PLD3 in non-familial Alzheimer's disease

Heilmann, Stefanie; Drichel, Dmitriy; Clarimón, Jordi; Fernández, Victoria; Lacour, André; Wagner, Holger; Thelen, M.; Hernández, Isabel; Fortea, Juan; Alegret, Montserrat; Blesa, Rafael; Mauleón, Ana; Roca, Maiteé Rosende; Kornhuber, Johannes; Peters, Oliver; Heun, Reinhard; Frölich, Lutz; Hüll, Michael; Heneka, Michael T.; Rüther, Eckart; Riedel‐Heller, Steffi G.; Scherer, Martin; Wiltfang, Jens; Jessen, Frank; Becker, Tim; Tárraga, Lluís; Boada, Merçé; Maier, Wolfgang; Lleó, Alberto; Ruiz, Agustín; Nöthen, Markus M.; Ramı́rez, Alfredo

doi:10.1038/nature14039

Cited by 57 publications

(46 citation statements)

References 14 publications

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“…The most associated variant, p.V232M, was originally found to be associated with a 2- to 3-fold increase in AD risk [16]. Recent evidence and lack of replication in large cohorts make this finding controversial [17,18,19,20,21]. Associations at the MTHFR and CYP2D6 loci have also been observed through meta-analysis of GWAS data; however, association with disease remains controversial, and the associated odds ratios are small [22,23,24].…”

Section: Genetic Findingsmentioning

confidence: 99%

Defining the Genetic Architecture of Alzheimer's Disease: Where Next?

Sims

Williams²

2015

Neurodegener Dis

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Background: Late-onset Alzheimer's disease is a genetically complex disorder. For 17 years, APOE was the only known susceptibility gene for disease. Through mostly genome-wide association studies, 25 loci are now known to associate with late-onset Alzheimer's disease. These susceptibility loci are not randomly distributed with respect to their functions. In fact, pathway analysis implicates significant enrichment of immunity, endocytosis, cholesterol metabolism, and ubiquitination in disease. Summary: Twenty-five loci have now been reliably shown to associate with Alzheimer's disease. However, a significant proportion of genetic variation in disease pathology is yet to be detected. Rare variation is being investigated through exome chip and next-generation sequencing experiments, which have already identified new protective and risk variants. Using a polygenic risk score approach, it is now possible to identify population groups with the greatest and fewest biological susceptibilities to disease. This method has proved more effective in predicting disease status than individual, genome-wide significant variants of small/moderate effect. Future studies will establish the specific functional changes that contribute to disease by piloting novel cellular modelling techniques using reprogrammed induced pluripotent stem cells from individuals with selected risk profiles. This will allow a variety of models to be produced to help understand disease mechanisms and test new drug therapies. Key Messages: Alzheimer's disease is a polygenic trait that has been linked to deficits in immunity, endocytosis, cholesterol metabolism and ubiquitination. Future work will focus on identifying rare disease susceptibility loci, unpicking the functional significance of the known risk loci and piloting novel cellular modelling techniques.

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Section: Genetic Findingsmentioning

confidence: 99%

Defining the Genetic Architecture of Alzheimer's Disease: Where Next?

Sims

Williams²

2015

Neurodegener Dis

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“…The association results were challenged by four subsequent reports [96][97][98][99] . In one of them, a signal was observed but with borderline significance ( p = 0.03) [99] ; in another one, a weak signal was also noticed ( p = 0.02) but it was due to overtransmission of the variant to unaffected relatives [96] .…”

Section: Other Candidate Genes: Pld3 Unc5c and Akap9mentioning

confidence: 73%

“…In one of them, a signal was observed but with borderline significance ( p = 0.03) [99] ; in another one, a weak signal was also noticed ( p = 0.02) but it was due to overtransmission of the variant to unaffected relatives [96] . The other two studies gave nonsignificant results.…”

