An atlas of genetic influences on osteoporosis in humans and mice

Abstract

Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound (eBMD) in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with eBMD, in ~1.2M individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds-ratio=58, p=10 −75 ) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice lacking target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (p<0.0001). In-depth analysis of one gene, DAAM2 , showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence testing how to link associated-SNPs to causal genes, offers new insights into osteoporosis pathophysiology and highlights opportunities for drug development.

A Rare Mutation in SMAD9 Associated With High Bone Mass Identifies the SMAD-Dependent BMP Signaling Pathway as a Potential Anabolic Target for Osteoporosis

“…In the recent UK Biobank eBMD GWAS, LD score regression analyses suggested that the genetic architecture influencing male and female eBMD was largely shared with some significant differences between the sexes (rG = 0.91, SE = 0.012, p < 0.001), (17) consistent with earlier epidemiological studies. All individuals with c.65T>C, p. Leu22Pro SMAD9 HBM were female, reflecting the study design that favored those with a historical DXA scan who are more likely to be female.…”

“…Common variants intersecting SMAD9 associate with population-based measures of eBMD, as evidenced recently by fine-mapping of target genes (17,44) and from our gene-based tests of association presented here. Common variants intersecting SMAD9 associate with population-based measures of eBMD, as evidenced recently by fine-mapping of target genes (17,44) and from our gene-based tests of association presented here.…”

“…(57) An activating heterozygous p.Val90Met germline mutation, affecting the 4th α-helix of MH1 and close to the DNA binding interface, has been described in one pedigree with hamartomatous polyposis. (17) The phenotype we describe here contrasts with that of activating mutations of the BMP receptor, ACVR1, which increase BMP signaling. (58) Such examples of diverse phenotypes arising from mutations in differing exons of the same gene are well recognized, eg, differing mutations in FBN1 (Fibrillin 1) can cause Marfan syndrome (with associated tall stature) (OMIM#154700), acromicric dysplasias (with short stature) (OMIM#102370), or stiff skin syndrome (OMIM#184900).…”

“…(17) Gene-based tests of association were implemented in MAGMA v1.06 (18) using a multimodel approach combining association results from three separate gene analysis models: principal components regression, single-nucleotide polymorphism (SNP)-wise mean chi-square model (ie, test statistic derived as sum of -log(SNP p value)) and SNP-wise top chi-square model (test statistic derived as sum of -log(SNP p value) for top SNPs) to produce an aggregate p value corresponding to the association between each of the 19,361 protein coding genes (AE20 kb) and BMD, adjusting for age, sex, genotyping array, assessment center, and 20 ancestry informative principal components, with gene-based significance threshold (p < 2.87 × 10 −6 ). (17) Gene expression in murine osteocytes Whole transcriptome sequencing data from the primary osteocytes of four different bone types (tibia, femur, humerus, and calvaria) from mice (marrow removed, n = 8 per bone) were analyzed. nl/), an online database of publicly available summary results statistics from 4,155 GWAS from 295 unique studies across 2960 unique traits and 27 domains.…”

“…Common SMAD9-associated genetic variants and BMD Publicly available data from a recent population-based genomewide association study (GWAS) of eBMD (estimated BMD by heel ultrasound in the UK Biobank study) (17) were used to investigate variants surrounding both SMAD9 and CHRNA1. Regional association plots suggested that SNPs intersecting SMAD9 are strongly associated with eBMD (lead SNP rs12427846 [MAF 0.25], β 0.02, SE 0.002, p = 5.5 × 10 −16 ; Fig.…”