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Zhang, M. (author), Bouland, G.A. (author), Holstege, H. (author), Reinders, M.J.T. (author)Background and Objectives - With age, somatic mutations accumulated in human brain cells can lead to various neurologic disorders and brain tumors. Because the incidence rate of Alzheimer disease (AD) increases exponentially with age, investigating the association between AD and the accumulation of somatic mutation can help understand the...journal article 2023
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Zhang, M. (author), Ganz, Andrea B. (author), Rohde, Susan (author), Lorenz, Linda (author), Rozemuller, Annemieke J.M. (author), Reinders, M.J.T. (author), Hulsman, M. (author), Hoozemans, Jeroen J.M. (author), Holstege, H. (author)INTRODUCTION: Neuropathological substrates associated with neurodegeneration occur in brains of the oldest old. How does this affect cognitive performance?. METHODS: The 100-plus Study is an ongoing longitudinal cohort study of centenarians who self-report to be cognitively healthy; post mortem brain donation is optional. In 85 centenarian...journal article 2023
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van Bree, Elisabeth J. (author), Guimarães, Rita L.F.P. (author), Lundberg, Mischa (author), Blujdea, Elena R. (author), Rosenkrantz, Jimi L. (author), White, Fred T.G. (author), Reinders, M.J.T. (author), Holstege, H. (author), Jacobs, Frank M.J. (author)Genome-wide association studies (GWAS) have been highly informative in discovering disease-associated loci but are not designed to capture all structural variations in the human genome. Using long-read sequencing data, we discovered widespread structural variation within SINE-VNTR-Alu (SVA) elements, a class of great ape-specific transposable...journal article 2022
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van der Lee, S.J. (author), De Rojas, I. (author), Holstege, H. (author), Hulsman, M. (author), Reinders, M.J.T. (author), Tesi, N. (author), van Rooij, Jeroen (author), Zhao, Y. (author), Zhang, X. (author)Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage<br/>genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found...journal article 2022
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Holstege, H. (author), Hulsman, M.J. (author), Charbonnier, Camille (author), Grenier-Boley, Banjamin (author), Quenez, Olivier (author), Grozeva, Detelina (author), van Rooij, Jeroen G.J. (author), Reinders, M.J.T. (author), van der Lee, S.J. (author)Alzheimer’s disease (AD), the leading cause of dementia, has an estimated<br/>heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome...journal article 2022
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Zhang, M. (author), Ganz, Andrea B. (author), Rohde, Susan (author), Rozemuller, Annemieke J.M. (author), Bank, Netherlands Brain (author), Reinders, M.J.T. (author), Scheltens, Philip (author), Hulsman, M. (author), Hoozemans, Jeroen J.M. (author), Holstege, H. (author)Introduction: With increasing age, neuropathological substrates associated with Alzheimer's disease (AD) accumulate in brains of cognitively healthy individuals—are they resilient, or resistant to AD-associated neuropathologies?. Methods: In 85 centenarian brains, we correlated NIA (amyloid) stages, Braak (neurofibrillary tangle) stages, and...journal article 2022
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Tesi, N. (author), van der Lee, S.J. (author), Hulsman, M. (author), Holstege, H. (author), Reinders, M.J.T. (author)Genetic association studies are frequently used to study the genetic basis of numerous human phenotypes. However, the rapid interrogation of how well a certain genomic region associates across traits as well as the interpretation of genetic associations is often complex and requires the integration of multiple sources of annotation, which...journal article 2021
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Tesi, N. (author), van der Lee, S.J. (author), Hulsman, M. (author), Jansen, Iris E. (author), Stringa, N. (author), van Schoor, N.M. (author), Huisman, Martijn (author), Reinders, M.J.T. (author), Holstege, H. (author)Studying the genome of centenarians may give insights into the molecular mechanisms underlying extreme human longevity and the escape of age-related diseases. Here, we set out to construct polygenic risk scores (PRSs) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with...journal article 2021
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Tesi, N. (author), Hulsman, M. (author), van der Lee, S.J. (author), Jansen, Iris E. (author), Stringa, N. (author), van Schoor, Natasja M. (author), Scheltens, Philip (author), Reinders, M.J.T. (author), Holstege, H. (author)Human longevity is influenced by the genetic risk of age-related diseases. As Alzheimer’s disease (AD) represents a common condition at old age, an interplay between genetic factors affecting AD and longevity is expected. We explored this interplay by studying the prevalence of AD-associated single-nucleotide-polymorphisms (SNPs) in...journal article 2021
