Mouse genome-wide association and systems genetics identifies Lhfp as a regulator of bone mass

Larry D Mesner,John P Sundberg,Cheryl L Ackert-Bicknell,Daniel M Gatti,Gary A Churchill,Charles R Farber,Basel Al-Barghouthi,Dana A Godfrey,Gina M Calabrese,Benedikt Hallgrimsson

doi:10.1371/journal.pgen.1008123

Larry D Mesner, John P Sundberg + Show 8 more

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https://doi.org/10.1371/journal.pgen.1008123

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Abstract

Bone mineral density (BMD) is a strong predictor of osteoporotic fracture. It is also one of the most heritable disease-associated quantitative traits. As a result, there has been considerable effort focused on dissecting its genetic basis. Here, we performed a genome-wide association study (GWAS) in a panel of inbred strains to identify associations influencing BMD. This analysis identified a significant (P = 3.1 x 10−12) BMD locus on Chromosome 3@52.5 Mbp that replicated in two separate inbred strain panels and overlapped a BMD quantitative trait locus (QTL) previously identified in a F2 intercross. The association mapped to a 300 Kbp region containing four genes; Gm2447, Gm20750, Cog6, and Lhfp. Further analysis found that Lipoma HMGIC Fusion Partner (Lhfp) was highly expressed in bone and osteoblasts. Furthermore, its expression was regulated by a local expression QTL (eQTL), which overlapped the BMD association. A co-expression network analysis revealed that Lhfp was strongly connected to genes involved in osteoblast differentiation. To directly evaluate its role in bone, Lhfp deficient mice (Lhfp-/-) were created using CRISPR/Cas9. Consistent with genetic and network predictions, bone marrow stromal cells (BMSCs) from Lhfp-/- mice displayed increased osteogenic differentiation. Lhfp-/- mice also had elevated BMD due to increased cortical bone mass. Lastly, we identified SNPs in human LHFP that were associated (P = 1.2 x 10−5) with heel BMD. In conclusion, we used GWAS and systems genetics to identify Lhfp as a regulator of osteoblast activity and bone mass.

Highlights

It is currently estimated that half of all Americans over the age of 50 already have or are at high risk of developing osteoporosis [1]
Osteoporosis is a common, chronic disease characterized by low bone mineral density (BMD) that puts millions of Americans at high risk of fracture
Lipoma HMGIC Fusion Partner (Lhfp) is a genetic determinant of Bone mineral density (BMD)

Summary

Introduction

It is currently estimated that half of all Americans over the age of 50 already have or are at high risk of developing osteoporosis [1]. Bone mineral density (BMD) is used clinically to diagnose osteoporosis and beyond age, it is the single strongest predictor of the risk of fracture [2]. BMD is one of the most heritable disease-associated quantitative traits with studies demonstrating that up to 80% of the variance in peak bone mass is heritable [3,4,5,6]. Consistent with its high heritability, genome-wide association studies (GWASs) in humans have identified hundreds of loci for BMD [7,8,9]. There remains much to be discovered regarding the genetics of bone mass and genetic mapping efforts using mouse models is a complementary approach to identify novel regulators of bone mass [11,12,13]

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