Prof. Dr. Peter Heutink

Speaker and Group Leader
Professor Heutink is a Professor of Genome Biology of Neurodegenerative diseases at the Hertie Institute for Clinical Brain Research in Tübingen and a visiting researcher at RIKEN Center for Life Science Technologies, Yokohama, Japan

German Center for Neurodegenerative Diseases (DZNE)
Otfried-Müller-Str. 23
72076 Tübingen

peter.heutink(at)dzne.de
+49 (0) 7071 / 9254-050
+49 (0) 7071 / 9254-900

Group members

Name Phone
Michael Hruscha, Staff Technical Assistant +49 (0) 7071 / 9254-055
Dr. Elwira Pyz, Technical Assistant +49 (0) 7071 / 9254-059
Joachim Täger, Post-doc +49 (0) 7071 / 9254-061
Dr. Elisangela Bressan, Post-doc +49 (0) 7071 / 9254-053
Manmeet Bedi, Technical Assistant +49 (0) 7071 / 9254-062
Erika Lara Flores, Technical Assistant +49 (0) 7071 / 9254-061
Noemia Alves Fernandes, Technical Assistant +49 (0) 7071 / 9254-062
Dr. Tenzin Nyima, Post-doc +49 (0) 7071 / 9254-063
Javier Simón Sanchez, PhD, Scientist +49 (0) 7071 / 9254-250
Further group members (Uni/third party funding)
Ashutosh Dhingra, MSc, Scientist +49 (0) 7071 / 9254-062
Dr. Salvador Rodriguez-Nieto, Technical Assistant +49 (0) 7071 / 9254-053
group members Heutink lab

Selected publications

Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.

Jansen IE, Ye H, Heetveld S, Lechler MC, Michels H, Seinstra RI, Lubbe SJ, Drouet V, Lesage S, Majounie E, Gibbs JR, Nalls MA, Ryten M, Botia JA, Vandrovcova J, Simon-Sanchez J, Castillo-Lizardo M, Rizzu P, Blauwendraat C, Chouhan AK, Li Y, Yogi P, Amin N, van Duijn CM; International Parkinson’s Disease Genetics Consortium (IPGDC)., Morris HR, Brice A, Singleton AB, David DC, Nollen EA, Jain S, Shulman JM, Heutink P. Genome Biol. 2017 Jan 30;18(1):22. doi: 10.1186/s13059-017-1147-9.

Comprehensive promoter level expression quantitative trait loci analysis of the human frontal lobe.

Blauwendraat C, Francescatto M, Gibbs JR, Jansen IE, Simón-Sánchez J, Hernandez DG, Dillman AA, Singleton AB, Cookson MR, Rizzu P, Heutink P. Genome Med. 2016 Jun 10;8(1):65. doi: 10.1186/s13073-016-0320-1.

C9orf72 is differentially expressed in the central nervous system and myeloid cells and consistently reduced in C9orf72, MAPT and GRN mutation carriers.

Rizzu P, Blauwendraat C, Heetveld S, Lynes EM, Castillo-Lizardo M, Dhingra A, Pyz E, Hobert M, Synofzik M, Simón-Sánchez J, Francescatto M, Heutink P. Acta Neuropathol Commun. 2016 Apr 14;4(1):37. doi: 10.1186/s40478-016-0306-7.

Pilot whole-exome sequencing of a German early-onset Alzheimer's disease cohort reveals a substantial frequency of PSEN2 variants.

Blauwendraat C, Wilke C, Jansen IE, Schulte C, Simón-Sánchez J, Metzger FG, Bender B, Gasser T, Maetzler W, Rizzu P, Heutink P, Synofzik M. Neurobiol Aging. 2016 Jan;37:208.e11-7. doi: 10.1016/j.neurobiolaging.2015.09.016

DGEclust: differential expression analysis of clustered count data.

Vavoulis DV, Francescatto M, Heutink P, Gough J. Genome Biol. 2015 Feb 20;16:39. doi: 10.1186/s13059-015-0604-6.

Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease.

Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, DeStefano AL, Kara E, Bras J, Sharma M, Schulte C, Keller MF, Arepalli S, Letson C, Edsall C, Stefansson H, Liu X, Pliner H, Lee JH, Cheng R; International Parkinson's Disease Genomics Consortium (IPDGC).; Parkinson's Study Group (PSG) Parkinson's Research: The Organized GENetics Initiative (PROGENI).; 23andMe.; GenePD.; NeuroGenetics Research Consortium (NGRC).; Hussman Institute of Human Genomics (HIHG).; Ashkenazi Jewish Dataset Investigator.; Cohorts for Health and Aging Research in Genetic Epidemiology (CHARGE).; North American Brain Expression Consortium (NABEC).; United Kingdom Brain Expression Consortium (UKBEC).; Greek Parkinson's Disease Consortium.; Alzheimer Genetic Analysis Group., Ikram MA, Ioannidis JP, Hadjigeorgiou GM, Bis JC, Martinez M, Perlmutter JS, Goate A, Marder K, Fiske B, Sutherland M, Xiromerisiou G, Myers RH, Clark LN, Stefansson K, Hardy JA, Heutink P, Chen H, Wood NW, Houlden H, Payami H, Brice A, Scott WK, Gasser T, Bertram L, Eriksson N, Foroud T, Singleton AB. Nat Genet. 2014 Sep;46(9):989-93. doi: 10.1038/ng.3043.

Brain-specific noncoding RNAs are likely to originate in repeats and may play a role in up-regulating genes in cis.

Francescatto M, Vitezic M, Heutink P, Saxena A. Int J Biochem Cell Biol. 2014 Sep;54:331-7. doi: 10.1016/j.biocel.2014.06.014.

Frontotemporal dementia and its subtypes: a genome-wide association study.

Ferrari R, Hernandez DG, Nalls MA, Rohrer JD, Ramasamy A, Kwok JB, Dobson-Stone C, Brooks WS, Schofield PR, Halliday GM, Hodges JR, Piguet O, Bartley L, Thompson E, Haan E, Hernández I, Ruiz A, Boada M, Borroni B, Padovani A, Cruchaga C, Cairns NJ, Benussi L, Binetti G, Ghidoni R, Forloni G, Galimberti D, Fenoglio C, Serpente M, Scarpini E, Clarimón J, Lleó A, Blesa R, Waldö ML, Nilsson K, Nilsson C, Mackenzie IR, Hsiung GY, Mann DM, Grafman J, Morris CM, Attems J, Griffiths TD, McKeith IG, Thomas AJ, Pietrini P, Huey ED, Wassermann EM, Baborie A, Jaros E, Tierney MC, Pastor P, Razquin C, Ortega-Cubero S, Alonso E, Perneczky R, Diehl-Schmid J, Alexopoulos P, Kurz A, Rainero I, Rubino E, Pinessi L, Rogaeva E, St George-Hyslop P, Rossi G, Tagliavini F, Giaccone G, Rowe JB, Schlachetzki JC, Uphill J, Collinge J, Mead S, Danek A, Van Deerlin VM, Grossman M, Trojanowski JQ, van der Zee J, Deschamps W, Van Langenhove T, Cruts M, Van Broeckhoven C, Cappa SF, Le Ber I, Hannequin D, Golfier V, Vercelletto M, Brice A, Nacmias B, Sorbi S, Bagnoli S, Piaceri I, Nielsen JE, Hjermind LE, Riemenschneider M, Mayhaus M, Ibach B, Gasparoni G, Pichler S, Gu W, Rossor MN, Fox NC, Warren JD, Spillantini MG, Morris HR, Rizzu P, Heutink P, Snowden JS, Rollinson S, Richardson A, Gerhard A, Bruni AC, Maletta R, Frangipane F, Cupidi C, Bernardi L, Anfossi M, Gallo M, Conidi ME, Smirne N, Rademakers R, Baker M, Dickson DW, Graff-Radford NR, Petersen RC, Knopman D, Josephs KA, Boeve BF, Parisi JE, Seeley WW, Miller BL, Karydas AM, Rosen H, van Swieten JC, Dopper EG, Seelaar H, Pijnenburg YA, Scheltens P, Logroscino G, Capozzo R, Novelli V, Puca AA, Franceschi M, Postiglione A, Milan G, Sorrentino P, Kristiansen M, Chiang HH, Graff C, Pasquier F, Rollin A, Deramecourt V, Lebert F, Kapogiannis D, Ferrucci L, Pickering-Brown S, Singleton AB, Hardy J, Momeni P. Lancet Neurol. 2014 Jul;13(7):686-99. doi: 10.1016/S1474-4422(14)70065-1. 

A promoter-level mammalian expression atlas.

