Polygenetic Risk Scores for Major Psychiatric Disorders Among Schizophrenia Patients, Their First-Degree Relatives, and Healthy Participants

Abstract

Background The genetic etiology of schizophrenia (SCZ) overlaps with that of other major psychiatric disorders in samples of European ancestry. The present study investigated transethnic polygenetic features shared between Japanese SCZ or their unaffected first-degree relatives and European patients with major psychiatric disorders by conducting polygenic risk score (PRS) analyses. Methods To calculate PRSs for 5 psychiatric disorders (SCZ, bipolar disorder [BIP], major depressive disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder) and PRSs differentiating SCZ from BIP, we utilized large-scale European genome-wide association study (GWAS) datasets as discovery samples. PRSs derived from these GWASs were calculated for 335 Japanese target participants [SCZ patients, FRs, and healthy controls (HCs)]. We took these PRSs based on GWASs of European psychiatric disorders and investigated their effect on risk in Japanese SCZ patients and unaffected first-degree relatives. Results The PRSs obtained from European SCZ and BIP patients were higher in Japanese SCZ patients than in HCs. Furthermore, PRSs differentiating SCZ patients from European BIP patients were higher in Japanese SCZ patients than in HCs. Interestingly, PRSs related to European autism spectrum disorder were lower in Japanese first-degree relatives than in HCs or SCZ patients. The PRSs of autism spectrum disorder were positively correlated with a young onset age of SCZ. Conclusions These findings suggest that polygenic factors related to European SCZ and BIP and the polygenic components differentiating SCZ from BIP can transethnically contribute to SCZ risk in Japanese people. Furthermore, we suggest that reduced levels of an ASD-related genetic factor in unaffected first-degree relatives may help protect against SCZ development.

Polygenic risk scores for late smoking initiation associated with the risk of schizophrenia

“…As unaffected FRs share approximately half of the genetic risk of schizophrenia, PRSs for schizophrenia in unaffected FRs are intermediate between those of schizophrenia patients and HCs 29,33,34 . In addition to this evidence, we found that the PRSs for age at smoking initiation were higher in schizophrenia patients than in HCs, and those in FRs were intermediate between those in patients with schizophrenia and those in HCs.…”

“…The target sample ( n = 332) comprised 130 patients with schizophrenia (50 males/80 females, mean age ± SD: 42.9 ± 13.1 years), 56 of their unaffected FRs (40 parents/12 siblings/4 offspring, 18 males/38 females, 56.8 ± 15.6 years), and 146 HCs (97 males/49 females, 37.2 ± 14.1 years). All of these subjects participated in our previous study 29 . The study sample was recruited from the Schizophrenia Non-Affected Relative Project 29 , 39 .…”

“…All subjects were of Japanese descent and had no biological firstor second-degree relatives within their own diagnostic groups. A detailed description of sample recruitment and diagnosis has been provided previously 7,29,[39][40][41][42][43] . Briefly, each patient was diagnosed on the basis of unstructured clinical interviews, medical records, and clinical conferences according to the criteria in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).…”

“…On the other hand, the risks of schizophrenia and smokingrelated behaviors are mediated by not only genome-wide significant SNPs but also a polygenic component comprising the additive effects of a large number of common SNPs with weak effects 22,[24][25][26][27][28][29][30] . Consistent with the comorbidity of schizophrenia and cigarette smoking behaviors, genetic correlations between the risk of schizophrenia, and higher smoking initiation, later age at smoking initiation and greater smoking quantity have been indicated by linkage disequilibrium score regression (LDSC) and polygenic risk score (PRS) analyses using European-based GWASs from the PGC and TAG 27,28,31 .…”

Differences in Executive Function Among Patients With Schizophrenia, Their Unaffected First-Degree Relatives, and Healthy Participants

“…The participants consisted of 116 patients with SCZ (44 males/72 females, mean age ± SD: 44.0 ± 13.2 years), 62 unaffected FRs (29 mothers/19 fathers/8 sisters/2 brothers/3 offspring, 24 males/38 females, 59.4 ± 14.5 years), and 146 HCs (96 males/50 females, 37.0 ± 15.2 years). The study sample was recruited from the Schizophrenia Non-Affected Relative Project at Kanazawa Medical University ( Ohi et al, 2019b, 2020 ). All participants were of Japanese descent.…”