To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1016/j.biopsych.2016.05.024 Byline: Judith Verduijn [email@example.com] (a,b,*,1), Yuri Milaneschi (a,b,1), Wouter J. Peyrot (a,b), Jouke Jan Hottenga (a,b,c), Abdel Abdellaoui (c), Eco J.C. de Geus (b,c), Johannes H. Smit (a,b), Gerome Breen (d,e), Cathryn M. Lewis (d), Dorret I. Boomsma (c), Aartjan T.F. Beekman (a,b), Brenda W.J.H. Penninx (a,b) Keywords Clinical characteristics; Heterogeneity; Genetic load; Genetics; Major depressive disorder; Replication; Staging Abstract Background Limited successes of gene finding for major depressive disorder (MDD) may be partly due to phenotypic heterogeneity. We tested whether the genetic load for MDD, bipolar disorder, and schizophrenia (SCZ) is increased in phenotypically more homogenous MDD patients identified by specific clinical characteristics. Methods Patients (n = 1539) with a DSM-IV MDD diagnosis and control subjects (n = 1792) were from two large cohort studies (Netherlands Study of Depression and Anxiety and Netherlands Twin Register). Genomic profile risk scores (GPRSs) for MDD, bipolar disorder, and SCZ were based on meta-analysis results of the Psychiatric Genomics Consortium. Regression analyses (adjusted for year of birth, sex, three principal components) examined the association between GPRSs with characteristics and GPRSs with MDD subgroups stratified according to the most relevant characteristics. The proportion of liability variance explained by GPRSs for each MDD subgroup was estimated. Results GPRS-MDD explained 1.0% (p = 4.19e.sup.-09) of MDD variance, and 1.5% (p = 4.23e.sup.-09) for MDD endorsing nine DSM symptoms. GPRS--bipolar disorder explained 0.6% (p = 2.97e.sup.-05) of MDD variance and 1.1% (p = 1.30e.sup.-05) for MDD with age at onset Conclusions MDD patients with early age at onset and higher symptom severity have an increased genetic risk for three major psychiatric disorders, suggesting that it is useful to create phenotypically more homogenous groups when searching for genes associated with MDD. Author Affiliation: (a) Department of Psychiatry and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest; Amsterdam, the Netherlands (b) EMGO Institute for Health and Care Research; Amsterdam, the Netherlands (c) Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands (d) MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience; London, United Kingdom (e) National Institute for Health Research Mental Health Biomedical Research Centre (GB), South London and Maudsley National Health Service Foundation Trust, King's College London, London, United Kingdom * Address correspondence to: Judith Verduijn, M.D., VU University Medical Center/GGZ inGeest, Department of Psychiatry, A.J. Ernststraat 1187, Amsterdam 1081HL, Netherlands. Article History: Received 26 October 2015; Revised 2 May 2016; Accepted 24 May 2016 (footnote)1 JV and YM are joint first authors.