The impact of sex on gene expression across human tissues.
The impact of sex on gene expression across human tissues.
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DOI：
10.1126/science.aba3066
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发表时间：
2020-09-11
期刊：
影响因子：
--
通讯作者：
Stranger BE
中科院分区：
文献类型：
--
作者：
Oliva M;Muñoz-Aguirre M;Kim-Hellmuth S;Wucher V;Gewirtz ADH;Cotter DJ;Parsana P;Kasela S;Balliu B;Viñuela A;Castel SE;Mohammadi P;Aguet F;Zou Y;Khramtsova EA;Skol AD;Garrido-Martín D;Reverter F;Brown A;Evans P;Gamazon ER;Payne A;Bonazzola R;Barbeira AN;Hamel AR;Martinez-Perez A;Soria JM;GTEx Consortium;Pierce BL;Stephens M;Eskin E;Dermitzakis ET;Segrè AV;Im HK;Engelhardt BE;Ardlie KG;Montgomery SB;Battle AJ;Lappalainen T;Guigó R;Stranger BE
许多复杂的人类表型表现出性别分化的特征。然而，这些差异背后的分子机制在很大程度上仍然未知。我们通过基因型-组织表达项目（GTEx， v8版本）调查了44个人类组织来源，生成了基因表达和基因表达遗传调控的性别差异目录。我们证明，性别影响基因表达水平和细胞组成的组织样本在整个人体。总共有37%的基因在至少一个组织中表现出性别偏向的表达。我们鉴定了具有性别分化效应的顺式表达数量性状位点（eQTLs），并对其细胞起源进行了表征。通过整合性别偏倚的eqtl与全基因组关联研究数据，我们确定了58个基因-性状关联，这些关联是由单一性别基因表达的遗传调控驱动的。这些发现为人类转录组及其遗传调控中的性别差异提供了广泛的表征。许多复杂的人类表型，包括疾病，都表现出性别分化的特征。这些性别差异不同地归因于激素、性染色体、基因型×性别效应、行为差异和环境暴露的差异；然而，它们的机制和潜在的生物学原理在很大程度上仍然未知。基因型-组织表达（GTEx）项目提供了一个机会，通过调查许多以前没有以这种方式表征的组织，来调查人类转录组中性别差异的普遍性和遗传机制。为了描述人类转录组的性别差异及其调控，并发现性别和遗传如何相互作用以影响复杂性状和疾病，我们在GTEx项目（v8数据发布）调查的44个人体组织来源中生成了基因表达及其遗传调控的性别差异目录，分析了838个成年个体的16,245个rna测序样本和基因型。我们报告了基因表达水平、组织细胞类型组成和顺式表达数量性状位点（cis- eqtl）的性别差异。为了评估它们的影响，我们将这些结果与基因功能、转录因子结合注释和87个GWAS的全基因组关联研究（GWAS）汇总统计数据相结合。性别对基因表达的影响是普遍存在的（所有组织中有13294个性别偏向基因）。然而，这些影响很小，而且主要是组织特异性的。具有性别分化表达的基因主要不是由组织特异性基因表达驱动的，而是涉及多种生物功能，如药物和激素反应、胚胎发育和组织形态发生、受精、有性生殖和精子发生、脂肪代谢、癌症和免疫反应。然而，在女性中表达较高的x连锁基因暗示了x染色体失活的逃逸候选基因，而常染色体基因的性别偏倚表达暗示了激素相关的转录因子调控和其他转录因子的作用，以及表观遗传标记的性别分化分布，特别是组蛋白H3 Lys27三甲基化（H3K27me3）。基因表达的遗传调控中的性别差异要少见得多（所有组织中有369个性别偏倚的eqtl），并且具有高度的组织特异性。我们确定了58个由基因表达的遗传调控驱动的基因性状关联。这些基因座包括性别分化细胞类型丰度介导基因型-表型关联的基因座，以及性别可能在这种关联的潜在分子机制中发挥更直接作用的基因座。例如，我们在肝脏中发现了一个雌性特异性的己糖激酶HKDC1的eQTL，它影响怀孕雌性的葡萄糖代谢，随后反映在后代的出生体重上。通过将GTEx数据的性别意识分析与基因功能和转录因子结合注释相结合，我们描述了导致人类转录组和eqtl性别差异的组织特异性和组织共享驱动因素和机制。我们发现了多种性别分化的基因表达遗传效应，这些效应与复杂的性状遗传关联共定位，从而促进了GWAS信号的机制解释。由于许多表型的致病组织是未知的，因此对各种GTEx组织收集的分析可以作为研究性别偏倚性状基础的有力资源。这项工作提供了人类转录组及其遗传调控的性别差异的广泛表征。■性别影响组织中的基因表达及其基因调控。在44个GTEx人体组织源中测量了性别对基因表达的影响，并与838名受试者的基因型相结合。性别偏倚表达存在于许多生物学途径中，并与性别分化的转录调节有关。顺式中性别偏倚表达的数量性状位点（性别偏倚的eqtl）部分受细胞丰度介导，揭示了基因-性状之间的关联。TT、AT和AA是单核苷酸多态性的基因型；TF，转录因子。
Many complex human phenotypes exhibit sex-differentiated characteristics. However, the molecular mechanisms underlying these differences remain largely unknown. We generated a catalog of sex differences in gene expression and in the genetic regulation of gene expression across 44 human tissue sources surveyed by the Genotype-Tissue Expression project (GTEx, v8 release). We demonstrate that sex influences gene expression levels and cellular composition of tissue samples across the human body. A total of 37% of all genes exhibit sex-biased expression in at least one tissue. We identify cis expression quantitative trait loci (eQTLs) with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation of gene expression in a single sex. These findings provide an extensive characterization of sex differences in the human transcriptome and its genetic regulation. Many complex human pheno-types, including diseases, exhibit sex-differentiated characteristics. These sex differences have been variously attributed to hormones, sex chromosomes, genotype × sex effects, differences in behavior, and differences in environmental exposures; however, their mechanisms and underlying biology remain largely unknown. The Genotype-Tissue Expression (GTEx) project provides an opportunity to investigate the prevalence and genetic mechanisms of sex differences in the human transcriptome by surveying many tissues that have not previously been characterized in this manner. To characterize sex differences in the human transcriptome and its regulation, and to discover how sex and genetics interact to influence complex traits and disease, we generated a catalog of sex differences in gene expression and its genetic regulation across 44 human tissue sources surveyed by the GTEx project (v8 data release), analyzing 16,245 RNA-sequencing samples and genotypes of 838 adult individuals. We report sex differences in gene expression levels, tissue cell type composition, and