{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T04:11:17Z","timestamp":1775275877527,"version":"3.50.1"},"reference-count":78,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2022,3,17]],"date-time":"2022-03-17T00:00:00Z","timestamp":1647475200000},"content-version":"vor","delay-in-days":16,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Amyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disease that affects 1\/350 individuals in the United Kingdom. The cause of amyotrophic lateral sclerosis is unknown in the majority of cases. Two-sample Mendelian randomization enables causal inference between an exposure, such as the serum concentration of a specific metabolite, and disease risk. We obtained genome-wide association study summary statistics for serum concentrations of 566 metabolites which were population matched with a genome-wide association study of amyotrophic lateral sclerosis. For each metabolite, we performed Mendelian randomization using an inverse variance weighted estimate for significance testing. After stringent Bonferroni multiple testing correction, our unbiased screen revealed three metabolites that were significantly linked to the risk of amyotrophic lateral sclerosis: Estrone-3-sulphate and bradykinin were protective, which is consistent with literature describing a male preponderance of amyotrophic lateral sclerosis and a preventive effect of angiotensin-converting enzyme inhibitors which inhibit the breakdown of bradykinin. Serum isoleucine was positively associated with amyotrophic lateral sclerosis risk. All three metabolites were supported by robust Mendelian randomization measures and sensitivity analyses; estrone-3-sulphate and isoleucine were confirmed in a validation amyotrophic lateral sclerosis genome-wide association study. Estrone-3-sulphate is metabolized to the more active estradiol by the enzyme 17\u03b2-hydroxysteroid dehydrogenase 1; further, Mendelian randomization demonstrated a protective effect of estradiol and rare variant analysis showed that missense variants within HSD17B1, the gene encoding 17\u03b2-hydroxysteroid dehydrogenase 1, modify risk for amyotrophic lateral sclerosis. Finally, in a zebrafish model of C9ORF72-amyotrophic lateral sclerosis, we present evidence that estradiol is neuroprotective. Isoleucine is metabolized via methylmalonyl-CoA mutase encoded by the gene MMUT in a reaction that consumes vitamin B12. Multivariable Mendelian randomization revealed that the toxic effect of isoleucine is dependent on the depletion of vitamin B12; consistent with this, rare variants which reduce the function of MMUT are protective against amyotrophic lateral sclerosis. We propose that amyotrophic lateral sclerosis patients and family members with high serum isoleucine levels should be offered supplementation with vitamin B12.<\/jats:p>","DOI":"10.1093\/braincomms\/fcac069","type":"journal-article","created":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T04:17:46Z","timestamp":1647404266000},"source":"Crossref","is-referenced-by-count":21,"title":["Unbiased metabolome screen leads to personalized medicine strategy for amyotrophic lateral sclerosis"],"prefix":"10.1093","volume":"4","author":[{"given":"Sarah","family":"Boddy","sequence":"first","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahjabin","family":"Islam","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tobias","family":"Moll","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julian","family":"Kurz","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Burrows","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"McGown","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anushka","family":"Bhargava","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas H","family":"Julian","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Calum","family":"Harvey","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jack NG","family":"Marshall","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin PC","family":"Hall","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4418-7375","authenticated-orcid":false,"given":"Scott P","family":"Allen","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin P","family":"Kenna","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5188-5775","authenticated-orcid":false,"given":"Eleanor","family":"Sanderson","sequence":"additional","affiliation":[{"name":"Medical Research Council (MRC) Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tennore","family":"Ramesh","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael P","family":"Snyder","sequence":"additional","affiliation":[{"name":"Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pamela