Publications by authors named "Kevin P Kenna"

22 Publications

  • Page 1 of 1

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.

JAMA Neurol 2021 Aug 30. Epub 2021 Aug 30.

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

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.

Objective: To identify the genetic variants associated with juvenile ALS.

Design, Setting, And Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.

Main Outcomes And Measures: De novo variants present only in the index case and not in unaffected family members.

Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.

Conclusions And Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.
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http://dx.doi.org/10.1001/jamaneurol.2021.2598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406220PMC
August 2021

Advances in the genetic classification of amyotrophic lateral sclerosis.

Curr Opin Neurol 2021 Aug 2. Epub 2021 Aug 2.

Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK Department of Genetics Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, California, USA Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London National Institute for Health Research Biomedical Research Centre and Dementia Unit, South London and Maudsley NHS Foundation Trust and King's College London, London, UK.

Purpose Of Review: Amyotrophic lateral sclerosis (ALS) is an archetypal complex disease wherein disease risk and severity are, for the majority of patients, the product of interaction between multiple genetic and environmental factors. We are in a period of unprecedented discovery with new large-scale genome-wide association study (GWAS) and accelerating discovery of risk genes. However, much of the observed heritability of ALS is undiscovered and we are not yet approaching elucidation of the total genetic architecture, which will be necessary for comprehensive disease subclassification.

Recent Findings: We summarize recent developments and discuss the future. New machine learning models will help to address nonlinear genetic interactions. Statistical power for genetic discovery may be boosted by reducing the search-space using cell-specific epigenetic profiles and expanding our scope to include genetically correlated phenotypes. Structural variation, somatic heterogeneity and consideration of environmental modifiers represent significant challenges which will require integration of multiple technologies and a multidisciplinary approach, including clinicians, geneticists and pathologists.

Summary: The move away from fully penetrant Mendelian risk genes necessitates new experimental designs and new standards for validation. The challenges are significant, but the potential reward for successful disease subclassification is large-scale and effective personalized medicine.
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http://dx.doi.org/10.1097/WCO.0000000000000986DOI Listing
August 2021

Common and rare variant analyses combined with single-cell multiomics reveal cell-type-specific molecular mechanisms of COVID-19 severity.

medRxiv 2021 Jun 21. Epub 2021 Jun 21.

The determinants of severe COVID-19 in non-elderly adults are poorly understood, which limits opportunities for early intervention and treatment. Here we present novel machine learning frameworks for identifying common and rare disease-associated genetic variation, which outperform conventional approaches. By integrating single-cell multiomics profiling of human lungs to link genetic signals to cell-type-specific functions, we have discovered and validated over 1,000 risk genes underlying severe COVID-19 across 19 cell types. Identified risk genes are overexpressed in healthy lungs but relatively downregulated in severely diseased lungs. Genetic risk for severe COVID-19, within both common and rare variants, is particularly enriched in natural killer (NK) cells, which places these immune cells upstream in the pathogenesis of severe disease. Mendelian randomization indicates that failed NKG2D-mediated activation of NK cells leads to critical illness. Network analysis further links multiple pathways associated with NK cell activation, including type-I-interferon-mediated signalling, to severe COVID-19. Our rare variant model, PULSE, enables sensitive prediction of severe disease in non-elderly patients based on whole-exome sequencing; individualized predictions are accurate independent of age and sex, and are consistent across multiple populations and cohorts. Risk stratification based on exome sequencing has the potential to facilitate post-exposure prophylaxis in at-risk individuals, potentially based around augmentation of NK cell function. Overall, our study characterizes a comprehensive genetic landscape of COVID-19 severity and provides novel insights into the molecular mechanisms of severe disease, leading to new therapeutic targets and sensitive detection of at-risk individuals.
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http://dx.doi.org/10.1101/2021.06.15.21258703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240695PMC
June 2021

Genetic analysis of ALS cases in the isolated island population of Malta.

Eur J Hum Genet 2021 Apr 7;29(4):604-614. Epub 2021 Jan 7.

Centre for Molecular Medicine and Biobanking, Biomedical Sciences Building, University of Malta, Msida, Malta.

