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Article ; Online: Bioinformatics Strategies for the Analysis and Integration of Large-Scale Multiomics Data.

Tesi, Niccolo' / van der Lee, Sven / Hulsman, Marc / Holstege, Henne / Reinders, Marcel

The journals of gerontology. Series A, Biological sciences and medical sciences

2023 Volume 78, Issue 4, Page(s) 659–662

MeSH term(s)	Humans ; Multiomics ; Alzheimer Disease ; Computational Biology ; Genomics ; Biomarkers
Chemical Substances	Biomarkers
Language	English
Publishing date	2023-04-03
Publishing country	United States
Document type	Editorial ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	1223643-3
ISSN	1758-535X ; 1079-5006
ISSN (online)	1758-535X
ISSN	1079-5006
DOI	10.1093/gerona/glad005
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Article ; Online: Cognitively healthy centenarians are genetically protected against Alzheimer's disease.

Tesi, Niccolo' / van der Lee, Sven / Hulsman, Marc / van Schoor, Natasja M / Huisman, Martijn / Pijnenburg, Yolande / van der Flier, Wiesje M / Reinders, Marcel / Holstege, Henne

Alzheimer's & dementia : the journal of the Alzheimer's Association

2024

Abstract: Background: Alzheimer's disease (AD) prevalence increases with age, yet a small fraction of the population reaches ages > 100 years without cognitive decline. We studied the genetic factors associated with such resilience against AD.: Methods: Genome- ...

Abstract	Background: Alzheimer's disease (AD) prevalence increases with age, yet a small fraction of the population reaches ages > 100 years without cognitive decline. We studied the genetic factors associated with such resilience against AD. Methods: Genome-wide association studies identified 86 single nucleotide polymorphisms (SNPs) associated with AD risk. We estimated SNP frequency in 2281 AD cases, 3165 age-matched controls, and 346 cognitively healthy centenarians. We calculated a polygenic risk score (PRS) for each individual and investigated the functional properties of SNPs enriched/depleted in centenarians. Results: Cognitively healthy centenarians were enriched with the protective alleles of the SNPs associated with AD risk. The protective effect concentrated on the alleles in/near ANKH, GRN, TMEM106B, SORT1, PLCG2, RIN3, and APOE genes. This translated to >5-fold lower PRS in centenarians compared to AD cases (P = 7.69 × 10 Discussion: Maintaining cognitive health until extreme ages requires complex genetic protection against AD, which concentrates on the genes associated with the endolysosomal and immune systems. Highlights: Cognitively healthy cent enarians are enriched with the protective alleles of genetic variants associated with Alzheimer's disease (AD). The protective effect is concentrated on variants involved in the immune and endolysosomal systems. Combining variants into a polygenic risk score (PRS) translated to > 5-fold lower PRS in centenarians compared to AD cases, and ≈ 2-fold lower compared to middle-aged healthy controls.
Language	English
Publishing date	2024-04-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.13810
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Article ; Online: snpXplorer: a web application to explore human SNP-associations and annotate SNP-sets.

Tesi, Niccolo / van der Lee, Sven / Hulsman, Marc / Holstege, Henne / Reinders, Marcel J T

Nucleic acids research

2021 Volume 49, Issue W1, Page(s) W603–W612

Abstract: 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 ... ...

Abstract	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 involves advanced bioinformatic skills. We developed snpXplorer, an easy-to-use web-server application for exploring Single Nucleotide Polymorphisms (SNP) association statistics and to functionally annotate sets of SNPs. snpXplorer can superimpose association statistics from multiple studies, and displays regional information including SNP associations, structural variations, recombination rates, eQTL, linkage disequilibrium patterns, genes and gene-expressions per tissue. By overlaying multiple GWAS studies, snpXplorer can be used to compare levels of association across different traits, which may help the interpretation of variant consequences. Given a list of SNPs, snpXplorer can also be used to perform variant-to-gene mapping and gene-set enrichment analysis to identify molecular pathways that are overrepresented in the list of input SNPs. snpXplorer is freely available at https://snpxplorer.net. Source code, documentation, example files and tutorial videos are available within the Help section of snpXplorer and at https://github.com/TesiNicco/snpXplorer.
MeSH term(s)	Alzheimer Disease/genetics ; Gene Expression ; Genetic Association Studies ; Genomics ; Humans ; Linkage Disequilibrium ; Molecular Sequence Annotation ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; Software
Language	English
Publishing date	2021-05-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkab410
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Article ; Online: Interest in genetic susceptibility testing and disclosure of AD dementia risk in cognitively normal adults: a survey study.