FANTOM Consortium and the RIKEN PMI and CLST (DGT)., Forrest AR, Kawaji H, Rehli M, Baillie JK, de Hoon MJ, Haberle V, Lassmann T, Kulakovskiy IV, Lizio M, Itoh M, Andersson R, Mungall CJ, Meehan TF, Schmeier S, Bertin N, Jørgensen M, Dimont E, Arner E, Schmidl C, Schaefer U, Medvedeva YA, Plessy C, Vitezic M, Severin J, Semple C, Ishizu Y, Young RS, Francescatto M, Alam I, Albanese D, Altschuler GM, Arakawa T, Archer JA, Arner P, Babina M, Rennie S, Balwierz PJ, Beckhouse AG, Pradhan-Bhatt S, Blake JA, Blumenthal A, Bodega B, Bonetti A, Briggs J, Brombacher F, Burroughs AM, Califano A, Cannistraci CV, Carbajo D, Chen Y, Chierici M, Ciani Y, Clevers HC, Dalla E, Davis CA, Detmar M, Diehl AD, Dohi T, Drabløs F, Edge AS, Edinger M, Ekwall K, Endoh M, Enomoto H, Fagiolini M, Fairbairn L, Fang H, Farach-Carson MC, Faulkner GJ, Favorov AV, Fisher ME, Frith MC, Fujita R, Fukuda S, Furlanello C, Furino M, Furusawa J, Geijtenbeek TB, Gibson AP, Gingeras T, Goldowitz D, Gough J, Guhl S, Guler R, Gustincich S, Ha TJ, Hamaguchi M, Hara M, Harbers M, Harshbarger J, Hasegawa A, Hasegawa Y, Hashimoto T, Herlyn M, Hitchens KJ, Ho Sui SJ, Hofmann OM, Hoof I, Hori F, Huminiecki L, Iida K, Ikawa T, Jankovic BR, Jia H, Joshi A, Jurman G, Kaczkowski B, Kai C, Kaida K, Kaiho A, Kajiyama K, Kanamori-Katayama M, Kasianov AS, Kasukawa T, Katayama S, Kato S, Kawaguchi S, Kawamoto H, Kawamura YI, Kawashima T, Kempfle JS, Kenna TJ, Kere J, Khachigian LM, Kitamura T, Klinken SP, Knox AJ, Kojima M, Kojima S, Kondo N, Koseki H, Koyasu S, Krampitz S, Kubosaki A, Kwon AT, Laros JF, Lee W, Lennartsson A, Li K, Lilje B, Lipovich L, Mackay-Sim A, Manabe R, Mar JC, Marchand B, Mathelier A, Mejhert N, Meynert A, Mizuno Y, de Lima Morais DA, Morikawa H, Morimoto M, Moro K, Motakis E, Motohashi H, Mummery CL, Murata M, Nagao-Sato S, Nakachi Y, Nakahara F, Nakamura T, Nakamura Y, Nakazato K, van Nimwegen E, Ninomiya N, Nishiyori H, Noma S, Noma S, Noazaki T, Ogishima S, Ohkura N, Ohimiya H, Ohno H, Ohshima M, Okada-Hatakeyama M, Okazaki Y, Orlando V, Ovchinnikov DA, Pain A, Passier R, Patrikakis M, Persson H, Piazza S, Prendergast JG, Rackham OJ, Ramilowski JA, Rashid M, Ravasi T, Rizzu P, Roncador M, Roy S, Rye MB, Saijyo E, Sajantila A, Saka A, Sakaguchi S, Sakai M, Sato H, Savvi S, Saxena A, Schneider C, Schultes EA, Schulze-Tanzil GG, Schwegmann A, Sengstag T, Sheng G, Shimoji H, Shimoni Y, Shin JW, Simon C, Sugiyama D, Sugiyama T, Suzuki M, Suzuki N, Swoboda RK, 't Hoen PA, Tagami M, Takahashi N, Takai J, Tanaka H, Tatsukawa H, Tatum Z, Thompson M, Toyodo H, Toyoda T, Valen E, van de Wetering M, van den Berg LM, Verado R, Vijayan D, Vorontsov IE, Wasserman WW, Watanabe S, Wells CA, Winteringham LN, Wolvetang E, Wood EJ, Yamaguchi Y, Yamamoto M, Yoneda M, Yonekura Y, Yoshida S, Zabierowski SE, Zhang PG, Zhao X, Zucchelli S, Summers KM, Suzuki H, Daub CO, Kawai J, Heutink P, Hide W, Freeman TC, Lenhard B, Bajic VB, Taylor MS, Makeev VJ, Sandelin A, Hume DA, Carninci P, Hayashizaki Y. Nature. 2014 Mar 27;507(7493):462-70. doi: 10.1038/nature13182.

