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.

Genome-wide association analysis of age-at-onset traits using Cox mixed-effects models

“…For example, COXMEG completed the genome-wide analysis within one day for 10M SNPs in NIA-LOADFS (~3500 subjects) using one CPU thread. Our work will be of particular interest to many areas in epidemiology such as age-related diseases (He et al, 2016b;Kulminski et al, 2016) , behavior genetics (He et al, 2016a) and perhaps clinical trials, in which age-at-onset is a central concern. Moreover, the application of COXMEG includes, but is not limited to genetic data.…”

“…Age-at-onset and time-to-event are among the most important phenotypes of interest in cohort studies of age-related diseases (He et al, 2016a;Kulminski et al, 2016), and behavioral genetics (He et al, 2016b) as these phenotypes carry information on timing of events. Genome-wide association studies (GWAS) of time-to-event phenotypes are critical for gaining insights into the genetics of disease development and progression.…”

Suggestions from Geroscience for the Genetics of Age-Related Diseases

“…The paper by Kulminski et al [3] provides evidence for how fruitful this approach can be. The authors started by analysing the genetic predisposition to risks of major age-related diseases and mortality, taking advantage of GWAS data generated during the Atherosclerosis Risk in Communities Study (ARCS), and focused on two new promising SNPs (rs222826, rs 222827) on band 2q.22.…”

“…Thus, subsequent generations were exposed to quite different environmental conditions and pressures during the last century, and it is easy to predict that the risk/protective effects of specific alleles changed accordingly. In their causal inference analysis, Kulminski et al [3] noticed that the correlation of a given allele with a risky endophenotype is also sensitive to chronological age. This result is in line with the antagonistic pleiotropy theory suggesting that a given allele can play different roles at different ages and fits with the remodeling theory of aging [5], according to which the body of each individual undergoes a different or unexpected lifelong process of adaptation to the age-related accumulation of molecular and cellular damages and the consequent functional decline.…”

“…The paper by Kulminski et al [3] shows how complex the study of the genetics of age-related diseases is in a globalized and changing world. Some people think that a concerted effort to generate whole genome sequences will solve existing problems.…”