Polygenic Risk Score, Parental Socioeconomic Status, Family History of Psychiatric Disorders, and the Risk for Schizophrenia: A Danish Population-Based Study and Meta-analysis

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Esben Agerbo, professor at National Centre for Research-based Research & CIRRAU, Aarhus University

About the study

Schizophrenia is a debilitating and complex disorder that is influenced both by genetic and non-genetic factors but disentangling these factors is difficult.

Gene-environment interactions may be important in the etiology of schizophrenia. Studies have used psychiatric family history as a proxy for genetic liability rather than actual genetic variation, as perhaps no data set exists where gene environment interactions are identifiable. To our knowledge, no study has taken the gene-environment hypothesis further to estimate the proportion of an upstream factor that is mediated through the genetic liability for schizophrenia.

We used Denmark’s population-based registers, the Danish Neonatal Screening Biobank, and separate metadata from the largest published schizophrenia genome-wide association study to pursue the following questions: (1) How strongly is the risk for schizophrenia related to the mutual effect of the polygenic risk score, parental socioeconomic status, and family history of psychiatric disorders? (2) In theory, what fraction of cases could be prevented if no one was exposed to these factors? (3) Do familial backgrounds interact with an individual’s genetic liability so that specific subgroups of individuals are particularly risk prone? (4) How much of an excess risk associated with familial background is mediated through the offspring’s genetic makeup?

This paper was analogous to a previous genome-wide association study: Modelling the contribution of family history and variation in single nucleotide polymorphisms to risk of schizophrenia: a Danish national birth cohort-based study, where we basically asked the same research questions, but with a polygenic risk score that was based on 1848 single nucleotide polymorphisms located within 50 kilobases from exons in the top 39 candidate genes.

The article Polygenic Risk Score, Parental Socioeconomic Status, Family History of Psychiatric Disorders, and the Risk for SchizophreniaA Danish Population-Based Study and Meta-analysis was published in JAMA Psychiatry, 2015;72(7):635-641.

Facts about the study

  • The polygenic risk score, family history of mental disorders and parental socioeconomic status are strongly linked to the risk of schizophrenia, but the liability r-squared is very modest.
  • A family history of psychotic disorders and the polygenic risk score interacted [P(case-control)=0.026 and P(case-only)= 10^-6)]. This analysis suggested that subjects with such a history and a low genetic liability were not at increased risk, but the risk-increase with increasing liability was higher among those with a family history of psychotic disorders.
  • Approximately 17% of the excess risk associated with family history of psychosis was mediated through the polygenic risk score. This fraction increased to 48% (10%-94%) when the interaction was taken into account. The proportion of the excess risk associated with parental socioeconomic status mediated through the polygenic risk score was 28 %( −13%- 70%).

Further information

Esben Agerbo, professor, NCRR and CIRRAU, BSS, Aarhus University, Email: ea@econ.au.dk