Identifying Pleiotropic SNPs Associated With Femoral Neck and Heel Bone Mineral Density

Pei He; Xiang-He Meng; Xiao Zhang; Xu Lin; Qiang Zhang; Ri-Li Jiang; Martin R Schiller; Fei-Yan Deng; Hong-Wen Deng

doi:10.3389/fgene.2020.00772

Identifying Pleiotropic SNPs Associated With Femoral Neck and Heel Bone Mineral Density

Front Genet. 2020 Jul 22:11:772. doi: 10.3389/fgene.2020.00772. eCollection 2020.

Authors

Pei He^{1

2}, Xiang-He Meng^{2

3

4}, Xiao Zhang², Xu Lin^{2

5}, Qiang Zhang^{2

6}, Ri-Li Jiang², Martin R Schiller⁷, Fei-Yan Deng¹, Hong-Wen Deng^{2

3

4}

Affiliations

¹ Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, China.
² Center for Bioinformatics and Genomics, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, United States.
³ Center of Reproductive Health, System Biology and Data Information, School of Basic Medical Science, Central South University, Changsha, China.
⁴ Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, China.
⁵ Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
⁶ College of Public Health, Zhengzhou University, Zhengzhou, China.
⁷ Nevada Institute of Personalized Medicine, School of Life Sciences, University of Nevada, Las Vegas, Las Vegas, NV, United States.

Abstract

Background: Genome-wide association studies (GWASs) routinely identify loci associated with risk factors for osteoporosis. However, GWASs with relatively small sample sizes still lack sufficient power to ascertain the majority of genetic variants with small to modest effect size, which may together truly influence the phenotype. The loci identified only account for a small percentage of the heritability of osteoporosis. This study aims to identify novel genetic loci associated with DXA-derived femoral neck (FNK) bone mineral density (BMD) and quantitative ultrasound of the heel calcaneus estimated BMD (eBMD), and to detect shared/causal variants for the two traits, to assess whether the SNPs or putative causal SNPs associated with eBMD were also associated with FNK-BMD.

Methods: Novel loci associated with eBMD and FNK-BMD were identified by the genetic pleiotropic conditional false discovery rate (cFDR) method. Shared putative causal variants between eBMD and FNK-BMD and putative causal SNPs for each trait were identified by the colocalization method. Mendelian randomization analysis addresses the causal relationship between eBMD/FNK-BMD and fracture.

Results: We identified 9,500 (cFDR < 9.8E-6), 137 (cFDR < 8.9E-4) and 124 SNPs associated with eBMD, FNK-BMD, and both eBMD and FNK-BMD, respectively, with 37 genomic regions where there was a SNP that influences both eBMD and FNK-BMD. Most genomic regions only contained putative causal SNPs associated with eBMD and 3 regions contained two distinct putative causal SNPs influenced both traits, respectively. We demonstrated a causal effect of FNK-BMD/eBMD on fracture.

Conclusion: Most of SNPs or putative causal SNPs associated with FNK-BMD were also associated with eBMD. However, most of SNPs or putative causal SNPs associated with eBMD were not associated with FNK-BMD. The novel variants we identified may help to account for the additional proportion of variance of each trait and advance our understanding of the genetic mechanisms underlying osteoporotic fracture.

Keywords: Mendelian randomization; cFDR; causal; colocalization analysis; osteoporosis; pleiotropic.

Abstract

Grants and funding