Choline acetyltransferase variants and their influence in schizophrenia and olanzapine response

Choline acetyltransferase (ChAt) is extensively distributed throughout the CNS where, by catalyzing acetylcholine synthesis, it participates in modulating wide-ranging cholinergic-dependent functions including cognitive performance, sleep, arousal, movement, and visual information processing. Recently, compelling evidence has mounted implicating ChAt in schizophrenia. In particular, studies have identified significant reductions in ChAt activity in the nucleus accumbens and pontine tegmentum of such patients, which furthermore correlate significantly with measures of cognitive performance in the disorder. Similarly, elevated levels of choline, the acetylcholine precursor, have been identified among patients, implicating altered ChAt activity in these individuals. We sought to investigate the potential contribution of three ChAt gene polymorphisms in schizophrenia, and uncovered evidence for significant association between one of these, rs1880676G/A, and disease susceptibility among Basque individuals (genotypewise chi(2) = 20.7, P = 0.00003; allelewise chi(2) = 10.1, P = 0.002). A similar trend for association with susceptibility was observed for a second SNP, rs3810950G/A, (genotypwise chi(2) = 6.4, P = 0.05; allelewise chi(2) = 3.75, P = 0.05). Evidence was also uncovered for a potential influence of these polymorphisms on olanzapine treatment outcome among Spanish patients (F-statistic = 5.02, P = 0.03; F-statistic = 6.53, P = 0.02 respectively), and on improvements in positive symptoms in the case of rs3810950 (F-statistic = 5.3, P = 0.03) and general psychopathology in the case of rs1880676 and rs3810950 (F-statistic = 5.24, P = 0.03; F-statistic = 5.31, P = 0.03 respectively) during therapy. While more comprehensive studies are warranted to determine the precise contribution of ChAt mediated mechanisms in schizophrenia, our findings tentatively implicate a genetic influence of ChAt in the disorder's susceptibility and treatment.