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Background  Schizophrenia is a highly heritable disease with a polygenic mode of inheritance. Many studies have contributed to our understanding of the genetic underpinnings of schizophrenia, but little is known about how interactions among genes affect the risk of schizophrenia. This study aimed to assess the associations and interactions among genes that confer vulnerability to schizophrenia and to examine the moderating effect of neuropsychological impairment.    Methods  We analyzed 99 SNPs from 10 candidate genes in 1,512 subject samples. The permutation-based single-locus, multi-locus association tests, and a gene-based multifactorial dimension reduction procedure were used to examine genetic associations and interactions to schizophrenia.    Results  We found that no single SNP was significantly associated with schizophrenia. However, a risk haplotype, namely  A - T - C  of the SNP triplet rsDAO7-rsDAO8-rsDAO13 of the  DAO  gene, was strongly associated with schizophrenia. Interaction analyses identified multiple between-gene and within-gene interactions. Between-gene interactions including  DAO * DISC1   ,   DAO * NRG1  and  DAO * RASD2  and a within-gene interaction for  CACNG2  were found among schizophrenia subjects with severe sustained attention deficits, suggesting a modifying effect of impaired neuropsychological functioning. Other interactions such as the within-gene interaction of  DAO  and the between-gene interaction of  DAO  and  PTK2B  were consistently identified regardless of stratification by neuropsychological dysfunction. Importantly, except for the within-gene interaction of  CACNG2 , all of the identified risk haplotypes and interactions involved SNPs from  DAO .    Conclusions  These results suggest that  DAO , which is involved in the N-methyl- d -aspartate receptor regulation, signaling and glutamate metabolism, is the master gene of the genetic associations and interactions underlying schizophrenia. Besides, the interaction between  DAO  and  RASD2  has provided an insight in integrating the glutamate and dopamine hypotheses of schizophrenia.

The DAO Gene Is Associated with Schizophrenia and Interacts with Other Genes in the Taiwan Han Chinese Population