Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

Heritability, the proportion of phenotypic variance explained by genetic factors, can be estimated from pedigree data 1 , but such estimates are uninformative with respect to the underlying genetic architecture. Analyses of data from genome-wide association studies (GWAS) on unrelated individuals have shown that for human traits and disease, approximately one-third to two-thirds of heritability is captured by common SNPs 2-5 . It is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular if the causal variants are rare, or other reasons such as overestimation of heritability from pedigree data. Here we show that pedigree heritability for height and body mass index (BMI) appears to be fully recovered from whole-genome sequence (WGS) data on 21,620 unrelated individuals of European ancestry. We assigned 47.1 million genetic variants to groups based upon their minor allele frequencies (MAF) and linkage disequilibrium (LD) with variants nearby, and estimated and partitioned variation accordingly. The estimated heritability was 0.79 (SE 0.09) for height and 0.40 (SE 0.09) for BMI, consistent with pedigree estimates. Low-MAF variants in low LD with neighbouring variants were enriched for heritability, to a greater extent for protein altering variants, consistent with negative selection thereon. Cumulatively variants in the MAF range of 0.0001 to 0.1 explained 0.54 (SE 0.05) and 0.51 (SE 0.11) of heritability for height and BMI, respectively. Our results imply that the still missing heritability of complex traits and disease is accounted for by rare variants, in particular those in regions of low LD.

Fine-mapping to plausible causal variation may be more effective in multi-ancestry cohorts, particularly in the MHC, which has population-specific structure. To enable such studies, we constructed a large ( n = 21,546) HLA reference panel spanning five global populations based on whole-genome sequences. Despite population specific long-range haplotypes, we demonstrated accurate imputation at G-group resolution (94.2%, 93.7%, 97.8% and 93.7% in Admixed African (AA), East Asian (EAS), European (EUR) and Latino (LAT) populations). Applying HLA imputation to genome-wide association study (GWAS) data for HIV-1 viral load in three populations (EUR, AA and LAT), we obviated effects of previously reported associations from population-specific HIV studies and discovered a novel association at position 156 in HLA-B. We pinpointed the MHC association to three amino acid positions (97, 67 and 156) marking three consecutive pockets (C, B and D) within the HLA-B peptide binding groove, explaining 12.9% of trait variance.

BackgroundBlack persons have an excess burden of cardiovascular disease (CVD) compared with white persons. This burden persists after adjustment for socioeconomic status and other known CVD risk factors. This study evaluated the CVD burden and the socioeconomic gradient of CVD among black participants in the JHS (Jackson Heart Study).Methods and Results CVD burden was evaluated by comparing the observed prevalence of myocardial infarction, stroke, and hypertension in the JHS at baseline (2000–2004) with the expected prevalence according to US national surveys during a similar time period. The socioeconomic gradient of CVD was evaluated using logistic regression models. Compared with the national data, the JHS age‐ and sex‐standardized prevalence ratios for myocardial infarction, stroke, and hypertension were 1.07 (95% CI, 0.90–1.27), 1.46 (95% CI, 1.18–1.78), and 1.51 (95% CI, 1.42–1.60), respectively, in men and 1.50 (95% CI, 1.27–1.76), 1.33 (95% CI, 1.12–1.57), and 1.43 (95% CI, 1.37–1.50), respectively, in women. A significant and inverse relationship was observed between socioeconomic status and CVD within the JHS cohort. The strongest and most consistent socioeconomic correlate after adjusting for age and sex was income for myocardial infarction (odds ratio: 3.53; 95% CI, 2.31–5.40) and stroke (odds ratio: 3.73; 95% CI, 2.32–5.97), comparing the poor and affluent income categories.ConclusionsExcept for myocardial infarction in men, CVD burden in the JHS cohort was higher than expected. A strong inverse socioeconomic gradient of CVD was also observed within the JHS cohort.