Publications by authors named "Ashley R Jones"

24 Publications

  • Page 1 of 1

Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders.

Genome Biol 2021 Mar 26;22(1):90. Epub 2021 Mar 26.

Centre for Clinical Research, The University of Queensland, Brisbane, QLD, 4019, Australia.

Background: People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease.

Results: We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson's disease (and none with Alzheimer's disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights.

Conclusions: We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.
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http://dx.doi.org/10.1186/s13059-021-02275-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004462PMC
March 2021

Cross-reactive probes on Illumina DNA methylation arrays: a large study on ALS shows that a cautionary approach is warranted in interpreting epigenome-wide association studies.

NAR Genom Bioinform 2020 Dec 17;2(4):lqaa105. Epub 2020 Dec 17.

Department of Neurology, UMC Utrecht Brain Center, 3584 CG, Utrecht, the Netherlands.

Illumina DNA methylation arrays are a widely used tool for performing genome-wide DNA methylation analyses. However, measurements obtained from these arrays may be affected by technical artefacts that result in spurious associations if left unchecked. Cross-reactivity represents one of the major challenges, meaning that probes may map to multiple regions in the genome. Although several studies have reported on this issue, few studies have empirically examined the impact of cross-reactivity in an epigenome-wide association study (EWAS). In this paper, we report on cross-reactivity issues that we discovered in a large EWAS on the presence of the repeat expansion in ALS patients. Specifically, we found that that the majority of the significant probes inadvertently cross-hybridized to the locus. Importantly, these probes were not flagged as cross-reactive in previous studies, leading to novel insights into the extent to which cross-reactivity can impact EWAS. Our findings are particularly relevant for epigenetic studies into diseases associated with repeat expansions and other types of structural variation. More generally however, considering that most spurious associations were not excluded based on pre-defined sets of cross-reactive probes, we believe that the presented data-driven flag and consider approach is relevant for any type of EWAS.
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http://dx.doi.org/10.1093/nargab/lqaa105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745769PMC
December 2020

Genome-wide Meta-analysis Finds the ACSL5-ZDHHC6 Locus Is Associated with ALS and Links Weight Loss to the Disease Genetics.

Cell Rep 2020 10;33(4):108323

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.

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), 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.
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http://dx.doi.org/10.1016/j.celrep.2020.108323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610013PMC
October 2020

Relationship between smoking and ALS: Mendelian randomisation interrogation of causality.

J Neurol Neurosurg Psychiatry 2020 12 26;91(12):1312-1315. Epub 2020 Aug 26.

Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, King's College London, London, UK

Objective: Smoking has been widely studied as a susceptibility factor for amyotrophic lateral sclerosis (ALS), but results are conflicting and at risk of confounding bias. We used the results of recently published large genome-wide association studies and Mendelian randomisation methods to reduce confounding to assess the relationship between smoking and ALS.

Methods: Two genome-wide association studies investigating lifetime smoking (n=463 003) and ever smoking (n=1 232 091) were identified and used to define instrumental variables for smoking. A genome-wide association study of ALS (20 806 cases; 59 804 controls) was used as the outcome for inverse variance weighted Mendelian randomisation, and four other Mendelian randomisation methods, to test whether smoking is causal for ALS. Analyses were bidirectional to assess reverse causality.

Results: There was no strong evidence for a causal or reverse causal relationship between smoking and ALS. The results of Mendelian randomisation using the inverse variance weighted method were: lifetime smoking OR 0.94 (95% CI 0.74 to 1.19), p value 0.59; ever smoking OR 1.10 (95% CI 1 to 1.23), p value 0.05.

Conclusions: Using multiple methods, large sample sizes and sensitivity analyses, we find no evidence with Mendelian randomisation techniques that smoking causes ALS. Other smoking phenotypes, such as current smoking, may be suitable for future Mendelian randomisation studies.
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http://dx.doi.org/10.1136/jnnp-2020-323316DOI Listing
December 2020

C9orf72 intermediate expansions of 24-30 repeats are associated with ALS.

