Wei Shau-Ming, Gregory Michael D, Nash Tiffany, de Abreu E Gouvêa Andrea, Mervis Carolyn B, Cole Katherine M, Garvey Madeline H, Kippenhan J Shane, Eisenberg Daniel P, Kolachana Bhaskar, Schmidt Peter J, Berman Karen F
Behavioral Endocrinology Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
iScience. 2024 Feb 6;27(3):109113. doi: 10.1016/j.isci.2024.109113. eCollection 2024 Mar 15.
Pubertal timing, including age at menarche (AAM), is a heritable trait linked to lifetime health outcomes. Here, we investigate genetic mechanisms underlying AAM by combining genome-wide association study (GWAS) data with investigations of two rare genetic conditions clinically associated with altered AAM: Williams syndrome (WS), a 7q11.23 hemideletion characterized by early puberty; and duplication of the same genes (7q11.23 Duplication syndrome [Dup7]) characterized by delayed puberty. First, we confirm that AAM-derived polygenic scores in typically developing children (TD) explain a modest amount of variance in AAM (R = 0.09; p = 0.04). Next, we demonstrate that 7q11.23 copy number impacts AAM (WS < TD < Dup7; p = 1.2x10, η = 0.45) and pituitary volume (WS < TD < Dup7; p = 3x10, η = 0.2) with greater effect sizes. Finally, we relate an AAM-GWAS signal in 7q11.23 to altered expression in postmortem brains of (p = 1.7x10), a gene we also find differentially expressed with 7q11.23 copy number (p = 0.03). Collectively, these data explicate the role of 7q11.23 in pubertal onset, with and pituitary development as potential mediators.
青春期发育时间，包括初潮年龄（AAM），是一种与终生健康结果相关的可遗传特征。在此，我们通过将全基因组关联研究（GWAS）数据与对两种临床上与AAM改变相关的罕见遗传疾病的调查相结合，来研究AAM潜在的遗传机制：威廉姆斯综合征（WS），一种以青春期早熟为特征的7q11.23半侧缺失；以及相同基因的重复（7q11.23重复综合征[Dup7]），其特征为青春期延迟。首先，我们证实典型发育儿童（TD）中源自AAM的多基因评分解释了AAM中适度的方差量（R = 0.09；p = 0.04）。接下来，我们证明7q11.23拷贝数影响AAM（WS < TD < Dup7；p = 1.2×10，η = 0.45）和垂体体积（WS < TD < Dup7；p = 3×10，η = 0.2），且效应大小更大。最后，我们将7q11.23中的一个AAM - GWAS信号与死后大脑中的表达改变相关联（p = 1.7×10），我们还发现该基因随7q11.23拷贝数存在差异表达（p = 0.03）。总体而言，这些数据阐明了7q11.23在青春期开始中的作用，其中[基因名称]和垂体发育作为潜在的调节因子。 （注：原文中部分基因名称缺失部分信息，这里按照原文格式保留了缺失内容）
