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, 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, Müller-Myhsok, Bertram, Nyholt, Dale R., Oskarsson, Hogni, Owen, Michael J., Padmanabhan, Sandosh, Penninx, Brenda W. J. H., Pergadia, Michele L., Porteous, David J., Potash, James B., Preisig, Martin, Rivera, Margarita, Shi, Jianxin, Shyn, Stanley I., Sigurdsson, Engilbert, Smit, Johannes H., Smith, Blair H., Stefansson, Hreinn, Stefansson, Kari, Strohmaier, Jana, Sullivan, Patrick F., Thomson, Pippa, Thorgeirsson, Thorgeir E., Van der Auwera, Sandra, Weissman, Myrna M., CONVERGE consortium, CARDIoGRAM Consortium, GERAD1 Consortium, Breen, Gerome and Lewis, Cathryn M. (2016) 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. doi:10.1016/j.biopsych.2016.05.010

Author 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
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
Müller-Myhsok, Bertram
Nyholt, Dale R.
Oskarsson, Hogni
Owen, Michael J.
Padmanabhan, Sandosh
Penninx, Brenda W. J. H.
Pergadia, Michele L.
Porteous, David J.
Potash, James B.
Preisig, Martin
Rivera, Margarita
Shi, Jianxin
Shyn, Stanley I.
Sigurdsson, Engilbert
Smit, Johannes H.
Smith, Blair H.
Stefansson, Hreinn
Stefansson, Kari
Strohmaier, Jana
Sullivan, Patrick F.
Thomson, Pippa
Thorgeirsson, Thorgeir E.
Van der Auwera, Sandra
Weissman, Myrna M.
CONVERGE consortium
CARDIoGRAM Consortium
GERAD1 Consortium
Breen, Gerome
Lewis, Cathryn M.
Title Genome-wide association for major depression through age at onset stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
Journal name Biological Psychiatry   Check publisher's open access policy
ISSN 0006-3223
Publication date 2016-05-24
Sub-type Article (original research)
DOI 10.1016/j.biopsych.2016.05.010
Open Access Status Not yet assessed
Volume 81
Issue 4
Start page 325
End page 335
Total pages 11
Place of publication Philadelphia, PA, United States
Publisher Elsevier
Language eng
Formatted 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.
Keyword Major depressive disorder
Age at onset
Polygenic scoring
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ
Additional Notes Published online 24 May 2016. Article in Press

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