Microstructural differences in the thalamus and thalamic radiations in the congenitally deaf

There is evidence of both crossmodal and intermodal plasticity in the deaf brain. Here, we investigated whether sub-cortical plasticity, specifically of the thalamus, contributed to this reorganisation. We contrasted diffusion weighted magnetic resonance imaging data from 13 congenitally deaf and 13 hearing participants, all of whom had learnt British Sign Language after 10 years of age. Connectivity based segmentation of the thalamus revealed changes to mean and radial diffusivity in occipital and frontal regions, which may be linked to enhanced peripheral visual acuity, and differences in how visual attention is deployed in the deaf group. Using probabilistic tractography, tracts were traced between the thalamus and its cortical targets, and microstructural measurements were extracted from these tracts. Group differences were found in microstructural measurements of occipital, frontal, somatosensory, motor and parietal thalamo-cortical tracts. Our findings suggest there is sub-cortical plasticity in the deaf brain, and that white matter alterations can be found throughout the deaf brain, rather than being restricted to, or focussed in auditory cortex

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants

Gray matter injury associated with periventricular leukomalacia in the premature infant

Neuroimaging studies indicate reduced volumes of certain gray matter regions in survivors of prematurity with periventricular leukomalacia (PVL). We hypothesized that subacute and/or chronic gray matter lesions are increased in incidence and severity in PVL cases compared to non-PVL cases at autopsy. Forty-one cases of premature infants were divided based on cerebral white matter histology: PVL (n = 17) with cerebral white matter gliosis and focal periventricular necrosis; diffuse white matter gliosis (DWMG) (n = 17) without necrosis; and

Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the “Exome Array” to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121∗], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited

Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value OBFC1indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes

Association of exome sequences with plasma C-reactive protein levels in >9000 participants

C-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in ∼25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 × 10−6). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 × 10−15). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-ε2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 × 10−8), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In gene-based tests, a burden of rare/lower frequency variation in CRP in EAs (P ≤ 6.8 × 10−4) and in retinoic acid receptor-related orphan receptor α (RORA) in AAs (P = 1.7 × 10−3) were associated with CRP levels at the candidate gene level (P < 2.0 × 10−3). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels

Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease.

BACKGROUND: The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS: Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS: We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P=4.2×10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P=4.0×10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P=0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P=0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P=2.0×10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P=2.5×10(-7)). CONCLUSIONS: We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease. (Funded by the National Institutes of Health and others.).Supported by a career development award from the National Heart, Lung, and Blood Institute, National Institutes of Health (NIH) (K08HL114642 to Dr. Stitziel) and by the Foundation for Barnes–Jewish Hospital. Dr. Peloso is supported by the National Heart, Lung, and Blood Institute of the NIH (award number K01HL125751). Dr. Kathiresan is supported by a Research Scholar award from the Massachusetts General Hospital, the Donovan Family Foundation, grants from the NIH (R01HL107816 and R01HL127564), a grant from Fondation Leducq, and an investigator-initiated grant from Merck. Dr. Merlini was supported by a grant from the Italian Ministry of Health (RFPS-2007-3-644382). Drs. Ardissino and Marziliano were supported by Regione Emilia Romagna Area 1 Grants. Drs. Farrall and Watkins acknowledge the support of the Wellcome Trust core award (090532/Z/09/Z), the British Heart Foundation (BHF) Centre of Research Excellence. Dr. Schick is supported in part by a grant from the National Cancer Institute (R25CA094880). Dr. Goel acknowledges EU FP7 & Wellcome Trust Institutional strategic support fund. Dr. Deloukas’s work forms part of the research themes contributing to the translational research portfolio of Barts Cardiovascular Biomedical Research Unit, which is supported and funded by the National Institute for Health Research (NIHR). Drs. Webb and Samani are funded by the British Heart Foundation, and Dr. Samani is an NIHR Senior Investigator. Dr. Masca was supported by the NIHR Leicester Cardiovascular Biomedical Research Unit (BRU), and this work forms part of the portfolio of research supported by the BRU. Dr. Won was supported by a postdoctoral award from the American Heart Association (15POST23280019). Dr. McCarthy is a Wellcome Trust Senior Investigator (098381) and an NIHR Senior Investigator. Dr. Danesh is a British Heart Foundation Professor, European Research Council Senior Investigator, and NIHR Senior Investigator. Drs. Erdmann, Webb, Samani, and Schunkert are supported by the FP7 European Union project CVgenes@ target (261123) and the Fondation Leducq (CADgenomics, 12CVD02). Drs. Erdmann and Schunkert are also supported by the German Federal Ministry of Education and Research e:Med program (e:AtheroSysMed and sysINFLAME), and Deutsche Forschungsgemeinschaft cluster of excellence “Inflammation at Interfaces” and SFB 1123. Dr. Kessler received a DZHK Rotation Grant. The analysis was funded, in part, by a Programme Grant from the BHF (RG/14/5/30893 to Dr. Deloukas). Additional funding is listed in the Supplementary Appendix.This is the author accepted manuscript. The final version is available from the Massachusetts Medical Society via http://dx.doi.org/10.1056/NEJMoa150765

Imputation of coding variants in African Americans: better performance using data from the exome sequencing project

Summary: Although the 1000 Genomes haplotypes are the most commonly used reference panel for imputation, medical sequencing projects are generating large alternate sets of sequenced samples. Imputation in African Americans using 3384 haplotypes from the Exome Sequencing Project, compared with 2184 haplotypes from 1000 Genomes Project, increased effective sample size by 8.3–11.4% for coding variants with minor allele frequency <1%. No loss of imputation quality was observed using a panel built from phenotypic extremes. We recommend using haplotypes from Exome Sequencing Project alone or concatenation of the two panels over quality score-based post-imputation selection or IMPUTE2’s two-panel combination