Diet Matter?

Annals of Human Genetics — Tue, 15 Dec 2009 00:00:00 +0100

The Pro11Leu substitution in the AGXT gene, which causes primary hyperoxaluria type 1, is found with high frequency in some human populations (e.g., 5[ndash]20% in Caucasians). It has been suggested that this detrimental mutation could have been positively selected in populations with a meat-rich diet. In order to test this hypothesis, we investigated the occurrence of Pro11Leu in both herder and agriculturalist populations from Central Asia. We found a lower frequency of this detrimental mutation in herders, whose diet is more meat-rich, as compared to agriculturalists, which therefore challenges the universality of the previous claim. Furthermore, when combining our original data with previously published results, we could show that the worldwide genetic differentiation measured at the P...

Different Evolutionary Histories of the Coagulation Factor VII Gene in Human Populations?

Annals of Human Genetics — Tue, 15 Dec 2009 00:00:00 +0100

In conclusion, our data suggest, although do not prove, different evolutionary histories in the F7 promoter region between Mediterraneans and Amerindians. (Source: Annals of Human Genetics)

Epidemiological Approach to Identifying Genetic Predispositions for Atypical Hemolytic Uremic Syndrome

Annals of Human Genetics — Tue, 15 Dec 2009 00:00:00 +0100

Atypical hemolytic uremic syndrome (aHUS) is caused by several susceptibility genes. A registry including analyses of susceptibility genes, familial occurrence and genotype-phenotype correlation should provide classification insights. Registry data of 187 unrelated index patients included age at onset, gender, family history, relapse of aHUS and potentially triggering conditions. Mutation analyses were performed in the genes CFH, CD46 and CFI and in the six potential susceptibility genes, FHR1 to FHR5 and C4BP. Germline mutations were identified in 17% of the index cases; 12% in CFH, 3% in CD46 and 2% in CFI. Twenty-nine patients had heterozygous mutations and one each had a homozygous and compound heterozygous mutation. Mutations were not found in the genes FHR1-5 and C4BP. In 40% of the ...

HMGA2 Is Confirmed To Be Associated with Human Adult Height

Annals of Human Genetics — Sat, 21 Nov 2009 00:00:00 +0100

Recent genome-wide association studies have identified a novel polymorphism, rs1042725, in the HMGA2 gene for human adult height, a highly heritable complex trait. Replications in independent populations are needed to evaluate a positive finding and determine its generality. Thus, we performed a replication study to examine the associations between polymorphisms in HMGA2 and adult height in two US Caucasian populations (an unrelated sample of 998 subjects and a family-based sample of 8385 subjects) and a Chinese population (1638 unrelated Han subjects). We confirmed the association between rs1042725 in HMGA2 and adult height both in the unrelated and family-based Caucasian populations (overall P= 4.25 × 10[minus]9). Another two SNPs (rs7968902 and rs7968682), which were in high linkage di...

Attributing Hardy-Weinberg Disequilibrium to Population Stratification and Genetic Association in Case-Control Studies

Annals of Human Genetics — Fri, 20 Nov 2009 00:00:00 +0100

Loci exhibiting Hardy-Weinberg disequilibrium (HWD) are often excluded from association studies, because HWD may indicate genotyping error, population stratification or selection bias. For case-control studies, HWD can result from a genetic effect at the locus. We extend the modelling to accommodate both stratification and genetic effects. Theoretical genotype frequencies and HWD coefficients are derived under a general genetic model for a population with two strata. Maximum likelihood is used to estimate model parameters and a test for lack of fit identifies the models most consistent with the data. Simulations were used to assess the method. The technique was applied to a group of ethnically and clinically heterogeneous kidney stone formers and controls, both exhibiting HWD for the R990G...

Fitness Among Individuals with Early Childhood Deafness: Studies in Alumni Families from Gallaudet University

Annals of Human Genetics — Fri, 20 Nov 2009 00:00:00 +0100

The genetic fitness of an individual is influenced by their phenotype, genotype and family and social structure of the population in which they live. It is likely that the fitness of deaf individuals was quite low in the Western European population during the Middle Ages. The establishment of residential schools for deaf individuals nearly 400 years ago resulted in relaxed genetic selection against deaf individuals which contributed to the improved fitness of deaf individuals in recent times. As part of a study of deaf probands from Gallaudet University, we collected pedigree data, including the mating type and the number and hearing status of the children of 686 deaf adults and 602 of their hearing siblings. Most of these individuals had an onset of severe to profound hearing loss by earl...

Effect of Gene-environment Interactions on Mental Development in African American, Dominican, and Caucasian Mothers and Newborns

Annals of Human Genetics — Tue, 27 Oct 2009 00:00:00 +0100

The health impact of environmental toxins has gained increasing recognition over the years. Polycyclic aromatic hydrocarbons (PAHs) and environmental tobacco smoke (ETS) are known to affect nervous system development in children, but no studies have investigated how polymorphisms in PAH metabolic genes affect child cognitive development following PAH exposure during pregnancy. In two parallel prospective cohort studies of non-smoking African American and Dominican mothers and children in New York City and of Caucasian mothers and children in Krakow, Poland, we explored the effect of gene-PAH interaction on child mental development index (MDI). Genes known to play important roles in the metabolic activation or detoxification of PAHs were selected. Genetic variations in these genes could inf...

Variable selection method for quantitative trait analysis based on parallel genetic algorithm

Annals of Human Genetics — Thu, 01 Oct 2009 23:00:00 +0100

In this study, we use parallel genetic algorithm (PGA) to identify genetic and environmental factors in genetic association studies of complex human diseases. Our method can take account of both multiple markers across the genome and environmental factors, and also can be used to do fine mapping based on the results of haplotype analysis to select the markers that are associated with the quantitative traits. Using both simulated and real examples, we show that PGA is able to choose the variables correctly and is also an easy-to-use variable selection tool. (Source: Annals of Human Genetics)

A Variable-Sized Sliding-Window Approach for Genetic Association Studies via Principal Component Analysis

Annals of Human Genetics — Sun, 06 Sep 2009 23:00:00 +0100

In this study, we propose a new approach for genetic association analysis that is based on a variable-sized sliding-window framework and employs principal component analysis to find the optimum window size. With the help of the bisection algorithm in window-size searching, our method is more computationally efficient than available approaches. We evaluate the performance of the proposed method by comparing it with two other methods[mdash]a single-marker method and a variable-length Markov chain method. We demonstrate that, in most cases, the proposed method out-performs the other two methods. Furthermore, since the proposed method is based on genotype data, it does not require any computationally intensive phasing program to account for uncertain haplotype phase. (Source: Annals of Human G...

Binomial Mixture Model-based Association Tests under Genetic Heterogeneity

Annals of Human Genetics — Tue, 01 Sep 2009 23:00:00 +0100

Most of the existing association tests for population-based case-control studies are based on comparing the mean genotype scores between the case and control groups, which may not be efficient under genetic heterogeneity. Given that most common diseases are genetically heterogeneous, caused by mutations in multiple loci, it may be beneficial to fully account for genetic heterogeneity in an association test. Here we first propose a binomial mixture model for such a purpose and develop a corresponding mixture likelihood ratio test (MLRT) for a single locus. We also consider two methods to combine single-locus-based MLRTs across multiple loci in linkage disequilibrium to boost power when causal SNPs are not genotyped. We show with a wide spectrum of numerical examples that under genetic heter...

Validation Study of Genetic Associations with Coronary Artery Disease on Chromosome 3q13-21 and Potential Effect Modification by Smoking

Annals of Human Genetics — Mon, 24 Aug 2009 23:00:00 +0100

This study attempted to independently validate those associations. Eleven single nucleotide polymorphisms (SNPs) were examined (rs10934490, rs16834817, rs6810298, rs9289231, rs12637456, rs1444768, rs1444754, rs4234218, rs2335052, rs3803, rs2713604) in patients (N = 1618) from the Intermountain Heart Collaborative Study (IHCS). Given the higher smoking prevalence in CATHGEN than IHCS (41% vs. 11% in controls, 74% vs. 29% in cases), smoking stratification and genotype-smoking interactions were evaluated. Suggestive association was found for GATA2 (rs2713604, p = 0.057, OR = 1.2). Among smokers, associations were found in CDGAP (rs10934490, p = 0.019, OR = 1.6) and KALRN (rs12637456, p = 0.011, OR = 2.0) and suggestive association was found in MYLK (rs16834871, p = 0.051, OR = 1.8, adjusting ...

Genetic Evidence for Complexity in Ethnic Differentiation and History in East Africa

Annals of Human Genetics — Mon, 24 Aug 2009 23:00:00 +0100

The Afro-Asiatic and Nilo-Saharan language families come into contact in Western Ethiopia. Ethnic diversity is particularly high in the South, where the Nilo-Saharan Nyangatom and the Afro-Asiatic Daasanach dwell. Despite their linguistic differentiation, both populations rely on a similar agripastoralist mode of subsistence. Analysis of mitochondrial DNA extracted from Nyangatom and Daasanach archival sera revealed high levels of diversity, with most sequences belonging to the L haplogroups, the basal branches of the mitochondrial phylogeny. However, in sharp contrast with other Ethiopian populations, only 5% of the Nyangatom and Daasanach sequences belong to haplogroups M and N. The Nyangatom and Daasanach were found to be significantly differentiated, while each of them displays close a...

Tests of Association for Quantitative Traits in Nuclear Families Using Principal Components to Correct for Population Stratification

Annals of Human Genetics — Thu, 20 Aug 2009 23:00:00 +0100

Traditional transmission disequilibrium test (TDT) based methods for genetic association analyses are robust to population stratification at the cost of a substantial loss of power. We here describe a novel method for family-based association studies that corrects for population stratification with the use of an extension of principal component analysis (PCA). Specifically, we adopt PCA on unrelated parents in each family. We then infer principal components for children from those for their parents through a TDT-like strategy. Two test statistics within the variance-components model are proposed for association tests. Simulation results show that the proposed tests have correct type I error rates regardless of population stratification, and have greatly improved power over two popular TDT-...

Geographical Structure of the Y-chromosomal Genetic Landscape of the Levant: A coastal-inland contrast

Annals of Human Genetics — Sun, 16 Aug 2009 23:00:00 +0100

We have examined the male-specific phylogeography of the Levant and its surroundings by analyzing Y-chromosomal haplogroup distributions using 5874 samples (885 new) from 23 countries. The diversity within some of these haplogroups was also examined. The Levantine populations showed clustering in SNP and STR analyses when considered against a broad Middle-East and North African background. However, we also found a coastal-inland, east-west pattern of diversity and frequency distribution in several haplogroups within the small region of the Levant. Since estimates of effective population size are similar in the two regions, this strong pattern is likely to have arisen mainly from differential migrations, with different lineages introduced from the east and west. (Source: Annals of Human Gen...

The Reduced Folate Carrier (SLC19A1) c.80G>A Polymorphism is Associated with Red Cell Folate Concentrations Among Women

Annals of Human Genetics — Wed, 29 Jul 2009 23:00:00 +0100

Low folate status may be a consequence of suboptimal intake, transport or cellular utilization of folate and, together with elevated homocysteine, is a recognized risk factor or marker for several human pathologies. As folate transport across cell membranes is mediated in part by the reduced folate carrier (RFC1), variants within SLC19A1, the gene that encodes RFC1, may influence disease risk via an effect on folate and/or homocysteine levels. The present study was undertaken to assess the association between the SLC19A1 c.80G>A polymorphism and folate/homocysteine concentrations in healthy young adults from Northern Ireland. The SLC19A1 c.80G>A polymorphism was not strongly associated with either serum folate or homocysteine concentrations in either men or women. However, in women, but no...

