The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease

Zeitlow, Kahli; Charlambous, Lefko; Ng, Isaac; Gagrani, Sonal; Mihovilovic, Mirta; Luo, Shuhong; Rock, Daniel L.; Saunders, Ann M.; Roses, Allen D.; Gottschalk, William K.

doi:10.1016/j.bbadis.2017.07.031

Cited by 46 publications

(47 citation statements)

References 112 publications

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“…Given the tendency for human genomic repeats to have a negative phenotypic effect as they increase in length, 38,39 the finding that the largest expansion of the TOMM40-5239 repeat is protective is unusual at first glance. Our results align biologically in the case of the TOMM40-5239 repeat; however, as studies have shown that the expression of TOMM40 increases with size of TOMM40-5239 poly-T repeat [11][12][13] and that augmented TOMM40 expression confers subsequent mitochondrial protection. 11 TOMM40-5239 has additionally been identified as a transcriptional start site by the FANTOM project.…”

Section: Discussionsupporting

confidence: 90%

“…It contains an intronic poly-T repeat known as "TOMM40-5239," which varies in length by individual and race/ethnicity. The TOMM40-5239 length has been proposed to influence the transcription of APOE and thus modify the risk for LOAD, [7][8][9][10][11][12][13] although the significance of its association with LOAD remains controversial. [14][15][16][17][18][19] The TOMM40-5239 LOAD relationship has been analyzed by race in the context of global genetic ancestry but not by using adjustment for LGA within the TOMM40-APOE haplotype, allowing for misclassification, given sometimes common differences between LGA and global ancestry.…”

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confidence: 99%

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Use of local genetic ancestry to assess TOMM40 -523′ and risk for Alzheimer disease

Bussies

Rajabli

Griswold³

et al. 2020

Neurol Genet

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ObjectiveHere, we re-examine TOMM40-5239 as a race/ethnicity-specific risk modifier for late-onset Alzheimer disease (LOAD) with adjustment for local genomic ancestry (LGA) in Apolipoprotein E (APOE) «4 haplotypes. MethodsThe TOMM40-5239 size was determined by fragment analysis and whole genome sequencing in homozygous APOE «3 and APOE «4 haplotypes of African (AF) or European (EUR) ancestry. The risk for LOAD was assessed within groups by allele size. ResultsThe TOMM40-5239 length did not modify risk for LOAD in APOE «4 haplotypes with EUR or AF LGA. Increasing length of TOMM40-5239 was associated with a significantly reduced risk for LOAD in EUR APOE e3 haplotypes. ConclusionsAdjustment for LGA confirms that TOMM40-5239 cannot explain the strong differential risk for LOAD between APOE e4 with EUR and AF LGA. Our study does confirm previous reports that increasing allele length of the TOMM40-5239 repeat is associated with decreased risk for LOAD in carriers of homozygous APOE e3 alleles and demonstrates that this effect is occurring in those individuals with the EUR LGA APOE e3 allele haplotype. : FA = fragment analysis; WGS = whole genome sequencing. Comparison of TOMM40-5239 genotyping results between WGS and FA. Allele sizes are listed as number of T's. and risk for Alzheimer disease ′ -523 TOMM40 Use of local genetic ancestry to assess This information is current as of March 3, 2020 Services Updated Information & http://ng.neurology.org/content/6/2/e404.full.html including high resolution figures, can be found at: References http://ng.neurology.org/content/6/2/e404.full.html##ref-list-1 This article cites 38 articles, 2 of which you can access for free at: Citations http://ng.neurology.org/content/6/2/e404.full.html##otherarticles This article has been cited by 1 HighWire-hosted articles: Subspecialty Collections http://ng.neurology.org//cgi/collection/association_studies_in_genetics Association studies in genetics http://ng.neurology.org//cgi/collection/alzheimers_disease Alzheimer's disease following collection(s): This article, along with others on similar topics, appears in the Permissions & Licensing http://ng.neurology.org/misc/about.xhtml#permissions its entirety can be found online at: Information about reproducing this article in parts (figures,tables) or in Reprints http://ng.neurology.org/misc/addir.xhtml#reprintsus Information about ordering reprints can be found online: reserved. Online

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Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 99%

