Journal article
Efficient region-based test strategy uncovers genetic risk factors for functional outcome in bipolar disorder
European neuropsychopharmacology, Vol.29(1), pp.156-170
01/2019
DOI: 10.1016/j.euroneuro.2018.10.005
PMID: 30503783
Abstract
Genome-wide association studies of case-control status have advanced the understanding of the genetic basis of psychiatric disorders. Further progress may be gained by increasing sample size but also by new analysis strategies that advance the exploitation of existing data, especially for clinically important quantitative phenotypes. The functionally-informed efficient region-based test strategy (FIERS) introduced herein uses prior knowledge on biological function and dependence of genotypes within a powerful statistical framework with improved sensitivity and specificity for detecting consistent genetic effects across studies. As proof of concept, FIERS was used for the first genome-wide single nucleotide polymorphism (SNP)-based investigation on bipolar disorder (BD) that focuses on an important aspect of disease course, the functional outcome. FIERS identified a significantly associated locus on chromosome 15 (hg38: chr15:48965004 – 49464789 bp) with consistent effect strength between two independent studies (GAIN/TGen: European Americans, BOMA: Germans; n = 1592 BD patients in total). Protective and risk haplotypes were found on the most strongly associated SNPs. They contain a CTCF binding site (rs586758); CTCF sites are known to regulate sets of genes within a chromatin domain. The rs586758 – rs2086256 – rs1904317 haplotype is located in the promoter flanking region of the COPS2 gene, close to microRNA4716, and the EID1, SHC4, DTWD1 genes as plausible biological candidates. While implication with BD is novel, COPS2, EID1, and SHC4 are known to be relevant for neuronal differentiation and function and DTWD1 for psychopharmacological side effects. The test strategy FIERS that enabled this discovery is equally applicable for tag SNPs and sequence data.
Details
- Title: Subtitle
- Efficient region-based test strategy uncovers genetic risk factors for functional outcome in bipolar disorder
- Creators
- Monika Budde - Institute of Psychiatric Phenomics and Genomics, University Hospital, LMU Munich, Nussbaumstr. 7, Munich 80336, GermanyStefanie Friedrichs - Department of Genetic Epidemiology, University Medical Center Göttingen, Georg-August-University, Göttingen 37099, GermanyNey Alliey-Rodriguez - Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637, United StatesSeth Ament - Institute for Systems Biology, Seattle, WA 98109, United StatesJudith A Badner - Department of Psychiatry, Rush University Medical Center, Chicago, IL 60612, United StatesWade H Berrettini - Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, United StatesCinnamon S Bloss - University of California San Diego, La Jolla, CA 92093, United StatesWilliam Byerley - Department of Psychiatry, University of California at San Francisco, San Francisco, CA 94103, United StatesSven Cichon - Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel 4031, SwitzerlandAshley L Comes - Institute of Psychiatric Phenomics and Genomics, University Hospital, LMU Munich, Nussbaumstr. 7, Munich 80336, GermanyWilliam Coryell - University of Iowa Hospitals and Clinics, Iowa City, IA 52242, United StatesDavid W Craig - The Translational Genomics Research Institute, Phoenix, AZ 85004, United StatesFranziska Degenhardt - Institute of Human Genetics, School of Medicine & University Hospital Bonn, University of Bonn, Bonn 53127, GermanyHoward J Edenberg - Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, United StatesTatiana Foroud - Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United StatesAndreas J Forstner - Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel 4031, SwitzerlandJosef Frank - Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim 68159, GermanyElliot S Gershon - Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637, United StatesFernando S Goes - Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21287, United StatesTiffany A Greenwood - Department of Psychiatry, University of California San Diego, San Diego, CA 92093, United StatesYiran Guo - Center for Applied Genomics, Children's Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA 19104, United StatesMaria Hipolito - Department of Psychiatry and Behavioral Sciences, Howard University Hospital, Washington, DC 20060, United StatesLeroy Hood - Institute