The Late Pleistocene Colonization of South America: An Interdisciplinary Perspective

Annals of Human Genetics — Tue, 21 Jul 2009 23:00:00 +0100

In this article, we briefly review scenarios for the first peopling of the New World, including the Clovis First/Single Origin, Tripartite, and Dual Migration models. We then discuss bioanthropological, molecular genetic, archaeological and biogeographic evidence for the peopling of the continent. To conclude, we draw on different lines of evidence to make inferences concerning the timing, direction, and type of early human dispersion in South America. (Source: Annals of Human Genetics)

Founder Effects for ATM Gene Mutations in Italian Ataxia Telangiectasia Families

Annals of Human Genetics — Mon, 20 Jul 2009 23:00:00 +0100

We screened ATM gene mutations in 104 Italian Ataxia-Telangiectasia patients from 91 unrelated families (detection rate 90%) and found 21 recurrent mutations in 63 families. The majority (67%) of patients were compound heterozygotes, while 33% were homozygotes. To determine the existence of common haplotypes and potential founder effects, we analyzed five microsatellite markers within and flanking the ATM gene. Haplotype analysis was carried out in 48/63 families harbouring 16 of the 21 recurrent mutations. Forty different haplotypes were detected in the 48 A-T families studied. We found that the majority of patients with the same recurrent mutation originated from the same geographical area. All but one recurrent mutation analyzed displayed a common haplotype suggesting a single origin th...

A Regression-based Association Test for Case-control Studies that Uses Inferred Ancestral Haplotype Similarity

Annals of Human Genetics — Sun, 19 Jul 2009 23:00:00 +0100

Association methods based on haplotype similarity (HS) can overcome power and stability issues encountered in standard haplotype analyses. Current HS methods can be generally classified into evolutionary and two-sample approaches. We propose a new regression-based HS association method for case-control studies that incorporates covariate information and combines the advantages of the two classes of approaches by using inferred ancestral haplotypes. We first estimate the ancestral haplotypes of case individuals and then, for each individual, an ancestral-haplotype-based similarity score is computed by comparing that individual's observed genotype with the estimated ancestral haplotypes. Trait values are then regressed on the similarity scores. Covariates can easily be incorporated into this...

Haplotypes Encompassing the KIAA0391 and PSMA6 Gene Cluster Confer a Genetic Link for Myocardial Infarction and Coronary Artery Disease

Annals of Human Genetics — Wed, 15 Jul 2009 23:00:00 +0100

The role of the KIAA0391 and PSMA6 genes in predisposing individuals to disease is still not fully understood. We evaluated by molecular beacon-based genotyping assays the roles of five single nucleotide polymorphisms (SNPs) in the chromosomal region 14q13.2 harbouring the KIAA0391 and PSMA6 gene cluster in coronary artery disease (CAD) in the Saudi population. Two of the studied SNPs rs8008319 (denoted as 1) and rs7157492 (2), reside in the KIAA0391 locus, two others rs1048990 (3) and rs12878391 (4) are components of the PSMA6, while rs4981283 (5) resides downstream of both genes. In a study involving 1071 patients and 929 controls, none of the studied SNPs showed significant association with CAD. In contrast, two haplotypes consisting of 1A-2G-3C-4A-5A [O.R.(95% C.I.) = 1.49(0.95[ndash]2...

PedStr Software for Cutting Large Pedigrees for Haplotyping, IBD Computation and Multipoint Linkage Analysis

Annals of Human Genetics — Thu, 09 Jul 2009 23:00:00 +0100

We propose an automatic heuristic algorithm for splitting large pedigrees into fragments of no more than a user-specified bit size. The algorithm specifically aims to split large pedigrees where many close relatives are genotyped and to produce a set of sub-pedigrees for haplotype reconstruction, IBD computation or multipoint linkage analysis with the help of the Lander-Green-Kruglyak algorithm. We demonstrate that a set of overlapping pedigree fragments constructed with the help of our algorithm allows fast and effective haplotype reconstruction and detection of an allele's parental origin. Moreover, we compared pedigree fragments constructed with the help of our algorithm and existing programs PedCut and Jenti for multipoint linkage analysis. Our algorithm demonstrated significantly high...

Genomic Convergence of Genome-wide Investigations for Complex Traits

Annals of Human Genetics — Wed, 08 Jul 2009 23:00:00 +0100

In this study, a genomic convergence approach of GWAS and GWLS was implemented for the first time in order to identify genomic loci supported by both methods. A database with 376 GWLS and 102 GWAS for 19 complex traits was created. Data regarding the location and statistical significance for each genetic marker were extracted from articles or web-based databases. Convergence was quantified as the proportion of significant GWAS markers located within linked regions. Convergence was variable (0[ndash]73.3%) and was found to be significantly higher than expected by chance only for two of the 19 phenotypes. Seventy five loci of interest were identified, which being supported by independent lines of evidence, could merit prioritization in future investigations. Although convergence is supportiv...

Association Study and Mutation Analysis of Adiponectin Shows Association of Variants in APM1 with Complex Obesity in Women

Annals of Human Genetics — Sat, 04 Jul 2009 23:00:00 +0100

In conclusion, we found an association of an APM1 haplotype with obesity and found that APM1 mutations are not a common cause of monogenic obesity in our cohort. (Source: Annals of Human Genetics)

Combining Microarray-based Genomic Selection (MGS) with the Illumina Genome Analyzer Platform to Sequence Diploid Target Regions

Annals of Human Genetics — Tue, 30 Jun 2009 23:00:00 +0100

Novel methods of targeted sequencing of unique regions from complex eukaryotic genomes have generated a great deal of excitement, but critical demonstrations of these methods efficacy with respect to diploid genotype calling and experimental variation are lacking. To address this issue, we optimized microarray-based genomic selection (MGS) for use with the Illumina Genome Analyzer (IGA). A set of 202 fragments (304 kb total) contained within a 1.7 Mb genomic region on human chromosome X were MGS/IGA sequenced in ten female HapMap samples generating a total of 2.4 GB of DNA sequence. At a minimum coverage threshold of 5X, 93.9% of all bases and 94.9% of segregating sites were called, while 57.7% of bases (57.4% of segregating sites) were called at a 50X threshold. Data accuracy at known seg...

Testing Hardy-Weinberg Equilibrium using Family Data from Complex Surveys

Annals of Human Genetics — Fri, 05 Jun 2009 04:00:00 +0100

Genetic data collected during the second phase of the Third National Health and Nutrition Examination Survey (NHANES III) enable us to investigate the association of a wide variety of health factors with regard to genetic variation. The classic question when looking into the genetic variations in a population is whether the population is in the state of Hardy-Weinberg Equilibrium (HWE). Our objective was to develop test procedures using family data from complex surveys such as NHANES III. We developed six Pearson [chi]2 based tests for a diallelic locus of autosomal genes. The finite sample properties of the proposed test procedures were evaluated via Monte Carlo simulation studies and the Rao-Scott first order corrected test was recommended. Test procedures were applied to three loci from...

Multivariate Association Test Using Haplotype Trend Regression

Annals of Human Genetics — Mon, 01 Jun 2009 04:00:00 +0100

In this study, we propose a haplotype based test of association for multivariate quantitative traits in unrelated samples. Specifically, we extend a population based haplotype trend regression (HTR) approach to multivariate scenarios. We mainly focused on bivariate HTR, and the simulation results showed that the proposed method had correct pre-specified type-I error rates. The power of the proposed method was largely influenced by the size and source of correlation between variables, being greatest when correlation of a specific gene was opposite in sign to the residual correlation. (Source: Annals of Human Genetics)

Analysis of Gene Polymorphisms Associated with K+ Ion Circulation in the Inner Ear of Patients Susceptible and Resistant to Noise-induced Hearing Loss

Annals of Human Genetics — Thu, 28 May 2009 04:00:00 +0100

Noise-induced hearing loss (NIHL) is one of the leading occupational health risks in industrialized countries. It results from an interaction between environmental and genetic factors, however the nature of the genetic factors contributing to NIHL has not yet been clarified. Here, we investigated whether genetic variations in 10 genes putatively involved in the potassium recycling pathway in the inner ear may influence susceptibility to noise. 99 SNPs were genotyped in Polish noise-exposed workers, categorized into susceptible and resistant subjects. The most interesting results were obtained for KCNE1 and KCNQ4 as we replicated associations that were previously reported in a Swedish sample set, hence confirming that they are NIHL susceptibility genes. Additionally we report significant as...

Ancient DNA and Family Relationships in a Pompeian House

Annals of Human Genetics — Thu, 28 May 2009 04:00:00 +0100

This study revealed that six of the thirteen individuals are indeed closely related. (Source: Annals of Human Genetics)

Association between SNP Heterozygosity and Quantitative Traits in the Framingham Heart Study

Annals of Human Genetics — Thu, 28 May 2009 04:00:00 +0100

Associations between multilocus heterozygosity and fitness traits, also termed heterozygosity and fitness correlations (HFCs), have been reported in numerous organisms. These studies, in general, indicate a positive relationship between heterozygosity and fitness traits. We studied the association between genome-wide heterozygosity at 706 non-synonymous and synonymous SNPs and 19 quantitative traits, including morphological, biochemical and fitness traits in the Framingham Heart Study. Statistically significant association was found between heterozygosity and systolic and diastolic blood pressures as well as left ventricular diameter and wall thickness. These results suggest that heterozygosity may be associated with traits, such as blood pressure that closely track environmental variation...

Parkinson's Disease and Low Frequency Alleles Found Together Throughout LRRK2

Annals of Human Genetics — Thu, 21 May 2009 04:00:00 +0100

Mutations within LRRK2, most notably p.G2019S, cause Parkinson's disease (PD) in rare monogenic families, and sporadic occurrences in diverse populations. We investigated variation throughout LRRK2 (84 SNPs; genotype or diplotype found for 49 LD blocks) for 275 cases (European ancestry, onset at age 60 or older) and 275 neurologically healthy control subjects (NINDS Neurogenetics Repository). Three grade-of-membership groups, i.e. genetic risk sets, were identified that exactly matched many subjects (cases: 46, 4, 137; controls: 0, 178, 0), and distinguished 94% of the subjects (i.e. >50% likeness to one set). Set I, affected, carried certain low frequency alleles located in multiple functional domains. Set II was unaffected. Set III, also affected, resembled set II except for slightly ele...

First Genetic Insight into Libyan Tuaregs: A Maternal Perspective

Annals of Human Genetics — Wed, 20 May 2009 04:00:00 +0100

The Tuaregs are a semi-nomadic pastoralist people of northwest Africa. Their origins are still a matter of debate due to the scarcity of genetic and historical data. Here we report the first data on the mitochondrial DNA (mtDNA) genetic characterization of a Tuareg sample from Fezzan (Libyan Sahara). A total of 129 individuals from two villages in the Acacus region were genetically analysed. Both the hypervariable regions and the coding region of mtDNA were investigated. Phylogeographic investigation was carried out in order to reconstruct human migratory shifts in central Sahara, and to shed light on the origin of the Libyan Tuaregs. Our results clearly show low genetic diversity in the sample, possibly due to genetic drift and founder effect associated with the separation of Libyan Tuare...

