Genome-wide Association for Major Depression Through Age at Onset Stratification

Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

Robert A Power, Katherine E Tansey, Henriette Nørmølle Buttenschøn, Sarah Cohen-Woods, Tim Bigdeli, Lynsey S Hall, Zoltán Kutalik, S Hong Lee, Stephan Ripke, Stacy Steinberg, Alexander Teumer, Alexander Viktorin, Naomi R Wray, Volker Arolt, Bernard T Baune, Dorret I Boomsma, Anders D Børglum, Enda M Byrne, Enrique Castelao, Nick Craddock & 31 others Ian W Craig, Udo Dannlowski, Ian J Deary, Franziska Degenhardt, Andreas J Forstner, Scott D Gordon, Hans J Grabe, Jakob Grove, Steven P Hamilton, Caroline Hayward, Andrew C Heath, Lynne J Hocking, Georg Homuth, Jouke J Hottenga, Stefan Kloiber, Jesper Krogh, Mikael Landén, Maren Lang, Douglas F Levinson, Paul Lichtenstein, Susanne Lucae, Donald J MacIntyre, Pamela Madden, Patrik K E Magnusson, Nicholas G Martin, Andrew M McIntosh, Christel M Middeldorp, Yuri Milaneschi, Grant W Montgomery, Ole Mors, CONVERGE Consortium, CARDIoGRAM Consortium, GERAD1 Consortium

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset.

METHODS: Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer's disease, and coronary artery disease.

RESULTS: We identified one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11-1.21, p = 5.2 × 10(-11)). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD.

CONCLUSIONS: We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder.

Original languageEnglish
Pages (from-to)325-335
Number of pages11
JournalBiological Psychiatry
Volume81
Issue number4
Early online date24 May 2016
DOIs
Publication statusPublished - 15 Feb 2017

Fingerprint

Major Depressive Disorder
Genomics
Age of Onset
Psychiatry
Genome
Depression
Bipolar Disorder
Schizophrenia
Genome-Wide Association Study
Genetic Predisposition to Disease
Mood Disorders
Sample Size
Single Nucleotide Polymorphism
Meta-Analysis
Coronary Artery Disease
Alzheimer Disease
Odds Ratio
Confidence Intervals
Phenotype

Keywords

  • GWAS
  • Age at onset
  • Heterogeneity
  • Major depressive disorder
  • Polygenic scoring
  • Stratification
  • Journal Article

Cite this

Power, R. A., Tansey, K. E., Buttenschøn, H. N., Cohen-Woods, S., Bigdeli, T., Hall, L. S., ... CONVERGE Consortium, CARDIoGRAM Consortium, GERAD1 Consortium (2017). Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. Biological Psychiatry, 81(4), 325-335. https://doi.org/10.1016/j.biopsych.2016.05.010

Genome-wide Association for Major Depression Through Age at Onset Stratification : Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. / Power, Robert A; Tansey, Katherine E; Buttenschøn, Henriette Nørmølle; Cohen-Woods, Sarah; Bigdeli, Tim; Hall, Lynsey S; Kutalik, Zoltán; Lee, S Hong; Ripke, Stephan; Steinberg, Stacy; Teumer, Alexander; Viktorin, Alexander; Wray, Naomi R; Arolt, Volker; Baune, Bernard T; Boomsma, Dorret I; Børglum, Anders D; Byrne, Enda M; Castelao, Enrique; Craddock, Nick; Craig, Ian W; Dannlowski, Udo; Deary, Ian J; Degenhardt, Franziska; Forstner, Andreas J; Gordon, Scott D; Grabe, Hans J; Grove, Jakob; Hamilton, Steven P; Hayward, Caroline; Heath, Andrew C; Hocking, Lynne J; Homuth, Georg; Hottenga, Jouke J; Kloiber, Stefan; Krogh, Jesper; Landén, Mikael; Lang, Maren; Levinson, Douglas F; Lichtenstein, Paul; Lucae, Susanne; MacIntyre, Donald J; Madden, Pamela; Magnusson, Patrik K E; Martin, Nicholas G; McIntosh, Andrew M; Middeldorp, Christel M; Milaneschi, Yuri; Montgomery, Grant W; Mors, Ole; CONVERGE Consortium, CARDIoGRAM Consortium, GERAD1 Consortium.

In: Biological Psychiatry, Vol. 81, No. 4, 15.02.2017, p. 325-335.

