Graff, Mariaelisa

Several loci have been discovered and replicated for urine albumin-creatinine ratio (ACR), a measure of kidney function, in European populations; however, other ethnic populations such as African-Americans have been less studied for this trait. We examined the association of genetic variants on the Metabochip with natural log transformed ACR (ln(ACR)) in 4,629 African-Americans from the Population Architecture using Genomics and Epidemiology (PAGE) Study which includes participants from the Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health Study (CHS), Coronary Artery Risk Development in Young Adults (CARDIA), and Epidemiologic Architecture for Genes Linked to the Environment (EAGLE-BioVU) studies. We then replicated our findings in 1,533 African-American participants from the Multi-Ethnic Study of Atherosclerosis (MESA). Linear regression models were used to examine associations, assuming additive effects of the SNPs. Within each study, models were adjusted for age, field center (where applicable), and principal components of ancestry, and stratified by sex. Fixed effects inverse variance weighted meta-analysis was used to combine results from contributing studies. Array-wide statistical significance was concluded for SNP associations of p-value less than 2.8 x 10-7. Mean ln(ACR) ranged from 1.4 to 2.9 mg/g, average age ranged from 44 to 77 years, and percent female participants ranged from 59-65% in the contributing studies. Four SNPs were significantly associated array-wide with ACR in the discovery sample: rs17399841 in GRHL2 (β=-0.67, MAF=0.01, p=2.7x10-9), rs153914 near SPATA9/RHOBTB3 (β=-0.59, MAF=0.01, p=1.0x10-7), rs17439845 in LEF1 (β=-0.49, MAF=0.02, p=1.3x10-7), and rs11836243 near ZNF641/ANP32D (β=0.23, MAF=0.12, p=1.8x10-7). Of these four loci, only the association of rs17439845 with ACR replicated in MESA (β=-0.36, p=0.038), with a combined discovery-replication beta of -0.46 and p value of 1.8x10-8. Combined discovery-replication for rs17399841, rs153914, and rs11836243 no longer achieved array-wide significance (p-values 9.84x10-7, 1.98x10-5, and 1.32x10-4, respectively). LEF1 is a mediator in the Wnt signaling pathway, and has been previously implicated in systemic lupus erythematosus and osteoporosis, as well as previously associated with waist circumference, echocardiographic traits, bone mineral density, and blood count traits. Continuing studies in diverse populations are warranted to identify a set of loci important in contributing to the variation in ACR.

Abstract Coronary artery disease (CAD) is a leading cause of death, yet its genetic determinants are not fully elucidated. We report a multi-ethnic genome-wide association study of CAD involving nearly a quarter of a million cases, incorporating the largest cohorts to date of Whites, Blacks, and Hispanics from the Million Veteran Program with existing studies including CARDIoGRAMplusC4D, UK Biobank, and Biobank Japan. We verify substantial and nearly equivalent heritability of CAD across multiple ancestral groups, discover 107 novel loci including the first nine on the X-chromosome, identify the first eight genome-wide significant loci among Blacks and Hispanics, and demonstrate that two common haplotypes are largely responsible for the risk stratification at the well-known 9p21 locus in most populations except those of African origin where both haplotypes are virtually absent. We identify 15 loci for angiographically derived burden of coronary atherosclerosis, which robustly overlap with the strongest and earliest loci reported to date for clinical CAD. Phenome-wide association analyses of novel loci and externally validated polygenic risk scores (PRS) augment signals from the insulin resistance cluster of risk factors and consequences, extend previously established pleiotropic associations of loci with traditional risk factors to include smoking and family history, and confirm a substantially reduced transferability of existing PRS to Blacks. Downstream integrative genomic analyses reinforce the critical role of endothelial, fibroblast, and smooth muscle cells within the coronary vessel wall in CAD susceptibility. Our study highlights the value of a multi-ethnic design in efficiently characterizing the genetic architecture of CAD across all human populations.