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The development of a complex disease is an intricate interplay of genetic and environmental factors. "Heritability" is defined as the proportion of total trait variance due to genetic factors within a given population. Studies with monozygotic (MZ) and dizygotic (DZ) twins allow us to estimate heritability by fitting an "ACE" model which estimates the proportion of trait variance explained by additive genetic (A), common shared environment (C), and unique non-shared environmental (E) latent effects, thus helping us better understand disease risk and etiology. In this paper, we develop a flexible generalized estimating equations framework ("GEE2") for fitting twin ACE models that requires minimal distributional assumptions, rather only the first two moments need to be correctly specified. We prove that two commonly used methods for estimating heritability, the normal ACE model ("NACE") and Falconer's method, can both be fit within this unified GEE2 framework, which additionally provides robust standard errors. Although the traditional Falconer's method cannot directly adjust for covariates, we show that the corresponding GEE2 version ("GEE2-Falconer") can incorporate covariate effects for both mean and variance-level parameters (e.g. let heritability vary by sex or age). Given non-normal data, we show that the GEE2 models attain significantly better coverage of the true heritability compared to the traditional NACE and Falconer's methods. Finally, we demonstrate an important scenario where the NACE model produces biased estimates of heritability while Falconer's method remains unbiased. Overall, we recommend using the robust and flexible GEE2-Falconer model for estimating heritability in twin studies.

Genome-wide association studies have identified many individual genetic loci associated with multiple complex traits and common diseases. There are, however, few examples where the molecular basis of such pleiotropy has been elucidated. To address this challenge, we describe an integrative approach, focusing on the p.Ser219Gly (rs867186 A>G) variant in thePROCRgene (encoding the endothelial protein C receptor, EPCR), which has been associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. In a phenome scan of 12 cardiometabolic diseases and 24 molecular factors, we found thatPROCR-219Gly associated with higher plasma levels of zymogenic and activated protein C as well as coagulation factor VII. Using statistical colocalization and Mendelian randomization analyses, we uncovered shared genetic etiology across activated protein C, factor VII, CAD and VTE, identifying p.S219G as the likely causal variant at the locus. In a recall-by-genotype study of 52 healthy volunteers stratified by p.S219G, we detected 2.5-fold higher soluble EPCR levels and 1.2-fold higher protein C levels in plasma per effect allele, suggesting the allele induces EPCR shedding from the membrane of endothelial cells. Finally, in cell adhesion assays, we found that increasing concentrations of activated protein C, but not soluble EPCR, reduced leukocyte–endothelial cell adhesion, a marker for vascular inflammation. These results support a role for protein C as a causal factor in arterial and venous diseases, suggesting thatPROCR-219Gly protects against CAD through anti-inflammatory mechanisms while it promotes VTE risk through pro-thrombotic mechanisms. Overall, our study illustrates a multi-modal approach that can help reveal molecular underpinnings of cross-disease associations.

Essentials Galectin-3, an inflammatory biomarker, is involved in murine thrombogenesis. Galectin-3–binding protein is up-regulated in microparticles from deep venous thrombosis patients compared to control patients. In this prospective epidemiological study, participants with plasma galectin-3 concentrations in the highest quintile had a greater risk of incident venous thromboembolism than did those in the lowest quintile. The association of galectin-3 and VTE was not replicated in a second prospective study, but the meta-analyzed hazard ratio still indicated a positive association. Galectin-3 is associated positively with risk of venous thromboembolism. Background The inflammatory biomarker galectin-3 contributes to pathologic conditions such as heart failure and stimulates murine thrombogenesis. Its association with venous thromboembolism (VTE) has been sparsely studied. Objectives To assess the prospective association of plasma galectin-3 and the LGALS3 rs4644 SNP with VTE incidence. Methods We measured plasma galectin-3 in 9916 participants in the Atherosclerosis Risk in Communities (ARIC) study cohort in 1996-1998 and identified VTEs through 2013. Using Cox regression, we estimated the hazard ratio associating galectin-3 with incident VTE over a median of 13.9 years. Replication was sought in the Cardiovascular Health Study (CHS). Results ARIC included 21.8% blacks and 56.2% females with mean baseline age of 62.7 years. The incidence rate of VTE (n=389 events) increased across quintiles of galectin-3, with hazard ratios (95% CI) of 1 (reference), 1.13 (0.80-1.61), 1.00 (0.70-1.43), 1.36 (0.96-1.91), and 1.55 (1.09-2.19) (P-trend=.005), adjusted for age, sex, race, body mass index, diabetes status, and renal function. Results did not replicate in the CHS (124 VTE), but meta-analysis of both studies yielded a pooled hazard ratio (95% CI) for 1 SD increment in log galectin-3 of 1.10 (1.00-1.22). In ARIC, the C allele of rs4644 in the LGALS3 gene was associated with higher galectin-3 level, and in whites, with an increased rate of VTE. Conclusion Galectin-3 levels were associated positively with VTE incidence.

