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Sex Differences in the Genetic Basis of Morning Serum Cortisol Levels: Genome-Wide Screen Identifies Two Novel Loci Specific to Women

Departments of Health Studies (L.M.K.), Human Genetics (L.A.W., M.A., C.O.), and Obstetrics and Gynecology (C.O.), The University of Chicago, Chicago, Illinois 60637; Department of Chemistry and Biochemistry (S.W.G.), Brigham Young University, Provo, Utah 84602; School of Medicine (R.P.), University of South Dakota, Sioux Falls, South Dakota 57105; and Cardiovascular Endocrinology Section (G.H.W.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Lianne Kurina, Department of Health Studies, The University of Chicago, 5841 South Maryland Avenue, MC2007, Chicago, Illinois 60637. E-mail: lkurina{at}uchicago.edu.

Context: Relatively little is known about the influence of specific genes on cortisol levels, particularly morning cortisol levels.

Objective: The objective of this study was to identify quantitative trait loci associated with morning serum cortisol levels.

Design: We carried out a genome screen for morning serum cortisol using linkage and association methods tailored for use in large pedigrees. We conducted these analyses both in the whole sample and partitioned by sex.

Setting: This study was conducted on nine communal Hutterite farms in South Dakota.

Participants: The Hutterites are a young founder population who practice a communal, farming lifestyle in the western United States and in Canada. Hutterites (n = 504, 53% female) aged 11–89 yr from a single pedigree participated in this study.

Main Outcome Measures: The main outcome measures were markers significantly linked or associated with variation in morning serum cortisol levels.

Results: One genome-wide significant association was identified in the whole sample on 11p (D11S1981, P = 0.000092). Results of sex-partitioned analyses indicated that this association was restricted to females (females, P = 0.000084; males, P = 0.20). The 146-bp allele at this locus accounted for 7% of the variance in morning cortisol values in females, and females homozygous for the allele had an 89% increase in morning cortisol levels compared with female noncarriers. A second genome-wide significant association in females was identified on 14q (D14S74, P = 0.000091).

Conclusions: Our results suggest that the genetic determinants of morning cortisol levels may be different for men and women and that loci on 11p and 14q influence morning cortisol levels in women.

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