Waterink, Lisa / Masselink, Larissa A / van der Lee, Sven J / Visser, Leonie N C / Cleutjens, Solange / van der Schaar, Jetske / van Harten, Argonde C / Scheltens, Philip / Sikkes, Sietske A M / van der Flier, Wiesje M / Zwan, Marissa D

Alzheimer's research & therapy

2024 Volume 16, Issue 1, Page(s) 1

Abstract: Background: Apolipoprotein-E (APOE) genetic testing for Alzheimer's disease is becoming more important as clinical trials are increasingly targeting individuals carrying APOE-ε4 alleles. Little is known about the interest in finding out one's genetic ... ...

Abstract	Background: Apolipoprotein-E (APOE) genetic testing for Alzheimer's disease is becoming more important as clinical trials are increasingly targeting individuals carrying APOE-ε4 alleles. Little is known about the interest in finding out one's genetic risk for Alzheimer's disease in the general population. Our objective was to examine this in a sample of cognitively normal (CN) adults within a population-based online research registry with the goal to implement APOE-ε4 status for trial recruitment. Methods: An online survey was completed by 442 CN participants between the age of 49 and 75 years (56% female) from the Dutch Brain Research Registry. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia. The survey assessed interest in participation in research into, and disclosure of, genetic risk for dementia and knowing their genetic risk in different hypothetical risk scenarios (10%, 30%, and 50% genetic risk for dementia at age 85, corresponding to APOEε2/ε2 or ε2/ε3, APOEε3/ε4 or ε2ε4, and APOE-ε4/ε4 genotypes). Cochran's Q and post hoc McNemar tests were used to analyse differences in frequencies across scenarios. Results: Most participants were interested in participating in research into and disclosure of their genetic risk (81%). The most reported reason was to contribute to scientific research (94%). Interest was higher in males, whilst lower-educated participants were more often undecided. When provided with different risk scenarios, interest in knowing their risk was somewhat higher in the scenarios with higher risk, i.e. in the 50% (79%) compared to the 10% scenario (73%;χ Conclusions: Our findings indicate that the vast majority of CN adults participating in a research registry expresses interest in AD genetic risk research and disclosure. Interest in genetic risk disclosure is higher in scenarios corresponding to the APOE-ε4 genotype. This suggests APOE-ε4 screening within an online research registry is potentially a well-received method to accelerate inclusion for trials.
MeSH term(s)	Male ; Adult ; Humans ; Female ; Middle Aged ; Aged ; Aged, 80 and over ; Alzheimer Disease/diagnosis ; Alzheimer Disease/genetics ; Alzheimer Disease/epidemiology ; Disclosure ; Genotype ; Apolipoproteins E/genetics ; Genetic Predisposition to Disease/genetics ; Apolipoprotein E4/genetics
Chemical Substances	Apolipoproteins E ; Apolipoprotein E4
Language	English
Publishing date	2024-01-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-023-01364-w
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Article ; Online: The Role of Age-Related Clonal Hematopoiesis in Genetic Sequencing Studies.

Holstege, Henne / Hulsman, Marc / van der Lee, Sven J / van den Akker, Erik B

American journal of human genetics

2020 Volume 107, Issue 3, Page(s) 575–576

MeSH term(s)	DNA-Binding Proteins ; Dioxygenases ; Hematopoiesis ; High-Throughput Nucleotide Sequencing ; Humans ; Neurodegenerative Diseases ; Proto-Oncogene Proteins
Chemical Substances	DNA-Binding Proteins ; Proto-Oncogene Proteins ; Dioxygenases (EC 1.13.11.-) ; TET2 protein, human (EC 1.13.11.-)
Language	English
Publishing date	2020-08-08
Publishing country	United States
Document type	Letter ; Comment
ZDB-ID	219384-x
ISSN	1537-6605 ; 0002-9297
ISSN (online)	1537-6605
ISSN	0002-9297
DOI	10.1016/j.ajhg.2020.07.011
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Article ; Online: Cerebrospinal fluid proteomics in patients with Alzheimer's disease reveals five molecular subtypes with distinct genetic risk profiles.

Nature aging

2024 Volume 4, Issue 1, Page(s) 33–47

Abstract: Alzheimer's disease (AD) is heterogenous at the molecular level. Understanding this heterogeneity is critical for AD drug development. Here we define AD molecular subtypes using mass spectrometry proteomics in cerebrospinal fluid, based on 1,058 proteins, ...

