Title | Pleiotropic Associations of Allelic Variants in a 2q22 Region with Risks of Major Human Diseases and Mortality. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Kulminski, AM, He, L, Culminskaya, I, Loika, Y, Kernogitski, Y, Arbeev, KG, Loiko, E, Arbeeva, LS, Bagley, O, Duan, M, Yashkin, AP, Fang, F, Kovtun, M, Ukraintseva, S, Wu, D, Yashin, A |
Secondary Authors | Barsh, GS |
Journal | PLoS Genet |
Volume | 12 |
Issue | 11 |
Pagination | e1006314 |
Date Published | 2016 Nov |
ISSN Number | 1553-7404 |
Keywords | Activin Receptors, Type II, Atherosclerosis, Chromosomes, Human, Pair 2, Coronary Disease, Diabetes Mellitus, Female, Genetic Association Studies, Genetic Diseases, Inborn, Genetic Pleiotropy, Genetic Predisposition to Disease, Genome-Wide Association Study, Heart Failure, Homeodomain Proteins, Humans, Male, Repressor Proteins, Risk Factors, Stroke, Zinc Finger E-box Binding Homeobox 2 |
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. |
URL | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/27832070/ |
DOI | 10.1371/journal.pgen.1006314 |
User Guide Notes | |
Short Title | PLoS Genet |
Alternate Journal | PLoS Genet. |
Citation Key | 8822 |
PubMed ID | 27832070 |
PubMed Central ID | PMC5104356 |
Grant List | HHSN268201100012C / HL / NHLBI NIH HHS / United States RC4 AG039029 / AG / NIA NIH HHS / United States HHSN268201100009I / HL / NHLBI NIH HHS / United States HHSN268201100010C / HL / NHLBI NIH HHS / United States U01 AG009740 / AG / NIA NIH HHS / United States HHSN268201100008C / HL / NHLBI NIH HHS / United States HHSN268201100005G / HL / NHLBI NIH HHS / United States HHSN268201100008I / HL / NHLBI NIH HHS / United States HHSN268201100007C / HL / NHLBI NIH HHS / United States HHSN268201100011I / HL / NHLBI NIH HHS / United States HHSN268201100011C / HL / NHLBI NIH HHS / United States U01 HG004402 / HG / NHGRI NIH HHS / United States P30 AG034424 / AG / NIA NIH HHS / United States N02HL64278 / HL / NHLBI NIH HHS / United States HHSN268201100006C / HL / NHLBI NIH HHS / United States HHSN268201100005I / HL / NHLBI NIH HHS / United States P01 AG043352 / AG / NIA NIH HHS / United States HHSN268201100009C / HL / NHLBI NIH HHS / United States HHSN268201100005C / HL / NHLBI NIH HHS / United States N01HC25195 / HL / NHLBI NIH HHS / United States HHSN268201100007I / HL / NHLBI NIH HHS / United States RC2 AG036495 / AG / NIA NIH HHS / United States R01 AG047310 / AG / NIA NIH HHS / United States |