J","family":"Shaw","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"McDermott","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0873-8689","authenticated-orcid":false,"given":"Johnathan","family":"Cooper-Knock","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,3,17]]},"reference":[{"issue":"11","key":"2022041505503112000_fcac069-B1","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1016\/S1474-4422(14)70219-4","article-title":"Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study","volume":"13","author":"Al-Chalabi","year":"2014","journal-title":"Lancet Neurol"},{"key":"2022041505503112000_fcac069-B2","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1097\/WCO.0000000000000986","article-title":"Advances in the genetic classification of amyotrophic lateral sclerosis","volume":"2","author":"Cooper-Knock","year":"2021","journal-title":"Curr Opin Neurol"},{"issue":"7836","key":"2022041505503112000_fcac069-B3","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/s41586-020-2896-2","article-title":"A reference map of potential determinants for the human serum metabolome","volume":"588","author":"Bar","year":"2020","journal-title":"Nature"},{"issue":"7770","key":"2022041505503112000_fcac069-B4","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1038\/s41586-019-1443-5","article-title":"Potential roles of gut microbiome and metabolites in modulating ALS in mice","volume":"572","author":"Blacher","year":"2019","journal-title":"Nature"},{"issue":"3","key":"2022041505503112000_fcac069-B5","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1093\/brain\/awy353","article-title":"Astrocyte adenosine deaminase loss increases motor neuron toxicity in amyotrophic lateral sclerosis","volume":"142","author":"Allen","year":"2019","journal-title":"Brain"},{"issue":"12","key":"2022041505503112000_fcac069-B6","doi-asserted-by":"crossref","first-page":"2466","DOI":"10.1212\/WNL.43.12.2466","article-title":"Branched-chain amino acids and amyotrophic lateral sclerosis: a treatment failure?","volume":"43","year":"1993","journal-title":"Neurology"},{"issue":"5","key":"2022041505503112000_fcac069-B7","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1212\/WNL.47.5.1220","article-title":"A controlled trial of amino acid therapy in amyotrophic lateral sclerosis: I. Clinical, functional, and maximum isometric torque data","volume":"47","author":"Tandan","year":"1996","journal-title":"Neurology"},{"issue":"10","key":"2022041505503112000_fcac069-B8","first-page":"1141","article-title":"Clinical trials of ultra-high-dose methylcobalamin in ALS","volume":"59","author":"Izumi","year":"2007","journal-title":"Brain Nerve"},{"key":"2022041505503112000_fcac069-B9","doi-asserted-by":"crossref","first-page":"103397","DOI":"10.1016\/j.ebiom.2021.103397","article-title":"Physical exercise is a risk factor for amyotrophic lateral sclerosis: convergent evidence from Mendelian randomisation, transcriptomics and risk genotypes","volume":"68","author":"Julian","year":"2021","journal-title":"EBioMedicine"},{"key":"2022041505503112000_fcac069-B10","doi-asserted-by":"crossref","first-page":"j5375","DOI":"10.1136\/bmj.j5375","article-title":"Modifiable pathways in Alzheimer\u2019s disease: mendelian randomisation analysis","volume":"359","author":"Larsson","year":"2017","journal-title":"BMJ"},{"issue":"3","key":"2022041505503112000_fcac069-B11","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s00401-020-02181-3","article-title":"Large-scale pathway specific polygenic risk and transcriptomic community network analysis identifies novel functional pathways in Parkinson disease","volume":"140","author":"Bandres-Ciga","year":"2020","journal-title":"Acta Neuropathol"},{"issue":"6","key":"2022041505503112000_fcac069-B12","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1038\/ng.2982","article-title":"An atlas of genetic influences on human blood metabolites","volume":"46","author":"Shin","year":"2014","journal-title":"Nat Genet"},{"key":"2022041505503112000_fcac069-B13","doi-asserted-by":"crossref","first-page":"11122","DOI":"10.1038\/ncomms11122","article-title":"Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA","volume":"7","author":"Kettunen","year":"2016","journal-title":"Nat Commun"},{"issue":"9","key":"2022041505503112000_fcac069-B14","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1038\/ng.3622","article-title":"Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis","volume":"48","author":"van Rheenen","year":"2016","journal-title":"Nat Genet"},{"issue":"6","key":"2022041505503112000_fcac069-B15","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1016\/j.neuron.2018.02.027","article-title":"Genome-wide analyses identify KIF5A as a novel ALS gene","volume":"97","author":"Nicolas","year":"2018","journal-title":"Neuron"},{"issue":"2","key":"2022041505503112000_fcac069-B16","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/ng.2876","article-title":"Advantages and pitfalls in the application of mixed-model association