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

Benjamin Mullin, John Walsh, H.F. Zheng, S.J. Brown, G.L. Surdulescu, C. Curtis, G. Breen, F. Dudbridge, J.B. Richards, T.D. Spector, Scott Wilson

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    Abstract

    © 2016 Mullin et al. Background: 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. Results: 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 oestrog
    Original languageEnglish
    Article number136
    Pages (from-to)1-11
    Number of pages11
    JournalBMC Genomics
    Volume17
    Issue number1
    DOIs
    Publication statusPublished - 25 Feb 2016

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    Genome-Wide Association Study
    Bone Density
    Ligands
    Genes
    Body Size
    Meta-Analysis
    Secretory Pathway
    Quantitative Trait Loci
    Bone Diseases
    Temporal Lobe
    Computational Biology
    Cerebellum
    Osteoporosis
    Spine
    Cohort Studies
    Software
    Logistic Models
    Regression Analysis
    Genome
    Phenotype

    Cite this

    Mullin, Benjamin ; Walsh, John ; Zheng, H.F. ; Brown, S.J. ; Surdulescu, G.L. ; Curtis, C. ; Breen, G. ; Dudbridge, F. ; Richards, J.B. ; Spector, T.D. ; Wilson, Scott. / Genome-wide association study using family-based cohorts identifies the WLS and CCDC170/ESR1 loci as associated with bone mineral density. In: BMC Genomics. 2016 ; Vol. 17, No. 1. pp. 1-11.
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    abstract = "{\circledC} 2016 Mullin et al. Background: 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. Results: 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 oestrog",
    author = "Benjamin Mullin and John Walsh and H.F. Zheng and S.J. Brown and G.L. Surdulescu and C. Curtis and G. Breen and F. Dudbridge and J.B. Richards and T.D. Spector and Scott Wilson",
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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; Walsh, John; Zheng, H.F.; Brown, S.J.; Surdulescu, G.L.; Curtis, C.; Breen, G.; Dudbridge, F.; Richards, J.B.; Spector, T.D.; Wilson, Scott.

    In: BMC Genomics, Vol. 17, No. 1, 136, 25.02.2016, p. 1-11.

    Research output: Contribution to journalArticle

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    T1 - Genome-wide association study using family-based cohorts identifies the WLS and CCDC170/ESR1 loci as associated with bone mineral density

    AU - Mullin, Benjamin

    AU - Walsh, John

    AU - Zheng, H.F.

    AU - Brown, S.J.

    AU - Surdulescu, G.L.

    AU - Curtis, C.

    AU - Breen, G.

    AU - Dudbridge, F.

    AU - Richards, J.B.

    AU - Spector, T.D.

    AU - Wilson, Scott

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    AB - © 2016 Mullin et al. Background: 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. Results: 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 oestrog

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