Acta Neuropathol Commun 2019 07 17;7(1):115. Epub 2019 Jul 17.

Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK.

The expansion of a hexanucleotide repeat GGGGCC in C9orf72 is the most common known cause of ALS accounting for ~ 40% familial cases and ~ 7% sporadic cases in the European population. In most people, the repeat length is 2, but in people with ALS, hundreds to thousands of repeats may be observed. A small proportion of people have an intermediate expansion, of the order of 20 to 30 repeats in size, and it remains unknown whether intermediate expansions confer risk of ALS in the same way that massive expansions do. We investigated the association of this intermediate repeat with ALS by performing a meta-analysis of four previously published studies and a new British/Alzheimer's Disease Neuroimaging Initiative dataset of 1295 cases and 613 controls. The final dataset comprised 5071 cases and 3747 controls. Our meta-analysis showed association between ALS and intermediate C9orf72 repeats of 24 to 30 repeats in size (random-effects model OR = 4.2, 95% CI = 1.23-14.35, p-value = 0.02). Furthermore, we showed a different frequency of the repeat between the northern and southern European populations (Fisher's exact test p-value = 5 × 10). Our findings provide evidence for the association between intermediate repeats and ALS (p-value = 2 × 10) with direct relevance for research and clinical practice by showing that an expansion of 24 or more repeats should be considered pathogenic.
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http://dx.doi.org/10.1186/s40478-019-0724-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637621PMC
July 2019

Genome-wide survey of copy number variants finds MAPT duplications in progressive supranuclear palsy.

Mov Disord 2019 07 6;34(7):1049-1059. Epub 2019 May 6.

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.

Background: Progressive supranuclear palsy is a neurodegenerative tauopathy manifesting clinically as a progressive akinetic-rigid syndrome. In this study, we sought to identify genetic variants influencing PSP susceptibility through a genome-wide association analysis of a cohort of well-characterized patients who had participated in the Neuroprotection and Natural History in Parkinson Plus Syndromes and Blood Brain Barrier in Parkinson Plus Syndromes studies.

Methods: We genotyped single-nucleotide polymorphisms in 283 PSP cases from the United Kingdom, Germany, and France and compared these with genotypes from 4472 controls. Copy number variants were identified from genotyping data.

Results: We observed associations on chromosome 17 within or close to the MAPT gene and explored the genetic architecture at this locus. We confirmed the previously reported association of rs1768208 in the MOBP gene (P = 3.29 × 10 ) and rs1411478 in STX6 (P = 3.45 × 10 ). The population-attributable risk from the MAPT, MOBP, and STX6 single-nucleotide polymorphisms was found to be 0.37, 0.26, and 0.08, respectively. In addition, we found 2 instances of copy number variants spanning the MAPT gene in patients with PSP. These copy number variants include tau but few other genes within the chromosome 17 haplotype region, providing additional support for the direct pathogenicity of MAPT in PSP.

Conclusions: Clinicians should also be aware of MAPT duplication as a possible genetic cause of PSP, especially in patients presenting with young age at onset. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27702DOI Listing
July 2019

Predicting the future of ALS: the impact of demographic change and potential new treatments on the prevalence of ALS in the United Kingdom, 2020-2116.

Amyotroph Lateral Scler Frontotemporal Degener 2019 05 9;20(3-4):264-274. Epub 2019 Apr 9.

a Department of Basic and Clinical Neuroscience , King's College London, Maurice Wohl Clinical Neuroscience Institute , London , UK.

