Abstract only Introduction: MRI-defined brain infarcts (BI), most of which are small sub-cortical brain infarcts (SSBI), are highly prevalent in older persons. Most BI are covert, which is not ...associated with clinically overt stroke. Nonetheless, they are powerful predictors of future risk for stroke, cognitive decline, and dementia. Little is known about the genetic determinants of BI. Methods: We performed a trans-ethnic meta-analysis of GWAS of MRI-defined BI and SSBI in 20,949 participants belonging to 5 ethnic groups: Europeans, African-Americans, Hispanic-Americans, Malays, and Chinese. A total of 23 population-based studies from the CHARGE consortium participated in this effort, comprising of 3,726 cases and 17,223 controls for BI, 2,112 cases and 15,432 controls for SSBI. GWAS based on imputed genotypes using the 1000 Genomes phase 1, version 3 panel was performed in each study using logistic regression. Meta-analysis of association statistics was performed using a Bayesian partition model (MANTRA); secondary analyses used fixed effect (FE) inverse variance weighting. Loci with log 10 Bayesian factor (BF)>5 were considered genome-wide significant and loci with log 10 BF>4.5 and mean imputation accuracy score >0.80 were chosen for replication. Results: 33 variants (3 loci) reached genome-wide significance, in association with BI, on chromosome: 13q12 (Index SNP: log 10 BF=7, P FE =5.8х10 -9 , OR FE =1.2, minor allele frequency MAF=0.34), 5q23 (Index SNP: log 10 BF=6.5, P FE =1.8х10 -8 , OR FE =1.2, MAF=0.21) and 15q26 (Index SNP: log 10 BF=5.3, P FE =3.4х10 -7 , OR FE =1.8, MAF=0.03). These loci comprise genes involved in response to anti-hypertensive drugs, glucose transport, connective tissue assembly and synaptic transmission. Three additional loci showed suggestive associations (log 10 BF 4.5 to 5). Five of these six loci were associated with both BI and SSBI (Index SNP log 10 BF>2), but none reached genome-wide significance for SSBI. Conclusion: This large scale trans-ethnic GWAS meta-analysis identified three novel risk loci for MRI-defined BI. Replication analysis and functional validation are ongoing. These findings may provide novel insight into biological mechanisms underlying covert vascular brain injury
Background and Purpose: Periventricular white matter hyperintensities (WMH;PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first ...study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. Methods: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (NBEAL), 10q23.1 (TSPAN14/FAM231A), and 10q24.33 (SH3PXD2A).In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 (NOS3) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes:CALCRL(2q32.1),KLHL24(3q27.1),VCAN(5q27.1), andPOLR2F(22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. Conclusions: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.
Background: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological ...insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. Results: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. Conclusions: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.
Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genomewide ...association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are overrepresented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of similar to 105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ionchannel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.
Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V ...variant in the cholesteryl ester transfer protein (
gene. In this study, we investigate the association of
and HDL-C further to identify novel, independent
variants associated with HDL-C in humans.
We performed a meta-analysis of HDL-C within the
region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing.
The meta-analysis of HDL-C within the
region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and
variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (
=3.179 mg/dl (
value=5.25×10
),
=0.859 mg/dl (
value=9.51×10
)), and this finding suggests that these five novel variants may partly explain the association of
with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261.
The causal variants in
that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the
region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C.
Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting ...heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses. Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods. We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants. Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.
Atrial fibrillation (AF) is a heritable disease that affects more than thirty million individuals worldwide. Extensive efforts have been devoted to the study of genetic determinants of AF. The ...objective of our study is to examine the effect of gene-gene interaction on AF susceptibility. We performed a large-scale association analysis of gene-gene interactions with AF in 8,173 AF cases, and 65,237 AF-free referents collected from 15 studies for discovery. We examined putative interactions between genome-wide SNPs and 17 known AF-related SNPs. The top interactions were then tested for association in an independent cohort for replication, which included more than 2,363 AF cases and 114,746 AF-free referents. One interaction, between rs7164883 at the HCN4 locus and rs4980345 at the SLC28A1 locus, was found to be significantly associated with AF in the discovery cohorts (interaction OR = 1.44, 95% CI: 1.27-1.65, P = 4.3 x 10(-8)). Eight additional gene-gene interactions were also marginally significant (P < 5 x 10(-7)). However, none of the top interactions were replicated. In summary, we did not find significant interactions that were associated with AF susceptibility. Future increases in sample size and denser genotyping might facilitate the identification of gene-gene interactions associated with AF.
PDF
