Investigation of the human serotonin 6 (5-HT6) receptor gene in bipolar affective disorder and schizophrenia

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that mediates a wide range of central nervous functions by activating multiple 5-HT recept or subtypes. A possible irregularity of serotonergic neurotransmission has been implicated in a variety of neuropsychiatric diseases. In the present s tudy, we performed a systematic mutation scan of the complete coding region and splice junctions of the 5-HT6 receptor gene to explore the contributio n of this gene to the development of bipolar affective disorder and schizop hrenia. Investigating 137 unrelated individuals (including 45 bipolar affec tive patients, 46 schizophrenic patients, and 46 unrelated controls), we id entified six single base substitutions (126G/T, 267C/T, 873+30C/T, 873+128A /C, 1128G/C, 1376T/G). Comparing frequencies between patients and controls, we observed a significant overrepresentation of the 267C allele among bipo lar patients (P = 0.023 not corrected for multiple testing). This finding w as followed up in an independent sample of 105 bipolar family trios using a family-based association design. Fifty-one transmissions could be examined . In 30 cases allele 267C and in 21 cases allele 267T were transmitted to t he affected offspring. Although this result was far from statistical signif icance (transmission disequilibrium test = 1.59, P = 0.208), the limited nu mber of possible transmissions may have prevented detection of smaller effe cts. Our preliminary data suggest that bipolar affective disorder may be as sociated with variation in the 5-HT6 gene. It will be important to extend t he present analysis to larger samples. (C) 2000 Wiley-Liss, Inc.