To model the effects of demographic change under various scenarios of possible future treatment developments in ALS. Patients diagnosed with ALS at the King's College Hospital Motor Nerve Clinic between 2004 and 2017, and living within the London boroughs of Lambeth, Southwark, and Lewisham (LSL), were included as incident cases. We also ascertained incident cases from the Canterbury region over the same period. Future incidence of ALS was estimated by applying the calculated age- and sex-specific incidence rates to the UK population projections from 2020 to 2116. The number of prevalent cases for each future year was estimated based on an established method. Assuming constant incidence, we modelled four possible future prevalence scenarios by altering the median disease duration for varying subsets of the population, to represent the impact of new treatments. The total number of people newly diagnosed with ALS per year in the UK is projected to rise from a baseline of 1415 UK cases in 2010 to 1701 in 2020 and 2635 in 2116. Overall prevalence of ALS was predicted to increase from 8.58 per 100,000 persons in 2020 to 9.67 per 100,000 persons in 2116. Halting disease progression in patients with mutations would yield the greatest impact of the modelled treatment scenarios, increasing prevalence in the year 2066 from a baseline of 9.50 per 100,000 persons to 15.68 per 100,000 persons. Future developments in treatment would combine with the effects of demographic change to result in more people living longer with ALS.
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http://dx.doi.org/10.1080/21678421.2019.1587629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567553PMC
May 2019

Telomere length is greater in ALS than in controls: a whole genome sequencing study.

Amyotroph Lateral Scler Frontotemporal Degener 2019 05 1;20(3-4):229-234. Epub 2019 Apr 1.

a Department of Basic and Clinical Neuroscience , King's College London, Maurice Wohl Clinical Neuroscience Institute , London , UK.

Amyotrophic lateral sclerosis is a neurodegenerative disease of motor neurons resulting in progressive paralysis and death, typically within 3-5 years. Although the heritability of ALS is about 60%, only about 11% is explained by common gene variants, suggesting that other forms of genetic variation are important. Telomeres maintain DNA integrity during cellular replication and shorten naturally with age. Gender and age are risk factors for ALS and also associated with telomere length. We therefore investigated telomere length in ALS. We estimated telomere length by applying a bioinformatics analysis to whole genome sequence data of leukocyte-derived DNA from people with ALS and age and gender-matched matched controls in a UK population. We tested the association of telomere length with ALS and ALS survival. There were 1241 people with ALS and 335 controls. The median age for ALS was 62.5 years and for controls, 60.1 years, with a male-female ratio of 62:38. Accounting for age and sex, there was a 9% increase of telomere length in ALS compared to matched controls. Those with longer telomeres had a 16% increase in median survival. Of nine SNPs associated with telomere length, two were also associated with ALS: rs8105767 near the gene ( = 1.29 × 10) and rs6772228 ( = 0.001), which is in an intron for the gene. Longer telomeres in leukocyte-derived DNA are associated with ALS, and with increased survival in those with ALS.
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http://dx.doi.org/10.1080/21678421.2019.1586951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567548PMC
May 2019

ALSgeneScanner: a pipeline for the analysis and interpretation of DNA sequencing data of ALS patients.

Amyotroph Lateral Scler Frontotemporal Degener 2019 05 5;20(3-4):207-215. Epub 2019 Mar 5.

c UK Dementia Research Institute, King's College London , London , UK.

Amyotrophic lateral sclerosis (ALS, MND) is a neurodegenerative disease of upper and lower motor neurons resulting in death from neuromuscular respiratory failure, typically within two years of first symptoms. Genetic factors are an important cause of ALS, with variants in more than 25 genes having strong evidence, and weaker evidence available for variants in more than 120 genes. With the increasing availability of next-generation sequencing data, non-specialists, including health care professionals and patients, are obtaining their genomic information without a corresponding ability to analyze and interpret it. Furthermore, the relevance of novel or existing variants in ALS genes is not always apparent. Here we present ALSgeneScanner, a tool that is easy to install and use, able to provide an automatic, detailed, annotated report, on a list of ALS genes from whole-genome sequencing (WGS) data in a few hours and whole exome sequence data in about 1 h on a readily available mid-range computer. This will be of value to non-specialists and aid in the interpretation of the relevance of novel and existing variants identified in DNA sequencing data.
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http://dx.doi.org/10.1080/21678421.2018.1562553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567555PMC
May 2019

Younger age of onset in familial amyotrophic lateral sclerosis is a result of pathogenic gene variants, rather than ascertainment bias.

J Neurol Neurosurg Psychiatry 2019 03 30;90(3):268-271. Epub 2018 Sep 30.

