Identification of novel genetic loci for osteoporosis and/or rheumatoid arthritis using cFDR approach

Abstract

There are co-morbidity between osteoporosis (OP) and rheumatoid arthritis (RA). Some genetic risk factors have been identified for these two phenotypes respectively in previous research; however, they accounted for only a small portion of the underlying total genetic variances. Here, we sought to identify additional common genetic loci associated with OP and/or RA. The conditional false discovery rate (cFDR) approach allows detection of additional genetic factors (those respective ones as well as common pleiotropic ones) for the two associated phenotypes. We collected and analyzed summary statistics provided by large, multi-center GWAS studies of FNK (femoral neck) BMD (a major risk factor for osteoporosis) (n = 53,236) and RA (n = 80,799). The conditional quantile-quantile (Q-Q) plots can assess the enrichment of SNPs related to FNK BMD and RA, respectively. Furthermore, we identified shared loci between FNK BMD and RA using conjunction cFDR (ccFDR). We found strong enrichment of p-values in FNK BMD when conditional Q-Q was done on RA and vice versa. We identified 30 novel OP-RA associated pleiotropic loci that have not been reported in previous OP or RA GWAS, 18 of which located in the MHC (major histocompatibility complex) region previously reported to play an important role in immune system and bone health. We identified some specific novel polygenic factors for OP and RA respectively, and identified 30 novel OP-RA associated pleiotropic loci. These discovery findings may offer novel pathobiological insights, and suggest new targets and pathways for drug development in OP and RA patients.

Fig 1. Conditional QQ plots.

Conditional QQ plots of nominal versus empirical –log₁₀ p-values for (A) FNK BMD as a function of significance of the association with RA, and (B) RA as a function of significance of the association with FNK BMD. The diagonal line represents the null hypothesis.

Fig 2

A) ‘‘Conditional Manhattan plot” of conditional –log₁₀ FDR values for FNK BMD given RA (FNK BMD|RA); B) “Conditional Manhattan plot” of conditional –log₁₀ FDR values for RA given FNK BMD(RA|FNK BMD); C) “Conjunction Manhattan plot” of conjunction –log₁₀ FDR values for FNK BMD and RA. SNPs with conditional -log₁₀ FDR>1.3 (i.e. FDR<0.05) are shown above the red line.