Use of local genetic ancestry to assess TOMM40 -523′ and risk for Alzheimer disease

Bussies

Rajabli

Griswold³

et al. 2020

Neurol Genet

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“…More recently, a study from Zeitlow et al supported the hypothesis that deregulation of TOMM40 expression alters mitochondrial function, leading to pathophysiological consequences, including neurological defects [27]. Their data suggests that high expression levels of TOMM40 may be protective of mitochondrial function and could eventually be an interesting target for therapeutic intervention in AD [27]. The gene PVRL2, encodes the poliovirus receptor 2, a member of the immunoglobulin superfamily expressed in diverse cell tissues, including neurons and is recognized to be a risk factor contributing to AD pathogenesis [11].…”

Section: Discussionmentioning

confidence: 97%

“…TOMM40 has been recognized as a genetic risk factor for AD [25], namely through the association of the intronic SNP rs2075650, which in turn is known to be in tight linkage disequilibrium with the APOE locus [26]. More recently, a study from Zeitlow et al supported the hypothesis that deregulation of TOMM40 expression alters mitochondrial function, leading to pathophysiological consequences, including neurological defects [27]. Their data suggests that high expression levels of TOMM40 may be protective of mitochondrial function and could eventually be an interesting target for therapeutic intervention in AD [27].…”

Section: Discussionmentioning

confidence: 99%

Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer’s Disease Cerebrospinal Fluid Biomarkers

Matos

Ferreira

Herukka

et al. 2018

JAD

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Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer's disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (A␤ 1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF A␤ 1-42 is decreased due to the accumulation of A␤ 1-42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers A␤ 1-42 , t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within ten European consortium centers. Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I, and TOMM40, previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D, CD2AP, and CASS4, showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment.

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“…The upregulations observed for TOMM40 and CREBBP during CR can also be seen as protective. TOMM40 is part of a mitochondrial membrane protein translocase, supporting mitochondrial function (Zeitlow et al, 2017), and low expression and/or particular risk alleles of this protein are associated with Huntington's and Alzheimer's Disease (Shirendeb et al, 2011), (Chong et al, 2013). Of note, TOMM40 upregulation during CR goes together with APOE4 downregulation.…”

Section: From Gene Lists To Maps Of Healthspan Pathwaysmentioning

confidence: 99%

Healthspan pathway maps in C. elegans and humans highlight transcription, proliferation/biosynthesis and lipids

Moeller

Saul

Cohen

et al. 2018

Preprint

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The molecular basis of aging and of aging-associated diseases is being unraveled at an increasing pace. An extended healthspan, and not merely an extension of lifespan, has become the aim of medical practice. However, a precise definition of health and healthspan is not straightforward, and the causal molecular basis of health "per se" is largely unknown. Here, we define health based on the absence of diseases and dysfunctions. Based on an extensive review of the literature, in particular for humans and C. elegans, we compile a list of features of health and of the genes associated with them. Clusters of these genes based on molecular interaction data give rise to maps of healthspan pathways for humans, featuring the themes transcription initiation, proliferation and cholesterol/lipid processing, and for C. elegans, featuring the themes immune response, mitochondrion and biosynthesis based on genetic and compound intervention data, and lipids, biosynthesis and transcription based on WormBase compound intervention data. Overlaying healthspan-related gene expression data (describing effects of metabolic intervention associated with improvements in health) onto the aforementioned healthspan pathway maps, we observe the downregulation of Notch signalling in humans and of proliferation/cell-cycle in C. elegans. The former reflects the proinflammatory role of the Notch pathway. We identify transcription, proliferation/biosynthesis and lipids as a common theme on the annotation level, and proliferation-related kinases on the gene/protein level. Our literature-based data corpus, including visualization, is available as a reference for future investigations, at http://www.h2020awe.eu/index.php/pathways/.

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The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease

Cited by 46 publications

References 112 publications

Use of local genetic ancestry to assess TOMM40 -523′ and risk for Alzheimer disease

Use of local genetic ancestry to assess TOMM40 -523′ and risk for Alzheimer disease

Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer’s Disease Cerebrospinal Fluid Biomarkers

Healthspan pathway maps in C. elegans and humans highlight transcription, proliferation/biosynthesis and lipids

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