Gene by stress genome-wide interaction analysis and path analysis identify EBF1 as a cardiovascular and metabolic risk gene.

Singh, Abanish

Babyak, Michael A

Nolan, Daniel K

Brummett, Beverly H

Jiang, Rong

Siegler, Ilene C

Kraus, William E

Shah, Svati H

Williams, Redford B

Hauser, Elizabeth R

2024-03-07T20:42:12Z

2024-03-07T20:42:12Z

2015-06

We performed gene-environment interaction genome-wide association analysis (G × E GWAS) to identify SNPs whose effects on metabolic traits are modified by chronic psychosocial stress in the Multi-Ethnic Study of Atherosclerosis (MESA). In Whites, the G × E GWAS for hip circumference identified five SNPs within the Early B-cell Factor 1 (EBF1) gene, all of which were in strong linkage disequilibrium. The gene-by-stress interaction (SNP × STRESS) term P-values were genome-wide significant (Ps = 7.14E-09 to 2.33E-08, uncorrected; Ps = 1.99E-07 to 5.18E-07, corrected for genomic control). The SNP-only (without interaction) model P-values (Ps = 0.011-0.022) were not significant at the conventional genome-wide significance level. Further analysis of related phenotypes identified gene-by-stress interaction effects for waist circumference, body mass index (BMI), fasting glucose, type II diabetes status, and common carotid intimal-medial thickness (CCIMT), supporting a proposed model of gene-by-stress interaction that connects cardiovascular disease (CVD) risk factor endophenotypes such as central obesity and increased blood glucose or diabetes to CVD itself. Structural equation path analysis suggested that the path from chronic psychosocial stress to CCIMT via hip circumference and fasting glucose was larger (estimate = 0.26, P = 0.033, 95% CI = 0.02-0.49) in the EBF1 rs4704963 CT/CC genotypes group than the same path in the TT group (estimate = 0.004, P = 0.34, 95% CI = -0.004-0.012). We replicated the association of the EBF1 SNPs and hip circumference in the Framingham Offspring Cohort (gene-by-stress term P-values = 0.007-0.012) as well as identified similar path relationships. This observed and replicated interaction between psychosocial stress and variation in the EBF1 gene may provide a biological hypothesis for the complex relationship between psychosocial stress, central obesity, diabetes, and cardiovascular disease.

ejhg2014189

1018-4813

1476-5438

https://hdl.handle.net/10161/30354

eng

Springer Science and Business Media LLC

European journal of human genetics : EJHG

10.1038/ejhg.2014.189

https://creativecommons.org/licenses/by-nc/4.0

Humans

Obesity

Trans-Activators

Polymorphism, Single Nucleotide

Socioeconomic Factors

Atherosclerosis

Genome-Wide Association Study

Endophenotypes

Gene-Environment Interaction

Metabolic Syndrome

Gene by stress genome-wide interaction analysis and path analysis identify EBF1 as a cardiovascular and metabolic risk gene.

Journal article

Kraus, William E|0000-0003-1930-9684

Shah, Svati H|0000-0002-3495-2830

Williams, Redford B|0000-0002-8581-0648

Hauser, Elizabeth R|0000-0003-0367-9189

854

862

6

Duke

School of Medicine

School of Nursing

Trinity College of Arts & Sciences

Nursing

Basic Science Departments

Clinical Science Departments

Institutes and Centers

Biostatistics & Bioinformatics

Medicine

Psychiatry & Behavioral Sciences

Medicine, Cardiology

Duke Cancer Institute

Psychology & Neuroscience

Duke Clinical Research Institute

Duke Molecular Physiology Institute

Head and Neck Surgery & Communication Sciences

Psychiatry & Behavioral Sciences, Behavioral Medicine & Neurosciences

Head & Neck Surgical Oncology

Published

23