We are in a phase of unprecedented progress in identifying genetic loci that cause variation in traits ranging from growth and fitness in simple organisms to disease in humans. However, a mechanistic understanding of how these loci influence traits is lacking for the majority of loci. Studies of the genetics of gene expression have emerged as a key tool for linking DNA sequence variation to phenotypes. Here, we review recent insights into the molecular nature of regulatory variants and describe their influence on the transcriptome and the proteome. We discuss conceptual advances from studies in model organisms and present examples of complete chains of causality that link individual polymorphisms to changes in gene expression, which in turn result in physiological changes and, ultimately, disease risk.
At a glance
- Genetic studies on mutant enzymes in maize. III. Control of gene action in the synthesis of pH 7.5 esterase. Genetics 47, 1609–1615 (1962).
- Genetical genomics: the added value from segregation. Trends Genet. 17, 388–391 (2001). &
- Genetic dissection of transcriptional regulation in budding yeast. Science 296, 752–755 (2002).
This is the first genome-wide eQTL study, carried out in a cross between two yeast strains.
, , &
- Genetics of gene expression surveyed in maize, mouse and man. Nature 422, 297–302 (2003).
This is the first eQTL study in mammals (mice and humans) and in maize.
- Quantitative trait loci underlying gene product variation: a novel perspective for analyzing regulation of genome expression. Genetics 137, 289–301 (1994). , , &
- Genome-wide associations of gene expression variation in humans. PLoS Genet. 1, e78 (2005). et al.
- Population genomics of human gene expression. Nature Genet. 39, 1217–1224 (2007). et al.
- Common regulatory variation impacts gene expression in a cell type-dependent manner. Science 325, 1246–1250 (2009). et al.
- Genetic analysis of genome-wide variation in human gene expression. Nature 430, 743–747 (2004).
This is the first large eQTL study in human families.
- Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008). et al.
- Mapping determinants of human gene expression by regional and genome-wide association. Nature 437, 1365–1369 (2005).
References 7 and 11 are the first studies to use GWAS results to map eQTLs in humans.
- Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315, 848–853 (2007). et al.
- Genetics of global gene expression. Nature Rev. Genet. 7, 862–872 (2006).
This review presents the conceptual basis of eQTLs and provides a comprehensive overview of the first 5 years of eQTL discovery.
- Functional genomic architecture of predisposition to voluntary exercise in mice: expression QTL in the brain. Genetics 191, 643–654 (2012). , , , &
- Genetic influences on brain gene expression in rats selected for tameness and aggression. Genetics 198, 1277–1290 (2014). et al.
- Unraveling inflammatory responses using systems genetics and gene-environment interactions in macrophages. Cell 151, 658–670 (2012). et al.
- Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease. Nature Genet. 37, 243–253 (2005). et al.
- Genetic analysis of complex traits in the emerging collaborative cross. Genome Res. 21, 1213–1222 (2011). et al.
- Variations in DNA elucidate molecular networks that cause disease. Nature 452, 429–435 (2008). et al.
- An integrative genomics approach to infer causal associations between gene expression and disease. Nature Genet. 37, 710–717 (2005). et al.
- Genomic variation and its impact on gene expression in Drosophila melanogaster. PLoS Genet. 8, e1003055 (2012). et al.
- Genetic dissection of the Drosophila melanogaster female head transcriptome reveals widespread allelic heterogeneity. PLoS Genet. 10, e1004322 (2014). , , , &
- Global eQTL mapping reveals the complex genetic architecture of transcript-level variation in Arabidopsis. Genetics 175, 1441–1450 (2006). et al.
- Paternal dominance of trans-eQTL influences gene expression patterns in maize hybrids. Science 326, 1118–1120 (2009). et al.
- System-wide molecular evidence for phenotypic buffering in Arabidopsis. Nature Genet. 41, 166–167 (2009). et al.
- Regulatory network construction in Arabidopsis by using genome-wide gene expression quantitative trait loci. Proc. Natl Acad. Sci. 104, 1708–1713 (2007). et al.
- Expression variation in connected recombinant populations of Arabidopsis thaliana highlights distinct transcriptome architectures. BMC Genomics 13, 117 (2012). et al.
- RNA sequencing reveals the complex regulatory network in the maize kernel. Nature Commun. 4, 2832 (2013). et al.
