Identification of PLCL1 gene for hip bone size variation in females in a genome-wide association study

Yao Zhong Liu, Scott G. Wilson, Liang Wang, Xiao Gang Liu, Yan Fang Guo, Jian Li, Han Yan, Panos Deloukas, Nicole Soranzo, Usha Chinnapen-Horsley, Alesandra Cervino, Frances M. Williams, Dong Hai Xiong, Yin Ping Zhang, Tian Bo Jin, Shawn Levy, Christopher J. Papasian, Betty M. Drees, James J. Hamilton, Robert R. ReckerTim D. Spector, Hong Wen Deng

Research output: Contribution to journalArticle

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Abstract

Osteoporosis, the most prevalent metabolic bone disease among older people, increases risk for low trauma hip fractures (HF) that are associated with high morbidity and mortality. Hip bone size (BS) has been identified as one of the key measurable risk factors for HF. Although hip BS is highly genetically determined, genetic factors underlying the trait are still poorly defined. Here, we performed the first genome-wide association study (GWAS) of hip BS interrogating ∼380,000 SNPs on the Affymetrix platform in 1,000 homogeneous unrelated Caucasian subjects, including 501 females and 499 males. We identified a gene, PLCL1 (phospholipase c-like 1), that had four SNPs associated with hip BS at, or approaching, a genome-wide significance level in our female subjects; the most significant SNP, rs7595412, achieved a p value of 3.72×10-7. The gene's importance to hip BS was replicated using the Illumina genotyping platform in an independent UK cohort containing 1,216 Caucasian females. Two SNPs of the PLCL1 gene, rs892515 and rs9789480, surrounded by the four SNPs identified in our GWAS, achieved p values of 8.62×10-3 and 2.44×10-3, respectively, for association with hip S. Imputation analyses on our GWAS and the UK samples further confirmed the replication signals; eight SNPs of the gene achieved combined imputed p values-5 in the two samples. The PLCL1 gene's relevance to HF was also observed in a Chinese sample containing 403 females, including 266 with HF and 177 control subjects. A SNP of the PLCL1 gene, rs3771362 that is only ∼0.6 kb apart from the most significant SNP detected in our GWAS (rs7595412), achieved a p value of 7.66×10-3 (odds ratio = 0.26) for association with HF. Additional biological support for the role of PLCL1 in BS comes from previous demonstrations that the PLCL1 protein inhibits IP3 (inositol 1,4,5-trisphosphate)-mediated calcium signaling, an important pathway regulating mechanical sensing of bone cells. Our findings suggest that PLCL1 is a ovel gene associated with variation in Hip BS, and provide new insights into the pathogenesis of HF.

Original languageEnglish
Article numbere3160
JournalPLoS One
Volume3
Issue number9
DOIs
StatePublished - Sep 8 2008

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Pelvic Bones
Phospholipases
Genome-Wide Association Study
hip fractures
hips
Single Nucleotide Polymorphism
Hip Fractures
Bone
Genes
bones
genes
developmental orthopedic disease
Bone and Bones
Inositol 1,4,5-Trisphosphate
Calcium Signaling
phospholipases
genome-wide association study
Metabolic Bone Diseases
osteoporosis
sampling

All Science Journal Classification (ASJC) codes

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Liu, Y. Z., Wilson, S. G., Wang, L., Liu, X. G., Guo, Y. F., Li, J., ... Deng, H. W. (2008). Identification of PLCL1 gene for hip bone size variation in females in a genome-wide association study. PLoS One, 3(9), [e3160]. https://doi.org/10.1371/journal.pone.0003160

Identification of PLCL1 gene for hip bone size variation in females in a genome-wide association study. / Liu, Yao Zhong; Wilson, Scott G.; Wang, Liang; Liu, Xiao Gang; Guo, Yan Fang; Li, Jian; Yan, Han; Deloukas, Panos; Soranzo, Nicole; Chinnapen-Horsley, Usha; Cervino, Alesandra; Williams, Frances M.; Xiong, Dong Hai; Zhang, Yin Ping; Jin, Tian Bo; Levy, Shawn; Papasian, Christopher J.; Drees, Betty M.; Hamilton, James J.; Recker, Robert R.; Spector, Tim D.; Deng, Hong Wen.

