Background and objectives: Parkinson’s disease (PD) and schizophrenia often share symptomatology. Psychotic symptoms are prevalent in patients with PD, and similar motor symptoms with extrapyramidal signs are frequently observed in antipsychotic-naïve patients with schizophrenia as well as premorbid families. However, few studies have examined the relationship between PD and schizophrenia. We performed this study to evaluate whether genetic variants which increase PD risk influence the risk of developing schizophrenia, and vice versa. Materials and Methods: Two-sample Mendelian randomization (TSMR) with summary statistics from large-scale genome-wide association studies (GWAS) was applied. Summary statistics were extracted for these instruments from GWAS of PD and schizophrenia; Results: We found an increase in the risk of schizophrenia per one-standard deviation (SD) increase in the genetically-predicted PD risk (inverse-variance weighted method, odds ratio = 1.10; 95% confidence interval, 1.05−1.15; p = 3.49 × 10−5). The association was consistent in sensitivity analyses, including multiple TSMR methods, analysis after removing outlier variants with potential pleiotropic effects, and analysis after applying multiple GWAS subthresholds. No relationships were evident between PD and smoking or other psychiatric disorders, including attention deficit hyperactivity disorder, autism spectrum disorder, bipolar affective disorder, major depressive disorder, Alzheimer’s disease, or alcohol dependence. However, we did not find a reverse relationship; genetic variants increasing schizophrenia risk did not alter the risk of PD; Conclusions: Overall, our findings suggest that increased genetic risk of PD can be associated with increased risk of schizophrenia. This association supports the intrinsic nature of the psychotic symptom in PD rather than medication or environmental effects. Future studies for possible comorbidities and shared genetic structure between the two diseases are warranted.

Occupational attainment, which represents middle-age cognitive activities, is a known proxy marker of cognitive reserve for Alzheimer's disease. Previous genome-wide association studies (GWAS) have identified numerous genetic variants and revealed the genetic architecture of educational attainment, another marker of cognitive reserve. However, the genetic architecture and heritability for occupational attainment remain elusive. We performed a large-scale GWAS of occupational attainment with 248,847 European individuals from the UK Biobank using the proportional odds logistic mixed model method. In this analysis, we defined occupational attainment using the classified job levels formulated in the UK Standard Occupational Classification system considering the individual professional skill and academic level. We identified 30 significant loci (P < 5 × 10−8); 12 were novel variants, unassociated with other traits. Among them, four lead variants were associated with genes expressed in brain tissues by expression quantitative trait loci mapping from 10 brain regions: rs13002946, rs3741368, rs11654986, and rs1627527. The single nucleotide polymorphism (SNP)-based heritability was estimated to be 8.5% (s.e. = 0.004) and partitioned heritability was enriched in the central nervous system and brain tissues. Genetic correlation analysis showed shared genetic backgrounds between occupational attainment and multiple traits, including education, intelligence, leisure activities, life satisfaction, and neuropsychiatric disorders. In two-sample Mendelian randomization (MR) analysis, we demonstrated that high occupation levels were associated with reduced risk for Alzheimer's disease (OR = 0.78, 95% CI = 0.65–0.92 in inverse variance weighted (IVW) method; OR = 0.73, 95% CI = 0.57–0.92 in the weighted median (WM) method). This causal relationship between occupational attainment and Alzheimer's disease was robust in additional sensitivity analysis that excluded potentially pleiotropic SNPs (OR = 0.72, 95% CI = 0.57–0.91 in the IVW method; OR = 0.72, 95% CI = 0.53–0.97 in the WM method). Multivariable MR confirmed that occupational attainment had an independent effect on the risk for Alzheimer’s disease even after taking educational attainment into account (OR = 0.72, 95% CI = 0.54–0.95 in the IVW method; OR = 0.68, 95% CI = 0.48–0.97 in the WM method). Overall, our analyses provide insights into the genetic architecture of occupational attainment and demonstrate that occupational attainment is a potential causal protective factor for Alzheimer's disease as a proxy marker of cognitive reserve.

Cardiovascular disease (CVD), the leading cause of death globally, is associated with complicated underlying risk factors. We develop an artificial intelligence model to identify CVD using multimodal data, including clinical risk factors and fundus photographs from the Samsung Medical Center (SMC) for development and internal validation and from the UK Biobank for external validation. The multimodal model achieves an area under the receiver operating characteristic curve (AUROC) of 0.781 (95% confidence interval [CI] 0.766–0.798) in the SMC and 0.872 (95% CI 0.857–0.886) in the UK Biobank. We further observe a significant association between the incidence of CVD and the predicted risk from at-risk patients in the UK Biobank (hazard ratio [HR] 6.28, 95% CI 4.72–8.34). We visualize the importance of individual features in photography and traditional risk factors. The results highlight that non-invasive fundus photography can be a possible predictive marker for CVD.