Genome-Wide association analyses identify SPOCKas a key novel gene underlying age at menarche

Yao Zhong Liu; Yan Fang Guo; Liang Wang; Li Jun Tan; Xiao Gang Liu; Yu Fang Pei; Han Yan; Dong Hai Xiong; Fei Yan Deng; Na Yu; Yin Ping Zhang; Lei Zhang; Shu Feng Lei; Xiang Ding Chen; Hong Bin Liu; Xue Zhen Zhu; Shawn Levy; Christopher J. Papasian; Betty M. Drees; James J. Hamilton; Robert R. Recker; Hong Wen Deng

doi:10.1371/journal.pgen.1000420

Genome-Wide association analyses identify SPOCKas a key novel gene underlying age at menarche

Yao Zhong Liu, Yan Fang Guo, Liang Wang, Li Jun Tan, Xiao Gang Liu, Yu Fang Pei, Han Yan, Dong Hai Xiong, Fei Yan Deng, Na Yu, Yin Ping Zhang, Lei Zhang, Shu Feng Lei, Xiang Ding Chen, Hong Bin Liu, Xue Zhen Zhu, Shawn Levy, Christopher J. Papasian, Betty M. Drees, James J. HamiltonRobert R. Recker, Hong Wen Deng

Department of Medicine

Research output: Contribution to journal › Article › peer-review

58 Scopus citations

Abstract

For females, menarche is a most significant physiological event. Age at menarche (AAM) is a trait with high genetic determination and is associated with major complex diseases in women. However, specific genes for AAM variation are largely unknown. To identify genetic factors underlying AAM variation, a genome-wide association study (GWAS) examining about 380,000 SNPs was conducted in 477 Caucasian women. A follow-up replication study was performed to validate our major GWAS findings using two independent Caucasian cohorts with 854 siblings and 762 unrelated subjects, respectively, and one Chinese cohort of 1,387 unrelated subjects-all females. Our GWAS identified a novel gene, SPOCK (Sparc/Osteonectin, CWCV, and Kazal-like domains proteoglycan), which had seven SNPs associated with AAM with genome-wide false discovery rate (FDR) q-3 and 4.37 ×10^-3, respectively, in the Chinese cohort and combined p values (obtained by Fisher's method) of 5.19×10^-5 and 1.02×10^-4, respectively, in all three replication cohorts. Interestingly, SPOCK can inhibit activation of MMP-2 (matrix metalloproteinase-2), a key factor promoting endometrial menstrual breakdown and onset of menstrual bleeding. Our findings, together with the functional relevance, strongly supported that the SPOCK gene underlies variation of AAM. Copyright:

Original language	English (US)
Journal	PLoS genetics
Volume	5
Issue number	3
DOIs	https://doi.org/10.1371/journal.pgen.1000420
State	Published - Mar 2009

All Science Journal Classification (ASJC) codes

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

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Liu, Y. Z., Guo, Y. F., Wang, L., Tan, L. J., Liu, X. G., Pei, Y. F., Yan, H., Xiong, D. H., Deng, F. Y., Yu, N., Zhang, Y. P., Zhang, L., Lei, S. F., Chen, X. D., Liu, H. B., Zhu, X. Z., Levy, S., Papasian, C. J., Drees, B. M., ... Deng, H. W. (2009). Genome-Wide association analyses identify SPOCKas a key novel gene underlying age at menarche. PLoS genetics, 5(3). https://doi.org/10.1371/journal.pgen.1000420

Liu, YZ, Guo, YF, Wang, L, Tan, LJ, Liu, XG, Pei, YF, Yan, H, Xiong, DH, Deng, FY, Yu, N, Zhang, YP, Zhang, L, Lei, SF, Chen, XD, Liu, HB, Zhu, XZ, Levy, S, Papasian, CJ, Drees, BM, Hamilton, JJ, Recker, RR & Deng, HW 2009, 'Genome-Wide association analyses identify SPOCKas a key novel gene underlying age at menarche', PLoS genetics, vol. 5, no. 3. https://doi.org/10.1371/journal.pgen.1000420

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title = "Genome-Wide association analyses identify SPOCKas a key novel gene underlying age at menarche",

abstract = "For females, menarche is a most significant physiological event. Age at menarche (AAM) is a trait with high genetic determination and is associated with major complex diseases in women. However, specific genes for AAM variation are largely unknown. To identify genetic factors underlying AAM variation, a genome-wide association study (GWAS) examining about 380,000 SNPs was conducted in 477 Caucasian women. A follow-up replication study was performed to validate our major GWAS findings using two independent Caucasian cohorts with 854 siblings and 762 unrelated subjects, respectively, and one Chinese cohort of 1,387 unrelated subjects-all females. Our GWAS identified a novel gene, SPOCK (Sparc/Osteonectin, CWCV, and Kazal-like domains proteoglycan), which had seven SNPs associated with AAM with genome-wide false discovery rate (FDR) q-3 and 4.37 ×10-3, respectively, in the Chinese cohort and combined p values (obtained by Fisher's method) of 5.19×10-5 and 1.02×10-4, respectively, in all three replication cohorts. Interestingly, SPOCK can inhibit activation of MMP-2 (matrix metalloproteinase-2), a key factor promoting endometrial menstrual breakdown and onset of menstrual bleeding. Our findings, together with the functional relevance, strongly supported that the SPOCK gene underlies variation of AAM. Copyright:",