INTRODUCTION: Venous thromboembolism incidence rates are 30–100% higher in American blacks than whites. We examined (a) the degree to which differences in the frequencies of socioeconomic, lifestyle, and medical risk factors, and genetic variants explain the excess venous thromboembolism risk in blacks and (b) whether some risk factors are more strongly associated with venous thromboembolism in blacks compared with whites. METHODS: We measured venous thromboembolism risk factors in black or white participants of the Atherosclerosis Risk in Communities study in 1987–89 and followed them prospectively through 2015 for venous thromboembolism incidence. RESULTS: Over a mean of 22 years, we identified 332 venous thromboembolisms in blacks and 578 in whites, yielding 65% higher crude incidence rates per 1,000 person-years in blacks. The age and sex-adjusted hazard ratio (95% CI) of venous thromboembolism for blacks, compared with whites, was 2.04 (1.76, 2.37) for follow-up >10 years, and was attenuated to 1.14 (0.89, 1.46), when adjusted for baseline confounders or mediators of the race association, which tended to be more common in blacks. For example, adjustment for just baseline weight, family income, and plasma factor VIII concentration reduced the regression coefficient for race by 75%. There were no significant (p

Context Vitamin D inadequacy is common in the adult population of the United States. Although the genetic determinants underlying vitamin D inadequacy have been studied in people of European ancestry, less is known about populations with Hispanic or African ancestry. Objective The Trans-Ethnic Evaluation of Vitamin D (TRANSCEN-D) genomewide association study (GWAS) consortium was assembled to replicate genetic associations with 25-hydroxyvitamin D [25(OH)D] concentrations from the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) meta-analyses of European ancestry and to identify genetic variants related to vitamin D concentrations in African and Hispanic ancestries. Design Ancestry-specific (Hispanic and African) and transethnic (Hispanic, African, and European) meta-analyses were performed with Meta-Analysis Helper software (METAL). Patients or Other Participants In total, 8541 African American and 3485 Hispanic American (from North America) participants from 12 cohorts and 16,124 European participants from SUNLIGHT were included in the study. Main Outcome Measures Blood concentrations of 25(OH)D were measured for all participants. Results Ancestry-specific analyses in African and Hispanic Americans replicated single nucleotide polymorphisms (SNPs) in GC (2 and 4 SNPs, respectively). An SNP (rs79666294) near the KIF4B gene was identified in the African American cohort. Transethnic evaluation replicated GC and DHCR7 region SNPs. Additionally, the transethnic analyses revealed SNPs rs719700 and rs1410656 near the ANO6/ARID2 and HTR2A genes, respectively. Conclusions Ancestry-specific and transethnic GWASs of 25(OH)D confirmed findings in GC and DHCR7 for African and Hispanic American samples and revealed findings near KIF4B, ANO6/ARID2, and HTR2A. The biological mechanisms that link these regions with 25(OH)D metabolism warrant further investigation.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type-specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits. Marie-Curie Initial Training Network NETSIM British Heart Foundation RG/09/12/28096 National Institutes for Health RP-PG-0310-1002 Wellcome Trust 098051 info:eu-repo/grantAgreement/EC/FP7/282510