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK

Objective: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease of motor neurons with a median survival of 2 years. Familial ALS has a younger age of onset than apparently sporadic ALS. We sought to determine whether this younger age of onset is a result of ascertainment bias or has a genetic basis.

Methods: Samples from people with ALS were sequenced for 13 ALS genes. To determine the effect of genetic variation, age of onset was compared in people with sporadic ALS carrying a pathogenic gene variant and those who do not; to determine the effect of family history, we compared those with genetic sporadic ALS and familial ALS.

Results: There were 941 people with a diagnosis of ALS, 100 with familial ALS. Of 841 with apparently sporadic ALS, 95 carried a pathogenic gene variant. The mean age of onset in familial ALS was 5.3 years younger than for apparently sporadic ALS (p=6.0×10, 95% CI 2.8 to 7.8 years). The mean age of onset of genetic sporadic ALS was 2.9 years younger than non-genetic sporadic ALS (p=0.011, 95% CI 0.7 to 5.2 years). There was no difference between the mean age of onset in genetic sporadic ALS and familial ALS (p=0.097).

Conclusions: People with familial ALS have an age of onset about 5 years younger than those with apparently sporadic ALS, and we have shown that this is a result of Mendelian gene variants lowering the age of onset, rather than ascertainment bias.
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http://dx.doi.org/10.1136/jnnp-2018-319089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518463PMC
March 2019

Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases.

Mol Neurodegener 2018 08 8;13(1):41. Epub 2018 Aug 8.

Interdepartmental Program in Bioinformatics, University of California, Los Angeles, CA, 90095, USA.

Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease for which the genetic contribution is incompletely understood.

Methods: We conducted a joint analysis of 5,523,934 imputed SNPs in two newly-genotyped progressive supranuclear palsy cohorts, primarily derived from two clinical trials (Allon davunetide and NNIPPS riluzole trials in PSP) and a previously published genome-wide association study (GWAS), in total comprising 1646 cases and 10,662 controls of European ancestry.

Results: We identified 5 associated loci at a genome-wide significance threshold P < 5 × 10, including replication of 3 loci from previous studies and 2 novel loci at 6p21.1 and 12p12.1 (near RUNX2 and SLCO1A2, respectively). At the 17q21.31 locus, stepwise regression analysis confirmed the presence of multiple independent loci (localized near MAPT and KANSL1). An additional 4 loci were highly suggestive of association (P < 1 × 10). We analyzed the genetic correlation with multiple neurodegenerative diseases, and found that PSP had shared polygenic heritability with Parkinson's disease and amyotrophic lateral sclerosis.

Conclusions: In total, we identified 6 additional significant or suggestive SNP associations with PSP, and discovered genetic overlap with other neurodegenerative diseases. These findings clarify the pathogenesis and genetic architecture of PSP.
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http://dx.doi.org/10.1186/s13024-018-0270-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6083608PMC
August 2018

Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials.

Neurology 2017 Oct 4;89(18):1915-1922. Epub 2017 Oct 4.

From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute Centre (A.R.J., W.S., A.S., C.E.S., A.A.-C.), Department of Basic and Clinical Neuroscience, King's College London; Sheffield Institute for Translational Neuroscience (SITraN) (P.J.S.), University of Sheffield, South Yorkshire; Department of Clinical Neuroscience (P.N.L.), Trafford Centre for Biomedical Research, Brighton and Sussex Medical School, Falmer, Brighton; The Walton Centre NHS Trust (C.A.Y.), Liverpool, UK; Istituti Clinici Scientifici Maugeri IRCSS (G.M.), Milan; Department of Neuroscience (J.M.), Sant'Agostino-Estense Hospital and University of Modena and Reggio Emilia, Modena; Department of Neurology (G.B.), Azienda Universitario Ospedaliera di Cagliari and University of Cagliari; Istituti Clinici Scientifici Maugeri IRCSS (P.V.), Mistretta, Italy; Rijnstate Ziekenhuis (E.V.), Arnhem, the Netherlands; Rita Levi Montalcini' Department of Neuroscience (A.C.), ALS Centre, University of Torino; and Azienda Ospedaliera Città della Salute e della Scienza (A.C.), Turin, Italy.