In: PLoS One, Vol. 3, No. 9, e3160, 08.09.2008.

Research output: Contribution to journalArticle

Liu, YZ, Wilson, SG, Wang, L, Liu, XG, Guo, YF, Li, J, Yan, H, Deloukas, P, Soranzo, N, Chinnapen-Horsley, U, Cervino, A, Williams, FM, Xiong, DH, Zhang, YP, Jin, TB, Levy, S, Papasian, CJ, Drees, BM, Hamilton, JJ, Recker, RR, Spector, TD & Deng, HW 2008, 'Identification of PLCL1 gene for hip bone size variation in females in a genome-wide association study', PLoS One, vol. 3, no. 9, e3160. https://doi.org/10.1371/journal.pone.0003160
Liu, Yao Zhong ; Wilson, Scott G. ; Wang, Liang ; Liu, Xiao Gang ; Guo, Yan Fang ; Li, Jian ; Yan, Han ; Deloukas, Panos ; Soranzo, Nicole ; Chinnapen-Horsley, Usha ; Cervino, Alesandra ; Williams, Frances M. ; Xiong, Dong Hai ; Zhang, Yin Ping ; Jin, Tian Bo ; Levy, Shawn ; Papasian, Christopher J. ; Drees, Betty M. ; Hamilton, James J. ; Recker, Robert R. ; Spector, Tim D. ; Deng, Hong Wen. / Identification of PLCL1 gene for hip bone size variation in females in a genome-wide association study. In: PLoS One. 2008 ; Vol. 3, No. 9.
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abstract = "Osteoporosis, the most prevalent metabolic bone disease among older people, increases risk for low trauma hip fractures (HF) that are associated with high morbidity and mortality. Hip bone size (BS) has been identified as one of the key measurable risk factors for HF. Although hip BS is highly genetically determined, genetic factors underlying the trait are still poorly defined. Here, we performed the first genome-wide association study (GWAS) of hip BS interrogating ∼380,000 SNPs on the Affymetrix platform in 1,000 homogeneous unrelated Caucasian subjects, including 501 females and 499 males. We identified a gene, PLCL1 (phospholipase c-like 1), that had four SNPs associated with hip BS at, or approaching, a genome-wide significance level in our female subjects; the most significant SNP, rs7595412, achieved a p value of 3.72×10-7. The gene's importance to hip BS was replicated using the Illumina genotyping platform in an independent UK cohort containing 1,216 Caucasian females. Two SNPs of the PLCL1 gene, rs892515 and rs9789480, surrounded by the four SNPs identified in our GWAS, achieved p values of 8.62×10-3 and 2.44×10-3, respectively, for association with hip S. Imputation analyses on our GWAS and the UK samples further confirmed the replication signals; eight SNPs of the gene achieved combined imputed p values-5 in the two samples. The PLCL1 gene's relevance to HF was also observed in a Chinese sample containing 403 females, including 266 with HF and 177 control subjects. A SNP of the PLCL1 gene, rs3771362 that is only ∼0.6 kb apart from the most significant SNP detected in our GWAS (rs7595412), achieved a p value of 7.66×10-3 (odds ratio = 0.26) for association with HF. Additional biological support for the role of PLCL1 in BS comes from previous demonstrations that the PLCL1 protein inhibits IP3 (inositol 1,4,5-trisphosphate)-mediated calcium signaling, an important pathway regulating mechanical sensing of bone cells. Our findings suggest that PLCL1 is a ovel gene associated with variation in Hip BS, and provide new insights into the pathogenesis of HF.",
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AU - Guo, Yan Fang

AU - Li, Jian

AU - Yan, Han

AU - Deloukas, Panos

AU - Soranzo, Nicole

AU - Chinnapen-Horsley, Usha

AU - Cervino, Alesandra

AU - Williams, Frances M.

AU - Xiong, Dong Hai

AU - Zhang, Yin Ping

AU - Jin, Tian Bo

AU - Levy, Shawn

AU - Papasian, Christopher J.

AU - Drees, Betty M.

AU - Hamilton, James J.

AU - Recker, Robert R.

AU - Spector, Tim D.

AU - Deng, Hong Wen

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