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

Monika Budde, Stefanie Friedrichs, Ney Alliey-Rodriguez, Seth Ament, Judith A. Badner, Wade H. Berrettini, Cinnamon S. Bloss, William Byerley, Sven Cichon, Ashley L. Comes, William Coryell, David W. Craig, Franziska Degenhardt, Howard J. Edenberg, Tatiana Foroud, Andreas J. Forstner, Josef Frank, Elliot S. Gershon, Fernando S. Goes, Tiffany A. GreenwoodYiran Guo, Maria Hipolito, Leroy Hood, Brendan J. Keating, Daniel L. Koller, William B. Lawson, Chunyu Liu, Pamela B. Mahon, Melvin G. McInnis, Francis J. McMahon, Sandra M. Meier, Thomas W. Mühleisen, Sarah S. Murray, Caroline M. Nievergelt, John I. Nurnberger, Evaristus A. Nwulia, James B. Potash, Danjuma Quarless, John Rice, Jared C. Roach, William A. Scheftner, Nicholas J. Schork, Tatyana Shekhtman, Paul D. Shilling, Erin N. Smith, Fabian Streit, Jana Strohmaier, Szabolcs Szelinger, Jens Treutlein, Stephanie H. Witt, Peter P. Zandi, Peng Zhang, Sebastian Zöllner, Heike Bickeböller, Peter G. Falkai, John R. Kelsoe, Markus M. Nöthen, Marcella Rietschel, Thomas G. Schulze, Dörthe Malzahn

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)156-170
Number of pages15
JournalEuropean Neuropsychopharmacology
Volume29
Issue number1
DOIs
StatePublished - Jan 2019

Fingerprint

Bipolar Disorder
Single Nucleotide Polymorphism
Haplotypes
Genes
Chromosomes, Human, Pair 15
Genome-Wide Association Study
Genetic Promoter Regions
Sample Size
Chromatin
Psychiatry
Binding Sites
Genotype
Genome
Phenotype
Sensitivity and Specificity

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Biological Psychiatry
  • Pharmacology (medical)

Cite this

Budde, M., Friedrichs, S., Alliey-Rodriguez, N., Ament, S., Badner, J. A., Berrettini, W. H., ... Malzahn, D. (2019). Efficient region-based test strategy uncovers genetic risk factors for functional outcome in bipolar disorder. European Neuropsychopharmacology, 29(1), 156-170. https://doi.org/10.1016/j.euroneuro.2018.10.005

Efficient region-based test strategy uncovers genetic risk factors for functional outcome in bipolar disorder. / Budde, Monika; Friedrichs, Stefanie; Alliey-Rodriguez, Ney; Ament, Seth; Badner, Judith A.; Berrettini, Wade H.; Bloss, Cinnamon S.; Byerley, William; Cichon, Sven; Comes, Ashley L.; Coryell, William; Craig, David W.; Degenhardt, Franziska; Edenberg, Howard J.; Foroud, Tatiana; Forstner, Andreas J.; Frank, Josef; Gershon, Elliot S.; Goes, Fernando S.; Greenwood, Tiffany A.; Guo, Yiran; Hipolito, Maria; Hood, Leroy; Keating, Brendan J.; Koller, Daniel L.; Lawson, William B.; Liu, Chunyu; Mahon, Pamela B.; McInnis, Melvin G.; McMahon, Francis J.; Meier, Sandra M.; Mühleisen, Thomas W.; Murray, Sarah S.; Nievergelt, Caroline M.; Nurnberger, John I.; Nwulia, Evaristus A.; Potash, James B.; Quarless, Danjuma; Rice, John; Roach, Jared C.; Scheftner, William A.; Schork, Nicholas J.; Shekhtman, Tatyana; Shilling, Paul D.; Smith, Erin N.; Streit, Fabian; Strohmaier, Jana; Szelinger, Szabolcs; Treutlein, Jens; Witt, Stephanie H.; Zandi, Peter P.; Zhang, Peng; Zöllner, Sebastian; Bickeböller, Heike; Falkai, Peter G.; Kelsoe, John R.; Nöthen, Markus M.; Rietschel, Marcella; Schulze, Thomas G.; Malzahn, Dörthe.