for Systems Biology, Seattle, WA 98109, United StatesBrendan J Keating - Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-5159, United StatesDaniel L Koller - Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United StatesWilliam B Lawson - Dell Medical School, University of Texas at Austin, Austin, TX 78723, United StatesChunyu Liu - SUNY Upstate Medical University, Syracuse, NY 13210, United StatesPamela B Mahon - Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21287, United StatesMelvin G McInnis - Department of Psychiatry, University of Michigan, Ann Arbor, MI 48105, United StatesFrancis J McMahon - U.S. Department of Health & Human Services, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20894, United StatesSandra M Meier - Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim 68159, GermanyThomas W Mühleisen - Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel 4031, SwitzerlandSarah S Murray - Scripps Genomic Medicine & The Scripps Translational Sciences Institute (STSI), La Jolla, CA 92037, United StatesCaroline M Nievergelt - Department of Psychiatry, University of California San Diego, San Diego, CA 92093, United StatesJohn I Nurnberger - Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, United StatesEvaristus A Nwulia - Department of Psychiatry and Behavioral Sciences, Howard University Hospital, Washington, DC 20060, United StatesJames B Potash - Department of Psychiatry, Carver College of Medicine, University of Iowa School of Medicine, Iowa City, IA 52242, United StatesDanjuma Quarless - University of California San Diego, La Jolla, CA 92093, United StatesJohn Rice - Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United StatesJared C Roach - Institute for Systems Biology, Seattle, WA 98109, United StatesWilliam A Scheftner - Rush University Medical Center, Chicago, IL 60612, United StatesNicholas J Schork - University of California San Diego, La Jolla, CA 92093, United StatesTatyana Shekhtman - Department of Psychiatry, University of California San Diego, San Diego, CA 92093, United StatesPaul D Shilling - Department of Psychiatry, University of California San Diego, San Diego, CA 92093, United StatesErin N Smith - Scripps Genomic Medicine & The Scripps Translational Sciences Institute (STSI), La Jolla, CA 92037, United StatesFabian Streit - Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim 68159, GermanyJana Strohmaier - Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim 68159, GermanySzabolcs Szelinger - The Translational Genomics Research Institute, Phoenix, AZ 85004, United StatesJens Treutlein - Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim 68159, GermanyStephanie H Witt - Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim 68159, GermanyPeter P Zandi - Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, United StatesPeng Zhang - Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, United StatesSebastian Zöllner - Department of Psychiatry, University of Michigan, Ann Arbor, MI 48105, United StatesHeike Bickeböller - Department of Genetic Epidemiology, University Medical Center Göttingen, Georg-August-University, Göttingen 37099, GermanyPeter G Falkai - Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich 80336, GermanyJohn R Kelsoe - Department of Psychiatry, University of California San Diego, San Diego, CA 92093, United StatesMarkus M Nöthen - Institute of Human Genetics, School of Medicine & University Hospital Bonn, University of Bonn, Bonn 53127, GermanyMarcella Rietschel - Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim 68159, GermanyThomas G Schulze - Institute of Psychiatric Phenomics and Genomics, University Hospital, LMU Munich, Nussbaumstr. 7, Munich 80336, GermanyDörthe Malzahn - Department of Genetic Epidemiology, University Medical Center Göttingen, Georg-August-University, Göttingen 37099, Germany
- Resource Type
- Journal article
- Publication Details
- European neuropsychopharmacology, Vol.29(1), pp.156-170
- DOI
- 10.1016/j.euroneuro.2018.10.005
- PMID
- 30503783
- NLM abbreviation
- Eur Neuropsychopharmacol
- ISSN
- 0924-977X
- eISSN
- 1873-7862
- Publisher
- Elsevier B.V
- Grant note
- DOI: 10.13039/501100001711, name: Swiss National Science Foundation, award: 310030_156791; name: European Union's Horizon 2020 Research and Innovation Programme, award: 7202070
- Language
- English
- Date published
- 01/2019
- Academic Unit
- Psychiatry
- Record Identifier
- 9984003478702771
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