- Genome-wide expression quantitative trait loci (eQTL) analysis in maize. BMC Genomics 12, 336 (2011). , , , &
- Expression quantitative trait locus mapping across water availability environments reveals contrasting associations with genomic features in Arabidopsis. Plant Cell 25, 3266–3279 (2013). et al.
- Selection at linked sites shapes heritable phenotypic variation in C. elegans. Science 330, 372–376 (2010). , &
- Mapping determinants of gene expression plasticity by genetical genomics in C. elegans. PLoS Genet. 2, e222 (2006). et al.
- Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors. Nature Genet. 35, 57–64 (2003). et al.
- Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190–1195 (2012). et al.
- The genetic basis of evolutionary change in gene expression levels. Phil. Trans. R. Soc. B 365, 2581–2590 (2010). &
- Inherited variation in gene expression. Annu. Rev. Genomics Hum. Genet. 10, 313–332 (2009). , &
- Determining causality and consequence of expression quantitative trait loci. Hum. Genet. 133, 727–735 (2014). &
- Cellular genomics for complex traits. Nature Rev. Genet. 13, 215–220 (2012).
- Global properties and functional complexity of human gene regulatory variation. PLoS Genet. 9, e1003501 (2013).
- Systems genetics approaches to understand complex traits. Nature Rev. Genet. 15, 34–48 (2014). &
- Local regulatory variation in Saccharomyces cerevisiae. PLoS Genet. 1, e25 (2005). , , &
- Evolutionary changes in cis and trans gene regulation. Nature 430, 85–88 (2004). , &
- Transcriptome genetics using second generation sequencing in a Caucasian population. Nature 464, 773–777 (2010). et al.
- Understanding mechanisms underlying human gene expression variation with RNA sequencing. Nature 464, 768–772 (2010). et al.
- Cis-acting expression quantitative trait loci in mice. Genome Res. 15, 681–691 (2005). , , &
- Allelic variation in human gene expression. Science 297, 1143 (2002). , , , &
- Characterizing the genetic basis of transcriptome diversity through RNA-sequencing of 922 individuals. Genome Res. 24, 14–24 (2014). et al.
- The evolution of gene expression QTL in Saccharomyces cerevisiae. PLoS ONE 2, e678 (2007). &
- Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes. Nature Genet. 39, 1208–1216 (2007). et al.
- Gene–environment interaction in yeast gene expression. PLoS Biol. 6, e83 (2008). &
- Natural genetic variation impacts expression levels of coding, non-coding, and antisense transcripts in fission yeast. Mol. Syst. Biol. 10, 764 (2014). et al.
- Systems-level approaches reveal conservation of trans-regulated genes in the rat and genetic determinants of blood pressure in humans. Cardiovasc. Res. 97, 653–665 (2013). et al.
- Uncovering regulatory pathways that affect hematopoietic stem cell function using 'genetical genomics'. Nature Genet. 37, 225–232 (2005). et al.
- Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function. Nature Genet. 37, 233–242 (2005). et al.
- Integrating large-scale functional genomic data to dissect the complexity of yeast regulatory networks. Nature Genet. 40, 854–861 (2008). et al.
- Genetic interactions between polymorphisms that affect gene expression in yeast. Nature 436, 701–703 (2005). , , &
- Comparative analysis of proteome and transcriptome variation in mouse. PLoS Genet. 7, e1001393 (2011). et al.
- Genetic inheritance of gene expression in human cell lines. Am. J. Hum. Genet. 75, 1094–1105 (2004). et al.
- Heritability and tissue specificity of expression quantitative trait loci. PLoS Genet. 2, e172 (2006). et al.
- Expression quantitative trait loci: replication, tissue- and sex-specificity in mice. Genetics 185, 1059–1068 (2010). et al.
- Single-tissue and cross-tissue heritability of gene expression via identity-by-descent in related or unrelated individuals. PLoS Genet. 7, e1001317 (2011). et al.
- Mapping cis- and trans-regulatory effects across multiple tissues in twins. Nature Genet. 44, 1084–1089 (2012). et al.
- Heritability and genomics of gene expression in peripheral blood. Nature Genet. 46, 430–437 (2014). et al.
- Common SNPs explain a large proportion of the heritability for human height. Nature Genet. 42, 565–569 (2010). et al.