Research output: Contribution to journalArticle

Power, RA, Tansey, KE, Buttenschøn, HN, Cohen-Woods, S, Bigdeli, T, Hall, LS, Kutalik, Z, Lee, SH, Ripke, S, Steinberg, S, Teumer, A, Viktorin, A, Wray, NR, Arolt, V, Baune, BT, Boomsma, DI, Børglum, AD, Byrne, EM, Castelao, E, Craddock, N, Craig, IW, Dannlowski, U, Deary, IJ, Degenhardt, F, Forstner, AJ, Gordon, SD, Grabe, HJ, Grove, J, Hamilton, SP, Hayward, C, Heath, AC, Hocking, LJ, Homuth, G, Hottenga, JJ, Kloiber, S, Krogh, J, Landén, M, Lang, M, Levinson, DF, Lichtenstein, P, Lucae, S, MacIntyre, DJ, Madden, P, Magnusson, PKE, Martin, NG, McIntosh, AM, Middeldorp, CM, Milaneschi, Y, Montgomery, GW, Mors, O & CONVERGE Consortium, CARDIoGRAM Consortium, GERAD1 Consortium 2017, 'Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium', Biological Psychiatry, vol. 81, no. 4, pp. 325-335. https://doi.org/10.1016/j.biopsych.2016.05.010
Power, Robert A ; Tansey, Katherine E ; Buttenschøn, Henriette Nørmølle ; Cohen-Woods, Sarah ; Bigdeli, Tim ; Hall, Lynsey S ; Kutalik, Zoltán ; Lee, S Hong ; Ripke, Stephan ; Steinberg, Stacy ; Teumer, Alexander ; Viktorin, Alexander ; Wray, Naomi R ; Arolt, Volker ; Baune, Bernard T ; Boomsma, Dorret I ; Børglum, Anders D ; Byrne, Enda M ; Castelao, Enrique ; Craddock, Nick ; Craig, Ian W ; Dannlowski, Udo ; Deary, Ian J ; Degenhardt, Franziska ; Forstner, Andreas J ; Gordon, Scott D ; Grabe, Hans J ; Grove, Jakob ; Hamilton, Steven P ; Hayward, Caroline ; Heath, Andrew C ; Hocking, Lynne J ; Homuth, Georg ; Hottenga, Jouke J ; Kloiber, Stefan ; Krogh, Jesper ; Landén, Mikael ; Lang, Maren ; Levinson, Douglas F ; Lichtenstein, Paul ; Lucae, Susanne ; MacIntyre, Donald J ; Madden, Pamela ; Magnusson, Patrik K E ; Martin, Nicholas G ; McIntosh, Andrew M ; Middeldorp, Christel M ; Milaneschi, Yuri ; Montgomery, Grant W ; Mors, Ole ; CONVERGE Consortium, CARDIoGRAM Consortium, GERAD1 Consortium. / Genome-wide Association for Major Depression Through Age at Onset Stratification : Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. In: Biological Psychiatry. 2017 ; Vol. 81, No. 4. pp. 325-335.
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title = "Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium",
abstract = "BACKGROUND: Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset.METHODS: Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer's disease, and coronary artery disease.RESULTS: We identified one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, odds ratio: 1.16, 95{\%} confidence interval: 1.11-1.21, p = 5.2 × 10(-11)). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD.CONCLUSIONS: We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder.",
keywords = "GWAS, Age at onset, Heterogeneity, Major depressive disorder, Polygenic scoring, Stratification, Journal Article",
author = "Power, {Robert A} and Tansey, {Katherine E} and Buttensch{\o}n, {Henriette N{\o}rm{\o}lle} and Sarah Cohen-Woods and Tim Bigdeli and Hall, {Lynsey S} and Zolt{\'a}n Kutalik and Lee, {S Hong} and Stephan Ripke and Stacy Steinberg and Alexander Teumer and Alexander Viktorin and Wray, {Naomi R} and Volker Arolt and Baune, {Bernard T} and Boomsma, {Dorret I} and B{\o}rglum, {Anders D} and Byrne, {Enda M} and Enrique Castelao and Nick Craddock and Craig, {Ian W} and Udo Dannlowski and Deary, {Ian J} and Franziska Degenhardt and Forstner, {Andreas J} and Gordon, {Scott D} and Grabe, {Hans J} and Jakob Grove and Hamilton, {Steven P} and Caroline Hayward and Heath, {Andrew C} and Hocking, {Lynne J} and Georg Homuth and Hottenga, {Jouke J} and Stefan Kloiber and Jesper Krogh and Mikael Land{\'e}n and Maren Lang and Levinson, {Douglas F} and Paul Lichtenstein and Susanne Lucae and MacIntyre, {Donald J} and Pamela Madden and Magnusson, {Patrik K E} and Martin, {Nicholas G} and McIntosh, {Andrew M} and Middeldorp, {Christel M} and Yuri Milaneschi and Montgomery, {Grant W} and Ole Mors and {CONVERGE Consortium, CARDIoGRAM Consortium, GERAD1 Consortium}",
note = "The PGC was funded by National Institute of Mental Health (NIMH) Grant Nos. MH085520 (to PFS) and MH080403. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization Grant No. NWO 480-05-003 (to D. Posthuma) and the department of Psychology, Vrije Universiteit Amsterdam along with a supplement from the Dutch Brain Foundation. The Bonn/Mannheim GWAS was supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Genome Research Network Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia Grant Nos. 01GS08144 and 01GS08147, under the auspices of the National Genome Research Network plus, and through the Integrated Network Integrated Understanding of Causes and Mechanisms in Mental Disorders, under the auspices of the e:Med Programme Grant Nos. 01ZX1314A and 01ZX1314G. The Bonn/Mannheim GWAS was also supported by the German Research Foundation (DFG) Grant Nos. FOR2107, RI908/11-1, and NO246/10-1. The