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

Cell Rep. 2020 Oct 27;33(4):108323. doi: 10.1016/j.celrep.2020.108323.

Authors

Alfredo Iacoangeli¹, Tian Lin², Ahmad Al Khleifat³, Ashley R Jones³, Sarah Opie-Martin³, Jonathan R I Coleman⁴, Aleksey Shatunov³, William Sproviero³, Kelly L Williams⁵, Fleur Garton², Restuadi Restuadi², Anjali K Henders², Karen A Mather⁶, Merilee Needham⁷, Susan Mathers⁸, Garth A Nicholson⁹, Dominic B Rowe¹⁰, Robert Henderson¹¹, Pamela A McCombe¹², Roger Pamphlett¹³, Ian P Blair¹⁰, David Schultz¹⁴, Perminder S Sachdev¹⁵, Stephen J Newhouse¹⁶, Petroula Proitsi³, Isabella Fogh¹⁷, Shyuan T Ngo¹⁸, Richard J B Dobson¹⁶, Naomi R Wray¹⁹, Frederik J Steyn²⁰, Ammar Al-Chalabi²¹

Affiliations

¹ Department of Biostatistics and Health Informatics, King's College London, London, UK; Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, London, UK; National Institute for Health Research Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and King's College London, London, UK. Electronic address: alfredo.iacoangeli@kcl.ac.uk.
² Institute for Molecular Bioscience, The University of Queensland, Brisbane, Brisbane QLD 4072, Australia.
³ Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, London, UK.
⁴ National Institute for Health Research Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and King's College London, London, UK; Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
⁵ Centre for Motor Neuron Disease Research, Macquarie University, Sidney NSW 2109, Australia.
⁶ Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney NSW, Australia; Neuroscience Research Australia, Randwick NSW, Australia.
⁷ Fiona Stanley Hospital, 11 Robin Warren Drive, Murdoch Perth WA 6150, Australia; Notre Dame University, 32 Mouat Street, Fremantle WA 6160, Australia; Murdoch University, 90 South Street, Murdoch WA 6150, Australia.
⁸ Calvary Health Care Bethlehem, Parkdale VIC 3195, Australia.
⁹ ANZAC Research Institute, Concord Repatriation General Hospital, Sydney NSW 2139, Australia.
¹⁰ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
¹¹ Centre for Clinical Research, The University of Queensland, Brisbane QLD, Australia; Queensland Brain Institute, The University of Queensland, Brisbane QLD, Australia.
¹² Centre for Clinical Research, The University of Queensland, Brisbane QLD, Australia; Department of Neurology, Royal Brisbane and Women's Hospital, Brisbane QLD, Australia.
¹³ Brain and Mind Centre, The University of Sydney, Sydney NSW, Australia.
¹⁴ Flinders Medical Centre, Bedford Park SA 5042, Australia.
¹⁵ Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney NSW, Australia; Neuropsychiatric Institute, Prince of Wales Hospital, Sydney NSW Australia.
¹⁶ Department of Biostatistics and Health Informatics, King's College London, London, UK; National Institute for Health Research Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and King's College London, London, UK; Institute of Health Informatics, University College London, London, UK.
¹⁷ Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, London, UK; Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy.
¹⁸ Centre for Clinical Research, The University of Queensland, Brisbane QLD, Australia; Queensland Brain Institute, The University of Queensland, Brisbane QLD, Australia; Department of Neurology, Royal Brisbane and Women's Hospital, Brisbane QLD, Australia; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane QLD, Australia.
¹⁹ Institute for Molecular Bioscience, The University of Queensland, Brisbane, Brisbane QLD 4072, Australia; Queensland Brain Institute, The University of Queensland, Brisbane QLD, Australia.
²⁰ Centre for Clinical Research, The University of Queensland, Brisbane QLD, Australia; Department of Neurology, Royal Brisbane and Women's Hospital, Brisbane QLD, Australia; School of Biomedical Sciences, The University of Queensland, Brisbane QLD, Australia.
²¹ Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, London, UK; King's College Hospital, Bessemer Road, London SE5 9RS, UK.

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.

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.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Acyltransferases / adverse effects*
Amyotrophic Lateral Sclerosis / complications*
Amyotrophic Lateral Sclerosis / genetics
Genetic Predisposition to Disease
Genome-Wide Association Study / methods*
Humans
Polymorphism, Single Nucleotide / genetics*
Weight Loss / genetics*

Substances

ZDHHC6 protein, human
Acyltransferases

Abstract

Publication types

MeSH terms

Substances

Grants and funding