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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

Iacoangeli, A., Lin, T., Al Khleifat, A., Jones, A.R., Opie-Martin, S., Coleman, J.R.I., Shatunov, A., Sproviero, W., Williams, K.L., Garton, F., Restuadi, R., Henders, A.K., Mather, K.A., Needham, M., Mathers, S., Nicholson, G., Rowe, D.B., Henderson, R., McCombe, P.A., Pamphlett, R., Blair, I.P., Schultz, D., Sachdev, P.S., Newhouse, S.J., Proitsi, P., Fogh, I., Ngo, S.T., Dobson, R.J.B., Wray, N.R., Steyn, F.J. and Al-Chalabi, A. (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). Art. 108323.

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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.

Item Type: Journal Article
Murdoch Affiliation: Centre for Molecular Medicine and Innovative Therapeutics (CMMIT)
Publisher: Elsevier Inc.
Copyright: © 2020 The Author(s).
United Nations SDGs: Goal 3: Good Health and Well-Being
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