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. 2017 Feb 15;81(4):325-335.
doi: 10.1016/j.biopsych.2016.05.010. Epub 2016 May 24.

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

Robert A Power  1 Katherine E Tansey  2 Henriette Nørmølle Buttenschøn  3 Sarah Cohen-Woods  4 Tim Bigdeli  5 Lynsey S Hall  6 Zoltán Kutalik  7 S Hong Lee  8 Stephan Ripke  9 Stacy Steinberg  10 Alexander Teumer  11 Alexander Viktorin  12 Naomi R Wray  13 Volker Arolt  14 Bernard T Baune  4 Dorret I Boomsma  15 Anders D Børglum  16 Enda M Byrne  13 Enrique Castelao  17 Nick Craddock  2 Ian W Craig  1 Udo Dannlowski  18 Ian J Deary  19 Franziska Degenhardt  20 Andreas J Forstner  20 Scott D Gordon  21 Hans J Grabe  22 Jakob Grove  16 Steven P Hamilton  23 Caroline Hayward  24 Andrew C Heath  25 Lynne J Hocking  26 Georg Homuth  27 Jouke J Hottenga  15 Stefan Kloiber  28 Jesper Krogh  29 Mikael Landén  30 Maren Lang  31 Douglas F Levinson  32 Paul Lichtenstein  12 Susanne Lucae  28 Donald J MacIntyre  6 Pamela Madden  25 Patrik K E Magnusson  12 Nicholas G Martin  21 Andrew M McIntosh  33 Christel M Middeldorp  15 Yuri Milaneschi  34 Grant W Montgomery  21 Ole Mors  35 Bertram Müller-Myhsok  36 Dale R Nyholt  37 Hogni Oskarsson  38 Michael J Owen  2 Sandosh Padmanabhan  39 Brenda W J H Penninx  34 Michele L Pergadia  40 David J Porteous  24 James B Potash  41 Martin Preisig  17 Margarita Rivera  42 Jianxin Shi  43 Stanley I Shyn  44 Engilbert Sigurdsson  45 Johannes H Smit  34 Blair H Smith  46 Hreinn Stefansson  10 Kari Stefansson  10 Jana Strohmaier  31 Patrick F Sullivan  47 Pippa Thomson  48 Thorgeir E Thorgeirsson  10 Sandra Van der Auwera  22 Myrna M Weissman  49 CONVERGE Consortium, CARDIoGRAM Consortium, GERAD1 ConsortiumGerome Breen  1 Cathryn M Lewis  50
Affiliations
Free PMC article

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

Robert A Power et al. Biol Psychiatry. .
Free PMC article

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.

Figures

Figure 1.
Figure 1
Distribution of age at onset across the nine studies included in the discovery analysis. Mid-gray band shows interquartile range across all studies excluding GenRED (Genetics of Recurrent Early-Onset Depression), which recruited only cases onset at 30 years or less. GAIN, Genetic Association Information Network; GSK, GlaxoSmithKline; MPIP, Max Planck Institute of Psychiatry; NESDA, Netherlands Study of Depression and Anxiety; NTR, Netherlands Twin Register.
Figure 2.
Figure 2
Evidence for association and effect size for rs7647854 on chromosome 3, with cases split into nonoverlapping quartiles by age at onset within discovery studies. O, octile.
Figure 3.
Figure 3
Polygenic risk profile scoring analysis of bipolar disorder, schizophrenia, Alzheimer’s disease, and coronary artery disease within the major depressive disorder (MDD) discovery studies (excluding GenRED [Genetics of Recurrent Early-Onset Depression]). We calculated the proportion of variance explained (Nagelkerkeʼs R2) by subtraction of a full model (covariates + polygenic risk score) from a reduced model (covariates only). AAO, age at onset; O, octile; PGC, Psychiatric Genomics Consortium.

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