TY - JOUR
T1 - Efficient region-based test strategy uncovers genetic risk factors for functional outcome in bipolar disorder
AU - Budde, Monika
AU - Friedrichs, Stefanie
AU - Alliey-Rodriguez, Ney
AU - Ament, Seth
AU - Badner, Judith A.
AU - Berrettini, Wade H.
AU - Bloss, Cinnamon S.
AU - Byerley, William
AU - Cichon, Sven
AU - Comes, Ashley L.
AU - Coryell, William
AU - Craig, David W.
AU - Degenhardt, Franziska
AU - Edenberg, Howard J.
AU - Foroud, Tatiana
AU - Forstner, Andreas J.
AU - Frank, Josef
AU - Gershon, Elliot S.
AU - Goes, Fernando S.
AU - Greenwood, Tiffany A.
AU - Guo, Yiran
AU - Hipolito, Maria
AU - Hood, Leroy
AU - Keating, Brendan J.
AU - Koller, Daniel L.
AU - Lawson, William B.
AU - Liu, Chunyu
AU - Mahon, Pamela B.
AU - McInnis, Melvin G.
AU - McMahon, Francis J.
AU - Meier, Sandra M.
AU - Mühleisen, Thomas W.
AU - Murray, Sarah S.
AU - Nievergelt, Caroline M.
AU - Nurnberger, John I.
AU - Nwulia, Evaristus A.
AU - Potash, James B.
AU - Quarless, Danjuma
AU - Rice, John
AU - Roach, Jared C.
AU - Scheftner, William A.
AU - Schork, Nicholas J.
AU - Shekhtman, Tatyana
AU - Shilling, Paul D.
AU - Smith, Erin N.
AU - Streit, Fabian
AU - Strohmaier, Jana
AU - Szelinger, Szabolcs
AU - Treutlein, Jens
AU - Witt, Stephanie H.
AU - Zandi, Peter P.
AU - Zhang, Peng
AU - Zöllner, Sebastian
AU - Bickeböller, Heike
AU - Falkai, Peter G.
AU - Kelsoe, John R.
AU - Nöthen, Markus M.
AU - Rietschel, Marcella
AU - Schulze, Thomas G.
AU - Malzahn, Dörthe
N1 - Funding Information:
This research was funded by the Deutsche Forschungsgemeinschaft DFG (grants Klinische Forschergruppe (KFO) 241/ PsyCourse SCHU 1603/4-1, SCHU 1603/5-1, BI 576/5-1, FA 241/16-1 and SCHU 1603/7-1; Research Training Group “Scaling Problems in Statistics” RTG 1644; FOR2107: RI908/11-1 and NO246/10-1; as well as HEIDE DFG RI908/8-1), and by the German Federal Ministry of Education and Research (BMBF, grants: IntegraMent 01ZX1314G, 01ZX1314A, 01ZX1314K, SysMedAlcoholism 01ZX1311A). Thomas G. Schulze was also supported by the Dr. Lisa-Oehler-Foundation (Kassel, Germany).
Funding Information:
Sven Cichon acknowledges support by the Swiss National Science Foundation (SNSF grant 310030_156791 to SC) and from the European Union's Horizon 2020 Research and Innovation Programme under Grant Agreement No. 7202070 (HBP SGA1).
