Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis (original) (raw)
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Acknowledgements
The work of the contributing groups was supported by various grants from governmental and charitable bodies. Details are provided in the Supplementary Note.
Author information
Author notes
- Wouter van Rheenen, Aleksey Shatunov and Cathryn M Lewis: These authors contributed equally to this work.
- Ammar Al-Chalabi, Leonard H van den Berg and Jan H Veldink: These authors jointly directed this work.
Authors and Affiliations
- Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands
Wouter van Rheenen, Annelot M Dekker, Frank P Diekstra, Rick A A van der Spek, Perry TC van Doormaal, Gijs H P Tazelaar, Max Koppers, Anna M Blokhuis, Kristel R van Eijk, Oliver Harschnitz, Raymond D Schellevis, William J Brands, Jelena Medic, Hylke M Blauw, Michael A van Es, Leonard H van den Berg & Jan H Veldink - Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK
Aleksey Shatunov, Isabella Fogh, William Sproviero, Ashley R Jones, Kuang Lin, Simon Topp, Christopher E Shaw, Bradley N Smith, John Powell & Ammar Al-Chalabi - Population Genetics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland
Russell L McLaughlin - Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
Sara L Pulit, Androniki Menelaou & Paul I W de Bakker - Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
Urmo Võsa & Lude Franke - MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
Simone de Jong, Charles Curtis, Cathryn M Lewis & Gerome Breen - NIHR Biomedical Research Centre for Mental Health, Maudsley Hospital and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
Simone de Jong, Charles Curtis & Gerome Breen - Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia
Matthew R Robinson, Jian Yang, Naomi R Wray & Peter M Visscher - Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy
Isabella Fogh, Nicola Ticozzi, Cinzia Tiloca, Antonia Ratti & Vincenzo Silani - Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands
Max Koppers, Anna M Blokhuis, Oliver Harschnitz & R Jeroen Pasterkamp - Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
Kevin P Kenna, Robert H Brown & John E Landers - Academic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute, Dublin, Ireland
Alice Vajda & Orla Hardiman - Department of Neurology, Beaumont Hospital, Dublin, Ireland
Alice Vajda & Orla Hardiman - Department of Pathophysiology and Tranplantation, 'Dino Ferrari' Center, Università degli Studi di Milano, Milan, Italy
Nicola Ticozzi, Antonia Ratti & Vincenzo Silani - Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia
Boris Rogelj - Biomedical Research Institute BRIS, Ljubljana, Slovenia
Boris Rogelj - Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Katarina Vrabec & Metka Ravnik-Glavač - Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Metka Ravnik-Glavač - Ljubljana ALS Centre, Institute of Clinical Neurophysiology, University Medical Centre Ljubljana, Ljubljana, Slovenia
Blaž Koritnik, Janez Zidar, Lea Leonardis & Leja Dolenc Grošelj - Institut du Cerveau et de la Moelle Epinière, INSERM U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06, UMRS 1127, Paris, France
Stéphanie Millecamps & François Salachas - Département de Neurologie, Centre de Référence Maladies Rares SLA Ile de France, Hôpital de la Pitié-Salpêtrière, Paris, France
François Salachas - GRC-UPMC SLA et Maladies du Motoneurone, Paris, France
François Salachas - Ramsay Generale de Santé, Hôpital Peupliers, Paris, France
Vincent Meininger - Réseau SLA Ile de France, Paris, France,
Vincent Meininger - Institute of Physiology, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
Mamede de Carvalho & Susana Pinto - Department of Neurosciences, Hospital de Santa Maria–CHLN, Lisbon, Portugal
Mamede de Carvalho & Susana Pinto - Department of Neurology, Hospital San Rafael, Madrid, Spain
