A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis

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.

Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

“…Interestingly, we observed for the first time, a genome-wide significant common variant association signal within the NEK1 locus, where NEK1 was previously shown to harbor rare variants associated with ALS . The recently reported association at the ACSL5-ZDHHC6 locus 10,18 did not reach the threshold for genome-wide significance (rs58854276, PEUR = 5.4 × 10 -5 , PASN = 4.9 × 10 -7 , Pcomb = 6.5 × -8 , Supplementary Figure 17, Supplementary Table 19), despite that our analysis includes all data from the original discovery studies. Table 1.…”

“…The European ancestries analysis identified 12 loci reaching genomewide significance (P < 5.0 × 10 -8 , Supplementary Figure 1). Of these, 8 were present in GWAS of ALS in Asian ancestries 8,10 and all showed a consistent direction of effects (Pbinom = 3.9 × 10 -3 ). The genetic overlap between ALS risk in European and Asian ancestries resulted in a trans-ancestry genetic correlation of 0.57 (SE = 0.28) for genetic effect and 0.58 (SE = 0.30) for genetic impact, which were not statistically significant different from unity (P = 0.13 and 0.16, respectively).…”

Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

“…3,4 To date, partially overlapping GWASs have identified up to six genome-wide significant loci, explaining a small proportion of the genetic susceptibility to ALS. [5][6][7][8][9][10] Some of these loci found in GWAS harbor rare variants with large effects also present in familial cases (e.g. C9orf72 and TBK1).…”

Pathogenic Genome Signatures That Damage Motor Neurons in Amyotrophic Lateral Sclerosis

“…ACSL5 can induce A1 astrocytes, leading to motor neuron death and ALS progression. Overexpression of ACSL5, similar to the previously discovered gene GPX3, is associated with rapid weight loss in humans [8,20]. Although the mentioned genes above have been identified as ALS associated genes, the study on their contribution to ALS pathogenesis is still limited.…”

“…Many genetic variants that contribute to the missing heritability of ALS are yet to be discovered. Nowadays, the number of studies on finding novel ALS genes and their functions on disease pathogenesis is growing quickly [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. This review discusses the current genetic understanding and landscape of ALS and summarizes its disease mechanisms.…”