Identification of Novel Potentially-pleiotropic Variants Associated With Osteoporosis and Obesity Using cFDR method

Hu Y1, Tan LJ1, Chen XD1, Liu Z1, Min SS1, Zeng Q1, Shen H2, Deng HW1,2.

J Clin Endocrinol Metab. 2017 Nov 14. doi: 10.1210/jc.2017-01531. [Epub ahead of print]

Abstract
CONTEXT:

Genome-wide association studies (GWASs) have been successful in identifying loci associated with osteoporosis and obesity. However, the findings just explain a small fraction of the total genetic variance.
OBJECTIVE:

The aim of this study was to identify novel pleiotropic genes important in osteoporosis and obesity.
DESIGN AND SETTING:

A pleiotropic conditional false discovery rate (cFDR) method was applied to three independent GWAS summary statistics of femoral neck bone mineral density (FN BMD), body mass index (BMI) and waist-hip ratio (WHR). Next, differential expression analysis was performed for the potentially pleiotropic genes and weighted genes co-expression analysis (WGCNA) was conducted to identify functional connections between the suggested pleiotropic genes and known osteoporosis/obesity genes using transcriptomic expression datasets in osteoporosis/obesity related cells.
RESULTS:

We identified 7 potentially pleiotropic loci, that is rs3759579 (MARK3), rs2178950 (TRPS1), rs1473 (PUM1), rs9825174 (XXYLT1), rs2047937 (ZNF423), rs17277372 (DNM3), and rs335170 (PRDM6), associated with osteoporosis and obesity. Of these loci, PUM1 gene differentially expressed in osteoporosis related cells (B lymphocytes) and obesity related cells (adipocytes). WGCNA showed that PUM1 positively interacted with several known osteoporosis genes (AKAP11, JAG1 and SPTBN1). ZNF423 was the highly connected intramodular hub gene and interconnected with 21 known osteoporosis related genes, including JAG1, EN1 and FAM3C.
CONCLUSIONS:

Our study identified 7 potentially pleiotropic genes associated with osteoporosis and obesity. The findings may provide new insights into potentially genetic determination and co-determination mechanism of osteoporosis and obesity

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