Abstract	Alzheimer's disease (AD) is heterogenous at the molecular level. Understanding this heterogeneity is critical for AD drug development. Here we define AD molecular subtypes using mass spectrometry proteomics in cerebrospinal fluid, based on 1,058 proteins, with different levels in individuals with AD (n = 419) compared to controls (n = 187). These AD subtypes had alterations in protein levels that were associated with distinct molecular processes: subtype 1 was characterized by proteins related to neuronal hyperplasticity; subtype 2 by innate immune activation; subtype 3 by RNA dysregulation; subtype 4 by choroid plexus dysfunction; and subtype 5 by blood-brain barrier impairment. Each subtype was related to specific AD genetic risk variants, for example, subtype 1 was enriched with TREM2 R47H. Subtypes also differed in clinical outcomes, survival times and anatomical patterns of brain atrophy. These results indicate molecular heterogeneity in AD and highlight the need for personalized medicine.
MeSH term(s)	Humans ; Alzheimer Disease/genetics ; Proteomics
Language	English
Publishing date	2024-01-09
Publishing country	United States
Document type	Journal Article
ISSN	2662-8465
ISSN (online)	2662-8465
DOI	10.1038/s43587-023-00550-7
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Article: Quantitative trait loci mapping of circulating metabolites in cerebrospinal fluid to uncover biological mechanisms involved in brain-related phenotypes.

Reus, Lianne M / Boltz, Toni / Francia, Marcelo / Bot, Merel / Ramesh, Naren / Koromina, Maria / Pijnenburg, Yolande A L / den Braber, Anouk / van der Flier, Wiesje M / Visser, Pieter Jelle / van der Lee, Sven J / Tijms, Betty M / Teunissen, Charlotte E / Loohuis, Loes Olde / Ophoff, Roel A

bioRxiv : the preprint server for biology

2023

Abstract: Genomic studies of molecular traits have provided mechanistic insights into complex disease, though these lag behind for brain-related traits due to the inaccessibility of brain tissue. We leveraged cerebrospinal fluid (CSF) to study neurobiological ... ...

Abstract	Genomic studies of molecular traits have provided mechanistic insights into complex disease, though these lag behind for brain-related traits due to the inaccessibility of brain tissue. We leveraged cerebrospinal fluid (CSF) to study neurobiological mechanisms
Language	English
Publishing date	2023-09-27
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.26.559021
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Article ; Online: What does heritability of Alzheimer's disease represent?

Baker, Emily / Leonenko, Ganna / Schmidt, Karl Michael / Hill, Matthew / Myers, Amanda J / Shoai, Maryam / de Rojas, Itziar / Tesi, Niccoló / Holstege, Henne / van der Flier, Wiesje M / Pijnenburg, Yolande A L / Ruiz, Agustin / Hardy, John / van der Lee, Sven / Escott-Price, Valentina

PloS one

2023 Volume 18, Issue 4, Page(s) e0281440

Abstract: Introduction: Both late-onset Alzheimer's disease (AD) and ageing have a strong genetic component. In each case, many associated variants have been discovered, but how much missing heritability remains to be discovered is debated. Variability in the ... ...

Abstract	Introduction: Both late-onset Alzheimer's disease (AD) and ageing have a strong genetic component. In each case, many associated variants have been discovered, but how much missing heritability remains to be discovered is debated. Variability in the estimation of SNP-based heritability could explain the differences in reported heritability. Methods: We compute heritability in five large independent cohorts (N = 7,396, 1,566, 803, 12,528 and 3,963) to determine whether a consensus for the AD heritability estimate can be reached. These cohorts vary by sample size, age of cases and controls and phenotype definition. We compute heritability a) for all SNPs, b) excluding APOE region, c) excluding both APOE and genome-wide association study hit regions, and d) SNPs overlapping a microglia gene-set. Results: SNP-based heritability of late onset Alzheimer's disease is between 38 and 66% when age and genetic disease architecture are correctly accounted for. The heritability estimates decrease by 12% [SD = 8%] on average when the APOE region is excluded and an additional 1% [SD = 3%] when genome-wide significant regions were removed. A microglia gene-set explains 69-84% of our estimates of SNP-based heritability using only 3% of total SNPs in all cohorts. Conclusion: The heritability of neurodegenerative disorders cannot be represented as a single number, because it is dependent on the ages of cases and controls. Genome-wide association studies pick up a large proportion of total AD heritability when age and genetic architecture are correctly accounted for. Around 13% of SNP-based heritability can be explained by known genetic loci and the remaining heritability likely resides around microglial related genes.
MeSH term(s)	Humans ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; Alzheimer Disease/genetics ; Genetic Loci ; Polymorphism, Single Nucleotide ; Apolipoproteins E/genetics
Chemical Substances	Apolipoproteins E
Language	English
Publishing date	2023-04-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0281440
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Article ; Online: Association of MGMT and BIN1 genes with Alzheimer's disease risk across sex and APOE ε4 status.

