Emmanouil T Dermitzakis

Publications of Emmanouil T Dermitzakis

• Tandem repeat sequence variation as causative cis eQTLs for protein-coding gene expression variation: The case of CSTB.

  Authors: Christelle Borel, Eugenia Migliavacca, Audrey Letourneau, Maryline Gagnebin, Frédérique Béna, M Reza Sailani, Emmanouil T Dermitzakis, Andrew J Sharp, Stylianos E Antonarakis

  Human mutation. 05/2012;

  Association studies have revealed expression quantitative trait loci (eQTLs) for a large number of genes. However, the causative variants that regulate gene expression levels are generally unknown.Association studies have revealed expression quantitative trait loci (eQTLs) for a large number of genes. However, the causative variants that regulate gene expression levels are generally unknown. We hypothesized that copy number variation of sequence repeats contribute to the expression variation of some genes. Our laboratory has previously identified that the rare expansion of a repeat c.-174CGGGGCGGGGCG in the promoter region of the CSTB gene causes a silencing of the gene, resulting in progressive myoclonus epilepsy. Here, we genotyped the repeat length and quantified CSTB expression by qRT-PCR in 173 lymphoblast (LCLs) and fibroblast samples from the GenCord collection. The majority of alleles contain either 2 or 3 copies of this repeat. Independent analysis revealed that the c.-174CGGGGCGGGGCG repeat length is strongly associated with CSTB expression (P = 3.14 × 10(-11) ) in LCLs only. Examination of both genotyped and imputed SNPs within 2Mb of CSTB revealed that the dodecamer repeat represents the strongest cis-eQTL for CSTB in LCLs. We conclude that the common 2 or 3 copy variation is likely the causative cis-eQTL for CSTB expression variation. More broadly, we propose that polymorphic tandem repeats may represent the causative variation of a fraction of cis-eQTLs in the genome.

• Analysis of case-control association studies with known risk variants.

  Authors: Noah Zaitlen, Bogdan Pasaniuc, Nick Patterson, Samuela Pollack, Benjamin Voight, Leif Groop, David Altshuler, Brian E Henderson, Laurence N Kolonel, Loic Le Marchand, Kevin Waters, Christopher A Haiman, Barbara E Stranger, Emmanouil T Dermitzakis, Peter Kraft, Alkes L Price

  Bioinformatics (Oxford, England). 05/2012;

  MOTIVATION: The question of how to best utilize information from known associated variants when conducting disease association studies has yet to be answered. Some studies compute a marginal P-valueMOTIVATION: The question of how to best utilize information from known associated variants when conducting disease association studies has yet to be answered. Some studies compute a marginal P-value for each SNP independently, ignoring previously discovered variants. Other studies include known variants as covariates in logistic regression, but a weakness of this standard conditioning strategy is that it does not account for disease prevalence and non-random ascertainment, which can induce a correlation structure between candidate variants and known associated variants even if the variants lie on different chromosomes. Here, we propose a new conditioning approach, which is based in part on the classical technique of liability threshold modeling. Roughly, this method estimates model parameters for each known variant while accounting for the published disease prevalence from the epidemiological literature. RESULTS: We show via simulation and application to empirical data sets that our approach outperforms both the no conditioning strategy and the standard conditioning strategy, with a properly controlled false-positive rate. Furthermore, in multiple data sets involving diseases of low prevalence, standard conditioning produces a severe drop in test statistics whereas our approach generally performs as well or better than no conditioning. Our approach may substantially improve disease gene discovery for diseases with many known risk variants. AVAILABILITY: LTSOFT software http://www.hsph.harvard.edu/faculty/alkes-price/software/ (source code and executables will be made available prior to publication of the paper) CONTACT: nzaitlen@hsph.harvard.edu.

• Extent, causes, and consequences of small RNA expression variation in human adipose tissue.

