Dissecting the Genetic Heterogeneity of Depression Through Age at Onset

Robert A. Power, Robert Keers, Mandy Y. Ng, Amy W. Butler, Rudolf Uher, Sarah Cohen-Woods, Marcus Ising, Nick Craddock, Michael J. Owen, Ania Korszun, Lisa Jones, Ian Jones, Michael Gill, John P. Rice, Joanna Hauser, Neven Henigsberg, Wolfgang Maier, Astrid Zobel, Ole Mors, Anna S. PlacentinoMarcella Rietschel, Daniel Souery, Dejan Kozel, Martin Preisig, Susanne Lucae, Elisabeth B. Binder, Katherine J. Aitchison, Federica Tozzi, Pierandrea Muglia, Gerome Breen, Ian W. Craig, Anne E. Farmer, Bertram Müller-Myhsok, Peter Mcguffin, Cathryn M. Lewis

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28 Scopus citations


Genome-wide studies in major depression have identified few replicated associations, potentially due to heterogeneity within the disorder. Several studies have suggested that age at onset (AAO) can distinguish sub-types of depression with specific heritable components. This paper investigates the role of AAO in the genetic susceptibility for depression using genome-wide association data on 2,746 cases and 1,594 screened controls from the RADIANT studies, with replication performed in 1,471 cases and 1,403 controls from two Munich studies. Three methods were used to analyze AAO: First a time-to-event analysis with controls censored, secondly comparing controls to case-subsets defined using AAO cut-offs, and lastly analyzing AAO as a quantitative trait. In the time-to-event analysis three SNPs reached suggestive significance (P<5E-06), overlapping with the original case-control analysis of this study. In a case-control analysis using AAO thresholds, SNPs in 10 genomic regions showed suggestive association though again none reached genome-wide significance. Lastly, case-only analysis of AAO as a quantitative trait resulted in 5 SNPs reaching suggestive significance. Sex specific analysis was performed as a secondary analysis, yielding one SNP reaching genome-wide significance in early-onset males. No SNPs achieved significance in the replication study after correction for multiple testing. Analysis of AAO as a quantitative trait did suggest that, across all SNPs, common genetic variants explained a large proportion of the variance (51%, P=0.04). This study provides the first focussed analysis of the genetic contribution to AAO in depression, and establishes a statistical framework that can be applied to a quantitative trait underlying any disorder.

Original languageEnglish
Pages (from-to)859-868
Number of pages10
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume159 B
Issue number7
StatePublished - Oct 2012


  • Age at onset
  • Depression
  • Heterogeneity


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