Petretto Enrico Giuseppe

Associate Professor

Email

Education
2003   PhD in Biochemistry, Biology and Molecular Biotechnologies, University of Sassari (UNISS), Italy
2000   MSc in Statistical Genetics, University of Pavia, Italy
1998   Master Degree in Physical Chemistry, University of Sassari (UNISS), Italy

Professional Experience
2012   Tenured Group Head, Medical Research Council (MRC)-Clinical Sciences Centre (CSC), UK
2011   Senior Lecturer in Genomic Medicine, Imperial College London, UK
2009   Associated Group Head, Medical Research Council (MRC)-Clinical Sciences Centre (CSC), UK
2007   Lecturer in Genomic Medicine, Imperial College London, UK
2003-2007   Career Development Fellowship (Statistical Geneticist), Imperial College London, UK
2000-2003   Statistical Geneticist, Shardna Life Sciences Genomics Company, Italy
1999 (Jun-Dec)   Statistical Geneticist, C.N.R. Institute of Population Genetics, Italy

Understanding how genetic information is decoded to produce the complex regulatory systems driving disease remains a great challenge in biomedical sciences. However, the increasing availability of high-dimensional molecular, cellular and phenotypic data now allows a comprehensive investigation of the complex genetic and regulatory mechanisms that underlie the disease process.

My research lab focuses on the systems-level integration of genetic, functional genomic and phenotypic data to identify causal determinants and pathways of complex traits and disease, with a focus on cardio-metabolic, inflammatory and neuropsychiatric disorders. To this aim, I have developed an integrated genetic and gene-network approach, called Systems-Genetics, to determine the consequences of key genetic variants ('master genetic regulators') on functional gene-networks in disease. The research program in Systems-Genetics combines computational approaches and statistical modeling of high-throughput genomics and phenotyping of disease systems. In collaboration with world-leading laboratories, these approaches are applied to humans, animal model systems, and further integrated across species using comparative genomics, to provide a detailed map of the genetic control of functional gene-networks and pathways that are dysregulated in disease. Ultimately, the identification of primary genetic regulators of disease-associated functional networks will uncover novel determinants and therapeutic targets for complex diseases, which are not captured by traditional genetic strategies based on single-gene variant analysis.

To date, using Systems-Genetics we have uncovered several genes regulating functional gene-networks underling disease processes, including EBI2 regulating an anti-viral expression network and type 1 diabetes risk, KCNN4 and its co-regulatory network underlying cell multinucleation in inflammatory disease and SESN3 as a master genetic regulator of a proconvulsant gene network in human epileptic hippocampus. Our Systems-Genetics strategy will be further developed to study cardio-metabolic traits and disease, with the aim of deciphering the primary genetic factors and regulatory networks underlying these.

INTEGRATIVE GENOMICS IN COMPLEX DISEASE

(*equal contribution, ¶corresponding author)