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Mokveld, T.O. (author), Linthorst, J. (author), Al-Ars, Z. (author), Holstege, H. (author), Reinders, M.J.T. (author)The practical use of graph-based reference genomes depends on the ability to align reads to them. Performing substring queries to paths through these graphs lies at the core of this task. The combination of increasing pattern length and encoded variations inevitably leads to a combinatorial explosion of the search space. Instead of heuristic...journal article 2020
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- van den Akker, E.B. (author), Makrodimitris, S. (author), Hulsman, M. (author), Brugman, Martijn H. (author), Nikolic, Tatjana (author), Bradley, Ted (author), Waisfisz, Quinten (author), Baas, Frank (author), Reinders, M.J.T. (author), Holstege, H. (author) journal article 2020
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Tesi, N. (author), van der Lee, S.J. (author), Hulsman, M. (author), Jansen, Iris E. (author), Stringa, N. (author), van Schoor, N.M. (author), Scheltens, Philip (author), van der Flier, Wiesje M. (author), Huisman, Martijn (author), Reinders, M.J.T. (author), Holstege, H. (author)Developing Alzheimer’s disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what...journal article 2020
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Linthorst, J. (author), Meert, Wim (author), Hestand, Matthew S. (author), Korlach, Jonas (author), Vermeesch, Joris Robert (author), Reinders, M.J.T. (author), Holstege, H. (author)The human genome harbors numerous structural variants (SVs) which, due to their repetitive nature, are currently underexplored in short-read whole-genome sequencing approaches. Using single-molecule, real-time (SMRT) long-read sequencing technology in combination with FALCON-Unzip, we generated a de novo assembly of the diploid genome of a...journal article 2020
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Deelen, J (author), D., Evans (author), Dan E., Arking (author), Tesi, N. (author), M, Nygaard (author), Liu, Xiaoming (author), Mary K., Wojczynski (author), Reinders, M.J.T. (author), Holstege, H. (author)Human longevity is heritable, but genome-wide association (GWA) studies have had limitedsuccess. Here, we perform two meta-analyses of GWA studies of a rigorous longevityphenotype definition including 11,262/3484 cases surviving at or beyond the age corre-sponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose...journal article 2019
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Tesi, N. (author), van der Lee, S.J. (author), Hulsman, M. (author), Jansen, Iris E. (author), Stringa, N. (author), van Schoor, N.M. (author), Meijers-Heijboer, Hanne (author), Reinders, M.J.T. (author), Holstege, H. (author)The detection of genetic loci associated with Alzheimer’s disease (AD) requires large numbers of cases and controls because variant effect sizes are mostly small. We hypothesized that variant effect sizes should increase when individuals who represent the extreme ends of a disease spectrum are considered, as their genomes are assumed to be...journal article 2019
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Holstege, H. (author), van der Lee, S.J. (author), Hulsman, M. (author), Hang Wong, Tsz (author), van Rooij, Jeroen G.J. (author), Weiss, Marjan (author), Louwersheimer, Eva (author), Wolters, Frank J, (author), Amin, Najaf (author), Reinders, M.J.T. (author)Accumulating evidence suggests that genetic variants in the SORL1 gene are associated with Alzheimer disease (AD), but a strategy to identify which variants are pathogenic is lacking. In a discovery sample of 115 SORL1 variants detected in 1908 Dutch AD cases and controls, we identified the variant characteristics associated with SORL1...journal article 2017
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Straver, R. (author), Sistermans, E.A. (author), Holstege, H. (author), Visser, A. (author), Oudejans, C.B.M. (author), Reinders, M.J.T. (author)Genetic disorders can be detected by prenatal diagnosis using Chorionic Villus Sampling, but the 1:100 chance to result in miscarriage restricts the use to fetuses that are suspected to have an aberration. Detection of trisomy 21 cases noninvasively is now possible owing to the upswing of next-generation sequencing (NGS) because a small...journal article 2013
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De Ronde, J.J. (author), Klijn, C. (author), Velds, A. (author), Holstege, H. (author), Reinders, M.J.T. (author), Jonkers, J. (author), Wessels, L.F.A. (author)Background: Most approaches used to find recurrent or differential DNA Copy Number Alterations (CNA) in array Comparative Genomic Hybridization (aCGH) data from groups of tumour samples depend on the discretization of the aCGH data to gain, loss or no-change states. This causes loss of valuable biological information in tumour samples, which are...journal article 2010
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Klijn, C.N. (author), Holstege, H. (author), De Ridder, J. (author), Liu, X. (author), Reinders, M. (author), Jonkers, J. (author), Wessels, L. (author)Tumor formation is in part driven by DNA copy number alterations (CNAs), which can be measured using microarray-based Comparative Genomic Hybridization (aCGH). Multiexperiment analysis of aCGH data from tumors allows discovery of recurrent CNAs that are potentially causal to cancer development. Until now, multiexperiment aCGH data analysis has...journal article 2008