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

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Alfredo Iacoangeli, Tian Lin, Ahmad Al Khleifat, Ashley R Jones, Sarah Opie-Martin, Jonathan R I Coleman, Aleksey Shatunov, William Sproviero, Kelly L Williams, Fleur Garton, Restuadi Restuadi, Anjali K Henders, Karen A Mather, Merilee Needham, Susan Mathers, Garth A Nicholson, Dominic B Rowe, Robert Henderson, Pamela A McCombe, Roger Pamphlett & 11 more Ian P Blair, David Schultz, Perminder S Sachdev, Stephen J Newhouse, Petroula Proitsi, Isabella Fogh, Shyuan T Ngo, Richard J B Dobson, Naomi R Wray, Frederik J Steyn, Ammar Al-Chalabi

Original languageEnglish
Pages (from-to)108323
JournalCell Reports
Volume33
Issue number4
DOIs
Published27 Oct 2020

King's Authors

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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