Bipolar disorder with binge eating behavior: A genome-wide association study implicates PRR5-ARHGAP8

Susan L. McElroy, Stacey J. Winham, Alfredo B. Cuellar-Barboza, Colin L. Colby, Ada Man Choi Ho, Hugues Sicotte, Beth R. Larrabee, Scott Crow, Mark A. Frye, Joanna M. Biernacka

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Bipolar disorder (BD) is associated with binge eating behavior (BE), and both conditions are heritable. Previously, using data from the Genetic Association Information Network (GAIN) study of BD, we performed genome-wide association (GWA) analyses of BD with BE comorbidity. Here, utilizing data from the Mayo Clinic BD Biobank (969 BD cases, 777 controls), we performed a GWA analysis of a BD subtype defined by BE, and case-only analysis comparing BD subjects with and without BE. We then performed a meta-analysis of the Mayo and GAIN results. The meta-analysis provided genome-wide significant evidence of association between single nucleotide polymorphisms (SNPs) in PRR5-ARHGAP8 and BE in BD cases (rs726170 OR = 1.91, P = 3.05E-08). In the meta-analysis comparing cases with BD with comorbid BE vs. non-BD controls, a genome-wide significant association was observed at SNP rs111940429 in an intergenic region near PPP1R2P5 (p = 1.21E-08). PRR5-ARHGAP8 is a read-through transcript resulting in a fusion protein of PRR5 and ARHGAP8. PRR5 encodes a subunit of mTORC2, a serine/threonine kinase that participates in food intake regulation, while ARHGAP8 encodes a member of the RhoGAP family of proteins that mediate cross-talk between Rho GTPases and other signaling pathways. Without BE information in controls, it is not possible to determine whether the observed association reflects a risk factor for BE in general, risk for BE in individuals with BD, or risk of a subtype of BD with BE. The effect of PRR5-ARHGAP8 on BE risk thus warrants further investigation.

Original languageEnglish (US)
Article number40
JournalTranslational psychiatry
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

Bibliographical note

Funding Information:
This study was supported by funding from the Marriott Family Foundation and the Mayo Clinic Center for Individualized Medicine. Funding support for the Whole Genome Association Study of Bipolar Disorder was provided by the National Institute of Mental Health (NIMH) and the genotyping of samples was provided through the Genetic Association Information Network (GAIN). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI/SAIC-Frederick, Inc. (SAIC-F) subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute, Inc. Biorepository operations were funded through an SAIC-F subcontract to Van Andel Institute (10ST1035). Additional data repository and project management were provided by SAIC-F (HHSN261200800001E). The Brain Bank was supported by a supplement to University of Miami grants DA006227 and DA033684 and to contract N01MH000028. Statistical Methods development grants were made to the University of Geneva (MH090941 and MH101814), the University of Chicago (MH090951, MH090937, MH101820, MH101825), the University of North Carolina-Chapel Hill (MH090936 and MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University St Louis (MH101810), and the University of Pennsylvania (MH101822). The UK Brain Expression Consortium (BRAINEAC) was supported by the MRC through the MRC Sudden Death Brain Bank (C. S.), a Project Grant (G0901254 to J. H. and M. W.) and Training Fellowship (G0802462 to M. R.). D.T. was supported by the King Faisal Specialist Hospital and Research Centre, Saudi Arabia. Computing facilities used at King's College London were supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London.

Funding Information:
This study was supported by funding from the Marriott Family Foundation and the Mayo Clinic Center for Individualized Medicine. Funding support for the Whole Genome Association Study of Bipolar Disorder was provided by the National Institute of Mental Health (NIMH) and the genotyping of samples was provided through the Genetic Association Information Network (GAIN). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI/ SAIC-Frederick, Inc. (SAIC-F) subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute, Inc. Biorepository operations were funded through an SAIC-F subcontract to Van Andel Institute (10ST1035). Additional data repository and project management were provided by SAIC-F (HHSN261200800001E). The Brain Bank was supported by a supplement to University of Miami grants DA006227 and DA033684 and to contract N01MH000028. Statistical Methods development grants were made to the University of Geneva (MH090941 and MH101814), the University of Chicago (MH090951, MH090937, MH101820, MH101825), the University of North Carolina–Chapel Hill (MH090936 and MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University St Louis (MH101810), and the University of Pennsylvania (MH101822). The UK Brain Expression Consortium (BRAINEAC) was supported by the MRC through the MRC Sudden Death Brain Bank (C. S.), a Project Grant (G0901254 to J. H. and M. W.) and Training Fellowship (G0802462 to M. R.). D.T. was supported by the King Faisal Specialist Hospital and Research Centre, Saudi Arabia. Computing facilities used at King’s College London were supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London.

Funding Information:
Dr. S. L. Mc. E has been a consultant to or member of the scientific advisory board of Avanir, Bracket, F. Hoffmann-La Roche Ltd., MedAvante, Mitsubishi Tanabe Pharma Corporation, Myriad, Naurex, Novo Nordisk, Shire, and Sunovion. She has also been a principal or coinvestigatoron studies sponsored by Alkermes, Allergan, Azevan Pharmaceuticals, Forest, Marriott Foundation, Myriad, National Institute of Mental Health, Naurex, Novo Nordisk, Shire, Sunovion, and Takeda Pharmaceutical Company Limited. She is also an inventor on United States Patent No. 6,323,236 B2, Use of Sulfamate Derivatives for Treating Impulse ControlDisorders, and along with the patent’s assignee, University of Cincinnati, Cincinnati, Ohio, hasreceived payments from Johnson and Johnson, which has exclusive rights under the patent. Dr. M. A. F. has received grant support from Assurex Health, Myriad, Pfizer, Marriott Foundationand Mayo Foundation; has been a consultant to Janssen Global Services, LLC, Mitsubishi Tanabe Pharma Corporation, Myriad, Sunovion, and Teva Pharmaceuticals; has received CME/Travel Support/presentation from CME Outfitters Inc. and Sunovion. The remaining authors declare that they have no conflict of interest.

Publisher Copyright:
© 2018 The Author(s).

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