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Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study.

https://arctichealth.org/en/permalink/ahliterature141194
Source
Lancet Neurol. 2010 Oct;9(10):978-85
Publication Type
Article
Date
Oct-2010
Author
Hannu Laaksovirta
Terhi Peuralinna
Jennifer C Schymick
Sonja W Scholz
Shaoi-Lin Lai
Liisa Myllykangas
Raimo Sulkava
Lilja Jansson
Dena G Hernandez
J Raphael Gibbs
Michael A Nalls
David Heckerman
Pentti J Tienari
Bryan J Traynor
Author Affiliation
Department of Neurology, Helsinki University Central Hospital and Molecular Neurology Programme, Biomedicum, University of Helsinki, Helsinki, Finland.
Source
Lancet Neurol. 2010 Oct;9(10):978-85
Date
Oct-2010
Language
English
Publication Type
Article
Keywords
Adult
Aged
Aged, 80 and over
Amyotrophic Lateral Sclerosis - enzymology - epidemiology - genetics
Chromosomes, Human, Pair 9 - genetics
Cohort Studies
Female
Finland - epidemiology
Genetic Loci - genetics
Genetic Predisposition to Disease - epidemiology - genetics
Genome-Wide Association Study - methods
Humans
Male
Middle Aged
Polymorphism, Single Nucleotide - genetics
Superoxide Dismutase - genetics
Young Adult
Abstract
The genetic cause of amyotrophic lateral sclerosis (ALS) is not well understood. Finland is a well suited location for a genome-wide association study of ALS because the incidence of the disease is one of the highest in the world, and because the genetic homogeneity of the Finnish population enhances the ability to detect risk loci. We aimed to identify genetic risk factors for ALS in the Finnish population.
We did a genome-wide association study of Finnish patients with ALS and control individuals by use of Illumina genome-wide genotyping arrays. DNA was collected from patients who attended an ALS specialty clinic that receives referrals from neurologists throughout Finland. Control samples were from a population-based study of elderly Finnish individuals. Patients known to carry D90A alleles of the SOD1 gene (n=40) were included in the final analysis as positive controls to assess whether our genome-wide association study was able to detect an association signal at this locus.
We obtained samples from 442 patients with ALS and 521 control individuals. After quality control filters were applied, 318?167 single nucleotide polymorphisms (SNPs) from 405 people with ALS and 497 control individuals were available for analysis. We identified two association peaks that exceeded genome-wide significance. One was located on chromosome 21q22 (rs13048019, p=2·58×10(-8)), which corresponds to the autosomal recessive D90A allele of the SOD1 gene. The other was detected in a 232 kb block of linkage disequilibrium (rs3849942, p=9·11×10(-11)) in a region of chromosome 9p that was previously identified in linkage studies of families with ALS. Within this region, we defined a 42-SNP haplotype that was associated with significantly increased risk of ALS (p=7·47×10(-33) when people with familial ALS were compared with controls, odds ratio 21·0, 95% CI 11·2-39·1) and which overlapped with an association locus recently reported for frontotemporal dementia. For the 93 patients with familial ALS, the population attributable risk for the chromosome 9p21 locus was 37·9% (95% CI 27·7-48·1) and that for D90A homozygosity was 25·5% (16·9-34·1).
The chromosome 9p21 locus is a major cause of familial ALS in the Finnish population. Our data suggest the presence of a founder mutation for chromosome 9p21-linked ALS. Furthermore, the overlap with the risk haplotype recently reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases.
National Institutes of Health and National Institute on Aging, Microsoft Research, ALS Association, Helsinki University Central Hospital, Finnish Academy, Finnish Medical Society Duodecim, and Kuopio University.
Notes
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PubMed ID
20801718 View in PubMed
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A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.

https://arctichealth.org/en/permalink/ahliterature131029
Source
Neuron. 2011 Oct 20;72(2):257-68
Publication Type
Article
Date
Oct-20-2011
Author
Alan E Renton
Elisa Majounie
Adrian Waite
Javier Simón-Sánchez
Sara Rollinson
J Raphael Gibbs
Jennifer C Schymick
Hannu Laaksovirta
John C van Swieten
Liisa Myllykangas
Hannu Kalimo
Anders Paetau
Yevgeniya Abramzon
Anne M Remes
Alice Kaganovich
Sonja W Scholz
Jamie Duckworth
Jinhui Ding
Daniel W Harmer
Dena G Hernandez
Janel O Johnson
Kin Mok
Mina Ryten
Danyah Trabzuni
Rita J Guerreiro
Richard W Orrell
James Neal
Alex Murray
Justin Pearson
Iris E Jansen
David Sondervan
Harro Seelaar
Derek Blake
Kate Young
Nicola Halliwell
Janis Bennion Callister
Greg Toulson
Anna Richardson
Alex Gerhard
Julie Snowden
David Mann
David Neary
Michael A Nalls
Terhi Peuralinna
Lilja Jansson
Veli-Matti Isoviita
Anna-Lotta Kaivorinne
Maarit Hölttä-Vuori
Elina Ikonen
Raimo Sulkava
Michael Benatar
Joanne Wuu
Adriano Chiò
Gabriella Restagno
Giuseppe Borghero
Mario Sabatelli
David Heckerman
Ekaterina Rogaeva
Lorne Zinman
Jeffrey D Rothstein
Michael Sendtner
Carsten Drepper
Evan E Eichler
Can Alkan
Ziedulla Abdullaev
Svetlana D Pack
Amalia Dutra
Evgenia Pak
John Hardy
Andrew Singleton
Nigel M Williams
Peter Heutink
Stuart Pickering-Brown
Huw R Morris
Pentti J Tienari
Bryan J Traynor
Author Affiliation
Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Source
Neuron. 2011 Oct 20;72(2):257-68
Date
Oct-20-2011
Language
English
Publication Type
Article
Keywords
Alleles
Amyotrophic Lateral Sclerosis - genetics
Chromosomes, Human, Pair 9
Female
Finland
Frontotemporal Dementia - genetics
Genetic Predisposition to Disease
Genotype
Haplotypes
Humans
Male
Microsatellite Repeats
Pedigree
Polymorphism, Single Nucleotide
Abstract
The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.
Notes
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PubMed ID
21944779 View in PubMed
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