title: 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.
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.
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, United States of America.
authors.forename: Zihuai
authors.initials: Z
authors.lastname: He
authors.affiliation: Life Sciences Program, Northrop Grumman Health Division, McLean, Virginia, United States of America.
authors.forename: Erin K
authors.initials: EK
authors.lastname: Payne
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, United States of America.
authors.forename: Bhramar
authors.initials: B
authors.lastname: Mukherjee
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, United States of America.
authors.forename: Seunggeun
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Epidemiology, University of Michigan, Ann Arbor, United States of America.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Smith
authors.affiliation: Department of Epidemiology, University of Michigan, Ann Arbor, United States of America.
authors.forename: Erin B
authors.initials: EB
authors.lastname: Ware
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, United States of America.
authors.forename: Brisa N
authors.initials: BN
authors.lastname: Sánchez
authors.affiliation: Department of Medicine, Division of Geriatrics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, United States of America.
authors.forename: Teresa E
authors.initials: TE
authors.lastname: Seeman
authors.affiliation: Department of Epidemiology, University of Michigan, Ann Arbor, United States of America.
authors.forename: Sharon L R
authors.initials: SL
authors.lastname: Kardia
authors.affiliation: Department of Epidemiology, Drexel University, Philadelphia, United States of America.
authors.forename: Ana V
authors.initials: AV
authors.lastname: Diez Roux
mesh_terms: D001741:Black or African American; D000368:Aged; D000369:Aged, 80 and over; D050197:Atherosclerosis / Q000097:blood* / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D002940:Circadian Rhythm / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D006630:Hispanic or Latino; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D008297:Male; D008875:Middle Aged; D018343:Receptors, Adrenergic, beta-2 / Q000097:blood / Q000235:genetics*; D012044:Regression Analysis; D013312:Stress, Physiological / Q000235:genetics*; D014481:United States; D044465:White People
chemical_list: C553443:ADRB2 protein, human; D018343:Receptors, Adrenergic, beta-2; D006854:Hydrocortisone