Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia

Rosas, Irene; Martı́nez, Carmen; Coto, Eliécer; Clarimón, Jordi; Lleó, Alberto; Illán-Gala, Ignacio; Dols‐Icardo, Oriol; Borroni, Barbara; Almeida, Maria Rosário; Zee, Julie van der; Broeckhoven, Christine Van; Bruni, Amalia C.; Anfossi, Maria; Bernardi, Livia; Maletta, Raffaele; Serpente, María; Galimberti, Daniela; Scarpini, Elio; Rossi, Giacomina; Caroppo, Paola; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; Nacmias, Benedetta; Sorbi, Sandro; Piaceri, Irene; Bagnoli, Silvia; Antonell, Anna; Sánchez‐Valle, Raquel; Casa-Fages, Beatriz De la; Grandas, Francisco; Díez-Fairén, Mónica; Pástor, Pau; Ferrari, Raffaele; Ifgc,; Queimaliños-Perez, Daniel; Pérez-Oliveira, Sergio; Álvarez, Victoria; Menéndez-González, Manuel

doi:10.1016/j.neurobiolaging.2020.08.018

Cited by 11 publications

(8 citation statements)

References 36 publications

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“…Of these LXR targets, APOE levels appear to be a particularly important link between lipids, inflammation and neurodegeneration (Figure 3). Consistent with clinical data linking lipids and inflammation to neurodegenerative disease, APOE is an intercellular lipid transporter whose genomic sequence variation influences the onset and progression of cognitive decline in dementias, PD and NPC1 [49,50,100–106]. Recent data demonstrate that sequence variation in GBA further accelerates cognitive decline in PD patients carrying at least one copy of the APOE disease allele, inferring a significant consequence of concomitant sphingolipid and cholesterol accumulation in the human brain [103].…”

Section: Lipid Clearance Supports Adaptive Homeostasis Limiting Infla...mentioning

confidence: 80%

Upstream lipid and metabolic systems are potential causes of Alzheimer's disease, Parkinson's disease and dementias

2022

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Brain health requires circuits, cells and molecular pathways to adapt when challenged and to promptly reset once the challenge has resolved. Neurodegeneration occurs when adaptability becomes confined, causing challenges to overwhelm neural circuitry. Studies of rare and common neurodegenerative diseases suggest that the accumulation of lipids can compromise circuit adaptability. Using microglia as an example, we review data that suggest increased lipid concentrations cause dysfunctional inflammatory responses to immune challenges, leading to Alzheimer's disease, Parkinson's disease and dementia. We highlight current approaches to treat lipid metabolic and clearance pathways and identify knowledge gaps towards restoring adaptive homeostasis in individuals who are at‐risk of losing cognition.

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Section: Lipid Clearance Supports Adaptive Homeostasis Limiting Infla...mentioning

confidence: 80%

Upstream lipid and metabolic systems are potential causes of Alzheimer's disease, Parkinson's disease and dementias

2022

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“…ADAMTS5 , at the centre of functional network 2, is a metalloprotease recently shown to play a role in cortical development through interactions with reelin and DISC1 38 . Interestingly, a variant of TP53 , which is implicated in the top functional networks for executive function and processing speed, has been described as a disease modifier in fronto-temporal dementia 52 .…”

Section: Discussionmentioning

confidence: 99%

Genome-wide interaction study with major depression identifies novel variants associated with cognitive function

et al. 2021

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Major Depressive Disorder (MDD) often is associated with significant cognitive dysfunction. We conducted a meta-analysis of genome-wide interaction of MDD and cognitive function using data from 4 large European cohorts in a total of 3510 MDD cases and 6057 controls. In addition, we conducted analyses using polygenic risk scores (PRS) based on data from the Psychiatric Genomics Consortium (PGC) on the traits of MDD, Bipolar disorder (BD), Schizophrenia (SCZ), and mood instability (MIN). Functional exploration contained gene expression analyses and Ingenuity Pathway Analysis (IPA®). We identified a set of significantly interacting single nucleotide polymorphisms (SNPs) between MDD and the genome-wide association study (GWAS) of cognitive domains of executive function, processing speed, and global cognition. Several of these SNPs are located in genes expressed in brain, with important roles such as neuronal development ( REST ), oligodendrocyte maturation ( TNFRSF21 ), and myelination ( ARFGEF1 ). IPA® identified a set of core genes from our dataset that mapped to a wide range of canonical pathways and biological functions ( MPO , FOXO1 , PDE3A , TSLP , NLRP9 , ADAMTS5 , ROBO1 , REST ). Furthermore, IPA® identified upstream regulator molecules and causal networks impacting on the expression of dataset genes, providing a genetic basis for further clinical exploration (vitamin D receptor, beta-estradiol, tadalafil). PRS of MIN and meta-PRS of MDD, MIN and SCZ were significantly associated with all cognitive domains. Our results suggest several genes involved in physiological processes for the development and maintenance of cognition in MDD, as well as potential novel therapeutic agents that could be explored in patients with MDD associated cognitive dysfunction.

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“…In FTLD, one of the most heterogeneous clinical features is the age of onset, even in the same family pedigree [ 26 ]. Due to the high hereditability of this group of disorders [ 5 ], some genetic studies have been performed in this field, showing the presence of genes potentially affecting the age of onset [ 27 , 28 , 29 , 34 , 35 ]. However, this issue is still far from being fully addressed.…”

Section: Discussionmentioning

confidence: 99%

The PINK1 p.Asn521Thr Variant Is Associated with Earlier Disease Onset in GRN/C9orf72 Frontotemporal Lobar Degeneration

Rossi

Benussi

Mehmeti

et al. 2022

IJMS

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Genetic frontotemporal lobar degeneration (FTLD) is characterized by heterogeneous phenotypic expression, with a disease onset highly variable even in patients carrying the same mutation. Herein we investigated if variants in lysosomal genes modulate the age of onset both in FTLD due to GRN null mutations and C9orf72 expansion. In a total of 127 subjects (n = 74 GRN mutations and n = 53 C9orf72 expansion carriers), we performed targeted sequencing of the top 98 genes belonging to the lysosomal pathway, selected based on their high expression in multiple brain regions. We described an earlier disease onset in GRN/C9orf72 pedigrees in subjects carrying the p.Asn521Thr variant (rs1043424) in PTEN-induced kinase 1 (PINK1), a gene that is already known to be involved in neurodegenerative diseases. We found that: (i) the PINK1 rs1043424 C allele is significantly associated with the age of onset; (ii) every risk C allele increases hazard by 2.11%; (iii) the estimated median age of onset in homozygous risk allele carriers is 10–12 years earlier than heterozygous/wild type homozygous subjects. A replication study in GRN/C9orf72 negative FTLD patients confirmed that the rs1043424 C allele was associated with earlier disease onset (−5.5 years in CC versus A carriers). Understanding the potential mechanisms behind the observed modulating effect of the PINK1 gene in FTLD might prove critical for identifying biomarkers and/or designing drugs to modify the age of onset, especially in GRN/C9orf72-driven disease.

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Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia

Cited by 11 publications

References 36 publications

Upstream lipid and metabolic systems are potential causes of Alzheimer's disease, Parkinson's disease and dementias

Upstream lipid and metabolic systems are potential causes of Alzheimer's disease, Parkinson's disease and dementias

Genome-wide interaction study with major depression identifies novel variants associated with cognitive function

The PINK1 p.Asn521Thr Variant Is Associated with Earlier Disease Onset in GRN/C9orf72 Frontotemporal Lobar Degeneration

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