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