cis expression quantitative trait loci (cis-eQTLs). To assess their impact, we integrated these results with gene function, transcription factor binding annotation, and genome-wide association study (GWAS) summary statistics of 87 GWASs. Sex effects on gene expression are ubiquitous (13,294 sex-biased genes across all tissues). However, these effects are small and largely tissue-specific. Genes with sex-differentiated expression are not primarily driven by tissue-specific gene expression and are involved in a diverse set of biological functions, such as drug and hormone response, embryonic development and tissue morphogenesis, fertilization, sexual reproduction and spermatogenesis, fat metabolism, cancer, and immune response. Whereas X-linked genes with higher expression in females suggest candidates for escape from X-chromosome inactivation, sex-biased expression of autosomal genes suggests hormone-related transcription factor regulation and a role for additional transcription factors, as well as sex-differentiated distribution of epigenetic marks, particularly histone H3 Lys27 trimethylation (H3K27me3). Sex differences in the genetic regulation of gene expression are much less common (369 sex-biased eQTLs across all tissues) and are highly tissue-specific. We identified 58 gene-trait associations driven by genetic regulation of gene expression in a single sex. These include loci where sex-differentiated cell type abundances mediate genotype-phenotype associations, as well as loci where sex may play a more direct role in the underlying molecular mechanism of the association. For example, we identified a female-specific eQTL in liver for the hexokinase HKDC1 that influences glucose metabolism in pregnant females, which is subsequently reflected in the birth weight of the offspring. By integrating sex-aware analyses of GTEx data with gene function and transcription factor binding annotations, we describe tissue-specific and tissue-shared drivers and mechanisms contributing to sex differences in the human transcriptome and eQTLs. We discovered multiple sex-differentiated genetic effects on gene expression that colocalize with complex trait genetic associations, thereby facilitating the mechanistic interpretation of GWAS signals. Because the causative tissue is unknown for many phenotypes, analysis of the diverse GTEx tissue collection can serve as a powerful resource for investigations into the basis of sex-biased traits. This work provides an extensive characterization of sex differences in the human transcriptome and its genetic regulation. ■ Sex affects gene expression and its genetic regulation across tissues. Sex effects on gene expression were measured in 44 GTEx human tissue sources and integrated with genotypes of 838 subjects. Sex-biased expression is present in numerous biological pathways and is associated to sex-differentiated transcriptional regulation. Sex-biased expression quantitative trait loci in cis (sex-biased eQTLs) are partially mediated by cellular abundances and reveal gene-trait associations. TT, AT, and AA are genotypes for a single-nucleotide polymorphism; TF, transcription factor.
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DOI：
10.1210/jc.2018-00423
发表时间：
2018-12-01
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
--
作者：
García-Calzón S;Perfilyev A;de Mello VD;Pihlajamäki J;Ling C
通讯作者：
Ling C
DOI：
10.1098/rstb.2017.0021
发表时间：
2017-11-05
期刊：
Philosophical transactions of the Royal Society of London. Series B, Biological sciences
影响因子：
--
作者：
Brockdorff N
通讯作者：
Brockdorff N
影响因子：
9.8
作者：
Allen, Mariet;Carrasquillo, Minerva M.;Funk, Cory;Heavner, Benjamin D.;Zou, Fanggeng;Younkin, Curtis S.;Burgess, Jeremy D.;Chai, High-Seng;Crook, Julia;Eddy, James A.;Li, Hongdong;Logsdon, Ben;Peters, Mette A.;Dang, Kristen K.;Wang, Xue;Serie, Daniel;Wang, Chen;Thuy Nguyen;Lincoln, Sarah;Malphrus, Kimberly;Bisceglio, Gina;Li, Ma;Golde, Todd E.;Mangravite, Lara M.;Asmann, Yan;Price, Nathan D.;Petersen, Ronald C.;Graff-Radford, Neill R.;Dickson, Dennis W.;Younkin, Steven G.;Ertekin-Taner, Nilufer
通讯作者：
Ertekin-Taner, Nilufer
影响因子：
16.6
作者：
Castel, Stephane E.;Mohammadi, Pejman;Lappalainen, Tuuli
通讯作者：
Lappalainen, Tuuli
影响因子：
64.5
作者：
Astle, William J.;Elding, Heather;Soranzo, Nicole
通讯作者：
Soranzo, Nicole