Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder

A W Charney; D M Ruderfer; E A Stahl; J L Moran; K Chambert; R A Belliveau; L Forty; K Gordon-Smith; A Di Florio; P H Lee; E J Bromet; P F Buckley; M A Escamilla; A H Fanous; L J Fochtmann; D S Lehrer; D Malaspina; S R Marder; C P Morley; H Nicolini; D O Perkins; J J Rakofsky; M H Rapaport; H Medeiros; J L Sobell; E K Green; L Backlund; S E Bergen; A Juréus; M Schalling; P Lichtenstein; P Roussos; J A Knowles; I Jones; L A Jones; C M Hultman; R H Perlis; S M Purcell; S A McCarroll; C N Pato; M T Pato; N Craddock; M Landén; J W Smoller; P Sklar

doi:10.1038/tp.2016.242

Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder

Transl Psychiatry. 2017 Jan 10;7(1):e993. doi: 10.1038/tp.2016.242.

Authors

A W Charney¹, D M Ruderfer^{1

2}, E A Stahl^{1

2}, J L Moran³, K Chambert³, R A Belliveau³, L Forty⁴, K Gordon-Smith⁵, A Di Florio^{4

6}, P H Lee^{3

7

8}, E J Bromet⁹, P F Buckley¹⁰, M A Escamilla¹¹, A H Fanous^{12

13}, L J Fochtmann⁹, D S Lehrer¹⁴, D Malaspina¹⁵, S R Marder¹⁶, C P Morley^{17

18

19}, H Nicolini^{20

21}, D O Perkins⁶, J J Rakofsky²², M H Rapaport²², H Medeiros²³, J L Sobell²³, E K Green²⁴, L Backlund^{25

26}, S E Bergen^{3

27}, A Juréus²⁷, M Schalling²⁶, P Lichtenstein²⁷, P Roussos^{1

2

28}, J A Knowles^{23

29}, I Jones⁴, L A Jones⁵, C M Hultman^{1

27}, R H Perlis³⁰, S M Purcell^{1

2

28}, S A McCarroll^{3

31}, C N Pato^{23

29}, M T Pato^{23

29}, N Craddock⁴, M Landén^{27

32}, J W Smoller^{3

7

8

33}, P Sklar^{1

2

28}

Affiliations

¹ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.
² 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.
³ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁴ MRC Centre for Psychiatric Genetics and Genomics, Cardiff Unviersity, Cardiff, UK.
⁵ Department of Psychological Medicine, University of Worcester, Worcester, UK.
⁶ Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁷ Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
⁸ Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
⁹ Department of Psychiatry, Stony Brook University, Stony Brook, NY, USA.
¹⁰ Department of Psychiatry, Georgia Regents University Medical Center, Augusta, GA, USA.
¹¹ Center of Excellence in Neuroscience, Department of Psychiatry, Texas Tech University Health Sciences Center at El Paso, El Paso, TX, USA.
¹² Department of Psychiatry, Veterans Administration Medical Center, Washington, DC, USA.
¹³ Department of Psychiatry, Georgetown University, Washington, DC, USA.
¹⁴ Department of Psychiatry, Wright State University, Dayton, OH, USA.
¹⁵ Department of Psychiatry, New York University, New York, NY, USA.
¹⁶ Department of Psychiatry, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁷ Department of Psychiatry and Behavioral Science, State University of New York, Upstate Medical University, Syracuse, NY, USA.
¹⁸ Departments of Family Medicine, State University of New York, Upstate Medical University, Syracuse, NY, USA.
¹⁹ Department of Public Health and Preventive Medicine, State University of New York, Upstate Medical University, Syracuse, NY, USA.
²⁰ Center for Genomic Sciences, Universidad Autónoma de la Ciudad de México, Mexico City, Mexico.
²¹ Department of Psychiatry, Carracci Medical Group, Mexico City, Mexico.
²² Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
²³ Department of Psychiatry and the Behavioral Sciences, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.
²⁴ School of Biomedical and Health Sciences, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth University, Plymouth, UK.
²⁵ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
²⁶ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
²⁷ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁸ Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.
²⁹ Zilkha Neurogenetic Institute, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.
³⁰ Center for Experimental Therapeutics, Massachusetts General Hospital, Boston, MA, USA.
³¹ Department of Genetics, Harvard Medical School, Boston, MA, USA.
³² Institute of Neuroscience and Physiology, Sahlgenska Academy at the Gothenburg University, Gothenburg, Sweden.
³³ Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.

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.

MeSH terms

Aminopeptidases / genetics
Ankyrins / genetics
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
Genome-Wide Association Study
Genotype
Humans
Nerve Tissue Proteins / genetics
Nuclear Proteins / genetics
Phenotype
Polymorphism, Single Nucleotide
Psychotic Disorders / genetics*
Psychotic Disorders / psychology

Substances

ADD3 protein, human
ANK3 protein, human
Ankyrins
CACNA1C protein, human
Calcium Channels, L-Type
Calmodulin-Binding Proteins
Cytoskeletal Proteins
Nerve Tissue Proteins
Nuclear Proteins
SYNE1 protein, human
Aminopeptidases
X-Pro aminopeptidase

Abstract

MeSH terms

Substances

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