  1. Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease
    N Hübner, CA Wallace*, H Zimdahl*, E Petretto*, H Schulz, F Maciver, M Mueller, O Hummel, J Monti, V Zidek, A Musilova, V Kren, H Causton, L Game, G Born, S Schmidt, A Muller, SA Cook, TW Kurtz, J Whittaker, M Pravenec, TJ Aitman.
    Nature Genetics 2005 37:243-253
  2. Integrated genomic approaches implicate osteoglycin (Ogn) in the regulation of left ventricular mass
    E Petretto*, R Sarwar*, I Grieve, H Lu, MK Kumaran, PJ Muckett, J Mangion, B Schroen, M Benson, PP Punjabi, SK Prasad, DJ Pennell, C Kiesewetter, ES Tasheva, LM Corpuz, MD Webb, GW Conrad, TW Kurtz, V Kren, J Fischer, N Hubner, YM Pinto, M Pravenec, TJ Aitman, SA Cook. 
    Nature Genetics 2008 40:546-552
  3. Identification of renal Cd36 as a determinant of blood pressure and risk for hypertension
    M Pravenec, P Churchill, O Viklicky, L Kazdova, TJ Aitman, E Petretto, N Hübner, C Wallace, H Zimdahl, V Zidek, V Landa, J Dunbar, A Bidani, K Griffin, N Qi, J Wang, T Kurtz. 
    Nature Genetics 2008 40:952-954
  4. Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function 
    C McDermott-Roe, J Ye, R Ahmed, X Sun, A Serafín, J Ware, L Bottolo, P Muckett, X Cañas, J Zhang, G C Rowe, R Buchan, H Lu, A Braithwaite, M Mancini, D Hauton, R Martí, E García-Arumí, N Hubner, H Jacob, T Serikawa, V Zidek, F Papousek, F Kolar, M Cardona, M Ruiz-Meana, D García-Dorado, J X Comella, L E Felkin, P JR Barton, Z Arany, M Pravenec, E Petretto, D Sanchis, SA Cook. 
    Nature 2011 478:114-118
  5. Genome sequencing reveals loci under artificial selection that underlie disease phenotypes in the laboratory rat
    SS Atanur, AG Diaz, K Maratou, A Sarkis, M Rotival, L Game, MR Tschannen, PJ Kaisaki, GW Otto, M C J Ma, TM Keane, O Hummel, K Saar, W Chen, V Guryev, K Gopalakrishnan, MR Garrett, B Joe, L Citterio, G Bianchi, M McBride, A Dominiczak, DJ Adams, T Serikawa, P Flicek, E Cuppen, N Hubner, E Petretto, D Gauguier, A Kwitek, H Jacob, TJ Aitman.
    Cell 2013 154:691-703
  6. Genetic analysis of the cardiac methylome at single nucleotide resolution in a model of human cardiovascular disease
    MD Johnson, M Mueller, M Adamowicz-Brice, MJ Collins, P Gellert, K Maratou, PK Srivastava, M Rotival, S Butt, L Game, SS Atanur, N Silver, PJ Norsworthy, SR Langley, E Petretto, M Pravenec, TJ Aitman.
    PLoS Genetics 2014 10(12):e1004813

STRUCTURAL VARIANTS IN COMPLEX DISEASE

  1. Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans 
    TJ Aitman, R Dong, TJ Vyse, PJ Norsworthy, MD Johnson, J Smith, J Mangion, C Roberton-Lowe, AJ Marshall, E Petretto, MD Hodges, G Bhangal, SG Patel, K Sheehan-Rooney, M Duda, PR Cook, DJ Evans, J Domin, J Flint, JJ Boyle, DC Pusey, HT Cook. 
    Nature 2006 439:851-855
  2. FCGR3B copy number variation is associated with susceptibility to systemic but not organ-specific autoimmunity
    M Fanciulli*, PJ Norsworthy*, E Petretto*, R Dong, L Harper, L Kamesh, JM Heward, SCL Gough, A de Smith, AIF Blakemore, P Froguel, CJ Owen, SHS Pearce, L Teixeira, L Guillevin, DS Cunninghame Graham, CD Pusey, HT Cook, TJ Vyse and TJ Aitman. 
    Nature Genetics 2007 39:721-72