Haplotype Analysis of the Stromelysin-1 (MMP3) and Gelatinase B (MMP9) Genes in Relation to Coronary Heart Disease

Annals of Human Genetics — Fri, 15 May 2009 04:00:00 +0100

The functional genetic polymorphisms present in the promoters of stromelysin-1 (MMP3) and gelatinase B (MMP9) have been shown to be associated with angiographically measured atherosclerosis; however, haplotype analysis of the genetic polymorphisms occurring in the promoters and coding regions of MMP3 and MMP9 has been infrequently performed in the past. The aim of this study was to analyze the occurrence of the -1612 5A/6A, -376C/G, and Glu45Lys polymorphisms of MMP3 and the -1562C/T and R279Q polymorphisms of MMP9 and their relation to the risk of coronary heart disease (CHD; stenosis [ge]50% of the diameter in at least one major coronary artery) in a Chinese Han population. The present study involved 1373 patients with CHD and 695 healthy controls. The Glu45Lys polymorphism of MMP3 was s...

Inter- and Extra-Indian Admixture and Genetic Diversity in Reunion Island Revealed by Analysis of Mitochondrial DNA

Annals of Human Genetics — Tue, 21 Apr 2009 04:00:00 +0100

Reunion Island is a French territory located in the western Indian Ocean. The genetic pattern of the Reunionese population has been shaped by contributions from highly contrasting regions of the world. Over the last 350 years, several migration waves and cultural and socio-economic factors have led to the emergence of six main ethnic groups in Reunion. India is one of the principal regions that contributed to the setting up of the Reunionese population. Diversity, demographic and admixture analyses were performed on mtDNA variation of the Reunionese of Indian ancestry, including the Malbar and Zarab ethnic groups, in order to question their history. Using a phylogeographical approach, we generated and analysed quantitative data on the contribution of the Indian parental populations. Furthe...

Genetic Admixture in Brazilians Exposed to Infection with Leishmania chagasi

Annals of Human Genetics — Mon, 20 Apr 2009 04:00:00 +0100

Visceral leishmaniasis (VL) in northeast Brazil is a disease caused by infection with the protozoan Leishmania chagasi. Infection leads to variable clinical outcomes ranging from asymptomatic infection to potentially fatal disease. Prior studies suggest the genetic background of the host contributes to the development of different outcomes after infection, although it is not known if ancestral background itself influences outcomes. VL is endemic in peri-urban areas around the city of Natal in northeast Brazil. The population of northeast Brazil is a mixture of distinct racial and ethnic groups. We hypothesized that some sub-populations may be more susceptible than others to develop different clinical outcomes after L. chagasi infection. Using microsatellite markers, we examined whether adm...

SNP Discovery and Haplotype Analysis in the Segmentally Duplicated DRD5 Coding Region

Annals of Human Genetics — Mon, 20 Apr 2009 04:00:00 +0100

The dopamine receptor 5 gene (DRD5) holds much promise as a candidate locus for contributing to neuropsychiatric disorders and other diseases influenced by the dopaminergic system, as well as having potential to affect normal behavioral variation. However, detailed analyses of this gene have been complicated by its location within a segmentally duplicated chromosomal region. Microsatellites and SNPs upstream from the coding region have been used for association studies, but we find, using bioinformatics resources, that these markers all lie within a previously unrecognized second segmental duplication (SD). In order to accurately analyze the DRD5 locus for polymorphisms in the absence of contaminating pseudogene sequences, we developed a fast and reliable method for sequence analysis and g...

The Cost Effectiveness of Duplicate Genotyping for Testing Genetic Association

Annals of Human Genetics — Fri, 10 Apr 2009 04:00:00 +0100

We consider a modification to the traditional genome wide association (GWA) study design: duplicate genotyping. Duplicate genotyping (re-genotyping some of the samples) has long been suggested for quality control reasons; however, it has not been evaluated for its statistical cost-effectiveness. We demonstrate that when genotyping error rates are at least m%, duplicate genotyping provides a cost-effective (more statistical power for the same price) design alternative when relative genotype to phenotype/sample acquisition costs are no more than m%. In addition to cost and error rate, duplicate genotyping is most cost-effective for SNPs with low minor allele frequency. In general, relative genotype to phenotype/sample acquisition costs will be low when following up a limited number of SNPs i...

Spastic Paraplegia, Optic Atrophy, and Neuropathy: New Observations, Locus Refinement, and Exclusion of Candidate Genes

Annals of Human Genetics — Sun, 29 Mar 2009 04:00:00 +0100

SPOAN is an autosomal recessive neurodegenerative disorder which was recently characterized by our group in a large inbred Brazilian family with 25 affected individuals. This condition is clinically defined by: 1. congenital optic atrophy; 2. progressive spastic paraplegia with onset in infancy; and 3. progressive motor and sensory axonal neuropathy. Overall, we are now aware of 68 SPOAN patients (45 females and 23 males, with age ranging from 5 to 72 years), 44 of which are presented here for the first time. They were all born in the same geographic micro region. Those 68 patients belong to 43 sibships, 40 of which exhibit parental consanguinity. Sixty-one patients were fully clinically evaluated and 64 were included in the genetic investigation. All molecularly studied patients are homoz...

New Mutations of EXT1 and EXT2 Genes in German Patients with Multiple Osteochondromas

Annals of Human Genetics — Sun, 29 Mar 2009 04:00:00 +0100

Mutations in either the EXT1 or EXT2 genes lead to Multiple Osteochondromas (MO), an autosomal dominantly inherited disorder. This is a report on clinical findings and results of molecular analyses of both genes in 23 German patients affected by MO. Mutation screening was performed by using denaturing high performance liquid chromatography (dHPLC) and automated sequencing. In 17 of 23 patients novel pathogenic mutations have been identified; eleven in the EXT1 and six in the EXT2 gene. Five patients were carriers of recurrent mutations in the EXT2 gene (p.Asp227Asn, p.Gln172X, p.Gln258X) and one patient had no detectable mutation. To demonstrate their pathogenic effect on transcription, two complex mutations in EXT1 and EXT2 and three splice site mutations were characterized by mRNA invest...

Using Case-parent Triads to Estimate Relative Risks Associated with a Candidate Haplotype

Annals of Human Genetics — Sun, 29 Mar 2009 04:00:00 +0100

Estimating haplotype relative risks in a family-based study is complicated by phase ambiguity and the many parameters needed to quantify relative risks for all possible diplotypes. This problem becomes manageable if a particular haplotype has been implicated previously as relevant to risk. We fit log-linear models to estimate the risks associated with a candidate haplotype relative to the aggregate of other haplotypes. Our approach uses existing haplotype-reconstruction algorithms but requires assumptions about the distribution of haplotypes among triads in the source population. We consider three levels of stringency for those assumptions: Hardy-Weinberg Equilibrium (HWE), random mating, and no assumptions at all. We assessed our method's performance through simulations encompassing a ran...

Evaluating the Ability of Tree-Based Methods and Logistic Regression for the Detection of SNP-SNP Interaction

Annals of Human Genetics — Thu, 12 Mar 2009 04:00:00 +0100

In conclusion, tree-based methods and LR are important statistical tools for the detection of unknown interactions among true risk-associated SNPs with marginal effects and in the presence of a significant number of noise SNPs. In pure interaction models, RF performs reasonably well in the presence of large sample sizes and low percentages of missing data. However, when the study design is suboptimal (unfavourable to detect interaction in terms of e.g. sample size and MAF) there is a high chance of detecting false, spurious associations. (Source: Annals of Human Genetics)

CALHM1 Polymorphism is not Associated with Late-onset Alzheimer Disease

Annals of Human Genetics — Sun, 08 Mar 2009 05:00:00 +0100

Data suggests that the P86L polymorphism (rs2986017) in the calcium homeostasis modulator 1 (CALHM1) gene interferes with CALHM1 functionality, increases A[beta] levels, and is associated with late-onset Alzheimer's disease (LOAD). Previous studies have demonstrated association with P86L and LOAD in three of five case-control cohorts, and a joint analysis of all datasets showed association with a p-value of 2 × 10[minus]10 and an allele-specific odds ratio of 1.44 (2,043 cases, 1,361 controls total). In this short communication we attempt to replicate these results in our case-control cohort (510 cases, 524 controls). We show no association between P86L and LOAD despite having sufficient power to detect at the reported odds ratios, and briefly discuss potential reasons for the discrepancy...

High-resolution Melting Facilitates Mutation Screening of PYGM in Patients with McArdle Disease

Annals of Human Genetics — Sun, 08 Mar 2009 05:00:00 +0100

Mutations in PYGM, encoding the muscle-specific glycogen phosphorylase (myophosphorylase), are responsible for McArdle disease. Among Caucasians, a large proportion of patients are homozygous for the R50X mutation, but other mutations can affect all the 20 exons of PYGM, making mutation detection laborious. We have developed a high-resolution melting (HRM) assay for mutation detection in PYGM. Twelve McArdle patients were investigated, in whom pre-screening had ruled out homozygosity or compound heterozygosity for the two common G205S and R50X mutations. In total, we identified 16 different variations. Thirteen of these are pathogenic, and three were classified as polymorphisms. Nine variations had not previously been described. One of the novel mutations, c.2430C > T, was initially predic...

Reply to Parson

Annals of Human Genetics — Tue, 17 Feb 2009 05:00:00 +0100

(Source: Annals of Human Genetics)

Robust Tests for Single-marker Analysis in Case-Control Genetic Association Studies

Annals of Human Genetics — Thu, 05 Feb 2009 05:00:00 +0100

Choosing an appropriate single-marker association test is critical to the success of case-control genetic association studies. An ideal single-marker analysis should have robust performance across a wide range of potential disease risk models. MAX was designed specifically to achieve such robustness. In this work, we derived the power calculation formula for MAX and conducted a comprehensive power comparison between MAX and two other commonly used single-marker tests, the one-degree-of-freedom (1-df) Cochran-Armitage trend test and the 2-df Pearson [chi]2 test. We used a single-marker disease risk model and a two-marker haplotype risk model to explore the performances of the above three tests. We found that each test has its own "sweet" spots. Among the three tests considered, MAX appears ...

Detection of Rare Nonsynonymous Variants in TGFB1 in Otosclerosis Patients

Annals of Human Genetics — Wed, 04 Feb 2009 05:00:00 +0100

Otosclerosis is one of the most common forms of hearing loss in the European population. We have identified a SNP in the TGFB1 (transforming growth factor beta 1) gene that is associated with susceptibility to otosclerosis. The protective allele of this variant, with isoleucine at position 263 of the protein, is more biologically active than the risk allele, which has a threonine in this position. Because recent studies have shown that not only common, but also rare variants can be involved in complex diseases, we performed DNA sequence analysis of the exons and intron-exon boundaries of TGFB1 in 755 otosclerosis patients and 877 control samples. We found 3 different nonsynonymous variants (E29, A29 and I241) in four otosclerosis patients, but no such changes were found in controls. In sil...

Interactions Between HERC2, OCA2 and MC1R May Influence Human Pigmentation Phenotype

Annals of Human Genetics — Wed, 04 Feb 2009 05:00:00 +0100

Human pigmentation is a polygenic trait which may be shaped by different kinds of gene[ndash]gene interactions. Recent studies have revealed that interactive effects between HERC2 and OCA2 may be responsible for blue eye colour determination in humans. Here we performed a population association study, examining important polymorphisms within the HERC2 and OCA2 genes. Furthermore, pooling these results with genotyping data for MC1R, ASIP and SLC45A2 obtained for the same population sample we also analysed potential genetic interactions affecting variation in eye, hair and skin colour. Our results confirmed the association of HERC2 rs12913832 with eye colour and showed that this SNP is also significantly associated with skin and hair colouration. It is also concluded that OCA2 rs1800407 is i...