Objective: To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatment with lithium carbonate, but that the treatment effect was lost in a large cohort of nonresponders.

Methods: Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the and genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype.

Results: Clinical data were available for 518 of the 606 participants. Overall, treatment with lithium carbonate did not improve 12-month survival (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.7-1.4; = 0.96). Both the and genotype were independent predictors of survival (HR 2.4, 95% CI 1.3-4.3; = 0.006 and HR 2.5, 95% CI 1.1-5.2; = 0.032, respectively). The effect of lithium was different for carriers ( = 0.027), but not for carriers ( = 0.22). The 12-month survival probability for carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2-69.1) to 69.7% (95% CI 50.4-96.3).

Conclusions: This study incorporated genetic data into past ALS trials to determine treatment effects in a genetic post hoc analysis. Our results suggest that we should reorient our strategies toward finding treatments for ALS, start focusing on genotype-targeted treatments, and standardize genotyping in order to optimize randomization and analysis for future clinical trials.
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http://dx.doi.org/10.1212/WNL.0000000000004606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664299PMC
October 2017

A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK.

Brain 2017 Jun;140(6):1611-1618

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, SE5 9RX, UK.

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation in a panel of known amyotrophic lateral sclerosis genes in 1126 patient samples and 613 controls. About 10% of patients were predicted to carry a pathological expansion of the C9orf72 gene. We found an increased burden of rare variants in patients within the untranslated regions of known disease-causing genes, driven by SOD1, TARDBP, FUS, VCP, OPTN and UBQLN2. We found 11 patients (1%) carried more than one pathogenic variant (P = 0.001) consistent with an oligogenic basis of amyotrophic lateral sclerosis. These findings show that the genetic architecture of amyotrophic lateral sclerosis is complex and that variation in the regulatory regions of associated genes may be important in disease pathogenesis.
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http://dx.doi.org/10.1093/brain/awx082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445258PMC
June 2017

ATXN2 trinucleotide repeat length correlates with risk of ALS.

Neurobiol Aging 2017 03 24;51:178.e1-178.e9. Epub 2016 Nov 24.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

We investigated a CAG trinucleotide repeat expansion in the ATXN2 gene in amyotrophic lateral sclerosis (ALS). Two new case-control studies, a British dataset of 1474 ALS cases and 567 controls, and a Dutch dataset of 1328 ALS cases and 691 controls were analyzed. In addition, to increase power, we systematically searched PubMed for case-control studies published after 1 August 2010 that investigated the association between ATXN2 intermediate repeats and ALS. We conducted a meta-analysis of the new and existing studies for the relative risks of ATXN2 intermediate repeat alleles of between 24 and 34 CAG trinucleotide repeats and ALS. There was an overall increased risk of ALS for those carrying intermediate sized trinucleotide repeat alleles (odds ratio 3.06 [95% confidence interval 2.37-3.94]; p = 6 × 10), with an exponential relationship between repeat length and ALS risk for alleles of 29-32 repeats (R = 0.91, p = 0.0002). No relationship was seen for repeat length and age of onset or survival. In contrast to trinucleotide repeat diseases, intermediate ATXN2 trinucleotide repeat expansion in ALS does not predict age of onset but does predict disease risk.
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http://dx.doi.org/10.1016/j.neurobiolaging.2016.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302215PMC
March 2017

Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2016 Oct - Nov;17(7-8):593-599. Epub 2016 Sep 1.

a Maurice Wohl Clinical Neuroscience Institute, King's College London, Institute of Psychiatry, Psychology and Neuroscience , London , UK.

