Nested Association Between Genetic Variation in Tryptophan Hydroxylase II, Bipolar Affective Disorder, and Suicide Attempts

Background: Bipolar affective disorder (BPAD) is a common mental illness that is strongly associated with suicide. Suicidal behavior is thought to result from an interaction of genetic, neurobiological, and psychosocial factors and tends to cluster in families, suggesting specific familial factors distinct from those that underlie BPAD itself. Serotonin signaling has long been implicated in both BPAD and suicide, and the gene encoding the brain-expressed isoform of tryptophan hydroxlyase (TPH2) has been described. Markers in TPH2 have been implicated in suicide and major depressive disorder, but the results across studies are inconsistent. No studies have examined TPH2 in large samples of subjects with BPAD and suicide attempts (SA). We tested for a relationship between genetic variation in TPH2 and risk for BPAD and SA in a large family sample. Methods: The sample consisted of 2018 members of 670 families, ascertained through a sibling pair affected with bipolar I, bipolar II, or schizoaffective-bipolar disorder and diagnosed under DSM-III/IV criteria. Three single nucleotide polymorphisms representing the common haplotypes spanning TPH2 were analyzed. Results: Single-marker analysis failed to detect significant genetic association with BPAD or SA, but the number of informative families was small. Haplotype analysis showed significant association with both BPAD and SA, and the same haplotype was significantly associated with both BPAD and SA in a replication sample. Case-only analysis, stratified by SA, suggested that TPH2 was not an independent genetic risk factor for SA in this sample. Conclusions: The TPH2 might contribute to the risk of both BPAD and SA in families with BPAD. Further studies are needed to uncover the functional genetic variation that accounts for the observed associations.