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

Robert Power; Katherine Tansey; Henriette Nørmølle  Buttenschøn; Sarah  Cohen-Woods; Tim Bigdeli; Psychiatric Genomics Consortium MDD Working Group; Lynsey S. Hall; Zoltán Kutalik; S. Hong Lee; Stephan Ripke; Stacy Steinberg; Alexander Teumer; Alexander Viktorin; Naomi R Wray; Bernard T. Baune; Dorret I Boomsma; Anders D Børglum; Enda M. Byrne; Enrique Castelao; Nick Craddock; Ian Craig; Udo Dannlowski; Ian J. Deary; Franziska Degenhardt; Andreas J. Forstner; Scott D. Gordon; Hans Joergen Grabe; Jakob Grove; Steven P. Hamilton; Caroline Hayward; Andrew C. Heath; Lynne J. Hocking; Georg Homuth; Jouke J. Hottenga; Stefan Kloiber; Jesper Krogh; Mikael Landen; Maren  Lang; Douglas F. Levinson; Paul Lichtenstein; Susanne Lucae; Pamela A.F. Madden; Donald J Macintyre; Patrik K.E.  Magnusson; Nicholas G. Martin; Andrew M  McIntosh; Christel M. Middeldorp; Yuri Milaneschi; Grant W. Montgomery; Ole Mors; Bertram Müller-Myhsok; Dale R. Nyholt; Hogni Oskarsson; Michael J. Owen; Sandosh Padmanabhan; Brenda W.J.H.   Penninx; Michele L. Pergadia; David J Porteous; James B. Potash; Martin Preisig; Margarita Rivera Sanchez; Jianxin Shi; Engilbert Sigurdsson; Stanley I Shyn; Johannes H. Smit; Blair H. Smith; Hreinn Stefansson; Kari Stefansson; Jana Strohmaier; Patrick F. Sullivan; Pippa  Thomson; Thorgeir E. Thorgeirsson; Sandra Van der Auwera Affiliations; Myrna M. Weissman; Cardiogram Consortium; Gerome Daniel Breen; Cathryn Mair Lewis; CONVERGE Consortium; GERAD1 Consortium:

doi:10.1016/j.biopsych.2016.05.010

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

Robert Power, Katherine Tansey, Henriette Nørmølle Buttenschøn, Sarah Cohen-Woods, Tim Bigdeli, Psychiatric Genomics Consortium MDD Working Group, Lynsey S. Hall, Zoltán Kutalik, S. Hong Lee, Stephan Ripke, Stacy Steinberg, Alexander Teumer, Alexander Viktorin, Naomi R Wray, Bernard T. Baune, Dorret I Boomsma, Anders D Børglum, Enda M. Byrne, Enrique Castelao, Nick CraddockIan Craig, Udo Dannlowski, Ian J. Deary, Franziska Degenhardt, Andreas J. Forstner, Scott D. Gordon, Hans Joergen Grabe, Jakob Grove, Steven P. Hamilton, Caroline Hayward, Andrew C. Heath, Lynne J. Hocking, Georg Homuth, Jouke J. Hottenga, Stefan Kloiber, Jesper Krogh, Mikael Landen, Maren Lang, Douglas F. Levinson, Paul Lichtenstein, Susanne Lucae, Pamela A.F. Madden, Donald J Macintyre, Patrik K.E. Magnusson, Nicholas G. Martin, Andrew M McIntosh, Christel M. Middeldorp, Yuri Milaneschi, Grant W. Montgomery, Ole Mors, Bertram Müller-Myhsok, Dale R. Nyholt, Hogni Oskarsson, Michael J. Owen, Sandosh Padmanabhan, Brenda W.J.H. Penninx, Michele L. Pergadia, David J Porteous, James B. Potash, Martin Preisig, Margarita Rivera Sanchez, Jianxin Shi, Engilbert Sigurdsson, Stanley I Shyn, Johannes H. Smit, Blair H. Smith, Hreinn Stefansson, Kari Stefansson, Jana Strohmaier, Patrick F. Sullivan, Pippa Thomson, Thorgeir E. Thorgeirsson, Sandra Van der Auwera Affiliations, Myrna M. Weissman, Cardiogram Consortium, Gerome Daniel Breen, Cathryn Mair Lewis, CONVERGE Consortium, GERAD1 Consortium:

