TY - JOUR
T1 - Understanding the complex genetic architecture connecting rheumatoid arthritis, osteoporosis and inflammation
T2 - discovering causal pathways
AU - CHARGE Inflammation Working Group
AU - Kasher, Melody
AU - Williams, Frances M.K.
AU - Freidin, Maxim B.
AU - Malkin, Ida
AU - Cherny, Stacey S.
AU - Livshits, Gregory
AU - Benjamin, Emelia
AU - Chasman, Daniel I.
AU - Dehghan, Abbas
AU - Ahluwalia, Tarunveer Singh
AU - Meigs, James
AU - Tracy, Russell
AU - Alizadeh, Behrooz Z.
AU - Ligthart, Symen
AU - Bis, Josh
AU - Eiriksdottir, Gudny
AU - Pankratz, Nathan
AU - Gross, Myron
AU - Rainer, Alex
AU - Snieder, Harold
AU - Wilson, James G.
AU - Psaty, Bruce M.
AU - Dupuis, Josee
AU - Prins, Bram
AU - Vaso, Urmo
AU - Stathopoulou, Maria
AU - Franke, Lude
AU - Lehtimaki, Terho
AU - Koenig, Wolfgang
AU - Jamshidi, Yalda
AU - Siest, Sophie
AU - Abbasi, Ali
AU - Uitterlinden, Andre G.
AU - Abdollahi, Mohammadreza
AU - Schnabel, Renate
AU - Schick, Ursula M.
AU - Nolte, Ilja M.
AU - Kraja, Aldi
AU - Hsu, Yi Hsiang
AU - Tylee, Daniel S.
AU - Zwicker, Alyson
AU - Uher, Rudolf
AU - Davey-Smith, George
AU - Morrison, Alanna C.
AU - Hicks, Andrew
AU - Van Duijn, Cornelia M.
AU - Ward-Caviness, Cavin
AU - Boerwinkle, Eric
AU - Rotter, J.
AU - Rice, Ken
N1 - Publisher Copyright:
© 2022 The Author(s). Published by Oxford University Press.
PY - 2022/8/15
Y1 - 2022/8/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85137126102&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddac061
DO - 10.1093/hmg/ddac061
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C2 - 35349660
AN - SCOPUS:85137126102
SN - 0964-6906
VL - 31
SP - 2810
EP - 2819
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 16
ER -