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May 2, 2011

Genetic Indeterminism, the 5-HTTLPR, and the Paths Forward in Neuropsychiatric Genetics

Author Affiliations

Author Affiliations: Departments of Pharmacology (Drs Blakely and Veenstra-VanderWeele), Psychiatry (Dr Veenstra-VanderWeele), and Pediatrics (Drs Blakely and Veenstra-VanderWeele) and Center for Molecular Neuroscience (Drs Blakely and Veenstra-VanderWeele), Vanderbilt University School of Medicine, Nashville, Tennessee.

Arch Gen Psychiatry. 2011;68(5):457-458. doi:10.1001/archgenpsychiatry.2011.34

The serotonin transporter gene (5-HTT, SERT, SLC6A4) is arguably both the most and least loved gene in psychiatric genetics. Fifteen years ago, the discovery of a common, functional promoter polymorphism (5-HTTLPR) that modulates SERT expression1 launched innumerable association studies. In part, this flurry of activity arose from the common nature of 5-HTTLPR variants. White individuals exhibit approximately a 40/60 split in allele frequency for “short” (s) vs “long” (l) alleles, respectively. Not surprisingly, initial findings from these studies caught the imagination of clinicians and patients alike: finally a gene that could explain our neuroticism1 or maybe depression or maybe . . . ah, well, complex brain disorders are, after all, complex. With inconsistent findings, feelings about the 5-HTTLPR among many psychiatric geneticists moved from excitement to consternation.

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