Genome-wide association for major depression through age at onset stratification

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., consortium, CONVERGE, Consortium, CARDIoGRAM, Consortium, GERAD, Breen, Gerome, & Lewis, Cathryn M. (2016) Genome-wide association for major depression through age at onset stratification. Biological Psychiatry. (In Press)

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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. Keywords

Major Depressive Disorder; GWAS; Age at Onset; Polygenic Scoring; heterogeneity; stratification

Impact and interest:

4 citations in Scopus
5 citations in Web of Science®
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ID Code: 97899
Item Type: Journal Article
Refereed: Yes
DOI: 10.1016/j.biopsych.2016.05.010
ISSN: 00063223
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Statement: Under a Creative Commons Attribution Licence
Deposited On: 03 Aug 2016 06:05
Last Modified: 01 Jul 2017 04:57

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