Genome-wide association analyses identify SPOCK as a key novel gene underlying age at menarche.
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 variatio...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2009-03-01
|
| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC2652107?pdf=render |
| _version_ | 1818063422727651328 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Yao-Zhong Liu |
| collection | DOAJ |
| description | 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<0.05. Six most significant SNPs of the gene were selected for validation in three independent replication cohorts. All of the six SNPs were replicated in at least one cohort. In particular, SNPs rs13357391 and rs1859345 were replicated both within and across different ethnic groups in all three cohorts, with p values of 5.09 x 10(-3) and 4.37 x 10(-3), respectively, in the Chinese cohort and combined p values (obtained by Fisher's method) of 5.19 x 10(-5) and 1.02 x 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. |
| first_indexed | 2024-12-10T14:19:51Z |
| format | Article |
| id | doaj.art-26443f05a98645249de97e3f50af903b |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-10T14:19:51Z |
| publishDate | 2009-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-26443f05a98645249de97e3f50af903b2022-12-22T01:45:14ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042009-03-0153e100042010.1371/journal.pgen.1000420Genome-wide association analyses identify SPOCK as a key novel gene underlying age at menarche.Yao-Zhong LiuYan-Fang GuoLiang WangLi-Jun TanXiao-Gang LiuYu-Fang PeiHan YanDong-Hai XiongFei-Yan DengNa YuYin-Ping ZhangLei ZhangShu-Feng LeiXiang-Ding ChenHong-Bin LiuXue-Zhen ZhuShawn LevyChristopher J PapasianBetty M DreesJames J HamiltonRobert R ReckerHong-Wen DengFor 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<0.05. Six most significant SNPs of the gene were selected for validation in three independent replication cohorts. All of the six SNPs were replicated in at least one cohort. In particular, SNPs rs13357391 and rs1859345 were replicated both within and across different ethnic groups in all three cohorts, with p values of 5.09 x 10(-3) and 4.37 x 10(-3), respectively, in the Chinese cohort and combined p values (obtained by Fisher's method) of 5.19 x 10(-5) and 1.02 x 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.http://europepmc.org/articles/PMC2652107?pdf=render |
| spellingShingle | 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 Genome-wide association analyses identify SPOCK as a key novel gene underlying age at menarche. PLoS Genetics |
| title | Genome-wide association analyses identify SPOCK as a key novel gene underlying age at menarche. |
| title_full | Genome-wide association analyses identify SPOCK as a key novel gene underlying age at menarche. |
| title_fullStr | Genome-wide association analyses identify SPOCK as a key novel gene underlying age at menarche. |
| title_full_unstemmed | Genome-wide association analyses identify SPOCK as a key novel gene underlying age at menarche. |
| title_short | Genome-wide association analyses identify SPOCK as a key novel gene underlying age at menarche. |
| title_sort | genome wide association analyses identify spock as a key novel gene underlying age at menarche |
| url | http://europepmc.org/articles/PMC2652107?pdf=render |
| work_keys_str_mv | AT yaozhongliu genomewideassociationanalysesidentifyspockasakeynovelgeneunderlyingageatmenarche AT yanfangguo genomewideassociationanalysesidentifyspockasakeynovelgeneunderlyingageatmenarche AT liangwang genomewideassociationanalysesidentifyspockasakeynovelgeneunderlyingageatmenarche AT lijuntan genomewideassociationanalysesidentifyspockasakeynovelgeneunderlyingageatmenarche AT xiaogangliu genomewideassociationanalysesidentifyspockasakeynovelgeneunderlyingageatmenarche AT yufangpei genomewideassociationanalysesidentifyspockasakeynovelgeneunderlyingageatmenarche AT hanyan genomewideassociationanalysesidentifyspockasakeynovelgeneunderlyingageatmenarche AT donghaixiong genomewideassociationanalysesidentifyspockasakeynovelgeneunderlyingageatmenarche AT feiyandeng genomewideassociationanalysesidentifyspockasakeynovelgeneunderlyingageatmenarche AT nayu genomewideassociationanalysesidentifyspockasakeynovelgeneunderlyingageatmenarche AT yinpingzhang genomewideassociationanalysesidentifyspockasakeynovelgeneunderlyingageatmenarche AT leizhang genomewideassociationanalysesidentifyspockasakeynovelgeneunderlyingageatmenarche AT shufenglei genomewideassociationanalysesidentifyspockasakeynovelgeneunderlyingageatmenarche AT xiangdingchen genomewideassociationanalysesidentifyspockasakeynovelgeneunderlyingageatmenarche AT hongbinliu genomewideassociationanalysesidentifyspockasakeynovelgeneunderlyingageatmenarche AT xuezhenzhu genomewideassociationanalysesidentifyspockasakeynovelgeneunderlyingageatmenarche AT shawnlevy genomewideassociationanalysesidentifyspockasakeynovelgeneunderlyingageatmenarche AT christopherjpapasian genomewideassociationanalysesidentifyspockasakeynovelgeneunderlyingageatmenarche AT bettymdrees genomewideassociationanalysesidentifyspockasakeynovelgeneunderlyingageatmenarche AT jamesjhamilton genomewideassociationanalysesidentifyspockasakeynovelgeneunderlyingageatmenarche AT robertrrecker genomewideassociationanalysesidentifyspockasakeynovelgeneunderlyingageatmenarche AT hongwendeng genomewideassociationanalysesidentifyspockasakeynovelgeneunderlyingageatmenarche |