Polygenic Risk Scores Differentiating Schizophrenia From Bipolar Disorder Are Associated With Premorbid Intelligence in Schizophrenia Patients and Healthy Subjects

Abstract

Background Impairments in intelligence are more severe in patients with schizophrenia (SCZ) than in patients with bipolar disorder (BD) despite clinical and genetic similarities between the disorders. Genetic loci differentiating SCZ from BD, i.e., SCZ-specific risk, have been identified. Polygenetic [risk] scores (PGSs) for SCZ-specific risk are higher in SCZ patients than in healthy controls (HCs). However, the influence of genetic risk on impaired intelligence is poorly understood. Here, we investigated whether SCZ-specific risk could predict impairments in intelligence in SCZ patients and HCs. Methods Large-scale genome-wide association study (GWAS) datasets related to SCZ vs BD, childhood intelligence (CHI) and adulthood intelligence (n=12,441-282,014) were utilized to compute PGSs. PGSs derived from the GWASs were calculated for 130 patients with SCZ and 146 HCs. Premorbid and current intelligence and the decline were measured in SCZ patients and HCs. Correlations between PGSs and intelligence functions were investigated. Results High PGSs for SCZ-specific risk were correlated with low premorbid intelligence in SCZ patients and HCs (β=-0.17, p=4.12×10 -3). The correlation was still significant after adjusting for diagnostic status (β=-0.13, p=0.024). There were no significant correlations between PGSs for SCZ-specific risk and current intelligence or intelligence decline (p>0.05). PGSs for CHI were lower in SCZ patients than in HCs (R 2=0.025, p=0.025), while the PGSs for CHI were not significantly correlated with premorbid and current intelligence, the decline or the PGSs for SCZ-specific risk (p>0.05). Conclusions These findings suggest that genetic factors differentiating SCZ from BD might affect the pathogenesis of SCZ and/or pathological differences between SCZ and BD via the impairment of premorbid intelligence, i.e., crystallized intelligence, while genetic factors for CHI might affect the pathogenesis of SCZ not via impaired impairments in intelligence.

Cognitive performances across individuals at high genetic risk for schizophrenia, high genetic risk for bipolar disorder, and low genetic risks: a combined polygenic risk score approach

“…All participants were of Japanese descent and had no biological first-or seconddegree relatives within their own diagnostic groups. The participants were recruited from the Schizophrenia Non-Affected Relative Project (SNARP) (Kataoka et al, 2020;Ohi et al, 2020aOhi et al, , 2020bOhi et al, , 2021aOhi et al, , 2019Ohi et al, , 2017a. The patients and their unaffected FRs were recruited from Kanazawa Medical University Hospital.…”

“…A detailed description of the genotyping, quality control (QC), and imputation procedures applied in the study sample has been provided previously (Ohi et al, 2020a(Ohi et al, , 2020b(Ohi et al, , 2021a. Briefly, venous blood was collected from the participants, and genomic DNA was extracted from whole-blood samples.…”

“…By investigating causality using summary-data-based Mendelian randomization, we recently demonstrated that low cognitive performance was bidirectionally associated with a high risk of SCZ and that cognitive impairment unidirectionally affected SCZ-specific genetic factors (Ohi et al, 2021c). Furthermore, we have recently investigated whether polygenetic risk scores (PRSs) differentiating SCZ from BD were associated with the risk of SCZ and intelligence (Ohi et al, 2020b(Ohi et al, , 2021a. The PRS analysis quantifies the combined effects of single-nucleotide polymorphisms (SNPs) across the whole genome on a given clinical outcome, computed as a weighted summation of effect sizes (odds ratios; ORs) of multiple independent SNPs.…”

Overlap between genetic variants associated with schizophrenia spectrum disorders and intelligence quotient: a systematic review

“…28 Accordingly, the large-scale genome-wide association study (GWAS) by Savage and colleagues 29 identified 205 genomic loci associated with intelligence, which they found to be enriched in genes expressed in the brain. Moreover, Ohi and colleagues 30 found that genetic factors differentiating schizophrenia from bipolar disorder were related specifically to low premorbid intelligence. Thus, the identification of genetic variants that contribute to risk of schizophrenia and low IQ could provide insights into the biological correlates of the disorder.…”

Mitochondrial Genetic Variants Associated with Bipolar Disorder and Schizophrenia in a Japanese Population

“…al., 2020a;Ohi et al, 2020b;Ohi et al, 2021). Brie y, venous blood was collected from the participants, and genomic DNA was extracted from whole-blood samples.…”