Case-control association testing by graphical modeling for the Genetic Analysis Workshop 17 mini-exome sequence data

We generalize recent work on graphical models for linkage disequilibrium to estimate the conditional independence structure between all variables for individuals in the Genetic Analysis Workshop 17 unrelated individuals data set. Using a stepwise approach for computational efficiency and an extension of our previously described methods, we estimate a model that describes the relationships between the disease trait, all quantitative variables, all covariates, ethnic origin, and the loci most strongly associated with these variables. We performed our analysis for the first 50 replicate data sets. We found that our approach was able to describe the relationships between the outcomes and covariates and that it could correctly detect associations of disease with several loci and with a reasonable false-positive detection rate

Admixture mapping of coronary artery calcification in African Americans from the NHLBI family heart study

BACKGROUND: Coronary artery calcification (CAC) is an imaging biomarker of coronary atherosclerosis. In European Americans, genome-wide association studies (GWAS) have identified several regions associated with coronary artery disease. However, few large studies have been conducted in African Americans. The largest meta-analysis of CAC in African Americans failed to identify genome-wide significant variants despite being powered to detect effects comparable to effects identified in European Americans. Because CAC is different in prevalence and severity in African Americans and European Americans, admixture mapping is a useful approach to identify loci missed by GWAS. RESULTS: We applied admixture mapping to the African American cohort of the Family Heart Study and identified one genome-wide significant region on chromosome 12 and three potential regions on chromosomes 6, 15, and 19 that are associated with CAC. Follow-up studies using previously reported GWAS meta-analysis data suggest that the regions identified on chromosome 6 and 15 contain variants that are possibly associated with CAC. The associated region on chromosome 6 contains the gene for BMP-6, which is expressed in vascular calcific lesions. CONCLUSIONS: Our results suggest that admixture mapping can be a useful hypothesis-generating tool to identify genomic regions that contribute to complex diseases in genetically admixed populations. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12863-015-0196-x) contains supplementary material, which is available to authorized users

High-coverage whole-genome sequencing of the expanded 1000 Genomes Project cohort including 602 trios

The 1000 Genomes Project (1kGP) is the largest fully open resource of whole-genome sequencing (WGS) data consented for public distribution without access or use restrictions. The final, phase 3 release of the 1kGP included 2,504 unrelated samples from 26 populations and was based primarily on low-coverage WGS. Here, we present a high-coverage 3,202-sample WGS 1kGP resource, which now includes 602 complete trios, sequenced to a depth of 30X using Illumina. We performed single-nucleotide variant (SNV) and short insertion and deletion (INDEL) discovery and generated a comprehensive set of structural variants (SVs) by integrating multiple analytic methods through a machine learning model. We show gains in sensitivity and precision of variant calls compared to phase 3, especially among rare SNVs as well as INDELs and SVs spanning frequency spectrum. We also generated an improved reference imputation panel, making variants discovered here accessible for association studies

Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci

Few studies have explored the impact of rare variants (minor allele frequency \u3c 1%) on highly heritable plasma metabolites identified in metabolomic screens. The Finnish population provides an ideal opportunity for such explorations, given the multiple bottlenecks and expansions that have shaped its history, and the enrichment for many otherwise rare alleles that has resulted. Here, we report genetic associations for 1391 plasma metabolites in 6136 men from the late-settlement region of Finland. We identify 303 novel association signals, more than one third at variants rare or enriched in Finns. Many of these signals identify genes not previously implicated in metabolite genome-wide association studies and suggest mechanisms for diseases and disease-related traits

Unilateral Handgrip Holds to Failure Result in Sex-Dependent Contralateral Facilitation