Robust Quantitative Trait Association Tests in the Parent-Offspring Triad Design: Conditional Likelihood-Based Approaches

Annals of Human Genetics — Sun, 01 Feb 2009 05:00:00 +0100

Association studies, based on either population data or familial data, have been widely applied to mapping of genes underlying complex diseases. In family-based association studies, using case-parent triad families, the popularly used transmission/disequilibrium test (TDT) was proposed for avoidance of spurious association results caused by other confounders such as population stratification. Originally, the TDT was developed for analysis of binary disease data. Extending it to allow for quantitative trait analysis of complex diseases and for robust analysis of binary diseases against the uncertainty of mode of inheritance has been thoroughly discussed. Nevertheless, studies on robust analysis of quantitative traits for complex diseases received relatively less attention. In this paper, we...

Candidate Gene Association Study for Noise-induced Hearing Loss in Two Independent Noise-exposed Populations

Annals of Human Genetics — Sat, 31 Jan 2009 05:00:00 +0100

In this study, we performed an association study for NIHL based on a candidate gene approach. 644 Single Nucleotide Polymorphisms (SNPs) in 53 candidate genes were analyzed in two independent NIHL sample sets, a Swedish set and part of a Polish set. Eight SNPs with promising results were selected and analysed in the remaining part of the Polish samples. One SNP in PCDH15 (rs7095441), resulted in significant associations in both sample sets while two SNPs in MYH14 (rs667907 and rs588035), resulted in significant associations in the Polish sample set and significant interactions with noise exposure level in the Swedish sample set. Calculation of odds ratios revealed a significant association of rs588035 with NIHL in the Swedish high noise exposure level group. Our studies suggest that PCDH15...

Variants in Intron 13 of the ELMO1 Gene are Associated with Diabetic Nephropathy in African Americans

Annals of Human Genetics — Sat, 31 Jan 2009 05:00:00 +0100

Variants in the engulfment and cell motility 1 (ELMO1) gene are associated with nephropathy due to type 2 diabetes mellitus (T2DM) in a Japanese cohort. We comprehensively evaluated this gene in African American (AA) T2DM patients with end-stage renal disease (ESRD). Three hundred and nine HapMap tagging SNPs and 9 reportedly associated SNPs were genotyped in 577 AA T2DM-ESRD patients and 596 AA non-diabetic controls, plus 43 non-diabetic European American controls and 45 Yoruba Nigerian samples for admixture adjustment. Replication analyses were conducted in 558 AA with T2DM-ESRD and 564 controls without diabetes. Extension analyses included 328 AA with T2DM lacking nephropathy and 326 with non-diabetic ESRD. The original and replication analyses confirmed association with four SNPs in in...

Pearson's Test, Trend Test, and MAX Are All Trend Tests with Different Types of Scores

Annals of Human Genetics — Sat, 31 Jan 2009 05:00:00 +0100

Pearson's test is one of the most commonly used statistics for testing genetic association of case-control data. The trend test is another one which assumes a dose-response model between the risk of the disease and genotypes. To apply the trend test, a set of ordered scores is assigned a priori based on the underlying genetic model. Pearson's test is model-free and robust, but is less powerful for common genetic models. MAX is another robust test statistic, which takes the maximum of the trend tests over a family of scientifically plausible genetic models. We show that the three test statistics are all trend tests but with different types of scores; whether the scores are prespecified or data-driven, or whether the scores are ordered (restricted) or not ordered (unrestricted). We then prov...

Testing for linkage and Hardy-Weinberg disequilibrium

Annals of Human Genetics — Sat, 31 Jan 2009 05:00:00 +0100

This paper concerns several important points when testing for Hardy-Weinberg equilibrium (HWE) and linkage disequilibrium (LD) in genetics. First, we challenge the necessity of using exclusively two-sided tests for LD. Next, we show that the exact 2-sided tests based on the most popular measures of LD are not equivalent, and neither are the standard statistical tests even though the 1-sided tests are equivalent. We show how this results in different inference about LD for two data sets consisting of small groups of markers. Finally, we advocate the use of the conditional p-value for both LD and HWE testing. An important advantage of this p-value is that equivalent 1-sided tests are transformed into equivalent 2-sided tests. (Source: Annals of Human Genetics)

Analysis of RET, ZEB2, EDN3 and GDNF Genomic Rearrangements in 80 Patients with Hirschsprung Disease (Using multiplex ligation-dependent probe amplification)

Annals of Human Genetics — Thu, 29 Jan 2009 05:00:00 +0100

Hirschsprung disease (HSCR) is transmitted in a complex pattern of inheritance and is mostly associated with variants in the RET proto-oncogene. However, RET mutations are only identified in 15[ndash]20% of sporadic HSCR cases and solely in 50% of the familial cases. Since genomic rearrangements in particularly sensitive areas of the RET proto-oncogene and/or associated genes may account for the HSCR phenotype in patients without other detectable RET variants, the aim of the present study was to identify rearrangements in the coding sequence of RET as well as in three HSCR-associated genes (ZEB2, EDN3 and GDNF) in HSCR patients by using Multiplex Ligation-dependent Probe Amplification (MLPA). We have screened 80 HSCR patients for genomic rearrangements in RET, ZEB2, EDN3 and GDNF and did n...

Testing for Genetic Association With Constrained Models Using Triads

Annals of Human Genetics — Wed, 28 Jan 2009 05:00:00 +0100

It has been shown that it is preferable to use a robust model that incorporated constraints on the genotype relative risk rather than rely on a model that assumes the disease operates in a recessive or dominant fashion. Previous methods are applicable to case-control studies, but not to family based studies of case children along with their parents (triads). We show here how to implement analogous constraints while analyzing triad data. The likelihood, conditional on the parents genotype, is maximized over the appropriately constrained parameter space. The asymptotic distribution for the maximized likelihood ratio statistic is found and used to estimate the null distribution of the test statistics. The properties of several methods of testing for association are compared by simulation. The...

Distinct clinical characteristics of Tuberous Sclerosis Complex patients with no mutation identified

Annals of Human Genetics — Mon, 29 Dec 2008 05:00:00 +0100

Tuberous Sclerosis Complex (TSC) is a multi-system disorder that is highly variable in its clinical presentation. Current molecular diagnostic methods permit identification of mutations in either TSC1 or TSC2 in 75[ndash]85% of TSC patients. Here we examine the clinical characteristics of those TSC patients who have no mutation identified (NMI). A retrospective review of our patient population that had comprehensive testing for mutations in TSC1/TSC2 identified 23/157 (15%) that were NMI. NMI patients had a lower incidence of brain findings on imaging studies, neurological features, and renal findings than those with TSC2 mutations. In contrast, NMI patients had a lower incidence of seizures than TSC patients with TSC1 mutations, but had a higher incidence of both renal angiomyolipomas and...

Inbreeding Coefficients for X-linked and Autosomal Genes in Consanguineous Marriages in Spanish Populations: The Case of Guipúzcoa (Basque Country)

Annals of Human Genetics — Sun, 28 Dec 2008 05:00:00 +0100

Inbreeding patterns over the past two centuries have been studied more extensively in Spain and Italy than anywhere else in Europe. Consanguinity studies in mainland Spain have shown that populations settled along the Cantabrian cornice share inbreeding patterns that distinguish them from other populations further south. A visual representation of spatial variations of two key inbreeding variables is presented here for the first time via contour maps. This paper also analyzes time trends of mean inbreeding coefficients for X-linked (Fx) and autosomal genes (F) (1862[ndash]1995) together with variations in Fx/F ratios in Guipúzcoa, the most autochthonous Spanish Basque province. Because close cousin marriages are a mark of identity of the study population, we evaluated the contribution of ...

Heterogeneous Disease Modeling for Hardy-Weinberg Disequilibrium in Case-Control Studies: Application to Renal Stones and Calcium-Sensing Receptor Polymorphisms

Annals of Human Genetics — Sun, 28 Dec 2008 05:00:00 +0100

Renal stone formation due to hypercalciuria is a relatively common disorder with clear evidence for genetic predisposition, but cryptic phenotypic heterogeneity has hampered identification of candidate genes. The R990G single-nucleotide polymorphism (SNP) of the calcium sensing receptor (CASR) gene has been associated with hypercalciuria in stone formers and shows the appropriate functional phenotype in cell culture. In our preliminary association analysis of a case-control cohort, however, we observed significant Hardy-Weinberg disequilibrium (HWD) for the cases (n= 223), but not controls (n= 676) at the R990G locus, pointing us toward the general disease model incorporating HWD. Because there is an adjacent CASR SNP, A986S, which is in negative linkage disequilibrium with R990G, we exten...

The Complex and Diversified Mitochondrial Gene Pool of Berber Populations

Annals of Human Genetics — Thu, 04 Dec 2008 05:00:00 +0100

The mitochondrial DNA variation of 295 Berber-speakers from Morocco (Asni, Bouhria and Figuig) and the Egyptian oasis of Siwa was evaluated by sequencing a portion of the control region (including HVS-I and part of HVS-II) and surveying haplogroup-specific coding region markers. Our findings show that the Berber mitochondrial pool is characterized by an overall high frequency of Western Eurasian haplogroups, a somehow lower frequency of sub-Saharan L lineages, and a significant (but differential) presence of North African haplogroups U6 and M1, thus occupying an intermediate position between European and sub-Saharan populations in PCA analysis. A clear and significant genetic differentiation between the Berbers from Maghreb and Egyptian Berbers was also observed. The first are related to E...

Association of a Polymorphism in the Intron 7 of the SREBF1 Gene with Osteonecrosis of the Femoral Head in Koreans

Annals of Human Genetics — Fri, 28 Nov 2008 05:00:00 +0100

Reduction or disruption of the blood supply to the bone is involved in the pathogenesis of osteonecrosis of the femoral head (ONFH). An altered lipid metabolism is one of the major risk factors for ONFH. Sterol regulatory element binding protein, SREBF1 activates genes regulating lipid biosynthesis. The aim of this study was to examine the association between the polymorphisms of the SREBF1 gene and ONFH susceptibility in the Korean population. The SREBF1 gene in 24 unrelated Korean individuals was sequenced and two polymorphisms were detected. Two variants, IVS6 [minus] 48 C > T and IVS7 + 117 A > G, were genotyped in 423 ONFH patients and 348 controls. The genotype frequency of IVS7 + 117 A > G in ONFH patients was significantly different from that of the control group with P value < 0.0...

Large Allele Frequency Differences between Human Continental Groups are more Likely to have Occurred by Drift During range Expansions than by Selection

Annals of Human Genetics — Wed, 26 Nov 2008 05:00:00 +0100

In this study, we examined 772 STRs, 210 diallelic indels, and 2834 SNPs typed in 53 human populations worldwide under the HGDP-CEPH Diversity Panel to determine to which extent allele frequency differs among four regions (Africa, Eurasia, East Asia, and America). We find that large allele frequency differences between continents are surprisingly common, and that Africa and America show the largest number of loci with extreme frequency differences. Moreover, more STR alleles have increased rather than decreased in frequency outside Africa, as expected under allelic surfing. Finally, there is no relationship between the extent of allele frequency differences and proximity to genes, as would be expected under selection. We therefore conclude that most of the observed large allele frequency d...

