Effect of the 5-HTTLPR polymorphism in the serotonin transporter gene on major depressive disorder and related comorbid disorders

Objectives The serotonin transporter gene (5-HTT) has been proposed as a candidate gene for major depressive disorder (MDD). Association studies, however, have revealed inconsistent results. This could be because of the phenotypic heterogeneity of MDD, as it often presents with comorbid disorders such as generalized anxiety disorder (GAD), alcohol-related disorders, and dysthymia. Methods In this exploratory study, we performed regression analyses with generalized estimating equations in patients with familial MDD (n = 233) in order to explore whether a polymorphism in the serotonin transporter gene (5-HTTLPR) is differentially associated with MDD and a comorbid disorder compared with MDD without that particular comorbidity. As in general, GAD is more common in females and alcohol-related disorders are more common in males, the analyses were stratified for sex. Results Comorbid dysthymia was less common in s-allele carriers with MDD (P<0.05) than in patients homozygous for the long allele. In the sex-specific analyses, an association between the 5-HTTLPR and comorbid alcohol use disorders was observed in females, with s-carriers reporting significantly less alcohol use disorders. The relationship with comorbid GAD differed by sex with male s-carriers reporting more comorbid GAD than female s-carriers. Conclusion The effect of the 5-HTTLPR polymorphism on MDD is codependent on the presence of comorbid disorders and sex. In this study, the s-allele of the 5-HTTLPR polymorphism was associated with significantly lower rates of particular lifetime comorbid disorders. Therefore, the presence of comorbid psychiatric disorders should be taken into account to clarify the association of the 5-HTTLPR polymorphism with MDD phenotypes. Psychiatr Genet 19:39-44 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.