Application of systems biology approach identifies and validates GRB2 as a risk gene for schizophrenia in the Irish Case Control Study of Schizophrenia (ICCSS) sample

Recently, we prioritized 160 schizophrenia candidate genes (SZGenes) by integrating multiple lines of evidence and subsequently identified twenty-four pathways in which these 160 genes are overrepresented. Among them, four neurotransmitter-related pathways were top ranked. In this study, we extended our previous pathway analysis by applying a systems biology approach to identifying candidate genes for schizophrenia. We constructed protein–protein interaction subnetworks for four neurotransmitter-related pathways and merged them to obtain a general neurotransmitter network, from which five candidate genes stood out. We tested the association of four genes (GRB2, HSPA5, YWHAG, and YWHAZ) in the Irish Case–Control Study of Schizophrenia (ICCSS) sample (1021 cases and 626 controls). Interestingly, six of the seven tested SNPs in GRB2 showed significant signal, two of which (rs7207618 and rs9912608) remained significant after permutation test or Bonferroni correction, suggesting that GRB2 might be a risk gene for schizophrenia in Irish population. To our knowledge, this is the first report of GRB2 being significantly associated with schizophrenia in a specific population. Our results suggest that the systems biology approach is promising for identification of candidate genes and understanding the etiology of complex diseases.