prof. dr. J.H. (Jan Herman) Veldink Full Professor
- Neurology & Neurosurgery
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 (http://biorxiv.org/content/early/2016/12/19/093831).This 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, www.projectmine.com).The 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 (https://progeny.umcutrecht.nl) 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: http://databrowser.projectmine.com. 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.
1. Gene discovery in Amyotrophic Lateral Sclerosis. Al-Chalabi A, Van den Berg LH, Veldink JH. Nature Reviews Neurology, 2017 Feb;13(2):96-104
2. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia. McLaughlin, R, Schijven D, ..., Veldink JH. Nature Communications, 2017 Mar 21;8:14774. doi: 10.1038/ncomms14774.
3. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Van Rheenen, ..., Pasterkamp RJ, ..., Veldink JH. Nature Genetics, 2016, 1043–1048.
In this paper, I built a custom reference panel using whole genome sequences from ALS patients and controls, 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 genetic architecture of ALS.
4. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. Kenna KP, Van Doormaal PTC, ..., Veldink JH. Nature Genetics, 2016, 48, 1037–1042.
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, rare variant burden testing in a large sample of fALS patients and controls, and replicating in a large international sample of sALS patients and controls using exome chip and whole genome sequencing data.
5. C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: genome-wide meta-analysis. Diekstra FP, ..., Pasterkamp RJ, ..., Veldink JH. Annals of Neurology, 2014 Jul;76(1):120-33.
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).
6. Are CHCHD10 mutations indeed associated with familial amyotrophic lateral sclerosis? Van Rheenen W, Diekstra FP, ..., Veldink JH. Brain. 2014 Dec;137(Pt 12): e313.
7. NIPA1 polyalanine repeat expansions are associated with amyotrophic lateral sclerosis. Blauw HM, ..., Veldink JH. Human Molecular Genetics. 2012 Jun 1;21(11):2497-502.
In this paper, I showed, with a specifically designed fragment length analysis, that NIPA1 repeat expansions have a role in ALS. There is a growing body of evidence that repeat expansions are crucial in ALS (C9orf72, ATXN2, NIPA1).
8. Evidence for an oligogenic basis of amyotrophic lateral sclerosis. Van Blitterswijk M, Van Es MA, ..., de Bakker PI, van den Berg LH, Veldink JH. Human Molecular Genetics. 2012 Sep 1;21(17):3776-84.
In this paper, I was the first to show that mutations in multiple “ALS genes” can be present in large cohort of fALS patients, more often than expected by chance.
9. A large genome scan for rare CNVs in amyotrophic lateral sclerosis. Blauw HM, Al-Chalabi A, ..., Veldink JH. Human Molecular Genetics. 2010 1;21(17):3776-84.
This was the first genome-wide copy number analysis of ALS, for which I trained for at UCLA, Los Angeles during my 6 months stay there. This study directed us toward the NIPA1 locus.
10. Genome-wide association study identifies 19p13.3 UNC13A and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Veldink JH, Van Es MA, ..., Ophoff RA, van den Berg LH. Nature Genetics. 2009 Oct;41(10):1083-7.
In this GWAS, I was the first to show that a hitherto elusive fALS locus (9p21) showed a genetic connection between fALS and sALS by genome-wide association study (GWAS) including ~4.500 sALS 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.
Sporadic consultancy for pharma industry in the context of gene therapy for ALS
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