Genetic isolates are compelling tools for mapping genes of inherited disorders. The archipelago of Malta, a sovereign microstate in the south of Europe is home to a geographically and culturally isolated population. Here, we investigate the epidemiology and genetic profile of Maltese patients with amyotrophic lateral sclerosis (ALS), identified throughout a 2-year window. Cases were largely male (66.7%) with a predominant spinal onset of symptoms (70.8%). Disease onset occurred around mid-age (median age: 64 years, men; 59.5 years, female); 12.5% had familial ALS (fALS). Annual incidence rate was 2.48 (95% CI 1.59-3.68) per 100,000 person-years. Male-to-female incidence ratio was 1.93:1. Prevalence was 3.44 (95% CI 2.01-5.52) cases per 100,000 inhabitants on 31 December 2018. Whole-genome sequencing allowed us to determine rare DNA variants that change the protein-coding sequence of ALS-associated genes. Interestingly, the Maltese ALS patient cohort was found to be negative for deleterious variants in C9orf72, SOD1, TARDBP or FUS genes, which are the most commonly mutated ALS genes globally. Nonetheless, ALS-associated repeat expansions were identified in ATXN2 and NIPA1. Variants predicted to be damaging were also detected in ALS2, DAO, DCTN1, ERBB4, SETX, SCFD1 and SPG11. A total of 40% of patients with sporadic ALS had a rare and deleterious variant or repeat expansion in an ALS-associated gene, whilst the genetic cause of two thirds of fALS cases could not be pinpointed to known ALS genes or risk loci. This warrants further studies to elucidate novel genes that cause ALS in this unique population isolate.
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http://dx.doi.org/10.1038/s41431-020-00767-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115635PMC
April 2021

Rare Variant Burden Analysis within Enhancers Identifies CAV1 as an ALS Risk Gene.

Cell Rep 2020 12;33(9):108456

Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK. Electronic address:

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease. CAV1 and CAV2 organize membrane lipid rafts (MLRs) important for cell signaling and neuronal survival, and overexpression of CAV1 ameliorates ALS phenotypes in vivo. Genome-wide association studies localize a large proportion of ALS risk variants within the non-coding genome, but further characterization has been limited by lack of appropriate tools. By designing and applying a pipeline to identify pathogenic genetic variation within enhancer elements responsible for regulating gene expression, we identify disease-associated variation within CAV1/CAV2 enhancers, which replicate in an independent cohort. Discovered enhancer mutations reduce CAV1/CAV2 expression and disrupt MLRs in patient-derived cells, and CRISPR-Cas9 perturbation proximate to a patient mutation is sufficient to reduce CAV1/CAV2 expression in neurons. Additional enrichment of ALS-associated mutations within CAV1 exons positions CAV1 as an ALS risk gene. We propose CAV1/CAV2 overexpression as a personalized medicine target for ALS.
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http://dx.doi.org/10.1016/j.celrep.2020.108456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710676PMC
December 2020

repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization.

Brain Commun 2020 19;2(2):fcaa064. Epub 2020 May 19.

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute, King's College London, London SE5 9NU, UK.

Increasingly, repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. To date, several repeat expansions have been genetically associated with the disease: intronic repeat expansions in , polyglutamine expansions in and polyalanine expansions in . Together with previously published data, the identification of an amyotrophic lateral sclerosis patient with a family history of spinocerebellar ataxia type 1, caused by polyglutamine expansions in , suggested a similar disease association for the repeat expansion in . We, therefore, performed a large-scale international study in 11 700 individuals, in which we showed a significant association between intermediate repeat expansions and amyotrophic lateral sclerosis (=3.33 × 10). Subsequent functional experiments have shown that ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances amyotrophic lateral sclerosis phenotypes in , further emphasizing the role of polyglutamine repeat expansions in the pathophysiology of amyotrophic lateral sclerosis.
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http://dx.doi.org/10.1093/braincomms/fcaa064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425293PMC
May 2020

The project MinE databrowser: bringing large-scale whole-genome sequencing in ALS to researchers and the public.

