Shared Genetic Architecture Between Rheumatoid Arthritis and Varying Osteoporotic Phenotypes

Kasher, Melody; Freidin, Maxim B.; Williams, Frances; Cherny, Stacey S.; Malkin, Ida; Livshits, Gregory

doi:10.1002/jbmr.4491

Cited by 8 publications

(5 citation statements)

References 84 publications

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“…MRE analyses between RA and varying OP phenotypes were suggestive of pleiotropy, which was previously shown by us ( 20 ) using polygenic risk score analysis in addition to colocalization and gene enrichment analyses and it is consistent with previous reports ( 18 , 21 ). Several loci have been discovered in relation to both phenotypes, particularly in the major histocompatibility complex ( 18 , 21 ).…”

Section: Discussionsupporting

confidence: 91%

Understanding the complex genetic architecture connecting rheumatoid arthritis, osteoporosis and inflammation: discovering causal pathways

Kasher

Williams

Freidin

et al. 2022

Human Molecular Genetics

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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.

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Section: Discussionsupporting

confidence: 91%

Understanding the complex genetic architecture connecting rheumatoid arthritis, osteoporosis and inflammation: discovering causal pathways

Kasher

Williams

Freidin

et al. 2022

Human Molecular Genetics

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“…Overall, these results are consistent with previous literature indicating connections between autoimmune diseases like SLE, RA, UC and CD and blood tissue [66][67][68], and SLE and RA and regulatory T cells [69][70][71][72][73], and UC and CD and natural killer cells [74][75][76][77]. Moreover, in addition to identifying a few candidate genes (RASA2, TXNDC11, THADA) for SLE, RA, UC and CD that have previously been linked to other allergy, thyroid or metabolic traits, we also validated previous findings linking the PLCL1, IL2RA and UHRF1BP1 genes to SLE and RA [33,[78][79][80][81][82][83][84], and the ATG16L1, C5orf56 and IKZF3 genes to UC and CD [44][45][46][85][86][87][88][89].…”

Section: Discussionsupporting

confidence: 85%

multi-GPA-Tree: Statistical approach for pleiotropy informed and functional annotation tree guided prioritization of GWAS results

Khatiwada,

Yilmaz,

Wolf

et al. 2023

PLoS Comput Biol

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Genome-wide association studies (GWAS) have successfully identified over two hundred thousand genotype-trait associations. Yet some challenges remain. First, complex traits are often associated with many single nucleotide polymorphisms (SNPs), most with small or moderate effect sizes, making them difficult to detect. Second, many complex traits share a common genetic basis due to ‘pleiotropy’ and and though few methods consider it, leveraging pleiotropy can improve statistical power to detect genotype-trait associations with weaker effect sizes. Third, currently available statistical methods are limited in explaining the functional mechanisms through which genetic variants are associated with specific or multiple traits. We propose multi-GPA-Tree to address these challenges. The multi-GPA-Tree approach can identify risk SNPs associated with single as well as multiple traits while also identifying the combinations of functional annotations that can explain the mechanisms through which risk-associated SNPs are linked with the traits. First, we implemented simulation studies to evaluate the proposed multi-GPA-Tree method and compared its performance with existing statistical approaches. The results indicate that multi-GPA-Tree outperforms existing statistical approaches in detecting risk-associated SNPs for multiple traits. Second, we applied multi-GPA-Tree to a systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), and to a Crohn’s disease (CD) and ulcertive colitis (UC) GWAS, and functional annotation data including GenoSkyline and GenoSkylinePlus. Our results demonstrate that multi-GPA-Tree can be a powerful tool that improves association mapping while facilitating understanding of the underlying genetic architecture of complex traits and potential mechanisms linking risk-associated SNPs with complex traits.

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“…Although studies on the associations between RA and osteoporotic phenotypes have been conducted, 23,32,37,40,65,69 including inflammatory factors, 49 studies on the relationship of CLBP with other MSK abnormalities remain limited; however, molecular genetic studies are lacking.…”

Section: Introductionmentioning

confidence: 99%

Insights into the pleiotropic relationships between chronic back pain and inflammation-related musculoskeletal conditions: rheumatoid arthritis and osteoporotic abnormalities

Kasher

Williams

Freidin

et al. 2022

Pain

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Shared Genetic Architecture Between Rheumatoid Arthritis and Varying Osteoporotic Phenotypes

Cited by 8 publications

References 84 publications

Understanding the complex genetic architecture connecting rheumatoid arthritis, osteoporosis and inflammation: discovering causal pathways

Understanding the complex genetic architecture connecting rheumatoid arthritis, osteoporosis and inflammation: discovering causal pathways

multi-GPA-Tree: Statistical approach for pleiotropy informed and functional annotation tree guided prioritization of GWAS results

Insights into the pleiotropic relationships between chronic back pain and inflammation-related musculoskeletal conditions: rheumatoid arthritis and osteoporotic abnormalities

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