Identification of PDXDC1 as a novel pleiotropic susceptibility locus shared between lumbar spine bone mineral density and birth weight

Author:

Song Yu-Qian,Hu Shi-Di,Lin Xu,Meng Xiang-He,Wang Xiao,Zhang Yin-Hua,Peng Cheng,Gong Rui,Xu Tao,Zhang Tong,Li Chen-Zhong,Pan Dao-Yan,Yang Jia-Yi,Greenbaum Jonathan,Shen JieORCID,Deng Hong-Wen

Abstract

Abstract An increasing number of epidemiological studies have suggested that birth weight (BW) may be a determinant of bone health later in life, although the underlying genetic mechanism remains unclear. Here, we applied a pleiotropic conditional false discovery rate (cFDR) approach to the genome-wide association study (GWAS) summary statistics for lumbar spine bone mineral density (LS BMD) and BW, aiming to identify novel susceptibility variants shared between these two traits. We detected 5 novel potential pleiotropic loci which are located at or near 7 different genes (NTAN1, PDXDC1, CACNA1G, JAG1, FAT1P1, CCDC170, ESR1), among which PDXDC1 and FAT1P1 have not previously been linked to these phenotypes. To partially validate the findings, we demonstrated that the expression of PDXDC1 was dramatically reduced in ovariectomized (OVX) mice in comparison with sham-operated (SHAM) mice in both the growth plate and trabecula bone. Furthermore, immunohistochemistry assay with serial sections showed that both osteoclasts and osteoblasts express PDXDC1, supporting its potential role in bone metabolism. In conclusion, our study provides insights into some shared genetic mechanisms for BMD and BW as well as a novel potential therapeutic target for the prevention of OP in the early stages of the disease development. Key messages We investigated pleiotropy-informed enrichment between LS BMD and BW. We identified genetic variants related to both LS BMD and BW by utilizing a cFDR approach. PDXDC1 is a novel pleiotropic gene which may be related to both LS BMD and BW. Elevated expression of PDXDC1 is related to higher BMD and lower ratio n-6/n-3 PUFA indicating a bone protective effect of PDXDC1.

Funder

foundation for the national institutes of health

the edward g. schlieder endowment fund to tulane university

the science and technology program of guangzhou

national natural science foundation of china

the phd start-up fund of natural science foundation of guangdong province

medical science and technology foundation of guangdong province

guangzhou planed project of science and technology

Publisher

Springer Science and Business Media LLC

Subject

Genetics (clinical),Drug Discovery,Molecular Medicine

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