학술논문
Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder.
Document Type
article
Author
Charney, AW; Ruderfer, DM; Stahl, EA; Moran, JL; Chambert, K; Belliveau, RA; Forty, L; Gordon-Smith, K; Di Florio, A; Lee, PH; Bromet, EJ; Buckley, PF; Escamilla, MA; Fanous, AH; Fochtmann, LJ; Lehrer, DS; Malaspina, D; Marder, SR; Morley, CP; Nicolini, H; Perkins, DO; Rakofsky, JJ; Rapaport, MH; Medeiros, H; Sobell, JL; Green, EK; Backlund, L; Bergen, SE; Juréus, A; Schalling, M; Lichtenstein, P; Roussos, P; Knowles, JA; Jones, I; Jones, LA; Hultman, CM; Perlis, RH; Purcell, SM; McCarroll, SA; Pato, CN; Pato, MT; Craddock, N; Landén, M; Smoller, JW; Sklar, P
Source
Translational psychiatry. 7(1)
Subject
Language
Abstract
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-h2=0.35; BD II SNP-h2=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.