Insight into the genetic etiology of Alzheimer's disease: A comprehensive review of the role of rare variants

Hoogmartens, Julie; Cacace, Rita; Broeckhoven, Christine Van

doi:10.1002/dad2.12155

Cited by 58 publications

(73 citation statements)

References 190 publications

(364 reference statements)

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“…We successfully replicated the rare variant based association of TREM2, SORL1, and the APOE locus (TOMM40). However, we were unable to replicate previous associations with APP, PSEN1, PSEN2, ABCA7, BIN1, UNC5C, AKAP9, NOTCH3, CLU, PLGC2, and ABI3 (Supplementary Table 5) 8,9 . Only three of these genes have nominal significance in any of the variant aggregation analyses (pLOF+missense: ABCA7: P=1.56x10 -3 ; ABI3: P=4.3x10 -3 ; PSEN1: P=0.04).…”

Section: Replication Of Known Ad Locicontrasting

confidence: 71%

“…Rare variants (minor allele frequency (MAF) <0.01) contributing to Alzheimer's disease (AD) have frequently been identified, first by family-based linkage studies [1][2][3] , and later by exome sequencing 4,5 and whole gene sequencing 6,7 . Through these methods multiple genes have been reliably associated with AD through rare variants 8,9 . The samples sizes for these studies generally ranges from a few thousand individuals 7 to tens of thousands 10 .…”

Section: Introductionmentioning

confidence: 99%

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Rare Variant Aggregation in 148,508 Exomes Identifies Genes Associated with Proxy Alzheimer’s disease/Dementia

Wightman

Savage

Leeuw

et al. 2021

Preprint

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We generated a proxy Alzheimer's disease phenotype for 148,508 individuals in the UK biobank in order to perform exome-wide rare variant aggregation analyses to identify genes associated with proxy Alzheimer's disease. We identified four genes significantly associated with the proxy phenotype, three of which have been previously associated with clinically diagnosed Alzheimer's disease (SORL1, TREM2, and TOMM40). We identified one gene (HEXA) which has not been previously associated with Alzheimer's disease but is known to contribute to neurodegenerative disease. Here we show that proxy Alzheimer's disease can capture some of the rare variant association signal for Alzheimer's disease and can be used to highlight genes and variants of interest. The proxy phenotype allows for the utilisation of large genetic databases without clinically diagnosed Alzheimer's disease patients to uncover variants and genes that contribute to Alzheimer's disease.

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Section: Replication Of Known Ad Locicontrasting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Rare Variant Aggregation in 148,508 Exomes Identifies Genes Associated with Proxy Alzheimer’s disease/Dementia

Wightman

Savage

Leeuw

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…org/ mutat ions). Altogether, pathogenic mutations in these three genes account for approximately 7% of the EOAD cases, with a 6% contribution from PSEN1 and ~ 1% from the other two genes [23]. The majority of the APP mutations are missense that occurs in or around the Aβ sequence and lead to either overproduction of total Aβ or increased Aβ42/Aβ40 ratio.…”

Section: Early-onset Alzheimer's Diseasementioning

confidence: 99%

“…With the exception of two mutations (p.Ala673Val and one amino acid deletion, p.Glu693Δ), which are autosomal recessive, all other APP mutations are autosomal dominant [16,24]. Two de novo APP duplications have also been described [23]. Overproduction of Aβ is also a key feature in Down syndrome patients who have three copies of the APP containing chromosome 21 and develop a neuropathology that is indistinguishable from AD [24].…”

Section: Early-onset Alzheimer's Diseasementioning

confidence: 99%

Genomics and Functional Genomics of Alzheimer's Disease

Kamboh

2022

Neurotherapeutics

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Alzheimer’s disease (AD) is a complex and multifactorial neurodegenerative disease. Due to its long clinical course and lack of an effective treatment, AD has become a major public health problem in the USA and worldwide. Due to variation in age-at-onset, AD is classified into early-onset (< 60 years) and late-onset (≥ 60 years) forms with early-onset accounting for only 5–10% of all cases. With the exception of a small number of early-onset cases that are afflicted because of high penetrant single gene mutations in APP, PSEN1, and PSEN2 genes, AD is genetically heterogeneous, especially the late-onset form having a polygenic or oligogenic risk inheritance. Since the identification of APOE as the most significant risk factor for late-onset AD in 1993, the path to the discovery of additional AD risk genes had been arduous until 2009 when the use of large genome-wide association studies opened up the discovery gateways that led the identification of ~ 95 additional risk loci from 2009 to early 2022. This article reviews the history of AD genetics followed by the potential molecular pathways and recent application of functional genomics methods to identify the causal AD gene(s) among the many genes that reside within a single locus. The ultimate goal of integrating genomics and functional genomics is to discover novel pathways underlying the AD pathobiology in order to identify drug targets for the therapeutic treatment of this heterogeneous disorder.

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“…In approximately 90% of patients, symptoms manifest after the age of 65 years. The genes APP, PSEN1, and PSEN2 are causally linked with AD, and an increasing number of risk genes are being identified [1]. Major neuropathological hallmarks are extracellular amyloid-β plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau, partnered by gliosis and loss of neurons and synapses.…”

Section: Intergenic Variantsmentioning

confidence: 99%

Uncovering the impact of noncoding variants in neurodegenerative brain diseases

et al. 2022

Self Cite

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Neurodegenerative brain diseases (NBDs) are characterized by cognitive decline and movement impairments caused by neuronal loss in different brain regions. A large fraction of the genetic heritability of NBDs is not explained by the current known mutations. Genome-wide association studies identified novel diseaserisk loci, adding to the genetic basis of NBDs. Many of the associated variants reside in noncoding regions with distinct molecular functions. Genetic variation in these regions can alter functions and contribute to disease pathogenesis. Here, we discuss noncoding variants associated with NBDs. Methods for better functional interpretation of noncoding variation will expand our knowledge of the genetic architecture of NBDs and broaden the routes for therapeutic strategies. Noncoding elements in brain neurodegenerationNeurodegenerative brain diseases (NBDs) are neuropathologically characterized by protein aggregates that prompt progressive deterioration and loss of synaptic function. Pathological hallmarks differ between diseases. The clinical presentation depends on the affected brain regions and includes a range of cognitive and movement impairments (Box 1). Most studies so far have focused on the coding part to identify the genetic cause of NBDs. However, only a part of the heritability of NBDs is explained by coding mutations in genes causally linked with each disease [1-4]. Genome-wide association studies (GWAS) (see Glossary) have identified common genetic variants associated with various NBDs. Approximately 16-36% and 28% of the heritability of Parkinson's disease (PD) and of Alzheimer's disease (AD), respectively, can be explained by GWAS variants [5,6]. A considerable fraction of the variants is located in noncoding genome regions ). Functional modeling of variants has revealed disease-related mechanisms and explained part of the missing genetic etiology.

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Insight into the genetic etiology of Alzheimer's disease: A comprehensive review of the role of rare variants

Cited by 58 publications

References 190 publications

Rare Variant Aggregation in 148,508 Exomes Identifies Genes Associated with Proxy Alzheimer’s disease/Dementia

Rare Variant Aggregation in 148,508 Exomes Identifies Genes Associated with Proxy Alzheimer’s disease/Dementia

Genomics and Functional Genomics of Alzheimer's Disease

Uncovering the impact of noncoding variants in neurodegenerative brain diseases

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