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

Wightman, Douglas P; Savage, Jeanne E.; Leeuw, Christiaan A. de; Jansen, Iris E.; Posthuma, Daniëlle

doi:10.1101/2021.10.17.21265070

Cited by 3 publications

(4 citation statements)

References 43 publications

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“… 63 A similar approach on 148,508 individuals, of whom 22,080 had at least one parent with AD/dementia or AD diagnosis themselves, found a nominally significant enrichment of rare ABCA7 variants in disease, although an OR was not reported. 64 Power in this cohort to find significance may have been decreased by the proxy approach in which not all 22,080 AD‐classified individuals actually developed AD, carried risk variants or may have had parents with other types of dementia. Nevertheless, all these studies strongly imply that rare variants in ABCA7 are risk‐increasing for AD with higher effects than the common genetic risk factors.…”

Section: Abca7 Ad‐associated Variantsmentioning

confidence: 92%

The ABC's of Alzheimer risk gene ABCA7

Duchateau,

Wawrzyniak,

Sleegers

2024

Alzheimer's & Dementia

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Alzheimer's disease (AD) is a growing problem worldwide. Since ABCA7’s identification as a risk gene, it has been extensively researched for its role in the disease. We review its recently characterized structure and what the mechanistic insights teach us about its function. We furthermore provide an overview of identified ABCA7 mutations, their presence in different ancestries and protein domains and how they might cause AD. For ABCA7 PTC variants and a VNTR expansion, haploinsufficiency is proposed as the most likely mode‐of‐action, although splice events could further influence disease risk. Overall, the need to better understand expression of canonical ABCA7 and its isoforms in disease is indicated. Finally, ABCA7's potential functions in lipid metabolism, phagocytosis, amyloid deposition, and the interplay between these three, is described. To conclude, in this review, we provide a comprehensive overview and discussion about the current knowledge on ABCA7 in AD, and what research questions remain.Highlights Alzheimer's risk‐increasing variants in ABCA7 can be found in up to 7% of AD patients. We review the recently characterized protein structure of ABCA7. We present latest insights in genetics, expression patterns, and functions of ABCA7.

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Section: Abca7 Ad‐associated Variantsmentioning

confidence: 92%

The ABC's of Alzheimer risk gene ABCA7

Duchateau,

Wawrzyniak,

Sleegers

2024

Alzheimer's & Dementia

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“…Some genes have multiple loci that are differentially associated with AD, e.g., TREM2, SORL1, ABCA7. Made with reference to three GWAS datasets [11,14,15]. J Exp Neurol.…”

Section: Genetics Of Alzheimer's Diseasementioning

confidence: 99%

An Updated Overview of Alzheimer’s Disease

Prikas

2022

Journal of Experimental Neurology

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“…As a highly heritable disorder, genetic factors contribute significantly to the development of AD. The heritability of AD is approximately 60% to 80%, first estimated from genetic twin studies [3] and later corroborated with large-scale genome-wide association studies (GWAS) [4,5]. Delineating the strong genetic component in AD has become a major objective in AD research, as it provides an opportunity to 1) understand the disease etiology and risks, 2) characterize pathophysiological pathways, and 3) identify biological features as potential diagnostic and prognostic markers.…”

Section: Introductionmentioning

confidence: 98%

“…To date, large-scale GWAS have reported more than 80 putative AD-associated loci and genes [4][5][6][7][8], among which, the Apolipoprotein E (APOE) E4 allele on chromosome 19 has been shown to have the largest genetic risk towards AD. Conventionally, AD GWAS have focused on single time point measurements with less emphasis on dynamic phenotypes in a repeated measures setting.…”

Section: Introductionmentioning

confidence: 99%

Detecting time-varying genetic effects in Alzheimer’s disease using a longitudinal GWAS model

Zhuang,

Xu,

Amei

et al. 2023

Preprint

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Background. The development and progression of Alzheimer's disease (AD) is a complex process that can change over time, during which genetic influences on phenotypes may also fluctuate. Incorporating longitudinal phenotypes in genome wide association studies (GWAS) could help unmask genetic loci with time-varying effects. In this study, we incorporated a varying coefficient test in a longitudinal GWAS model to identify single nucleotide polymorphisms (SNPs) that may have time- or age- dependent effects in AD. Methods. Genotype data from 1,877 participants in the Alzheimer's Neuroimaging Data Initiative (ADNI) were imputed using the Haplotype Reference Consortium (HRC) panel, resulting in 9,573,130 SNPs. Subjects' longitudinal impairment status at each visit was considered as a binary and clinical phenotype. Participants' composite standardized uptake value ratio (SUVR) derived from each longitudinal amyloid PET scan was considered as a continuous and biological phenotype. The retrospective varying coefficient mixed model association test (RVMMAT) was used in longitudinal GWAS to detect time-varying genetic effects on the impairment status and SUVR measures. Post-hoc analyses were performed on genome-wide significant SNPs, including 1) pathway analyses; 2) age-stratified genotypic comparisons and regression analyses; and 3) replication analyses using data from the National Alzheimer's Coordinating Center (NACC). Results. Our model identified 244 genome-wide significant SNPs that revealed time-varying genetic effects on the clinical impairment status in AD; among which, 12 SNPs on chromosome 19 were successfully replicated using data from NACC. Post-hoc age-stratified analyses indicated that for most of these 244 SNPs, the maximum genotypic effect on impairment status occurred between 70 to 80 years old, and then declined with age. Our model further identified 73 genome-wide significant SNPs associated with the temporal variation of amyloid accumulation. For these SNPs, an increasing genotypic effect on PET-SUVR was observed as participants' age increased. Functional pathway analyses on significant SNPs for both phenotypes highlighted the involvement and disruption of immune responses- and neuroinflammation- related pathways in AD. Conclusion. We demonstrate that longitudinal GWAS models with time-varying coefficients can boost the statistical power in AD-GWAS. In addition, our analyses uncovered potential time-varying genetic variants on repeated measurements of clinical and biological phenotypes in AD.

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

Cited by 3 publications

References 43 publications

The ABC's of Alzheimer risk gene ABCA7

The ABC's of Alzheimer risk gene ABCA7

An Updated Overview of Alzheimer’s Disease

Detecting time-varying genetic effects in Alzheimer’s disease using a longitudinal GWAS model

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