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Genome-wide association study using family-based cohorts identifies the WLS and CCDC170/ESR1 loci as associated with bone mineral density.

ABSTRACT: Osteoporosis is a common and debilitating bone disease that is characterised by a low bone mineral density (BMD), a highly heritable trait. Genome-wide association studies (GWAS) have proven to be very successful in identifying common genetic variants associated with BMD adjusted for age, gender and weight, however a large portion of the genetic variance for this trait remains unexplained. There is evidence to suggest significant genetic correlation between body size traits and BMD. It has also recently been suggested that unintended bias can be introduced as a result of adjusting a phenotype for a correlated trait. We performed a GWAS meta-analysis in two populations (total n = 6,696) using BMD data adjusted for only age and gender, in an attempt to identify genetic variants associated with BMD including those that may have potential pleiotropic effects on BMD and body size traits.We observed a single variant, rs2566752, associated with spine BMD at the genome-wide significance level in the meta-analysis (P = 3.36 × 10(-09)). Logistic regression analysis also revealed an association between rs2566752 and fracture rate in one of our study cohorts (P = 0.017, n = 5,654). This is an intronic variant located in the wntless Wnt ligand secretion mediator (WLS) gene (1p31.3), a known BMD locus which encodes an integral component of the Wnt ligand secretion pathway. Bioinformatics analyses of variants in moderate LD with rs2566752 produced strong evidence for a regulatory role for the variants rs72670452, rs17130567 and rs1430738. Expression quantitative trait locus (eQTL) analysis suggested that the variants rs12568456 and rs17130567 are associated with expression of the WLS gene in whole blood, cerebellum and temporal cortex brain tissue (P = 0.034-1.19 × 10(-23)). Gene-wide association testing using the VErsatile Gene-based Association Study 2 (VEGAS2) software revealed associations between the coiled-coil domain containing 170 (CCDC170) gene, located adjacent to the oestrogen receptor 1 (ESR1) gene, and BMD at the spine, femoral neck and total hip sites (P = 1.0 × 10(-06), 2.0 × 10(-06) and 2.0 × 10(-06) respectively).Genetic variation at the WLS and CCDC170/ESR1 loci were found to be significantly associated with BMD adjusted for only age and gender at the genome-wide level in this meta-analysis.

SUBMITTER: Mullin BH

PROVIDER: S-EPMC4766752 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Genome-wide association study using family-based cohorts identifies the WLS and CCDC170/ESR1 loci as associated with bone mineral density.

Mullin Benjamin H BH Walsh John P JP Zheng Hou-Feng HF Brown Suzanne J SJ Surdulescu Gabriela L GL Curtis Charles C Breen Gerome G Dudbridge Frank F Richards J Brent JB Spector Tim D TD Wilson Scott G SG

BMC genomics 20160225

<h4>Background</h4>Osteoporosis is a common and debilitating bone disease that is characterised by a low bone mineral density (BMD), a highly heritable trait. Genome-wide association studies (GWAS) have proven to be very successful in identifying common genetic variants associated with BMD adjusted for age, gender and weight, however a large portion of the genetic variance for this trait remains unexplained. There is evidence to suggest significant genetic correlation between body size traits an ...[more]

PMID: 26911590

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Project description:Previous genome-wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta-analyses of these results have identified numerous single-nucleotide polymorphisms (SNPs) of modest effect at genome-wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta-analysis restricted to premenopausal white women from four cohorts (n?=?4061 women, aged 20 to 45 years) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. After imputation, age- and weight-adjusted bone-mineral density (BMD) values were tested for association with each SNP. Association of an SNP in the WNT16 gene (rs3801387; p?=?1.7?×?10(-9) ) and multiple SNPs in the ESR1/C6orf97 region (rs4870044; p?=?1.3?×?10(-8) ) achieved genome-wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven replication cohorts that included premenopausal women of European, Hispanic-American, and African-American descent (combined n?=?5597 for femoral neck; n?=?4744 for lumbar spine). When the data from the discovery and replication cohorts were analyzed jointly, the evidence was more significant (WNT16 joint p?=?1.3?×?10(-11) ; ESR1/C6orf97 joint p?=?1.4?×?10(-10) ). Multiple independent association signals were observed with spine BMD at the ESR1 region after conditioning on the primary signal. Analyses of femoral neck BMD also supported association with SNPs in WNT16 and ESR1/C6orf97 (p?<?1?×?10(-5) ). Our results confirm that several of the genes contributing to BMD variation across a broad age range in both sexes have effects of similar magnitude on BMD of the spine in premenopausal women. These data support the hypothesis that variants in these genes of known skeletal function also affect BMD during the premenopausal period.

Project description:Aiming to identify more genomic loci associated with bone mineral density (BMD), we conducted a joint association analysis of 2 genome-wide association study (GWAS) by the integrative association method multi-trait analysis of GWAS (MTAG). The first one is the single GWAS of estimated heel BMD (eBMD) in the UK biobank (UKB) cohort (N = 426,824), and the second one is the GWAS meta-analysis of total body BMD (TB-BMD) in 66,628 participants from 30 studies. Approximate conditional association analysis was performed in the identified novel loci to identify secondary association signal. Statistical fine-mapping was conducted to prioritize plausible credible risk variants (CRVs). Candidate genes were prioritized based on the analyses of cis- expression quantitative trait locus (cis-eQTL) and cis-protein QTL (cis-pQTL) information as well as the functional category of the SNP. By integrating the information carried in over 490,000 participants, this largest joint analysis of BMD GWAS identified 12 novel genomic loci at the genome-wide significance level (GWS, p = 5.0 × 10-8), nine of which were for eBMD and four were for TB-BMD, explaining an additional 0.11 and 0.23% heritability for the two traits, respectively. These loci include 1p33 (lead SNP rs10493130, peBMD = 3.19 × 10-8), 5q13.2 (rs4703589, peBMD = 4.78 × 10-8), 5q31.3 (rs9324887, pTB-BMD = 1.36 × 10-9), 6p21.32 (rs6905837, peBMD = 3.32 × 10-8), 6q14.1 (rs10806234, peBMD = 2.63 × 10-8), 7q21.11 (rs10806234, pTB-BMD = 3.37 × 10-8), 8q24.12 (rs11995866, peBMD = 6.72 × 10-9), 12p13.31 (rs1639122, peBMD = 4.43 × 10-8), 12p12.1 (rs58489179, peBMD = 4.74 × 10-8), 12q24.23 (rs75499226, peBMD = 1.44 × 10-8), 19q13.31 (rs7255083, pTB-BMD = 2.18 × 10-8) and 22q11.23 (rs13056137, pTB-BMD = 2.54 × 10-8). All lead SNPs in these 12 loci are nominally significant in both original studies as well as consistent in effect direction between them, providing solid evidence of replication. Approximate conditional analysis identified one secondary signal in 5q13.2 (rs11738874, pconditional = 5.06 × 10-9). Statistical fine-mapping analysis prioritized 269 CRVs. A total of 65 candidate genes were prioritized, including those with known biological function to bone development (such as FGF1, COL11A2 and DEPTOR). Our findings provide novel insights into a better understanding of the genetic mechanism underlying bone development as well as candidate genes for future functional investigation.

Dataset Information

Genome-wide association study using family-based cohorts identifies the WLS and CCDC170/ESR1 loci as associated with bone mineral density.

Publications

Genome-wide association study using family-based cohorts identifies the WLS and CCDC170/ESR1 loci as associated with bone mineral density.

Similar Datasets

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