Identifying causal brain structures and proteins for osteoarthritis: A large-scale genetic correlation study based on brain imaging-derived phenotypes, transcriptome and proteome

Abstract

This study aimed to validate the causal associations of brain structures with osteoarthritis (OA) and then describe key causal genes and proteins in brain related to OA risk. To explore the genetic correlation and causal relationship between brain structures and OA, linkage disequilibrium score regression (LDSC) and mendelian randomization (MR) were employed. Then a transcriptome-wide association study (TWAS), MR and Bayesian colocalization analysis were conducted, integrating human brain transcriptomes (N=2,970) with OA GWAS findings (N=826,690). Concurrently, a proteome-wide association study (PWAS) was carried out, combining GWAS summary data with human brain proteomes (N=152) provided by Banner using the FUSION pipeline. Finally single cell RNA-Seq (scRNA) eQTL data were used to explore the causal genes in brain cells associated with OA. The amalgamation of results from LDSC and MR provides insight into the brain structures majorly associated with OA, including bilateral putamen, amygdala nuclei, thalamic nuclei, insula, superior temporal gyrus, among others. In cortical tissue, seven genes (CLEC18A, CORO7, ERGIC3, EXOSC6, FEZ2, SPPL2A and UQCC1) displayed significant associations with knee OA risk, alongside five genes (COLGALT2, GNL3, OMA1, PPM1M and RAD9A) connected to hip OA risk. Furthermore, proteins related to knee (ICA1L), hip (DGKE), and thumb (SNAP47) OA have been identified. The MR analysis of scRNA found that CPNE1 in excitatory neuronsand EMILIN2 in OPCs/COPs were causally associated with knee OA, along with protein levels identified in the PWAS. This exploration of the genetics of OA associated with the brain-joint axis has advanced our understanding of the pathogenesis of OA.