In: European Neuropsychopharmacology, Vol. 29, No. 1, 01.2019, p. 156-170.

Research output: Contribution to journalArticle

Budde, M, Friedrichs, S, Alliey-Rodriguez, N, Ament, S, Badner, JA, Berrettini, WH, Bloss, CS, Byerley, W, Cichon, S, Comes, AL, Coryell, W, Craig, DW, Degenhardt, F, Edenberg, HJ, Foroud, T, Forstner, AJ, Frank, J, Gershon, ES, Goes, FS, Greenwood, TA, Guo, Y, Hipolito, M, Hood, L, Keating, BJ, Koller, DL, Lawson, WB, Liu, C, Mahon, PB, McInnis, MG, McMahon, FJ, Meier, SM, Mühleisen, TW, Murray, SS, Nievergelt, CM, Nurnberger, JI, Nwulia, EA, Potash, JB, Quarless, D, Rice, J, Roach, JC, Scheftner, WA, Schork, NJ, Shekhtman, T, Shilling, PD, Smith, EN, Streit, F, Strohmaier, J, Szelinger, S, Treutlein, J, Witt, SH, Zandi, PP, Zhang, P, Zöllner, S, Bickeböller, H, Falkai, PG, Kelsoe, JR, Nöthen, MM, Rietschel, M, Schulze, TG & Malzahn, D 2019, 'Efficient region-based test strategy uncovers genetic risk factors for functional outcome in bipolar disorder', European Neuropsychopharmacology, vol. 29, no. 1, pp. 156-170. https://doi.org/10.1016/j.euroneuro.2018.10.005
Budde, Monika ; Friedrichs, Stefanie ; Alliey-Rodriguez, Ney ; Ament, Seth ; Badner, Judith A. ; Berrettini, Wade H. ; Bloss, Cinnamon S. ; Byerley, William ; Cichon, Sven ; Comes, Ashley L. ; Coryell, William ; Craig, David W. ; Degenhardt, Franziska ; Edenberg, Howard J. ; Foroud, Tatiana ; Forstner, Andreas J. ; Frank, Josef ; Gershon, Elliot S. ; Goes, Fernando S. ; Greenwood, Tiffany A. ; Guo, Yiran ; Hipolito, Maria ; Hood, Leroy ; Keating, Brendan J. ; Koller, Daniel L. ; Lawson, William B. ; Liu, Chunyu ; Mahon, Pamela B. ; McInnis, Melvin G. ; McMahon, Francis J. ; Meier, Sandra M. ; Mühleisen, Thomas W. ; Murray, Sarah S. ; Nievergelt, Caroline M. ; Nurnberger, John I. ; Nwulia, Evaristus A. ; Potash, James B. ; Quarless, Danjuma ; Rice, John ; Roach, Jared C. ; Scheftner, William A. ; Schork, Nicholas J. ; Shekhtman, Tatyana ; Shilling, Paul D. ; Smith, Erin N. ; Streit, Fabian ; Strohmaier, Jana ; Szelinger, Szabolcs ; Treutlein, Jens ; Witt, Stephanie H. ; Zandi, Peter P. ; Zhang, Peng ; Zöllner, Sebastian ; Bickeböller, Heike ; Falkai, Peter G. ; Kelsoe, John R. ; Nöthen, Markus M. ; Rietschel, Marcella ; Schulze, Thomas G. ; Malzahn, Dörthe. / Efficient region-based test strategy uncovers genetic risk factors for functional outcome in bipolar disorder. In: European Neuropsychopharmacology. 2019 ; Vol. 29, No. 1. pp. 156-170.
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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.",
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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

PY - 2019/1

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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.

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KW - Hypothesis-driven GWAS

KW - Kernel score test

KW - Linkage disequilibrium

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