METHODS AND APPROACHES FOR SYSTEMS-GENETICS

  1. Heritability and tissue-specificity of expression QTLs
    E Petretto¶, J Mangion, N Dickens, SA Cook, MK Kumaran, H Lu, J Fischer, H Maatz, V Kren, M Pravenec, N Hubner, TJ Aitman. 
    PLoS Genetics 2006 2:e172
  2. Repeatability of published microarray gene expression analyses 
    JPA Ioannidis, DB Allison*, CA Ball*, I Coulibaly*, X Cu*, AC Culhane*, M Falchi*, C Furlanello*, L Game*, G Jurman*, T Mehta*, J Mangion*, M Nitzberg*, GP Page*, E Petretto* and V van Noort*. 
    Nature Genetics 2009 41:149-155
  3. New insights into the genetic control of gene expression using a Bayesian multi-tissue approach
    E Petretto*, L Bottolo*, SR Langley, M Heinig, C McDermott-Roe, R Sarwar, M Pravenec, N Hubner, TJ Aitman, SA Cook, S Richardson. 
    PLoS Computational Biology 2010 6:e1000737
  4. Bayesian detection of expression quantitative trait loci hot-spots
    L Bottolo, E Petretto, S Blankenberg, F Cambien, SA Cook, L Tiret, S Richardson. 
    Genetics 2011 189:1449-1459
  5. ESS++: a C++ object-oriented algorithm for Bayesian stochastic search model exploration 
    L Bottolo, M Chadeau-Hyam, DI Hastie, SR Langley, E Petretto, L Tiret, D Tregouet, S Richardson. 
    Bioinformatics 2011 27:587-8
  6. GUESS-ing polygenic associations with multiple phenotypes using a GPU-based Evolutionary Stochastic Search algorithm 
    L Bottolo, M Chadeau-Hyam, DI Hastie, T Zeller, B Liquet, P Newcombe, L Yengo, PS Wild, A Schillert, A Ziegler, SF Nielsen, BG Nordestgaard, A Tybjærg-Hansen, WK Ho, R Castagné, T Munzel, D Tregouet, M Falchi, F Cambien, B Balkau, A Butterworth, P Froguel, J Danesh, E Petretto, S Blankenberg, L Tiret, S Richardson. 
    PLoS Genetics 2013 8:e1003657
  7. Multi-tissue analysis of co-expression networks by Higher-Order Generalized Singular Value Decomposition identifies functionally coherent transcriptional modules
    X Xiao, A Moreno-Moral, M Rotival, L Bottolo andE Petretto¶. 
    PLoS Genetics 2014 10(1):e1004006 
  8. EvoTol: a protein-sequence based evolutionary intolerance framework for disease-gene prioritisation.
    OJ Rackham, HA Shihab, MR Johnson and E Petretto¶.
    Nucleic Acids Research. 2014 (Dec 29. pii: gku1322)
  9. MT-HESS: an efficient Bayesian approach for simultaneous association detection in OMICS datasets, with application to eQTL mapping in multiple tissues.
    A Lewin, H Saadi, JE Peters, A Moreno-Moral, JC Lee, KGC Smith, E Petretto, L Bottolo and S Richardson.
    Bioinformatics. 2015 (Oct 26. pii: btv568)
  10. Web-based Gene Pathogenicity Analysis (WGPA): A web platform to interpret gene pathogenicity from personal genome data.
    JJ Diaz-Montana, O Rackham, N Diaz-Diaz and E Petretto¶.
    Bioinformatics. 2015 (Oct 21. pii: btv598)
  11. A Bayesian approach for analysis of whole-genome bisulphite sequencing data identifies disease-associated changes in DNA methylation
    OJL Rackham, SR Langley, T Oates, E Vradi, N Harmston, PK Srivastava, J Behmoaras, P Dellaportas¶, L Bottolo¶ & E Petretto¶.
    Genetics 2017

