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bioRxiv · 10.1101/2021.11.04.467171

Identification of known and novel long non-coding RNAs potentially responsible for the effects of BMD GWAS loci

Abood, A.·Mesner, L.·Rosenow, W.·Al-Barghouthi, B. M.·Horwitz, N.·Morgan, E. F.·Gerstenfeld, L. C.·Farber, C. R.
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Abstract

Osteoporosis, characterized by low bone mineral density (BMD), is the most common complex disease affecting bone and constitutes a major societal health problem. Genome-wide association studies (GWASs) have identified over 1100 associations influencing BMD. It has been shown that perturbations to long non-coding RNAs (lncRNAs) influence BMD and the activities of bone cells; however, the extent to which lncRNAs are involved in the genetic regulation of BMD is unknown. Here, we combined the analysis of allelic imbalance (AI) in human acetabular bone fragments with a transcriptome-wide association study (TWAS) and expression quantitative trait loci (eQTL) colocalization analysis using data from the Genotype-Tissue Expression (GTEx) project to identify lncRNAs potentially responsible for GWAS associations. We identified 27 lncRNAs in bone that are located in proximity to a BMD GWAS association and harbor SNPs demonstrating AI. Using GTEx data we identified an additional 31 lncRNAs whose expression was associated (FDR correction<0.05) with BMD through TWAS and had a colocalizing eQTL (regional colocalization probability (RCP)>0.1). The 58 lncRNAs are located in 43 BMD associations. To further support a causal role for the identified lncRNAs, we show that 23 of the 58 lncRNAs are differentially expressed as a function of osteoblast differentiation. Our approach identifies lncRNAs that are potentially responsible for BMD GWAS associations and suggest that lncRNAs play a role in the genetics of osteoporosis.

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Abood, A., Mesner, L., Rosenow, W., Al-Barghouthi, B. M., Horwitz, N., Morgan, E. F., Gerstenfeld, L. C., Farber, C. R.. 2021-11-08. Identification of known and novel long non-coding RNAs potentially responsible for the effects of BMD GWAS loci. https://doi.org/10.1101/2021.11.04.467171

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