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Proc Natl Acad Sci U S A. 2004 Aug 17;101(33):12358-63. Epub 2004 Aug 9.

Sexual dichotomy of an interaction between early adversity and the serotonin transporter gene promoter variant in rhesus macaques.

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  • 1Primate Unit, Laboratory of Clinical Studies, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Poolesville, MD 20837, USA.


A polymorphism in the human serotonin transporter gene promoter (5-HTTLPR) is associated with anxiety and increased risk for developing depression in the face of adversity. Here, we report that among infant rhesus macaques, an orthologous polymorphism (rh5-HTTLPR) interacts with adversity in the form of peer rearing to influence adrenocorticotropic hormone (ACTH) response to stress and, further, that this interaction is sexually dichotomous. ACTH responses to separation are higher in l/s than in l/l males. In females, however, it is only among those with a history of adversity that the s allele is associated with increased ACTH responses to stress. Of interest, peer-reared animals, in particular females carrying the s allele, also exhibit lower cortisol responses to stress, a pattern that has been recognized in association with certain stress-related neuropsychiatric disorders. By extension, our findings suggest the intriguing possibility that human females carrying the 5-HTTLPR s allele could be more vulnerable to the effects of early adversity. This interactive effect may underlie the increased incidence of certain stress-related disorders in women.

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