- 1998). & Genetics and Analysis of Quantitative Traits (Sinauer Associates,
- Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles. Nature Genet. 44, 502–510 (2012). et al.
- Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression. Science 343, 1246949 (2014). et al.
- Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans. PLoS Genet. 7, e1002367 (2011). et al.
- A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature 467, 460–464 (2010).
This study reveals a physiologically important regulatory network in monocytes that is conserved between rats and humans, and that is affected by genetic variation in both species.
- Systematic identification of trans eQTLs as putative drivers of known disease associations. Nature Genet. 45, 1238–1243 (2013).
With >5,000 samples, this meta-analysis is the largest human eQTL study so far. The authors use the large sample size to identify >100 trans-eQTLs.
- Trans-eQTLs reveal that independent genetic variants associated with a complex phenotype converge on intermediate genes, with a major role for the HLA. PLoS Genet. 7, e1002197 (2011). et al.
- Cis and trans effects of human genomic variants on gene expression. PLoS Genet. 10, e1004461 (2014). et al.
- Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes. Science 344, 519–523 (2014). et al.
- Common genetic variants modulate pathogen-sensing responses in human dendritic cells. Science 343, 1246980 (2014). et al.
- Heritable individual-specific and allele-specific chromatin signatures in humans. Science 328, 235–239 (2010). et al.
- Effects of sequence variation on differential allelic transcription factor occupancy and gene expression. Genome Res. 22, 860–869 (2012). et al.
- Variation in transcription factor binding among humans. Science 328, 232–235 (2010). et al.
- Effect of natural genetic variation on enhancer selection and function. Nature 503, 487–492 (2013). et al.
- Quantitative genetics of CTCF binding reveal local sequence effects and different modes of X-chromosome association. PLoS Genet. 10, e1004798 (2014). et al.
- DNase I sensitivity QTLs are a major determinant of human expression variation. Nature 482, 390–394 (2012). et al.
- Genetic landscape of open chromatin in yeast. PLoS Genet. 9, e1003229 (2013). et al.
- DNA methylation contributes to natural human variation. Genome Res. 23, 1363–1372 (2013). et al.
- DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines. Genome Biol. 12, R10 (2011). et al.
- Methylation QTLs are associated with coordinated changes in transcription factor binding, histone modifications, and gene expression levels. PLoS Genet. 10, e1004663 (2014). et al.
- Passive and active DNA methylation and the interplay with genetic variation in gene regulation. eLife 2, e00523 (2013). et al.
- Contribution of genetic variation to transgenerational inheritance of DNA methylation. Genome Biol. 15, R73 (2014). et al.
- Noisy splicing drives mRNA isoform diversity in human cells. PLoS Genet. 6, e1001236 (2010). , , &
- Transcriptome and genome sequencing uncovers functional variation in humans. Nature 501, 506–511 (2013).
This is the first paper to integrate fully sequenced genomes with RNA sequencing-based transcriptomes in a large human population, which provides many important insights into the functional diversity of the genetics of the transcriptome.
- The genetic basis for individual differences in mRNA splicing and APOBEC1 editing activity in murine macrophages. Genome Res. 24, 377–389 (2014). , , &
- Genetic regulation of human adipose microRNA expression and its consequences for metabolic traits. Hum. Mol. Genet. 22, 3023–3037 (2013). et al.
- Extent, causes, and consequences of small RNA expression variation in human adipose tissue. PLoS Genet. 8, e1002704 (2012). et al.
- Genetic and epigenetic regulation of human lincRNA gene expression. Am. J. Hum. Genet. 93, 1015–1026 (2013). , , &
- Human disease-associated genetic variation impacts large intergenic non-coding RNA expression. PLoS Genet. 9, e1003201 (2013). et al.
- The contribution of RNA decay quantitative trait loci to inter-individual variation in steady-state gene expression levels. PLoS Genet. 8, e1003000 (2012). et al.
- Rare and common regulatory variation in population-scale sequenced human genomes. PLoS Genet. 7, e1002144 (2011). , , &
- ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).
- Identification of genetic variants that affect histone modifications in human cells. Science 342, 747–749 (2013). et al.
- Coordinated effects of sequence variation on DNA binding, chromatin structure, and transcription. Science 342, 744–747 (2013). et al.