International audience; Coagulation factor XI (FXI) has become increasingly interesting for its role in pathogenesis of thrombosis. While elevated plasma levels of FXI have been associated with venous thromboembolism and ischemic stroke, its deficiency is associated with mild bleeding. We aimed to determine novel genetic and post-transcriptional plasma FXI regulators.We performed a genome-wide association study (GWAS) for plasma FXI levels, using novel data imputed to the 1000 Genomes reference panel. Individual GWAS analyses, including a total of 16,169 European individuals from the ARIC, GHS, MARTHA and PROCARDIS studies, were meta-analysed and further replicated in 2,045 individuals from the F5L family, GAIT2 and MEGA studies. Additional association with activated partial thromboplastin time (aPTT) was tested for the top SNPs. In addition, a study on the effect of miRNA on FXI regulation was performed using in silico prediction tools and in vitro luciferase assays.Three loci showed robust, replicating association with circulating FXI levels: KNG1 (rs710446, P-value = 2.07 × 10−302), F11 (rs4253417, P-value = 2.86 × 10−193), and a novel association in GCKR (rs780094, P-value = 3.56 ×10−09), here for the first time implicated in FXI regulation. The two first SNPs (rs710446 and rs4253417) also associated with aPTT. Conditional and haplotype analyses demonstrated a complex association signal, with additional novel SNPs modulating plasma FXI levels in both the F11 and KNG1 loci. Finally, eight miRNAs were predicted to bind F11 mRNA. Over-expression of either miR-145 or miR-181 significantly reduced the luciferase activity in cells transfected with a plasmid containing FXI-3’UTR.These results should open the door to new therapeutic targets for thrombosis prevention.

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

Although estimating the five parameters of an unknown Generalized Normal Laplace (GNL) density by minimizing the distance between the empirical and true characteristic functions seems appealing, the approach cannot be advocated in practice. This conclusion is based on extensive numerical simulations in which a fast minimization procedure delivers deceiving estimators with values that are quite far away from the truth. These findings can be predicted by the very large values obtained for the true asymptotic variances of the estimators of the five parameters of the true GNL density.

Background— Fibrinogen is both central to blood coagulation and an acute-phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels. Methods and Results— We conducted a genome-wide association analysis on 6 population-based studies, the Rotterdam Study, the Framingham Heart Study, the Cardiovascular Health Study, the Atherosclerosis Risk in Communities Study, the Monitoring of Trends and Determinants in Cardiovascular Disease/KORA Augsburg Study, and the British 1958 Birth Cohort Study, including 22 096 participants of European ancestry. Four loci were marked by 1 or more single-nucleotide polymorphisms that demonstrated genome-wide significance ( P −8 ). These included a single-nucleotide polymorphism located in the fibrinogen β chain ( FGB ) gene and 3 single-nucleotide polymorphisms representing newly identified loci. The high-signal single-nucleotide polymorphisms were rs1800789 in exon 7 of FGB ( P =1.8�10 −30 ), rs2522056 downstream from the interferon regulatory factor 1 ( IRF1 ) gene ( P =1.3�10 −15 ), rs511154 within intron 1 of the propionyl coenzyme A carboxylase ( PCCB ) gene ( P =5.9�10 −10 ), and rs1539019 on the NLR family pyrin domain containing 3 isoforms ( NLRP3 ) gene ( P =1.04�10 −8 ). Conclusions— Our findings highlight biological pathways that may be important in regulation of inflammation underlying cardiovascular disease.

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including similar to 120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci ; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10−8) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10−10); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10−8); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10−8). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.

International audience; Venous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE. Nine loci reached the genome-wide significance level of 5 × 10(-8) including six already known to associate with VTE (ABO, F2, F5, F11, FGG, and PROCR) and three unsuspected loci. SNPs mapping to these latter were selected for replication in three independent case-control studies totaling 3,009 VTE-affected individuals and 2,586 control subjects. This strategy led to the identification and replication of two VTE-associated loci, TSPAN15 and SLC44A2, with lead risk alleles associated with odds ratio for disease of 1.31 (p = 1.67 × 10(-16)) and 1.21 (p = 2.75 × 10(-15)), respectively. The lead SNP at the TSPAN15 locus is the intronic rs78707713 and the lead SLC44A2 SNP is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury. We further showed that these two variants did not associate with known hemostatic plasma markers. TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers. Our findings uncovered unexpected actors of VTE etiology and pave the way for novel mechanistic concepts of VTE pathophysiology.

