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

Abstract

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. INTRODUCTIONAlthough mortality attributable to cardiovascular disease (CVD) has declined in the United States, the burden of disease remains high. 1 It remains the leading cause of illness and death worldwide. Hypertension, obesity, dyslipidemia, insulin resistance and type II diabetes mellitus, and physical inactivity are among the eight risk factors that account for 61% of cardiovascular deaths. These same risk factors account for over three quarters of ischemic heart disease. 2 These risk factors are influenced by both environmental exposures and genetic background and the heritability of these risk factors can be as high as 77%, 3 making it difficult to clearly separate CVD risk factors into genetic and nongenetic categories. The INTERHEART study has evaluated the effect of both physical and psychosocial factors on the risk of myocardial infarction and has shown that a higher prevalence of psychological stress and other psychosocial factors like depression account for 34% of the population attributable risk for myocardial infarction, independently of physical risk factors. 4 The co-occ...

Computing a Synthetic Chronic Psychosocial Stress Measurement in Multiple Datasets and its Application in the Replication of G × E Interactions of the EBF1 Gene

“…We validated the computed scores of chronic psychosocial stress by observing moderately strong and significant correlations with the self‐rated chronic psychosocial stress in the Multi‐Ethnic Study of Atherosclerosis Cohort (Rho = 0.23, P < 0.0001) and with the measures of depressive symptoms in five datasets (Rho = 0.15–0.42, P s = 0.005 to <0.0001) and by comparing the distributions of the self‐rated and computed measures. Finally, we demonstrate the utility of this computed chronic psychosocial stress variable by providing three additional replications of our previous finding of gene‐by‐stress interaction with central obesity traits [Singh et al., ].…”

“…We applied the foregoing method of computing a chronic psychosocial stress measure and performing subsequent analysis on the following datasets, using the available relevant psychosocial and socioeconomic data, genotypic data of EBF1 SNP rs4704963 (or LD SNP rs17056278) genotyped in genome‐wide array or as individually genotyped candidate SNPs, and phenotypic data for central obesity trait (hip circumference or BMI). MESA : The original GWAS study [Singh et al., ] used the MESA dataset because it had a self‐rated chronic psychosocial stress (chronic burden) variable [Bild et al., , Shivpuri et al., ]. In the current work, we used this dataset to compare the self‐rated chronic psychosocial stress measure with computed chronic psychosocial stress scores.…”

The importance of gene–environment interactions in human obesity

“…The interaction reached genome-wide significance among the subset of 2460 Whites in the Multi-Ethnic Study of Atherosclerosis (MESA) but was not significant among Chinese Americans, Blacks or Hispanics. This study reported that the impact of risk allele carriage in EBF1 on hip circumference was greater among participants with a greater chronic stress burden [161]. The authors also replicated the interaction between psychosocial stress and three of the original five SNPs (rs17056278 C>G, rs17056298 C>G and rs17056318 T>C) in EBF1 in the Framingham Offspring cohort [161].…”

“…This study reported that the impact of risk allele carriage in EBF1 on hip circumference was greater among participants with a greater chronic stress burden [161]. The authors also replicated the interaction between psychosocial stress and three of the original five SNPs (rs17056278 C>G, rs17056298 C>G and rs17056318 T>C) in EBF1 in the Framingham Offspring cohort [161]. A subsequent analysis by the same research group replicated the EBF1 × psychosocial stress interaction on obesity (waist circumference or BMI) in the Family Heart Study Whites and at trend level in the Duke Caregiver study [162].…”

“…A recent genome-wide interaction analysis identified a significant interaction between psychosocial stress and five SNPs within the Early B-cell Factor 1 (EBF1) gene and hip circumference [161]. The interaction reached genome-wide significance among the subset of 2460 Whites in the Multi-Ethnic Study of Atherosclerosis (MESA) but was not significant among Chinese Americans, Blacks or Hispanics.…”