Do Current Measures of Polygenic Risk for Mental Disorders Contribute to Population Variance in Mental Health?

Abstract

The polygenic risk score (PRS) allows for quantification of the relative contributions of genes and environment in population-based studies of mental health. We analyzed the impact of transdiagnostic schizophrenia PRS and measures of familial and environmental risk on the level of and change in general mental health (Short-Form-36 mental health) in the Netherlands Mental Health Survey and Incidence Study-2 general population sample, interviewed 4 times over a period of 9 years, yielding 8901 observations in 2380 individuals. Schizophrenia PRS, family history, somatic pain, and a range of environmental risks and social circumstances were included in the regression model of level of and change in mental health. We calculated the relative contribution of each (group of) risk factor(s) to the variance in (change in) mental health. In the combined model, familial and environmental factors explained around 17% of the variance in mental health, of which around 5% was explained by age and sex, 30% by social circumstances, 16% by pain, 22% by environmental risk factors, 24% by family history, and 3% by PRS for schizophrenia (PRS-SZ). Results were similar, but attenuated, for the model of mental health change over time. Childhood trauma and gap between actual and desired social status explained most of the variance. PRS for bipolar disorder, cross-disorder, and depression explained less variance in mental health than PRS-SZ. Polygenic risk for mental suffering, derived from significance-testing in massive samples, lacks impact in analyses focusing on prediction in a general population epidemiological setting. Social-environmental circumstances, particularly childhood trauma and perceived status gap, drive most of the attributable variation in population mental health.

Examining the association between exposome score for schizophrenia and functioning in schizophrenia, siblings, and healthy controls: Results from the EUGEI study

“…These results were consistent with previous findings of an investigation of PRS-SCZ in the EUGEI and GROUP datasets that revealed an association of PRS-SCZ with subthreshold psychosis phenotypes in unaffected siblings but not in healthy participants [61]. In siblings, who share genetic composition largely with patients, environment may be a more important factor for determining the level of functioning [62]. Furthermore, the differences found between unaffected siblings, healthy controls, and patients might be driven by specific patterns of gene-environment and environment-environment interactions.…”

Precision psychiatry: promise for the future or rehash of a fossilised foundation?

“…Members of the DSM workgroups have therefore not been able to include biological evidence in the criteria for the most important mental disorders (American Psychiatric Association, 2013). Given this state of affairs, without clear hypotheses or directions to guide us towards future findings that would be able to yield discrete clinical distinctions, it remains debatable whether precision psychiatry, using the same translational approaches, will ever be able to provide any diagnostic, prognostic or therapeutic benefit to clinical practice (Marsman et al, 2020; van Os, 2018).…”

Predictive Performance of Exposome Score for Schizophrenia in the General Population

“…However, PRS-SCZ is not distinctly associated with schizophrenia but is also associated with several psychiatric and other medical conditions 4 , 6 , 7 and subclinical multidimensional phenotypes, 7–10 as well as general mental and physical health outcomes. 11 , 12 …”