PLD3 variants in population studies

Lee, Sven J. van der; Holstege, Henne; Wong, Tsz Hang; Jakobsdóttir, Jóhanna; Bis, Joshua C.; Chouraki, Vincent; Rooij, Jeroen G.J. van; Grove, Megan L.; Smith, Albert V.; Amin, Najaf; Choi, Seung Hoan; Beiser, Alexa; García, Melissa; IJcken, Wilfred F. J. van; Pijnenburg, Yolande A.L.; Louwersheimer, Eva; Brouwer, Rutger W. W.; Hout, Mirjam C G N van den; Oole, Edwin; Eirkisdottir, Gudny; Levy, Daniel; Rotter, Jerome I.; Emilsson, Valur; O’Donnell, Christopher J.; Aspelund, Thor; Uitterlinden, André G.; Launer, Lenore J.; Hofman, Albert; Boerwinkle, Eric; Psaty, Bruce M.; DeStefano, Anita L.; Scheltens, Philip; Seshadri, Sudha; Swieten, John van; Gudnason, Vilmundur; Flier, Wiesje M. van der; Ikram, M. Arfan; Duijn, Cornelia M. van

doi:10.1038/nature14038

Cited by 51 publications

(37 citation statements)

References 14 publications

(16 reference statements)

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“…Exome sequencing of a Turkish family with AD identified a mutation in NOTCH3 (R1231C) (Guerreiro et al, 2012), which has previously been implicated in a subtype of vascular dementia, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). A 2014 study by Cruchaga and colleagues (2014) identified rare coding variants in the chromosome 19q13.2 gene PLD3 , encoding an enzyme of the phospholipase D family, however this association not been observed consistently in follow-up studies (Cruchaga and Goate, 2015; Heilmann et al, 2015; Hooli et al, 2015; Lambert et al, 2015; van der Lee et al, 2015). …”

Section: Genetics Of Alzheimer Disease: Late-onset Alzheimer Disease mentioning

confidence: 99%

Genomic variants, genes, and pathways of Alzheimer's disease: An overview

Naj

Schellenberg

2016

American J of Med Genetics Pt B

165

125

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Alzheimer’s disease (AD) (MIM: 104300) is a highly heritable disease with great complexity in its genetic contributors, and represents the most common form of dementia. With the gradual aging of the world’s population, leading to increased prevalence of AD, and the substantial cost of care for those afflicted, identifying the genetic causes of disease represents a critical effort in identifying therapeutic targets. Here we provide a comprehensive review of genomic studies of AD, from the earliest linkage studies identifying monogenic contributors to early-onset forms of AD to the genome-wide and rare variant association studies of recent years that are being used to characterize the mosaic of genetic contributors to late-onset AD (LOAD), and which have identified approximately ~20 genes with common variants contributing to LOAD risk. In addition, we explore studies employing alternative approaches to identify genetic contributors to AD, including studies of AD-related phenotypes and multi-variant association studies such as pathway analyses. Finally, we introduce studies of next-generation sequencing, which have recently helped identify multiple low-frequency and rare variant contributors to AD, and discuss on-going efforts with next-generation sequencing studies to develop statistically well-powered and comprehensive genomic studies of AD. Through this review, we help uncover the many insights the genetics of AD have provided into the pathways and pathophysiology of AD.

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Section: Genetics Of Alzheimer Disease: Late-onset Alzheimer Disease mentioning

confidence: 99%

Genomic variants, genes, and pathways of Alzheimer's disease: An overview

Naj

Schellenberg

2016

American J of Med Genetics Pt B

165

125

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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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“…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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PLD3 variants in population studies

Cited by 51 publications

References 14 publications

Genomic variants, genes, and pathways of Alzheimer's disease: An overview

Genomic variants, genes, and pathways of Alzheimer's disease: An overview

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

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

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