Haplotype-Based Linkage of Tryptophan Hydroxylase 2 to Suicide Attempt, Major Depression, and Cerebrospinal Fluid 5-Hydroxyindoleacetic Acid in 4 Populations

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Abstract
Serotonergic dysfunction is one cause of negative mood states, including anxiety and depression.1 In addition, serotonin modulates sleep, food intake, and many other behaviors. Low serotonin turnover leads to behavioral disinhibition, causing impulsive aggression and antisocial behaviors in humans2,3 and irritable aggression in rodents, for example, after inhibition of tryptophan hydroxylase (TPH) with parachlorophenylalanine. Serotonergic hypofunction has also been implicated in suicide.4,5 5-Hydroxyindoleacetic acid (5-HIAA), an oxidative metabolite measurable in cerebrospinal fluid (CSF), indexes serotonin turnover, at least in the frontal cortex,6 and has been repeatedly correlated to impulsive behaviors.2,3 Cerebrospinal fluid 5-HIAA shows substantial heritability in rhesus macaques,7 and there are strong indications that CSF 5-HIAA is also heritable in humans, where the question has been addressed only in a relatively small sample.8 However, CSF 5-HIAA levels are also affected by a variety of environmental factors, including alcohol exposure,9,10 stress,11 diet,12 and selective serotonin reuptake inhibitors.13 Serotonergic dysfunction seems to be a cause and consequence of substance abuse.9,10 Linkage studies of serotonin-related genes to behavior are numerous and include coherent findings that implicate serotonin transporter functional variation in anxiety and dysphoria14-16 and in obsessive-compulsive disorder17 (Xiangzhang Hu, PhD, R.L., and D.G., unpublished data, 2005).