Genome-wide association analyses identify SPOCK as a key novel gene underlying age at menarche.
Genome-wide association analyses identify SPOCK as a key novel gene underlying age at menarche.
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DOI：
10.1371/journal.pgen.1000420
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发表时间：
2009-03
期刊：
影响因子：
4.5
通讯作者：
Deng HW
中科院分区：
文献类型：
--
作者：
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
对于女性来说，初潮是一个最重要的生理事件。初潮年龄（AAM）是一个具有高度遗传决定性的特征，与女性的主要复杂疾病有关。然而，AAM变异的特定基因在很大程度上是未知的。为了确定AAM变异背后的遗传因素，在477名高加索妇女中进行了全基因组关联研究（GWAS），检查了约380，000个SNP。我们进行了一项随访重复研究，以验证我们的主要GWAS研究结果，使用了两个独立的高加索队列，分别有854名兄弟姐妹和762名无关受试者，以及一个中国队列，有1,387名无关受试者，均为女性。我们的GWAS鉴定了一个新基因，SPOCK（Sparc/Osteonectin，CWCV和Kazal样结构域蛋白聚糖），它有7个与AAM相关的SNP，全基因组错误发现率（FDR）q<0.05。选择该基因的六个最显著的SNP在三个独立的复制队列中进行验证。所有六个SNP在至少一个队列中重复。特别是，SNPs rs 13357391和rs 1859345在所有三个队列中的不同种族内和跨种族都有重复，在中国队列中的p值分别为5.09×10−3和4.37×10−3，在所有三个重复队列中的合并p值（通过Fisher方法获得）分别为5.19×10−5和1.02×10−4。有趣的是，SPOCK可以抑制MMP-2（基质金属蛋白酶-2）的活化，MMP-2是促进子宫内膜月经破裂和月经出血的关键因素。我们的研究结果，以及功能相关性，强烈支持SPOCK基因的基础AAM的变化。月经初潮是女性生命中的一个生理里程碑。初潮年龄（AAM）与许多常见的女性健康问题有关。AAM主要由遗传因素决定。然而，特定的基因和相关的机制AAM基本上是未知的。在这里，利用人类遗传学领域的最新技术进展，我们在一组高加索妇女中发现了与AAM变异相关的基因SPOCK中的多个遗传变异。这种关联随后不仅在两个独立的高加索妇女群体中得到证实，而且在一个中国妇女群体中也跨越了种族界限。此外，SPOCK还具有调节月经周期中的关键因子MMP-2的功能，这为我们的研究结果提供了进一步的支持。我们的研究为进一步研究该基因提供了坚实的基础，这可能有助于揭示月经初潮时间的潜在机制以及AAM与女性健康的关系。
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 5.09×10−3 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. Menarche is a physical milestone in a woman's life. Age at menarche (AAM) is related to many common female health problems. AAM is mainly determined by genetic factors. However, the specific genes and the associated mechanisms underlying AAM are largely unknown. Here, taking advantage of the most recent technological advances in the field of human genetics, we identified multiple genetic variants in a gene, SPOCK, which are associated with AAM variation in a group of Caucasian women. This association was subsequently confirmed not only in two independent groups of Caucasian women but also across ethnic boundaries in one group of Chinese women. In addition, SPOCK has a function in regulating a key factor involved in menstrual cycles, MMP-2, which provides further support to our findings. Our study provides a solid basis for further investigation of the gene, which may help to reveal the underlying mechanisms for the timing of menarche and for AAM's relationship with women's health in general.
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