An atlas of active enhancers across human cell types and tissues.

Andersson R, Gebhard C, Miguel-Escalada I, Hoof I, Bornholdt J, Boyd M, Chen Y, Zhao X, Schmidl C, Suzuki T, Ntini E, Arner E, Valen E, Li K, Schwarzfischer L, Glatz D, Raithel J, Lilje B, Rapin N, Bagger FO, Jørgensen M, Andersen PR, Bertin N, Rackham O, Burroughs AM, Baillie JK, Ishizu Y, Shimizu Y, Furuhata E, Maeda S, Negishi Y, Mungall CJ, Meehan TF, Lassmann T, Itoh M, Kawaji H, Kondo N, Kawai J, Lennartsson A, Daub CO, Heutink P, Hume DA, Jensen TH, Suzuki H, Hayashizaki Y, Müller F; FANTOM Consortium., Forrest AR, Carninci P, Rehli M, Sandelin A. Nature. 2014 Mar 27;507(7493):455-61. doi: 10.1038/nature12787.

Regional differences in gene expression and promoter usage in aged human brains.
Pardo LM, Rizzu P, Francescatto M, Vitezic M, Leday GG, Sanchez JS, Khamis A, Takahashi H, van de Berg WD, Medvedeva YA, van de Wiel MA, Daub CO, Carninci P, Heutink P. Neurobiol Aging. 2013 Jul;34(7):1825-36. doi: 10.1016/j.neurobiolaging.2013.01.005.

Genetic comorbidities in Parkinson’s disease.

Nalls MA, Saad M, Noyce AJ, Keller MF, Schrag A, Bestwick JP, Traynor BJ, Gibbs JR, Hernandez DG, Cookson MR, Morris HR, Williams N, Gasser T, Heutink P, Wood N, Hardy J, Martinez M, Singleton AB; for the International Parkinson's Disease Genomics Consortium (IPDGC); The Wellcome Trust Case Control Consortium 2 (WTCCC2); North American Brain Expression Consortium (NABEC); the United Kingdom Brain Expression Consortium (UKBEC). Hum Mol Genet. 2013 Sep 20. [Epub ahead of print]

Neurodegeneration: new road leads back to the synapse.

Heutink P, Verhage M. Neuron. 2012 Sep 20; 75(6): 935-8.

Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease.

Keller MF, Saad M, Bras J, Bettella F, Nicolaou N, Simón-Sánchez J, Mittag F,  Büchel F, Sharma M, Gibbs JR, Schulte C, Moskvina V, Durr A, Holmans P, Kilarski  LL, Guerreiro R, Hernandez DG, Brice A, Ylikotila P, Stefánsson H, Majamaa K, Morris HR, Williams N, Gasser T, Heutink P, Wood NW, Hardy J, Martinez M, Singleton AB, Nalls MA; Internationa Parkinson's Disease Genomics Consortium (IPDGC); Wellcome Trust Case Control Consortium 2 (WTCCC2). Hum Mol Genet. 2012 Nov 15; 21(22): 4996-5009.

Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study.

Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S, Chiò A, Restagno G, Nicolaou N, Simon-Sanchez J, van Swieten JC, Abramzon Y, Johnson JO,  Sendtner M, Pamphlett R, Orrell RW, Mead S, Sidle KC, Houlden H, Rohrer JD, Morrison KE, Pall H, Talbot K, Ansorge O; Chromosome 9-ALS/FTD Consortium; French research network on FTLD/FTLD/ALS; ITALSGEN Consortium, Hernandez DG, Arepalli S, Sabatelli M, Mora G, Corbo M, Giannini F, Calvo A, Englund E, Borghero G, Floris  GL, Remes AM, Laaksovirta H, McCluskey L, Trojanowski JQ, Van Deerlin VM, Schellenberg GD, Nalls MA, Drory VE, Lu CS, Yeh TH, Ishiura H, Takahashi Y, Tsuji S, Le Ber I, Brice A, Drepper C, Williams N, Kirby J, Shaw P, Hardy J, Tienari PJ*, Heutink P*, Morris HR*, Pickering-Brown S*, Traynor BJ*. Lancet Neurol. 2012 Apr; 11(4): 323-30. * shared last authors

The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions.