  Authors: Leopold Parts, Asa K Hedman, Sarah Keildson, Andrew J Knights, Cei Abreu-Goodger, Martijn van de Bunt, José Afonso Guerra-Assunção, Nenad Bartonicek, Stijn van Dongen, Reedik Mägi [......] Kerrin S Small, Daniel Glass, Anton J Enright, John Winn, Panos Deloukas, Emmanouil T Dermitzakis, Mark I McCarthy, Timothy D Spector, Richard Durbin, Cecilia M Lindgren

  PLoS genetics. 05/2012; 8(5):e1002704.

  Small RNAs are functional molecules that modulate mRNA transcripts and have been implicated in the aetiology of several common diseases. However, little is known about the extent of their variabilitySmall RNAs are functional molecules that modulate mRNA transcripts and have been implicated in the aetiology of several common diseases. However, little is known about the extent of their variability within the human population. Here, we characterise the extent, causes, and effects of naturally occurring variation in expression and sequence of small RNAs from adipose tissue in relation to genotype, gene expression, and metabolic traits in the MuTHER reference cohort. We profiled the expression of 15 to 30 base pair RNA molecules in subcutaneous adipose tissue from 131 individuals using high-throughput sequencing, and quantified levels of 591 microRNAs and small nucleolar RNAs. We identified three genetic variants and three RNA editing events. Highly expressed small RNAs are more conserved within mammals than average, as are those with highly variable expression. We identified 14 genetic loci significantly associated with nearby small RNA expression levels, seven of which also regulate an mRNA transcript level in the same region. In addition, these loci are enriched for variants significant in genome-wide association studies for body mass index. Contrary to expectation, we found no evidence for negative correlation between expression level of a microRNA and its target mRNAs. Trunk fat mass, body mass index, and fasting insulin were associated with more than twenty small RNA expression levels each, while fasting glucose had no significant associations. This study highlights the similar genetic complexity and shared genetic control of small RNA and mRNA transcripts, and gives a quantitative picture of small RNA expression variation in the human population.

• Epigenome-Wide Scans Identify Differentially Methylated Regions for Age and Age-Related Phenotypes in a Healthy Ageing Population.

  Authors: Jordana T Bell, Pei-Chien Tsai, Tsun-Po Yang, Ruth Pidsley, James Nisbet, Daniel Glass, Massimo Mangino, Guangju Zhai, Feng Zhang, Ana Valdes [......] Robin M Murray, Elin Grundberg, Asa K Hedman, Alexandra Nica, Kerrin S Small, Emmanouil T Dermitzakis, Mark I McCarthy, Jonathan Mill, Tim D Spector, Panos Deloukas

  PLoS genetics. 04/2012; 8(4):e1002629.

  Age-related changes in DNA methylation have been implicated in cellular senescence and longevity, yet the causes and functional consequences of these variants remain unclear. To elucidate the role ofAge-related changes in DNA methylation have been implicated in cellular senescence and longevity, yet the causes and functional consequences of these variants remain unclear. To elucidate the role of age-related epigenetic changes in healthy ageing and potential longevity, we tested for association between whole-blood DNA methylation patterns in 172 female twins aged 32 to 80 with age and age-related phenotypes. Twin-based DNA methylation levels at 26,690 CpG-sites showed evidence for mean genome-wide heritability of 18%, which was supported by the identification of 1,537 CpG-sites with methylation QTLs in cis at FDR 5%. We performed genome-wide analyses to discover differentially methylated regions (DMRs) for sixteen age-related phenotypes (ap-DMRs) and chronological age (a-DMRs). Epigenome-wide association scans (EWAS) identified age-related phenotype DMRs (ap-DMRs) associated with LDL (STAT5A), lung function (WT1), and maternal longevity (ARL4A, TBX20). In contrast, EWAS for chronological age identified hundreds of predominantly hyper-methylated age DMRs (490 a-DMRs at FDR 5%), of which only one (TBX20) was also associated with an age-related phenotype. Therefore, the majority of age-related changes in DNA methylation are not associated with phenotypic measures of healthy ageing in later life. We replicated a large proportion of a-DMRs in a sample of 44 younger adult MZ twins aged 20 to 61, suggesting that a-DMRs may initiate at an earlier age. We next explored potential genetic and environmental mechanisms underlying a-DMRs and ap-DMRs. Genome-wide overlap across cis-meQTLs, genotype-phenotype associations, and EWAS ap-DMRs identified CpG-sites that had cis-meQTLs with evidence for genotype-phenotype association, where the CpG-site was also an ap-DMR for the same phenotype. Monozygotic twin methylation difference analyses identified one potential environmentally-mediated ap-DMR associated with total cholesterol and LDL (CSMD1). Our results suggest that in a small set of genes DNA methylation may be a candidate mechanism of mediating not only environmental, but also genetic effects on age-related phenotypes.

