Association between Stress Response Genes and Features of Diurnal Cortisol Curves in the Multi-Ethnic Study of Atherosclerosis: A New Multi-Phenotype Approach for Gene-Based Association Tests

PLoS One. 2015 May 20;10(5):e0126637. doi: 10.1371/journal.pone.0126637. eCollection 2015.

Abstract

The hormone cortisol is likely to be a key mediator of the stress response that influences multiple physiologic systems that are involved in common chronic disease, including the cardiovascular system, the immune system, and metabolism. In this paper, a candidate gene approach was used to investigate genetic contributions to variability in multiple correlated features of the daily cortisol profile in a sample of European Americans, African Americans, and Hispanic Americans from the Multi-Ethnic Study of Atherosclerosis (MESA). We proposed and applied a new gene-level multiple-phenotype analysis and carried out a meta-analysis to combine the ethnicity specific results. This new analysis, instead of a more routine single marker-single phenotype approach identified a significant association between one gene (ADRB2) and cortisol features (meta-analysis p-value=0.0025), which was not identified by three other commonly used existing analytic strategies: 1. Single marker association tests involving each single cortisol feature separately; 2. Single marker association tests jointly testing for multiple cortisol features; 3. Gene-level association tests separately carried out for each single cortisol feature. The analytic strategies presented consider different hypotheses regarding genotype-phenotype association and imply different costs of multiple testing. The proposed gene-level analysis integrating multiple cortisol features across multiple ethnic groups provides new insights into the gene-cortisol association.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Atherosclerosis / blood*
  • Atherosclerosis / ethnology
  • Atherosclerosis / genetics*
  • Atherosclerosis / pathology
  • Black or African American
  • Circadian Rhythm / physiology
  • Female
  • Gene Expression Regulation
  • Genetic Association Studies
  • Hispanic or Latino
  • Humans
  • Hydrocortisone / blood*
  • Male
  • Middle Aged
  • Receptors, Adrenergic, beta-2 / blood
  • Receptors, Adrenergic, beta-2 / genetics*
  • Regression Analysis
  • Stress, Physiological / genetics*
  • United States
  • White People

Substances

  • ADRB2 protein, human
  • Receptors, Adrenergic, beta-2
  • Hydrocortisone

Associated data

  • dbGaP/PHS000209.V1​3.P3

Grants and funding