Dataset Information

The role of variation at A?PP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease.

ABSTRACT: Rare mutations in A?PP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at A?PP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.

SUBMITTER: Gerrish A

PROVIDER: S-EPMC4118466 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease.

Gerrish Amy A Russo Giancarlo G Richards Alexander A Moskvina Valentina V Ivanov Dobril D Harold Denise D Sims Rebecca R Abraham Richard R Hollingworth Paul P Chapman Jade J Hamshere Marian M Pahwa Jaspreet Singh JS Dowzell Kimberley K Williams Amy A Jones Nicola N Thomas Charlene C Stretton Alexandra A Morgan Angharad R AR Lovestone Simon S Powell John J Proitsi Petroula P Lupton Michelle K MK Brayne Carol C Rubinsztein David C DC Gill Michael M Lawlor Brian B Lynch Aoibhinn A Morgan Kevin K Brown Kristelle S KS Passmore Peter A PA Craig David D McGuinness Bernadette B Todd Stephen S Johnston Janet A JA Holmes Clive C Mann David D Smith A David AD Love Seth S Kehoe Patrick G PG Hardy John J Mead Simon S Fox Nick N Rossor Martin M Collinge John J Maier Wolfgang W Jessen Frank F Kölsch Heike H Heun Reinhard R Schürmann Britta B van den Bussche Hendrik H Heuser Isabella I Kornhuber Johannes J Wiltfang Jens J Dichgans Martin M Frölich Lutz L Hampel Harald H Hüll Michael M Rujescu Dan D Goate Alison M AM Kauwe John S K JS Cruchaga Carlos C Nowotny Petra P Morris John C JC Mayo Kevin K Livingston Gill G Bass Nicholas J NJ Gurling Hugh H McQuillin Andrew A Gwilliam Rhian R Deloukas Panagiotis P Davies Gail G Harris Sarah E SE Starr John M JM Deary Ian J IJ Al-Chalabi Ammar A Shaw Christopher E CE Tsolaki Magda M Singleton Andrew B AB Guerreiro Rita R Mühleisen Thomas W TW Nöthen Markus M MM Moebus Susanne S Jöckel Karl-Heinz KH Klopp Norman N Wichmann H-Erich HE Carrasquillo Minerva M MM Pankratz V Shane VS Younkin Steven G SG Jones Lesley L Holmans Peter A PA O'Donovan Michael C MC Owen Michael J MJ Williams Julie J

Journal of Alzheimer's disease : JAD 20120101 2

Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 ...[more]

PMID: 22027014

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Project description:BackgroundAmyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series.Methods and findingsWe report here a novel update (2012-2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers-total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid β (Aβ)42-in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification.ConclusionsOur findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.

Dataset Information

The role of variation at A?PP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease.

Publications

The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease.

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