- Extensive variation in chromatin states across humans. Science 342, 750–752 (2013). et al.
- From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature 466, 714–719 (2010).
This paper provides an example of how a regulatory sequence change leads to gene expression variation at a distant gene, which in turn influences cholesterol levels and the risk for myocardial infarction.
- 9p21 DNA variants associated with coronary artery disease impair interferon-γ signalling response. Nature 470, 264–268 (2011). et al.
- Differential contributions of rare and common, coding and noncoding Ret mutations to multifactorial Hirschsprung disease liability. Am. J. Hum. Genet. 87, 60–74 (2010). et al.
- A regulatory SNP causes a human genetic disease by creating a new transcriptional promoter. Science 312, 1215–1217 (2006). et al.
- The molecular mechanism of a cis-regulatory adaptation in yeast. PLoS Genet. 9, e1003813 (2013). et al.
- Learning a prior on regulatory potential from eQTL data. PLoS Genet. 5, e1000358 (2009). et al.
- Genetic architecture of ethanol-responsive transcriptome variation in Saccharomyces cerevisiae strains. Genetics 198, 369–382 (2014). , , &
- Proteasomal degradation of human CYP1B1: effect of the Asn453Ser polymorphism on the post-translational regulation of CYP1B1 expression. Mol. Pharmacol. 67, 435–443 (2005). et al.
- Reproducibility of high-throughput mRNA and small RNA sequencing across laboratories. Nature Biotech. 31, 1015–1022 (2013). et al.
- A genome-wide association study identifies protein quantitative trait loci (pQTLs). PLoS Genet. 4, e1000072 (2008). et al.
- Identification of quantitative trait loci underlying proteome variation in human lymphoblastoid cells. Mol. Cell. Proteomics 9, 1383–1399 (2010). et al.
- Identification and validation of genetic variants that influence transcription factor and cell signaling protein levels. Am. J. Hum. Genet. 95, 194–208 (2014). et al.
- Impact of regulatory variation from RNA to protein. Science 347, 664–667 (2015).
This is the first paper to present an integrated analysis of the genetics of mRNA levels, translation and protein abundance in humans.
- A complete mass-spectrometric map of the yeast proteome applied to quantitative trait analysis. Nature 494, 266–270 (2013). et al.
- Identification of cis-regulatory variation influencing protein abundance levels in human plasma. Hum. Mol. Genet. 21, 3719–3726 (2012). et al.
- Quantitative trait loci mapping of the mouse plasma proteome (pQTL). Genetics 193, 601–608 (2012). et al.
- Identification of genetic variants influencing the human plasma proteome. Proc. Natl Acad. Sci. 110, 4673–4678 (2013). et al.
- Variation and genetic control of protein abundance in humans. Nature 499, 79–82 (2013). et al.
- Integrative phenomics reveals insight into the structure of phenotypic diversity in budding yeast. Genome Res. 23, 1496–1504 (2013). et al.
- Genetic basis of proteome variation in yeast. Nature Genet. 39, 1369–1375 (2007). et al.
- Genetic variation shapes protein networks mainly through non-transcriptional mechanisms. PLoS Biol. 9, e1001144 (2011). et al.
- Genetics of single-cell protein abundance variation in large yeast populations. Nature 506, 494–497 (2014). , , , &
- Heritability and genetic basis of protein level variation in an outbred population. Genome Res. 24, 1363–1370 (2014).
References 121 and 122 pioneer the use of pools of hundreds of thousands of yeast cells to identify pQTLs and provide important insights into the genetics of protein versus mRNA levels.
- Global quantification of mammalian gene expression control. Nature 473, 337–342 (2011). et al.
- System wide analyses have underestimated protein abundances and the importance of transcription in mammals. PeerJ 2, e270 (2014). , &
- Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324, 218–223 (2009). , , &
- Genetic influences on translation in yeast. PLoS Genet. 10, e1004692 (2014). , , &
- Extensive and coordinated control of allele-specific expression by both transcription and translation in Candida albicans. Genome Res. 24, 963–973 (2014). , &
- The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer. Nature Genet. 41, 882–884 (2009). et al.
- Mice lacking a MYC enhancer that includes human SNP rs6983267 are resistant to intestinal tumors. Science 338, 1360–1363 (2012). et al.
