title: Using Clinical Characteristics to Identify Which Patients With Major Depressive Disorder Have a Higher Genetic Load for Three Psychiatric Disorders.
abstract: 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.
  
  
  
  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.
  
  
  
  GPRS-MDD explained 1.0% (p = 4.19e-09) of MDD variance, and 1.5% (p = 4.23e-09) for MDD endorsing nine DSM symptoms. GPRS-bipolar disorder explained 0.6% (p = 2.97e-05) of MDD variance and 1.1% (p = 1.30e-05) for MDD with age at onset <18 years. GPRS-SCZ explained 2.0% (p = 6.15e-16) of MDD variance, 2.6% (p = 2.88e-10) for MDD with higher symptom severity, and 2.3% (p = 2.26e-13) for MDD endorsing nine DSM symptoms. An independent sample replicated the same pattern of stronger associations between cases with more DSM symptoms, as compared to overall MDD, and GPRS-SCZ.
  
  
  
  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.
authors: Department of Psychiatry and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest; Amsterdam, the Netherlands; EMGO Institute for Health and Care Research; Amsterdam, the Netherlands. Electronic address: judithverduijn@gmail.com.
authors: Judith
authors: J
authors: Verduijn
authors: Department of Psychiatry and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest; Amsterdam, the Netherlands; EMGO Institute for Health and Care Research; Amsterdam, the Netherlands.
authors: Yuri
authors: Y
authors: Milaneschi
authors: Department of Psychiatry and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest; Amsterdam, the Netherlands; EMGO Institute for Health and Care Research; Amsterdam, the Netherlands.
authors: Wouter J
authors: WJ
authors: Peyrot
authors: Department of Psychiatry and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest; Amsterdam, the Netherlands; EMGO Institute for Health and Care Research; Amsterdam, the Netherlands; Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands.
authors: Jouke Jan
authors: JJ
authors: Hottenga
authors: Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands.
authors: Abdel
authors: A
authors: Abdellaoui
authors: EMGO Institute for Health and Care Research; Amsterdam, the Netherlands; Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands.
authors: Eco J C
authors: EJC
authors: de Geus
authors: Department of Psychiatry and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest; Amsterdam, the Netherlands; EMGO Institute for Health and Care Research; Amsterdam, the Netherlands.
authors: Johannes H
authors: JH
authors: Smit
authors: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience; London, United Kingdom; 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.
authors: Gerome
authors: G
authors: Breen
authors: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience; London, United Kingdom.
authors: Cathryn M
authors: CM
authors: Lewis
authors: Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands.
authors: Dorret I
authors: DI
authors: Boomsma
authors: Department of Psychiatry and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest; Amsterdam, the Netherlands; EMGO Institute for Health and Care Research; Amsterdam, the Netherlands.
authors: Aartjan T F
authors: ATF
authors: Beekman
authors: Department of Psychiatry and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest; Amsterdam, the Netherlands; EMGO Institute for Health and Care Research; Amsterdam, the Netherlands.
authors: Brenda W J H
authors: BWJH
authors: Penninx
mesh_terms: D000328:Adult; D017668:Age of Onset; D001714:Bipolar Disorder / Q000175:diagnosis / Q000235:genetics*; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D040741:Genetic Load; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011569:Psychiatric Status Rating Scales; D012307:Risk Factors; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics*
keywords: Clinical characteristics; Genetic load; Genetics; Heterogeneity; Major depressive disorder; Replication; Staging