Pleiotropic Associations of Allelic Variants in a 2q22 Region with Risks of Major Human Diseases and Mortality.
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.
Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC United States of America.
Alexander M
AM
Kulminski
Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC United States of America.
Liang
L
He
Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC United States of America.
Irina
I
Culminskaya
Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC United States of America.
Yury
http://orcid.org/0000-0001-6730-7320
Y
Loika
Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC United States of America.
Yelena
http://orcid.org/0000-0002-3980-225X
Y
Kernogitski
Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC United States of America.
Konstantin G
http://orcid.org/0000-0002-4195-7832
KG
Arbeev
Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC United States of America.
Elena
E
Loiko
Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC United States of America.
Liubov
L
Arbeeva
Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC United States of America.
Olivia
O
Bagley
Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC United States of America.
Matt
http://orcid.org/0000-0001-6067-3192
M
Duan
Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC United States of America.
Arseniy
A
Yashkin
Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC United States of America.
Fang
F
Fang
Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC United States of America.
Mikhail
http://orcid.org/0000-0001-9660-4316
M
Kovtun
Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC United States of America.
Svetlana V
SV
Ukraintseva
Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC United States of America.
Deqing
D
Wu
Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC United States of America.
Anatoliy I
AI
Yashin
D030301:Activin Receptors, Type II / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics / Q000401:mortality; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D003327:Coronary Disease / Q000235:genetics / Q000401:mortality; D003920:Diabetes Mellitus / Q000235:genetics / Q000401:mortality; D005260:Female; D056726:Genetic Association Studies; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000401:mortality; D058685:Genetic Pleiotropy; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006333:Heart Failure / Q000235:genetics / Q000401:mortality; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D012097:Repressor Proteins / Q000235:genetics*; D012307:Risk Factors; D020521:Stroke / Q000235:genetics / Q000401:mortality; D000074165:Zinc Finger E-box Binding Homeobox 2
D018398:Homeodomain Proteins; D012097:Repressor Proteins; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D030301:Activin Receptors, Type II; C425585:activin receptor type II-A