Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association studies (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of 185 thousand CAD cases and controls, interrogating 6.7 million common (MAF>0.05) as well as 2.7 million low frequency (0.005

BackgroundCoronary artery disease (CAD) has substantial heritability and a polygenic architecture. However, the potential of genomic risk scores to help predict CAD outcomes has not been evaluated comprehensively, because available studies have involved limited genomic scope and limited sample sizes.ObjectivesThis study sought to construct a genomic risk score for CAD and to estimate its potential as a screening tool for primary prevention.MethodsUsing a meta-analytic approach to combine large-scale, genome-wide, and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS) consisting of 1.7 million genetic variants. We externally tested metaGRS, both by itself and in combination with available data on conventional risk factors, in 22,242 CAD cases and 460,387 noncases from the UK Biobank.ResultsThe hazard ratio (HR) for CAD was 1.71 (95% confidence interval [CI]: 1.68 to 1.73) per SD increase in metaGRS, an association larger than any other externally tested genetic risk score previously published. The metaGRS stratified individuals into significantly different life course trajectories of CAD risk, with those in the top 20% of metaGRS distribution having an HR of 4.17 (95% CI: 3.97 to 4.38) compared with those in the bottom 20%. The corresponding HR was 2.83 (95% CI: 2.61 to 3.07) among individuals on lipid-lowering or antihypertensive medications. The metaGRS had a higher C-index (C = 0.623; 95% CI: 0.615 to 0.631) for incident CAD than any of 6 conventional factors (smoking, diabetes, hypertension, body mass index, self-reported high cholesterol, and family history). For men in the top 20% of metaGRS with >2 conventional factors, 10% cumulative risk of CAD was reached by 48 years of age.ConclusionsThe genomic score developed and evaluated here substantially advances the concept of using genomic information to stratify individuals with different trajectories of CAD risk and highlights the potential for genomic screening in early life to complement conventional risk prediction.

No abstract

GPCR accessory proteins ͉ receptor signalling ͉ receptor trafficking T he melanocortin receptor (MCR) family is involved in a diverse range of physiologic and disease processes (1). MC1R is important in pigmentation, MC2R in steroidogenesis, and MC5R has an exocrine function especially in sebaceous gland secretion. MC3R and MC4R are both highly expressed in the brain and play key roles in energy homeostasis. Mutations in MC4R are the most common cause of monogenic obesity. More recently, fat mass, weight, risk of obesity, and insulin resistance were associated with common variants near the MC4R locus (2, 3). Both MC4R knockout mice and humans with MC4R mutations display early-onset obesity associated with hyperphagia (4, 5). MC3R knockout mice, however, develop a milder phenotype with later-onset obesity (6, 7).We previously identified MRAP (melanocortin-2-receptor accessory protein), a small transmembrane protein, as an MC2R accessory protein, enabling the functional expression of MC2R in transfected cells. The identification of MRAP provides a molecular explanation for the difficulties encountered in the expression of the MC2R in nonadrenal cell lines (8). Furthermore, mutations in MRAP result in the autosomal recessive disorder familial glucocorticoid deficiency type 2 (9).Here we report the identification and characterization of a unique MRAP homologue encoded by C6orf117 on human chromosome 6q14.3, which we have named MRAP2. We show that both MRAP and MRAP2 can modulate the signaling of all 5 MCRs. MRAP2 is primarily expressed in human brain and adrenal gland. In the brain, MRAP2 expression is seen in the hypothalamus (10), a site that also expresses a high level of MC3R and MC4R (6,11). MRAP expression in the hypothalamus has also been demonstrated by in situ hybridization (12). These findings suggest that MRAP and MRAP2 may regulate MC3R and MC4R function in the central nervous system. Results MRAP2:A Unique Homologue of MRAP. The human MRAP2 gene consists of 4 exons, and its protein product comprises 205 aa residues, with a predicted molecular mass of 23.5 kDa (Fig. 1A). MRAP2 is homologous to MRAP, with 39% amino acid identity to MRAP in the N-terminal and transmembrane domains (Fig. 1B). The protein is highly conserved through vertebrates (supporting information Fig. S1) and like MRAP has no predicted signal sequence.