• Patterns of cis regulatory variation in diverse human populations.

  Authors: Barbara E Stranger, Stephen B Montgomery, Antigone S Dimas, Leopold Parts, Oliver Stegle, Catherine E Ingle, Magda Sekowska, George Davey Smith, David Evans, Maria Gutierrez-Arcelus, Alkes Price, Towfique Raj, James Nisbett, Alexandra C Nica, Claude Beazley, Richard Durbin, Panos Deloukas, Emmanouil T Dermitzakis

  PLoS genetics. 04/2012; 8(4):e1002639.

  The genetic basis of gene expression variation has long been studied with the aim to understand the landscape of regulatory variants, but also more recently to assist in the interpretation andThe genetic basis of gene expression variation has long been studied with the aim to understand the landscape of regulatory variants, but also more recently to assist in the interpretation and elucidation of disease signals. To date, many studies have looked in specific tissues and population-based samples, but there has been limited assessment of the degree of inter-population variability in regulatory variation. We analyzed genome-wide gene expression in lymphoblastoid cell lines from a total of 726 individuals from 8 global populations from the HapMap3 project and correlated gene expression levels with HapMap3 SNPs located in cis to the genes. We describe the influence of ancestry on gene expression levels within and between these diverse human populations and uncover a non-negligible impact on global patterns of gene expression. We further dissect the specific functional pathways differentiated between populations. We also identify 5,691 expression quantitative trait loci (eQTLs) after controlling for both non-genetic factors and population admixture and observe that half of the cis-eQTLs are replicated in one or more of the populations. We highlight patterns of eQTL-sharing between populations, which are partially determined by population genetic relatedness, and discover significant sharing of eQTL effects between Asians, European-admixed, and African subpopulations. Specifically, we observe that both the effect size and the direction of effect for eQTLs are highly conserved across populations. We observe an increasing proximity of eQTLs toward the transcription start site as sharing of eQTLs among populations increases, highlighting that variants close to TSS have stronger effects and therefore are more likely to be detected across a wider panel of populations. Together these results offer a unique picture and resource of the degree of differentiation among human populations in functional regulatory variation and provide an estimate for the transferability of complex trait variants across populations.

• Insights into hominid evolution from the gorilla genome sequence.

  Authors: Aylwyn Scally, Julien Y Dutheil, LaDeana W Hillier, Gregory E Jordan, Ian Goodhead, Javier Herrero, Asger Hobolth, Tuuli Lappalainen, Thomas Mailund, Tomas Marques-Bonet [......] Chris P Ponting, Michael A Quail, Oliver A Ryder, Stephen M Searle, Wesley C Warren, Richard K Wilson, Mikkel H Schierup, Jane Rogers, Chris Tyler-Smith, Richard Durbin

  Nature. 03/2012; 483(7388):169-75.

  Gorillas are humans' closest living relatives after chimpanzees, and are of comparable importance for the study of human origins and evolution. Here we present the assembly and analysis of a genomeGorillas are humans' closest living relatives after chimpanzees, and are of comparable importance for the study of human origins and evolution. Here we present the assembly and analysis of a genome sequence for the western lowland gorilla, and compare the whole genomes of all extant great ape genera. We propose a synthesis of genetic and fossil evidence consistent with placing the human-chimpanzee and human-chimpanzee-gorilla speciation events at approximately 6 and 10 million years ago. In 30% of the genome, gorilla is closer to human or chimpanzee than the latter are to each other; this is rarer around coding genes, indicating pervasive selection throughout great ape evolution, and has functional consequences in gene expression. A comparison of protein coding genes reveals approximately 500 genes showing accelerated evolution on each of the gorilla, human and chimpanzee lineages, and evidence for parallel acceleration, particularly of genes involved in hearing. We also compare the western and eastern gorilla species, estimating an average sequence divergence time 1.75 million years ago, but with evidence for more recent genetic exchange and a population bottleneck in the eastern species. The use of the genome sequence in these and future analyses will promote a deeper understanding of great ape biology and evolution.

