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Pleiotropic Associations of Allelic Variants in a 2q22 Region with Risks of Major Human Diseases and Mortality.
- Source :
-
PLoS genetics [PLoS Genet] 2016 Nov 10; Vol. 12 (11), pp. e1006314. Date of Electronic Publication: 2016 Nov 10 (Print Publication: 2016). - Publication Year :
- 2016
-
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.<br />Competing Interests: The authors have declared that no competing interests exist.
- Subjects :
- Atherosclerosis genetics
Atherosclerosis mortality
Chromosomes, Human, Pair 2 genetics
Coronary Disease genetics
Coronary Disease mortality
Diabetes Mellitus genetics
Diabetes Mellitus mortality
Female
Genetic Association Studies
Genetic Diseases, Inborn mortality
Genetic Pleiotropy
Genetic Predisposition to Disease
Heart Failure genetics
Heart Failure mortality
Humans
Male
Risk Factors
Stroke genetics
Stroke mortality
Zinc Finger E-box Binding Homeobox 2
Activin Receptors, Type II genetics
Genetic Diseases, Inborn genetics
Genome-Wide Association Study
Homeodomain Proteins genetics
Repressor Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7404
- Volume :
- 12
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- PLoS genetics
- Publication Type :
- Academic Journal
- Accession number :
- 27832070
- Full Text :
- https://doi.org/10.1371/journal.pgen.1006314