Pleiotropic Associations of Allelic Variants in a 2q22 Region with Risks of Major Human Diseases and Mortality

Abstract

Gaining insights into genetic predisposition to age-related diseases and lifespan is a challenging task complicated by the elusive role of evolution in these phenotypes. To gain more insights, we combined methods of genome-wide and candidate-gene studies. Genome-wide scan in the Atherosclerosis Risk in Communities (ARIC) Study (N = 9,573) was used to pre-select promising loci. Candidate-gene methods were used to comprehensively analyze associations of novel uncommon variants in Caucasians (minor allele frequency~2.5%) located in band 2q22.3 with risks of coronary heart disease (CHD), heart failure (HF), stroke, diabetes, cancer, neurodegenerative diseases (ND), and mortality in the ARIC study, the Framingham Heart Study (N = 4,434), and the Health and Retirement Study (N = 9,676). We leveraged the analyses of pleiotropy, age-related heterogeneity, and causal inferences. Meta-analysis of the results from these comprehensive analyses shows that the minor allele increases risks of death by about 50% (p = 4.6×10-9), CHD by 35% (p = 8.9×10-6), HF by 55% (p = 9.7×10-5), stroke by 25% (p = 4.0×10-2), and ND by 100% (p = 1.3×10-3). This allele also significantly influences each of two diseases, diabetes and cancer, in antagonistic fashion in different populations. Combined significance of the pleiotropic effects was p = 6.6×10-21. Causal mediation analyses show that endophenotypes explained only small fractions of these effects. This locus harbors an evolutionary conserved gene-desert region with non-coding intergenic sequences likely involved in regulation of protein-coding flanking genes ZEB2 and ACVR2A. This region is intensively studied for mutations causing severe developmental/genetic disorders. Our analyses indicate a promising target region for interventions aimed to reduce risks of many major human diseases and mortality.

Fig 1. Probability of remaining free of coronary heart disease (CHD) for the rs222826_T allele carriers.

(A) The Atherosclerosis Risk in Communities Study (ARIC), (B, D) the Framingham Heart Study (FHS) original (FHS_C1) cohort, (C) the FHS Offspring (FHSO) cohort. HR denotes hazard ratio, HR_all in panel (B) denotes the estimates for the entire FHS_C1 sample. HR₆₅₊ in (D) denotes the estimates for onsets of CHD at ages 65 years and older. N = n/m denotes the size of the entire sample (n) and the number of CHD cases (m) for major allele homozygotes (CC, blue color) and minor allele carriers (CT+TT, red color). P shows p-values.

Fig 2. A flowchart of the analyses in this study.

All analyses were conducted for whites. Major focus of these analyses was on two uncommon SNPs with minor allele frequency (MAF) ~2.5%. Given this MAF and the available sample size in ARIC, FHS, and HRS, the analyses were conducted for men and women combined to increase the sample of the minor allele carriers.