GenRED GWAS project was supported by NIMH R01 Grant Nos. MH061686 (to DFL), MH059542 (to W.H. Coryell), MH075131 (W.B. Lawson), MH059552 (JBP), MH059541 (W.A. Scheftner), and MH060912 (MMW). Max Planck Institute of Psychiatry MARS study was supported by the BMBF Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression by Grant No. 01ES0811. Genotyping was supported by the Bavarian Ministry of Commerce, and the BMBF in the framework of the National Genome Research Network by Grant Nos. NGFN2 and NGFN-Plus, FKZ 01GS0481 and 01GS08145. The Netherlands Study of Depression and Anxiety and the Netherlands Twin Register contributed to Genetic Association Information Network (GAIN)-MDD and to MDD2000. Funding for NTR/NESDA was from the following: the Netherlands Organization for Scientific Research (MagW/ZonMW Grant Nos. 904-61-090, 985-10- 002, 904-61-193, 480-04-004, 400-05-717, 912-100-20; Spinozapremie Grant No. 56-464-14192; Geestkracht program Grant No. 10-000-1002); the Center for Medical Systems Biology (NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure, Vrije Universiteit’s Institutes for Health and Care Research and Neuroscience Campus Amsterdam, BIC/BioAssist/RK (Grant No. 2008.024); the European Science Foundation (Grant No. EU/QLRT-2001-01254); the European Community’s Seventh Framework Program (Grant No. FP7/2007-2013); ENGAGE (Grant No. HEALTH-F4-2007-201413); and the European Science Council (Grant No. ERC 230374). Genotyping was funded in part by the GAIN of the Foundation for the US National Institutes of Health, and analysis was supported by grants from GAIN and the NIMH (Grant No. MH081802). Funding for the QIMR samples was provided by the Australian National Health and Medical Research Council (Grant Nos. 241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613608, 613674, 619667), the Australian Research Council (Grant Nos. FT0991360, FT0991022), the FP-5 GenomEUtwin Project (Grant No. QLG2-CT-2002-01254), and the US National Institutes of Health (Grant Nos. AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951), and the Center for Inherited Disease Research (Baltimore, MD). RADIANT was funded by the following: a joint grant from the UK Medical Research Council and GlaxoSmithKline (Grant No. G0701420); the National Institute for Health Research Specialist Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation Trust and the Institute of Psychiatry, King’s College London; the UK Medical Research Council (Grant No. G0000647), and the Marie Curie Industry-Academia Partnership and Pathways (Grant No. 286213). The GENDEP study was funded by a European Commission Framework 6 grant (EC Contract Ref.: LSHB-CT-2003-503428). Genotyping of STAR*D was supported by NIMH Grant No. MH072802 (to SPH). STAR*D was funded by NIMH Grant No. N01MH90003 to the University of Texas Southwestern Medical Center at Dallas (to A.J. Rush). The CoLaus/PsyCoLaus study was supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (Grant Nos. 3200B0–105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, 33CS30-148401) and two grants from GlaxoSmithKline Clinical Genetics. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grant Nos. 01ZZ9603, 01ZZ0103, 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg–West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (Grant No. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg–West Pomerania. SHIP-LEGEND is funded by the DFG (Grant No. GR 1912/5-1). The TwinGene study was supported by the Swedish Ministry for Higher Education, the Swedish Research Council (Grant No. M-2005-1112), GenomEUtwin (Grant Nos. EU/QLRT-2001-01254, QLG2-CT-2002-01254), the Swedish Foundation for Strategic Research and the US National Institutes of Health (Grant No. U01 DK066134). The collection of PRISME control subjects and genotyping of the 883 Danish control subjects was supported by grants from The Danish Strategic Research Council, The Stanley Research Foundation, and H. Lundbeck A/S. The Muenster Depression cohorts were supported by the European Union (Grant No. N Health-F2-2008-222963) and by grants from the DFG (Grant Nos. FOR 2107 and DA1151/5-1 [to UD]), Innovative Medizinische Forschung of the Medical Faculty of Mu¨nster (Grant Nos. DA120903, DA111107, and DA211012 [all to UD]). Generation Scotland is supported by a Wellcome Trust Strategic Award “Stratifying Resilience and Depression Longitudinally” (Reference No.: 104036/Z/14/Z) and core support from the Chief Scientist Office of the Scottish Government Health Directorates (Grant No. CZD/16/6) and the Scottish Funding Council (Grant No. HR03006). Supplementary material cited in this article is available online at http:// dx.doi.org/10.1016/j.biopsych.2016.05.010.",
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pages = "325--335",
journal = "Biological Psychiatry",
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}

