Iacoangeli, A;
Lin, T;
Al Khleifat, A;
Jones, AR;
Opie-Martin, S;
Coleman, JRI;
Shatunov, A;
... Al-Chalabi, A; + view all
(2020)
Genome-wide Meta-analysis Finds the ACSL5-ZDHHC6 Locus Is Associated with ALS and Links Weight Loss to the Disease Genetics.
Cell Reports
, 33
(4)
, Article 108323. 10.1016/j.celrep.2020.108323.
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Abstract
We meta-analyze amyotrophic lateral sclerosis (ALS) genome-wide association study (GWAS) data of European and Chinese populations (84,694 individuals). We find an additional significant association between rs58854276 spanning ACSL5-ZDHHC6 with ALS (p = 8.3 × 10−9), with replication in an independent Australian cohort (1,502 individuals; p = 0.037). Moreover, B4GALNT1, G2E3-SCFD1, and TRIP11-ATXN3 are identified using a gene-based analysis. ACSL5 has been associated with rapid weight loss, as has another ALS-associated gene, GPX3. Weight loss is frequent in ALS patients and is associated with shorter survival. We investigate the effect of the ACSL5 and GPX3 single-nucleotide polymorphisms (SNPs), using longitudinal body composition and weight data of 77 patients and 77 controls. In patients’ fat-free mass, although not significant, we observe an effect in the expected direction (rs58854276: −2.1 ± 1.3 kg/A allele, p = 0.053; rs3828599: −1.0 ± 1.3 kg/A allele, p = 0.22). No effect was observed in controls. Our findings support the increasing interest in lipid metabolism in ALS and link the disease genetics to weight loss in patients.
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