Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10−8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10−4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10−11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities
The data were incorporated into a meta-analysis with a large-scale genome-wide association studies (GWAS) involving 20,806 patients diagnosed with ALS and 53,439 control subjects of European ancestry[6]
The region in ACSL5 was discovered as a novel risk locus for sporadic ALS by meta-analysis between Japanese and European datasets and was replicated in the Chinese dataset and another Japanese dataset
Summary
Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10−4). Using a gene-based analysis of the full multiethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3 These results advance our understanding of the genetic basis of sporadic ALS. We report analyses of novel genome-wide association study data of 1173 sporadic ALS cases and 8925 normal controls in a Japanese population and meta-analysis with the largest ALS study in a European population[6]. The discovery of novel risk genes advances our understanding of ALS aetiology
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