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; 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

doi:10.1016/j.celrep.2020.108323

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

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

Research output: Contribution to journal › Article › peer-review

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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 language	English
Article number	108323
Pages (from-to)	1-9
Number of pages	14
Journal	Cell Reports
Volume	33
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2020.108323
Publication status	Published - 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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Publisher version (open access)Final published version, 1.45 MBLicence: CC BY-NC-ND

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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. A., Rowe, D. B., Henderson, R., McCombe, P. A., ... 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), 1-9. Article 108323. https://doi.org/10.1016/j.celrep.2020.108323

@article{d59720a0e84c4a5c8fd13e660ef929c2,

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

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{\textquoteright} 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.",

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",

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

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.",

year = "2020",

month = oct,

day = "27",

doi = "10.1016/j.celrep.2020.108323",

language = "English",

volume = "33",

pages = "1--9",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Elsevier",

number = "4",

}

Iacoangeli, A, Lin, T, Al Khleifat, A, Jones, AR, Opie-Martin, S, Coleman, JRI, Shatunov, A, Sproviero, W, Williams, KL, Garton, F, Restuadi, R, Henders, AK, Mather, KA, Needham, M, Mathers, S, Nicholson, GA, Rowe, DB, Henderson, R, McCombe, PA, Pamphlett, R, Blair, IP, Schultz, D, Sachdev, PS, Newhouse, SJ, Proitsi, P, Fogh, I, Ngo, ST, Dobson, RJB, Wray, NR, Steyn, FJ & 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, vol. 33, no. 4, 108323, pp. 1-9. https://doi.org/10.1016/j.celrep.2020.108323

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

N1 - 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.

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/1078901

UR - http://purl.org/au-research/grants/nhmrc/1113400

UR - http://purl.org/au-research/grants/nhmrc/1151854

UR - http://purl.org/au-research/grants/nhmrc/401162

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

SP - 1

EP - 9

JO - Cell Reports

JF - Cell Reports

IS - 4

M1 - 108323

ER -

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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Keywords

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