Hum Mol Genet. 2022 Mar 29:ddac061. doi: 10.1093/hmg/ddac061. Online ahead of print.
ABSTRACT
INTRODUCTION: Rheumatoid arthritis (RA) and osteoporosis (OP) are two comorbid complex inflammatory conditions with evidence of shared genetic background and causal relationships. We aimed to clarify the genetic architecture underlying RA and various OP phenotypes whilst additionally considering an inflammatory component, C-reactive protein (CRP).
MATERIAL AND METHODS: Genome-wide association study summary (GWAS) statistics were acquired from the GEFOS consortium, CHARGE consortium, and UK Biobank. Mendelian randomization (MR) was used to detect the presence of causal relationships. Colocalization analysis was performed to determine shared genetic variants between CRP and OP phenotypes. Analysis of pleiotropy between traits due to shared causal SNPs was performed using pleiotropic analysis under composite null hypothesis (PLACO).
RESULTS: MR analysis was suggestive of horizontal pleiotropy between RA and OP traits. RA was a significant causal risk factor for CRP (β = 0.027, 95%CI = 0.016 to 0.038). There was no evidence of CRP → OP causal relationship, but horizontal pleiotropy was apparent. Colocalization established shared genomic regions between CRP and OP including GCKR and SERPINA1 genes. Pleiotropy arising from shared causal SNPs revealed through the colocalization analysis were all confirmed by PLACO. These genes were found to be involved in the same molecular function ‘protein binding’ (GO:0005515) associated with RA, OP and CRP.
DISCUSSION: We identified three major components explaining the epidemiological relationship among RA, OP and inflammation: (1) Pleiotropy explains a portion of the shared genetic relationship between RA and OP, albeit polygenically; (2) RA contributes to CRP elevation; (3) CRP, which is influenced by RA, demonstrated pleiotropy with OP.
PMID:35349660 | DOI:10.1093/hmg/ddac061