methods","volume":"46","author":"Yang","year":"2014","journal-title":"Nat Genet"},{"issue":"4","key":"2022041505503112000_fcac069-B17","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1001\/jamapsychiatry.2018.4175","article-title":"Assessment of bidirectional relationships between physical activity and depression among adults: a 2-sample Mendelian randomization study","volume":"76","author":"Choi","year":"2019","journal-title":"JAMA Psychiatry"},{"key":"2022041505503112000_fcac069-B18","article-title":"Evaluation of the causal effects between subjective wellbeing and cardiometabolic health: mendelian randomisation study","volume":"362","author":"Wootton","year":"2018","journal-title":"BMJ"},{"key":"2022041505503112000_fcac069-B19","article-title":"A review of Mendelian randomization in amyotrophic lateral sclerosis","volume":"16","author":"Julian","year":"2021","journal-title":"Brain"},{"issue":"21","key":"2022041505503112000_fcac069-B20","doi-asserted-by":"crossref","first-page":"3555","DOI":"10.1093\/bioinformatics\/btv402","article-title":"LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants","volume":"31","author":"Machiela","year":"2015","journal-title":"Bioinformatics"},{"issue":"6","key":"2022041505503112000_fcac069-B21","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1093\/ije\/dyx028","article-title":"Two-sample Mendelian randomization: avoiding the downsides of a powerful, widely applicable but potentially fallible technique","volume":"45","author":"Hartwig","year":"2016","journal-title":"Int J Epidemiol"},{"issue":"7","key":"2022041505503112000_fcac069-B22","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1002\/gepi.21758","article-title":"Mendelian randomization analysis with multiple genetic variants using summarized data","volume":"37","author":"Burgess","year":"2013","journal-title":"Genet Epidemiol"},{"issue":"4","key":"2022041505503112000_fcac069-B23","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1002\/gepi.21965","article-title":"Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator","volume":"40","author":"Bowden","year":"2016","journal-title":"Genet Epidemiol"},{"issue":"6","key":"2022041505503112000_fcac069-B24","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1093\/ije\/dyx102","article-title":"Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption","volume":"46","author":"Hartwig","year":"2017","journal-title":"Int J Epidemiol"},{"issue":"9","key":"2022041505503112000_fcac069-B25","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0222362","article-title":"Robust methods in Mendelian randomization via penalization of heterogeneous causal estimates","volume":"14","author":"Rees","year":"2019","journal-title":"PLoS One"},{"issue":"4","key":"2022041505503112000_fcac069-B26","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1002\/gepi.22295","article-title":"A comparison of robust Mendelian randomization methods using summary data","volume":"44","author":"Slob","year":"2020","journal-title":"Genet Epidemiol"},{"issue":"5","key":"2022041505503112000_fcac069-B27","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases","volume":"50","author":"Verbanck","year":"2018","journal-title":"Nat Genet"},{"issue":"6","key":"2022041505503112000_fcac069-B28","first-page":"1961","article-title":"Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I2 statistic","volume":"45","author":"Bowden","year":"2016","journal-title":"Int J Epidemiol"},{"key":"2022041505503112000_fcac069-B29","doi-asserted-by":"crossref","first-page":"186","DOI":"10.12688\/wellcomeopenres.15555.1","article-title":"Guidelines for performing Mendelian randomization investigations","volume":"4","author":"Burgess","year":"2019","journal-title":"Wellcome Open Res"},{"issue":"513","key":"2022041505503112000_fcac069-B30","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1080\/01621459.2014.994705","article-title":"Instrumental variables estimation with some invalid instruments and its application to Mendelian randomization","volume":"111","author":"Kang","year":"2016","journal-title":"J Am Stat Assoc"},{"issue":"5","key":"2022041505503112000_fcac069-B31","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1007\/s10654-017-0255-x","article-title":"Interpreting findings from Mendelian randomization using the MR-Egger method","volume":"32","author":"Burgess","year":"2017","journal-title":"Eur J Epidemiol"},{"issue":"3","key":"2022041505503112000_fcac069-B32","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: a tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"Am J Hum Genet"},{"issue":"6","key":"2022041505503112000_fcac069-B33","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1093\/ije\/dyx034","article-title":"MendelianRandomization: an R package for performing Mendelian randomization analyses using summarized data","volume":"46","author":"Yavorska","year":"2017","journal-title":"Int