Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder

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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 ... view all 45 authors (2017)
  • Publisher: Nature Publishing Group
  • Journal: Translational Psychiatry, volume 7, issue 1, page e993 (eissn: 2158-3188)
  • Related identifiers: doi: 10.1038/tp.2016.242, pmc: PMC5545718
  • Subject: RC0321 | Original Article | BF | R1

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