Research output: Contribution to journal › Article › peer-review

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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 GWAS revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age-at-onset (AAO) in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by AAO.
Method: Discovery case-control GWASs were performed where cases were stratified using increasing/decreasing AAO-cutoffs; significant SNPs were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 controls for sub-setting. Polygenic score analysis was used to examine if differences in shared genetic risk exists between earlier and adult onset MDD with commonly co-morbid disorders of schizophrenia, bipolar disorder, Alzheimer’s disease, and coronary artery disease.
Results: We identify one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, OR=1.16, 95%CI=1.11-1.21, p=5.2x10-11). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset.
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 language	English
Pages (from-to)	325-335
Journal	Biological psychiatry
Volume	81
Issue number	4
Early online date	24 May 2016
DOIs	https://doi.org/10.1016/j.biopsych.2016.05.010
Publication status	Published - 15 Feb 2017

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Power, R., Tansey, K., Buttenschøn, H. N., Cohen-Woods, S., Bigdeli, T., Psychiatric Genomics Consortium MDD Working Group, Hall, L. S., Kutalik, Z., Hong Lee, S., Ripke, S., Steinberg, S., Teumer, A., Viktorin, A., Wray, N. R., Baune, B. T., Boomsma, D. I., Børglum, A. D., Byrne, E. M., Castelao, E., ... GERAD1 Consortium: (2017). Genome-wide Association for Major Depression Through Age at Onset Stratification. Biological psychiatry, 81(4), 325-335. https://doi.org/10.1016/j.biopsych.2016.05.010

@article{36e29a44f8d14ce098819b30cbb5a193,

title = "Genome-wide Association for Major Depression Through Age at Onset Stratification",

abstract = "Background: Major depressive disorder (MDD) is a disabling mood disorder and, despite a known heritable component, a large meta-analysis of GWAS revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age-at-onset (AAO) in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by AAO. Method: Discovery case-control GWASs were performed where cases were stratified using increasing/decreasing AAO-cutoffs; significant SNPs were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 controls for sub-setting. Polygenic score analysis was used to examine if differences in shared genetic risk exists between earlier and adult onset MDD with commonly co-morbid disorders of schizophrenia, bipolar disorder, Alzheimer{\textquoteright}s disease, and coronary artery disease.Results: We identify one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, OR=1.16, 95%CI=1.11-1.21, p=5.2x10-11). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset. 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. ",

author = "Robert Power and Katherine Tansey and Buttensch{\o}n, {Henriette N{\o}rm{\o}lle} and Sarah Cohen-Woods and Tim Bigdeli and {Psychiatric Genomics Consortium MDD Working Group} and Hall, {Lynsey S.} and Zolt{\'a}n Kutalik and {Hong Lee}, S. and Stephan Ripke and Stacy Steinberg and Alexander Teumer and Alexander Viktorin and Wray, {Naomi R} 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 Ian Craig and Udo Dannlowski and Deary, {Ian J.} and Franziska Degenhardt and Forstner, {Andreas J.} and Gordon, {Scott D.} and Grabe, {Hans Joergen} 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 Landen and Maren Lang and Levinson, {Douglas F.} and Paul Lichtenstein and Susanne Lucae and Madden, {Pamela A.F.} and Macintyre, {Donald J} 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 Bertram M{\"u}ller-Myhsok and Nyholt, {Dale R.} and Hogni Oskarsson and Owen, {Michael J.} and Sandosh Padmanabhan and Penninx, {Brenda W.J.H.} and Pergadia, {Michele L.} and Porteous, {David J} and Potash, {James B.} and Martin Preisig and {Rivera Sanchez}, Margarita and Jianxin Shi and Engilbert Sigurdsson and Shyn, {Stanley I} and Smit, {Johannes H.} and Smith, {Blair H.} and Hreinn Stefansson and Kari Stefansson and Jana Strohmaier and Sullivan, {Patrick F.} and Pippa Thomson and Thorgeirsson, {Thorgeir E.} and {Van der Auwera Affiliations}, Sandra and Weissman, {Myrna M.} and Cardiogram Consortium and Breen, {Gerome Daniel} and Lewis, {Cathryn Mair} and {CONVERGE Consortium} and {GERAD1 Consortium:}",