author = "Liu, {Yao Zhong} and Guo, {Yan Fang} and Liang Wang and Tan, {Li Jun} and Liu, {Xiao Gang} and Pei, {Yu Fang} and Han Yan and Xiong, {Dong Hai} and Deng, {Fei Yan} and Na Yu and Zhang, {Yin Ping} and Lei Zhang and Lei, {Shu Feng} and Chen, {Xiang Ding} and Liu, {Hong Bin} and Zhu, {Xue Zhen} and Shawn Levy and Papasian, {Christopher J.} and Drees, {Betty M.} and Hamilton, {James J.} and Recker, {Robert R.} and Deng, {Hong Wen}",

year = "2009",

month = mar,

doi = "10.1371/journal.pgen.1000420",

language = "English (US)",

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journal = "PLoS Genetics",

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AU - Liu, Yao Zhong

AU - Guo, Yan Fang

AU - Wang, Liang

AU - Tan, Li Jun

AU - Liu, Xiao Gang

AU - Pei, Yu Fang

AU - Yan, Han

AU - Xiong, Dong Hai

AU - Deng, Fei Yan

AU - Yu, Na

AU - Zhang, Yin Ping

AU - Zhang, Lei

AU - Lei, Shu Feng

AU - Chen, Xiang Ding

AU - Liu, Hong Bin

AU - Zhu, Xue Zhen

AU - Levy, Shawn

AU - Papasian, Christopher J.

AU - Drees, Betty M.

AU - Hamilton, James J.

AU - Recker, Robert R.

AU - Deng, Hong Wen

PY - 2009/3

Y1 - 2009/3

N2 - For females, menarche is a most significant physiological event. Age at menarche (AAM) is a trait with high genetic determination and is associated with major complex diseases in women. However, specific genes for AAM variation are largely unknown. To identify genetic factors underlying AAM variation, a genome-wide association study (GWAS) examining about 380,000 SNPs was conducted in 477 Caucasian women. A follow-up replication study was performed to validate our major GWAS findings using two independent Caucasian cohorts with 854 siblings and 762 unrelated subjects, respectively, and one Chinese cohort of 1,387 unrelated subjects-all females. Our GWAS identified a novel gene, SPOCK (Sparc/Osteonectin, CWCV, and Kazal-like domains proteoglycan), which had seven SNPs associated with AAM with genome-wide false discovery rate (FDR) q-3 and 4.37 ×10-3, respectively, in the Chinese cohort and combined p values (obtained by Fisher's method) of 5.19×10-5 and 1.02×10-4, respectively, in all three replication cohorts. Interestingly, SPOCK can inhibit activation of MMP-2 (matrix metalloproteinase-2), a key factor promoting endometrial menstrual breakdown and onset of menstrual bleeding. Our findings, together with the functional relevance, strongly supported that the SPOCK gene underlies variation of AAM. Copyright:

AB - For females, menarche is a most significant physiological event. Age at menarche (AAM) is a trait with high genetic determination and is associated with major complex diseases in women. However, specific genes for AAM variation are largely unknown. To identify genetic factors underlying AAM variation, a genome-wide association study (GWAS) examining about 380,000 SNPs was conducted in 477 Caucasian women. A follow-up replication study was performed to validate our major GWAS findings using two independent Caucasian cohorts with 854 siblings and 762 unrelated subjects, respectively, and one Chinese cohort of 1,387 unrelated subjects-all females. Our GWAS identified a novel gene, SPOCK (Sparc/Osteonectin, CWCV, and Kazal-like domains proteoglycan), which had seven SNPs associated with AAM with genome-wide false discovery rate (FDR) q-3 and 4.37 ×10-3, respectively, in the Chinese cohort and combined p values (obtained by Fisher's method) of 5.19×10-5 and 1.02×10-4, respectively, in all three replication cohorts. Interestingly, SPOCK can inhibit activation of MMP-2 (matrix metalloproteinase-2), a key factor promoting endometrial menstrual breakdown and onset of menstrual bleeding. Our findings, together with the functional relevance, strongly supported that the SPOCK gene underlies variation of AAM. Copyright:

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Genome-Wide association analyses identify SPOCKas a key novel gene underlying age at menarche

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