Genome-wide meta-analysis finds the ACSL5-ZDHHC6 locus is associated with ALS and links weight loss to the disease genetics

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 others 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

*Corresponding author for this work

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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.

Original languageEnglish
Article number108323
Pages (from-to)1-9
Number of pages14
JournalCell Reports
Volume33
Issue number4
DOIs
Publication statusPublished - 27 Oct 2020

Bibliographical note

Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • amyotrophic lateral sclerosis
  • cross-ethnic meta-analysis
  • eQTLs
  • fat-free mass
  • genetics
  • genome-wide association study
  • genomics
  • longitudinal study
  • motor neuron disease
  • weight loss

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