ORIGINAL ARTICLE Polymorphisms in the dopamine D4 receptor gene (DRD4) contribute to individual differences in human sexual behavior: desire, arousal and sexual function IZ Ben Zion 1 , R Tessler 2 , L Cohen 3 , E Lerer 4 , Y Raz 5 , R Bachner-Melman 2 , I Gritsenko 6 , L Nemanov 6 , AH Zohar 7 , RH Belmaker 1 , J Benjamin 1 and RP Ebstein 2,6 1 Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel; 2 Department of Psychology, Mount Scopus, Hebrew University, Jerusalem, Israel; 3 Department of Education, Hebrew University, Jerusalem, Israel; 4 Neurobiology, Hebrew University, Jerusalem, Israel; 5 Brain and Behavioral Sciences, Hebrew University, Jerusalem, Israel; 6 S. Herzog Memorial Hospital, Jerusalem, Israel; and 7 Department of Psychology, Behavioral Sciences, Ruppin Academic Center, Emek Hefer, Israel Although there is some evidence from twin studies that individual differences in sexual behavior are heritable, little is known about the specific molecular genetic design of human sexuality. Recently, a specific dopamine D4 receptor (DRD4) agonist was shown in rats to induce penile erection through a central mechanism. These findings prompted us to examine possible association between the well-characterized DRD4 gene and core phenotypes of human sexual behavior that included desire, arousal and function in a group of 148 nonclinical university students. We observed association between the exon 3 repeat region, and the C- 521T and C-616G promoter region SNPs, with scores on scales that measure human sexual behavior. The single most common DRD4 5-locus haplotype (19%) was significantly associated with Desire, Function and Arousal scores. The current results are consistent with animal studies that show a role for dopamine and specifically the DRD4 receptor in sexual behavior and suggest that one pathway by which individual variation in human desire, arousal and function are mediated is based on allelic variants coding for differences in DRD4 receptor gene expression and protein concentrations in key brain areas. Molecular Psychiatry advance online publication, 18 April 2006; doi:10.1038/sj.mp.4001832 Keywords: sexual behavior; dopamine D4 receptor gene; DRD4; polymorphism; haplotype; family study Many animal studies have characterized the neuro- chemical pathways that modulate various facets of sexual behavior including the critical appetitive, arousal and consummatory stages. 1 Notably, a specific dopamine D4 agonist has recently been shown to induce penile erection in rats via a central mechanism and, moreover, additional D4 agonists are in devel- opment for the treatment of human sexual dysfunc- tion. 2 Based on these animal experiments, we hypothesized that individual allelic differences in the dopamine D4 receptor gene (DRD4) might also contribute to differences in human sexual desire, arousal and function. We studied 148 subjects with an online question- naire on sexual desire, arousal and function. Five polymorphisms were genotyped across the DRD4 gene: three promoter region SNPs (C-521T, C-616G, A-809G), 120 bp tandem duplication in the promoter region and the exon 3 repeat region that codes for amino acids comprising the third cytoplasmic loop of the receptor. Men and women significantly differed on desire and function scores Males scored higher on desire and showed less ‘dysfunction’ than women (Table 1 legend). Associations between desire, arousal, func- tion and DRD4 (single locus analysis) are shown in Table 1a analyzed by PBAT. 3 Notably, the DRD4 exon 3 most common D4.4 repeat was negatively associated with desire. Carriers of the D4.4 repeat displayed less desire (Table 1a) and carriers of the rarer (4%) 4.2 repeat showed increased desire scores (dominant model). The C-521T ‘T’ allele showed higher desire scores. The C-616G C allele was associated with higher function and desire scores. Using UNPHASED, 4 significant negative associa- tion was observed between a five locus haplotype, that captures all the genetic information on the DRD4 gene available for these subjects, and desire and function scores (Table 1b). The single, and by far most Received 12 December 2005; revised 6 February 2006; accepted 3 March 2006 Correspondence: Professor RP Ebstein, Scheinfeld Center for Genetic Studies in the Social Sciences, Department of Psychology, Hebrew University, Mt. Scopus, Jerusalem 91905 (and S. Herzog Memorial Hospital), Israel. E-mail: ebstein@mscc.huji.ac.il Molecular Psychiatry (2006), 1–5 & 2006 Nature Publishing Group All rights reserved 1359-4184/06 $30.00 www.nature.com/mp