Genotypic Association Analysis Using Discordant-Relative-Pairs

Annals of Human Genetics — Tue, 25 Nov 2008 05:00:00 +0100

In practice, family-based design has been widely used in disease-gene association analysis. The major advantage of such design is that it is not subject to spurious association due to population structure such as population stratification (PS) and admixture. A disadvantage is that parental genotypes are hard to obtain if the disease is late onset for which a discordant-relative-pair design is useful. Designs of such kind include full-sib-pair, half-sib-pair, first-cousin-pair, and so on. The closer the relatedness of the pair, the less possible that they are subject to population stratification. On the other hand, the association test using close relative-pairs may be less powerful due to over-matching. Trade-off between these two factors (population structure and over-matching) is the maj...

Population Structure in Contemporary Sweden—A Y-Chromosomal and Mitochondrial DNA Analysis

Annals of Human Genetics — Fri, 24 Oct 2008 04:00:00 +0100

In conclusion, our study yielded valuable information of the structure of the Swedish population, and demonstrated the usefulness of biobanks as a source of population genetic research. Our sampling strategy, nonselective on the current population rather than stratified according to ancestry, is informative for capturing the contemporary variation in the increasingly panmictic populations of the world. (Source: Annals of Human Genetics)

A Novel Point Variant in NTRK3, R645C, Suggests a Role of this Gene in the Pathogenesis of Hirschsprung Disease

Annals of Human Genetics — Wed, 22 Oct 2008 04:00:00 +0100

Hirschsprung disease (HSCR) is a developmental disorder characterized by the absence of ganglion cells in the myenteric and submucosal plexuses due to a defect in the migration process of neural crest neuroblasts. Manifestation of the disease has been linked to the dysfunction of two principal signalling pathways involved in the enteric nervous system (ENS) formation: the RET-GDNF and the EDN3-EDNRB receptor systems. However, the NTF3/NTRK3 signalling pathway plays an essential role in the development of the ENS suggesting a potential role for those genes in the pathogenesis of HSCR. We have sought to evaluate the candidature of the NTRK3 gene, which encodes the TrkC receptor, as a susceptibility gene for Hirschsprung disease. Using dHPLC technology we have screened the NTRK3 coding region...

R58fs Mutation in the HGD Gene in a Family with Alkaptonuria in the UAE

Annals of Human Genetics — Tue, 21 Oct 2008 04:00:00 +0100

This study was conducted to determine the prevalence of alkaptonuria in the UAE population and to identify the genotype of affected individuals. In a 3 stage sampling technique 2981 pupils from Government schools in Al Ain and private schools in Dubai were selected to take part in the study, of whom 2857 provided urine samples. Urine collected was analysed for homogentisic acid by gas chromatography-mass spectrometry. Genomic DNA was isolated from the white blood cells of all family members of the affected case following standard established protocols. Specific PRC primers were designed to amplify all 14 exons of the HGD gene with the flanking intronic sequences including the splice site sequences. 2857 children returned a viable urine sample, of which one was highly positive for homogenti...

A Genetic Study of the Ghrelin and Growth Hormone Secretagogue Receptor (GHSR) Genes and Stature

Annals of Human Genetics — Wed, 15 Oct 2008 04:00:00 +0100

Growth and nutrition are interrelated and influenced by multiple genetic and environmental factors. We studied whether common variants in ghrelin and ghrelin receptor (GHSR) genes could play a role in stature variation in the general population and in families ascertained for obesity. Selected tagging SNPs in the ghrelin and GHSR genes were genotyped in 263 Caucasian families recruited for childhood obesity (1,275 subjects), and in 287 families from a general population (1,072 subjects). We performed familial testing for associations in the entire population and in a sub-set of the samples selected for a case-control study. In the case-control study for height (cases were selected from the obese cohort with mean ZH = 3.17 ± 0.15 confidence interval (CI) versus controls with mean ZH 0.14 �...

Analysis of RYR1 Haplotype Profile in Patients with Malignant Hyperthermia

Annals of Human Genetics — Wed, 15 Oct 2008 04:00:00 +0100

This study represents a new approach to characterising patients at risk of malignant hyperthermia (MH) through the use of a recently published method for identifying high-risk haplotypes in candidate genes. We present analysis based upon the largest standardised and genotyped database of MH patients worldwide. We used unphased RYR1 SNP data directly to (1) assess RYR1 haplotype frequency differences between susceptible cases and control groups and (2) analyse population-based association via clustering of RYR1 haplotypes based on disease risk. Our results show a significant difference in RYR1 haplotype frequency between susceptible cases and UK Caucasian population controls. Furthermore we identify a high-risk cluster of haplotypes that is associated with the commonest UK MH mutation p.G24...

Impact and Quantification of the Sources of Error in DNA Pooling Designs

Annals of Human Genetics — Wed, 15 Oct 2008 04:00:00 +0100

The analysis of genome wide variation offers the possibility of unravelling the genes involved in the pathogenesis of disease. Genome wide association studies are also particularly useful for identifying and validating targets for therapeutic intervention as well as for detecting markers for drug efficacy and side effects. The cost of such large-scale genetic association studies may be reduced substantially by the analysis of pooled DNA from multiple individuals. However, experimental errors inherent in pooling studies lead to a potential increase in the false positive rate and a loss in power compared to individual genotyping. Here we quantify various sources of experimental error using empirical data from typical pooling experiments and corresponding individual genotyping counts using tw...

Identifying Rarer Genetic Variants for Common Complex Diseases: Diseased Versus Neutral Discovery Panels

Annals of Human Genetics — Tue, 07 Oct 2008 04:00:00 +0100

The power of genetic association studies to identify disease susceptibility alleles fundamentally relies on the variants studied. The standard approach is to determine a set of tagging-SNPs (tSNPs) that capture the majority of genomic variation in regions of interest by exploiting local correlation structures. Typically, tSNPs are selected from neutral discovery panels - collections of individuals comprehensively genotyped across a region. We investigated the implications of discovery panel design on tSNP performance in association studies using realistically-simulated sequence data. We found that discovery panels of 24 sequenced 'neutral' individuals (similar to NIEHS or HapMap ENCODE data) were sufficient to select well-powered tSNPs to identify common susceptibility alleles. For less co...

In search of the Pre- and Post-Neolithic Genetic Substrates in Iberia: Evidence from Y-Chromosome in Pyrenean Populations

Annals of Human Genetics — Fri, 19 Sep 2008 04:00:00 +0100

The male-mediated genetic legacy of the Pyrenean population was assessed through the analysis of 12 Y-STR and 27 Y-SNP loci in a sample of 169 males from 5 main geographical areas in the Spanish Pyrenees: Cinco Villas (Western Pyrenees), Jacetania and Valle de Arán (Central Pyrenees) and Alto Urgel and Cerdaña (Eastern Pyrenees). In the Iberian context, the Pyrenean samples present some specificities, being characterizeded by a high proportion of chromosomes R1b1b2-M269 (including the usually uncommon R1b1b2d-SRY2627 and R1b1b2c-M153 types) or I2a2-M26 and low proportions of other haplogroups. Our results indicate that an old pre-Neolithic substrate is preponderant in populations of the whole Pyrenean fringe. However, AMOVA revealed a high level of substructure within Pyrenean population...

New Powerful Approaches for Family-based Association Tests with Longitudinal Measurements

Annals of Human Genetics — Tue, 16 Sep 2008 04:00:00 +0100

We discuss several new powerful family-based approaches for testing genetic association when the traits are obtained from longitudinal or repeated measurement studies. The popular approach FBAT-PC is based on a linear combination of the individual traits. We propose a one-sided modification, FBAT-PCM, which has a closed-form expression and is always more powerful. We also present two approaches FBAT-LC and FBAT-LCC based on linear combination of the univariate test statistics. Furthermore, all three approaches are shown to be unified to a general form. Through simulation studies, we compare the power of these tests under different models of genetic effect sizes. Compared to original FBAT-PC, our modification achieves a power gain of up to 50%. In addition, all three new approaches gain sub...

PKU in Minas Gerais State, Brazil: Mutation Analysis

Annals of Human Genetics — Tue, 16 Sep 2008 04:00:00 +0100

This work was undertaken in order to ascertain the PKU mutational spectrum in Minas Gerais, Brazil, the relative frequency of the mutations in the State and the origin of these mutations by haplotype determination. Minas Gerais is a trihybrid population formed by miscegenation from Europeans, Africans and Amerindians. All 13 exons of the PAH gene from 78 PKU patients were analyzed, including splicing sites and the promoter region. We identified 30 different mutations and 98% of the PAH alleles were established. A new mutation (Q267X) was identified as well. The most common mutations found were V388M (21.2), R261Q (16.0%), IVS10-11G>A (15.3%), I65T (5.8%), IVS2+5G>C (5.8%), R252W (5.1%), IVS2+5G>A (4.5%), P281L (3.8%) and L348V (3.2%). These nine mutations correspond to 80% of the PKU allel...

Testing Association with Interactions by Partitioning Chi-Squares

Annals of Human Genetics — Tue, 16 Sep 2008 04:00:00 +0100

Gene-gene interaction plays an important role in association studies for complex diseases. There have been different approaches to incorporating gene-gene interactions in candidate gene or genome-wide association studies, especially for those genes with no marginal effects but with interaction effects. However, there is no general agreement on how interaction should be tested and how main effects and interaction effects act on a significance signal. In this paper, we propose a test of the null hypothesis of no association in terms of interaction effects for two unlinked loci, which is a 4 degrees of freedom (df) chi-square for two SNPs. The test, derived by contrasting inter-locus disequilibrium measures between cases and controls, can be viewed as the interaction component of the total Pe...

Power, Validity, Bias and Robustness of Family-based Association Analysis Methods in the Presence of Linkage for Late Onset Diseases

Annals of Human Genetics — Tue, 09 Sep 2008 04:00:00 +0100

This study demonstrates that the genetic effect does not need to be extreme to invalidate tests that ignore familial correlation and confirms that analogous methods using robust variance estimation provide a valid alternative at little cost to power. Overall R-CLR is the best-performing method among these alternatives for the analysis of extended sibship data. (Source: Annals of Human Genetics)

Identification and Characterization of CFTR Gene Mutations in Indian CF Patients

Annals of Human Genetics — Mon, 08 Sep 2008 04:00:00 +0100

This study was performed on Indian CF patients (n = 50) to investigate the spectrum of mutations in the CFTR gene and their association with intragenic and extragenic marker haplotypes. We report identification of 14 previously known and eight novel mutations, namely 3986-3987delC, 876-6del4, 1792InsA, L69H, S158N, Q493L, I530L and E1329Q. The frequency of delta F508 was found to be 27%. Absolute linkage between delta F508 and the KM.19-GATT-TUB9-M470V-T854T haplotype (2-2-1-1-1) predicts a relatively recent appearance of delta F508 in Indian CF patients. Low frequency of delta F508 mutation and detection of eight novel and thirteen rare mutations reflect a heterogeneous spectrum of mutations in Indian CF patients. Failure to detect mutations in 34% of alleles indicates the possible presen...

Linkage and Association Study of Late-Onset Alzheimer Disease Families Linked to 9p21.3

Annals of Human Genetics — Sat, 30 Aug 2008 04:00:00 +0100

A chromosomal locus for late-onset Alzheimer disease (LOAD) has previously been mapped to 9p21.3. The most significant results were reported in a sample of autopsy-confirmed families. Linkage to this locus has been independently confirmed in AD families from a consanguineous Israeli-Arab community. In the present study we analyzed an expanded clinical sample of 674 late-onset AD families, independently ascertained by three different consortia. Sample subsets were stratified by site and autopsy-confirmation. Linkage analysis of a dense array of SNPs across the chromosomal locus revealed the most significant results in the 166 autopsy-confirmed families of the NIMH sample. Peak HLOD scores of 4.95 at D9S741 and 2.81 at the nearby SNP rs2772677 were obtained in a dominant model. The linked re...

