Association between the 5 ' UTR variant C178T of the serotonin receptor gene HTR3A and bipolar affective disorder

Serotonin receptor type 3 is a ligand-gated ion channel implicated in behav ioural disorders. Our objective was to identify nucleotide variants in a sp ecific portion of the 5' region of the serotonin receptor gene (HTR3A) cont aining upstream open reading frames (uORFs) and to investigate their effect on bipolar disease. Mutations in uORFs have been recently shown to cause d isease by changing expression on the translational level. We identified one polymorphism, C195T, and one missense mutation, C178T (Pro(16)Ser) within an upstream open reading frame. No significant association was found betwee n the C195T polymorphism and bipolar affective disorder. A significant asso ciation was, however, found between the variant C178T in 156 patients with bipolar disorder compared to 156 healthy controls (P=0.00016). To investiga te the relevance of this variant on gene expression, luciferase reporter co nstructs containing the C178T (Pro(16)Ser) allele were established and comp ared to the C178T plus C195T and wild-type alleles. Reporter constructs con taining the C178T (Pro(16)Ser) allele drove 245% and 138% expression compar ed to the wild-type allele. These findings show that the C178T(Pro(16)Ser) variant in HTR3A may represent a functional variant and affect the suscepti bility to bipolar disorder. Pharmacogenetics 11:471-475 (C) 2001 Lippincott Williams & Wilkins.