Jesus S Mora - Neurology Department, Hospital de la Santa Creu i Sant Pau de Barcelona, Autonomous University of Barcelona, Barcelona, Spain
Ricardo Rojas-García - Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain
Ricardo Rojas-García - Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA
Meraida Polak & Jonathan D Glass - Emory ALS Center, Emory University School of Medicine, Atlanta, Georgia, USA
Meraida Polak & Jonathan D Glass - Euan MacDonald Centre for Motor Neuron Disease Research, Edinburgh, UK
Siddharthan Chandran, Shuna Colville & Robert Swingler - Centre for Neuroregeneration and Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
Siddharthan Chandran - Faculty of Medicine, University of Southampton, Southampton, UK
Karen E Morrison - Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK
Pamela J Shaw - Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK
John Hardy & Alan Pittman - Department of Clinical Neuroscience, Institute of Neurology, University College London, London, UK
Richard W Orrell & Katie Sidle - Reta Lila Weston Institute, Institute of Neurology, University College London, London, UK
Alan Pittman - Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, UK
Pietro Fratta - Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, London, UK
Andrea Malaspina - North-East London and Essex Regional Motor Neuron Disease Care Centre, London, UK
Andrea Malaspina - Department of Neurology, Hannover Medical School, Hannover, Germany
Susanne Petri - Department of Neurology, Otto von Güricke University Magdeburg, Magdeburg, Germany
Susanne Abdulla - Institute of Clinical Neurobiology, University Hospital Würzburg, Würzburg, Germany
Carsten Drepper & Michael Sendtner - Department of Neurology, Charité University Hospital, Humboldt University, Berlin, Germany
Thomas Meyer - Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands
Roel A Ophoff - Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
Roel A Ophoff - Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA
Roel A Ophoff & Kim A Staats - Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
Martina Wiedau-Pazos - Department of Neurology, University of California, San Francisco, San Francisco, California, USA
Catherine Lomen-Hoerth - Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
Vivianna M Van Deerlin & John Q Trojanowski - Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
Lauren Elman & Leo McCluskey - Neurodegeneration Research Laboratory, Boǧaziçi University, Istanbul, Turkey
A Nazli Basak, Ceren Tunca & Hamid Hamzeiy - Neurology Department, Istanbul Medical School, Istanbul University, Istanbul, Turkey
Yesim Parman - Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
Thomas Meitinger, Peter Lichtner & Milena Radivojkov-Blagojevic - INSERM U930, Université François Rabelais, Tours, France
Christian R Andres, Cindy Maurel, Philippe Corcia & Patrick Vourc'h - Département de Pharmacologie Clinique, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France
Gilbert Bensimon & Christine A M Payan - UPMC, Pharmacologie, Paris VI, Paris, France
Gilbert Bensimon - BESPIM, CHU de Nîmes, Nîmes, France
Gilbert Bensimon & Christine A M Payan - Department of Neurology, Ulm University, Ulm, Germany
Bernhard Landwehrmeyer, Albert C Ludolph, Jochen H Weishaupt & Peter M Andersen - INSERM U1127, Hôpital de la Pitié-Salpêtrière, Paris, France
Alexis Brice - CNRS UMR 7225, Hôpital de la Pitié-Salpêtrière, Paris, France
Alexis Brice - Sorbonne Universités, UPMC Paris 06, UMRS 1127, Hôpital de la Pitié-Salpêtrière, Paris, France
Alexis Brice - Institut du Cerveau et de la Moelle Epinière, Hôpital de la Pitié-Salpêtrière, Paris, France
Alexis Brice - Département de Génétique, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France
Alexis Brice - Genethon, CNRS UMR 8587, Evry, France