Simón-Sánchez J, Dopper EG, Cohn-Hokke PE, Hukema RK, Nicolaou N, Seelaar H, de Graaf JR, de Koning I, van Schoor NM, Deeg DJ, Smits M, Raaphorst J, van den Berg LH, Schelhaas HJ, De Die-Smulders CE, Majoor-Krakauer D, Rozemuller AJ, Willemsen R, Pijnenburg YA, Heutink P, van Swieten JC. Brain. 2012 Mar; 135(Pt 3):723-35.

Somatic retrotransposition alters the genetic landscape of the human brain.

Baillie JK, Barnett MW, Upton KR, Gerhardt DJ, Richmond TA, de Sapio F, Brennan P, Rizzu P, Sarah Smith S, Fell M, Talbot RT, Gustincich S, Freeman TC, Mattick JS,Hume DA, Heutink P, Carninci P, Jeddeloh JA, Faulkner GJ. Nature 2011 Oct 30; 479(7374): 534-7

A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD.

Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, Kalimo H, Paetau A, Abramzon Y, Remes AM, Kaganovich A, Scholz SW, Duckworth J, Ding J, Harmer DW, Hernandez DG, Johnson JO, Mok K, Ryten M, Trabzuni D, Guerreiro RJ, Orrell RW, Neal J, Murray A, Pearson J, Jansen IE, Sondervan D, Seelaar H, Blake D, Young K, Halliwell N, Callister JB, Toulson G, Richardson A, Gerhard A, Snowden J, Mann D, Neary D, Nalls MA, Peuralinna T, Jansson L, Isoviita VM, Kaivorinne AL, Hölttä-Vuori M, Ikonen E, Sulkava R, Benatar M, Wuu J, Chiò A, Restagno G, Borghero G, Sabatelli M; The ITALSGEN Consortium, Heckerman D, Rogaeva E, Zinman L, Rothstein JD, Sendtner M, Drepper C, Eichler EE, Alkan C, Abdullaev Z, Pack SD, Dutra A, Pak E, Hardy J, Singleton A, Williams NM, Heutink P*, Pickering-Brown S*, Morris HR*, Tienari PJ*, Traynor BJ*. Neuron 2011 Sep 21; 72(2): 257-68 * shared last authors

A two-stage meta-analysis identifies several new loci for Parkinson's disease.

International Parkinson's Disease Genomics Consortium (IPDGC); Wellcome Trust Case Control Consortium 2 (WTCCC2). PLoS Genet. 2011 Jun; 7(6):e1002142.

Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy.

Höglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wang LS, Klei L, Rademakers, R, de Silva R, Litvan I, Riley DE, van Swieten JC, Heutink P, Wszolek ZK, Uitti, RJ, Vandrovcova J, Hurtig HI, Gross RG, Maetzler W, Goldwurm S, Tolosa E, Borroni, B, Pastor P; PSP Genetics Study Group, Cantwell LB, Han MR, Dillman A, van der Brug MP, Gibbs JR, Cookson MR, Hernandez DG, Singleton AB, Farrer MJ, Yu CE, Golbe LI, Revesz T, Hardy J, Lees AJ, Devlin B, Hakonarson H, Müller U, Schellenberg GD. Nat Genet. 2011 Jun 19; 43(7):699-705.

Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies.

International Parkinson Disease Genomics Consortium, Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin UM, Saad M, Simón-Sánchez J, Schulte C, Lesage S, Sveinbjörnsdóttir S, Stefánsson K, Martinez M, Hardy J, Heutink P, Brice A, Gasser T, Singleton AB, Wood NW. Lancet. 2011 Feb 19; 377(9766):641-9.

Genome-wide association study confirms extant PD risk loci among the Dutch.

Simón-Sánchez J, van Hilten JJ, van de Warrenburg B, Post B, Berendse HW, Arepalli S, Hernandez DG, de Bie RM, Velseboer D, Scheffer H, Bloem B, van Dijk KD, Rivadeneira F, Hofman A, Uitterlinden AG, Rizzu P, Bochdanovits Z, Singleton AB, Heutink P. Eur J Hum Genet. 2011 Jan 19(6):655-61

From single genes to gene networks: high-throughput-high-content screening for neurological disease.

Jain S, Heutink P. Neuron. 2010 Oct 21; 68(2):207-17.

