Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia

• Published in: Molecular psychiatry Vol. 19; no. 9; pp. 1017 - 1024
• Main Authors: Ruderfer, D M, Fanous, A H, Ripke, S, McQuillin, A, Amdur, R L, Gejman, P V, O'Donovan, M C, Andreassen, O A, Djurovic, S, Hultman, C M, Kelsoe, J R, Jamain, S, Landén, M, Leboyer, M, Nimgaonkar, V, Nurnberger, J, Smoller, J W, Craddock, N, Corvin, A, Sullivan, P F, Holmans, P, Sklar, P, Kendler, K S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2014; Nature Publishing Group
• Subjects: 692/699/476/1333; 692/699/476/1799; 692/700/139/1512; Affective disorders; Behavioral Sciences; Biological Psychology; Bipolar disorder; Bipolar Disorder - diagnosis; Bipolar Disorder - genetics; Bipolar Disorder - psychology; Calcium Channels, L-Type - genetics; Case-Control Studies; Cell Cycle Proteins - genetics; Complications and side effects; Factor Analysis, Statistical; Genetic aspects; Genetic Predisposition to Disease; Genetics; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Health risk assessment; Hospitals; Humans; Life Sciences; Medical Genetics and Genomics; Medicine; Medicine & Public Health; Medicinsk genetik och genomik; Mental disorders; Mental health; Neurosciences; Neurovetenskaper; Nuclear Proteins - genetics; Odds Ratio; original-article; Patient outcomes; Pharmacotherapy; Phenotype; Phosphatidylinositol 3-Kinases - genetics; Polymorphism, Single Nucleotide; Psychiatric research; Psychiatry; Psykiatri; Risk factors; Schizophrenia; Schizophrenia - diagnosis; Schizophrenia - genetics; Schizophrenic Psychology; Twins; Working groups; United Kingdom; New York; Sweden; United Kingdom > UK; United States > US; Virginia; Massachusetts; bipolar; schizophrenia; clinical symptoms; polygenic; cross disorder
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/mp.2013.138

Bipolar disorder and schizophrenia are two often severe disorders with high heritabilities. Recent studies have demonstrated a large overlap of genetic risk loci between these disorders but diagnostic and molecular distinctions still remain. Here, we perform a combined genome-wide association study (GWAS) of 19 779 bipolar disorder (BP) and schizophrenia (SCZ) cases versus 19 423 controls, in addition to a direct comparison GWAS of 7129 SCZ cases versus 9252 BP cases. In our case–control analysis, we identify five previously identified regions reaching genome-wide significance ( CACNA1C, IFI44L, MHC, TRANK1 and MAD1L1 ) and a novel locus near PIK3C2A . We create a polygenic risk score that is significantly different between BP and SCZ and show a significant correlation between a BP polygenic risk score and the clinical dimension of mania in SCZ patients. Our results indicate that first, combining diseases with similar genetic risk profiles improves power to detect shared risk loci and second, that future direct comparisons of BP and SCZ are likely to identify loci with significant differential effects. Identifying these loci should aid in the fundamental understanding of how these diseases differ biologically. These findings also indicate that combining clinical symptom dimensions and polygenic signatures could provide additional information that may someday be used clinically.