- Evolution of transcription factor binding in metazoans — mechanisms and functional implications. Nature Rev. Genet. 15, 221–233 (2014). , &
- A molecular basis for classic blond hair color in Europeans. Nature Genet. 46, 748–752 (2014).
This study uses transgenic mice to show that a genetic change in a human regulatory element contributes to blond hair.
, , , &
- Exit from exit: resetting the cell cycle through Amn1 inhibition of G protein signaling. Cell 112, 697–709 (2003). , , , &
- Overlapping and distinct roles of the duplicated yeast transcription factors Ace2p and Swi5p. Mol. Microbiol. 40, 422–432 (2001). , , &
- Chitinase is required for cell separation during growth of Saccharomyces cerevisiae. J. Biol. Chem. 266, 19758–19767 (1991). &
- Nonlinear fitness consequences of variation in expression level of a eukaryotic gene. Mol. Biol. Evol. 30, 448–456 (2013). et al.
- Genotype–environment interactions reveal causal pathways that mediate genetic effects on phenotype. PLoS Genet. 9, e1003803 (2013). et al.
- Single nucleotide variants in transcription factors associate more tightly with phenotype than with gene expression. PLoS Genet. 10, e1004325 (2014).
References 135–137 are examples of how the powerful experimental tools in yeast provide conceptual insights into the relationship between eQTLs and higher-order phenotypes.
- Genetic interactions between transcription factors cause natural variation in yeast. Science 323, 498–501 (2009). , &
- Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. Am. J. Hum. Genet. 95, 535–552 (2014).
This study uses elegant whole-genome methods to estimate the relative contribution of functional genomic annotations to the heritability of several human traits and shows that by far the largest fraction is due to variants in putative regulatory elements.
- The accessible chromatin landscape of the human genome. Nature 489, 75–82 (2012). et al.
- Candidate causal regulatory effects by integration of expression QTLs with complex trait genetic associations. PLoS Genet. 6, e1000895 (2010). et al.
- Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genet. 6, e1000888 (2010). et al.
- Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014).
- Cross-tissue and tissue-specific eQTLs: partitioning the heritability of a complex trait. Am. J. Hum. Genet. 95, 521–534 (2014). et al.
- An enhancer polymorphism at the cardiomyocyte intercalated disc protein NOS1AP locus is a major regulator of the QT interval. Am. J. Hum. Genet. 94, 854–869 (2014). et al.
- The Genotype–Tissue Expression (GTEx) project. Nature Genet. 45, 580–585 (2013). et al.
- Powerful identification of cis-regulatory SNPs in human primary monocytes using allele-specific gene expression. PLoS ONE 7, e52260 (2012). et al.
- Genetics and beyond — the transcriptome of human monocytes and disease susceptibility. PLoS ONE 5, e10693 (2010). et al.
- Allelic expression mapping across cellular lineages to establish impact of non-coding SNPs. Mol. Syst. Biol. 10, 754 (2014). et al.
- Intersection of population variation and autoimmunity genetics in human T cell activation. Science 345, 1254665 (2014).
References 16, 67, 74 and 150 detect previously hidden eQTLs in purified populations of primary immune cells once they are stimulated with triggers of the immune response.
- Interindividual variation in human T regulatory cells. Proc. Natl Acad. Sci. 111, E1111–E1120 (2014). et al.
- Impact of natural genetic variation on gene expression dynamics. PLoS Genet. 9, e1003514 (2013). , &
- Expression quantitative trait loci are highly sensitive to cellular differentiation state. PLoS Genet. 5, e1000692 (2009). et al.
- The promise of induced pluripotent stem cells in research and therapy. Nature 481, 295–305 (2012). &
- Genetic background drives transcriptional variation in human induced pluripotent stem cells. PLoS Genet. 10, e1004432 (2014). et al.
- Characterizing the genetic basis of innate immune response in TLR4-activated human monocytes. Nature Commun. 5, 5236 (2014). et al.
- Deciphering the genetic architecture of variation in the immune response to Mycobacterium tuberculosis infection. Proc. Natl Acad. Sci. 109, 1204–1209 (2012). et al.
- Genetics of gene expression in immunity to infection. Curr. Opin. Immunol. 30, 63–71 (2014). &
- Integrative genomic analysis of the human immune response to influenza vaccination. eLife 2, e00299 (2013). et al.