TY - JOUR

T1 - Genome-wide Association for Major Depression Through Age at Onset Stratification

T2 - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

AU - Power, Robert A

AU - Tansey, Katherine E

AU - Buttenschøn, Henriette Nørmølle

AU - Cohen-Woods, Sarah

AU - Bigdeli, Tim

AU - Hall, Lynsey S

AU - Kutalik, Zoltán

AU - Lee, S Hong

AU - Ripke, Stephan

AU - Steinberg, Stacy

AU - Teumer, Alexander

AU - Viktorin, Alexander

AU - Wray, Naomi R

AU - Arolt, Volker

AU - Baune, Bernard T

AU - Boomsma, Dorret I

AU - Børglum, Anders D

AU - Byrne, Enda M

AU - Castelao, Enrique

AU - Craddock, Nick

AU - Craig, Ian W

AU - Dannlowski, Udo

AU - Deary, Ian J

AU - Degenhardt, Franziska

AU - Forstner, Andreas J

AU - Gordon, Scott D

AU - Grabe, Hans J

AU - Grove, Jakob

AU - Hamilton, Steven P

AU - Hayward, Caroline

AU - Heath, Andrew C

AU - Hocking, Lynne J

AU - Homuth, Georg

AU - Hottenga, Jouke J

AU - Kloiber, Stefan

AU - Krogh, Jesper

AU - Landén, Mikael

AU - Lang, Maren

AU - Levinson, Douglas F

AU - Lichtenstein, Paul

AU - Lucae, Susanne

AU - MacIntyre, Donald J

AU - Madden, Pamela

AU - Magnusson, Patrik K E

AU - Martin, Nicholas G

AU - McIntosh, Andrew M

AU - Middeldorp, Christel M

AU - Milaneschi, Yuri

AU - Montgomery, Grant W

AU - Mors, Ole

AU - CONVERGE Consortium, CARDIoGRAM Consortium, GERAD1 Consortium

N1 - The PGC was funded by National Institute of Mental Health (NIMH) Grant Nos. MH085520 (to PFS) and MH080403. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Scientific Organization Grant No. NWO 480-05-003 (to D. Posthuma) and the department of Psychology, Vrije Universiteit Amsterdam along with a supplement from the Dutch Brain Foundation. The Bonn/Mannheim GWAS was supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Genome Research Network Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia Grant Nos. 01GS08144 and 01GS08147, under the auspices of the National Genome Research Network plus, and through the Integrated Network Integrated Understanding of Causes and Mechanisms in Mental Disorders, under the auspices of the e:Med Programme Grant Nos. 01ZX1314A and 01ZX1314G. The Bonn/Mannheim GWAS was also supported by the German Research Foundation (DFG) Grant Nos. FOR2107, RI908/11-1, and NO246/10-1. The GenRED GWAS project was supported by NIMH R01 Grant Nos. MH061686 (to DFL), MH059542 (to W.H. Coryell), MH075131 (W.B. Lawson), MH059552 (JBP), MH059541 (W.A. Scheftner), and MH060912 (MMW). Max Planck Institute of Psychiatry MARS study was supported by the BMBF Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression by Grant No. 01ES0811. Genotyping was supported by the Bavarian Ministry of Commerce, and the BMBF in the framework of the National Genome Research Network by Grant Nos. NGFN2 and NGFN-Plus, FKZ 01GS0481 and 01GS08145. The Netherlands Study of Depression and Anxiety and the Netherlands Twin Register contributed to Genetic Association Information Network (GAIN)-MDD and to MDD2000. Funding for NTR/NESDA was from the following: the Netherlands Organization for Scientific Research (MagW/ZonMW Grant Nos. 904-61-090, 985-10- 002, 904-61-193, 480-04-004, 400-05-717, 912-100-20; Spinozapremie Grant No. 56-464-14192; Geestkracht program Grant No. 10-000-1002); the Center for Medical Systems Biology (NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure, Vrije Universiteit’s Institutes for Health and Care Research and Neuroscience Campus Amsterdam, BIC/BioAssist/RK (Grant No. 2008.024); the European Science Foundation (Grant No. EU/QLRT-2001-01254); the European Community’s Seventh Framework Program (Grant No. FP7/2007-2013); ENGAGE (Grant No. HEALTH-F4-2007-201413); and the European Science Council (Grant No. ERC 230374). Genotyping was funded in part by the GAIN of the Foundation for the US National Institutes of Health, and analysis was supported by grants from GAIN and the NIMH (Grant No. MH081802). Funding for the QIMR samples was provided by the Australian National Health and Medical Research Council (Grant Nos. 241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613608, 