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RESEARCH PRODUCT
A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis
Claudia CaponnettoCynthia CrewsStephen BergerFederica TorriAdriano ChiòStephen J. ChanockNicole WasheckaLuigi FerrucciEugene Z. OddoneJeffrey D. RothsteinElizabeth M. C. FisherAndrea CalvoSonja W. ScholzSonja W. ScholzIlaria BartolomeiShiao Lin LaiShiao Lin LaiGilles ThomasMaria Rosaria MonsurròJames R. ConnorH.-erich WichmannFederica LombardoDavid J. HunterDavid J. HunterMario SabatelliGiovanni Luigi MancardiJennifer C. SchymickJennifer C. SchymickDalia KasperaviciuteMike A. NallsKevin TalbotSilke SchmidtJack M. GuralnikJinhui DingBryan J. TraynorBryan J. TraynorGabriele SicilianoLucie BruijnAmelia ConteKalliopi MarinouSibylle JabonkaGabriella RestagnoAngela BrittonGabriele MoraGabriele MoraChristian GiegerDietrich A. StephanJessica MandrioliTravis DunkleyFabio GianniniFabrizio SalviZachary SimmonsLydia Coulter KweeRoberto MutaniDena G. HernandezDena G. HernandezPatrizia SolaIan RaffertyRichard W. OrrellMichael SendtnerAndrew B. SingletonGioacchino TedeschiMarcus BeckSampath ArepalliVincenzo La BellaSara LupoliHon Chung FungHon Chung FungStefania BandinelliJohn HardyJohn HardyErik P. PioroFabio MacciardiStefania BattistiniCecilia CarlesiFrancesca ValentinoJ. Raphael GibbsJ. Raphael Gibbssubject
amyotrophic lateral sclerosisLinkage disequilibriumPopulationamyotrophic lateral sclerosis; genetics; GWASingle-nucleotide polymorphismGenome-wide association studyBiologyGWAPolymorphism Single Nucleotide03 medical and health sciences0302 clinical medicineGenotypeGeneticsmedicineHumansPolymorphismAmyotrophic lateral sclerosiseducationMolecular BiologyGenetics (clinical)030304 developmental biologyGenetics0303 health scienceseducation.field_of_studyGenomeSLA wide genome screeningGenome HumanAssociation Studies ArticlesCase-control studySingle NucleotideGeneral MedicineOdds ratiomedicine.diseaseSettore MED/26 - NEUROLOGIAAmyotrophic Lateral Sclerosis; genetics Case-Control Studies Genome; Human Genome-Wide Association Study Humans Polymorphism; Single NucleotideCase-Control Studies030217 neurology & neurosurgeryHumanGenome-Wide Association Studydescription
The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 x 10(-7) and 1.16 x 10(-6)], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2009-04-01 | Human Molecular Genetics |