Converging evidence from exome sequencing and common variants implicates target genes for osteoporosis

In this study, we leveraged the combined evidence of rare coding variants and common alleles to identify therapeutic targets for osteoporosis. We undertook a large-scale multiancestry exome-wide association study for estimated bone mineral density, which showed that the burden of rare coding alleles in 19 genes was associated with estimated bone mineral density (P<3.6x10(-7)). These genes were highly enriched for a set of known causal genes for osteoporosis (65-fold; P=2.5x10(-5)). Exome-wide significant genes had 96-fold increased odds of being the top ranked effector gene at a given GWAS locus (P=1.8x10(-10)). By integrating proteomics Mendelian randomization evidence, we prioritized CD109 (cluster of differentiation 109) as a gene for which heterozygous loss of function is associated with higher bone density. CRISPR-Cas9 editing of CD109 in SaOS-2 osteoblast-like cell lines showed that partial CD109 knockdown led to increased mineralization. This study demonstrates that the convergence of common and rare variants, proteomics and CRISPR can highlight new bone biology to guide therapeutic development. Analysis of exome sequencing data identifies a burden of rare coding variants in 19 genes associated with bone mineral density. Integrated analyses show convergence of common- and rare-variant signals and highlight likely effector genes influencing osteoporosis risk.

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Medicinsk genetik hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Medical Genetics hsv//eng
cell-adhesion molecule-1
mendelian randomization
bone mass
identification
determinants
instruments
ultrasound
expression
heel
gwas
Genetics & Heredity

Sosina, O. A. (author)
Bovijn, J. (author)
Laurent, L. (author)
Sharma, V. (author)
Akbari, P. (author)
Forgetta, V. (author)
Jiang, L. (author)
Kosmicki, J. A. (author)
Banerjee, N. (author)
Morris, J. A. (author)
Oerton, E. (author)
Jones, M. (author)
LeBlanc, M. G. (author)
Idone, V. (author)
Overton, J. D. (author)
Reid, J. G. (author)
Cantor, M. (author)
Abecasis, G. R. (author)
Goltzman, D. (author)
Greenwood, C. M. T. (author)
Langenberg, C. (author)
Baras, A. (author)
Economides, A. N. (author)
Ferreira, M. A. R. (author)
Hatsell, S. (author)
Ohlsson, Claes,1965Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition,Centre for Bone and Arthritis Research,Institute of Medicine, Department of Internal Medicine and Clinical Nutrition(Swepub:gu)xohlcl (author)
Richards, J. B. (author)
Lotta, L. A. (author)
Regeneron Genetics, Ctr (author)
Göteborgs universitetInstitutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition (creator_code:org_t)

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Medical Genetics

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