Understanding the complex genetic architecture connecting rheumatoid arthritis, osteoporosis and inflammation: discovering causal pathways. Issue 16 (29th March 2022)

• Record Type: Journal Article
• Authors: Kasher, Melody; Williams, Frances M K; Freidin, Maxim B; Malkin, Ida; Cherny, Stacey S; Livshits, Gregory
• Is Part Of: Human molecular genetics. Volume 31:Issue 16(2022)
• Page Start: 2810
• Page End: 2819
• Publication Date: 2022-03-29
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddac061
• Languages: English
• ISSNs: 0964-6906

Abstract

Abstract: 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 while additionally considering an inflammatory component, C-reactive protein (CRP). Genome-wide association study summary statistics were acquired from the GEnetic Factors for OSteoporosis Consortium, Cohorts for Heart and Aging Research 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 owing to shared causal single nucleotide polymorphisms (SNPs) was performed using PL eiotropic A nalysis under CO mposite null hypothesis (PLACO). 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% confidence interval = 0.016–0.038). 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 was 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. 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 and (3) CRP, which is influenced by RA, demonstrated pleiotropy with OP.