A systematic meta-analysis of the association of Neuregulin 1 (NRG1), D-amino acid oxidase (DAO), and DAO activator (DAOA)/G72 polymorphisms with schizophrenia

The glutamate hypothesis of schizophrenia is related to the proposed dysregulation of d-amino acid oxidase (DAO), DAO activator (DAOA)/G72, and Neuregulin 1 (NRG1) genes. Genetic studies have shown significant associations between DAO, DAOA, NRG1 single-nucleotide polymorphisms (SNPs), and schizophrenia. The systematic literature search yielded 6, 5, and 18 new studies for DAO, DAOA, and NRG1 published after 2011 and not included in the previous SchizophreniaGene (SZGene) meta-analysis. We conducted meta-analyses of 20, 23, and 48 case-control studies, respectively, to comprehensively evaluate the association of 8 DAO, 12 DAOA, and 14 NRG1 SNPs with schizophrenia. The updated meta-analyses resulted in the following findings: the C-allele of DAO rs4623951 was associated with schizophrenia across all pooled studies [Odds ratio (OR) = 0.88, 95% confidence interval (CI) = 0.79-0.98, p = 0.02, N = 3143]; however, no new reports could be included. The G-allele of DAOA rs778293 was associated with schizophrenia in Asian patients (OR = 1.17, 95% CI = 1.08-1.27, p = 0.00008, N = 6117), and the T-allele of DAOA rs3916971 was associated with schizophrenia across all studies (OR = 0.84, 95% CI = 0.73-0.96, p = 0.01, N = 1765). Again, for both SNPs, no new eligible studies were available. After adding new reports, the T-allele of NRG1 SNP8NRG241930 (rs62510682) across all studies (OR = 0.95, 95% CI = 0.91-0.997, p = 0.04, N = 22,898) and in Caucasian samples (OR = 0.95, 95% CI = 0.90-0.99, p = 0.03, N = 16,014), and the C-allele of NRG1 rs10503929 across all studies (OR = 0.89, 95% CI = 0.81-0.97, p = 0.01, N = 6844) and in Caucasian samples (OR = 0.89, 95% CI = 0.81-0.98, p = 0.01, N = 6414) were protective against schizophrenia. Our systematic meta-analysis is the most updated one for the association of DAO, DAOA, and NRG1 SNPs with schizophrenia.