year = "2017",

month = feb,

day = "15",

doi = "10.1016/j.biopsych.2016.05.010",

language = "English",

volume = "81",

pages = "325--335",

journal = "Biological psychiatry",

issn = "0006-3223",

publisher = "Elsevier",

number = "4",

}

Power, R , Tansey, K, Buttenschøn, HN, Cohen-Woods, S, Bigdeli, T, Psychiatric Genomics Consortium MDD Working Group, Hall, LS, Kutalik, Z, Hong Lee, S, Ripke, S, Steinberg, S, Teumer, A, Viktorin, A, Wray, NR, Baune, BT, Boomsma, DI, Børglum, AD, Byrne, EM, Castelao, E, Craddock, N, Craig, I, 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, Landen, M, Lang, M, Levinson, DF, Lichtenstein, P, Lucae, S, Madden, PAF, Macintyre, DJ, Magnusson, PKE, Martin, NG, McIntosh, AM, Middeldorp, CM, Milaneschi, Y, Montgomery, GW, Mors, O, Müller-Myhsok, B, Nyholt, DR, Oskarsson, H, Owen, MJ, Padmanabhan, S, Penninx, BWJH, Pergadia, ML, Porteous, DJ, Potash, JB, Preisig, M, Rivera Sanchez, M, Shi, J, Sigurdsson, E, Shyn, SI, Smit, JH, Smith, BH, Stefansson, H, Stefansson, K, Strohmaier, J, Sullivan, PF, Thomson, P, Thorgeirsson, TE, Van der Auwera Affiliations, S, Weissman, MM, Consortium, C, Breen, GD , Lewis, CM, CONVERGE Consortium & GERAD1 Consortium: 2017, 'Genome-wide Association for Major Depression Through Age at Onset Stratification', Biological psychiatry, vol. 81, no. 4, pp. 325-335. https://doi.org/10.1016/j.biopsych.2016.05.010

TY - JOUR

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

AU - Power, Robert

AU - Tansey, Katherine

AU - Buttenschøn, Henriette Nørmølle

AU - Cohen-Woods, Sarah

AU - Bigdeli, Tim

AU - Psychiatric Genomics Consortium MDD Working Group

AU - Hall, Lynsey S.

AU - Kutalik, Zoltán

AU - Hong Lee, S.

AU - Ripke, Stephan

AU - Steinberg, Stacy

AU - Teumer, Alexander

AU - Viktorin, Alexander

AU - Wray, Naomi R

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

AU - Dannlowski, Udo

AU - Deary, Ian J.

AU - Degenhardt, Franziska

AU - Forstner, Andreas J.

AU - Gordon, Scott D.

AU - Grabe, Hans Joergen

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 - Landen, Mikael

AU - Lang, Maren

AU - Levinson, Douglas F.

AU - Lichtenstein, Paul

AU - Lucae, Susanne

AU - Madden, Pamela A.F.

AU - Macintyre, Donald J

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 - Müller-Myhsok, Bertram

AU - Nyholt, Dale R.

AU - Oskarsson, Hogni

AU - Owen, Michael J.

AU - Padmanabhan, Sandosh

AU - Penninx, Brenda W.J.H.

AU - Pergadia, Michele L.

AU - Porteous, David J

AU - Potash, James B.

AU - Preisig, Martin

AU - Rivera Sanchez, Margarita

AU - Shi, Jianxin

AU - Sigurdsson, Engilbert

AU - Shyn, Stanley I

AU - Smit, Johannes H.

AU - Smith, Blair H.

AU - Stefansson, Hreinn

AU - Stefansson, Kari

AU - Strohmaier, Jana

AU - Sullivan, Patrick F.

AU - Thomson, Pippa

AU - Thorgeirsson, Thorgeir E.

AU - Van der Auwera Affiliations, Sandra

AU - Weissman, Myrna M.

AU - Consortium, Cardiogram

AU - Breen, Gerome Daniel

AU - Lewis, Cathryn Mair

AU - CONVERGE Consortium

AU - GERAD1 Consortium:

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 GWAS revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age-at-onset (AAO) in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by AAO. Method: Discovery case-control GWASs were performed where cases were stratified using increasing/decreasing AAO-cutoffs; significant SNPs were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 controls for sub-setting. Polygenic score analysis was used to examine if differences in shared genetic risk exists between earlier and adult onset MDD with commonly co-morbid disorders of schizophrenia, bipolar disorder, Alzheimer’s disease, and coronary artery disease.Results: We identify one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, OR=1.16, 95%CI=1.11-1.21, p=5.2x10-11). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset. 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 GWAS revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age-at-onset (AAO) in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by AAO. Method: Discovery case-control GWASs were performed where cases were stratified using increasing/decreasing AAO-cutoffs; significant SNPs were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 controls for sub-setting. Polygenic score analysis was used to examine if differences in shared genetic risk exists between earlier and adult onset MDD with commonly co-morbid disorders of schizophrenia, bipolar disorder, Alzheimer’s disease, and coronary artery disease.Results: We identify one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, OR=1.16, 95%CI=1.11-1.21, p=5.2x10-11). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset. 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.

U2 - 10.1016/j.biopsych.2016.05.010

DO - 10.1016/j.biopsych.2016.05.010

M3 - Article

SN - 0006-3223

VL - 81

SP - 325

EP - 335

JO - Biological psychiatry

JF - Biological psychiatry

IS - 4

ER -

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

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