Our objective was to identify whether rare genetic variation in amyotrophic lateral sclerosis (ALS) candidate survival genes modifies ALS survival. Candidate genes were selected based on evidence for modifying ALS survival. Each tail of the extreme 1.5% of survival was selected from the UK MND DNA Bank and all samples available underwent whole genome sequencing. A replication set from the Netherlands was used for validation. Sequences of candidate survival genes were extracted and variants passing quality control with a minor allele frequency ≤0.05 were selected for association testing. Analysis was by burden testing using SKAT. Candidate survival genes UNC13A, KIFAP3, and EPHA4 were tested for association in a UK sample comprising 25 short survivors and 25 long survivors. Results showed that only SNVs in UNC13A were associated with survival (p = 6.57 × 10). SNV rs10419420:G > A was found exclusively in long survivors (3/25) and rs4808092:G > A exclusively in short survivors (4/25). These findings were not replicated in a Dutch sample. In conclusion, population specific rare variants of UNC13A may modulate survival in ALS.
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http://dx.doi.org/10.1080/21678421.2016.1213852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125285PMC
October 2017

Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.

Nat Genet 2016 09 25;48(9):1043-8. Epub 2016 Jul 25.

Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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http://dx.doi.org/10.1038/ng.3622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556360PMC
September 2016

NEK1 variants confer susceptibility to amyotrophic lateral sclerosis.

Nat Genet 2016 09 25;48(9):1037-42. Epub 2016 Jul 25.

Neurogenetics Group, Division of Brain Sciences, Imperial College London, London, UK.

To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.
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http://dx.doi.org/10.1038/ng.3626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5560030PMC
September 2016

Identification of miRNAs as Potential Biomarkers in Cerebrospinal Fluid from Amyotrophic Lateral Sclerosis Patients.

Neuromolecular Med 2016 Dec 27;18(4):551-560. Epub 2016 Apr 27.

Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy.

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disorder. Since no diagnostic laboratory test exists, the identification of specific biomarkers could be fundamental in clinical practice. microRNAs (miRNAs) are considered promising biomarkers for neurodegenerative diseases. The aim of the study was to identify a CSF miRNA set that could differentiate ALS from non-ALS condition. miRNA profiling in CSF from ALS patients (n = 24; eight with C9orf72 expansion) and unaffected control subjects (n = 24) by quantitative reverse transcription PCR identified fourteen deregulated miRNAs. Validation experiments confirmed eight miRNAs as significantly deregulated in ALS. No significant differences were observed between ALS patients with or without C9orf72 expansion. The receiver operator characteristic (ROC) curve analyses revealed the highest diagnostic accuracy for the upregulated miR181a-5p and the downregulated miR21-5p and miR15b-5p. The miR181a-5p/miR21-5p and miR181a-5p/miR15b-5p ratios detected ALS with 90 and 85 % sensitivity and 87 and 91 % specificity, respectively, confirming the application potential as disease biomarkers. These deregulated miRNAs are implicated in apoptotic way and provide insight into processes responsible for motor neuron degeneration.
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http://dx.doi.org/10.1007/s12017-016-8396-8DOI Listing
December 2016

Regionality of disease progression predicts prognosis in amyotrophic lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2015 17;16(7-8):442-7. Epub 2015 Jun 17.

a Department of Basic and Clinical Neuroscience , Institute of Psychiatry, Psychology & Neuroscience, King's College London , UK.

Amyotrophic lateral sclerosis (ALS) is a devastating neurological syndrome in which motor neurons degenerate relentlessly. Although the site of onset and the rate of spread have been studied extensively, little is known about whether focal as opposed to diffuse disease affects prognosis. We therefore tested the hypothesis that regionality of disease burden is a prognostic factor in ALS. We analysed clinical data from two large multicentre, longitudinal trials. Regionality was defined as the difference in progression rates in three domains as measured by the revised ALS Functional Rating Scale, omitting the respiratory domain from analysis. We used death by trial end as the outcome variable and tested this by logistic regression against predictor variables including regionality and overall rate of disease progression. There were 561 patients. Regionality of disease was independently associated with significantly higher chance of death by study end (odds ratio most diffuse against most focal category 0.354 (0.191, 0.657), p = 0.001), with a direct relationship between degree of regionality and odds of death. We have shown using clinical trial data that focal disease is associated with a worse prognosis in ALS. Measures of regionality warrant further independent consideration in the development of future prognostic models.
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http://dx.doi.org/10.3109/21678421.2015.1051987DOI Listing
August 2016

Stratified gene expression analysis identifies major amyotrophic lateral sclerosis genes.