Role of COL4A1 in small-vessel disease and hemorrhagic stroke.

Gould, DB, Phalan, FC, van Mil, SE, Sundberg, JP, Vahedi, K, Massin, P, Bousser, MG, Heutink, P, Miner, JH, Tournier-Lasserve, E, John, SW. The New England journal of medicine. 2006; 354:1489-1496

Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly.

Gould, DB, Phalan, FC, Breedveld, GJ, van Mil, SE, Smith, RS, Schimenti, JC, Aguglia, U, van der Knaap, MS, Heutink, P, John, SW. Science 2005; 308:1167-1171

Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism.

Bonifati, V, Rizzu, P, van Baren, MJ, Schaap, O, Breedveld, GJ, Krieger, E, Dekker, MC, Squitieri, F, Ibanez, P, Joosse, M, van Dongen, JW, Vanacore, N, van Swieten, JC, Brice, A, Meco, G, van Duijn, CM, Oostra, BA, Heutink, P. Science (New York, N.Y.) 2003; 299:256-259

Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17.

Hutton, M, Lendon, CL, Rizzu, P, Baker, M, Froelich, S, Houlden, H, Pickering-Brown, S, Chakraverty, S, Isaacs, A, Grover, A, Hackett, J, Adamson, J, Lincoln, S, Dickson, D, Davies, P, Petersen, RC, Stevens, M, de Graaff, E, Wauters, E, van Baren, J, Hillebrand, M, Joosse, M, Kwon, JM, Nowotny, P, Che, LK, Norton, J, Morris, JC, Reed, LA, Trojanowski, J, Basun, H, Lannfelt, L, Neystat, M, Fahn, S, Dark, F, Tannenberg, T, Dodd, PR, Hayward, N, Kwok, JB, Schofield, PR, Andreadis, A, Snowden, J, Craufurd, D, Neary, D, Owen, F, Oostra, BA, Hardy, J, Goate, A, van Swieten, J, Mann, D, Lynch, T, Heutink, P. Nature. 1998; 393:702-705

Curriculum vitae

Peter Heutink studied Biology at the University of Amsterdam. He received his PhD in Human Genetics in 1993 from the Erasmus University Rotterdam where he worked on developing approaches to identify genes for diseases with a complex inheritance. In 1994 he started his own research group at the Erasmus University Rotterdam focusing on identifying genes for human diseases using linkage analysis and positional cloning approaches. From 1997 the focused shifted towards neurological diseases especially Frontal Temporal Dementia (FTD) and Parkinson’s disease (PD) and his group identified mutations in for example the MAPT, DJ-1, FGF14, TITF1 genes for FTD, PD, ataxia and chorea. In 2003 he moved to the VU University Medical Center where he started the research section of Medical Genomics and helped to build the Center for Neurogenomics and Cognitive Research and the Neuroscience Campus Amsterdam. During this time he contributed to the identification of genetic risk factors for FTD, PD, PSP and several psychiatric disorders using Genome Wide Association Studies and his group developed statistical methods to detect genetic epistasis and to perform analysis on gene networks instead of single genes. He also received an affiliation at the RIKEN Omics Center in Yokohama Japan working on the Functional Annotation of the Mammalian Genome (FANTOM) and participates in the FANTOM5 and 6 consortia (http://fantom.gsc.riken.jp). In 2012 he moved to DZNE Tübingen where he started the research group Genomics for Neurodegenerative Diseases and became the site speaker.


Areas of investigation/research focus

The underlying causes for neurodegenerative disease are still largely unknown but there is clear evidence that genetic risk factors play an important role. The identification of such genetic risk factors provides us with important starting points to study the molecular processes that lead to disease as they act at the very beginning of the disease process.

The research focus of our group is therefore to identify genetic risk factors for neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Frontal-Temporal Dementia/Motor Neuron Disease, Progressive Supranuclear Palsy and Ataxia in close collaboration with our clinical partners and to characterize the biological consequences of these mutations and risk factors by using molecular biology and genomic approaches. (For an essay on our approaches, see; Jain S, Heutink P. From single genes to gene networks: high-throughput-high-content screening for neurological disease. Neuron. 2010 Oct 21; 68(2):207-17). 

