A genome-wide association study of sporadic ALS in a homogenous Irish population.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive limb or bulbar weakness. Efforts to elucidate the disease-associated loci have to date produced conflicting results. One strategy to improve power in genome-wide studies is to genotype a genetically homogenous population. Such a population exhibits extended linkage disequilibrium (LD) and lower allelic heterogeneity to facilitate disease gene mapping. We sought to identify associated variants for ALS in the Irish, a stable population of relatively homogenous genetic background, and to replicate these findings in larger genetically out-bred populations. We conducted a genome-wide association study in 432 Irish individuals using Illumina HumanHap 550K single nucleotide polymorphism chips. We demonstrated extended LD and increased homogeneity in the Irish sample when compared to an out-bred population of mixed European ancestry. The Irish scan identified 35 loci associated with P-values below 0.0001. For replication, we identified seven chromosomal regions commonly associated in a joint analysis of genome-wide data on 958 ALS cases and 932 controls from Ireland and the previously published datasets from the US and The Netherlands. When pooled, the strongest association was a variant in the gene encoding DPP6, a component of type A neuronal transmembrane potassium channels. Further confirmation of the candidate loci is warranted in additional genome-wide datasets. We have made our individual genotyping data publicly available, contributing to a powerful world-wide resource to refine our understanding of the genetics of sporadic ALS.
Department of Clinical Neurological Sciences, Royal College of Surgeons in Ireland, Dublin 2, Ireland. scronin@rcsi.ie
Simon
S
Cronin
Stephen
S
Berger
Jinhui
J
Ding
Jennifer C
JC
Schymick
Nicole
N
Washecka
Dena G
DG
Hernandez
Matthew J
MJ
Greenway
Daniel G
DG
Bradley
Bryan J
BJ
Traynor
Orla
O
Hardiman
D000368:Aged; D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7; D015331:Cohort Studies; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005828:Genetics, Population; D015894:Genome, Human; D006801:Humans; D007494:Ireland / Q000453:epidemiology; D015810:Linkage Disequilibrium; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010447:Peptide Hydrolases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D015221:Potassium Channels / Q000235:genetics; D011336:Probability; D013223:Statistics as Topic
D009419:Nerve Tissue Proteins; D015221:Potassium Channels; C503535:DPP6 protein, human; D010447:Peptide Hydrolases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases