1. ¹Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, USA
2. ²Department of Genetics, Duke University Medical Center, USA
3. ³Department of Anesthesiology, Duke University Medical Center, USA
4. ⁴Department of Pharmacology and Cancer Biology, Duke University Medical Center, USA
5. ⁵Department of Pathology, Duke University Medical Center, USA

Correspondence: Dr RB Williams, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box 3926, Durham, NC 27710, USA. Tel: +1 919 684 3863; Fax: +1 919 681 8960; E-mail: redfordw@acpub.duke.edu

^*Supported by National Heart, Lung, and Blood Institute Grant P01HL36587, National Institute of Mental Health Grant K05MH79482, Clinical Research Unit Grant M01RR30, and the Duke University Behavioral Medicine Research Center.

Received 9 August 2002; Accepted 16 August 2002.

Abstract

Central nervous system (CNS) serotonergic function affects a wide range of biological and behavioral functions affecting health and disease. Our objective in this study was to determine whether functional polymorphisms of the genes that encode for the serotonin transporter promoter (5HTTLPR) and monoamine oxidase A (MAOA-uVNTR) are associated with CNS serotonin turnover—indexed by cerebrospinal fluid levels of 5-hydroxyindoleacetic acid (5-HIAA)—in a community sample of healthy adults. Subjects were 165 community volunteers without current medical or psychiatric illness, stratified with respect to ethnicity, gender, and socioeconomic status who underwent inpatient evaluation in the General Clinical Research Center of a university medical center. A significant ethnicitygenotype interaction (P=0.008) indicated that, compared to the long/long and long/short genotypes, the 5HTTLPR short/short genotype was associated with higher CSF 5-HIAA levels in African Americans, but with lower levels in Caucasians. A gendergenotype interaction (P=0.04) indicated that 5HTTLPR short/short genotype was associated with higher 5-HIAA levels in women but with lower levels in men. MAOA-uVNTR 3.5 and 4 repeat alleles were associated with higher 5-HIAA (P=0.03) levels in men, but were unrelated to 5-HIAA levels in women. These findings suggest that effects of serotonin-related gene polymorphisms on CNS serotonergic function vary as a function of both ethnicity and gender. Further research will be required to determine the mechanism(s) underlying these differential effects. In the meanwhile, both ethnicity and gender should be taken into account in research evaluating effects of these and related polymorphisms on CNS serotonergic function, as well as the broad range of biological and behavioral functions that are regulated by CNS serotonergic function.