title: Polygenic Risk Score, Parental Socioeconomic Status, Family History of Psychiatric Disorders, and the Risk for Schizophrenia: A Danish Population-Based Study and Meta-analysis.
abstract: OBJECTIVE
  Schizophrenia has a complex etiology influenced both by genetic and nongenetic factors but disentangling these factors is difficult.
  
  
  OBJECTIVE
  To estimate (1) how strongly the risk for schizophrenia relates to the mutual effect of the polygenic risk score, parental socioeconomic status, and family history of psychiatric disorders; (2) the fraction of cases that could be prevented if no one was exposed to these factors; (3) whether family background interacts with an individual's genetic liability so that specific subgroups are particularly risk prone; and (4) to what extent a proband's genetic makeup mediates the risk associated with familial background.
  
  
  METHODS
  We conducted a nested case-control study based on Danish population-based registers. The study consisted of 866 patients diagnosed as having schizophrenia between January 1, 1994, and December 31, 2006, and 871 matched control individuals. Genome-wide data and family psychiatric and socioeconomic background information were obtained from neonatal biobanks and national registers. Results from a separate meta-analysis (34,600 cases and 45,968 control individuals) were applied to calculate polygenic risk scores.
  
  
  METHODS
  Polygenic risk scores, parental socioeconomic status, and family psychiatric history.
  
  
  METHODS
  Odds ratios (ORs), attributable risks, liability R2 values, and proportions mediated.
  
  
  RESULTS
  Schizophrenia was associated with the polygenic risk score (OR, 8.01; 95% CI, 4.53-14.16 for highest vs lowest decile), socioeconomic status (OR, 8.10; 95% CI, 3.24-20.3 for 6 vs no exposures), and a history of schizophrenia/psychoses (OR, 4.18; 95% CI, 2.57-6.79). The R2 values were 3.4% (95% CI, 2.1-4.6) for the polygenic risk score, 3.1% (95% CI, 1.9-4.3) for parental socioeconomic status, and 3.4% (95% CI, 2.1-4.6) for family history. Socioeconomic status and psychiatric history accounted for 45.8% (95% CI, 36.1-55.5) and 25.8% (95% CI, 21.2-30.5) of cases, respectively. There was an interaction between the polygenic risk score and family history (P = .03). A total of 17.4% (95% CI, 9.1-26.6) of the effect associated with family history of schizophrenia/psychoses was mediated through the polygenic risk score.
  
  
  CONCLUSIONS
  Schizophrenia was associated with the polygenic risk score, family psychiatric history, and socioeconomic status. Our study demonstrated that family history of schizophrenia/psychoses is partly mediated through the individual's genetic liability.
authors.affiliation: Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark2National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark3Centre for Integrated Register-Based Research, Aarhus University, Aarhus, Denmark.
authors.forename: Esben
authors.initials: E
authors.lastname: Agerbo
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden5Department of Genetics, University of North Carolina at Chapel Hill.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Sullivan
authors.affiliation: Bioinformatic Research Centre, Aarhus University, Aarhus, Denmark.
authors.forename: Bjarni J
authors.initials: BJ
authors.lastname: Vilhjálmsson
authors.affiliation: Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark2National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark3Centre for Integrated Register-Based Research, Aarhus University, Aarhus, Denmark.
authors.forename: Carsten B
authors.initials: CB
authors.lastname: Pedersen
authors.affiliation: Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark7Department P, Aarhus University Hospital, Risskov, Denmark.
authors.forename: Ole
authors.initials: O
authors.lastname: Mors
authors.affiliation: Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark7Department P, Aarhus University Hospital, Risskov, Denmark8Department of Biomedicine and Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
authors.forename: Anders D
authors.initials: AD
authors.lastname: Børglum
authors.affiliation: Danish Center for Neonatal Screening, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: David M
authors.initials: DM
authors.lastname: Hougaard
authors.affiliation: Danish Center for Neonatal Screening, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Mads V
authors.initials: MV
authors.lastname: Hollegaard
authors.affiliation: Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark2National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.
authors.forename: Sandra
authors.initials: S
authors.lastname: Meier
authors.affiliation: Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston11Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.affiliation: The Queensland Brain Institute, University of Queensland, St Lucia, Australia.
authors.forename: Naomi R
authors.initials: NR
authors.lastname: Wray
authors.affiliation: Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark2National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark3Centre for Integrated Register-Based Research, Aarhus University, Aarhus, Denmark.
authors.forename: Preben B
authors.initials: PB
authors.lastname: Mortensen
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics; D016022:Case-Control Studies; D003718:Denmark / Q000453:epidemiology; D005190:Family; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D020412:Multifactorial Inheritance; D016017:Odds Ratio; D010290:Parents; D011618:Psychotic Disorders / Q000235:genetics; D012307:Risk Factors; D012559:Schizophrenia / Q000453:epidemiology / Q000235:genetics*; D012923:Social Class