Dataset Information

Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects.

ABSTRACT: Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

SUBMITTER: Medina-Gomez C

PROVIDER: S-EPMC5777980 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects.

Medina-Gomez Carolina C Kemp John P JP Trajanoska Katerina K Luan Jian'an J Chesi Alessandra A Ahluwalia Tarunveer S TS Mook-Kanamori Dennis O DO Ham Annelies A Hartwig Fernando P FP Evans Daniel S DS Joro Raimo R Nedeljkovic Ivana I Zheng Hou-Feng HF Zhu Kun K Atalay Mustafa M Liu Ching-Ti CT Nethander Maria M Broer Linda L Porleifsson Gudmar G Mullin Benjamin H BH Handelman Samuel K SK Nalls Mike A MA Jessen Leon E LE Heppe Denise H M DHM Richards J Brent JB Wang Carol C Chawes Bo B Schraut Katharina E KE Amin Najaf N Wareham Nick N Karasik David D Van der Velde Nathalie N Ikram M Arfan MA Zemel Babette S BS Zhou Yanhua Y Carlsson Christian J CJ Liu Yongmei Y McGuigan Fiona E FE Boer Cindy G CG Bønnelykke Klaus K Ralston Stuart H SH Robbins John A JA Walsh John P JP Zillikens M Carola MC Langenberg Claudia C Li-Gao Ruifang R Williams Frances M K FMK Harris Tamara B TB Akesson Kristina K Jackson Rebecca D RD Sigurdsson Gunnar G den Heijer Martin M van der Eerden Bram C J BCJ van de Peppel Jeroen J Spector Timothy D TD Pennell Craig C Horta Bernardo L BL Felix Janine F JF Zhao Jing Hua JH Wilson Scott G SG de Mutsert Renée R Bisgaard Hans H Styrkársdóttir Unnur U Jaddoe Vincent W VW Orwoll Eric E Lakka Timo A TA Scott Robert R Grant Struan F A SFA Lorentzon Mattias M van Duijn Cornelia M CM Wilson James F JF Stefansson Kari K Psaty Bruce M BM Kiel Douglas P DP Ohlsson Claes C Ntzani Evangelia E van Wijnen Andre J AJ Forgetta Vincenzo V Ghanbari Mohsen M Logan John G JG Williams Graham R GR Bassett J H Duncan JHD Croucher Peter I PI Evangelou Evangelos E Uitterlinden Andre G AG Ackert-Bicknell Cheryl L CL Tobias Jonathan H JH Evans David M DM Rivadeneira Fernando F

American journal of human genetics 20180101 1

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide ...[more]

PMID: 29304378

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Project description:To identify genetic loci influencing bone accrual, we performed a genome-wide association scan for total-body bone mineral density (TB-BMD) variation in 2,660 children of different ethnicities. We discovered variants in 7q31.31 associated with BMD measurements, with the lowest P = 4.1 × 10(-11) observed for rs917727 with minor allele frequency of 0.37. We sought replication for all SNPs located ± 500 kb from rs917727 in 11,052 additional individuals from five independent studies including children and adults, together with de novo genotyping of rs3801387 (in perfect linkage disequilibrium (LD) with rs917727) in 1,014 mothers of children from the discovery cohort. The top signal mapping in the surroundings of WNT16 was replicated across studies with a meta-analysis P = 2.6 × 10(-31) and an effect size explaining between 0.6%-1.8% of TB-BMD variance. Conditional analyses on this signal revealed a secondary signal for total body BMD (P = 1.42 × 10(-10)) for rs4609139 and mapping to C7orf58. We also examined the genomic region for association with skull BMD to test if the associations were independent of skeletal loading. We identified two signals influencing skull BMD variation, including rs917727 (P = 1.9 × 10(-16)) and rs7801723 (P = 8.9 × 10(-28)), also mapping to C7orf58 (r(2) = 0.50 with rs4609139). Wnt16 knockout (KO) mice with reduced total body BMD and gene expression profiles in human bone biopsies support a role of C7orf58 and WNT16 on the BMD phenotypes observed at the human population level. In summary, we detected two independent signals influencing total body and skull BMD variation in children and adults, thus demonstrating the presence of allelic heterogeneity at the WNT16 locus. One of the skull BMD signals mapping to C7orf58 is mostly driven by children, suggesting temporal determination on peak bone mass acquisition. Our life-course approach postulates that these genetic effects influencing peak bone mass accrual may impact the risk of osteoporosis later in life.

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Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects.

Publications

Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects.

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