Le Borgne, Julie / Amouyel, Philippe / Andreassen, Ole / Frikke-Schmidt, Ruth / Hiltunen, Mikko / Ingelsson, Martin / Ramirez, Alfredo / Rossi, Giacomina / Ruiz, Agustin / Sanchez-Juan, Pascual / Sims, Rebecca / Sleegers, Kristel / Tsolaki, Magda / van der Lee, Sven J / Williams, Julie / Lambert, Jean-Charles / Bellenguez, Céline

Alzheimer's & dementia : the journal of the Alzheimer's Association

2023 Volume 20, Issue 3, Page(s) 2282–2284

MeSH term(s)	Humans ; Apolipoprotein E4/genetics ; Alzheimer Disease/genetics ; Apolipoproteins E/genetics ; Nuclear Proteins/genetics ; Tumor Suppressor Proteins/genetics ; Adaptor Proteins, Signal Transducing/genetics ; DNA Modification Methylases ; DNA Repair Enzymes
Chemical Substances	Apolipoprotein E4 ; Apolipoproteins E ; BIN1 protein, human ; Nuclear Proteins ; Tumor Suppressor Proteins ; Adaptor Proteins, Signal Transducing ; MGMT protein, human (EC 2.1.1.63) ; DNA Modification Methylases (EC 2.1.1.-) ; DNA Repair Enzymes (EC 6.5.1.-)
Language	English
Publishing date	2023-12-02
Publishing country	United States
Document type	Letter
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.13550
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Article ; Online: Mapping the genetic landscape of early-onset Alzheimer's disease in a cohort of 36 families.

Mol, Merel O / van der Lee, Sven J / Hulsman, Marc / Pijnenburg, Yolande A L / Scheltens, Phillip / Seelaar, Harro / van Swieten, John C / Kaat, Laura Donker / Holstege, Henne / van Rooij, Jeroen G J

Alzheimer's research & therapy

2022 Volume 14, Issue 1, Page(s) 77

Abstract: Background: Many families with clinical early-onset Alzheimer's disease (EOAD) remain genetically unexplained. A combination of genetic factors is not standardly investigated. In addition to monogenic causes, we evaluated the possible polygenic ... ...

Abstract	Background: Many families with clinical early-onset Alzheimer's disease (EOAD) remain genetically unexplained. A combination of genetic factors is not standardly investigated. In addition to monogenic causes, we evaluated the possible polygenic architecture in a large series of families, to assess if genetic testing of familial EOAD could be expanded. Methods: Thirty-six pedigrees (77 patients) were ascertained from a larger cohort of patients, with relationships determined by genetic data (exome sequencing data and/or SNP arrays). All families included at least one AD patient with symptom onset <70 years. We evaluated segregating rare variants in known dementia-related genes, and other genes or variants if shared by multiple families. APOE was genotyped and duplications in APP were assessed by targeted test or using SNP array data. We computed polygenic risk scores (PRS) compared with a reference population-based dataset, by imputing SNP arrays or exome sequencing data. Results: In eight families, we identified a pathogenic variant, including the genes APP, PSEN1, SORL1, and an unexpected GRN frameshift variant. APOE-ε4 homozygosity was present in eighteen families, showing full segregation with disease in seven families. Eight families harbored a variant of uncertain significance (VUS), of which six included APOE-ε4 homozygous carriers. PRS was not higher in the families combined compared with the population mean (beta 0.05, P = 0.21), with a maximum increase of 0.61 (OR = 1.84) in the GRN family. Subgroup analyses indicated lower PRS in six APP/PSEN1 families compared with the rest (beta -0.22 vs. 0.10; P = 0.009) and lower APOE burden in all eight families with monogenic cause (beta 0.29 vs. 1.15, P = 0.010). Nine families remained without a genetic cause or risk factor identified. Conclusion: Besides monogenic causes, we suspect a polygenic disease architecture in multiple families based on APOE and rare VUS. The risk conveyed by PRS is modest across the studied families. Families without any identified risk factor render suitable candidates for further in-depth genetic evaluation.
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Apolipoproteins E/genetics ; Cohort Studies ; Heterozygote ; Humans ; LDL-Receptor Related Proteins/genetics ; Membrane Transport Proteins/genetics ; Whole Exome Sequencing
Chemical Substances	Apolipoproteins E ; LDL-Receptor Related Proteins ; Membrane Transport Proteins ; SORL1 protein, human
Language	English
Publishing date	2022-06-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-022-01018-3
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