We carried out a genome-wide association study (GWAS) for general cognitive ability (GCA) plus three other analyses of GWAS data that aggregate the effects of multiple single-nucleotide polymorphisms (SNPs) in various ways. Our multigenerational sample comprised 7,100 Caucasian participants, drawn from two longitudinal family studies, who had been assessed with an age-appropriate IQ test and had provided DNA samples passing quality screens. We conducted the GWAS across ∼ 2.5 million SNPs (both typed and imputed), using a generalized least-squares method appropriate for the different family structures present in our sample, and subsequently conducted gene-based association tests. We also conducted polygenic prediction analyses under five-fold cross-validation, using two different schemes of weighting SNPs. Using parametric bootstrapping, we assessed the performance of this prediction procedure under the null. Finally, we estimated the proportion of variance attributable to all genotyped SNPs as random effects with software GCTA. The study is limited chiefly by its power to detect realistic single-SNP or single-gene effects, none of which reached genome-wide significance, though some genomic inflation was evident from the GWAS. Unit SNP weights performed about as well as least-squares regression weights under cross-validation, but the performance of both increased as more SNPs were included in calculating the polygenic score. Estimates from GCTA were 35% of phenotypic variance at the recommended biological-relatedness ceiling. Taken together, our results concur with other recent studies: they support a substantial heritability of GCA, arising from a very large number of causal SNPs, each of very small effect. We place our study in the context of the literature-both contemporary and historical-and provide accessible explication of our statistical methods.

Multi-locus effect modeling is a powerful approach for detection of genes influencing a complex disease. Especially for rare variants, we need to analyze multiple variants together to achieve adequate power for detection. In this paper, we propose several parsimonious branching model techniques to assess the joint effect of a group of rare variants in a case-control study. These models implement a data reduction strategy within a likelihood framework and use a weighted score test to assess the statistical significance of the effect of the group of variants on the disease. The primary advantage of the proposed approach is that it performs model-averaging over a substantially smaller set of models supported by the data and thus gains power to detect multi-locus effects. We illustrate these proposed approaches on simulated and real data and study their performance compared to several existing rare variant detection approaches. The primary goal of this paper is to assess if there is any gain in power to detect association by averaging over a number of models instead of selecting the best model. Extensive simulations and real data application demonstrate the advantage the proposed approach in presence of causal variants with opposite directional effects along with a moderate number of null variants in linkage disequilibrium.

Coagulation factor VIII and von Willebrand factor (VWF) are key proteins in procoagulant activation. Higher FVIII coagulant activity (FVIII :C) and VWF antigen (VWF :Ag) are risk factors for cardiovascular disease and venous thromboembolism. Beyond associations with ABO blood group, genetic determinants of FVIII and VWF are not well understood, especially in non European-American populations. We performed a genetic association study of FVIII :C and VWF:Ag that assessed 50,000 gene-centric single nucleotide polymorphisms (SNPs) in 18,556 European Americans (EAs) and 5,047 African Americans (AAs) from five population-based cohorts. Previously unreported associations for FVIII :C were identified in both AAs and EAs with KNG1 (most significantly associated SNP rs710446, Ile581Thr, Ile581Thr, P = 5.10 × 10(-7) in EAs and P = 3.88 × 10(-3) in AAs) and VWF rs7962217 (Gly2705Arg,P = 6.30 × 10(-9) in EAs and P = 2.98 × 10(-2) in AAs. Significant associations for FVIII :C were also observed with F8/TMLHE region SNP rs12557310 in EAs (P = 8.02 × 10(-10) ), with VWF rs1800380 in AAs (P = 5.62 × 10(-11) ), and with MAT1A rs2236568 in AAs (P51.69 × 10(-6) ). We replicated previously reported associations of FVIII :C and VWF :Ag with the ABO blood group, VWF rs1063856(Thr789Ala), rs216321 (Ala852Gln), and VWF rs2229446 (Arg2185Gln). Findings from this study expand our understanding of genetic influences for FVIII :C and VWF :Ag in both EAs and AAs.