Amyotroph Lateral Scler Frontotemporal Degener 2019 08;20(5-6):432-440

a Department of Neurology , Brain Center Rudolf Magnus, University Medical Center Utrecht , Utrecht , The Netherlands.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive fatal neurodegenerative disease affecting one in 350 people. The aim of Project MinE is to elucidate the pathophysiology of ALS through whole-genome sequencing at least 15,000 ALS patients and 7500 controls at 30× coverage. Here, we present the Project MinE data browser ( databrowser.projectmine.com ), a unique and intuitive one-stop, open-access server that provides detailed information on genetic variation analyzed in a new and still growing set of 4366 ALS cases and 1832 matched controls. Through its visual components and interactive design, the browser specifically aims to be a resource to those without a biostatistics background and allow clinicians and preclinical researchers to integrate Project MinE data into their own research. The browser allows users to query a transcript and immediately access a unique combination of detailed (meta)data, annotations and association statistics that would otherwise require analytic expertise and visits to scattered resources.
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http://dx.doi.org/10.1080/21678421.2019.1606244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893599PMC
August 2019

Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort.

Neurobiol Aging 2019 02 22;74:234.e9-234.e15. Epub 2018 Sep 22.

Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address:

NIPA1 (nonimprinted in Prader-Willi/Angelman syndrome 1) mutations are known to cause hereditary spastic paraplegia type 6, a neurodegenerative disease that phenotypically overlaps to some extent with amyotrophic lateral sclerosis (ALS). Previously, a genomewide screen for copy number variants found an association with rare deletions in NIPA1 and ALS, and subsequent genetic analyses revealed that long (or expanded) polyalanine repeats in NIPA1 convey increased ALS susceptibility. We set out to perform a large-scale replication study to further investigate the role of NIPA1 polyalanine expansions with ALS, in which we characterized NIPA1 repeat size in an independent international cohort of 3955 patients with ALS and 2276 unaffected controls and combined our results with previous reports. Meta-analysis on a total of 6245 patients with ALS and 5051 controls showed an overall increased risk of ALS in those with expanded (>8) GCG repeat length (odds ratio = 1.50, p = 3.8×10). Together with previous reports, these findings provide evidence for an association of an expanded polyalanine repeat in NIPA1 and ALS.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893598PMC
February 2019

ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function.

Neurobiol Aging 2018 11 25;71:266.e1-266.e10. Epub 2018 Jun 25.

Department of Neurology, University of Massachusetts Medical School, Worcester, MA.

Mutations in TANK binding kinase 1 (TBK1) have been linked to amyotrophic lateral sclerosis. Some TBK1 variants are nonsense and are predicted to cause disease through haploinsufficiency; however, many other mutations are missense with unknown functional effects. We exome sequenced 699 familial amyotrophic lateral sclerosis patients and identified 16 TBK1 novel or extremely rare protein-changing variants. We characterized a subset of these: p.G217R, p.R357X, and p.C471Y. Here, we show that the p.R357X and p.G217R both abolish the ability of TBK1 to phosphorylate 2 of its kinase targets, IRF3 and optineurin, and to undergo phosphorylation. They both inhibit binding to optineurin and the p.G217R, within the TBK1 kinase domain, reduces homodimerization, essential for TBK1 activation and function. Finally, we show that the proportion of TBK1 that is active (phosphorylated) is reduced in 5 lymphoblastoid cell lines derived from patients harboring heterozygous missense or in-frame deletion TBK1 mutations. We conclude that missense mutations in functional domains of TBK1 impair the binding and phosphorylation of its normal targets, implicating a common loss of function mechanism, analogous to truncation mutations.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983933PMC
November 2018

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.

Neuron 2018 03;97(6):1268-1283.e6

Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
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http://dx.doi.org/10.1016/j.neuron.2018.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867896PMC
March 2018

Transcription factor Pebbled/RREB1 regulates injury-induced axon degeneration.

Proc Natl Acad Sci U S A 2018 02 2;115(6):1358-1363. Epub 2018 Jan 2.

Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01655;

Genetic studies of Wallerian degeneration have led to the identification of signaling molecules (e.g., dSarm/Sarm1, Axundead, and Highwire) that function locally in axons to drive degeneration. Here we identify a role for the CH zinc finger transcription factor Pebbled [Peb, Ras-responsive element binding protein 1 (RREB1) in mammals] in axon death. Loss of Peb in glutamatergic sensory neurons results in either complete preservation of severed axons, or an axon death phenotype where axons fragment into large, continuous segments, rather than completely disintegrate. Peb is expressed in developing and mature sensory neurons, suggesting it is required to establish or maintain their competence to undergo axon death. mutant phenotypes can be rescued by human RREB1, and they exhibit dominant genetic interactions with mutants, linking to the axon death signaling cascade. Surprisingly, Peb is only able to fully block axon death signaling in glutamatergic, but not cholinergic sensory neurons, arguing for genetic diversity in axon death signaling programs in different neuronal subtypes. Our findings identify a transcription factor that regulates axon death signaling, and mutant phenotypes of partial fragmentation reveal a genetically accessible step in axon death signaling.
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http://dx.doi.org/10.1073/pnas.1715837115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819420PMC
February 2018

Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis.

