prof. dr. J.H. (Jan Herman) Veldink

prof. dr. J.H. (Jan Herman) Veldink

Full Professor
prof. dr. J.H. (Jan Herman) Veldink
  • Neurologen

Research Programs




The overall aim of my research is to understand the genetic and environmental causes of ALS and related diseases, and to understand how one mutation has various clinical outcomes. I have a past performance with innovations both in the development of a custom reference panel that allowed the interrogation of rare genetic variation in a large sample of genotyped cases and controls (Van Rheenen et al., Nat Genet 2016), and the development of a tool that is near perfectly able to detect the C9orf72 repeat expansion in WGS data ( tool can also be used for any other large repeat expansion in any other disease. Currently, I am leading a large-scale international collaboration (Project MinE, project is in the process of whole-genome sequencing 15,000 ALS cases and 7,500 population-matched controls (with > 10,000 genomes completed already). Upon completion, the project will have standardized phenotype information, whole-genome sequence data, SNP-array data, and methylation data for every sample. I am deeply passionate about making science more reproducible and transparent for the scientific community and the general public. Consequently, I have successfully implemented a shared international clinical database ( containing detailed core clinical data and data on environmental exposures and lifestyle factors on thousands of international (Irish, Italian, Belgian, German, Dutch, Swiss, and British) samples. I have also setup a FAIR ICT solution for Project MinE at SURFsara, by adhering to a “franchise” model: international collaborators keep full control of their data, and support is available to help input data. Project MinE results are freely accessible online using the databrowser I setup: Access to data can be requested at that site as well. This is combined with my skills as a clinician who sees patients on a weekly basis, together with my extensive international collaborations, published track record in bioinformatics, statistics, epidemiology and on the successful translation, through collaboration, of findings in relevant 
neurobiological models.

Selected publications:

1. Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Van Rheenen W,…Veldink JH. Nature Genetics, 2021, accepted for publication.

In this recent GWAS in ALS I included 29,612 ALS patients and 122,656 controls which identified 15 risk loci. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and a new cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which I prioritized genes either through rare variants, short tandem repeat expansions or regulatory effects. 

2. Cross-reactive probes on Illumina DNA methylation arrays: a large study on ALS shows that a cautionary approach is warranted in interpreting epigenome-wide association studies. Hop PJ, …Veldink JH. NAR Genom Bioinform 2020 Dec 17;2(4), doi: 10.1093/nargab/lqaa105.

In this technical methodology study, I present an unexpected high number of methylation probes as present on Illumina methylation arrays, that cross-hybridize with the repeat expansion in C9orf72, and other genes, leading to potential false positive results. The data used are available on zenodo. 

3. The effect of SMN gene dosage on ALS risk and disease severity. Moisse M, .... Veldink JH*, Van Damme P*. Annals of Neurology, 2021 Jan 2, doi: 10.1002/ana.26009. *shared last author.

In this paper we convincingly showed that structural variations (SVs) in the SMN1 and SMN2 genes are not related to ALS risk and disease progression. This suggests that changing SMN protein levels in the physiological range may not modify ALS disease course. This is negative genetic study is an important finding in the light of emerging therapies targeted at smn deficiencies. Detecting SMN SVs is challenging in WGS data. 

4. Gene discovery in Amyotrophic Lateral Sclerosis: implications for clinical management. Al-Chalabi A, Van den Berg LH, Veldink JH. Nature Reviews Neurology, 2017 Feb;13(2):96-104, doi: 10.1038/nrneurol.2016.182.

In this paper, we review the various levels of evidence in ALS genetics and their relevance in the clinic.

5. Detection of long repeat expansions from PCR-free whole-genome sequence data. Dolzhenko, E., Van Vugt Joke J F A, ....,Veldink JH*, Eberle MA*. Genome Research, 2017, 27(11), 1895–1903, doi: 10.1101/gr.225672.117. *shared last author.

This paper describes ExpansionHunter I co-developed with Illumina: a tool that can reliably detect long repeat expansions, including in C9orf72, in whole genome sequencing data.

6. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia. McLaughlin, …Veldink JH. Nature Communications, 2017 Mar 21;8:14774, doi: 10.1038/ncomms14774.

In this paper, I was the first to show a significant genetic correlation between ALS and schizophrenia. 

7. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Van Rheenen, ..., Veldink JH. Nature Genetics, 2016, 1043–1048, doi: 10.1038/ng.3622.

In this paper, I built a custom reference panel using whole genome sequences from ALS patients and controls (the first 2,000 in Project MinE) and used this to impute a large sample of GWAS-ed patients and controls. In combination with a mixed linear model-based association testing framework, I was able to identify 6 loci associated with ALS, including one new ALS risk gene C21orf2. Also, I describe here, for the first time, the rare variant genetic architecture of ALS. 

8. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. Kenna KP, Van Doormaal PTC, ..., Veldink JH*, Landers JE*. Nature Genetics, 2016, 48, 1037–1042, doi: 10.1038/ng.3626. *shared last author.

In this study, converging evidence allowed me to identify NEK1 as ALS risk gene: using 4 whole genome sequenced patients from an isolate from the Netherlands, identified through genealogy, and through rare variant burden testing in a large sample of familial ALS patients and controls, and replicating in a large international sample of sporadic ALS patients and controls using exome chip and whole genome sequencing data.

9. C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: genome-wide meta-analysis. Diekstra FP, ..., Veldink JH. Annals of Neurology, 2014 Jul;76(1):120-33, doi: 10.1002/ana.24198.

This is the study on a combined analysis of FTD and ALS, by meta-analyzing ALS data with a relatively small sample of pathology proven TDP-43 FTD patients further showing that specific genetic variants can have various clinical outcomes (ALS or FTD). This was the first report on UNC13A in FTD.

10. Genome-wide association study identifies 19p13.3 UNC13A and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Van Es MA*, Veldink JH*, …, Ophoff RA, van den Berg LH. Nature Genetics. 2009 Oct;41(10):1083-7, doi: 10.1038/ng.442. *shared first author.

In this GWAS, I was the first to show that a hitherto elusive familial ALS locus (9p21) showed a genetic connection between familial ALS and sporadic ALS by genome-wide association study (GWAS) including ~4.500 sporadic ALS patients. There were two genome-wide significant loci, one in UNC13A and one in 9p21. Two years later, the latter turned out to be a tag SNP on a haplotype containing the unstable intronic hexanucleotide repeat in C9orf72, which is present in 8-10% of all patients with ALS regardless of their family history, and is the most common, high penetrant, mutation found in ALS.

Side Activities

Member Committee for the Scientific Use of Supercomputers (WGS), NWO

Fellowship and Awards

Brainfoundation Personal Fellowship grant “Copy number variation detection in ALS”, 2007

FP7 grant: Euro-MOTOR European multidisciplinary ALS network identification to cure motor neuron degeneration. (co-coordinator), 2010

Thierry Latran grant: Functional characterization of two novel susceptibility loci in sporadic ALS, 2010

International Young Investigator ENCALS award, 2011

E-Rare-2 Call "European Research Projects on Rare Diseases driven by Young Investigators": PYRAMID (PhenotYpe Research for ALS ModIfyer Discovery), coordinator, 2012/13

ERC Consolidator grant EScORIAL, 2018

In 2020, I was awarded the Healey Center International Prize for Innovation in ALS. This is a global award celebrating excellence in research for a team that catalyzes exceptional discoveries leading to a transformative advance in therapy development in ALS. I received this together with 7 international collaborators for Project MinE.

In 2021, I was personally awarded by the American Academy of Neurology (AAN) with the Sheila Essey award for ALS research. The Sheila Essey Award is given “in recognition of my outstanding achievements in ALS research”, mainly for the genetic and clinical datasets I setup, collected, curated, and made available to a wide scientific audience and the discoveries that resulted from this until now.

