TY - JOUR
T1 - Genome-wide Meta-analysis Finds the ACSL5-ZDHHC6 Locus Is Associated with ALS and Links Weight Loss to the Disease Genetics
AU - Iacoangeli, Alfredo
AU - Lin, Tian
AU - Al Khleifat, Ahmad
AU - Jones, Ashley R.
AU - Opie-Martin, Sarah
AU - Coleman, Jonathan R.I.
AU - Shatunov, Aleksey
AU - Sproviero, William
AU - Williams, Kelly L.
AU - Garton, Fleur
AU - Restuadi, Restuadi
AU - Henders, Anjali K.
AU - Mather, Karen A.
AU - Needham, Merilee
AU - Mathers, Susan
AU - Nicholson, Garth A.
AU - Rowe, Dominic B.
AU - Henderson, Robert
AU - McCombe, Pamela A.
AU - Pamphlett, Roger
AU - Blair, Ian P.
AU - Schultz, David
AU - Sachdev, Perminder S.
AU - Newhouse, Stephen J.
AU - Proitsi, Petroula
AU - Fogh, Isabella
AU - Ngo, Shyuan T.
AU - Dobson, Richard J.B.
AU - Wray, Naomi R.
AU - Steyn, Frederik J.
AU - Al-Chalabi, Ammar
PY - 2020/10/27
Y1 - 2020/10/27
N2 - 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.
AB - 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.
KW - amyotrophic lateral sclerosis
KW - cross-ethnic meta-analysis
KW - eQTLs
KW - fat-free mass
KW - genetics
KW - genome-wide association study
KW - genomics
KW - longitudinal study
KW - motor neuron disease
KW - weight loss
UR - https://www.scopus.com/pages/publications/85094601779
UR - http://purl.org/au-research/grants/NHMRC/401162
UR - http://purl.org/au-research/grants/NHMRC/1405325
U2 - 10.1016/j.celrep.2020.108323
DO - 10.1016/j.celrep.2020.108323
M3 - Article
C2 - 33113361
AN - SCOPUS:85094601779
SN - 2211-1247
VL - 33
JO - Cell Reports
JF - Cell Reports
IS - 4
M1 - 108323
ER -