Faculty Collaboration Database

Genome-wide association analyses identify SPOCK as a key novel gene underlying age at menarche. PLoS Genet 2009 Mar;5(3):e1000420

Date

03/14/2009

Pubmed ID

19282985

Pubmed Central ID

PMC2652107

DOI

10.1371/journal.pgen.1000420

Scopus ID

2-s2.0-63449113425 (requires institutional sign-in at Scopus site)   59 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<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.

Author List

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

MESH terms used to index this publication - Major topics in bold

Adult
Age Factors
Aging
Female
Genome-Wide Association Study
Humans
Menarche
Middle Aged
Polymorphism, Single Nucleotide
Proteoglycans