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.
Many animal studies have characterized the neurochemical 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 development for the treatment of human sexual dysfunction.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 questionnaire 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, function 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 association 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 frequent (∼19%) five locus haplotype of the five DRD4 polymorphisms (C-521T, C-616G, A-809G, EXON 3, 120 bp tandem duplication) genotyped was C-G-G-4-2; this haplotype was negatively associated with desire and function. Overall, similar results were obtained with FBAT. Carriers of this haplotype displayed less desire and functioned less well. Interestingly, carriers of the rarer 5-locus haplotype containing the exon 3 ‘7’ repeat showed increased desire scores. Similar results were observed when categorical grouping of desire, arousal and function scores were analyzed (Table 1c). The most common C-G-G-4-2 haplotype was negatively associated with scores on three measures of human sexual behavior that is Desire, arousal and function.
The current results show for the first time significant association between a common genetic polymorphism and three critical facets of human sexual behavior-desire, arousal and function. Five-locus haplotype analysis, which captures all the genetic information available on these subjects, that included three purportedly functional polymorphisms (C-521T,5 120 bp tandem duplication6 and the exon 3 repeat7 showed significant association between the DRD4 gene and desire, arousal and function. Weaknesses of the research are the relatively small number of subjects inventoried (N=148), albeit a robust family-based association test was employed, as well as not correcting for multiple testing for reasons explained in the Table legend. Clearly, these novel findings are only suggestive of association and await replication in a larger, independently-recruited sample.
We also suggest the notion that association between DRD4 and sexual attitudes and behavior may help to clarify the intriguing evolutionary history of the DRD4 exon 3 repeat region elucidated by Kidd et al.8 They estimated that the D4.7 allele arose before the upper Paleolithic era and further hypothesized that the seven repeat had a selective advantage in certain environments, that is a resource-depleted, time-critical or rapidly changing environments might select for individuals with ‘response ready’ adaptations, whereas resource-rich, time-optimal or little-changing environments might select against such adaptations. Such a ‘response ready’ adaptation could have contributed to the out-of-Africa exodus and that allele frequencies of genes associated with these behaviors for example, D4.7, been positively selected for. We have inferred, based on evidence that the D4.4 allele partially contributes to self-report measures of altruism,9 that the balanced maintenance of both the D4.4 and D4.7 repeats in the evolution of Homo sapiens is possibly related to the need for diverse behavioral phenotypes involving altruistic and prosocial (D4.4) vs a more aggressive, novelty-seeking type (D4.7) of individual. The present results suggest yet a third source of possible adaptive advantage to the D4.7 allele which may be related to greater sexual desire, easier arousability and better sexual function associated with this polymorphism.
The current investigation suggests that specific DRD4 agonists may not only be valuable for problems of erectile dysfunction but also for problems related to desire, arousal and function in both sexes. Importantly, future clinical investigations of D4 agonists might benefit from a pharmacogenetic strategy by stratifying individual responses by DRD4 genotype. Psychotherapeutic approaches to sexual disorders such as hypoactive sexual desire disorder in females (HSDD) might also benefit from the concept that individual differences have a genetic component and that both high and low levels of sexual desire may be adaptational and not in themselves a cause for guilt or treatment.
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This research was partially supported by the Israel Science Foundation founded by the Israel Academy of Sciences and Humanities (RPE) and the Israel Association of University Women (RBM). We would like to thank all the subjects and their family members who so willingly participated in this research.
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