ANK3 as a risk gene for schizophrenia: new data in Han Chinese and meta analysis

Histological and neuroimaging evidence supports the hypothesis that neuronal disconnectivity may be involved in the pathogenesis of schizophrenia. A genome-wide association study (GWAS) showed a single nucleotide polymorphism (SNP), rs10761482 in ankyrin 3 (ANK3), a major neuron-enriched gene, was associated with schizophrenia although inconsistent results had been reported. Two meta analyses reported another SNP rs10994336 in ANK3 gene confers risk to bipolar disorder (BD). Due to evidence of genetic overlap between schizophrenia and BD, we investigated common findings by analyzing the association of ANK3 polymorphisms (rs10761482, rs10994336, and two missenses, rs3808942 and rs3808943) with schizophrenia, using the Han Chinese population. A total of 516 schizophrenia cases, 400 controls, and 81 trios of early onset schizophrenia were recruited for association studies. Furthermore, the published datasets were combined with our results to determine the effect of the loci on schizophrenia. Our association study showed the frequencies of C allele of rs10761482 and T allele of rs10994336 were higher in patients than in controls. Furthermore, allele condition analyses indicated the association signal observed at rs10761482 and rs10994336 was independent. A haplotype analysis revealed the rs10761482-rs3808942-rs3808943 haplotype was associated with schizophrenia. The frequency of the T-T-T haplotype was higher in patients than in controls. In the transmission disequilibrium test analysis, the C allele of rs10761482 and the rs10761482-rs3808942-rs3808943 haplotype were preferentially transmitted in the trios. Meta analysis incorporating previous and current studies also showed rs10761482 and rs10994336 were associated with schizophrenia. We conclude that ANK3 gene has a major influence on susceptibility to schizophrenia across populations.