Using Linkage Analysis to Identify Quantitative Trait Loci for Sleep Apnea in Relationship to Body Mass Index

Annals of Human Genetics — Wed, 27 Aug 2008 04:00:00 +0100

To understand the genetics of sleep apnea, we evaluated the relationship between the apnea hypopnea index (AHI) and body mass index (BMI) through linkage analysis to identify genetic loci that may influence AHI and BMI jointly and AHI independent of BMI. Haseman-Elston sibling regression was conducted on AHI, AHI adjusted for BMI and BMI in African-American and European-American pedigrees. A comparison of the magnitude of linkage peaks was used to assess the relationship between AHI and BMI. In EAs, the strongest evidence for linkage to AHI was on 6q23-25 and 10q24-q25, both decreasing after BMI adjustment, suggesting loci with pleiotropic effects. Also, a promising area of linkage to AHI but not BMI was observed on 6p11-q11 near the orexin-2 receptor, suggesting BMI independent pathways. ...

Efficient Association Study Design Via Power-Optimized Tag SNP Selection

Annals of Human Genetics — Thu, 14 Aug 2008 04:00:00 +0100

Discovering statistical correlation between causal genetic variation and clinical traits through association studies is an important method for identifying the genetic basis of human diseases. Since fully resequencing a cohort is prohibitively costly, genetic association studies take advantage of local correlation structure (or linkage disequilibrium) between single nucleotide polymorphisms (SNPs) by selecting a subset of SNPs to be genotyped (tag SNPs). While many current association studies are performed using commercially available high-throughput genotyping products that define a set of tag SNPs, choosing tag SNPs remains an important problem for both custom follow-up studies as well as designing the high-throughput genotyping products themselves. The most widely used tag SNP selection...

The Population Genetics of Familial Mediterranean Fever: A Meta-Analysis Study

Annals of Human Genetics — Wed, 06 Aug 2008 04:00:00 +0100

In conclusion, the MEFV mutation pattern is non-uniform regarding distribution, phenotypic expression, neutrality and population genetics characteristics. Jews are the candidate population for founder effects in MEFV. (Source: Annals of Human Genetics)

U-Statistics-based Tests for Multiple Genes in Genetic Association Studies

Annals of Human Genetics — Wed, 06 Aug 2008 04:00:00 +0100

As our understanding of biological pathways and the genes that regulate these pathways increases, consideration of these biological pathways has become an increasingly important part of genetic and molecular epidemiology. Pathway-based genetic association studies often involve genotyping of variants in genes acting in certain biological pathways. Such pathway-based genetic association studies can potentially capture the highly heterogeneous nature of many complex traits, with multiple causative loci and multiple alleles at some of the causative loci. In this paper, we develop two nonparametric test statistics that consider simultaneously the effects of multiple markers. Our approach, which is based on data-adaptive U-statistics, can handle both qualitative data such as case-control data an...

A Model Incorporating Potential Skewed X-Inactivation in MZ Girls Suggests that X-Linked QTLs Exist for Several Social Behaviours Including Autism Spectrum Disorder

Annals of Human Genetics — Tue, 29 Jul 2008 04:00:00 +0100

Sex differences in the frequency and patterns of behaviours are frequently observed and largely unexplained. We have investigated the possible role of X-linked genes in the aetiology of social behaviour problems, including those involved in autistic spectrum disorders. A novel approach has been implemented. This is based on predictions following from stochastic patterns of X-inactivation of lower concordance of monozygous female (MZF) twins than MZM twins for behaviours underpinned by X-linked QTLs and the converse that DZF twins are expected to correlate more strongly for X-linked traits than DZM twins because unlike males, females always have at least one X chromosome in common. These expectations were tested in an ongoing longitudinal cohort study in which all twins born in England and ...

Correlation of Population Parameters Leading to Power Differences In Association Studies with Population Stratification

Annals of Human Genetics — Thu, 24 Jul 2008 04:00:00 +0100

The power of statistical tests to measure effect sizes in the presence of population stratification is an important issue for the design and analysis of population-based association studies. Comparisons of statistical tests have shown that the power of different statistical approaches varies in different genetic scenarios. However, the impact of stratified population parameters on statistical power is not yet understood in a general statistical framework, particularly the impact of correlated population parameters. To investigate such impact in detail, we implemented a genetic model for population-based association studies with stratified samples and evaluated the impact on power with different genetic scenarios. The investigation shows that correlation between disease prevalence and risk ...

Can the Allelic Test be Retired from Analysis of Case-Control Association Studies?

Annals of Human Genetics — Thu, 24 Jul 2008 04:00:00 +0100

It has been stated that, when Hardy-Weinberg equilibrium (HWE) holds in the combined case-control samples, the allelic test is asymptotically equivalent to the trend test (for the additive model) for testing genetic association, and hence the allelic test should not be used. A recent publication shows that the allelic test and the trend test are asymptotically equivalent when HWE holds in the population. It is known that, when HWE does not hold, the trend test can still be used while the allelic test is no longer valid. Therefore, the allelic test is either not valid or is asymptotically equivalent to the trend test. It appears that the allelic test is a nuisance test. Can it be retired from the analysis of case-control association studies? It all depends on data and model assumptions. We ...

Probability that a Two-Stage Genome-Wide Association Study will Detect a Disease-Associated SNP and Implications for Multistage Designs

Annals of Human Genetics — Thu, 24 Jul 2008 04:00:00 +0100

Large two-stage genome-wide association studies (GWASs) have been shown to reduce required genotyping with little loss of power, compared to a one-stage design, provided a substantial fraction of cases and controls, [pi]sample, is included in stage 1. However, a number of recent GWASs have used [pi]sample < 0.2. Moreover, standard power calculations are not applicable because SNPs are selected in stage 1 by ranking their p-values, rather than comparing each SNP's statistic to a fixed critical value. We define the detection probability (DP) of a two-stage design as the probability that a given disease-associated SNP will have a p-value among the lowest ranks of p-values at stage 1, and, among those SNPs selected at stage 1, at stage 2. For 8000 cases and 8000 controls available for study an...

Dystrophin Nonsense Mutations Can Generate Alternative Rescue Transcripts in Lymphocytes

Annals of Human Genetics — Thu, 24 Jul 2008 04:00:00 +0100

Secondary alterations in splicing have been reported to produce semi-functional mRNA from several nonsense mutations in the dystrophin gene. Disruptions of exonic splicing enhancers by single nucleotide changes are thought to underlie such alterations. The precise frequencies of such nonsense mutation-dependent splicing alterations, however, remain unknown. Here we analyzed the splicing patterns of dystrophin mRNA in lymphocytes from 38 patients with dystrophinopathies due to nonsense mutations in the dystrophin gene. In seven of the cases (18%), we observed partial skipping of the nonsense-encoding exon. Two of the seven cases, however, exhibited complex activation of a nonsense mutation-created splice site, which resulted in the generation of novel transcripts. Examination of cis-regulat...

Erratum

Annals of Human Genetics — Fri, 18 Jul 2008 04:00:00 +0100

(Source: Annals of Human Genetics)

Cholesteryl Ester Transfer Protein (CETP) Genetic Variation and Early Onset of Non-Fatal Myocardial Infarction

Annals of Human Genetics — Tue, 15 Jul 2008 04:00:00 +0100

In this study we examined whether common genetic variation in the CETP gene is related to early-onset non-fatal MI risk in a population-based case-control study from western Washington State. Genotyping for the CETP [minus]2708 G/A, [minus]971 A/G, [minus]629 A/C, Intron-I TaqI G/A and exon-14 A/G (I405V) SNPs was performed in 578 cases with first acute non-fatal MI and in 666 demographically similar controls, free of clinical cardiovascular disease, identified randomly from the community. In-person interviews and non-fasting blood specimens provided data on coronary heart disease risk factors. In men, there was little evidence for an association between single SNPs and MI risk, but in women the age- and race-adjusted OR was found to be significant in 4 out of the 5 CETP single variants. H...

Identification of Association of Common AGGF1 Variants with Susceptibility for Klippel-Trenaunay Syndrome Using the Structure Association Program

Annals of Human Genetics — Sun, 13 Jul 2008 04:00:00 +0100

Klippel-Trenaunay syndrome (KTS) is a severe congenital disorder characterized by capillary malformations, venous malformations or varicose veins, and hypertrophy of the affected tissues. The angiogenic factor gene AGGF1 was previously identified as a candidate susceptibility gene for KTS, but further genetic studies are needed to firmly establish the genetic relationship between AGGF1 and KTS. We analyzed HapMap data and identified two tagSNPs, rs13155212 and rs7704267 that capture information for all common variants in AGGF1. The two SNPs were genotyped in 173 Caucasian KTS patients and 477 Caucasian non-KTS controls, and both significantly associated with susceptibility for KTS (P= 0.004 and 0.013, respectively). Permutation testing also showed a significant empirical P value for the as...

European Mathematical Genetics Meeting, Rotterdam, the Netherlands, 10th–11th April 2008

Annals of Human Genetics — Wed, 09 Jul 2008 04:00:00 +0100

Conclusion[ndash] This is a simple and powerful method in analyzing co-segregation. We present a plain algorithm which does not need linkage packages. It can be easily run in the counseling setting as it requires only two affected genotyped persons, gender and the age of onset for breast and/or ovarian cancer. HD_IBD [ndash] a new method for tracing allelic inheritance in deep complex pedigrees F. Besnier and Ö. Carlborg Department of Animal Breeding and Genetics, Swedish University of Agricultural Science & Linnaeus Centre for Bioinformatics, Uppsala University, Sweden Linkage analysis to detect QTL in complex pedigrees is often limited by the ability to trace marker-alleles from ancestor to descendants to e.g. construct IBD matrices for use in variance component analysis. Most available...

A Whole Genome Linkage Scan Identifies Multiple Chromosomal Regions Influencing Adiposity-Related Traits among Samoans

Annals of Human Genetics — Tue, 08 Jul 2008 04:00:00 +0100

We conducted a genome-wide scan in 46 pedigrees, with 671 phenotyped adults, from the independent nation of Samoa to map quantitative trait loci (QTLs) for adiposity-related phenotypes, including body mass index (BMI), abdominal circumference (ABDCIR), percent body fat (%BFAT), and fasting serum leptin and adiponectin. A set of 378 autosomal and 14 X chromosomal microsatellite markers were genotyped in 572 of the adults. Significant genetic correlations (0.82[ndash]0.96) were detected between pairs of BMI, ABDCIR, %BFAT and leptin. Suggestive linkages were found on 13q31 (LOD = 2.30 for leptin, LOD = 2.48 for %BFAT, LOD = 2.04 for ABDCIR, and LOD = 2.09 for BMI) and on 9p22 (LOD = 3.08 for ABDCIR and LOD = 2.53 for %BFAT). Furthermore, bivariate linkage analyses indicated that the genetic ...

HMBS Mutations in Chinese Patients with Acute Intermittent Porphyria

Annals of Human Genetics — Tue, 08 Jul 2008 04:00:00 +0100

Acute intermittent porphyria (AIP), an autosomal dominant disorder, is caused by partial deficiency of hydroxymethylbilane synthase (HMBS) affecting heme biosynthesis. Patients with AIP are characterized by recurrent abdominal pain, port-wine urine, and motor paresis. The disease can be provoked by changes in hormone levels, drugs and fasting. Molecular analysis for twenty-four unrelated Chinese AIP patients from Taiwan identified twenty-five HMBS mutations. There were 10 missense (40%), four nonsense (16%), five frame-shift (20%) and six splice site (24%) mutations. More than a half (15/25, 60%) of these mutations are predicted to produce a truncated protein. Four (c.33 + 5C>A, Arg26Cys, Arg26His, Arg325X) occurred more than once among the 24 families and one individual carried two mutati...

