title: Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder.
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.
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.
authors.forename: A W
authors.initials: AW
authors.lastname: Charney
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.|Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Ruderfer
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.|Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Stahl
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Moran
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Chambert
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Belliveau
authors.affiliation: MRC Centre for Psychiatric Genetics and Genomics, Cardiff Unviersity, Cardiff, UK.
authors.forename: L
authors.initials: L
authors.lastname: Forty
authors.affiliation: Department of Psychological Medicine, University of Worcester, Worcester, UK.
authors.forename: K
authors.initials: K
authors.lastname: Gordon-Smith
authors.affiliation: MRC Centre for Psychiatric Genetics and Genomics, Cardiff Unviersity, Cardiff, UK.|Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: A
authors.initials: A
authors.lastname: Di Florio
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.|Department of Psychiatry, Harvard Medical School, Boston, MA, USA.|Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: P H
authors.initials: PH
authors.lastname: Lee
authors.affiliation: Department of Psychiatry, Stony Brook University, Stony Brook, NY, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Bromet
authors.affiliation: Department of Psychiatry, Georgia Regents University Medical Center, Augusta, GA, USA.
authors.forename: P F
authors.initials: PF
authors.lastname: Buckley
authors.affiliation: Center of Excellence in Neuroscience, Department of Psychiatry, Texas Tech University Health Sciences Center at El Paso, El Paso, TX, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Escamilla
authors.affiliation: Department of Psychiatry, Veterans Administration Medical Center, Washington, DC, USA.|Department of Psychiatry, Georgetown University, Washington, DC, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Fanous
authors.affiliation: Department of Psychiatry, Stony Brook University, Stony Brook, NY, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Fochtmann
authors.affiliation: Department of Psychiatry, Wright State University, Dayton, OH, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Lehrer
authors.affiliation: Department of Psychiatry, New York University, New York, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Malaspina
authors.affiliation: Department of Psychiatry, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Marder
authors.affiliation: Department of Psychiatry and Behavioral Science, State University of New York, Upstate Medical University, Syracuse, NY, USA.|Departments of Family Medicine, State University of New York, Upstate Medical University, Syracuse, NY, USA.|Department of Public Health and Preventive Medicine, State University of New York, Upstate Medical University, Syracuse, NY, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Morley
authors.affiliation: Center for Genomic Sciences, Universidad Autónoma de la Ciudad de México, Mexico City, Mexico.|Department of Psychiatry, Carracci Medical Group, Mexico City, Mexico.
authors.forename: H
authors.initials: H
authors.lastname: Nicolini
authors.affiliation: Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: D O
authors.initials: DO
authors.lastname: Perkins
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Rakofsky
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Rapaport
authors.affiliation: Department of Psychiatry and the Behavioral Sciences, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Medeiros
authors.affiliation: Department of Psychiatry and the Behavioral Sciences, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Sobell
authors.affiliation: School of Biomedical and Health Sciences, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth University, Plymouth, UK.
authors.forename: E K
authors.initials: EK
authors.lastname: Green
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.|Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Backlund
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.|Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: S E
authors.initials: SE
authors.lastname: Bergen
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Juréus
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Schalling
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Lichtenstein
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.|Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.|Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.
authors.forename: P
authors.initials: P
authors.lastname: Roussos
authors.affiliation: Department of Psychiatry and the Behavioral Sciences, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.|Zilkha Neurogenetic Institute, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Knowles
authors.affiliation: MRC Centre for Psychiatric Genetics and Genomics, Cardiff Unviersity, Cardiff, UK.
authors.forename: I
authors.initials: I
authors.lastname: Jones
authors.affiliation: Department of Psychological Medicine, University of Worcester, Worcester, UK.
authors.forename: L A
authors.initials: LA
authors.lastname: Jones
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.|Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: C M
authors.initials: CM
authors.lastname: Hultman
authors.affiliation: Center for Experimental Therapeutics, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Perlis
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.|Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.|Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Purcell
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.|Department of Genetics, Harvard Medical School, Boston, MA, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: McCarroll
authors.affiliation: Department of Psychiatry and the Behavioral Sciences, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.|Zilkha Neurogenetic Institute, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: C N
authors.initials: CN
authors.lastname: Pato
authors.affiliation: Department of Psychiatry and the Behavioral Sciences, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.|Zilkha Neurogenetic Institute, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Pato
authors.affiliation: MRC Centre for Psychiatric Genetics and Genomics, Cardiff Unviersity, Cardiff, UK.
authors.forename: N
authors.initials: N
authors.lastname: Craddock
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Institute of Neuroscience and Physiology, Sahlgenska Academy at the Gothenburg University, Gothenburg, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Landén
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.|Department of Psychiatry, Harvard Medical School, Boston, MA, USA.|Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.|Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Smoller
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.|Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.|Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.
authors.forename: P
authors.initials: P
authors.lastname: Sklar
mesh_terms: D000626:Aminopeptidases / Q000235:genetics; D017487:Ankyrins / Q000235:genetics; D001714:Bipolar Disorder / Q000145:classification / Q000235:genetics* / Q000523:psychology; D020746:Calcium Channels, L-Type / Q000235:genetics; D002148:Calmodulin-Binding Proteins / Q000235:genetics; D016022:Case-Control Studies; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D003598:Cytoskeletal Proteins; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011618:Psychotic Disorders / Q000235:genetics* / Q000523:psychology; D000099291:Adducins
chemical_list: D000626:Aminopeptidases; D017487:Ankyrins; D020746:Calcium Channels, L-Type; D002148:Calmodulin-Binding Proteins; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C102021:ADD3 protein, human; D000099291:Adducins; C490613:ANK3 protein, human; C079146:CACNA1C protein, human; C415465:SYNE1 protein, human; C022750:X-Pro aminopeptidase