Research Output (268)

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Johnson Janel O, Chia Ruth, Miller Danny E, Li Rachel, Kumaran Ravindran, Abramzon Yevgeniya, Alahmady Nada, Renton Alan E, Topp Simon D, Gibbs J Raphael, Cookson Mark R, Sabir Marya S, Dalgard Clifton L, Troakes Claire, Jones Ashley R, Shatunov Aleksey, Iacoangeli Alfredo, Al Khleifat Ahmad, Ticozzi Nicola, Silani Vincenzo, Gellera Cinzia, Blair Ian P, Dobson-Stone Carol, Kwok John B, Bonkowski Emily S, Palvadeau Robin, Tienari Pentti J, Morrison Karen E, Shaw Pamela J, Al-Chalabi Ammar, Brown Robert H, Calvo Andrea, Mora Gabriele, Al-Saif Hind, Gotkine Marc, Leigh Fawn, Chang Irene J, Perlman Seth J, Glass Ian, Scott Anna I, Shaw Christopher E, Basak A Nazli, Landers John E, Chiò Adriano, Crawford Thomas O, Kenna Kevin P, McLaughlin Russell L, van Rheenen Wouter, Veldink Jan H, van den Berg Leonard H, 30 aug 2021, In: JAMA Neurology. 78 , p. 1236-1248 13 p.

Advances in the genetic classification of amyotrophic lateral sclerosis

Cooper-Knock Johnathan, Harvey Calum, Zhang Sai, Moll Tobias, Timpanaro Ilia Sarah, Kenna Kevin P, Iacoangeli Alfredo, Veldink Jan H 2 aug 2021, In: Current Opinion in Neurology. 34 , p. 756-764

Genetic analysis of ALS cases in the isolated island population of Malta

Borg Rebecca, Farrugia Wismayer Maia, Bonavia Karl, Farrugia Wismayer Andrew, Vella Malcolm, van Vugt Joke J F A, Kenna Brendan J, Kenna Kevin P, Vassallo Neville, Veldink Jan H, Cauchi Ruben J apr 2021, In: European Journal of Human Genetics. 29 , p. 604-614 11 p.

The Effect of SMN Gene Dosage on ALS Risk and Disease Severity

Moisse Matthieu, Zwamborn Ramona A J, van Vugt Joke, van der Spek Rick, van Rheenen Wouter, Kenna Brendan, Van Eijk Kristel, Kenna Kevin, Corcia Philippe, Couratier Philippe, Vourc'h Patrick, Hardiman Orla, McLaughin Russell, Gotkine Marc, Drory Vivian, Ticozzi Nicola, Silani Vincenzo, de Carvalho Mamede, Mora Pardina Jesús S, Povedano Monica, Andersen Peter M, Weber Markus, Başak Nazli A, Chen Xiao, Eberle Michael A, Al-Chalabi Ammar, Shaw Chris, Shaw Pamela J, Morrison Karen E, Landers John E, Glass Jonathan D, Robberecht Wim, van Es Michael, van den Berg Leonard, Veldink Jan, Van Damme Philip, apr 2021, In: Annals of Neurology. 89 , p. 686-697 12 p.

Erratum:Rare variant burden analysis within enhancers identifies CAV1 as an ALS risk gene (Cell Reports (2020) 33(9), (S2211124720314455), (10.1016/j.celrep.2020.108456))

Cooper-Knock Johnathan, Zhang Sai, Kenna Kevin P, Moll Tobias, Franklin John P, Allen Samantha, Nezhad Helia Ghahremani, Iacoangeli Alfredo, Yacovzada Nancy Y, Eitan Chen, Hornstein Eran, Elhaik Eran, Celadova Petra, Bose Daniel, Farhan Sali, Fishilevich Simon, Lancet Doron, Morrison Karen E, Shaw Christopher E, Al-Chalabi Ammar, Veldink Jan H, Kirby Janine, Snyder Michael P, Shaw Pamela J, 2 feb 2021, In: Cell Reports. 34