- Linking disease associations with regulatory information in the human genome. Genome Res. 22, 1748–1759 (2012). , , , &
- Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature http://dx.doi.org/10.1038/nature13835 (2014). et al.
- All SNPs are not created equal: genome-wide association studies reveal a consistent pattern of enrichment among functionally annotated SNPs. PLoS Genet. 9, e1003449 (2013). et al.
- Chromatin marks identify critical cell types for fine mapping complex trait variants. Nature Genet. 45, 124–130 (2012). et al.
- Joint analysis of functional genomic data and genome-wide association studies of 18 human traits. Am. J. Hum. Genet. 94, 559–573 (2014).
- Integrating functional data to prioritize causal variants in statistical fine-mapping studies. PLoS Genet. 10, e1004722 (2014). et al.
- Bayesian method to incorporate hundreds of functional characteristics with association evidence to improve variant prioritization. PLoS ONE 9, e98122 (2014).
References 164–166 are examples of the formal integration of functional genomic information and genetic variation.
, , &
- GPA: a statistical approach to prioritizing GWAS results by integrating pleiotropy and annotation. PLoS Genet. 10, e1004787 (2014). , , , &
- Using functional annotation for the empirical determination of Bayes factors for genome-wide association study analysis. PLoS ONE 6, e14808 (2011). , , &
- Dissecting the regulatory architecture of gene expression QTLs. Genome Biol. 13, R7 (2012). et al.
- Integrative modeling of eQTLs and cis-regulatory elements suggests mechanisms underlying cell type specificity of eQTLs. PLoS Genet. 9, e1003649 (2013). , &
- Statistical framework for joint eQTL analysis in multiple tissues. PLoS Genet. 9, e1003486 (2013). , , &
- Robust prediction of expression differences among human individuals using only genotype information. PLoS Genet. 9, e1003396 (2013). &
- Using prior information from the medical literature in GWAS of oral cancer identifies novel susceptibility variant on chromosome 4 — the AdAPT method. PLoS ONE 7, e36888 (2012). et al.
- Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 10, e1004383 (2014). et al.
- Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448, 470–473 (2007). et al.
- Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes. Nature Genet. 43, 561–564 (2011). et al.
- Mapping complex disease traits with global gene expression. Nature Rev. Genet. 10, 184–194 (2009). , , , &
- A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007). et al.
- Inactivation of the Fto gene protects from obesity. Nature 458, 894–898 (2009). et al.
- Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature 507, 371–375 (2014). et al.
- Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra- and interchromosomal interactions. Nature Genet. 38, 1341–1347 (2006). et al.
- Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture–on-chip (4C). Nature Genet. 38, 1348–1354 (2006). et al.
- Chromosome conformation capture carbon copy (5C): a massively parallel solution for mapping interactions between genomic elements. Genome Res. 16, 1299–1309 (2006). et al.
- Unbiased analysis of potential targets of breast cancer susceptibility loci by capture Hi-C. Genome Res. 24, 1854–1868 (2014). et al.
- Capturing chromosome conformation. Science 295, 1306–1311 (2002). , , &
- Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009). et al.
- Investigating human disease using stem cell models. Nature Rev. Genet. 15, 625–639 (2014). , &
- Reconstructing lineage hierarchies of the distal lung epithelium using single-cell RNA-seq. Nature 509, 371–375 (2014). et al.
- Massively parallel single-cell RNA-seq for marker-free decomposition of tissues into cell types. Science 343, 776–779 (2014). et al.
- The landscape of genetic complexity across 5,700 gene expression traits in yeast. Proc. Natl Acad. Sci. 102, 1572–1577 (2005). &
- Detection and replication of epistasis influencing transcription in humans. Nature 508, 249–253 (2014). et al.
- Genetic interactions affecting human gene expression identified by variance association mapping. eLife 3, e01381 (2014). et al.
- Another explanation for apparent epistasis. Nature 514, E3–E5 (2014). et al.
- Gene–gene and gene–environment interactions detected by transcriptome sequence analysis in twins. Nature Genet. 47, 88–91 (2015). et al.
