Shared genetic architecture and causal relationship between frailty and schizophrenia

The complex relationship between frailty and schizophrenia has yet to be fully understood. This study aims to clarify their relationship by investigating their genetic links. We hypothesize a shared genetic architecture and a bidirectional causal relationship between the two conditions. Utilizing summary genetic data from European genome-wide association studies, we analyzed genetic associations through global and local correlations, shared genomic loci, tissue enrichments, and functional genes. Bidirectional Mendelian Randomization (MR) was employed to infer causality. Our findings show a positive genetic correlation between frailty and schizophrenia (LDSC: r_g = 0.117, p = 6.686 × 10^-7; HDL: r_g = 0.101, p = 5.63 × 10^-13) and local correlations in three genomic regions (chr9: 94167203-96671698, p = 2.21 × 10^-6; chr11: 112459488-114257728, p = 1.01 × 10^-5; and chr18: 77149991-78017158, p = 9.57 × 10^-6). We identified 111 genomic loci associated with both conditions and demonstrated that genetic variants for frailty and schizophrenia share tissue enrichments and functional genes in brain. MR analysis suggests that frailty increases the likelihood of schizophrenia (OR: 1.763, 95% CI: 1.259-2.468, p = 0.001) and vice versa (β: 0.012, 95% CI: 0.006-0.018, p < 0.001). Our research supports the presence of a shared genetic basis and bidirectional causality between frailty and schizophrenia. These findings necessitate further investigation in diverse populations to confirm and expand on this genetic understanding.