J Epidemiol"},{"issue":"4","key":"2022041505503112000_fcac069-B34","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1093\/aje\/kwu283","article-title":"Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects","volume":"181","author":"Burgess","year":"2015","journal-title":"Am J Epidemiol"},{"issue":"3","key":"2022041505503112000_fcac069-B35","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1093\/ije\/dyy262","article-title":"An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings","volume":"48","author":"Sanderson","year":"2019","journal-title":"Int J Epidemiol"},{"key":"2022041505503112000_fcac069-B36","doi-asserted-by":"crossref","first-page":"5434","DOI":"10.1002\/sim.9133","article-title":"Testing and correcting for weak and pleiotropic instruments in two-sample multivariable Mendelian randomization","volume":"40","author":"Sanderson","year":"2021","journal-title":"Stat Med"},{"issue":"7708","key":"2022041505503112000_fcac069-B37","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41586-018-0175-2","article-title":"Genomic atlas of the human plasma proteome","volume":"558","author":"Sun","year":"2018","journal-title":"Nature"},{"issue":"3","key":"2022041505503112000_fcac069-B38","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/ng.3211","article-title":"LD Score regression distinguishes confounding from polygenicity in genome-wide association studies","volume":"47","author":"Bulik-Sullivan","year":"2015","journal-title":"Nat Genet"},{"issue":"11","key":"2022041505503112000_fcac069-B39","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1038\/ng.3406","article-title":"An atlas of genetic correlations across human diseases and traits","volume":"47","author":"Bulik-Sullivan","year":"2015","journal-title":"Nat Genet"},{"issue":"5-6","key":"2022041505503112000_fcac069-B40","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1080\/21678421.2019.1606244","article-title":"The Project MinE databrowser: bringing large-scale whole-genome sequencing in ALS to researchers and the public","volume":"20","author":"van der Spek","year":"2019","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"issue":"7616","key":"2022041505503112000_fcac069-B41","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of protein-coding genetic variation in 60,706 humans","volume":"536","author":"Lek","year":"2016","journal-title":"Nature"},{"issue":"1","key":"2022041505503112000_fcac069-B42","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1093\/nar\/29.1.87","article-title":"The zebrafish information network (ZFIN): a resource for genetic, genomic and developmental research","volume":"29","author":"Sprague","year":"2001","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"2022041505503112000_fcac069-B43","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/s40478-018-0629-7","article-title":"Stable transgenic C9orf72 zebrafish model key aspects of the ALS\/FTD phenotype and reveal novel pathological features","volume":"6","author":"Shaw","year":"2018","journal-title":"Acta Neuropathol Commun"},{"key":"2022041505503112000_fcac069-B44","doi-asserted-by":"crossref","article-title":"The MRC IEU OpenGWAS data infrastructure","author":"Elsworth","DOI":"10.1101\/2020.08.10.244293"},{"issue":"5","key":"2022041505503112000_fcac069-B45","doi-asserted-by":"crossref","first-page":"439","DOI":"10.3109\/17482961003610853","article-title":"The sex ratio in amyotrophic lateral sclerosis: a population based study","volume":"11","author":"Manjaly","year":"2010","journal-title":"Amyotroph Lateral Scler"},{"issue":"1","key":"2022041505503112000_fcac069-B46","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1001\/jamaneurol.2014.3367","article-title":"Angiotensin-converting enzyme inhibitors and amyotrophic lateral sclerosis risk: a total population\u2013based case-control study","volume":"72","author":"Lin","year":"2015","journal-title":"JAMA Neurol"},{"issue":"12","key":"2022041505503112000_fcac069-B47","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1038\/nbt.2749","article-title":"Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data","volume":"31","author":"Denny","year":"2013","journal-title":"Nat Biotechnol"},{"key":"2022041505503112000_fcac069-B48","author":"Yen","year":"2004","journal-title":"Yen and Jaffe\u2019s reproductive endocrinology: Physiology. Pathophysiology, and Clinical Management"},{"issue":"2","key":"2022041505503112000_fcac069-B49","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1080\/10408363.2016.1252310","article-title":"Clinical implications of estrone sulfate measurement in laboratory medicine","volume":"54","author":"Rezvanpour","year":"2017","journal-title":"Crit Rev Clin Lab Sci"},{"issue":"1","key":"2022041505503112000_fcac069-B50","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1677\/joe.0.0600003","article-title":"Estimation of