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Eur Neuropsychopharmacol. 2019 Jan;29(1):156-170. doi: 10.1016/j.euroneuro.2018.10.005. Epub 2018 Nov 29.

Efficient region-based test strategy uncovers genetic risk factors for functional outcome in bipolar disorder.

Author information

1
Institute of Psychiatric Phenomics and Genomics, University Hospital, LMU Munich, Nussbaumstr. 7, Munich 80336, Germany.
2
Department of Genetic Epidemiology, University Medical Center Göttingen, Georg-August-University, Göttingen 37099, Germany.
3
Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637, United States.
4
Institute for Systems Biology, Seattle, WA 98109, United States.
5
Department of Psychiatry, Rush University Medical Center, Chicago, IL 60612, United States.
6
Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, United States.
7
University of California San Diego, La Jolla, CA 92093, United States.
8
Department of Psychiatry, University of California at San Francisco, San Francisco, CA 94103, United States.
9
Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel 4031, Switzerland; Institute of Medical Genetics and Pathology, University Hospital Basel, Basel 4031, Switzerland; Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich 52425, Germany.
10
Institute of Psychiatric Phenomics and Genomics, University Hospital, LMU Munich, Nussbaumstr. 7, Munich 80336, Germany; International Max Planck Research School for Translational Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
11
University of Iowa Hospitals and Clinics, Iowa City, IA 52242, United States.
12
The Translational Genomics Research Institute, Phoenix, AZ 85004, United States.
13
Institute of Human Genetics, School of Medicine & University Hospital Bonn, University of Bonn, Bonn 53127, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn 53127, Germany.
14
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, United States; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
15
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
16
Institute of Human Genetics, School of Medicine & University Hospital Bonn, University of Bonn, Bonn 53127, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn 53127, Germany; Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel 4031, Switzerland; Department of Psychiatry (UPK), University of Basel, Basel 4012, Switzerland.
17
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim 68159, Germany.
18
Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21287, United States.
19
Department of Psychiatry, University of California San Diego, San Diego, CA 92093, United States.
20
Center for Applied Genomics, Children's Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA 19104, United States; Beijing Genomics Institute at Shenzhen, Shenzhen 518083, China.
21
Department of Psychiatry and Behavioral Sciences, Howard University Hospital, Washington, DC 20060, United States.
22
Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-5159, United States; Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-5158, United States.
23
Dell Medical School, University of Texas at Austin, Austin, TX 78723, United States.
24
SUNY Upstate Medical University, Syracuse, NY 13210, United States.
25
Department of Psychiatry, University of Michigan, Ann Arbor, MI 48105, United States.
26
U.S. Department of Health & Human Services, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20894, United States.
27
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim 68159, Germany; National Centre for Register-Based Research, Aarhus University, Aarhus V 8210, Denmark.
28
Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich 52425, Germany; Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel 4031, Switzerland.
29
Scripps Genomic Medicine & The Scripps Translational Sciences Institute (STSI), La Jolla, CA 92037, United States; Department of Pathology, University of California San Diego, La Jolla, CA 92093, United States.
30
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
31
Department of Psychiatry, Carver College of Medicine, University of Iowa School of Medicine, Iowa City, IA 52242, United States.
32
J. Craig Venter Institute, La Jolla, CA 92037, United States; University of California San Diego, La Jolla, CA 92093, United States.
33
Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States.
34
Rush University Medical Center, Chicago, IL 60612, United States.
35
J. Craig Venter Institute, La Jolla, CA 92037, United States; The Translational Genomics Research Institute, Phoenix, AZ 85004, United States; University of California San Diego, La Jolla, CA 92093, United States.
36
Scripps Genomic Medicine & The Scripps Translational Sciences Institute (STSI), La Jolla, CA 92037, United States; Department of Pediatrics and Rady's Children's Hospital, School of Medicine, University of California San Diego, La Jolla, CA 92037, United States.
37
Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, United States.
38
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, United States.
39
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, United States; Department of Psychiatry, University of Michigan, Ann Arbor, MI 48105, United States.
40
Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich 80336, Germany.
41
Institute of Psychiatric Phenomics and Genomics, University Hospital, LMU Munich, Nussbaumstr. 7, Munich 80336, Germany; Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim 68159, Germany; Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21287, United States; U.S. Department of Health & Human Services, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20894, United States. Electronic address: Thomas.Schulze@med.uni-muenchen.de.
42
Department of Genetic Epidemiology, University Medical Center Göttingen, Georg-August-University, Göttingen 37099, Germany. Electronic address: mz@mzbiostatistics.de.

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.

KEYWORDS:

Functional annotation; Global Assessment of Functioning; Hypothesis-driven GWAS; Kernel score test; Linkage disequilibrium; Psychiatric disorder

PMID:
30503783
DOI:
10.1016/j.euroneuro.2018.10.005
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