Neurobiol Aging 2015 May 19;36(5):2006.e1-9. Epub 2015 Feb 19.

Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. Electronic address:

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons resulting in progressive paralysis. Gene expression studies of ALS only rarely identify the same gene pathways as gene association studies. We hypothesized that analyzing tissues by matching on degree of disease severity would identify different patterns of gene expression from a traditional case-control comparison. We analyzed gene expression changes in 4 postmortem central nervous system regions, stratified by severity of motor neuron loss. An overall comparison of cases (n = 6) and controls (n = 3) identified known ALS gene, SOX5, as showing differential expression (log2 fold change = 0.09, p = 5.5 × 10(-5)). Analyses stratified by disease severity identified expression changes in C9orf72 (p = 2.77 × 10(-3)), MATR3 (p = 3.46 × 10(-3)), and VEGFA (p = 8.21 × 10(-4)), all implicated in ALS through genetic studies, and changes in other genes in pathways involving RNA processing and immune response. These findings suggest that analysis of gene expression stratified by disease severity can identify major ALS genes and may be more efficient than traditional case-control comparison.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.02.017DOI Listing
May 2015

Health utility decreases with increasing clinical stage in amyotrophic lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2014 Jun 7;15(3-4):285-91. Epub 2014 Feb 7.

Department of Clinical Neuroscience, Institute of Psychiatry , King's College London, London.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease typically causing death within three years. Understanding the impact of disease on patients using health utility at different stages of ALS would allow meaningful cost-benefit analysis of new potential therapies. A common health-related quality of life measurement, developed and validated for the UK, is the EQ-5D. Using clinical trial data from the LiCALS study, we calculated health utility using the EQ-5D for each King's ALS clinical stage from 214 patients. We analysed whether health utility, and other health-related measures, significantly changed between each of the clinical stages. Results showed that mean health utility decreased by 0.487 (the scale runs from 1 to - 0.594) between clinical stages 2A and 4. Emotional states, measured using the Hospital Anxiety and Depression Scale (HADS), showed worsening depression and anxiety scores as ALS progressed. Age of onset, disease onset, gender and treatment group were not predictors of EQ-5D, depression or anxiety. In conclusion, increasing severity of King's ALS Clinical Stage is associated with a progressive decrease in EQ-5D health utility. This is useful for cost-benefit analysis of new therapies and validates this ALS clinical staging system.
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http://dx.doi.org/10.3109/21678421.2013.872149DOI Listing
June 2014

Genetic ablation of phospholipase C delta 1 increases survival in SOD1(G93A) mice.

Neurobiol Dis 2013 Dec 19;60:11-7. Epub 2013 Aug 19.

Laboratory of Neurobiology, Belgium; Leuven Research Institute of Neuroscience and Disease (LIND), KU Leuven, Belgium; Vesalius Research Center, VIB, Belgium. Electronic address:

Amyotrophic Lateral Sclerosis (ALS) is a devastating progressive neurodegenerative disease, resulting in selective motor neuron degeneration and paralysis. Patients die approximately 3-5 years after diagnosis. Disease pathophysiology is multifactorial, including excitotoxicity, but is not yet fully understood. Genetic analysis has proven fruitful in the past to further understand genes modulating the disease and increase knowledge of disease mechanisms. Here, we revisit a previously performed microsatellite analysis in ALS and focus on another hit, PLCD1, encoding phospholipase C delta 1 (PLCδ1), to investigate its role in ALS. PLCδ1 may contribute to excitotoxicity as it increases inositol 1,4,5-trisphosphate (IP3) formation, which releases calcium from the endoplasmic reticulum through IP3 receptors. We find that expression of PLCδ1 is increased in ALS mouse spinal cord and in neurons from ALS mice. Furthermore, genetic ablation of this protein in ALS mice significantly increases survival, but does not affect astrogliosis, microgliosis, aggregation or the amount of motor neurons at end stage compared to ALS mice with PLCδ1. Interestingly, genetic ablation of PLCδ1 prevents nuclear shrinkage of motor neurons in ALS mice at end stage. These results indicate that PLCD1 contributes to ALS and that PLCδ1 may be a new target for future studies.
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http://dx.doi.org/10.1016/j.nbd.2013.08.006DOI Listing
December 2013

Residual association at C9orf72 suggests an alternative amyotrophic lateral sclerosis-causing hexanucleotide repeat.