• A systematic survey of loss-of-function variants in human protein-coding genes.

  Authors: Daniel G MacArthur, Suganthi Balasubramanian, Adam Frankish, Ni Huang, James Morris, Klaudia Walter, Luke Jostins, Lukas Habegger, Joseph K Pickrell, Stephen B Montgomery [......] Yingrui Li, Richard A Gibbs, Steven A McCarroll, Emmanouil T Dermitzakis, Jonathan K Pritchard, Jeffrey C Barrett, Jennifer Harrow, Matthew E Hurles, Mark B Gerstein, Chris Tyler-Smith

  Science (New York, N.Y.). 02/2012; 335(6070):823-8.

  Genome-sequencing studies indicate that all humans carry many genetic variants predicted to cause loss of function (LoF) of protein-coding genes, suggesting unexpected redundancy in the human genome.Genome-sequencing studies indicate that all humans carry many genetic variants predicted to cause loss of function (LoF) of protein-coding genes, suggesting unexpected redundancy in the human genome. Here we apply stringent filters to 2951 putative LoF variants obtained from 185 human genomes to determine their true prevalence and properties. We estimate that human genomes typically contain ~100 genuine LoF variants with ~20 genes completely inactivated. We identify rare and likely deleterious LoF alleles, including 26 known and 21 predicted severe disease-causing variants, as well as common LoF variants in nonessential genes. We describe functional and evolutionary differences between LoF-tolerant and recessive disease genes and a method for using these differences to prioritize candidate genes found in clinical sequencing studies.

• BLUEPRINT to decode the epigenetic signature written in blood.

  Authors: David Adams, Lucia Altucci, Stylianos E Antonarakis, Juan Ballesteros, Stephan Beck, Adrian Bird, Christoph Bock, Bernhard Boehm, Elias Campo, Andrea Caricasole [......] Salvatore Spicuglia, Michael Stratton, Hendrik G Stunnenberg, Amos Tanay, David Torrents, Alfonso Valencia, Edo Vellenga, Martin Vingron, Jörn Walter, Spike Willcocks

  Nature biotechnology. 01/2012; 30(3):224-6.

• Epistatic selection between coding and regulatory variation in human evolution and disease.

  Authors: Tuuli Lappalainen, Stephen B Montgomery, Alexandra C Nica, Emmanouil T Dermitzakis

  American journal of human genetics. 09/2011; 89(3):459-63.

  Interaction (nonadditive effects) between genetic variants has been highlighted as an important mechanism underlying phenotypic variation, but the discovery of genetic interactions in humans hasInteraction (nonadditive effects) between genetic variants has been highlighted as an important mechanism underlying phenotypic variation, but the discovery of genetic interactions in humans has proved difficult. In this study, we show that the spectrum of variation in the human genome has been shaped by modifier effects of cis-regulatory variation on the functional impact of putatively deleterious protein-coding variants. We analyzed 1000 Genomes population-scale resequencing data from Europe (CEU [Utah residents with Northern and Western European ancestry from the CEPH collection]) and Africa (YRI [Yoruba in Ibadan, Nigeria]) together with gene expression data from arrays and RNA sequencing for the same samples. We observed an underrepresentation of derived putatively functional coding variation on the more highly expressed regulatory haplotype, which suggests stronger purifying selection against deleterious coding variants that have increased penetrance because of their regulatory background. Furthermore, the frequency spectrum and impact size distribution of common regulatory polymorphisms (eQTLs) appear to be shaped in order to minimize the selective disadvantage of having deleterious coding mutations on the more highly expressed haplotype. Interestingly, eQTLs explaining common disease GWAS signals showed an enrichment of putative epistatic effects, suggesting that some disease associations might arise from interactions increasing the penetrance of rare coding variants. In conclusion, our results indicate that regulatory and coding variants often modify the functional impact of each other. This specific type of genetic interaction is detectable from sequencing data in a genome-wide manner, and characterizing these joint effects might help us understand functional mechanisms behind genetic associations to human phenotypes-including both Mendelian and common disease.

• Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

  Authors: Rona J Strawbridge, Josée Dupuis, Inga Prokopenko, Adam Barker, Emma Ahlqvist, Denis Rybin, John R Petrie, Mary E Travers, Nabila Bouatia-Naji, Antigone S Dimas [......] Anna L Gloyn, George V Dedoussis, Valeriya Lyssenko, James B Meigs, Inês Barroso, Richard M Watanabe, Erik Ingelsson, Claudia Langenberg, Anders Hamsten, Jose C Florez

  Diabetes. 08/2011; 60(10):2624-34.

  Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

• Rare and common regulatory variation in population-scale sequenced human genomes.

  Authors: Stephen B Montgomery, Tuuli Lappalainen, Maria Gutierrez-Arcelus, Emmanouil T Dermitzakis

  PLoS genetics. 07/2011; 7(7):e1002144.

  Population-scale genome sequencing allows the characterization of functional effects of a broad spectrum of genetic variants underlying human phenotypic variation. Here, we investigate the influencePopulation-scale genome sequencing allows the characterization of functional effects of a broad spectrum of genetic variants underlying human phenotypic variation. Here, we investigate the influence of rare and common genetic variants on gene expression patterns, using variants identified from sequencing data from the 1000 genomes project in an African and European population sample and gene expression data from lymphoblastoid cell lines. We detect comparable numbers of expression quantitative trait loci (eQTLs) when compared to genotypes obtained from HapMap 3, but as many as 80% of the top expression quantitative trait variants (eQTVs) discovered from 1000 genomes data are novel. The properties of the newly discovered variants suggest that mapping common causal regulatory variants is challenging even with full resequencing data; however, we observe significant enrichment of regulatory effects in splice-site and nonsense variants. Using RNA sequencing data, we show that 46.2% of nonsynonymous variants are differentially expressed in at least one individual in our sample, creating widespread potential for interactions between functional protein-coding and regulatory variants. We also use allele-specific expression to identify putative rare causal regulatory variants. Furthermore, we demonstrate that outlier expression values can be due to rare variant effects, and we approximate the number of such effects harboured in an individual by effect size. Our results demonstrate that integration of genomic and RNA sequencing analyses allows for the joint assessment of genome sequence and genome function.

• Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes.

  Authors: Kerrin S Small, Asa K Hedman, Elin Grundberg, Alexandra C Nica, Gudmar Thorleifsson, Augustine Kong, Unnur Thorsteindottir, So-Youn Shin, Hannah B Richards, Nicole Soranzo, Kourosh R Ahmadi, Cecilia M Lindgren, Kari Stefansson, Emmanouil T Dermitzakis, Panos Deloukas, Timothy D Spector, Mark I McCarthy

  Nature genetics. 06/2011; 43(6):561-4.

  Genome-wide association studies have identified many genetic variants associated with complex traits. However, at only a minority of loci have the molecular mechanisms mediating these associationsGenome-wide association studies have identified many genetic variants associated with complex traits. However, at only a minority of loci have the molecular mechanisms mediating these associations been characterized. In parallel, whereas cis regulatory patterns of gene expression have been extensively explored, the identification of trans regulatory effects in humans has attracted less attention. Here we show that the type 2 diabetes and high-density lipoprotein cholesterol-associated cis-acting expression quantitative trait locus (eQTL) of the maternally expressed transcription factor KLF14 acts as a master trans regulator of adipose gene expression. Expression levels of genes regulated by this trans-eQTL are highly correlated with concurrently measured metabolic traits, and a subset of the trans-regulated genes harbor variants directly associated with metabolic phenotypes. This trans-eQTL network provides a mechanistic understanding of the effect of the KLF14 locus on metabolic disease risk and offers a potential model for other complex traits.

