title: Polygenic interactions with environmental adversity in the aetiology of major depressive disorder.
abstract: BACKGROUND
  Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene-environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD.
  
  
  METHODS
  The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them.
  
  
  RESULTS
  PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10(-6)). SLEs and CT were also associated with MDD status (p = 2.19 × 10(-4) and p = 5.12 × 10(-20), respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples.
  
  
  CONCLUSIONS
  CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene-environment interactions in complex traits.
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre,Institute of Psychiatry, Psychology & Neuroscience,King's College London,London,UK.
authors.forename: N
authors.initials: N
authors.lastname: Mullins
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre,Institute of Psychiatry, Psychology & Neuroscience,King's College London,London,UK.
authors.forename: R A
authors.initials: RA
authors.lastname: Power
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre,Institute of Psychiatry, Psychology & Neuroscience,King's College London,London,UK.
authors.forename: H L
authors.initials: HL
authors.lastname: Fisher
authors.affiliation: Division of Genetics and Molecular Medicine,King's College London School of Medicine,Guy's Hospital,London,UK.
authors.forename: K B
authors.initials: KB
authors.lastname: Hanscombe
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre,Institute of Psychiatry, Psychology & Neuroscience,King's College London,London,UK.
authors.forename: J
authors.initials: J
authors.lastname: Euesden
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre,Institute of Psychiatry, Psychology & Neuroscience,King's College London,London,UK.
authors.forename: R
authors.initials: R
authors.lastname: Iniesta
authors.affiliation: Department of Psychiatry and Behavioral Sciences,Stanford University,Stanford, CA,USA.
authors.forename: D F
authors.initials: DF
authors.lastname: Levinson
authors.affiliation: Department of Psychiatry,Columbia University and New York State Psychiatric Institute,New York, NY,USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Weissman
authors.affiliation: Department of Psychiatry,University of Iowa,Iowa City, IA,USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Potash
authors.affiliation: Division of Cancer Epidemiology and Genetics,National Cancer Institute,Bethesda, MD,USA.
authors.forename: J
authors.initials: J
authors.lastname: Shi
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre,Institute of Psychiatry, Psychology & Neuroscience,King's College London,London,UK.
authors.forename: R
authors.initials: R
authors.lastname: Uher
authors.affiliation: Discipline of Psychiatry,School of Medicine,University of Adelaide,Adelaide,South Australia,Australia.
authors.forename: S
authors.initials: S
authors.lastname: Cohen-Woods
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre,Institute of Psychiatry, Psychology & Neuroscience,King's College London,London,UK.
authors.forename: M
authors.initials: M
authors.lastname: Rivera
authors.affiliation: Department of Psychiatry,School of Clinical and Experimental Medicine,University of Birmingham,Birmingham,UK.
authors.forename: L
authors.initials: L
authors.lastname: Jones
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics,Neuroscience and Mental Health Research Institute,Cardiff University,Cardiff,UK.
authors.forename: I
authors.initials: I
authors.lastname: Jones
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics,Neuroscience and Mental Health Research Institute,Cardiff University,Cardiff,UK.
authors.forename: N
authors.initials: N
authors.lastname: Craddock
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics,Neuroscience and Mental Health Research Institute,Cardiff University,Cardiff,UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Owen
authors.affiliation: Barts and The London Medical School,Queen Mary University of London,London,UK.
authors.forename: A
authors.initials: A
authors.lastname: Korszun
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre,Institute of Psychiatry, Psychology & Neuroscience,King's College London,London,UK.
authors.forename: I W
authors.initials: IW
authors.lastname: Craig
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre,Institute of Psychiatry, Psychology & Neuroscience,King's College London,London,UK.
authors.forename: A E
authors.initials: AE
authors.lastname: Farmer
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre,Institute of Psychiatry, Psychology & Neuroscience,King's College London,London,UK.
authors.forename: P
authors.initials: P
authors.lastname: McGuffin
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre,Institute of Psychiatry, Psychology & Neuroscience,King's College London,London,UK.
authors.forename: G
authors.initials: G
authors.lastname: Breen
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre,Institute of Psychiatry, Psychology & Neuroscience,King's College London,London,UK.
authors.forename: C M
authors.initials: CM
authors.lastname: Lewis
mesh_terms: D000328:Adult; D000069586:Adult Survivors of Child Adverse Events / Q000523:psychology* / Q000706:statistics & numerical data; D003865:Major Depressive Disorder / Q000453:epidemiology / Q000235:genetics* / Q000523:psychology; D005260:Female; D059647:Gene-Environment Interaction; D006801:Humans; D008016:Life Change Events; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance; D012307:Risk Factors; D013315:Stress, Psychological / Q000453:epidemiology / Q000235:genetics* / Q000523:psychology; D055815:Young Adult
keywords: Depression; gene-environment interactions; genetics; polygenic risk scoring