SCFD1 expression quantitative trait loci in amyotrophic lateral sclerosis are differentially expressed

Iacoangeli Alfredo, Fogh Isabella, Selvackadunco Sashika, Topp Simon D, Shatunov Aleksey, van Rheenen Wouter, Al-Khleifat Ahmad, Opie-Martin Sarah, Ratti Antonia, Calvo Andrea, Van Damme Philip, Robberecht Wim, Chio Adriano, Dobson Richard J, Hardiman Orla, Shaw Christopher E, van den Berg Leonard H, Andersen Peter M, Smith Bradley N, Silani Vincenzo, Veldink Jan H, Breen Gerome, Troakes Claire, Al-Chalabi Ammar, Jones Ashley R, 2021, In: Brain communications. 3

Significant out-of-sample classification from methylation profile scoring for amyotrophic lateral sclerosis

Nabais Marta F., Lin Tian, Benyamin Beben, Williams Kelly L., Garton Fleur C., Vinkhuyzen Anna A.E., Zhang Futao, Vallerga Costanza L., Restuadi Restuadi, Freydenzon Anna, Zwamborn Ramona A.J., Hop Paul J., Robinson Matthew R., Gratten Jacob, Visscher Peter M., Hannon Eilis, Mill Jonathan, Brown Matthew A., Laing Nigel G., Mather Karen A., Sachdev Perminder S., Ngo Shyuan T., Steyn Frederik J., Wallace Leanne, Henders Anjali K., Needham Merrilee, Veldink Jan H., Mathers Susan, Nicholson Garth, Rowe Dominic B., Henderson Robert D., McCombe Pamela A., Pamphlett Roger, Yang Jian, Blair Ian P., McRae Allan F., Wray Naomi R. 1 dec 2020, In: npj Genomic Medicine. 5 , p. 1-9

Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors

Bakker Mark K., van der Spek Rick A.A., van Rheenen Wouter, Morel Sandrine, Bourcier Romain, Hostettler Isabel C., Alg Varinder S., van Eijk Kristel R., Koido Masaru, Akiyama Masato, Terao Chikashi, Matsuda Koichi, Walters Robin, Lin Kuang, Li Liming, Millwood Iona Y., Chen Zhengming, Rouleau Guy A., Zhou Sirui, Rannikmäe Kristiina, Sudlow Cathie L.M., Houlden Henry, van den Berg Leonard H., Dina Christian, Naggara Olivier, Gentric Jean Christophe, Shotar Eimad, Eugène François, Desal Hubert, Winsvold Bendik S., Børte Sigrid, Johnsen Marianne Bakke, Brumpton Ben M., Sandvei Marie Søfteland, Willer Cristen J., Hveem Kristian, Zwart John Anker, Verschuren W. M.Monique, Friedrich Christoph M., Hirsch Sven, Schilling Sabine, Dauvillier Jérôme, Martin Olivier, Bian Zheng, Chen Junshi, Klijn Catharina J.M., Rinkel Gabriel J.E., Lindgren Antti, Veldink Jan H., Ruigrok Ynte M., , , , , , , dec 2020, In: Nature Genetics. 52 , p. 1303-1313 11 p.

Blood metal levels and amyotrophic lateral sclerosis risk:a prospective cohort

Peters Susan, Broberg Karin, Gallo Valentina, Levi Michael, Kippler Maria, Vineis Paolo, Veldink Jan, van den Berg Leonard, Middleton Lefkos, Travis Ruth C, Bergmann Manuela M, Palli Domenico, Grioni Sara, Tumino Rosario, Elbaz Alexis, Vlaar Tim, Mancini Francesca, Kühn Tilman, Katzke Verena, Agudo Antonio, Goñi Fernando, Gómez Jesús-Humberto, Rodríguez-Barranco Miguel, Merino Susana, Barricarte Aurelio, Trichopoulou Antonia, Jenab Mazda, Weiderpass Elisabete, Vermeulen Roel 17 okt 2020, In: Annals of Neurology. 89 , p. 125-133 9 p.

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