SYSTEMS-GENETICS APPROACHES TO COMPLEX TRAITS AND DISEASE

  1. A trans-acting locus regulates an anti-viral expression network and type 1 diabetes riskM Heinig*, E Petretto*, C Wallace, L Bottolo, M Rotival, H Lu, Y Li, R Sarwar, SR Langley, A Bauerfeind, O Hummel, Y Lee, S Paskas, C Rintisch, K Saar, J Cooper, R Buchan, EE Gray, JG Cyster, Cardiogenics Consortium, J Erdmann, Ch Hengstenberg, S Maouche, WH Ouwehand, CM Rice, NJ Samani, H Schunkert, AH Goodall, H Schulz, H Roider, M Vingron, S Blankenberg, T Münzel, T Zeller, S Szymczak, A Ziegler, L Tiret, DJ Smyth, M Pravenec,  TJ Aitman, F Cambien, D Clayton, JA Todd, N Hubner, SA Cook. Nature 2010 467:460-464
  2. Systems-level approaches reveal conservation of trans-regulated genes in the rat and genetic determinants of blood pressure in humansSR Langley, L Bottolo, J Kunes, J Zicha, V Zidek, N Hubner, SA Cook, M Pravenec, TJ Aitman, E Petretto¶. Cardiovascular Research 2013 97:653-665
  3. Expression profiling of subplate reveals a spatially and temporally dynamic gene network and disease association with autism and schizophreniaA Hoerder-Suabedissen, FM Oeschger, ML Krishnan, TG Belgard, WZ Wang, S Lee, C Webber, E Petretto, AD Edwards, Z Molnár. Proceedings of the National Academy of Sciences USA 2013 110:3555-3560
  4. Transcriptional network analysis for the regulation of left ventricular hypertrophy and microvascular remodelingA Moreno-Moral, M Mancini, G D’Amati, P Camici and E Petretto¶. Journal of Cardiovascular Translational Research 2013 6:931-944
  5. Kcnn4 is a regulator of macrophage multinucleation in bone homeostasis and inflammatory diseaseH Kang, A Kerloc’h, M Rotival, X Xu, Q Zhang, Z D’Souza, M Kim, J Carlson Scholz, JH Ko, PK Srivastava, T Rossetti, JR Genzen, W Cui, TJ Aitman, L Game, JE Melvin, A Hanidu, J Dimock, J Zheng, D Souza, A Behera, G Nabozny, HT Cook, D Bassett, GR Williams, J Li, A Vignery¶, E Petretto¶ and J Behmoaras¶. Cell Reports 2014 8(4):1210-1224
  6. Integrating phosphoproteome and transcriptome reveals new determinants of macrophage multinucleation.M Rotival, JH Ko, PK Srivastava, A Kerloc’h, A Montoya, C Mauro, P Faull, PR Cutillas, E Petretto¶ and J Behmoaras¶.          Molecular and Cellular Proteomics 2014 (Dec 22. pii: mcp.M114.043836)
  7. Systems-Genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampusMR Johnson¶, J Behmoaras, L Bottolo, ML Krishnan, K Pernhorst, PL Meza Santoscoy, T Rossetti, D Speed, PK Srivastava, M Chadeau-Hyam, N Hajji, A Dabrowska, M Rotival, B Razzaghi, S Kovac, K Wanisch, F Grillo, A Slaviero, SR Langley, K Shkura, P Roncon, T De, M Mattheisen, P Niehusmann, TJ O'Brien, S Petrovski, M von Lehe, P Hoffmann, J Eriksson, Alison Coffey, S Cichon, M Walker, M Simonato, B Danis, M Mazzuferi, P Foerch, S Schoch, De Paola, RM Kaminski, VT Cunliffe, AJ Becker¶ and E Petretto¶.Nature Communications 2015 (Jan 23;6:603. doi: 10.1038/ncomms7031)
  8. Systems genetics identifies a convergent gene network for cognition and neurodevelopmental diseaseMR Johnson¶, K Shkura, SR Langley, A Delahaye-Duriez, P Srivastava, WD Hill, OJL Rackham, G Davies, SE Harris, A Moreno-Moral, M Rotival, D Speed, S Petrovski, A Katz, O Rackham, CJ Steves, A Visconti, M Falchi,L Bottolo, T Rossetti, JM Starr, DC Liewald, B Danis, M Mazzuferi, P Foerch, A Grote, C Helmstäedter, AJ Becker, RM Kaminski, IJ Deary and E Petretto¶.         Nature Neuroscience 2016 (Feb;19(2):223-232. doi: 10.1038/nn.4205)