oestrone sulphate, estradiol-17beta and oestrone in peripheral plasma: concentrations during the menstrual cycle and in men","volume":"60","author":"Hawkins","year":"1974","journal-title":"J Endocrinol"},{"issue":"16","key":"2022041505503112000_fcac069-B51","doi-asserted-by":"crossref","first-page":"3493","DOI":"10.1097\/00001756-200011090-00019","article-title":"Protection of cultured spinal motor neurons by estradiol","volume":"11","author":"Nakamizo","year":"2000","journal-title":"Neuroreport"},{"issue":"3","key":"2022041505503112000_fcac069-B52","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1093\/brain\/awr365","article-title":"Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72","volume":"135","author":"Cooper-Knock","year":"2012","journal-title":"Brain"},{"issue":"2","key":"2022041505503112000_fcac069-B53","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1002\/ana.23780","article-title":"Early interneuron dysfunction in ALS: insights from a mutant sod1 zebrafish model","volume":"73","author":"McGown","year":"2013","journal-title":"Ann Neurol"},{"issue":"9-10","key":"2022041505503112000_fcac069-B54","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1242\/dmm.005538","article-title":"A genetic model of amyotrophic lateral sclerosis in zebrafish displays phenotypic hallmarks of motoneuron disease","volume":"3","author":"Ramesh","year":"2010","journal-title":"Dis Model Mech"},{"issue":"4 Suppl 2","key":"2022041505503112000_fcac069-B55","first-page":"47","article-title":"Clinical trials of riluzole in patients with ALS","author":"Miller","year":"1996","journal-title":"Neurology"},{"key":"2022041505503112000_fcac069-B56","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1146\/annurev-physiol-020518-114455","article-title":"Branched chain amino acids","volume":"81","author":"Neinast","year":"2019","journal-title":"Annu Rev Physiol"},{"issue":"4","key":"2022041505503112000_fcac069-B57","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1002\/jimd.12009","article-title":"Vitamin B12, folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation","volume":"42","author":"Froese","year":"2019","journal-title":"J Inherit Metab Dis"},{"issue":"4","key":"2022041505503112000_fcac069-B58","doi-asserted-by":"crossref","first-page":"255","DOI":"10.3109\/00365519209088356","article-title":"Serum methylmalonic acid before and after oral L-isoleucine loading in cobalamin-deficient patients","volume":"52","author":"Moelby","year":"1992","journal-title":"Scand J Clin Lab Invest"},{"issue":"4","key":"2022041505503112000_fcac069-B59","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1136\/jnnp-2018-319294","article-title":"Ultra-high-dose methylcobalamin in amyotrophic lateral sclerosis: a long-term phase II\/III randomised controlled study","volume":"90","author":"Kaji","year":"2019","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"1","key":"2022041505503112000_fcac069-B60","doi-asserted-by":"crossref","first-page":"359S","DOI":"10.3945\/ajcn.111.013458","article-title":"Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility","volume":"94","author":"Nexo","year":"2011","journal-title":"Am J Clin Nutr"},{"issue":"1","key":"2022041505503112000_fcac069-B61","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s10038-020-00845-2","article-title":"Unique roles of rare variants in the genetics of complex diseases in humans","volume":"66","author":"Momozawa","year":"2021","journal-title":"J Hum Genet"},{"issue":"6229","key":"2022041505503112000_fcac069-B62","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1126\/science.aaa3650","article-title":"Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways","volume":"347","author":"Cirulli","year":"2015","journal-title":"Science"},{"issue":"10","key":"2022041505503112000_fcac069-B63","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1038\/s41431-018-0177-4","article-title":"Project MinE: study design and pilot analyses of a large-scale whole-genome sequencing study in amyotrophic lateral sclerosis","volume":"26","author":"Project MinE ALS Sequencing Consortium","year":"2018","journal-title":"Eur J Hum Genet"},{"issue":"4","key":"2022041505503112000_fcac069-B64","doi-asserted-by":"crossref","first-page":"e17947","DOI":"10.1371\/journal.pone.0017947","article-title":"Disease-related changes in the cerebrospinal fluid metabolome in amyotrophic lateral sclerosis detected by GC\/TOFMS","volume":"6","author":"Wuolikainen","year":"2011","journal-title":"PLoS One"},{"issue":"3-4","key":"2022041505503112000_fcac069-B65","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1080\/21678421.2020.1730904","article-title":"A comprehensive serum lipidome profiling of amyotrophic lateral sclerosis","volume":"21","author":"Fern\u00c1ndez-Eulate","year":"2020","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"issue":"12","key":"2022041505503112000_fcac069-B66","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1136\/jnnp-2020-323611","article-title":"Untargeted