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 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.
Liu
Yao-Zhong
YZ
School of Medicine, University of Missouri Kansas City, Kansas City, Missouri, United States of America.
Guo
Yan-Fang
YF
Wang
Liang
L
Tan
Li-Jun
LJ
Liu
Xiao-Gang
XG
Pei
Yu-Fang
YF
Yan
Han
H
Xiong
Dong-Hai
DH
Deng
Fei-Yan
FY
Yu
Na
N
Zhang
Yin-Ping
YP
Zhang
Lei
L
Lei
Shu-Feng
SF
Chen
Xiang-Ding
XD
Liu
Hong-Bin
HB
Zhu
Xue-Zhen
XZ
Levy
Shawn
S
Papasian
Christopher J
CJ
Drees
Betty M
BM
Hamilton
James J
JJ
Recker
Robert R
RR
Deng
Hong-Wen
HW
D000328:Adult; D000367:Age Factors; D000375:Aging / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008572:Menarche / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011509:Proteoglycans / Q000235:genetics*; D044465:White People / Q000235:genetics
D011509:Proteoglycans; C504369:SPOCK1 protein, human