Genome-wide Association Studies (GWAS) Of Obesity Duration, Severity, And Distribution Trajectories In The Atherosclerosis Risk In Communities Study (ARIC)

Introduction: Despite decades of research linking obesity with cardiovascular disease (CVD) and its risk factors, major research gaps remain, with few studies evaluating the often-described but poorly understood heterogeneity in CVD risk observed within obese populations. One plausible, but largely unexplored source of heterogeneity in obesity-associated CVD risk is the impact of body fat distribution (central versus overall obesity), obesity duration and severity. Longitudinally assessed anthropometric measures and GWAS derived from these exposures may improve understanding of functional properties of loci associated with obesity and downstream influences on CVD. Methods: We respond to these research gaps by using 25 years of Atherosclerosis Risk in Communities (N=14,514, mean baseline age=54 years; 55% Female; 25.73% African-American) data and latent class mixed models to derive four longitudinal measures of obesity distribution, duration, and severity, operationalized as obesity subtypes. Genome wide association studies on the subclasses were conducted using logistic multi-variate regression models to test for associations between variants and BMI. Meta-analyses across race and sex were conducted in METAL. Functional properties of single nucleotide polymorphisms (SNP) were assessed in FUMA. Results: The four obesity subclasses were: decline (4.1%), stable/slow decline (67.8%) [referent], moderate increase (24.6%), and rapid increase (3.6%). The lead SNP from the decline group was known, on chromosome 7 (rs1196508, beta (SE) = -0.44 (0.089), p = 6.84x10 -7 , minor allele frequency (MAF) = 0.36), and nearest to a tyrosine phosphatase receptor, PTPRZ1 , in the central nervous system. We combined moderate and rapid increase for analyses; they shared a common top, unknown, SNP on chromosome 5 (rs76956550, beta (SE) = -0.37 (0.074), MAF=0.12), nearest to PGAM5P1 . The top SNP within the rapid increase group was unknown, on chromosome 14 (rs580888, beta(SE) = -0.57 (0.11), MAF=0.35), and nearest to the OTX2 gene, a transcription factor involved in production of dopaminergic neurons. Mutations of this gene are associated with pituitary hormone deficiency. Conclusion: Our GWAS of obesity subclasses demonstrated unique genetic and functional properties between groups, supporting the contention that CVD risk may differ across obese individuals. We intend to replicate our novel association of OTX2 with BMI, waist-to-hip ratio, and waist circumference in people who rapidly gained weight in other large longitudinal cohorts.