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ImportanceSchizophrenia has a complex etiology influenced both by genetic and nongenetic factors but disentangling these factors is difficult.ObjectiveTo 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.Design, settings, and participantsWe 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.ExposuresPolygenic risk scores, parental socioeconomic status, and family psychiatric history.Main outcomes and measuresOdds ratios (ORs), attributable risks, liability R2 values, and proportions mediated.ResultsSchizophrenia 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 and relevanceSchizophrenia 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.

Original publication




Journal article


JAMA psychiatry

Publication Date





635 - 641


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.


Humans, Genetic Predisposition to Disease, Odds Ratio, Risk Factors, Case-Control Studies, Family, Parents, Bipolar Disorder, Psychotic Disorders, Schizophrenia, Multifactorial Inheritance, Social Class, Denmark, Female, Male, Genetic Association Studies