Objective— Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases. We conducted a meta-analysis of genome-wide association studies to identify novel correlates of circulating levels of tPA. Approach and Results— Fourteen cohort studies with tPA measures (N=26 929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels ( P −8 ). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P =2.9×10 −14 ) within STXBP5 . The second locus is on 8p11.21. The lead SNP (rs3136739; P =1.3×10 −9 ) is intronic to POLB and PLAT . We identified a nonsynonymous SNP (rs2020921) in modest linkage disequilibrium with rs3136739 ( r 2 =0.50) within exon 5 of PLAT ( P =2.0×10 −8 ). The third locus is on 12q24.33, with the lead SNP (rs7301826; P =1.0×10 −9 ) within intron 7 of STX2 . We further found evidence for the association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased the release of tPA from vascular endothelial cells, whereas silencing STX2 increased the tPA release. Through an in silico lookup, we found no associations of the 3 lead SNPs with coronary artery disease or stroke. Conclusions— We identified 3 loci associated with circulating tPA levels, the PLAT region, STXBP5 , and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.

D-dimer, a fibrin degradation product, is related to risk of cardiovascular disease and venous thromboembolism. Genetic determinants of D-dimer are not well characterized; notably, few data have been reported for African American (AA), Asian, and Hispanic populations.We conducted a large-scale candidate gene association study to identify variants in genes associated with D-dimer levels in multi-ethnic populations. Four cohorts, comprising 6,848 European Americans (EAs), 2,192 AAs, 670 Asians, and 1,286 Hispanics in the National Heart, Lung, and Blood Institute Candidate Gene Association Resource consortium, were assembled. Approximately 50,000 genotyped single nucleotide polymorphisms (SNPs) in 2,000 cardiovascular disease gene loci were analyzed by linear regression, adjusting for age, sex, study site, and principal components in each cohort and ethnic group. Results across studies were combined within each ethnic group by meta-analysis.Twelve SNPs in coagulation factor V (F5) and 3 SNPs in the fibrinogen alpha chain (FGA) were significantly associated with D-dimer level in EAs with p2.0×10(-6). The signal for the most associated SNP in F5 (rs6025, factor V Leiden) was replicated in Hispanics (p=0.023), while that for the top functional SNP in FGA (rs6050) was replicated in AAs (p=0.006). No additional SNPs were significantly associated with D-dimer.Our study replicated previously reported associations of D-dimer with SNPs in F5 and FGA in EAs; we demonstrated replication of the association of D-dimer with FGA rs6050 in AAs and the factor V Leiden variant in Hispanics.

We carried out a genome-wide association study (GWAS) for general cognitive ability (GCA) plus three other analyses of GWAS data that aggregate the effects of multiple single-nucleotide polymorphisms (SNPs) in various ways. Our multigenerational sample comprised 7,100 Caucasian participants, drawn from two longitudinal family studies, who had been assessed with an age-appropriate IQ test and had provided DNA samples passing quality screens. We conducted the GWAS across ∼ 2.5 million SNPs (both typed and imputed), using a generalized least-squares method appropriate for the different family structures present in our sample, and subsequently conducted gene-based association tests. We also conducted polygenic prediction analyses under five-fold cross-validation, using two different schemes of weighting SNPs. Using parametric bootstrapping, we assessed the performance of this prediction procedure under the null. Finally, we estimated the proportion of variance attributable to all genotyped SNPs as random effects with software GCTA. The study is limited chiefly by its power to detect realistic single-SNP or single-gene effects, none of which reached genome-wide significance, though some genomic inflation was evident from the GWAS. Unit SNP weights performed about as well as least-squares regression weights under cross-validation, but the performance of both increased as more SNPs were included in calculating the polygenic score. Estimates from GCTA were 35% of phenotypic variance at the recommended biological-relatedness ceiling. Taken together, our results concur with other recent studies: they support a substantial heritability of GCA, arising from a very large number of causal SNPs, each of very small effect. We place our study in the context of the literature-both contemporary and historical-and provide accessible explication of our statistical methods.

