GWAS of ∼30,000 samples with bone mineral density at multiple skeletal sites and its clinical relevance on fracture prediction, genetic correlations and prioritization of drug targets
Author:
Qian Yu, Xia Jiangwei, Wang Pingyu, Xie Chao, Lin Hong-Li, Li Gloria Hoi-YeeORCID, Yuan Cheng-Da, Qiu Mo-Chang, Fang Yi-Hu, Yu Chun-Fu, Cai Xiang-Chun, Khederzadeh Saber, Zhao Pian-Pian, Yang Meng-Yuan, Zhong Jia-Dong, Li Xin, Guan Peng-Lin, Gu Jia-Xuan, Gai Si-Rui, Yi Xiang-Jiao, Tao Jian-Guo, Chen Xiang, Miao Mao-Mao, Jin Wen, Xu Lin, Xie Shu-Yang, Tian Geng, Yue Hua, Li Guangfei, Xiao Wenjin, Karasik DavidORCID, Xu Youjia, Yang Liu, Huang Fei, Cheung Ching-Lung, Zhang Zhenlin, Zheng Hou-Feng
Abstract
SummaryHere, we conducted genome-wide association studies (GWAS) of dual-energy X-ray absorptiometry (DXA)-derived bone mineral density (BMD) traits at 11 skeletal sites, within over 30,000 European individuals from the UK Biobank. A total of 92 unique and independent loci were identified for 11 DXA-derived BMD traits and fracture, including 5 novel loci (i.e.,ABCA1,CHSY1,CYP24A1,SWAP70andPAX1) and 2 sex-specific loci (i.e.,CYP19A1andCYP3A7). We demonstrated that polygenic risk scores (PRSs) were independently associated with fracture risk. Although incorporating multiple PRSs (metaPRS) with the clinical risk factors (i.e., the FRAX model) exhibited the highest predictive performance, the improvement was marginal in fracture prediction. The metaPRS were capable of stratifying individuals into different trajectories of fracture risk, but clinical risk factors played a more significant role in the stratification. Additionally, we uncovered genetic correlation and shared polygenicity between head BMD and intracranial aneurysm. And the joint associated genes such asPLCE1might play important roles in the shared genetic basis. Finally, by integrating gene expression, and GWAS datasets, we prioritized genes (e.g.ESR1,SREBF1,CCR1andNCOR1) encoding druggable human proteins along with their respective inhibitors/antagonists. In conclusion, this comprehensive investigation revealed new genetic basis for BMD and its clinical relevance on fracture prediction. More importantly, it was suggested that head BMD was genetically correlated with intracranial aneurysm. The prioritization of genetically supported targets implied the potential repurposing drugs (e.g. the n-3 PUFA supplement targeting SREBF1) for the prevention of osteoporosis.HighlightsNinety-two unique and independent genetic signals were associated with eleven DXA-derived BMD traits and fracture, including five previously unreported BMD loci.Although PRSs were independently associated with fracture risk, the predictive performance improved marginally compared to the clinical risk factors.Head BMD was genetically correlated with intracranial aneurysm and the joint-associated genes such asPLCE1might play important roles in the shared genetic basis.The prioritization of genetically-supported targets implied the potential repurposing drugs (for example the n-3 PUFA supplements targeting SREBF1) for the prevention of osteoporosis.
Publisher
Cold Spring Harbor Laboratory
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