A genome-wide cross-trait analysis identifies genomic correlation, pleiotropic loci, and causal relationship between sex hormone-binding globulin and rheumatoid arthritis

Author:

Jiang Yuan,Liu Qianwen,Alfredsson Lars,Klareskog Lars,Kockum Ingrid,Jiang Xia

Abstract

Abstract Background Our study aims to investigate an intrinsic link underlying sex hormone-binding globulin (SHBG) and rheumatoid arthritis (RA), which remains inconclusive in observational settings. Methods Summary statistics were collected from the largest GWAS(s) on SHBG adjusted for BMI (SHBGadjBMI; Noverall = 368,929; Nmen = 180,094; Nwomen = 188,908), crude SHBG (Noverall = 370,125; Nmen = 180,726; Nwomen = 189,473), and RA (Ncase = 22,350; Ncontrol = 74,823). A genome-wide cross-trait design was performed to quantify global and local genetic correlation, identify pleiotropic loci, and infer a causal relationship. Results Among the overall population, a significant global genetic correlation was observed for SHBGadjBMI and RA ($$r_{{\text{g}}}$$ r g  = 0.11, P = 1.0 × 10−4) which was further supported by local signal (1q25.2). A total of 18 independent pleiotropic SNPs were identified, of which three were highly likely causal variants and four were found to have effects on both traits through gene expression mediation. A putative causal association of SHBGadjBMI on RA was demonstrated (OR = 1.20, 95% CI = 1.01–1.43) without evidence of reverse causality (OR = 0.999, 95% CI = 0.997–1.000). Sex-specific analyses revealed distinct shared genetic regions (men: 1q32.1-q32.2 and 5p13.1; women: 1q25.2 and 22q11.21-q11.22) and diverse pleiotropic SNPs (16 in men and 18 in women, nearly half were sex-specific) underlying SHBGadjBMI and RA, demonstrating biological disparities between sexes. Replacing SHBGadjBMI with crude SHBG, a largely similar yet less significant pattern of results was observed. Conclusion Our cross-trait analysis suggests an intrinsic, as well as a sex-specific, link underlying SHBG and RA, providing novel insights into disease etiology.

Funder

Starting grant of Karolinska Institutet

Karolinska Institute

Publisher

Springer Science and Business Media LLC

Subject

Drug Discovery,Genetics,Molecular Biology,Molecular Medicine

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