metabolomics yields insight into ALS disease mechanisms","volume":"91","author":"Goutman","year":"2020","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"18","key":"2022041505503112000_fcac069-B67","first-page":"e2089","article-title":"Prediagnostic plasma metabolomics and the risk of amyotrophic lateral sclerosis","volume":"92","author":"Bjornevik","year":"2019","journal-title":"Neurology"},{"issue":"4","key":"2022041505503112000_fcac069-B68","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1002\/ana.25431","article-title":"Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis","volume":"85","author":"Bandres-Ciga","year":"2019","journal-title":"Ann Neurol"},{"issue":"7","key":"2022041505503112000_fcac069-B69","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1002\/sim.5659","article-title":"Severity of bias of a simple estimator of the causal odds ratio in Mendelian randomization studies","volume":"32","author":"Harbord","year":"2013","journal-title":"Stat Med"},{"issue":"2","key":"2022041505503112000_fcac069-B70","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1007\/s00415-012-6665-5","article-title":"Endogenous female reproductive hormones and the risk of amyotrophic lateral sclerosis","volume":"260","author":"de Jong","year":"2013","journal-title":"J Neurol"},{"issue":"11-12","key":"2022041505503112000_fcac069-B71","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1016\/j.bbadis.2006.05.002","article-title":"The role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis","volume":"1762","author":"Van Den Bosch","year":"2006","journal-title":"Biochim Biophys Acta"},{"issue":"1","key":"2022041505503112000_fcac069-B72","first-page":"77","article-title":"Characterization of structural and functional properties of human 17\u03b2-hydroxysteroid dehydrogenase type 1 using recombinant enzymes and site-directed mutagenesis","volume":"11","author":"Puranen","year":"1997","journal-title":"Mol Endocrinol"},{"issue":"11","key":"2022041505503112000_fcac069-B73","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1136\/jnnp-2014-308288","article-title":"A zebrafish model exemplifies the long preclinical period of motor neuron disease","volume":"85","author":"Ramesh","year":"2014","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"2022041505503112000_fcac069-B74","article-title":"Developing and validating a high-throughput drug screen in a zebrafish model of amyotrophic lateral sclerosis","author":"McGown"},{"issue":"4","key":"2022041505503112000_fcac069-B75","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1093\/ije\/dyaa288","article-title":"The use of negative control outcomes in Mendelian randomization to detect potential population stratification","volume":"50","author":"Sanderson","year":"2021","journal-title":"Int J Epidemiol"},{"key":"2022041505503112000_fcac069-B76","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.neurobiolaging.2021.04.013","article-title":"Amyotrophic lateral sclerosis alters the metabolic aging profile in patient derived fibroblasts","volume":"105","author":"Gerou","year":"2021","journal-title":"Neurobiol Aging"},{"issue":"6","key":"2022041505503112000_fcac069-B77","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/0197-0186(95)80004-5","article-title":"The imbalance of brain large-chain aminoacid availability in amyotrophic lateral sclerosis patients treated with high doses of branched-chain aminoacids","volume":"27","author":"Bastone","year":"1995","journal-title":"Neurochem Int"},{"issue":"18","key":"2022041505503112000_fcac069-B78","first-page":"e2081","article-title":"Prediagnostic plasma branched-chain amino acids and the risk of amyotrophic lateral sclerosis","volume":"92","author":"Bjornevik","year":"2019","journal-title":"Neurology"}],"container-title":["Brain Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/braincomms\/advance-article-pdf\/doi\/10.1093\/braincomms\/fcac069\/42947630\/fcac069.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/4\/2\/fcac069\/43383501\/fcac069.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/4\/2\/fcac069\/43383501\/fcac069.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,15]],"date-time":"2022-04-15T05:51:49Z","timestamp":1650001909000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/braincomms\/article\/doi\/10.1093\/braincomms\/fcac069\/6550088"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,1]]},"references-count":78,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,3,1]]}},"URL":"https:\/\/doi.org\/10.1093\/braincomms\/fcac069","relation":{},"ISSN":["2632-1297"],"issn-type":[{"value":"2632-1297","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,4,1]]},"published":{"date-parts":[[2022,3,1]]},"article-number":"fcac069"}}