No evidence that rare coding variants in ZNF804A confer risk of schizophrenia

Strong evidence that rare variants of relatively high penetrance are involved in the etiology of schizophrenia is currently restricted to the data from studies investigating copy number variants and major structural re-arrangements in that disorder. Global tests of the hypothesis of the involvement of fairly high penetrance rare single nucleotide changes or small insertion deletion events await the genesis of data from large-scale sequencing studies, meanwhile, a pragmatic approach to trying to detect such alleles is to target sequencing efforts on genes for which there is compelling evidence from other sources for their involvement in this disorder. We have undertaken a study, which aimed to identify whether rare (frequency ∼0.001%) coding variants in the schizophrenia susceptibility gene ZNF804A are involved in this disorder. We screened the coding regions of the gene in 517 schizophrenic cases and 501 controls, and genotyped rare non-synonymous variants in a case-control sample powered to detect association to rare alleles with an effect size (odds ratio) of 5. No single rare variant was associated with schizophrenia, nor was the burden of rare, or even fairly common, non-synonymous variants. Our results do not support the hypothesis that moderately rare non-synonymous variants at the ZNF804A locus are involved in schizophrenia susceptibility. © 2010 Wiley-Liss, Inc.