Genome-Wide Association Analyses Identify SPOCK as a Key Novel Gene Underlying Age at Menarche

School of Medicine, University of Missouri Kansas City, Kansas City, Missouri, United States of America.
PLoS Genetics (Impact Factor: 7.53). 03/2009; 5(3):e1000420. DOI: 10.1371/journal.pgen.1000420
Source: PubMed


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.

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Available from: Albert Z TANG, Oct 13, 2015
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    • "For age at menarche, four GWAS were published in 2009 (He et al., 2009; Liu et al., 2009; Perry et al., 2009; Sulem et al., 2009). The first studies identified novel association signals on chromosome 6q21 near lin-28 homolog B (Caenorhabditis elegans) (LIN28B) and an intergenic region on chromosome 9q31.3. "
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    ABSTRACT: Genetic factors contribute to risk for many common diseases affecting reproduction and fertility. In recent years, methods for genome-wide association studies (GWAS) have revolutionised gene discovery for common traits and diseases. Results of GWAS are documented in the Catalog of Published Genome-Wide Association Studies at the National Human Genome Research Institute and report over 70 publications for 32 traits and diseases associated with reproduction. These include endometriosis, uterine fibroids, age at menarche and age at menopause. Results that pass appropriate stringent levels of significance are generally well replicated in independent studies. Examples of genetic variation affecting twinning rate, infertility, endometriosis and age at menarche demonstrate that the spectrum of disease related variants for reproductive traits is similar to most other common diseases. GWAS "hits" provide novel insights into biological pathways and the translational value of these studies lies in discovery of novel gene targets for biomarkers, drug development and greater understanding of environmental factors contributing to disease risk. Results also show genetic data can help define sub-types of disease and co-morbidity with other traits and diseases. To date, many studies on reproductive traits have used relatively small samples. Future genetic marker studies in large samples with detailed phenotypic and clinical information will yield new insights into disease risk, disease classification and co-morbidity for many diseases associated with reproduction and infertility.
    Molecular Human Reproduction 08/2013; 20(1). DOI:10.1093/molehr/gat058 · 3.75 Impact Factor
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    • "Although menarche is mainly (50-70%) determined by genetic factors [49-51], environmental factors such as food insecurity have also a role in predicting age at menarche. Delayed age at menarche is associated with decreased fertility [52] poor reproductive function and other health problems including osteoporosis at later life [53], while early menarche is associated with breast cancer [54]. "
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