Journal article
Detecting significant genotype–phenotype association rules in bipolar disorder: market research meets complex genetics
International Journal of Bipolar Disorders, Vol.6(1), pp.1-10
12/2018
DOI: 10.1186/s40345-018-0132-x
PMCID: PMC6230336
PMID: 30415424
Abstract
Disentangling the etiology of common, complex diseases is a major challenge in genetic research. For bipolar disorder (BD), several genome-wide association studies (GWAS) have been performed. Similar to other complex disorders, major breakthroughs in explaining the high heritability of BD through GWAS have remained elusive. To overcome this dilemma, genetic research into BD, has embraced a variety of strategies such as the formation of large consortia to increase sample size and sequencing approaches. Here we advocate a complementary approach making use of already existing GWAS data: a novel data mining procedure to identify yet undetected genotype–phenotype relationships. We adapted association rule mining, a data mining technique traditionally used in retail market research, to identify frequent and characteristic genotype patterns showing strong associations to phenotype clusters. We applied this strategy to three independent GWAS datasets from 2835 phenotypically characterized patients with BD. In a discovery step, 20,882 candidate association rules were extracted.Two of these rules—one associated with eating disorder and the other with anxiety—remained significant in an independent dataset after robust correction for multiple testing. Both showed considerable effect sizes (odds ratio ~ 3.4 and 3.0, respectively) and support previously reported molecular biological findings.Our approach detected novel specific genotype–phenotype relationships in BD that were missed by standard analyses like GWAS. While we developed and applied our method within the context of BD gene discovery, it may facilitate identifying highly specific genotype–phenotype relationships in subsets of genome-wide data sets of other complex phenotype with similar epidemiological properties and challenges to gene discovery efforts.
Details
- Title: Subtitle
- Detecting significant genotype–phenotype association rules in bipolar disorder: market research meets complex genetics
- Creators
- René Breuer - 0000 0001 2190 4373 grid.7700.0 Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health Medical Faculty Mannheim/Heidelberg University Mannheim GermanyManuel Mattheisen - 0000 0001 1958 8658 grid.8379.5 Department of Psychiatry, Psychosomatics, and Psychotherapy University of Würzburg Würzburg GermanyJosef Frank - 0000 0001 2190 4373 grid.7700.0 Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health Medical Faculty Mannheim/Heidelberg University Mannheim GermanyBertram Krumm - 0000 0001 2190 4373 grid.7700.0 Department for Biostatistics, Central Institute of Mental Health Medical Faculty Mannheim/Heidelberg University Mannheim GermanyJens Treutlein - 0000 0001 2190 4373 grid.7700.0 Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health Medical Faculty Mannheim/Heidelberg University Mannheim GermanyLayla Kassem - Human Genetics Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health US Department of Health and Human Services Bethesda MD USAJana Strohmaier - 0000 0001 2190 4373 grid.7700.0 Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health Medical Faculty Mannheim/Heidelberg University Mannheim GermanyStefan Herms - 0000 0001 2240 3300 grid.10388.32 Institute of Human Genetics University of Bonn Bonn GermanyThomas Mühleisen - 0000 0001 2240 3300 grid.10388.32 Institute of Human Genetics University of Bonn Bonn GermanyFranziska Degenhardt - 0000 0001 2240 3300 grid.10388.32 Institute of Human Genetics University of Bonn Bonn GermanySven Cichon - 0000 0004 1937 0642 grid.6612.3 Department of Biomedicine University of Basel Basel SwitzerlandMarkus Nöthen - 0000 0001 2240 3300 grid.10388.32 Institute of Human Genetics University of Bonn Bonn GermanyGeorge Karypis - 0000000419368657 grid.17635.36 Department of Computer Science & Engineering University of Minnesota Minneapolis MN USAJohn Kelsoe - 0000 0001 2107 4242 grid.266100.3 Department of Psychiatry University of California San Diego San Diego USATiffany Greenwood - 0000 0001 2034 1839 grid.21155.32 BGI-Shenzhen, Beishan Industrial Zone Yantian District Shenzhen ChinaCaroline Nievergelt - 0000 0001 2107 4242 grid.266100.3 Department of Psychiatry University of California San Diego San Diego USAPaul Shilling - 0000 0001 2107 4242 grid.266100.3 Department of Psychiatry University of California San Diego San Diego USATatyana Shekhtman - 0000 0001 2107 4242 grid.266100.3 Department of Psychiatry University of California San Diego San Diego USAHoward Edenberg - 0000 0001 2287 3919 grid.257413.6 Department of Biochemistry and Molecular Biology Indiana University School of Medicine Indianapolis USADavid Craig - 0000 0004 0507 3225 grid.250942.8 