Founder Effect and Estimation of the Age of the c.892C>T (p.Arg298Cys) Mutation in LMNA Associated to Charcot-Marie-Tooth Subtype CMT2B1 in Families from North Western Africa

Annals of Human Genetics — Sat, 28 Jun 2008 04:00:00 +0100

CMT2B1, an axonal subtype (MIM 605588) of the Charcot-Marie-Tooth disease, is an autosomal recessive motor and sensory neuropathy characterized by progressive muscular and sensory loss in the distal extremities with chronic distal weakness. The genetic defect associated with the disease is, to date, a unique homozygous missense mutation, p.Arg298Cys (c.892C>T), in the LMNA gene. So far, this mutation has only been found in affected individuals originating from a restricted region of North Western Africa (northwest of Algeria and east of Morocco), strongly suggesting a founder effect. In order to address this hypothesis, genotyping of both STRs and intragenic SNPs was performed at the LMNA locus, at chromosome 1q21.2-q21.3, in 42 individuals affected with CMT2B1 from 25 Algerian families. O...

A Bayesian Spatial Multimarker Genetic Random-Effect Model for Fine-Scale Mapping

Annals of Human Genetics — Sat, 28 Jun 2008 04:00:00 +0100

Multiple markers in linkage disequilibrium (LD) are usually used to localize the disease gene location. These markers may contribute to the disease etiology simultaneously. In contrast to the single-locus tests, we propose a genetic random effects model that accounts for the dependence between loci via their spatial structures. In this model, the locus-specific random effects measure not only the genetic disease risk, but also the correlations between markers. In other words, the model incorporates this relation in both mean and covariance structures, and the variance components play important roles. We consider two different settings for the spatial relations. The first is our proposal, relative distance function (RDF), which is intuitive in the sense that markers nearby are likely to cor...

A Bayesian Spatial Multimarker Genetic Random-Effect Model for Fine-Scale Mapping

Annals of Human Genetics — Fri, 20 Jun 2008 18:42:27 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary Multiple markers in linkage disequilibrium (LD) are usually used to localize the disease gene location. These markers may contribute to the disease etiology simultaneously. In contrast to the single-locus tests, we propose a genetic random ... (Source: Annals of Human Genetics)

Identification of Association of Common AGGF1 Variants with Susceptibility for Klippel-Trenaunay Syndrome Using the Structure Association Program

Annals of Human Genetics — Wed, 18 Jun 2008 18:03:18 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary Klippel-Trenaunay syndrome (KTS) is a severe congenital disorder characterized by capillary malformations, venous malformations or varicose veins, and hypertrophy of the affected tissues. The angiogenic factor gene AGGF1 was previously identified ... (Source: Annals of Human Genetics)

Founder Effect and Estimation of the Age of the c.892C>T (p.Arg298Cys) Mutation in LMNA Associated to Charcot-Marie-Tooth Subtype CMT2B1 in Families from North Western Africa

Annals of Human Genetics — Thu, 12 Jun 2008 18:03:11 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary CMT2B1, an axonal subtype (MIM 605588) of the Charcot-Marie-Tooth disease, is an autosomal recessive motor and sensory neuropathy characterized by progressive muscular and sensory loss in the distal extremities with chronic distal weakness. The ... (Source: Annals of Human Genetics)

Using Population Mixtures to Optimize the Utility of Genomic Databases: Linkage Disequilibrium and Association Study Design in India

Annals of Human Genetics — Fri, 30 May 2008 18:03:24 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary When performing association studies in populations that have not been the focus of large-scale investigations of haplotype variation, it is often helpful to rely on genomic databases in other populations for study design and analysis – such as in ... (Source: Annals of Human Genetics)

Linkage Validation of RP25 Using the 10K GeneChip Array and Further Refinement of the Locus by New Linked Families

Annals of Human Genetics — Thu, 29 May 2008 18:03:14 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of retinal dystrophies, characterised by rod photoreceptor cell degeneration with autosomal recessive RP (arRP) as the commonest form worldwide. To date, a total of 26 ... (Source: Annals of Human Genetics)

Large-scale Molecular Analysis of a 34 Mb Interval on Chromosome 6q: Major Refinement of the RP25 Interval

Annals of Human Genetics — Thu, 29 May 2008 05:43:39 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary A large scale bioinformatics and molecular analysis of a 34 Mb interval on chromosome 6q12 was undertaken as part of our ongoing study to identify the gene responsible for an autosomal recessive retinitis pigmentosa (arRP) locus, RP25. Extensive ... (Source: Annals of Human Genetics)

Exact Trait-Model-Free Tests for Linkage Detection in Pedigrees

Annals of Human Genetics — Wed, 28 May 2008 18:03:18 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary A number of trait-model-free tests have been proposed for linkage detection between a genomic region and a trait. These tests involve testing the dependence in segregation between a trait and marker alleles by assigning a score to every possible ... (Source: Annals of Human Genetics)

Four SNPS on Chromosome 9p21 Confer Risk to Premature, Familial CAD and MI in an American Caucasian Population (GeneQuest)

Annals of Human Genetics — Tue, 27 May 2008 22:34:05 +0100

This study presents the first ... (Source: Annals of Human Genetics)

Cognitive Functioning and Survival in the Elderly: The SSADH C538T Polymorphism

Annals of Human Genetics — Tue, 27 May 2008 03:54:59 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary The variability of the Succinic Semialdehyde Dehydrogenase (SSADH, or ALDH5A1) gene affects both pathological and normal phenotypes correlated to cognitive function. We tested the association between the C538T polymorphism of the SSADH gene and ... (Source: Annals of Human Genetics)

A Genome-wide Scan in an Amish Pedigree with Parkinsonism

Annals of Human Genetics — Tue, 27 May 2008 03:53:18 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary The identification of familial Parkinson Disease (PD) genes is yielding important molecular pathogenetic insights. In an effort to identify additional PD genes, we studied an eight generation Amish pedigree with apparent autosomal dominant ... (Source: Annals of Human Genetics)

On the asymptotic equivalence of allelic and trend statistic under Hardy-Weinberg equilibrium

Annals of Human Genetics — Fri, 23 May 2008 18:04:24 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. (Source: Annals of Human Genetics)

Identifying Modifier Loci in Existing Genome Scan Data

Annals of Human Genetics — Tue, 20 May 2008 18:04:10 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary In many genetic disorders in which a primary disease-causing locus has been identified, evidence exists for additional trait variation due to genetic factors. These findings have led to studies seeking secondary ‘modifier’ loci. Identification of ... (Source: Annals of Human Genetics)

Contribution of Gender-Specific Genetic Factors to Osteoporosis Risk

Annals of Human Genetics — Fri, 16 May 2008 18:03:14 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary Common diseases result from the complex relationship between genetic and environmental factors. The aim of this review is to provide perspective for a conceptual framework aimed at studying the interplay of gender-specific genetic and ... (Source: Annals of Human Genetics)

Genetic Epidemiology of Subclinical Cardiovascular Disease in the Diabetes Heart Study

Annals of Human Genetics — Mon, 05 May 2008 18:10:00 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary A genome-wide linkage scan of 357 European American (EA) and 72 African American (AA) pedigrees multiplex for type 2 diabetes mellitus (T2DM) was performed with multipoint nonparametric QTL linkage analysis. Four subclinical measures of ... (Source: Annals of Human Genetics)

Correlation Analyses Reveal a Substantial Influence of Allelic Gaps on the Investigation of Genetic Diversity of Modern Human Populations with Microsatellites

Annals of Human Genetics — Mon, 05 May 2008 09:18:00 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary High intra-population genetic diversity and multiple measures of genetic variability at STR loci are useful in inferring past evolutionary history. However, STRs, categorized by their repeat motif size, differ in a number of aspects, requiring ... (Source: Annals of Human Genetics)

On the Origin of the Transthyretin Val30Met Familial Amyloid Polyneuropathy

Annals of Human Genetics — Mon, 05 May 2008 09:06:07 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary Transthyretin (TTR) familial amyloid polyneuropathy is a severe autosomal dominant neuropathy of adulthood, frequently linked to the pathogenic Val30Met variant of the TTR gene. The condition was initially described in northern Portugal, which is ... (Source: Annals of Human Genetics)

The Power and Robustness of Maximum LOD Score Statistics

Annals of Human Genetics — Mon, 14 Apr 2008 13:54:59 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary The maximum LOD score statistic is extremely powerful for gene mapping when calculated using the correct genetic parameter value. When the mode of genetic transmission is unknown, the maximum of the LOD scores obtained using several genetic ... (Source: Annals of Human Genetics)

TCF7L2 Polymorphisms are Associated with Type 2 Diabetes in Khatri Sikhs from North India: Genetic Variation Affects Lipid Levels

Annals of Human Genetics — Mon, 07 Apr 2008 18:03:11 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary Recently, the transcription factor-7-like 2 (TCF7L2) gene has been identified as the most important type 2 diabetes mellitus (T2DM) susceptibility gene. Common intronic polymorphisms in this gene have been found to be strongly associated with ... (Source: Annals of Human Genetics)

Family-Based Association Study of Polymorphisms in the RUNX2 Locus with Hand Bone Length and Hand BMD

Annals of Human Genetics — Sat, 29 Mar 2008 18:03:24 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary Osteoporosis is characterized by reduced bone strength. Bone size and bone mineral density (BMD) are major bone strength determinants. Identification of genes affecting the variability of these traits should improve prognosis and management of ... (Source: Annals of Human Genetics)

Y-Chromosome Analysis of Ancient Hungarian and Two Modern Hungarian-Speaking Populations from the Carpathian Basin

Annals of Human Genetics — Sat, 29 Mar 2008 00:59:51 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary The Hungarian population belongs linguistically to the Finno-Ugric branch of the Uralic family. The Tat C allele is an interesting marker in the Finno-Ugric context, distributed in all the Finno-Ugric-speaking populations, except for Hungarians. ... (Source: Annals of Human Genetics)

Quantification of the Genetic Component of Basal C-Reactive Protein Expression in SLE Nuclear Families

Annals of Human Genetics — Sat, 29 Mar 2008 00:52:24 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary C-reactive protein (CRP) is a heritable acute-phase plasma protein also expressed at low, basal, levels in healthy individuals. Elevated basal CRP has been associated with increased cardiovascular risk, while CRP dysregulation may be a feature of ... (Source: Annals of Human Genetics)

Investigation into the Ability of SNP Chipsets and Microsatellites to Detect Association with a Disease Locus

Annals of Human Genetics — Wed, 19 Mar 2008 18:05:27 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary We wished to investigate the ability of different SNP chipsets to detect association with a disease and to investigate the linkage disequilibrium (LD) relationships between microsatellites and nearby SNPs in order to assess their potential ... (Source: Annals of Human Genetics)

A Note on Allelic Tests in Case-Control Association Studies

Annals of Human Genetics — Tue, 18 Mar 2008 18:18:40 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary This paper reconsiders the relevant contribution of Sasieni in the validity of allele-based tests in case-control genetic association studies. In particular, the author clearly demonstrates that the classical chi-square test applied to allelic ... (Source: Annals of Human Genetics)