• Genome-wide association study identifies a common variant associated with risk of endometrial cancer.

  Authors: Amanda B Spurdle, Deborah J Thompson, Shahana Ahmed, Kaltin Ferguson, Catherine S Healey, Tracy O'Mara, Logan C Walker, Stephen B Montgomery, Emmanouil T Dermitzakis, Paul Fahey [......] Xiao-Ou Shu, Wei Zheng, Jirong Long, Yong-Bing Xiang, Mitul Shah, Jonathan Morrison, Kyriaki Michailidou, Paul D Pharoah, Alison M Dunning, Douglas F Easton

  Nature genetics. 05/2011; 43(5):451-4.

  Endometrial cancer is the most common malignancy of the female genital tract in developed countries. To identify genetic variants associated with endometrial cancer risk, we performed a genome-wideEndometrial cancer is the most common malignancy of the female genital tract in developed countries. To identify genetic variants associated with endometrial cancer risk, we performed a genome-wide association study involving 1,265 individuals with endometrial cancer (cases) from Australia and the UK and 5,190 controls from the Wellcome Trust Case Control Consortium. We compared genotype frequencies in cases and controls for 519,655 SNPs. Forty seven SNPs that showed evidence of association with endometrial cancer in stage 1 were genotyped in 3,957 additional cases and 6,886 controls. We identified an endometrial cancer susceptibility locus close to HNF1B at 17q12 (rs4430796, P = 7.1 × 10(-10)) that is also associated with risk of prostate cancer and is inversely associated with risk of type 2 diabetes.

• From expression QTLs to personalized transcriptomics.

  Authors: Stephen B Montgomery, Emmanouil T Dermitzakis

  Nature reviews. Genetics. 03/2011; 12(4):277-82.

  Approaches that combine expression quantitative trait loci (eQTLs) and genome-wide association (GWA) studies are offering new functional information about the aetiology of complex human traits andApproaches that combine expression quantitative trait loci (eQTLs) and genome-wide association (GWA) studies are offering new functional information about the aetiology of complex human traits and diseases. Improved study designs--which take into account technological advances in resolving the transcriptome, cell history and state, population of origin and diverse endophenotypes--are providing insights into the architecture of disease and the landscape of gene regulation in humans. Furthermore, these advances are helping to establish links between cellular effects and organismal traits.

• Genome-sequencing anniversary. Genome literacy.

  Authors: Emmanouil T Dermitzakis

  Science (New York, N.Y.). 02/2011; 331(6018):689-90.

• Corrigendum: Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes.

  Authors: Kerrin S Small, Asa K Hedman, Elin Grundberg, Alexandra C Nica, Gudmar Thorleifsson, Augustine Kong, Unnur Thorsteindottir, So Youn Shin, Hannah B Richards, Nicole Soranzo, Kourosh R Ahmadi, Cecilia M Lindgren, Kari Stefansson, Emmanouil T Dermitzakis, Panos Deloukas, Timothy D Spector, Mark I McCarthy

  Nature genetics. 01/2011; 43(10):1040.

• Identification of cis- and trans-regulatory variation modulating microRNA expression levels in human fibroblasts.

  Authors: Christelle Borel, Samuel Deutsch, Audrey Letourneau, Eugenia Migliavacca, Stephen B Montgomery, Antigone S Dimas, Charles E Vejnar, Homa Attar, Maryline Gagnebin, Corinne Gehrig, Emilie Falconnet, Yann Dupré, Emmanouil T Dermitzakis, Stylianos E Antonarakis

  Genome research. 01/2011; 21(1):68-73.

