Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis

Kemp, John P.; Morris, John A.; Medina‐Gomez, Carolina; Forgetta, Vincenzo; Warrington, Nicole M.; Youlten, Scott E.; Zheng, Jie; Gregson, Celia L; Grundberg, Elin; Trajanoska, Katerina; Logan, John G.; Pollard, Andrea S.; Sparkes, Penny C; Ghirardello, Elena J.; Allen, Rebecca S.; Leitch, Victoria; Butterfield, Natalie C.; Komla-Ebri, Davide; Adoum, Anne‐Tounsia; Curry, Katharine F.; White, Jacqueline K.; Kussy, Fiona; Greenlaw, Keelin; Xu, Changjiang; Harvey, Nicholas C.; Cooper, Cyrus; Adams, David J.; Greenwood, Celia M.T.; Maurano, Matthew T.; Kaptoge, Stephen; Rivadeneira, Fernando; Tobias, Jonathan H; Croucher, Peter I.; Ackert‐Bicknell, Cheryl; Bassett, J. H. Duncan; Williams, Graham R.; Richards, J. Brent; Evans, David M.

doi:10.1038/ng.3949

Cited by 423 publications

(494 citation statements)

References 65 publications

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“…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.…”

Section: Discussionsupporting

confidence: 79%

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

Gregson

Bergen

Leo

et al. 2019

Journal of Bone and Mineral Research

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Novel anabolic drug targets are needed to treat osteoporosis. Having established a large national cohort with unexplained high bone mass (HBM), we aimed to identify a novel monogenic cause of HBM and provide insight into a regulatory pathway potentially amenable to therapeutic intervention. We investigated a pedigree with unexplained HBM in whom previous sequencing had excluded known causes of monogenic HBM. Whole exome sequencing identified a rare (minor allele frequency 0.0023), highly evolutionarily conserved missense mutation in SMAD9 (c.65T>C, p.Leu22Pro) segregating with HBM in this autosomal dominant family. The same mutation was identified in another two unrelated individuals both with HBM. In silico protein modeling predicts the mutation severely disrupts the MH1 DNA‐binding domain of SMAD9. Affected individuals have bone mineral density (BMD) Z‐scores +3 to +5, mandible enlargement, a broad frame, torus palatinus/mandibularis, pes planus, increased shoe size, and a tendency to sink when swimming. Peripheral quantitative computed tomography (pQCT) measurement demonstrates increased trabecular volumetric BMD and increased cortical thickness conferring greater predicted bone strength; bone turnover markers are low/normal. Notably, fractures and nerve compression are not found. Both genome‐wide and gene‐based association testing involving estimated BMD measured at the heel in 362,924 white British subjects from the UK Biobank Study showed strong associations with SMAD9 (PGWAS = 6 × 10−16; PGENE = 8 × 10−17). Furthermore, we found Smad9 to be highly expressed in both murine cortical bone–derived osteocytes and skeletal elements of zebrafish larvae. Our findings support SMAD9 as a novel HBM gene and a potential novel osteoanabolic target for osteoporosis therapeutics. SMAD9 is thought to inhibit bone morphogenetic protein (BMP)‐dependent target gene transcription to reduce osteoblast activity. Thus, we hypothesize SMAD9 c.65T>C is a loss‐of‐function mutation reducing BMP inhibition. Lowering SMAD9 as a potential novel anabolic mechanism for osteoporosis therapeutics warrants further investigation. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

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Section: Discussionsupporting

confidence: 79%

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

Gregson

Bergen

Leo

et al. 2019

Journal of Bone and Mineral Research

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“…For the 149 genes located in the 32 genome-wide-significant loci ( r 2 >0.5 in Europeans or East Asians, or located ±50 kb from the lead SNP; Methods), we assigned an empirical functional score based on the presence and number of eQTLs, meQTLs, pQTLs, and other biological criteria 57,58 (Methods and Supplementary Table 24), reasoning that genes with a higher functional score would be more likely to be causal, although this score requires validation by experimental data.…”

Section: Resultsmentioning

confidence: 99%

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

2018

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Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

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“…Kemp et al [5] recently reported a largest genome-wide association study (GWAS) of BMD as estimated by quantitative ultrasound of the heel in 142,487 individuals from the UK Biobank. The summary results are publicly available in the GEFOS website.…”

Section: Methodsmentioning

confidence: 99%

“…Genome-wide association study (GWAS) and their meta-analysis are a powerful approach to identify common variants associated with complex traits including BMD. In the past decade, over one hundred BMD loci have been discovered by a number of GWAS studies [4–7], explaining 12% of BMD heritability [5]. However, the explained heritability only accounts for one-third of GWAS-attributable heritability [5].…”

Section: Introductionmentioning

confidence: 99%

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Joint study of two genome-wide association meta-analyses identified 20p12.1 and 20q13.33 for bone mineral density

Pei

Yan

et al. 2018

Bone

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In the present study, aiming to identify loci associated with osteoporosis, we conducted a joint association study of 2 independent genome-wide association meta-analyses of femoral neck and lumbar spine bone mineral densities (BMDs): 1) an in-house study of 6 samples involving 7484 subjects, and 2) the GEFOS-seq study of 7 samples involving 32,965 subjects. The in-house samples were imputed by the 1000 genomes project phase 3 reference panel. SNP-based association test was applied to 7,998,108 autosomal SNPs in each meta-analysis, and for each SNP the 2 association signals were then combined for joint analysis and for mutual replication. Combining the evidence from both studies, we identified 2 novel loci associated with BMDs at the genome-wide significance level (α=5.0×10): 20p12.1 (rs73100693 p=2.65×10, closest gene MACROD2) and 20q13.33 (rs2380128 p=3.44×10, OSBPL2). We also replicated 7 loci that were reported by two recent studies on heel and total body BMD. Our findings provide useful insights that enhance our understanding of bone development, osteoporosis and fracture pathogenesis.

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Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis

Cited by 423 publications

References 65 publications

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

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

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

Joint study of two genome-wide association meta-analyses identified 20p12.1 and 20q13.33 for bone mineral density

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