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

Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder.

Author information

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.

PMID:
28072414
PMCID:
PMC5545718
DOI:
10.1038/tp.2016.242
[Indexed for MEDLINE]
Free PMC Article

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