Functional gene group analysis identifies synaptic gene groups as risk factor for schizophrenia

Danielle Posthuma (1) , Esther S Lips (1) , L Niels Cornelisse (1) , Ruud F Toonen (1) , Josine L Min (1) , Christina Hultman (1) , International Schizophrenia Consortium (1) , Peter A Holmans (1) , Michael C. O'Donovan (1) , Shaun Purcell (1) , August Smit (1) , Matthijs Verhage (1) , Patrick Sullivan (1) , Peter M Visscher (1)

1 Functional Genomics

Schizophrenia is a highly heritable disorder with a polygenic pattern of inheritance and a population prevalence around 1 percent. Previous studies have implicated synaptic dysfunction in schizophrenia. We tested the accumulated association of genetic variants in expert curated synaptic gene groups with schizophrenia in 4,673 cases and 4,965 healthy controls, using functional gene group analysis. Identifying groups of genes with similar cellular function rather than genes in isolation may have clinical implications for finding additional drug targets. We found that a group of 1026 synaptic genes was significantly associated with the risk of schizophrenia (P < 7.6x10-11) and more strongly associated than 100 randomly drawn, matched control groups of genetic variants (P < .01). Subsequent analysis of synaptic sub-groups suggested that the strongest association signals are derived from three synaptic gene groups: intracellular signal transduction (P = 2.0x10-4), excitability (P = 9.0x10-4) and cell adhesion and trans-synaptic signaling (P = 2.4x10-3). These results are consistent with a role of synaptic dysfunction in schizophrenia and imply that impaired intracellular signal transduction in synapses, synaptic excitability and cell adhesion and trans-synaptic signaling play a role in the pathology of schizophrenia.

Mots clés: GWAS; ISC; gene group analysis; synapse; schizophrenia; genome-wide association; GAIN

Domaines: Psychiatrie et santé mentale

Danielle Posthuma, Esther S Lips, L Niels Cornelisse, Ruud F Toonen, Josine L Min, et al.. Functional gene group analysis identifies synaptic gene groups as risk factor for schizophrenia. Molecular Psychiatry, 2011, ⟨10.1038/mp.2011.117⟩. ⟨hal-00680704⟩