Examining the independent and joint effects of genomic and exposomic liabilities for schizophrenia across the psychosis spectrum

Abstract

Aims Psychosis spectrum disorder has a complex pathoetiology characterised by interacting environmental and genetic vulnerabilities. The present study aims to investigate the role of gene–environment interaction using aggregate scores of genetic (polygenic risk score for schizophrenia (PRS-SCZ)) and environment liability for schizophrenia (exposome score for schizophrenia (ES-SCZ)) across the psychosis continuum. Methods The sample consisted of 1699 patients, 1753 unaffected siblings, and 1542 healthy comparison participants. The Structured Interview for Schizotypy-Revised (SIS-R) was administered to analyse scores of total, positive, and negative schizotypy in siblings and healthy comparison participants. The PRS-SCZ was trained using the Psychiatric Genomics Consortiums results and the ES-SCZ was calculated guided by the approach validated in a previous report in the current data set. Regression models were applied to test the independent and joint effects of PRS-SCZ and ES-SCZ (adjusted for age, sex, and ancestry using 10 principal components). Results Both genetic and environmental vulnerability were associated with case-control status. Furthermore, there was evidence for additive interaction between binary modes of PRS-SCZ and ES-SCZ (above 75% of the control distribution) increasing the odds for schizophrenia spectrum diagnosis (relative excess risk due to interaction = 6.79, [95% confidential interval (CI) 3.32, 10.26], p < 0.001). Sensitivity analyses using continuous PRS-SCZ and ES-SCZ confirmed gene–environment interaction (relative excess risk due to interaction = 1.80 [95% CI 1.01, 3.32], p = 0.004). In siblings and healthy comparison participants, PRS-SCZ and ES-SCZ were associated with all SIS-R dimensions and evidence was found for an interaction between PRS-SCZ and ES-SCZ on the total (B = 0.006 [95% CI 0.003, 0.009], p < 0.001), positive (B = 0.006 [95% CI, 0.002, 0.009], p = 0.002), and negative (B = 0.006, [95% CI 0.004, 0.009], p < 0.001) schizotypy dimensions. Conclusions The interplay between exposome load and schizophrenia genetic liability contributing to psychosis across the spectrum of expression provide further empirical support to the notion of aetiological continuity underlying an extended psychosis phenotype.

Predictive Performance of Exposome Score for Schizophrenia in the General Population

“…Finally, the quantification of environmental liability as a single metric enhances statistical power over multiple testing of each exposure. 12 , 30 Certainly, the integration of ES-SCZ with electronic health records and molecular genetic markers, such as PRS-SCZ, has the potential to boost prediction in the future.…”

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

“…The Cannabis Experiences Questionnaire (0="none"; 1="only once or twice"; 2="a few times a year"; 3="a few times a month"; 4="once or more a week"; 5="everyday") and CIDI (0="none"; 1="less than weekly"; 2="weekly"; 3="daily") are Likert type scales. Following previous work [3,4,[37][38][39] a binary regular cannabis use variable was constructed by using the cut-off value of one or more per week during the lifetime period most frequent use.…”

“…The major strengths of our study were the use of two large independent datasets for test and replication; and the uniform measurement schedule and similar sampling strategy in both datasets. Furthermore, we used ES-SCZ that was previously constructed, validated, and demonstrated to perform better than other cumulative environmental scores in our study population [4,17,18]. However, it should be noted that ES-SCZ was limited by the availability of exposure assessment, and therefore did not include all known environmental exposures relevant for risk or course, such as obstetric and pregnancy complications, as well as exposures such as ethnic minority and migration that were deliberately excluded to increase the utility of ES-SCZ in applications combined with genetic data [17].…”

“…To estimate the cumulative environmental load, we calculated the ES-SCZ based on our formerly validated estimates [17]. Conforming to our previous studies [4,17], we constituted the ES-SCZ by summing log-odds weighted environmental exposures (each exposure defined as absent = "0" and present = "1") including cannabis use, hearing impairment, winter-birth, and childhood adversity domains (emotional and physical neglect; emotional, physical, and sexual abuse; and bullying). For ease of interpretation, a constant of 2 is added to ES-SCZ.…”

“…Schizophrenia spectrum disorders are complex heterogeneous disorders characterized by positive and negative psychotic symptoms, accompanied by deviations in cognition and functioning. The underlying etiopathology involves a multitude of genetic factors [1] and several environmental exposures [2] and their interactions [3][4][5]. These risk factors for schizophrenia spectrum disorders not only increase susceptibility to psychosis but may also influence prognosis and outcomes of schizophrenia spectrum disorders.…”