Sci Transl Med 2017 05;9(388)

Department of Genome Analysis, University of Amsterdam, Academic Medical Centre, P.O. Box 22700, 1100DE Amsterdam, Netherlands.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. We screened 751 familial ALS patient whole-exome sequences and identified six mutations including p.D40G in the gene in 13 individuals. The p.D40G mutation was absent from 70,000 control whole-exome sequences. This mutation segregated with disease in two kindreds and was present in another two unrelated cases ( = 0.0102), and all mutation carriers shared a common founder haplotype. Annexin A11-positive protein aggregates were abundant in spinal cord motor neurons and hippocampal neuronal axons in an ALS patient carrying the p.D40G mutation. Transfected human embryonic kidney cells expressing with the p.D40G mutation and other N-terminal mutations showed altered binding to calcyclin, and the p.R235Q mutant protein formed insoluble aggregates. We conclude that mutations in are associated with ALS and implicate defective intracellular protein trafficking in disease pathogenesis.
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http://dx.doi.org/10.1126/scitranslmed.aad9157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599403PMC
May 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

Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways.

Science 2015 Mar 19;347(6229):1436-41. Epub 2015 Feb 19.

Department of Basic and Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London SE5 8AF, UK.

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.
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http://dx.doi.org/10.1126/science.aaa3650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4437632PMC
March 2015

Homozygosity mapping in an Irish ALS case-control cohort describes local demographic phenomena and points towards potential recessive risk loci.

Genomics 2015 Apr 23;105(4):237-41. Epub 2015 Jan 23.

Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin 2, Ireland. Electronic address:

Runs of homozygosity are common in European populations and are indicative of consanguinity, restricted population size and recessively inherited traits. Here, we map runs of homozygosity (ROHs) in an Irish case-control cohort for amyotrophic lateral sclerosis (ALS), a devastating neurological condition with high heritability yet only partially established genetic cause. We compare the extent of homozygosity in the Irish cohort with a large British cohort and observe that ROHs are longer and more frequent in the Irish population than in the British, and that extent of ROHs is correlated with demographic factors within the island of Ireland. ROHs are also longer and more frequent in ALS cases compared to population-matched controls, supporting the hypothesis that recessively inherited loci play a pathogenic role in ALS. Comparing homozygous haplotypes between cases and controls reveals several potential recessive risk loci for ALS, including a genomic interval spanning ARHGEF1, a compelling ALS candidate gene.
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http://dx.doi.org/10.1016/j.ygeno.2015.01.002DOI Listing
April 2015

Second-generation Irish genome-wide association study for amyotrophic lateral sclerosis.

Neurobiol Aging 2015 Feb 6;36(2):1221.e7-13. Epub 2014 Sep 6.

Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Republic of Ireland.

Amyotrophic lateral sclerosis (ALS) is a heritable neurological disease for which the underlying genetic etiology is only partially understood. In Ireland, 83%-90% of cases are currently unexplained. Through large international collaborations, genome-wide association studies (GWASs) have succeeded in identifying a number of genomic loci that contribute toward ALS risk and age at onset. However, for the large proportion of risk that remains unexplained, population specificity of pathogenic variants could interfere with the detection of disease-associated loci. Single-population studies are therefore an important complement to larger international collaborations. In this study, we conduct a GWAS for ALS risk and age at onset in a large Irish ALS case-control cohort, using genome-wide imputation to increase marker density. Despite being adequately powered to detect associations of modest effect size, the study did not identify any locus associated with ALS risk or age at onset above the genome-wide significance threshold. Several speculative associations were, however, identified at loci that have been previously implicated in ALS. The lack of any clear association supports the conclusion that ALS is likely to be caused by multiple rare genetic risk factors. The findings of the present study highlight the importance of ongoing genetic research into the cause of ALS and its likely future challenges.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.08.030DOI Listing
February 2015

Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS.

