Search

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.

The hexonucleotide repeat expansion 'GGGGCC' at the C9ORF72 gene has been strongly linked with amyotrophic lateral sclerosis and frontotemporal dementia. There is some evidence for clinical and genetic overlap between frontotemporal dementia and schizophrenia. Here, we genotyped the repeat at C9ORF72 in a large Irish psychosis case-control sample (n = 2477). We found no carriers of >30 repeats. We found 7 samples with >22 repeats, 2 schizophrenia cases and 5 controls, but overall we observed no difference in the distribution of the repeat between our case and control samples. By using genome-wide association data to phase haplotypes at this gene, we investigated if carriers of the repeat expansion arose from a single common founder. All samples that carry 17 or more repeats also carry the founder haplotype and overall there is a very strong correlation between repeat length and the founder haplotype (Spearman rho = 0.714, p < 0.001). Our study provides further evidence to bolster the claim that carriers of the repeat expansion at C9ORF72 arose from a single common founder.

Mutations in UBQLN2 have been shown to be a cause of dominant X-linked amyotrophic lateral sclerosis (ALS). Occurrences of mutations in this gene vary across ALS populations. We screened UBQLN2 for mutations in a final cohort of 150 Irish ALS patients. Individuals who were from families with male-to-male transmission or who carried pathogenic hexanucleotide repeat expansions in C9orf72 were excluded. Apart from common synonymous variation, no sequence variants in UBQLN2 were observed. Mutations in UBQLN2 are therefore not a frequent cause of ALS in the Irish population.

The H63D polymorphism in HFE has frequently been associated with susceptibility to amyotrophic lateral sclerosis (ALS). Regarding the role of HFE in iron homeostasis, iron accumulation is considered an important process in ALS. Furthermore, novel therapeutic strategies are being developed targeting this process. Evidence for this genetic association is, however, limited to several small studies. For this reason we studied the H63D polymorphism in a large European cohort including 3962 ALS patients and 5072 control subjects from 7 countries. After meta-analysis of previous studies and current findings we conclude that the H63D polymorphism in HFE is not associated with susceptibility to ALS, age at disease onset, or survival. ispartof: Neurobiology of aging vol:34 issue:5 pages:1517- ispartof: location:United States status: published