Rare coding variants and X-linked loci associated with age at menarche.
Rare coding variants and X-linked loci associated with age at menarche.
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DOI：
10.1038/ncomms8756
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发表时间：
2015-08-04
影响因子：
16.6
通讯作者：
Perry JR
中科院分区：
文献类型：
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作者：
Lunetta KL;Day FR;Sulem P;Ruth KS;Tung JY;Hinds DA;Esko T;Elks CE;Altmaier E;He C;Huffman JE;Mihailov E;Porcu E;Robino A;Rose LM;Schick UM;Stolk L;Teumer A;Thompson DJ;Traglia M;Wang CA;Yerges-Armstrong LM;Antoniou AC;Barbieri C;Coviello AD;Cucca F;Demerath EW;Dunning AM;Gandin I;Grove ML;Gudbjartsson DF;Hocking LJ;Hofman A;Huang J;Jackson RD;Karasik D;Kriebel J;Lange EM;Lange LA;Langenberg C;Li X;Luan J;Mägi R;Morrison AC;Padmanabhan S;Pirie A;Polasek O;Porteous D;Reiner AP;Rivadeneira F;Rudan I;Sala CF;Schlessinger D;Scott RA;Stöckl D;Visser JA;Völker U;Vozzi D;Wilson JG;Zygmunt M;EPIC-InterAct Consortium;Generation Scotland;Boerwinkle E;Buring JE;Crisponi L;Easton DF;Hayward C;Hu FB;Liu S;Metspalu A;Pennell CE;Ridker PM;Strauch K;Streeten EA;Toniolo D;Uitterlinden AG;Ulivi S;Völzke H;Wareham NJ;Wellons M;Franceschini N;Chasman DI;Thorsteinsdottir U;Murray A;Stefansson K;Murabito JM;Ong KK;Perry JR
全基因组关联研究已经确定了100多个基因座在月经初潮时的年龄；然而，总的来说，这些基因座只解释了∼3%的性状变异。在这里，我们测试了192,974名欧洲血统女性中两个被忽视的变异来源：低频蛋白质编码变异和X染色体变异。5个错义/无义变异(ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1)与月经初潮年龄相关(次要等位基因频率0.08~4.6%；每个等位基因效应大小0.08~1.25年；P<；5×10−8)。此外，我们还在IGSF1(rs762080，P=9.4×10−13)和FAAH2(rs5914101，P=4.9×10−10)上发现了常见的X染色体基因座。突出显示的基因涉及细胞能量动态平衡、转录后基因沉默和脂肪酸酰胺信号传递。特发性性腺功能减退症(性腺功能减退症)的TACR3基因突变(p.W275X)与1.25年后的月经初潮有关(P=2.8x10−11)，说明了人口研究对估计已报道的致病突变的外显性的作用。总而言之，这些新的变异解释了∼0.5%的变异，表明这些被忽视的变异来源并不能实质上解释这一复杂特征的“缺失遗传性”。以前的研究已经将100多个基因组基因座与月经初潮年龄联系起来，但这项工作仅限于常见的常染色体变异。在这里，卢内塔等人。确定与罕见的蛋白质编码和X连锁变异的关联，暗示调节青春期时机的新机制。
More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08–4.6%; effect sizes 0.08–1.25 years per allele; P<5 × 10−8). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10−13) and FAAH2 (rs5914101, P=4.9 × 10−10). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10−11), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the ‘missing heritability' of this complex trait. Previous studies have linked over 100 genomic loci to age-at-menarche but that work was restricted to common autosomal variation. Here, Lunetta et al. identify associations with rare protein-coding and X-linked variants, implicating new mechanisms that regulate puberty timing.