  MicroRNAs (miRNAs) are regulatory noncoding RNAs that affect the production of a significant fraction of human mRNAs via post-transcriptional regulation. Interindividual variation of the miRNAMicroRNAs (miRNAs) are regulatory noncoding RNAs that affect the production of a significant fraction of human mRNAs via post-transcriptional regulation. Interindividual variation of the miRNA expression levels is likely to influence the expression of miRNA target genes and may therefore contribute to phenotypic differences in humans, including susceptibility to common disorders. The extent to which miRNA levels are genetically controlled is largely unknown. In this report, we assayed the expression levels of miRNAs in primary fibroblasts from 180 European newborns of the GenCord project and performed association analysis to identify eQTLs (expression quantitative traits loci). We detected robust expression for 121 miRNAs out of 365 interrogated. We have identified significant cis- (10%) and trans- (11%) eQTLs. Furthermore, we detected one genomic locus (rs1522653) that influences the expression levels of five miRNAs, thus unraveling a novel mechanism for coregulation of miRNA expression.

• The architecture of gene regulatory variation across multiple human tissues: the MuTHER study.

  Authors: Alexandra C Nica, Leopold Parts, Daniel Glass, James Nisbet, Amy Barrett, Magdalena Sekowska, Mary Travers, Simon Potter, Elin Grundberg, Kerrin Small [......] Cecilia M Lindgren, Krina T Zondervan, Nicole Soranzo, Inês Barroso, Richard Durbin, Kourosh Ahmadi, Panos Deloukas, Mark I McCarthy, Emmanouil T Dermitzakis, Timothy D Spector

  PLoS genetics. 01/2011; 7(2):e1002003.

  While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depthWhile there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, and fat. The samples (156 LCL, 160 skin, 166 fat) were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes). In addition, we apply factor analysis (FA) to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes). The unique study design (Matched Co-Twin Analysis--MCTA) permits immediate replication of eQTLs using co-twins (93%-98%) and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%-20%) have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits.

• Distinct clinical phenotypes associated with JAK2V617F reflect differential STAT1 signaling.

  Authors: Edwin Chen, Philip A Beer, Anna L Godfrey, Christina A Ortmann, Juan Li, Ana P Costa-Pereira, Catherine E Ingle, Emmanouil T Dermitzakis, Peter J Campbell, Anthony R Green

  Cancer cell. 11/2010; 18(5):524-35.

  The JAK2V617F mutation is associated with distinct myeloproliferative neoplasms, including polycythemia vera (PV) and essential thrombocythemia (ET), but it remains unclear how it generates disparateThe JAK2V617F mutation is associated with distinct myeloproliferative neoplasms, including polycythemia vera (PV) and essential thrombocythemia (ET), but it remains unclear how it generates disparate disorders. By comparing clonally-derived mutant and wild-type cells from individual patients, we demonstrate that the transcriptional consequences of JAK2V617F are subtle, and that JAK2V617F-heterozygous erythroid cells from ET and PV patients exhibit differential interferon signaling and STAT1 phosphorylation. Increased STAT1 activity in normal CD34-positive progenitors produces an ET-like phenotype, whereas downregulation of STAT1 activity in JAK2V617F-heterozygous ET progenitors produces a PV-like phenotype. Our results illustrate the power of clonal analysis, indicate that the consequences of JAK2V617F reflect a balance between STAT5 and STAT1 activation and are relevant for other neoplasms associated with signaling pathway mutations.

• Genevar: a database and Java application for the analysis and visualization of SNP-gene associations in eQTL studies.

  Authors: Tsun-Po Yang, Claude Beazley, Stephen B Montgomery, Antigone S Dimas, Maria Gutierrez-Arcelus, Barbara E Stranger, Panos Deloukas, Emmanouil T Dermitzakis

  Bioinformatics (Oxford, England). 10/2010; 26(19):2474-6.

  Genevar (GENe Expression VARiation) is a database and Java tool designed to integrate multiple datasets, and provides analysis and visualization of associations between sequence variation and geneGenevar (GENe Expression VARiation) is a database and Java tool designed to integrate multiple datasets, and provides analysis and visualization of associations between sequence variation and gene expression. Genevar allows researchers to investigate expression quantitative trait loci (eQTL) associations within a gene locus of interest in real time. The database and application can be installed on a standard computer in database mode and, in addition, on a server to share discoveries among affiliations or the broader community over the Internet via web services protocols. AVAILABILITY: http://www.sanger.ac.uk/resources/software/genevar.