613674, 619667), the Australian Research Council (Grant Nos. FT0991360, FT0991022), the FP-5 GenomEUtwin Project (Grant No. QLG2-CT-2002-01254), and the US National Institutes of Health (Grant Nos. AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951), and the Center for Inherited Disease Research (Baltimore, MD). RADIANT was funded by the following: a joint grant from the UK Medical Research Council and GlaxoSmithKline (Grant No. G0701420); the National Institute for Health Research Specialist Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation Trust and the Institute of Psychiatry, King’s College London; the UK Medical Research Council (Grant No. G0000647), and the Marie Curie Industry-Academia Partnership and Pathways (Grant No. 286213). The GENDEP study was funded by a European Commission Framework 6 grant (EC Contract Ref.: LSHB-CT-2003-503428). Genotyping of STAR*D was supported by NIMH Grant No. MH072802 (to SPH). STAR*D was funded by NIMH Grant No. N01MH90003 to the University of Texas Southwestern Medical Center at Dallas (to A.J. Rush). The CoLaus/PsyCoLaus study was supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (Grant Nos. 3200B0–105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, 33CS30-148401) and two grants from GlaxoSmithKline Clinical Genetics. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grant Nos. 01ZZ9603, 01ZZ0103, 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg–West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (Grant No. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg–West Pomerania. SHIP-LEGEND is funded by the DFG (Grant No. GR 1912/5-1). The TwinGene study was supported by the Swedish Ministry for Higher Education, the Swedish Research Council (Grant No. M-2005-1112), GenomEUtwin (Grant Nos. EU/QLRT-2001-01254, QLG2-CT-2002-01254), the Swedish Foundation for Strategic Research and the US National Institutes of Health (Grant No. U01 DK066134). The collection of PRISME control subjects and genotyping of the 883 Danish control subjects was supported by grants from The Danish Strategic Research Council, The Stanley Research Foundation, and H. Lundbeck A/S. The Muenster Depression cohorts were supported by the European Union (Grant No. N Health-F2-2008-222963) and by grants from the DFG (Grant Nos. FOR 2107 and DA1151/5-1 [to UD]), Innovative Medizinische Forschung of the Medical Faculty of Mu¨nster (Grant Nos. DA120903, DA111107, and DA211012 [all to UD]). Generation Scotland is supported by a Wellcome Trust Strategic Award “Stratifying Resilience and Depression Longitudinally” (Reference No.: 104036/Z/14/Z) and core support from the Chief Scientist Office of the Scottish Government Health Directorates (Grant No. CZD/16/6) and the Scottish Funding Council (Grant No. HR03006). Supplementary material cited in this article is available online at http:// dx.doi.org/10.1016/j.biopsych.2016.05.010.

PY - 2017/2/15

Y1 - 2017/2/15

N2 - BACKGROUND: Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset.METHODS: Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer's disease, and coronary artery disease.RESULTS: We identified one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11-1.21, p = 5.2 × 10(-11)). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD.CONCLUSIONS: We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder.

AB - BACKGROUND: Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset.METHODS: Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer's disease, and coronary artery disease.RESULTS: We identified one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11-1.21, p = 5.2 × 10(-11)). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD.CONCLUSIONS: We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder.

KW - GWAS

KW - Age at onset

KW - Heterogeneity

KW - Major depressive disorder

KW - Polygenic scoring

KW - Stratification

KW - Journal Article

U2 - 10.1016/j.biopsych.2016.05.010

DO - 10.1016/j.biopsych.2016.05.010

M3 - Article

VL - 81

SP - 325

EP - 335

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

IS - 4

ER -