Genome-wide Meta-analysis Finds the ACSL5-ZDHHC6 Locus Is Associated with ALS and Links Weight Loss to the Disease Genetics

Abstract

Highlights d Cross-ethnic meta-analysis finds an association between the ACSL5-ZDHHC6 locus and ALS d The ACSL5-ZDHHC6 association is replicated in an independent Australian cohort d ACSL5-ZDHHC6 lead SNP is in ACSL5 and is an eQTL of ZDHHC6 in brain tissues d ACSL5 SNPs might have an effect on fat-free mass in ALS patients

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.…”

An Integrative Transcriptome-Wide Analysis of Amyotrophic Lateral Sclerosis for the Identification of Potential Genetic Markers and Drug Candidates

“…Among the 55 TWAS genes, 35 were estimated to be up-regulated in ALS (Z-score > 0), whereas 20 to be down-regulated (Z-score < 0) ( Supplementary Table S2 ). Twenty out of the 27 uniquely identified genes have been reported as ALS-associated genes in previous studies [ 5 , 21 , 22 , 23 , 24 ]. In particular, the top three of those 27 genes, i.e., C9orf72-SMCR8 complex subunit ( C9orf72 ) ( p -value = 1.65 × 10 −28 and FDR = 4.03 × 10 −23 ), sec1 family domain containing 1 (SCFD1) ( p -value = 6.65 × 10 −8 and FDR = 5.07 × 10 −4 ), and ataxin 3 ( ATXN3 ) ( p -value = 3.14 × 10 −6 and FDR = 6.73 × 10 −3 ), are well-known ALS-associated genes [ 5 , 16 , 17 ].…”

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.…”

“…The remaining ALS patients, with no clear genetic linkage, are called sporadic ALS (sALS) [ 7 ]. At present, mutations in over 50 genes have been shown to contribute to the ALS pathogenesis [ 8 , 9 ]. Some of them such as SOD1 , C9orf72 , FUS , and TARDBP were shown to present deleterious mutations, while other variants mostly found by association studies rarely occur in the less frequent genes [ 8 , 9 , 10 ].…”

“…At present, mutations in over 50 genes have been shown to contribute to the ALS pathogenesis [ 8 , 9 ]. Some of them such as SOD1 , C9orf72 , FUS , and TARDBP were shown to present deleterious mutations, while other variants mostly found by association studies rarely occur in the less frequent genes [ 8 , 9 , 10 ]. Several studies have identified oxidative stress, glutamate excitotoxicity, apoptosis, neurofilament dysfunction, protein misfolding and aggregation, impairment of RNA processing, disrupted axonal transport, endosomal trafficking dysfunction, inflammation, and mitochondrial impairment as the molecular pathways which lead to the disease and indicate ALS pathogenesis.…”