document

Identifying Aging and Alzheimer Disease–Associated Somatic Variations in Excitatory Neurons From the Human Frontal Cortex

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

document

A hidden layer of structural variation in transposable elements reveals potential genetic modifiers in human disease-risk loci

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

document

New insights into the genetic etiology of Alzheimer’s disease and related dementias

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

document

Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease

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

document

Resilience and resistance to the accumulation of amyloid plaques and neurofibrillary tangles in centenarians: An age-continuous perspective

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

document

SnpXplorer: A web application to explore human SNP-associations and annotate SNP-sets

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

document

The Effect of Alzheimer’s Disease-Associated Genetic Variants on Longevity

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

document

CHOP: Haplotype-aware path indexing in population graphs

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

document

Dynamic clonal hematopoiesis and functional T-cell immunity in a supercentenarian

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

document

Immune response and endocytosis pathways are associated with the resilience against Alzheimer’s disease

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

document

Extreme enrichment of VNTR-associated polymorphicity in human subtelomeres: genes with most VNTRs are predominantly expressed in the brain

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

document

A meta-analysis of genome-wide association studies identifies multiple longevity genes

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

document

2D Representation of Transcriptomes by t-SNE Exposes Relatedness between Human Tissues

Taskesen, E. (author), Reinders, M.J.T. (author)

The GTEx Consortium reported that hierarchical clustering of RNA profiles from 25 unique tissue types among 1641 individuals accurately distinguished the tissue types, but a multidimensional scaling failed to generate a 2D projection of the data that separates tissue-subtypes. In this study we show that a projection by t-Distributed Stochastic...

journal article 2016

document

Shared Pathways Among Autism Candidate Genes Determined by Co-expression Network Analysis of the Developing Human Brain Transcriptome

Mahfouz, A. (author), Ziats, M.N. (author), Rennert, O.M. (author), Lelieveldt, B.P.F. (author), Reinders, M.J.T. (author)

Autism spectrum disorder (ASD) is a neurodevelopmental syndrome known to have a significant but complex genetic etiology. Hundreds of diverse genes have been implicated in ASD; yet understanding how many genes, each with disparate function, can all be linked to a single clinical phenotype remains unclear. We hypothesized that understanding...

journal article 2015

document

Proteny: Discovering and visualizing statistically significant syntenic clusters at the proteome level

Gehrmann, T. (author), Reinders, M.J.T. (author)

Background: With more and more genomes being sequenced, detecting synteny between genomes becomes more and more important. However, for microorganisms the genomic divergence quickly becomes large, resulting in different codon usage and shuffling of gene order and gene elements such as exons. Results: We present Proteny, a methodology to detect...

journal article 2015

document

Unbiased Quantitative Models of Protein Translation Derived from Ribosome Profiling Data

Gritsenko, A.A. (author), Hulsman, M. (author), Reinders, M.J.T. (author), De Ridder, D. (author)

Translation of RNA to protein is a core process for any living organism. While for some steps of this process the effect on protein production is understood, a holistic understanding of translation still remains elusive. In silico modelling is a promising approach for elucidating the process of protein synthesis. Although a number of...

journal article 2015

document

Hi-C Chromatin Interaction Networks Predict Co-expression in the Mouse Cortex

Babaei, S. (author), Mahfouz, A.M.E.T.A. (author), Hulsman, M. (author), Lelieveldt, B.P.F. (author), De Ridder, J. (author), Reinders, M.J.T. (author)

The three dimensional conformation of the genome in the cell nucleus influences important biological processes such as gene expression regulation. Recent studies have shown a strong correlation between chromatin interactions and gene co-expression. However, predicting gene co-expression from frequent long-range chromatin interactions remains...

journal article 2015

document

Insight into neutral and disease-associated human genetic variants through interpretable predictors

Van den Berg, B.A. (author), Reinders, M.J.T. (author), De Ridder, D. (author), De Beer, T.A.P. (author)

A variety of methods that predict human nonsynonymous single nucleotide polymorphisms (SNPs) to be neutral or disease-associated have been developed over the last decade. These methods are used for pinpointing disease-associated variants in the many variants obtained with next-generation sequencing technologies. The high performances of current...

journal article 2015

document

3D hotspots of recurrent retroviral insertions reveal long-range interactions with cancer genes

Babaei, S. (author), Akhtar, W. (author), De Jong, J. (author), Reinders, M.J.T. (author), De Ridder, J. (author)

Genomically distal mutations can contribute to the deregulation of cancer genes by engaging in chromatin interactions. To study this, we overlay viral cancer-causing insertions obtained in a murine retroviral insertional mutagenesis screen with genome-wide chromatin conformation capture data. Here we find that insertions tend to cluster in 3D...

journal article 2015

document

Integration of gene expression and DNA-methylation profiles improves molecular subtype classification in acute myeloid leukemia

Taskesen, E. (author), Babaei, S. (author), Reinders, M.J.M. (author), De Ridder, J. (author)

Background Acute Myeloid Leukemia (AML) is characterized by various cytogenetic and molecular abnormalities. Detection of these abnormalities is important in the risk-classification of patients but requires laborious experimentation. Various studies showed that gene expression profiles (GEP), and the gene signatures derived from GEP, can be used...

journal article 2015