Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder

• Published in: Translational psychiatry Vol. 7; no. 1; p. e993
• Main Authors: Charney, A W, Ruderfer, D M, Stahl, E A, Moran, J L, Chambert, K, Belliveau, R A, Forty, L, Gordon-Smith, K, Di Florio, A, Lee, P H, Bromet, E J, Buckley, P F, Escamilla, M A, Fanous, A H, Fochtmann, L J, Lehrer, D S, Malaspina, D, Marder, S R, Morley, C P, Nicolini, H, Perkins, D O, Rakofsky, J J, Rapaport, M H, Medeiros, H, Sobell, J L, Green, E K, Backlund, L, Bergen, S E, Juréus, A, Schalling, M, Lichtenstein, P, Roussos, P, Knowles, J A, Jones, I, Jones, L A, Hultman, C M, Perlis, R H, Purcell, S M, McCarroll, S A, Pato, C N, Pato, M T, Craddock, N, Landén, M, Smoller, J W, Sklar, P
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 2017; Nature Publishing Group
• Subjects: 1982; 1991; 631/208/212/748; 692/699/476/1333; Aminopeptidases - genetics; Ankyrins - genetics; archives of general psychiatry; Behavioral Sciences; Biological Psychology; Bipolar Disorder - classification; Bipolar Disorder - genetics; Bipolar Disorder - psychology; Calcium Channels, L-Type - genetics; Calmodulin-Binding Proteins - genetics; Case-Control Studies; Chromosomes, Human, Pair 10 - genetics; Cytoskeletal Proteins; depression; family; genome-wide association; Genome-Wide Association Study; Genotype; guffin p; Humans; ii disorder; illness; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Nerve Tissue Proteins - genetics; Neurosciences; Nuclear Proteins - genetics; Original; original-article; p1157; p764; Pharmacotherapy; Phenotype; Polymorphism, Single Nucleotide; Psychiatry; Psychotic Disorders - genetics; Psychotic Disorders - psychology; Psykiatri; risk loci; rshon es; schizophrenia; spectrum disorder; susceptibility; unipolar; v39; v48
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/tp.2016.242

We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P =3.28 × 10 −8 ) that includes the brain-enriched cytoskeleton protein adducin 3 ( ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P ( XPNPEP1) . Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP- h 2 =0.35; BD II SNP- h 2 =0.25; P =0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.