Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

• Published in: Nature neuroscience Vol. 18; no. 2; pp. 199 - 209
• Main Authors: O'Dushlaine, C., Rossin, L., Lee P., H., Duncan, L., Parikshak N., N., Newhouse, S., Ripke, S., Neale B., M., Purcell S., M., Posthuma, D., Nurnberger J., I., Lee S., H., Faraone S., V., Perlis R., H., Mowry B., J., Thapar, A., Goddard M., E., Witte J., S., Absher, D., Agartz, I., Akil, H., Amin, F., Andreassen O., A., Anjorin, A., Anney, R., Anttila, V., Arking D., E., Asherson, P., Azevedo M., H., Backlund, L., Badner J., A., Bailey A., J., Banaschewski, T., Barchas J., D., Barnes M., R., Barrett T., B., Bass, N., Battaglia, A., Bauer, M., Bayés, M., Bellivier, F., Bergen S., E., Berrettini, W., Betancur, Catalina, Bettecken, T., Biederman, J., Binder E., B., Black D., W., Blackwood D., H., Bloss C., S., Boehnke, M., Boomsma D., I., Breuer, R., Bruggeman, R., Cormican, P., Buccola N., G., Buitelaar J., K., Bunney W., E., Buxbaum J., D., Byerley W., F., Byrne E., M., Caesar, S., Cahn, W., Cantor R., M., Casas, M., Chakravarti, A., Chambert, K., Choudhury, K., Cichon, S., Mattheisen, M., Cloninger C., R., Collier D., A., Cook E., H., Coon, H., Cormand, B., Corvin, A., Coryell W., H., Craig D., W., Craig I., W., Crosbie, J., Cuccaro M., L., Curtis, D., Czamara, D., Datta, S., Dawson, G., Day, R., de Geus E., J., Degenhardt, F., Djurovic, S., Donohoe G., J., Doyle A., E., Duan, J., Dudbridge, F., Duketis, E., Ebstein R., P., Edenberg H., J., Elia, J., Ennis, S., Etain, B., Fanous, F.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2015; Nature Publishing Group
• Subjects: 631/114/2415; 631/208/205/2138; 631/378/1689/1414; 631/378/1689/1799; Animal Genetics and Genomics; Behavioral Sciences; Biological Techniques; Biomedicine; Brain; Brain - immunology; Brain - metabolism; Databases, Genetic; etiology; Genetic; Genetic aspects; Genetic Predisposition to Disease; Genetic Predisposition to Disease - genetics; genetics; Genome-Wide Association Study; Genome-Wide Association Study - methods; Genomics; Histones; Histones - genetics; Histones - metabolism; Humans; immunology; Life Sciences; Mental Disorders; Mental Disorders - etiology; Mental Disorders - genetics; Mental illness; metabolism; methods; Methylation; Neurobiology; Neurons and Cognition; Neurosciences; Physiological aspects; Psychiatry; Psykiatri; Risk factors; Signal Transduction; Signal Transduction - genetics; United States; Schizophrenia; Depression; Genome-wide association studies; Statistical methods
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/nn.3922

Better analytical methods are needed to extract biological meaning from genome-wide association studies (GWAS) of psychiatric disorders. Here the authors take GWAS data from over 60,000 subjects, including patients with schizophrenia, bipolar disorder and major depression, and identify common etiological pathways shared amongst them. Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.