Section: Other Candidate Genes: Pld3 Unc5c and Akap9mentioning

confidence: 99%

From Common to Rare Variants: The Genetic Component of Alzheimer Disease

Nicolas

Charbonnier²,

Campion³

2016

Hum Hered

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Alzheimer disease (AD) is a remarkable example of genetic heterogeneity. Extremely rare variants in the APP, PSEN1, or PSEN2 genes, or duplications of the APP gene cause autosomal dominant forms, generally with complete penetrance by the age of 65 years. Nonautosomal dominant forms are considered as a complex disorder with a high genetic component, whatever the age of onset. Although genetically heterogeneous, AD is defined by the same neuropathological criteria in all configurations. According to the amyloid cascade hypothesis, the Aβ peptide, which aggregates in AD brains, is a key player. APP, PSEN1, or PSEN2 gene mutations increase the production of more aggregation-prone forms of the Aβ peptide, triggering the pathological process. Several risk factors identified in association studies hit genes involved in Aβ production/secretion, aggregation, clearance, or toxicity. Among them, the APOE ε4 allele is a rare example of a common allele with a large effect size, the ORs ranging from 4 to 11-14 for heterozygous and homozygous carriers, respectively. In addition, genome-wide association studies have identified more than two dozen loci with a weak but significant association, the OR of the at-risk allele ranging from 1.08 to 1.30. Recently, the use of massive parallel sequencing has enabled the analysis of rare variants in a genome-wide manner. Two rare variants have been nominally associated with AD risk or protection (TREM2 p.R47H, MAF approximately 0.002, OR approximately 4 and APP p.A673T, MAF approximately 0.0005, OR approximately 0.2). Association analyses at the gene level identified rare loss-of-function and missense, predicted damaging, variants (MAF <0.01) in the SORL1 and ABCA7 genes associated with a moderate relative risk (OR approximately 5 and approximately 2.8, respectively). Although the latter analyses revealed association signals with moderately rare variants by collapsing them, the power to detect genes hit by extremely rare variants is still limited. An alternative approach is to consider the de novo paradigm, stating that de novo variants may contribute to AD genetics in sporadic patients. Here, we critically review AD genetics reports with a special focus on rare variants.

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“…Another study reported that PLD3 was expressed at significantly lower levels in neurons from AD brains compared with non-AD brains [141]. However, several follow up genomic studies failed to replicate the impact of PLD3 risk variants in sporadic AD cases [142,143]. More validation studies are needed to clarify functional relevance of PLD3 in AD pathogenesis.…”

Section: Phospholipase Dmentioning

confidence: 99%

Alzheimer’s Disease Risk Genes and Lipid Regulators

Gaamouch

Jing

Xia

et al. 2016

JAD

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Abstract. Brain lipid homeostasis plays an important role in Alzheimer's disease (AD) and other neurodegenerative disorders. Aggregation of amyloid-␤ peptide is one of the major events in AD. The complex interplay between lipids and amyloid-␤ accumulation has been intensively investigated. The proportions of lipid components including phospholipids, sphingolipids, and cholesterol are roughly similar across different brain regions under physiological conditions. However, disruption of brain lipid homeostasis has been described in AD and implicated in disease pathogenesis. Moreover, studies suggest that analysis of lipid composition in plasma and cerebrospinal fluid could improve our understanding of the disease development and progression, which could potentially serve as disease biomarkers and prognostic indicators for AD therapies. Here, we summarize the functional roles of AD risk genes and lipid regulators that modulate brain lipid homeostasis including different lipid species, lipid complexes, and lipid transporters, particularly their effects on amyloid processing, clearance, and aggregation, as well as neuro-toxicities that contribute to AD pathogenesis.

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PLD3 in non-familial Alzheimer's disease

Abstract: BRIEF COMMUNICATIONS ARISING G2015 Macmillan Publishers Limited. All rights reserved E 2 | N AT U R E | V O L 5 2 0 | 2 A P R I L 2 0 1 5 of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at

Cited by 57 publications

References 14 publications

Defining the Genetic Architecture of Alzheimer's Disease: Where Next?

Defining the Genetic Architecture of Alzheimer's Disease: Where Next?

From Common to Rare Variants: The Genetic Component of Alzheimer Disease

Alzheimer’s Disease Risk Genes and Lipid Regulators

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