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Original Investigation |

Exome Sequencing of Familial Bipolar Disorder

Fernando S. Goes, MD1; Mehdi Pirooznia, MD, PhD1; Jennifer S. Parla, PhD2; Melissa Kramer, BS2; Elena Ghiban, BA2; Senem Mavruk, BA2; Yun-Ching Chen, PhD3,4; Eric T. Monson, BS5; Virginia L. Willour, PhD5; Rachel Karchin, PhD3,4; Matthew Flickinger, PhD6; Adam E. Locke, PhD6; Shawn E. Levy, PhD7; Laura J. Scott, PhD6; Michael Boehnke, PhD6; Eli Stahl, PhD8,9; Jennifer L. Moran, PhD10; Christina M. Hultman, PhD11; Mikael Landén, MD11,12; Shaun M. Purcell, PhD8,9,10,13,14; Pamela Sklar, MD, PhD8,9,15; Peter P. Zandi, PhD16; W. Richard McCombie, PhD2; James B. Potash, MD, MPH5
[+] Author Affiliations
1Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland
2Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
3Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, Maryland
4Institute for Computational Medicine, The Johns Hopkins University, Baltimore, Maryland
5Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City
6Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor
7HudsonAlpha Institute of Biotechnology, Huntsville, Alabama
8Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York
9Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York
10Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
11Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
12Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
13Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
14Analytic and Translational Genetics Unit, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston
15Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
16Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
JAMA Psychiatry. 2016;73(6):590-597. doi:10.1001/jamapsychiatry.2016.0251.
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Importance  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.

Objective  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  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.

Results  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).

Conclusions and Relevance  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.

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Pedigrees of the 8 Families With Bipolar Disorder (BD) Selected for Sequencing

Dashed lines indicate the individuals who were sequenced. A square represents a male individual; a circle, a female individual; shading, an affected individual; and a slash mark, a deceased individual.

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