- Data and theory point to mainly additive genetic variance for complex traits. PLoS Genet. 4, e1000008 (2008). , &
- Influence of gene interaction on complex trait variation with multilocus models. Genetics 198, 355–367 (2014). &
- A statin-dependent QTL for GATM expression is associated with statin-induced myopathy. Nature 502, 377–380 (2013). et al.
- Development and applications of CRISPR–Cas9 for genome engineering. Cell 157, 1262–1278 (2014). , &
- CRISPR–Cas systems for editing, regulating and targeting genomes. Nature Biotech. 32, 347–355 (2014). &
- Tackling the widespread and critical impact of batch effects in high-throughput data. Nature Rev. Genet. 11, 733–739 (2010). et al.
- On the design and analysis of gene expression studies in human populations. Nature Genet. 39, 807–808 (2007). , , &
- Capturing heterogeneity in gene expression studies by surrogate variable analysis. PLoS Genet. 3, e161 (2007). &
- Bayesian framework to account for complex non-genetic factors in gene expression levels greatly increases power in eQTL studies. PLoS Comput. Biol. 6, e1000770 (2010). , , &
- Genetic and nongenetic variation revealed for the principal components of human gene expression. Genetics 195, 1117–1128 (2013). et al.
- Joint modelling of confounding factors and prominent genetic regulators provides increased accuracy in genetical genomics studies. PLoS Comput. Biol. 8, e1002330 (2012). , &
- Using probabilistic estimation of expression residuals (PEER) to obtain increased power and interpretability of gene expression analyses. Nature Protoc. 7, 500–507 (2012). , , , &
- Correction for hidden confounders in the genetic analysis of gene expression. Proc. Natl Acad. Sci. 107, 16465–16470 (2010). , , &
- Accurate discovery of expression quantitative trait loci under confounding from spurious and genuine regulatory hotspots. Genetics 180, 1909–1925 (2008). , &
- HEFT: eQTL analysis of many thousands of expressed genes while simultaneously controlling for hidden factors. Bioinformatics 30, 369–376 (2014). et al.
- Accounting for non-genetic factors by low-rank representation and sparse regression for eQTL mapping. Bioinformatics 29, 1026–1034 (2013). , , &
- Normalizing RNA-sequencing data by modeling hidden covariates with prior knowledge. PLoS ONE 8, e68141 (2013). et al.
- Joint genetic analysis of gene expression data with inferred cellular phenotypes. PLoS Genet. 7, e1001276 (2011). , , &
- Identifying the genetic determinants of transcription factor activity. Mol. Syst. Biol. 6, 412 (2010). &
- Harnessing natural sequence variation to dissect posttranscriptional regulatory networks in yeast. G3 (Bethesda) 4, 1539–1553 (2014). et al.
- The effects of genetic variation on gene expression dynamics during development. Nature 505, 208–211 (2013). &
- The Brisbane Systems Genetics Study: genetical genomics meets complex trait genetics. PLoS ONE 7, e35430 (2012). et al.
- Global analysis of the impact of environmental perturbation on cis-regulation of gene expression. PLoS Genet. 7, e1001279 (2011). et al.
- Genetic variability in the regulation of gene expression in ten regions of the human brain. Nature Neurosci. 17, 1418–1428 (2014). et al.
- Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants. PLoS Genet. 8, e1002707 (2012). et al.
- Temporal dynamics and genetic control of transcription in the human prefrontal cortex. Nature 478, 519–523 (2011). et al.
- Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet. 6, e1000952 (2010). et al.
- Genome-wide identification of expression quantitative trait loci (eQTLs) in human heart. PLoS ONE 9, e97380 (2014). et al.
- Identification, replication, and functional fine-mapping of expression quantitative trait loci in primary human liver tissue. PLoS Genet. 7, e1002078 (2011). et al.
- Mapping the genetic architecture of gene expression in human liver. PLoS Biol. 6, e107 (2008). et al.
- Lung eQTLs to help reveal the molecular underpinnings of asthma. PLoS Genet. 8, e1003029 (2012). et al.
- Putative cis-regulatory drivers in colorectal cancer. Nature 512, 87–90 (2014). et al.
- Expression QTL-based analyses reveal candidate causal genes and loci across five tumor types. Hum. Mol. Genet. 23, 5294–5302 (2014). et al.
- Integrative eQTL-based analyses reveal the biology of breast cancer risk loci. Cell 152, 633–641 (2013). et al.