title: Second-generation Irish genome-wide association study for amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a heritable neurological disease for which the underlying genetic etiology is only partially understood. In Ireland, 83%-90% of cases are currently unexplained. Through large international collaborations, genome-wide association studies (GWASs) have succeeded in identifying a number of genomic loci that contribute toward ALS risk and age at onset. However, for the large proportion of risk that remains unexplained, population specificity of pathogenic variants could interfere with the detection of disease-associated loci. Single-population studies are therefore an important complement to larger international collaborations. In this study, we conduct a GWAS for ALS risk and age at onset in a large Irish ALS case-control cohort, using genome-wide imputation to increase marker density. Despite being adequately powered to detect associations of modest effect size, the study did not identify any locus associated with ALS risk or age at onset above the genome-wide significance threshold. Several speculative associations were, however, identified at loci that have been previously implicated in ALS. The lack of any clear association supports the conclusion that ALS is likely to be caused by multiple rare genetic risk factors. The findings of the present study highlight the importance of ongoing genetic research into the cause of ALS and its likely future challenges.
authors.affiliation: Population Genetics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, College Green, Dublin, Republic of Ireland. Electronic address: mclaugr@tcd.ie.
authors.forename: Russell L
authors.initials: RL
authors.lastname: McLaughlin
authors.affiliation: Population Genetics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, College Green, Dublin, Republic of Ireland.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Kenna
authors.affiliation: Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Republic of Ireland.
authors.forename: Alice
authors.initials: A
authors.lastname: Vajda
authors.affiliation: Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Republic of Ireland.
authors.forename: Peter
authors.initials: P
authors.lastname: Bede
authors.affiliation: Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Republic of Ireland.
authors.forename: Marwa
authors.initials: M
authors.lastname: Elamin
authors.affiliation: Beaumont Hospital, Dublin, Republic of Ireland; Cork University Hospital, Cork, Republic of Ireland.
authors.forename: Simon
authors.initials: S
authors.lastname: Cronin
authors.affiliation: Department of Neurology, Royal Victoria Hospital, Belfast, Northern Ireland.
authors.forename: Colette G
authors.initials: CG
authors.lastname: Donaghy
authors.affiliation: Population Genetics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, College Green, Dublin, Republic of Ireland.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Bradley
authors.affiliation: Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Republic of Ireland.
authors.forename: Orla
authors.initials: O
authors.lastname: Hardiman
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D007494:Ireland / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012306:Risk
keywords: Amyotrophic lateral sclerosis; Genome-wide association study; Imputation; Irish population