Journal article
Exome Sequencing of Familial Bipolar Disorder
JAMA psychiatry (Chicago, Ill.), Vol.73(6), pp.590-597
06/01/2016
DOI: 10.1001/jamapsychiatry.2016.0251
PMCID: PMC5600716
PMID: 27120077
Abstract
Complex disorders, such as bipolar disorder (BD), likely result from the influence of both common and rare susceptibility alleles. While common variation has been widely studied, rare variant discovery has only recently become feasible with next-generation sequencing.
To utilize a combined family-based and case-control approach to exome sequencing in BD using multiplex families as an initial discovery strategy, followed by association testing in a large case-control meta-analysis.
We performed exome sequencing of 36 affected members with BD from 8 multiplex families and tested rare, segregating variants in 3 independent case-control samples consisting of 3541 BD cases and 4774 controls.
We used penalized logistic regression and 1-sided gene-burden analyses to test for association of rare, segregating damaging variants with BD. Permutation-based analyses were performed to test for overall enrichment with previously identified gene sets.
We found 84 rare (frequency <1%), segregating variants that were bioinformatically predicted to be damaging. These variants were found in 82 genes that were enriched for gene sets previously identified in de novo studies of autism (19 observed vs. 10.9 expected, P = .0066) and schizophrenia (11 observed vs. 5.1 expected, P = .0062) and for targets of the fragile X mental retardation protein (FMRP) pathway (10 observed vs. 4.4 expected, P = .0076). The case-control meta-analyses yielded 19 genes that were nominally associated with BD based either on individual variants or a gene-burden approach. Although no gene was individually significant after correction for multiple testing, this group of genes continued to show evidence for significant enrichment of de novo autism genes (6 observed vs 2.6 expected, P = .028).
Our results are consistent with the presence of prominent locus and allelic heterogeneity in BD and suggest that very large samples will be required to definitively identify individual rare variants or genes conferring risk for this disorder. However, we also identify significant associations with gene sets composed of previously discovered de novo variants in autism and schizophrenia, as well as targets of the FRMP pathway, providing preliminary support for the overlap of potential autism and schizophrenia risk genes with rare, segregating variants in families with BD.
Details
- Title: Subtitle
- Exome Sequencing of Familial Bipolar Disorder
- Creators
- Fernando S Goes - Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MarylandVirginia L Willour - Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa CityMehdi Pirooznia - Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MarylandJames B Potash - Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa CityJennifer S Parla - Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New YorkMelissa Kramer - Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New YorkElena Ghiban - Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New YorkSenem Mavruk - Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New YorkYun-Ching Chen - Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, Maryland4Institute for Computational Medicine, The Johns Hopkins University, Baltimore, MarylandEric T Monson - Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa CityRachel Karchin - Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, Maryland4Institute for Computational Medicine, The Johns Hopkins University, Baltimore, MarylandMatthew Flickinger - Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann ArborAdam E Locke - Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann ArborShawn E Levy - HudsonAlpha Institute of Biotechnology, Huntsville, AlabamaLaura J Scott - Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann ArborMichael Boehnke - Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann ArborEli Stahl - Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York9Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New YorkJennifer L Moran - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MassachusettsChristina M Hultman - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SwedenMikael Landén - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden12Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, SwedenShaun M Purcell - Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York9Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York10Stanley Center for PsychiatPamela Sklar - Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York9Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York15Friedman Brain Institute, IPeter P Zandi - Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MarylandW Richard McCombie - Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
- Resource Type
- Journal article
- Publication Details
- JAMA psychiatry (Chicago, Ill.), Vol.73(6), pp.590-597
- Publisher
- United States
- DOI
- 10.1001/jamapsychiatry.2016.0251
- PMID
- 27120077
- PMCID
- PMC5600716
- ISSN
- 2168-622X
- eISSN
- 2168-6238
- Grant note
- U01 MH105653 / NIMH NIH HHS R00 MH086049 / NIMH NIH HHS R01 MH094145 / NIMH NIH HHS K01 MH093809 / NIMH NIH HHS R01 MH087992 / NIMH NIH HHS T32 GM007337 / NIGMS NIH HHS R01 MH087979 / NIMH NIH HHS R01 MH106531 / NIMH NIH HHS T32 HG000040 / NHGRI NIH HHS
- Language
- English
- Date published
- 06/01/2016
- Academic Unit
- Psychiatry; Iowa Neuroscience Institute
- Record Identifier
- 9984070573402771
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