Body mass index (BMI), a simple weight-for-height index, is typically used to determine obesity status, but it is not an accurate way to measure one’s risk for obesity since body fat distribution can vary significantly from person to person with the same BMI. Body fat distribution is a strong and important risk factor for metabolic dysfunctions and obesity-related diseases. To further enhance our understanding of the genetic basis of body fat distribution, we performed whole genome sequence association analyses of waist-to-hip ratio (WHR) and waist circumference (WC) within the Trans-Omics for Precision Medicine Program (TOPMed) for both common and rare variants. Analyses were performed on 28,303 individuals from 12 cohorts. Using linear mixed models, we adjusted for age, age2, sex, BMI, ethnicity, cohort, and the first 10 principal components and then inverse normal transformed the residuals. To reduce computational burden, we first fit null models that exclude the genotypes, while adjusting for familial relatedness with an empirical kinship matrix. All subsequent analyses were done using GENESIS in R package. Single variant analyses were performed on variants with minor allele count of at least 25. At genome-wide significance of 5e-8, we confirmed three known loci associated with WHR (ZRANB3, p=5.3e-8; RSPO3, p=1.54e-8; KNTC1, p=4.73e-8) and three known loci for WC (JAZF1, p=5.63e-10; VEGFA, p=1.47e-8; ADAMTSL3, p=4.44e-8). SKAT was used to perform rare variant analyses, which included variants with minor allele frequency of 1% and those annotated as either loss of function, missense, or protein altering indels. We identified the same novel locus, AMMERCR1L, for WHR (p=2.59e-8) and WC (p=8.46e-6), although the association for WC was not genome-wide significant.
Our study replicated previously known genes associated with WHR and WC and discovered one novel locus that we plan to investigate further.