A Robust Linkage Analysis Method Using Combined Allele Sharing and Transmission Disequilibrium Information from Case-Parent Tetrad Families

Annals of Human Genetics — Fri, 14 Mar 2008 18:08:56 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary There are two types of linkage information, the allele sharing information and transmission disequilibrium information, that can be extracted from case-parent tetrad families for deriving statistics for test of linkage. By extracting allele ... (Source: Annals of Human Genetics)

Two-Stage Group Sequential Robust Tests in Family-Based Association Studies: Controlling Type I Error

Annals of Human Genetics — Thu, 06 Mar 2008 19:04:45 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary In family-based association studies, an optimal test statistic with asymptotic normal distribution is available when the underlying genetic model is known (e.g., recessive, additive, multiplicative, or dominant). In practice, however, genetic ... (Source: Annals of Human Genetics)

Update and Analysis of the University College London Low Density Lipoprotein Receptor Familial Hypercholesterolemia Database

Annals of Human Genetics — Wed, 05 Mar 2008 19:02:32 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary Familial hypercholesterolemia (FH) (OMIM 143890) is most commonly caused by variations in the LDLR gene which encodes the receptor for Low Density Lipoprotein (LDL) cholesterol particles. We have updated the University College London (UCL) LDLR ... (Source: Annals of Human Genetics)

Polymorphisms of the Tumor Suppressor Gene LSAMP are Associated with Left Main Coronary Artery Disease

Annals of Human Genetics — Tue, 04 Mar 2008 19:04:05 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary Previous association mapping on chromosome 3q13-21 detected evidence for association at the limbic system-associated membrane protein (LSAMP) gene in individuals with late-onset coronary artery disease (CAD). LSAMP has never been implicated in ... (Source: Annals of Human Genetics)

Efficient Approximation of P-value of the Maximum of Correlated Tests, with Applications to Genome-Wide Association Studies

Annals of Human Genetics — Mon, 03 Mar 2008 23:43:05 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary Genome-wide association study (GWAS), typically involving 100,000 to 500,000 single-nucleotide polymorphisms (SNPs), is a powerful approach to identify disease susceptibility loci. In a GWAS, single-marker analysis, which tests one SNP at a time, ... (Source: Annals of Human Genetics)

EMK: A Novel Program for Family-Based Allelic and Genotypic Association Tests on Quantitative Traits

Annals of Human Genetics — Thu, 28 Feb 2008 19:04:32 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary The QTDT program is a widely-used program for analyzing quantitative trait data, but the methods mainly test allelic association. Since the genotype of a marker is a direct observation for an individual, it is of interest to assess association at ... (Source: Annals of Human Genetics)

Mitochondrial DNA Variation in Karkar Islanders

Annals of Human Genetics — Thu, 28 Feb 2008 14:16:01 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary We analyzed 375 base pairs (bp) of the first hypervariable region (HVS-I) of the mitochondrial DNA (mtDNA) control region and intergenic COII/tRNALys 9-bp deletion from 47 Karkar Islanders (north coast of Papua New Guinea) belonging to the Waskia ... (Source: Annals of Human Genetics)

Age of SERPINA1 Gene PI Z Mutation: Swedish and Latvian Population Analysis

Annals of Human Genetics — Mon, 25 Feb 2008 19:06:30 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary Alpha 1-antitrypsin (A1AT) deficiency, one of the most common inborn errors of metabolism in Caucasians, is characterized by a low serum concentration of A1AT and a high risk of pulmonary emphysema and liver disease. The allelic frequency for the ... (Source: Annals of Human Genetics)

Exon Deletion in the Non-catalytic Domain of eIF2Bɛ Due to a Splice Site Mutation Leads to Infantile Forms of CACH/VWM with Severe Decrease of eIF2B GEF Activity

Annals of Human Genetics — Sat, 23 Feb 2008 02:40:49 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary The CACH/VWM syndrome is an autosomal recessive leukodystrophy characterized by a broad spectrum of clinical presentations and by diffuse cavitary degeneration of the white matter on MRI. Mutations responsible for this disorder are missense or ... (Source: Annals of Human Genetics)

Migration Waves to the Baltic Sea Region

Annals of Human Genetics — Fri, 22 Feb 2008 04:20:22 +0100

In this study, the population history of the Baltic Sea region, known to be affected by a variety of migrations and genetic barriers, was analyzed using both mitochondrial DNA and Y-chromosomal data. Over 1200 samples from Finland, Sweden, ... (Source: Annals of Human Genetics)

A Mutation Analysis of the Phenylalanine Hydroxylase (PAH) Gene in the Israeli Population

Annals of Human Genetics — Wed, 20 Feb 2008 19:02:16 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary Hyperphenylalaninemia (HPA) is a group of diseases characterized by a persistent elevation of phenylalanine levels in tissues and biological fluids. The most frequent form is phenylalanine hydroxylase deficiency, causing phenylketonuria (PKU). ... (Source: Annals of Human Genetics)

Significant Association Between TIM1 Promoter Polymorphisms and Protection Against Cerebral Malaria in Thailand

Annals of Human Genetics — Wed, 20 Feb 2008 03:47:43 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary Although cerebral malaria is a major life-threatening complication of Plasmodium falciparum infection, its pathophysiology is not well understood. Prolonged activation of the T helper type 1 (Th1) response characterized by the production of pro-... (Source: Annals of Human Genetics)

Genomewide Linkage Scan for Combined Obesity Phenotypes using Principal Component Analysis

Annals of Human Genetics — Wed, 06 Feb 2008 19:02:11 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary Traditional whole genome linkage scans for obesity were usually performed for a number of correlated obesity related phenotypes separately without considering their correlations. The purpose of this study was to identify quantitative trait loci (... (Source: Annals of Human Genetics)

The MTHFD1 Gene is not Involved in Cleft Lip with or Without Palate Onset Among the Italian Population

Annals of Human Genetics — Wed, 06 Feb 2008 08:13:03 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary Nonsyndromic cleft lip with or without cleft palate (CL/P) is the most common orofacial malformation, having a non-Mendelian and multifactorial aetiology. It has been shown that polymorphic variants of genes encoding key proteins of folate and ... (Source: Annals of Human Genetics)

Perturbation Analysis: A Simple Method for Filtering SNPs with Erroneous Genotyping in Genome-Wide Association Studies

Annals of Human Genetics — Wed, 06 Feb 2008 08:12:41 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary We introduce a simple and yet scientifically objective criterion for identifying SNPs with genotyping errors due to poor clustering. This yields a metric for assessing the stability of the assigned genotypes by evaluating the extent of ... (Source: Annals of Human Genetics)

Differential Y-chromosome Anatolian Influences on the Greek and Cretan Neolithic

Annals of Human Genetics — Tue, 05 Feb 2008 08:29:26 +0100

Annals of Human Genetics, Volume 72, Issue 2, Page 205-214, March 2008. Summary The earliest Neolithic sites of Europe are located in Crete and mainland Greece. A debate persists concerning whether these farmers originated in neighboring Anatolia and the role of maritime colonization. To address these issues 171 samples were ... (Source: Annals of Human Genetics)

Type 2 Diabetes Susceptibility Genes on Chromosome 1q21–24

Annals of Human Genetics — Tue, 05 Feb 2008 08:29:14 +0100

Annals of Human Genetics, Volume 72, Issue 2, Page 163-169, March 2008. Summary Type 2 diabetes (T2D) has been linked to chromosome 1q21–24 in multiple samples, including a Utah family sample. Variants in 13 of the numerous candidate genes in the 1q region were tested for association with T2D in a Utah case-control sample. ... (Source: Annals of Human Genetics)

Hypomutability at the Polyadenine Tract in SMN Intron 3 Shows the Invariability of the a-SMN Protein Structure

Annals of Human Genetics — Tue, 05 Feb 2008 08:29:13 +0100

Annals of Human Genetics, Volume 72, Issue 2, Page 288-291, March 2008. Summary Recently, the axonal-SMN (a-SMN) protein, which is generated by the gene responsible for spinal muscular atrophy (SMA), SMN, has been reported. Surprisingly, the a-SMN transcript includes the entire sequence of SMN intron 3. We had expected a ... (Source: Annals of Human Genetics)

Optimal Two-Stage Design for Case-Control Association Analysis Incorporating Genotyping Errors

Annals of Human Genetics — Wed, 23 Jan 2008 19:01:24 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary Two-stage design is a cost effective approach for identifying disease genes in genetic studies and it has received much attention recently. In general, there are two types of two-stage designs that differ on the methods and samples used to ... (Source: Annals of Human Genetics)

Reconstructing the Genealogy of a BRCA1 Founder Mutation by Phylogenetic Analysis

Annals of Human Genetics — Wed, 23 Jan 2008 10:28:08 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary Estimating the age of founder mutations may contribute to improve our knowledge of population genetics and evolutionary history of diseases. Previous haplotype analysis suggested that the BRCA1*1499insA mutation was a founder allele, probably ... (Source: Annals of Human Genetics)

Charcot-Marie-Tooth Disease: A Clinico-genetic Confrontation

Annals of Human Genetics — Wed, 23 Jan 2008 10:28:08 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary Charcot-Marie-Tooth disease (CMT) is the most common neuromuscular disorder. It represents a group of clinically and genetically heterogeneous inherited neuropathies. Here, we review the results of molecular genetic investigations and the ... (Source: Annals of Human Genetics)

Close Genetic Relationship Between Semitic-speaking and Indo-European-speaking Groups in Iran

Annals of Human Genetics — Mon, 21 Jan 2008 19:07:21 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary As part of a continuing investigation of the extent to which the genetic and linguistic relationships of populations are correlated, we analyzed mtDNA HV1 sequences, eleven Y chromosome bi-allelic markers, and 9 Y-STR loci in two neighboring ... (Source: Annals of Human Genetics)

Gene-Gene Interaction Between FGF20 and MAOB in Parkinson Disease

Annals of Human Genetics — Mon, 21 Jan 2008 05:28:57 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary The fibroblast growth factor 20 (FGF20) and monoamine oxidase B (MAOB) genes are associated with Parkinson Disease (PD) risk and both are in the dopamine bio-pathway. Therefore, we investigated the joint effect between polymorphisms in the FGF20 ... (Source: Annals of Human Genetics)

Mitochondrial DNA Variability in Slovaks, with Application to the Roma Origin

Annals of Human Genetics — Mon, 21 Jan 2008 05:28:55 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary To gain insight into the mitochondrial gene pool diversity of European populations, we studied mitochondrial DNA (mtDNA) variability in 207 subjects from western and eastern areas of Slovakia. Sequencing of two hypervariable segments, HVS I and ... (Source: Annals of Human Genetics)

Segmental Copy-Number Variation Observed in Japanese by Array-CGH

Annals of Human Genetics — Mon, 21 Jan 2008 05:28:54 +0100

In this study, we examined 80 unrelated Japanese individuals using a microarray (2,238 Bac-clones) based comparative genomic hybridization (array-CGH) assay. ... (Source: Annals of Human Genetics)

Study of Regions of Extended Homozygosity Provides a Powerful Method to Explore Haplotype Structure of Human Populations

Annals of Human Genetics — Mon, 21 Jan 2008 05:28:54 +0100

Annals of Human Genetics, Volume 0, Issue 0, Page ???, September 2003. Summary Previous investigations have reported linkage disequilibrium occurring between nearby polymorphisms, a block-like structure for such relationships, some instances where surprisingly few haplotypes are found and regions of extended homozygosity ... (Source: Annals of Human Genetics)