The Translational Genomics Research Institute Phoenix USASzabolcs Szelinger - 0000 0004 0507 3225 grid.250942.8 The Translational Genomics Research Institute Phoenix USAJohn Nurnberger - 0000 0001 2287 3919 grid.257413.6 Department of Psychiatry Indiana University School of Medicine Indianapolis USAElliot Gershon - 0000 0004 1936 7822 grid.170205.1 Department of Psychiatry and Behavioral Neuroscience University of Chicago Chicago USANey Alliey-Rodriguez - 0000 0004 1936 7822 grid.170205.1 Department of Psychiatry and Behavioral Neuroscience University of Chicago Chicago USAPeter Zandi - 0000 0001 2171 9311 grid.21107.35 Department of Mental Health John Hopkins Bloomberg School of Public Health Baltimore USAFernando Goes - 0000 0001 2171 9311 grid.21107.35 Department of Psychiatry and Behavioral Sciences John Hopkins School of Medicine Baltimore USANicholas Schork - grid.469946.0 J. Craig Venter Institute La Jolla USAErin Smith - 0000 0001 2107 4242 grid.266100.3 Department of Pediatrics and Rady’s Children’s Hospital, School of Medicine University of California San Diego La Jolla USADaniel Koller - 0000 0001 2287 3919 grid.257413.6 Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis USAPeng Zhang - 0000000086837370 grid.214458.e Department of Computational Medicine and Bioinformatics University of Michigan Ann Arbor USAJudith Badner - 0000 0004 1936 7822 grid.170205.1 Department of Psychiatry and Behavioral Neuroscience University of Chicago Chicago USAWade Berrettini - 0000 0004 1936 8972 grid.25879.31 Department of Psychiatry University of Pennsylvania Philadelphia USACinnamon Bloss - 0000 0001 2107 4242 grid.266100.3 University of California, San Diego La Jolla USAWilliam Byerley - 0000 0001 2297 6811 grid.266102.1 Department of Psychiatry University of California at San Francisco San Francisco USAWilliam Coryell - 0000 0004 0434 9816 grid.412584.e University of Iowa Hospitals and Clinics Iowa City USATatiana Foroud - 0000 0001 2287 3919 grid.257413.6 Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis USAYirin Guo - 0000 0001 0680 8770 grid.239552.a Center for Applied Genomics Children’s Hospital of Philadelphia, Abramson Research Center Philadelphia USAMaria Hipolito - 0000 0004 0427 2775 grid.411399.7 Department of Psychiatry and Behavioral Sciences Howard University Hospital Washington USABrendan Keating - 0000 0004 1936 8972 grid.25879.31 Institute for Translational Medicine and Therapeutics, School of Medicine University of Pennsylvania Philadelphia PA USAWilliam Lawson - 0000 0004 1936 9924 grid.89336.37 Dell Medical School University of Texas at Austin Austin USAChunyu Liu - 0000 0001 2175 0319 grid.185648.6 Department of Psychiatry University of Illinois at Chicago Chicago USAPamela Mahon - 0000 0001 2171 9311 grid.21107.35 Department of Psychiatry and Behavioral Sciences John Hopkins School of Medicine Baltimore USAMelvin McInnis - 0000000086837370 grid.214458.e Department of Psychiatry University of Michigan Ann Arbor USASarah Murray - 0000 0001 2107 4242 grid.266100.3 Department of Pathology University of California San Diego La Jolla USAEvaristus Nwulia - 0000 0004 1936 9924 grid.89336.37 Dell Medical School University of Texas at Austin Austin USAJames Potash - 0000 0004 1936 8294 grid.214572.7 Department of Psychiatry, Carver College of Medicine University of Iowa School of Medicine Iowa City USAJohn Rice - 0000 0001 2355 7002 grid.4367.6 Department of Psychiatry Washington University School of Medicine in St. Louis St. Louis USAWilliam Scheftner - 0000 0001 0705 3621 grid.240684.c Rush University Medical Center Chicago USASebastian Zöllner - 0000000086837370 grid.214458.e Department of Computational Medicine and Bioinformatics University of Michigan Ann Arbor USAFrancis McMahon - Human Genetics Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health US Department of Health and Human Services Bethesda MD USAMarcella Rietschel - 0000 0001 2190 4373 grid.7700.0 Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health Medical Faculty Mannheim/Heidelberg University Mannheim GermanyThomas Schulze - 0000 0004 1936 973X grid.5252.0 Institute of Psychiatric Phenomics and Genomics (IPPG) Ludwig-Maximilians-University, Munich Nußbaumstr. 7 80336 Munich Germany
- Resource Type
- Journal article
- Publication Details
- International Journal of Bipolar Disorders, Vol.6(1), pp.1-10
- DOI
- 10.1186/s40345-018-0132-x
- PMID
- 30415424
- PMCID
- PMC6230336
- NLM abbreviation
- Int J Bipolar Disord
- ISSN
- 2194-7511
- eISSN
- 2194-7511
- Publisher
- Springer Berlin Heidelberg; Berlin/Heidelberg
- Grant note
- 01GS08144; 01GS08147 / Bundesministerium für Bildung und Forschung (http://dx.doi.org/10.13039/501100002347) 242257 / FP7 Health (http://dx.doi.org/10.13039/100011272)
- Language
- English
- Date published
- 12/2018
- Academic Unit
- Psychiatry
- Record Identifier
- 9984003973902771
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