Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

CONVERGE Consortium, CARDIoGRAM Consortium, GERAD1 Consortium

Research output: Contribution to journalArticle

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 (US)
Pages (from-to)325-335
Number of pages11
JournalBiological Psychiatry
Volume81
Issue number4
DOIs
StatePublished - Feb 15 2017
Externally publishedYes

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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

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

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Genome-wide Association for Major Depression Through Age at Onset Stratification : Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. / CONVERGE Consortium, CARDIoGRAM Consortium, GERAD1 Consortium.

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

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.",
keywords = "Age at onset, GWAS, Heterogeneity, Major depressive disorder, Polygenic scoring, Stratification",
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T1 - Genome-wide Association for Major Depression Through Age at Onset Stratification

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

AU - CONVERGE Consortium, CARDIoGRAM Consortium, GERAD1 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 - Potash, James Bennett

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 - Age at onset

KW - GWAS

KW - Heterogeneity

KW - Major depressive disorder

KW - Polygenic scoring

KW - Stratification

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