Weighted burden analysis of exome-sequenced late onset Alzheimer’s cases and controls provides further evidence for a role for <i>PSEN1</i> and suggests involvement of the PI3K/Akt/GSK-3β and WNT signalling pathways

Curtis, David; Bakaya, Kaushiki; Sharma, Leona; Bandyopadhyay, Sreejan

doi:10.1101/596007

Cited by 3 publications

(2 citation statements)

References 46 publications

(46 reference statements)

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“…We used the CommonRare algorithm for binary traits with the adaptive sum method to account for common and rare variants within the PAM gene, using a MAF cutoff of 0.1% and considering the weight of the SNVs based on their detrimental effect on protein. SNV weights were assigned as previously described [74] and adapted as follows:…”

Section: Spatial Clustering Analysismentioning

confidence: 99%

Germline loss-of-functionPAMvariants are enriched in subjects with pituitary hypersecretion

Trivellin

Daly

Hernández-Ramírez

et al. 2023

Preprint

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Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. Following the identification of a loss-of-function variant (p.Arg703Gln) in the PAM gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated pituitary adenomas kindreds for PAM variants. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis. No germline CNVs or somatic single nucleotide variants (SNVs) were identified. We detected seven likely pathogenic heterozygous missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with GH excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or with different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, for splicing by minigene assays, and for amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs to diagnoses linked to pituitary gland hyperfunction. Identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.

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Section: Spatial Clustering Analysismentioning

confidence: 99%

Germline loss-of-functionPAMvariants are enriched in subjects with pituitary hypersecretion

Trivellin

Daly

Hernández-Ramírez

et al. 2023

Preprint

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“…Furthermore, TNAP expression and activity increases after tau addition to a neuron culture medium, thereby creating a positive feedback loop [ 102 , 112 , 260 , 261 ]. Additionally, exome sequencing analysis has recently identified genetic variants of some phosphatases that confer protection against AD [ 262 ]. However, the role of these variants in tau dephosphorylation remains unexplored.…”

Section: Extracellular Soluble Tau As the Main Driving Force Of Tomentioning

confidence: 99%

Microglia in Alzheimer’s Disease in the Context of Tau Pathology

2020

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Microglia are the cells that comprise the innate immune system in the brain. First described more than a century ago, these cells were initially assigned a secondary role in the central nervous system (CNS) with respect to the protagonists, neurons. However, the latest advances have revealed the complexity and importance of microglia in neurodegenerative conditions such as Alzheimer’s disease (AD), the most common form of dementia associated with aging. This pathology is characterized by the accumulation of amyloid-β peptide (Aβ), which forms senile plaques in the neocortex, as well as by the aggregation of hyperphosphorylated tau protein, a process that leads to the development of neurofibrillary tangles (NFTs). Over the past few years, efforts have been focused on studying the interaction between Aβ and microglia, together with the ability of the latter to decrease the levels of this peptide. Given that most clinical trials following this strategy have failed, current endeavors focus on deciphering the molecular mechanisms that trigger the tau-induced inflammatory response of microglia. In this review, we summarize the most recent studies on the physiological and pathological functions of tau protein and microglia. In addition, we analyze the impact of microglial AD-risk genes (APOE, TREM2, and CD33) in tau pathology, and we discuss the role of extracellular soluble tau in neuroinflammation.

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Analysis of 470,000 exome-sequenced UK Biobank participants identifies genes containing rare variants which confer dementia risk

Gibbons,

Curtis

2024

Preprint

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Background Previous studies have reported that rare coding variants in a handful of genes have major effects on risk of Alzheimer's disease (AD). A recent exome wide association study (ExWAS) of dementia in a subset of the UK Biobank cohort implicated a number of genes, including five which were novel. Here we report a similar analysis, carried out on the full cohort of 470,000 exome-sequenced participants. Methods A score was assigned to each participant depending on individual and/or parental diagnosis of dementia. Regression analysis including APOE e3 and e4 doses as covariates was applied to gene-wise tests for association with loss of function (LOF) and nonsynonymous variants. 45 tests using different pathogenicity predictors were applied to the first cohort of 200,000 participants. Subsequently the 100 genes showing strongest evidence for association were analysed in the second cohort of 270,000 participants, using only the best-performing predictor for each gene. Results Three genes achieved statistical significance, TREM2, SORL1 and ABCA7. The five genes reported as novel in the ExWAS did not produce any appreciable evidence for association in this study. The effects and frequencies of variants in different functional categories were characterised for these genes. Conclusions Rare coding variants in a small number of genes have important effects on dementia risk. Further study of individual variant effects might elucidate mechanisms of pathogenesis. Incorporating rare variant effects for individual risk assessment might become important if preventative treatments for dementia become available.

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Weighted burden analysis of exome-sequenced late onset Alzheimer’s cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK-3β and WNT signalling pathways

Cited by 3 publications

References 46 publications

Germline loss-of-functionPAMvariants are enriched in subjects with pituitary hypersecretion

Germline loss-of-functionPAMvariants are enriched in subjects with pituitary hypersecretion

Microglia in Alzheimer’s Disease in the Context of Tau Pathology

Analysis of 470,000 exome-sequenced UK Biobank participants identifies genes containing rare variants which confer dementia risk

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