There can be differences in fatigue characteristics between men and women. In some cases, these differences may be manifested in unique strength responses in the fatigued and non-fatigued limbs following a unilateral fatiguing task. PURPOSE: This study examined changes in maximal voluntary isometric contraction (MVIC) force following dominant (Dm) and nondominant (NDm) unilateral, isometric handgrip holds to failure (HTF) for the exercised ipsilateral (IPS) and non-exercised contralateral (CT) limbs. Sex- and hand- (Dm vs NDm) dependent responses in HTF time, performance fatiguability (PF, %D in MVIC) for the exercised IPS limb, as well as changes in MVIC force for the CT limb following the HTF were examined. METHODS: Ten men and 10 women (Age = 22.2 yrs) performed an isometric, HTF at 50% MVIC for the Dm and NDm hand on separate days. Prior to, and immediately after the HTF, a MVIC was performed on the IPS and CT limbs, in a randomized order. A 2 (hand [Dm, NDm]) x 2 (limb [IPS, CON]) x 2 (time [pre-HTF, post-HTF]) x 2 (sex [men, women]) mixed-model ANOVA was used to examine the MVIC force (kg) and a 2 (hand [Dm, NDm]) x 2 (sex [men, women]) mixed-model ANOVA was used to examine time for the HTF. RESULTS: The Dm (130.3 ± 36.8s) HTF (collapsed across sex) was significantly longer (p = 0.002) than the NDm (112.1 ± 34.3s). The men (collapsed across hand) demonstrated IPS (%Δ= 22.9 ± 10.8%) PF and CT facilitation (%Δ= -6.1 ±6.9%) following the HTF, while the women demonstrated differences in PF between the Dm and NDm hands for the IPS (%Δ Dm = 28.0 ± 9.4%; NDm = 32.3% ± 10.1%; p = 0.027), but not the CT limb (%Δ Dm= -1.6 ± 5.7%; NDm = 1.7 ± 5.9%). CONCLUSIONS: Despite the greater fatigue resistance for the Dm compared to the NDm hand, there were no differences in PF for the IPS side for the men, but lesser IPS PF for Dm compared to NDm hand for the women. The cross-over facilitation of the CT limb for men, but not women, following a unilateral, isometric handgrip HTF may be related to post-activation potentiation

Examination of Curcumin and Fenugreek Soluble Fiber Supplementation on Submaximal and Maximal Aerobic Performance Indices

This study examined the effects of curcumin and fenugreek soluble fiber supplementation on the ventilatory threshold (VT) and peak oxygen consumption (VO2 peak). Methods: Forty-five untrained men and women were randomly assigned to one of three supplementation groups: placebo (PLA, n = 13), 500 mg·day−1 CurQfen® (CUR, n = 14), or 300 mg·day−1 fenugreek soluble fiber (FEN, n = 18). Participants completed a maximal graded exercise test on a cycle ergometer to determine the VT and VO2 peak before (PRE) and after (POST) 28 days of daily supplementation. Separate, one-way analyses of covariance (ANCOVAs) were used to examine the between-group differences for adjusted POST VT and VO2 peak values, covaried for the respective PRE-test values. Results: The adjusted POST VT VO2 values for the CUR (mean SD = 1.593 0.157 L·min−1) and FEN (1.597 0.157 L·min−1) groups were greater than (p = 0.039 and p = 0.025, respectively) the PLA (1.465 0.155 L·min−1) group, but the FEN and CUR groups were not different (p = 0.943). There were no differences in the adjusted VO2 peak values (F = 0.613, p = 0.547) among groups. Conclusion: These findings indicated that fenugreek soluble fiber was responsible for the improvements in the submaximal performance index for both CUR and FEN groups

Somatic Dnmt3a inactivation leads to slow, canonical DNA methylation loss in murine hematopoietic cells

Mutations in the gene encoding DNA methyltransferase 3A

Rapid and accurate remethylation of DNA in Dnmt3a- deficient hematopoietic cells with restoration of DNMT3A activity

Here, we characterize the DNA methylation phenotypes of bone marrow cells from mice with hematopoietic deficiency o

A draft human pangenome reference

Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individual

Mapping and characterization of structural variation in 17,795 human genomes

Structural variants in more than 17,000 human genomes are mapped and characterized using whole-genome sequencing, showing how this type of variation contributes to rare deleterious coding and noncoding alleles. A key goal of whole-genome sequencing for studies of human genetics is to interrogate all forms of variation, including single-nucleotide variants, small insertion or deletion (indel) variants and structural variants. However, tools and resources for the study of structural variants have lagged behind those for smaller variants. Here we used a scalable pipeline(1)to map and characterize structural variants in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest, to our knowledge, whole-genome-sequencing-based structural variant resource so far. On average, individuals carry 2.9 rare structural variants that alter coding regions; these variants affect the dosage or structure of 4.2 genes and account for 4.0-11.2% of rare high-impact coding alleles. Using a computational model, we estimate that structural variants account for 17.2% of rare alleles genome-wide, with predicted deleterious effects that are equivalent to loss-of-function coding alleles; approximately 90% of such structural variants are noncoding deletions (mean 19.1 per genome). We report 158,991 ultra-rare structural variants and show that 2% of individuals carry ultra-rare megabase-scale structural variants, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and noncoding elements, and reveal trends that relate to element class and conservation. This work will help to guide the analysis and interpretation of structural variants in the era of whole-genome sequencing.Peer reviewe