Although twin, family, and adoption studies have shown that general cognitive ability (GCA) is substantially heritable, GWAS has not uncovered a genetic polymorphism replicably associated with this phenotype. However, most polymorphisms used in GWAS are common SNPs. The present study explores use of a different class of genetic variant, the copy-number variant (CNV), to predict GCA in a sample of 6,199 participants, combined from two longitudinal family studies. We aggregated low-frequency (

We report results from a genome wide association study (GWAS) of five quantitative indicators of behavioral disinhibition: nicotine, alcohol consumption, alcohol dependence, illicit drugs, and non-substance related behavioral disinhibition. The sample, consisting of 7,188 Caucasian individuals clustered in 2,300 nuclear families, was genotyped on over 520,000 SNP markers from Illumina’s Human 660W-Quad Array. Analysis of individual SNP associations revealed only one marker-component phenotype association, between rs1868152 and illicit drugs, with a p value below the standard genome-wide threshold of 5 × 10−8. Because we had analyzed five separate phenotypes, we do not consider this single association to be significant. However, we report 13 SNPs that were associated at p

Allogeneic hematopoietic cell transplant (HCT) is associated with a high morbidity and mortality. Adhesion molecules play an important role in endothelial activation and initiation of inflammatory response. We hypothesized that single nucleotide polymorphisms (SNPs) in the endothelial molecules may contribute to heterogeneity in HCT outcomes. We evaluated the association of 4 SNPs in ICAM1 (rs5498), PECAM1 (rs668 and rs1131012) and SELL (rs2229569) genes with acute and chronic graft-versus-host disease (GvHD) and those experiencing transplant-related mortality (TRM) within 1 year among 425 allogeneic HCT recipient-donor pairs. Using a Fine and Gray proportional hazards model to evaluate the association between genetic variants and clinical outcomes, after adjustment for recipient age, race, diagnosis, disease status, gender mismatch, cytomegalovirus serostatus, gender, donor type, conditioning regimen and year of transplant, only rs5498 in the ICAM1 gene among both recipients and donors was associated with a decreased risk of TRM (P ≤ 0.02). None of the SNPs were associated with acute or chronic GvHD risk. These findings suggest that genetic variants in the vascular adhesion molecules may be used to identify patients at high risk for TRM.

Background— Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels. Methods and Results— The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0×10 −8 and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2×10 −24 ), 4q25 (3.6×10 −12 ), 11q12 (2.0×10 −10 ), 13q34 (9.0×10 −259 ), and 20q11.2 (5.7×10 −37 ). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2×10 −22 ), 8p21 (1.3×10 −16 ), 9q34 (−324 ), 12p13 (1.7×10 −32 ), 12q23 (7.3×10 −10 ), 12q24.3 (3.8×10 −11 ), 14q32 (2.3×10 −10 ), and 19p13.2 (1.3×10 −9 ). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings were replicated. Conclusions— New genetic associations were discovered outside previously known biological pathways and may point to novel prevention and treatment targets of hemostasis disorders.