  9. A predictive computational framework for direct reprogramming between human cell typesOJL Rackham, J Firas, H Fang, ME Oates, ML Holmes, AS Knaupp, the FANTOM consortium, H Suzuki, CM Nefzger, CO Daub, JW Shin, E Petretto, ARR Forrest, Y Hayashizaki, JM Polo, J Gough.Nature Genetics 2016 (Jan 18. doi: 10.1038/ng.3487)
  10. Rare and common epilepsies converge on a shared gene regulatory network providing opportunities for novel antiepileptic drug discoveryA Delahaye-Duriez, PK Srivastava, K Shkura, SR Langley, L Laaniste, A Moreno-Moral, B Danis, M Mazzuferi, P Foerch, EV Gazina, K Richards, S Petrou, RM Kaminski, E Petretto¶ & MR Johnson¶.  Genome Biology 2016 17:245
  11. Genome-wide analysis of differential RNA editing in epilepsyPK Srivastava, M Bagnati, A Delahaye-Duriez, J-H Ko, M Rotival, SR Langley, K Shkura, M Mazzuferi, B Danis, J van Eyll, P Foerch, J Behmoaras, RM Kaminski, E Petretto¶ & MR Johnson¶.Genome Research 2017
  12. Integrative genomics of microglia implicates DLG4 (PSD95) in the white matter development of preterm infantsML Krishnan, J Van Steenwincke, A-L Schang, J Yan, J Arnadottir, T Le Charpentier, Z Csaba, P Dournaud, S Cipriani, C Auvynet, L Titomanlio, J Pansiot, G Ball, JP Boardman, AJ Walley, A Saxena, G Mirza, B Fleiss, AD Edwards*, E Petretto¶ & P Gressens¶. Nature Communications 2017
  13. Changes in macrophage transcriptome associate with systemic sclerosis and mediate GSDMA contribution to disease riskA Moreno-Moral*, M Bagnati*, S Koturan, J-H Ko, C Fonseca, N Harmston, L Game,  J Martin, V Ong, DJ Abraham, C. Denton, J Behmoaras¶ & E Petretto¶Annals of the Rheumatic Diseases 2018; 77(4):596-601
  14. A systems-level framework for drug discovery identifies Csf1r as an anti-epileptic drug targetPK Srivastava*, J van Eyll*, P Godard, M Mazzuferi, A Delahaye-Duriez, J Van Steenwinckel, P Gressens, B Danis, C Vandenplas, P Foerch, K Leclercq, G Mairet-Coello, A Cardenas, F Vanclef, L Laaniste, I Niespodziany, J Keaney, J Gasser, G Gillet, K Shkura, S-Ah Chong, J Behmoaras, I Kadiu, E Petretto¶, RM Kaminski¶ & MR Johnson¶. Nature Communications 9, Article number: 3561 (2018)
  15. WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signalling
    H Chen, A Moreno-Moral, F Pesce, N Devapragash, M Mancini, E Ling Heng, M Rotival, P K Srivastava, N Harmston, K Shkura, OJL Rackham, W-P Yu, Xi-Ming Sun, N Gui Zhen Tee, E Tan, PJR Barton, LE Felkin, E Lara-Pezzi, G Angelini, C Beltrami, M Pravenec, S Schafer, L Bottolo, N Hubner, Costanza Emanueli, SA Cook & E Petretto¶. 
    Nature Communications 2019; 10(1):3616 (¶ = corresponding author) IF 12.4
  16. A single-cell atlas of entorhinal cortex from individuals with Alzheimer's disease reveals cell-type-specific gene expression regulation
    A Grubman, G Chew, JF Ouyang, G Sun, XY Choo, C McLean, RK Simmons, S Buckberry, DB Vargas-Landin, D Poppe, J Pflueger, R Lister, OJL Rackham¶, E Petretto¶ & JM Polo¶.  Nature Neuroscience 2019; 22(12):2087-2097 (¶ = corresponding author) IF 19.9
  17. Whole-genome sequencing of Finnish type 1 diabetic siblings discordant for kidney disease reveals DNA variants associated with diabetic nephropathy
    J Guo, OJL Rackham, N Sandholm, B He, AM Österholm, E Valo, V Harjutsalo, C Forsblom, I Toppila, M Parkkonen, Q Li, W Zhu, N Harmston, S Chothani, MK Öhman, E Eng, Y Sun, E Petretto¶, PH Groop & K Tryggvason¶.  Journal of the American Society of Nephrology 2020;  31(2):309-323 (¶ = corresponding author) IF 8.6