Neuron 2014 Oct 22;84(2):324-31. Epub 2014 Oct 22.

Unidad de ELA, Instituto de Investigación Hospital 12 de Octubre de Madrid, SERMAS, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER U-723), 28041 Madrid, Spain.

Exome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family members prohibits comprehensive segregation analysis. To overcome this limitation, we performed an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS). The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability. These results further emphasize the role of cytoskeletal defects in ALS and demonstrate the power of gene-based rare variant analyses in situations where causal genes cannot be identified through traditional segregation analysis.
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http://dx.doi.org/10.1016/j.neuron.2014.09.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521390PMC
October 2014

Delineating the genetic heterogeneity of ALS using targeted high-throughput sequencing.

J Med Genet 2013 Nov 23;50(11):776-83. Epub 2013 Jul 23.

Smurfit Institute of Genetics, Trinity College, Dublin, Ireland.

Background: Over 100 genes have been implicated in the aetiology of amyotrophic lateral sclerosis (ALS). A detailed understanding of their independent and cumulative contributions to disease burden may help guide various clinical and research efforts.

Methods: Using targeted high-throughput sequencing, we characterised the variation of 10 Mendelian and 23 low penetrance/tentative ALS genes within a population-based cohort of 444 Irish ALS cases (50 fALS, 394 sALS) and 311 age-matched and geographically matched controls.

Results: Known or potential high-penetrance ALS variants were identified within 17.1% of patients (38% of fALS, 14.5% of sALS). 12.8% carried variants of Mendelian disease genes (C9orf72 8.78%; SETX 2.48%; ALS2 1.58%; FUS 0.45%; TARDBP 0.45%; OPTN 0.23%; VCP 0.23%. ANG, SOD1, VAPB 0%), 4.7% carried variants of low penetrance/tentative ALS genes and 9.7% (30% of fALS, 7.1% of sALS) carried previously described ALS variants (C9orf72 8.78%; FUS 0.45%; TARDBP 0.45%). 1.6% of patients carried multiple known/potential disease variants, including all identified carriers of an established ALS variant (p<0.01); TARDBP:c.859G>A(p.[G287S]) (n=2/2 sALS). Comparison of our results with those from studies of other European populations revealed significant differences in the spectrum of disease variation (p=1.7×10(-4)).

Conclusions: Up to 17% of Irish ALS cases may carry high-penetrance variants within the investigated genes. However, the precise nature of genetic susceptibility differs significantly from that reported within other European populations. Certain variants may not cause disease in isolation and concomitant analysis of disease genes may prove highly important.
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http://dx.doi.org/10.1136/jmedgenet-2013-101795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812897PMC
November 2013

Using reference databases of genetic variation to evaluate the potential pathogenicity of candidate disease variants.

Hum Mutat 2013 Jun 26;34(6):836-41. Epub 2013 Mar 26.

Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.

The potential pathogenicity of genetic variants identified in disease-based resequencing studies is often overlooked where variants have previously been reported in dbSNP, the 1000 genomes project, or the National Heart, Lung and Blood Institute Exome Sequencing Project (ESP). In this work, we estimate that collectively, these databases capture ∼52% of mutations (dbSNP 50.4%; 1000 genomes 4.8%; and ESP 10.2%) reported as disease causing within phenotype-based locus-specific databases (LSDBs). To investigate whether these mutations may simply represent benign population variants, we evaluated whether the carrier frequencies associated with mutations implicated in amyotrophic lateral sclerosis were higher than what could be accounted for by high-penetrance disease models. In doing so, we have questioned the veracity of 51 mutations, but also demonstrated that each of the three databases included credible disease variants. Our results demonstrate the benefits of using databases such as dbSNP, the 1000 genomes project, and the ESP to evaluate the pathogenicity of putative disease variants, and suggest that many disease mutations reported across LSDBs may not actually be pathogenic. However, they also demonstrate that even in the context of rare Mendelian disorders, the potential pathogenicity of variants reported by these databases should not be overlooked without proper evaluation.
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http://dx.doi.org/10.1002/humu.22303DOI Listing
June 2013
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