Funding Information:
Genotype and phenotype data of the European American BD sample were provided by the Collaborative Genomic Study of Bipolar Disorder and the Bipolar Genome Study. These consortia acknowledge funding support by the National Institute of Mental Health (NIMH) and genotyping provided through the Genetic Association Information Network (GAIN). Data and biomaterials were collected in or as part of the following projects that participated in the NIMH Bipolar Disorder Genetics Initiative. From 1991 to 1998, the principal Investigators and co-investigators were: Indiana University, Indianapolis, IN, U01 MH46282, John Nurnberger, M.D., Ph.D., Marvin Miller, M.D., Howard J. Edenberg, Ph.D. and Elizabeth Bowman, M.D.; Washington University, St. Louis, MO, U01 MH46280, Theodore Reich, M.D., Allison Goate, Ph.D., and John Rice, Ph.D.; Johns Hopkins University, Baltimore, MD, U01 MH46274, J. Raymond DePaulo, Jr., M.D., Sylvia Simpson, M.D., MPH, and Colin Stine, Ph.D.; NIMH Intramural Research Program, Clinical Neurogenetics Branch, Bethesda, MD, Elliot Gershon, M.D., Diane Kazuba, B.A., and Elizabeth Maxwell, M.S.W. From 1999 to 2007 (NIMH studies 1 and 40), the principal investigators and co-investigators were: Indiana University, Indianapolis, IN, R01 MH59545, John Nurnberger, M.D., Ph.D., Marvin J. Miller, M.D., Elizabeth S. Bowman, M.D., N. Leela Rau, M.D., P. Ryan Moe, M.D., Nalini Samavedy, M.D., Rif El-Mallakh, M.D. (at University of Louisville), Husseini Manji, M.D. (at Wayne State University, Johnson and Johnson), Debra A. Glitz, M.D. (at Wayne State University), Eric T. Meyer, Ph.D., M.S. (at Oxford University, UK), Carrie Smiley, R.N., Tatiana Foroud, Ph.D., Leah Flury, M.S., Danielle M. Dick, Ph.D. (at Virginia Commonwealth University), Howard J. Edenberg, Ph.D.; Washington University, St. Louis, MO, R01 MH059534, John Rice, Ph.D, Theodore Reich, M.D., Allison Goate, Ph.D., Laura Bierut, M.D. K02 DA21237; Johns Hopkins University, Baltimore, MD, R01 MH59533, Melvin McInnis, M.D., J. Raymond DePaulo, Jr., M.D., Dean F. MacKinnon, M.D., Francis M. Mondimore, M.D., James B. Potash, M.D., Peter P. Zandi, Ph.D, Dimitrios Avramopoulos, and Jennifer Payne; University of Pennsylvania, PA, R01 MH59553, Wade Berrettini, M.D., Ph.D.; University of California at Irvine, University of California at San Francisco, CA, R01 MH60068, William Byerley, M.D., Mark Vawter, M.D., and Sophia Vinogradov, M.D.; University of Iowa, IA, R01 MH059548, William Coryell, M.D., and Raymond Crowe, M.D.; University of Chicago, IL, R01 MH59535, Elliot Gershon, M.D., Judith Badner, Ph.D., Francis McMahon, M.D., Chunyu Liu, Ph.D., Alan Sanders, M.D., Maria Caserta, Steven Dinwiddie, M.D., Tu Nguyen, Donna Harakal; University of California at San Diego, CA, R01 MH59567, John Kelsoe, M.D., Rebecca McKinney, B.A.; Rush University, IL, R01 MH059556, William Scheftner, M.D., Howard M. Kravitz, D.O., M.P.H., Diana Marta, B.S., Annette Vaughn-Brown, M.S.N., R.N., and Laurie Bederow, M.A.; NIMH Intramural Research Program, Bethesda, MD, 1Z01MH002810-01, Francis J. McMahon, M.D., Layla Kassem, PsyD, Sevilla Detera-Wadleigh, Ph.D, Lisa Austin, Ph.D, Dennis L. Murphy, M.D.; Howard University, MH070013, William B. Lawson, M.D., Ph.D., Evaristus Nwulia, M.D., and Maria Hipolito, M.D. Furthermore, the Bipolar Genome Study was supported by the National Institutes of Health grants P50CA89392 from the National Cancer Institute and 5K02DA021237 from the National Institute of Drug Abuse.
Publisher Copyright:
© 2018 The Author(s)
PY - 2019/1
Y1 - 2019/1
N2 - 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.
AB - 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.
KW - Functional annotation
KW - Global Assessment of Functioning
KW - Hypothesis-driven GWAS
KW - Kernel score test
KW - Linkage disequilibrium
KW - Psychiatric disorder
UR - http://www.scopus.com/inward/record.url?scp=85057380167&partnerID=8YFLogxK
U2 - 10.1016/j.euroneuro.2018.10.005
DO - 10.1016/j.euroneuro.2018.10.005
M3 - Article
C2 - 30503783
AN - SCOPUS:85057380167
SN - 0924-977X
VL - 29
SP - 156
EP - 170
JO - European Neuropsychopharmacology
JF - European Neuropsychopharmacology
IS - 1
ER -