Finding new genetic risk factors

To identify new genetic risk factors we investigate families with neurodegenerative diseases as well as large cohorts of sporadic cases using SNP array genotyping and Massive Parallel Sequencing (MPS) approaches such as whole exome and whole genome sequencing. Prof. Heutink is currently is a member of the International Parkinsons Disease Genomics Consortium (IPDGC) and the International FTD genetics Consortium.

The data analysis is performed in close collaboration with Dr. Javier Simón-Sánchez who leads the joined research group Genetics and Epigenetics of Neurodegeneration. The research group "Genetics and Epigenetics of Neurodegeneration" has been jointly established at the Department of Neurodegenerative Diseases within the Hertie Institute for Clinical Brain Research (HIH) and the research group Genome Biology at the German Center for Neurodegenerative Diseases (DZNE). The group has a primary interest in the genetics and genomics of neurodegenerative disorders such as Parkinson's disease (PD), Progressive Supranuclear Palsy (PSP) or Frontotemporal Dementias (FTD). The research group "Genetics and Epigenetics of Neurodegeneration" aims to translate the meaning of previous genetic findings into testable biological hypotheses. Thus, we aim to expand previous work on genetic analysis to a more broader bioinformatic focus by integration of GWAS hits and Next Generation Sequencing (NGS) variants derived from whole-exome, targeted re-sequencing and whole genome sequencing approaches, with expression data from RNA sequencing (RNAseq) and Capped Analysis of Gene Expression (CAGE) experiments. This, in combination with the aforementioned epigenetic data, will help to further understand the genetic (or genomic) mechanisms underlying the etiology of various neurodegenerative disorders. 

Understanding the biology of genetic risk factors

The identification of new genetic risk factors allows us to investigate the biological consequences of the underlying mutations to the molecular pathways in which they function in human post-mortem brain and cellular models including primary neurons or patient derived induced pluripotent stem (iPS) cells. We use two main approaches to follow up these findings and to study the biological consequences of genetic mutations.

One approach aims to dissect and study the gene networks in which the risk factors are functioning by studying gene expression in patient post-mortem brain and patient derived cell lines such as iPS derived neurons. We aim to model complete transcriptional networks to identify key regulators of the affected pathways. We perform MPS based gene expression analysis for coding and noncoding RNA expression (RNAseq, CAGE) and combine this with epigenetic and proteomic data using integrative bioinformatics analysis. The work is performed in close collaboration with the Dutch Brain Bank and the group of Applied Genomics for Neurodegenerative diseases at the DZNE-Tübingen led by Dr. Patrizia Rizzu and the research group led by  Dr.  Javier Simón-Sánchez Genetics and Epigenetics of Neurodegeneration.

To validate and extend our findings and to understand the function of identified genes and non-coding RNAs we follow a second approach using cellular models such as neuroblastoma lines and neuronal differentiated patient derived iPS cell in which we can selectively overexpress or silence newly identified genetic risk factors or key regulatory genes and transcripts form identified pathways. This allows us to study the pathways that act downstream of these genes. We use a combination of “read outs” such as gene expression, epigenetic changes and imaging of reporter constructs or cell organelle morphology.

Our iPS based models are either derived from patients blood or fibroblasts or by using CRISPR/Cas9 genome editing. For our gene silencing experiments and cellular screens we use a genome wide lentiviral shRNA library originally developed by the Broad Institute, and CRISPR/Cas9 pooled libraries.

For our cellular screens, we have developed an automated cell culture system with integrated fluorescent and confocal microscopy to allow for high-throughput high-content cellular screening. This system allows us to perform high throughput cellular screens in which we can systematically perturb and analyse the effects of large numbers of genes in a longitudinal setup. The current system at Tübingen has been developed using our experience of an earlier system (Jain SSondervan D, Rizzu, P, Bochdanovits, Z, Caminda D, Heutink P. (2011). The complete automation of cell culture: Improvements for high-throughput and high-content screening. Journal of Biomolecular Screening 16(8): 932-9; Jain, S., van Kesteren, R. E., Heutink, P. High Content Screening in Neurodegenerative Diseases. J. Vis. Exp (59), e3452, doi:10.3791/3452 (2012).The system is available for other users. Please contact Prof. P. Heutink for more information.

Our integrative approach focuses on the translation of genetic findings into biologically verifiable hypotheses in cellular and animal models. Identified genes and gene networks can then be systematically explored to identify the most suitable targets for therapy development. (Jansen IE et al. Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing. Genome Biol. 2017 Jan 30;18(1):22. doi: 10.1186/s13059-017-1147-9.).