1. Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder
- Author
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Pamela Sklar, Paul Lichtenstein, Diana O. Perkins, Douglas M. Ruderfer, Lena Backlund, Humberto Nicolini, Stephen R. Marder, Phil Lee, Elaine K. Green, Roy H. Perlis, Martin Schalling, Jeffrey J. Rakofsky, Steven A. McCarroll, Evelyn J. Bromet, Jordan W. Smoller, Liz Forty, Dolores Malaspina, Janet L. Sobell, Richard A. Belliveau, Katherine Gordon-Smith, Jennifer L. Moran, Ian Jones, Sarah E. Bergen, A. Di Florio, Laura J. Fochtmann, Michael Escamilla, Helena Medeiros, Alexander W. Charney, Mikael Landén, Panos Roussos, A. H. Fanous, Mark Hyman Rapaport, Shaun Purcell, Kimberly Chambert, James A. Knowles, Carlos N. Pato, Douglas S. Lehrer, Nicholas John Craddock, M. T. Pato, Christopher P. Morley, Anders Juréus, Lisa Jones, Eli A. Stahl, Peter F. Buckley, and Christina M. Hultman
- Subjects
0301 basic medicine ,Oncology ,Bipolar Disorder ,Genome-wide association study ,Aminopeptidases ,0302 clinical medicine ,2.1 Biological and endogenous factors ,Psychology ,Pair 10 ,Aetiology ,Genetics ,Nuclear Proteins ,Single Nucleotide ,Serious Mental Illness ,L-Type ,3. Good health ,Psychiatry and Mental health ,Phenotype ,Mental Health ,Schizophrenia ,Public Health and Health Services ,Major depressive disorder ,Original Article ,Human ,Ankyrins ,medicine.medical_specialty ,Calcium Channels, L-Type ,Genotype ,Clinical Sciences ,BF ,Schizoaffective disorder ,Nerve Tissue Proteins ,Polymorphism, Single Nucleotide ,Genetic correlation ,Chromosomes ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Clinical Research ,Internal medicine ,medicine ,Humans ,Bipolar disorder ,Allele ,Polymorphism ,Biological Psychiatry ,Chromosomes, Human, Pair 10 ,Genetic heterogeneity ,Human Genome ,medicine.disease ,R1 ,Brain Disorders ,Cytoskeletal Proteins ,030104 developmental biology ,Psychotic Disorders ,Case-Control Studies ,RC0321 ,Calmodulin-Binding Proteins ,Calcium Channels ,030217 neurology & neurosurgery ,Genome-Wide Association Study - 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.
- Published
- 2017