Background There is a growing awareness that interaction between multiple genes play an important role in the risk of common, complex multi-factorial diseases. Many common diseases are affected by certain genotype combinations (associated with some genes and their interactions). The identification and characterization of these susceptibility genes and gene-gene interaction have been limited by small sample size and large number of potential interactions between genes. Several methods have been proposed to detect gene-gene interaction in a case control study. The penalized logistic regression (PLR), a variant of logistic regression with L 2 regularization, is a parametric approach to detect gene-gene interaction. On the other hand, the Multifactor Dimensionality Reduction (MDR) is a nonparametric and genetic model-free approach to detect genotype combinations associated with disease risk. Methods We compared the power of MDR and PLR for detecting two-way and three-way interactions in a case-control study through extensive simulations. We generated several interaction models with different magnitudes of interaction effect. For each model, we simulated 100 datasets, each with 200 cases and 200 controls and 20 SNPs. We considered a wide variety of models such as models with just main effects, models with only interaction effects or models with both main and interaction effects. We also compared the performance of MDR and PLR to detect gene-gene interaction associated with acute rejection(AR) in kidney transplant patients. Results In this paper, we have studied the power of MDR and PLR for detecting gene-gene interaction in a case-control study through extensive simulation. We have compared their performances for different two-way and three-way interaction models. We have studied the effect of different allele frequencies on these methods. We have also implemented their performance on a real dataset. As expected, none of these methods were consistently better for all data scenarios, but, generally MDR outperformed PLR for more complex models. The ROC analysis on the real dataset suggests that MDR outperforms PLR in detecting gene-gene interaction on the real dataset. Conclusion As one might expect, the relative success of each method is context dependent. This study demonstrates the strengths and weaknesses of the methods to detect gene-gene interaction.

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 identity-by-descent configuration of the pedigree members without modeling the trait, and then averaging the scores over all such configurations compatible with the observed marker genotypes and genealogical relationship of the pedigree members. In this paper we propose a permutation test as an alternative to the existing exact trait-model-free tests for linkage detection. The proposed test is computationally efficient and is applicable on complex multigeneration pedigree structures. In this paper, we have compared the performance of the permutation test with two other exact trait-model-free tests for linkage detection on simulated datasets. We have demonstrated that the proposed permutation test is fully robust against mispecification of marker allele frequencies and has very good power for linkage detection. The permutation test is implemented in the program lm_ibdtests within the framework of MORGAN 2.8 (http://www.stat.washington.edu/thompson/Genepi/MORGAN/Morgan.shtml).

We performed multipoint linkage analysis of the electrophysiological trait ECB21 on chromosome 4 in the full pedigrees provided by the Collaborative Study on the Genetics of Alcoholism (COGA). Three Markov chain Monte Carlo (MCMC)-based approaches were applied to the provided and re-estimated genetic maps and to five different marker panels consisting of microsatellite (STRP) and/or SNP markers at various densities. We found evidence of linkage near the GABRB1 STRP using all methods, maps, and marker panels. Difficulties encountered with SNP panels included convergence problems and demanding computations.

Our Markov chain Monte Carlo (MCMC) methods were used in linkage analyses of the Framingham Heart Study data using all available pedigrees. Our goal was to detect and map loci associated with covariate-adjusted traits log triglyceride (lnTG) and high-density lipoprotein cholesterol (HDL) using multipoint LOD score analysis, Bayesian oligogenic linkage analysis and identity-by-descent (IBD) scoring methods. Each method used all marker data for all markers on a chromosome. Bayesian linkage analysis detected a linkage signal on chromosome 7 for lnTG and HDL, corroborating previously published results. However, these results were not replicated in a classical linkage analysis of the data or by using IBD scoring methods. We conclude that Bayesian linkage analysis provides a powerful paradigm for mapping trait loci but interpretation of the Bayesian linkage signals is subjective. In the absence of a LOD score method accommodating genetically complex traits and linkage heterogeneity, validation of these signals remains elusive.

Centre for Surface Science, Department of Chemistry, Jadavpur University, Kolkata-700 032, India E-mail : cssju@yahoo.co.uk Fax : 91-33-4 734266 Manuscript received 19 March 2001 The systems consisting of azure (Az) dyes in presence of sonicated aqueous dispersion of phospholipid generate photovoltage when studied in a photoelectrochemical cell. A possible mechanism of photovoltage generation suggests the photoinduced electron transfer from phospholipid to Az dye in liposome. The electr·ode kinetics of the photoinduced redox reactions in the cell have also been studied to confirm the mechanism of photoinduced electron transfer as well as the interaction between Az dye and phospholipid.

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function. © 2011 Macmillan Publishers Limited. All rights reserved.