Neurobiol Aging 2013 Sep 12;34(9):2234.e1-7. Epub 2013 Apr 12.

King's College London, Institute of Psychiatry, Department of Clinical Neuroscience, London, UK.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons. Single-nucleotide polymorphism rs3849942 is associated with ALS, tagging a hexanucleotide repeat mutation in the C9orf72 gene. It is possible that there is more than 1 disease-causing genetic variation at this locus, in which case association might remain after removal of cases carrying the mutation. DNA from patients with ALS was therefore tested for the mutation. Genome-wide association testing was performed first using all samples, and then restricting the analysis to samples not carrying the mutation. rs3849942 and rs903603 were strongly associated with ALS when all samples were included (rs3849942, p = [3 × 2] × 10(-6), rank 7/442,057; rs903603, p = [7 × 6] × 10(-8), rank 2/442,057). Removal of the mutation-carrying cases resulted in loss of association for rs3849942 (p = [2 × 6] × 10(-3), rank 1225/442,068), but had little effect on rs903603 (p = [1 × 9] × 10(-5), rank 8/442,068). Those with a risk allele of rs903603 had an excess of apparent homozygosity for wild type repeat alleles, consistent with polymerase chain reaction failure of 1 allele because of massive repeat expansion. These results indicate residual association at the C9orf72 locus suggesting a second disease-causing repeat mutation.
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http://dx.doi.org/10.1016/j.neurobiolaging.2013.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753508PMC
September 2013

Development of a Smartphone App for a Genetics Website: The Amyotrophic Lateral Sclerosis Online Genetics Database (ALSoD).

JMIR Mhealth Uhealth 2013 Sep 4;1(2):e18. Epub 2013 Sep 4.

King's College London, Institute of Psychiatry, Department of Clinical Neuroscience, London, United Kingdom.

Background: The ALS Online Genetics Database (ALSoD) website holds mutation, geographical, and phenotype data on genes implicated in amyotrophic lateral sclerosis (ALS) and links to bioinformatics resources, publications, and tools for analysis. On average, there are 300 unique visits per day, suggesting a high demand from the research community. To enable wider access, we developed a mobile-friendly version of the website and a smartphone app.

Objective: We sought to compare data traffic before and after implementation of a mobile version of the website to assess utility.

Methods: We identified the most frequently viewed pages using Google Analytics and our in-house analytic monitoring. For these, we optimized the content layout of the screen, reduced image sizes, and summarized available information. We used the Microsoft .NET framework mobile detection property (HttpRequest.IsMobileDevice in the Request.Browser object in conjunction with HttpRequest.UserAgent), which returns a true value if the browser is a recognized mobile device. For app development, we used the Eclipse integrated development environment with Android plug-ins. We wrapped the mobile website version with the WebView object in Android. Simulators were downloaded to test and debug the applications.

Results: The website automatically detects access from a mobile phone and redirects pages to fit the smaller screen. Because the amount of data stored on ALSoD is very large, the available information for display using smartphone access is deliberately restricted to improve usability. Visits to the website increased from 2231 to 2820, yielding a 26% increase from the pre-mobile to post-mobile period and an increase from 103 to 340 visits (230%) using mobile devices (including tablets). The smartphone app is currently available on BlackBerry and Android devices and will be available shortly on iOS as well.

Conclusions: Further development of the ALSoD website has allowed access through smartphones and tablets, either through the website or directly through a mobile app, making genetic data stored on the database readily accessible to researchers and patients across multiple devices.
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http://dx.doi.org/10.2196/mhealth.2706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4114449PMC
September 2013