Overlap between Parkinson disease and Alzheimer disease in
            <i>ABCA7</i>
            functional variants

Nuytemans, Karen; Maldonado, Lizmarie; Ali, Aleena; John-Williams, Krista; Beecham, Gary W.; Martin, Eden R.; Scott, William K.; Vance, Jeffery M.

doi:10.1212/nxg.0000000000000044

Cited by 33 publications

(32 citation statements)

References 30 publications

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“…The detection of ABCA7 putative functional variants in participants with PSP, VaD, DLBD, and PA/AGD in this study, in addition to their recent implication in Parkinson disease, 7 suggests that this gene may be contributory to both AD and non-AD neuropathologies. Given evidence of its pleiotropic functions 12,13 including phagocytosis, cell signaling, lipid homeostasis, and Aβ metabolism, it is likely that ABCA7 dysfunction may contribute to both AD-specific and non-AD neuropathologies.…”

Section: Discussionmentioning

confidence: 55%

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ABCA7 loss-of-function variants, expression, and neurologic disease risk

et al. 2017

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Objective:To investigate and characterize putative “loss-of-function” (LOF) adenosine triphosphate–binding cassette, subfamily A member 7 (ABCA7) mutations reported to associate with Alzheimer disease (AD) risk.Methods:We genotyped 6 previously reported ABCA7 putative LOF variants in 1,465 participants with AD, 381 participants with other neuropathologies (non-AD), and 1,043 controls and assessed the overall mutational burden for association with different diagnosis groups. We measured brain ABCA7 protein and messenger RNA (mRNA) levels using Western blot and quantitative PCR, respectively, in 11 carriers of the 3 most common variants, and sequenced all 47 ABCA7 exons in these participants to screen for other coding variants.Results:At least one of the investigated variants was identified in 45 participants with late-onset Alzheimer disease, 12 participants with other neuropathologies, and 11 elderly controls. Association analysis revealed a significantly higher burden of these variants in participants with AD (p = 5.00E-04) and those with other neuropathologies (p = 8.60E-03) when compared with controls. Concurrent analysis of brain ABCA7 mRNA and protein revealed lower protein but not mRNA in p.L1403fs carriers, lower mRNA but not protein in p.E709fs carriers, and additional deleterious mutations in some c.5570+5G>C carriers.Conclusions:Our results suggest that LOF may not be a common mechanism for these ABCA7 variants and expand the list of neurologic diseases enriched for them.

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Section: Discussionmentioning

confidence: 55%

“…These initial studies were followed by replications and/or identification of additional rare ABCA7 putative LOF mutations in other AD cohorts, 4–6 in addition to one study in Parkinson disease. 7 …”

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confidence: 99%

ABCA7 loss-of-function variants, expression, and neurologic disease risk

et al. 2017

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“…Numerous studies have hinted at a shared genetic basis among neurodegenerative diseases. 43,44 Due to the convenience and efficiency of LDSC and the wide accessibility of GWAS summary statistics, several attempts have been made to estimate genetic correlation between neurodegenerative diseases. 9,45 To date, these efforts have not been as successful as similar studies on psychiatric diseases and immunerelated traits.…”

Section: Discussionmentioning

confidence: 99%

A Powerful Approach to Estimating Annotation-Stratified Genetic Covariance via GWAS Summary Statistics

et al. 2017

The American Journal of Human Genetics

163

215

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Despite the success of large-scale genome-wide association studies (GWASs) on complex traits, our understanding of their genetic architecture is far from complete. Jointly modeling multiple traits' genetic profiles has provided insights into the shared genetic basis of many complex traits. However, large-scale inference sets a high bar for both statistical power and biological interpretability. Here we introduce a principled framework to estimate annotation-stratified genetic covariance between traits using GWAS summary statistics. Through theoretical and numerical analyses, we demonstrate that our method provides accurate covariance estimates, thereby enabling researchers to dissect both the shared and distinct genetic architecture across traits to better understand their etiologies. Among 50 complex traits with publicly accessible GWAS summary statistics (N≈ 4.5 million), we identified more than 170 pairs with statistically significant genetic covariance. In particular, we found strong genetic covariance between late-onset Alzheimer disease (LOAD) and amyotrophic lateral sclerosis (ALS), two major neurodegenerative diseases, in single-nucleotide polymorphisms (SNPs) with high minor allele frequencies and in SNPs located in the predicted functional genome. Joint analysis of LOAD, ALS, and other traits highlights LOAD's correlation with cognitive traits and hints at an autoimmune component for ALS.

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“…While some studies have not uncovered any disease-associated variants, others were able to identify and functionally validate rare disease-associated variants (Farlow et al 2016;Jansen et al 2017;Sandor et al 2017;Shulskaya et al 2018;Germer et al 2019). Others point towards risk variants that are shared across PD and Alzheimer's disease (AD) (Nuytemans et al 2016). Importantly, none of these studies identified the same rare coding variants.…”

Section: Strategies To Uncover Missing Heritabilitymentioning

confidence: 99%

Missing heritability in Parkinson’s disease: the emerging role of non-coding genetic variation

2020

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Parkinson's disease (PD) is a neurodegenerative disorder caused by a complex interplay of genetic and environmental factors. For the stratification of PD patients and the development of advanced clinical trials, including causative treatments, a better understanding of the underlying genetic architecture of PD is required. Despite substantial efforts, genome-wide association studies have not been able to explain most of the observed heritability. The majority of PD-associated genetic variants are located in non-coding regions of the genome. A systematic assessment of their functional role is hampered by our incomplete understanding of genotype-phenotype correlations, for example through differential regulation of gene expression. Here, the recent progress and remaining challenges for the elucidation of the role of non-coding genetic variants is reviewed with a focus on PD as a complex disease with multifactorial origins. The function of gene regulatory elements and the impact of non-coding variants on them, and the means to map these elements on a genome-wide level, will be delineated. Moreover, examples of how the integration of functional genomic annotations can serve to identify disease-associated pathways and to prioritize disease-and cell type-specific regulatory variants will be given. Finally, strategies for functional validation and considerations for suitable model systems are outlined. Together this emphasizes the contribution of rare and common genetic variants to the complex pathogenesis of PD and points to remaining challenges for the dissection of genetic complexity that may allow for better stratification, improved diagnostics and more targeted treatments for PD in the future.

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Overlap between Parkinson disease and Alzheimer disease in ABCA7 functional variants

Cited by 33 publications

References 30 publications

ABCA7 loss-of-function variants, expression, and neurologic disease risk

ABCA7 loss-of-function variants, expression, and neurologic disease risk

A Powerful Approach to Estimating Annotation-Stratified Genetic Covariance via GWAS Summary Statistics

Missing heritability in Parkinson’s disease: the emerging role of non-coding genetic variation

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