Genetic risk for neurodegenerative disorders, and its overlap with cognitive ability and physical function

Hagenaars, Saskia P.; Radaković, Ratko; Crockford, Christopher; Fawns-Ritchie, Chloë; Harris, Sarah E.; Gale, Catharine R.; Deary, Ian J.

doi:10.1371/journal.pone.0198187

Cited by 18 publications

(15 citation statements)

References 47 publications

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“…Dementia is a clinical state caused by neurodegeneration and is characterized by a loss of function in cognitive domains and undesirable changes in behavior. Several types of neurodegenerative diseases were described [1,2,3,4], including Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), prion diseases, and Huntington’s disease, which may share clinical and pathologic features [5]. The common feature of the neurodegenerative diseases could be the abnormal protein aggregates in the central nervous system [6].…”

Section: Introductionmentioning

confidence: 99%

Analysis of 50 Neurodegenerative Genes in Clinically Diagnosed Early-Onset Alzheimer’s Disease

Giau

Senanarong

Bagyinszky

et al. 2019

IJMS

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Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and prion diseases have a certain degree of clinical, pathological, and molecular overlapping. Previous studies revealed that many causative mutations in AD, PD, and FTD/ALS genes could be found in clinical familial and sporadic AD. To further elucidate the missing heritability in early-onset Alzheimer’s disease (EOAD), we genetically characterized a Thai EOAD cohort by Next-Generation Sequencing (NGS) with a high depth of coverage, capturing variants in 50 previously recognized AD and other related disorders’ genes. A novel mutation, APP p.V604M, and the known causative variant, PSEN1 p.E184G, were found in two of the familiar cases. Remarkably, among 61 missense variants were additionally discovered from 21 genes out of 50 genes, six potential mutations including MAPT P513A, LRRK2 p.R1628P, TREM2 p.L211P, and CSF1R (p.P54Q and pL536V) may be considered to be probably/possibly pathogenic and risk factors for other dementia leading to neuronal degeneration. All allele frequencies of the identified missense mutations were compared to 622 control individuals. Our study provides initial evidence that AD and other neurodegenerative diseases may represent shades of the same disease spectrum, and consideration should be given to offer exactly embracing genetic testing to patients diagnosed with EOAD. Our results need to be further confirmed with a larger cohort from this area.

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Section: Introductionmentioning

confidence: 99%

Analysis of 50 Neurodegenerative Genes in Clinically Diagnosed Early-Onset Alzheimer’s Disease

Giau

Senanarong

Bagyinszky

et al. 2019

IJMS

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“…While cognitive dysfunction has been more frequently linked to genetic mutations causally associated with ALS, such as C9ORF72 repeat expansions [43], studies examining individual SNPs have demonstrated quantitative-trait modification of cognitive performance and cortical disease burden [24,25]. However, mounting evidence suggests that there are polygenic, rather than single allele, modifiers of disease risk and phenotype in ALS and related neurodegenerative diseases [22,23,26]. Our observation of polygenic association between of 27 SNPs and the ECAS ALS-Specific score, a combined measure of executive, language, and verbal fluency domains most commonly affected in ALS, is consistent with the idea of polygenic contribution to phenotypic variability in ALS.…”

Section: Discussionmentioning

confidence: 99%

“…22,24 However, mounting evidence suggests that there are polygenic, rather than single allele, modifiers of disease risk and phenotype in ALS and related neurodegenerative diseases. 16,17,24 Our observation of 26 genetic variants collectively associating with the ECAS ALS-Specific score -a combined measure of executive, language, and verbal fluency domains most commonly affected in ALS -is consistent with the idea of polygenic contribution to phenotypic variability in ALS. Notably, our observed polygenic association in the CReATe PGB Cohort appears specific to cognitive variability in ALS: we demonstrate relative independence of cognitive performance and motor disease severity (i.e.…”

Section: Discussionmentioning

confidence: 99%

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Machine learning suggests polygenic contribution to cognitive dysfunction in amyotrophic lateral sclerosis

Placek

Benatar

Wuu

et al. 2019

Preprint

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Amyotrophic lateral sclerosis (ALS) is a multi-system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients, however factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-learning technique, we observed that single nucleotide polymorphisms collectively associate with baseline cognitive performance in a large ALS patient cohort from the multicenter Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium (N=327). We demonstrate that a polygenic risk score derived using sCCA relates to longitudinal cognitive decline in the same cohort, and also to in vivo cortical thinning in the orbital frontal cortex, anterior cingulate cortex, lateral temporal cortex, premotor cortex, and hippocampus (N=114) as well as post mortem motor cortical neuronal loss (N=88) in independent ALS cohorts from the University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Our findings suggest that common genetic polymorphisms may exert a polygenic contribution to the risk of cortical disease vulnerability and cognitive dysfunction in ALS.

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“…Neurodegenerative diseases are a series of diseases with insidious onset and slow progression, characterized by aggregation of abnormal proteins in neurons and other cells, including AD, Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), DLB, and FTD etc. Neurodegenerative diseases have some neuropathology, clinical and/or genetic crossover 13,14 . For example, Parkinson’s disease dementia (PDD) has both α‐synuclein and Aβ deposits in the brain that may co‐cause the disease onset 15,16 .…”

Section: Introductionmentioning

confidence: 99%

Association of rare variants in neurodegenerative genes with familial Alzheimer’s disease

Zhang

Jiao

Xiao

et al. 2020

Ann Clin Transl Neurol

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Objective: To investigate the impact of rare variants underlying neurodegenerative-related genes to familial Alzheimer's disease (AD). Methods: We performed targeted sequencing of 277 neurodegenerative-related genes on probands from 75 Chinese AD families non-carrying causative mutation of dementia genes. Rare coding variants segregated in families were tested for association in an independent cohort of 506 patients with sporadic AD and 498 cognitively normal controls. East Asians data from the Exome Aggregation Consortium (ExAC) were used as a reference control. Results: A novel rare variant, P410S of PLD3 was found in an early-onset AD family. LRRK2 I2012T, a causative mutation of Parkinson's disease, was identified in another early-onset AD family. Missense variants in ABCA7 (P143S and A1507T) and CR1 (T239M) were significantly associated with familial AD (P = 0.005437, 0.001383, 0.000549), a missense variant in TREM2(S183C) was significantly associated with AD (P = 0.000396) when compared with the East Asian controls in ExAC database. A non-frameshift variant in FUS (G223del) was frequent in AD cases and significantly associated with familial AD (P = 0.008). Interpretation: Multiple rare coding variants of causal and risk neurodegenerative genes were presented in clinically diagnosed AD families that may confer risk of AD. Our data supported that the clinical, pathological, and genetic architectures of AD, PD, and FTD/ALS may overlapping. We propose that targeted sequencing on neurodegenerative-related genes is necessary for genetically unclear AD families.

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Genetic risk for neurodegenerative disorders, and its overlap with cognitive ability and physical function

Cited by 18 publications

References 47 publications

Analysis of 50 Neurodegenerative Genes in Clinically Diagnosed Early-Onset Alzheimer’s Disease

Analysis of 50 Neurodegenerative Genes in Clinically Diagnosed Early-Onset Alzheimer’s Disease

Machine learning suggests polygenic contribution to cognitive dysfunction in amyotrophic lateral sclerosis

Association of rare variants in neurodegenerative genes with familial Alzheimer’s disease

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