Safaa Saker-Delye - Department of Medical Genetics, Institut du Cerveau et de la Moelle Epinière, Hôptial Pitié-Salpêtrière, Paris, France
Alexandra Dürr - Department of Neurogenetics, Institute of Neurology, University College London, London, UK
Nicholas W Wood - PopGen Biobank and Institute of Epidemiology, Christian Albrechts University Kiel, Kiel, Germany
Lukas Tittmann & Wolfgang Lieb - Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
Andre Franke - Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, Heidelberg, Germany
Marcella Rietschel - Institute of Human Genetics, University of Bonn, Bonn, Germany
Sven Cichon & Markus M Nöthen - Department of Genomics, Life and Brain Center, Bonn, Germany
Sven Cichon & Markus M Nöthen - Division of Medical Genetics, University Hospital Basel, University of Basel, Basel, Switzerland
Sven Cichon - Department of Biomedicine, University of Basel, Basel, Switzerland
Sven Cichon - Institute of Neuroscience and Medicine INM-1, Research Center Juelich, Juelich, Germany
Sven Cichon - University of Lille, INSERM, CHU de Lille, Institut Pasteur de Lille, U1167-RID-AGE Risk Factor and Molecular Determinants of Aging Diseases, Lille, France
Philippe Amouyel - Bordeaux University, ISPED, Centre INSERM U1219–Epidemiologie Biostatistique et CIC-1401, CHU de Bordeaux, Pôle de Santé Publique, Bordeaux, France
Christophe Tzourio & Jean-François Dartigues - Department of Internal Medicine, Genetics Laboratory, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands
Andre G Uitterlinden, Fernando Rivadeneira & Karol Estrada - Department of Epidemiology, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands
Andre G Uitterlinden, Fernando Rivadeneira & Albert Hofman - Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
Albert Hofman - Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
Anneke J van der Kooi & Marianne de Visser - Department of Neurosciences, Experimental Neurology, Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven–University of Leuven, Leuven, Belgium
An Goris, Wim Robberecht & Philip Van Damme - Neuromuscular Diseases Unit/ALS Clinic, Kantonsspital St. Gallen, St. Gallen, Switzerland
Markus Weber - Laboratory of Experimental Neurobiology, IRCCS 'C. Mondino' National Institute of Neurology Foundation, Pavia, Italy
Orietta Pansarasa & Cristina Cereda - Neurologic Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Roberto Del Bo & Giacomo P Comi - Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases, Università del Piemonte Orientale, Novara, Italy
Sandra D'Alfonso - Department of Neurosciences, University of Padova, Padova, Italy
Cinzia Bertolin & Gianni Sorarù - Department of Neurology, Università del Piemonte Orientale, Novara, Italy
Letizia Mazzini - Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy
Viviana Pensato & Cinzia Gellera - 'Rita Levi Montalcini' Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy
Andrea Calvo, Cristina Moglia, Maura Brunetti, Federico Casale & Adriano Chio - Azienda Ospedaliera Città della Salute e della Scienza, Turin, Italy
Andrea Calvo, Cristina Moglia, Maura Brunetti & Adriano Chio - Department of Clinical Research in Neurology, University of Bari 'A. Moro' at Pia Fondazione 'Card. G. Panico', Tricase, Italy
Simona Arcuti, Rosa Capozzo, Chiara Zecca & Rosanna Tortelli - NEMO Clinical Center, Serena Onlus Foundation, Niguarda Ca' Granda Hostipal, Milan, Italy
Christian Lunetta - Department of Laboratory Medicine, Medical Genetics Unit, Niguarda Ca' Granda Hospital, Milan, Italy
Silvana Penco - Department of Neurology, Division of Neuroscience, Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, Milan, Italy
Nilo Riva - Department of Clinical and Experimental Sciences, Neurology Unit, University of Brescia, Brescia, Italy
Alessandro Padovani & Massimiliano Filosto - Project MinE Foundation, Rotterdam, the Netherlands
Bernard Muller & Robbert Jan Stuit - Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia
Ian Blair, Katharine Zhang, Emily P McCann, Jennifer A Fifita, Garth A Nicholson & Dominic B Rowe - University of Sydney, ANZAC Research Institute, Concord Hospital, Sydney, New South Wales, Australia
Garth A Nicholson - Department of Pathology, Stacey MND Laboratory, University of Sydney, Sydney, New South Wales, Australia
Roger Pamphlett - Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia
Matthew C Kiernan - Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany
Julian Grosskreutz, Otto W Witte, Thomas Ringer, Tino Prell & Beatrice Stubendorff - Institute of Human Genetics, Jena University Hospital, Jena, Germany
Ingo Kurth & Christian A Hübner - Department of Neurology, Brighton and Sussex Medical School Trafford Centre for Biomedical Research, University of Sussex, Falmer, UK
P Nigel Leigh - Department of Neuroscience, Laboratory of Neurological Diseases, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
Ettore Beghi & Elisabetta Pupillo - Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy
Giancarlo Logroscino - Department of Clinical Research in Neurology, Unit of Neurodegenerative Diseases, University of Bari 'Aldo Moro' at Pia Fondazione Cardinale G. Panico, Tricase, Italy
Giancarlo Logroscino - Vesalius Research Center, Laboratory of Neurobiology, VIB, Leuven, Belgium
Wim Robberecht & Philip Van Damme - Department of Neurology, University Hospitals Leuven, Leuven, Belgium
Wim Robberecht & Philip Van Damme - Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA
Tune H Pers - Division of Genetics, Boston Children's Hospital, Boston, Massachusetts, USA
Tune H Pers - Center for Basic Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA
Tune H Pers - Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA
Tune H Pers - Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA
Tune H Pers - Department of Pharmacology and Clinical Neurosience, Umeå University, Umeå, Sweden
Peter M Andersen - Centre SLA, CHRU de Tours, Tours, France
Philippe Corcia - Federation des Centres SLA Tours and Limoges, LITORALS, Tours, France
Philippe Corcia - Diamantina Institute, University of Queensland Translational Research Institute, Brisbane, Queensland, Australia
Peter M Visscher - Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
Paul I W de Bakker - Department of Medical and Molecular Genetics, King's College London, London, UK
Cathryn M Lewis
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Consortia
PARALS Registry
SLALOM Group
SLAP Registry
FALS Sequencing Consortium
SLAGEN Consortium
NNIPPS Study Group
Contributions
A.V., N.T., K.L., B.R., K.V., M.R.-G., B.K., J.Z., L.L., L.D.G., S.M., F.S., V.M., M.d.C., S. Pinto, J.S.M., R.R.-G., M.P., S. Chandran, S. Colville, R.S., K.E.M., P.J.S., J.H., R.W.O., A. Pittman, K.S., P.F., A. Malaspina, S.T., S. Petri, S. Abdulla, C.D., M.S., T. Meyer, R.A.O., K.A.S., M.W.-P., C.L.-H., V.M.V.D., J.Q.T., L.E., L. McCluskey, A.N.B., Y.P., T. Meitinger, P.L., M.R.-B., C.R.A., C. Maurel, G. Bensimon, B.L., A.B., C.A.M.P., S.S.-D., A.D., N.W.W., L.T., W.L., A.F., M.R., S. Cichon, M.M.N., P.A., C. Tzourio, J.-F.D., A.G.U., F.R., K.E., A.H., C. Curtis, H.M.B., A.J.v.d.K., M.d.V., A.G., M.W., C.E.S., B.N.S., O.P., C. Cereda, R.D.B., G.P.C., S.D'A., C.B., G.S., L. Mazzini, V.P., C.G., C. Tiloca, A.R., A. Calvo, C. Moglia, M.B., S. Arcuti, R.C., C.Z., C.L., S. Penco, N.R., A. Padovani, M.F., B.M., R.J.S., PARALS Registry, SLALOM Group, SLAP Registry, FALS Sequencing Consortium, SLAGEN Consortium, NNIPPS Study Group, I.B., G.A.N., D.B.R., R.P., M.C.K., J.G., O.W.W., T.R., B.S., I.K., C.A.H., P.N.L., F.C., A. Chìo, E.B., E.P., R.T., G.L., J.P., A.C.L., J.H.W., W.R., P.V.D., L.F., T.P., R.H.B., J.D.G., J.E.L., O. Hardiman, P.M.A., P.C., P.V., V.S., M.A.v.E., A.A.-C., L.H.v.d.B. and J.H.V. were involved in phenotyping, sample collection and management. W.v.R., A.S., A.M.D., R.L.M., F.P.D., R.A.A.v.d.S., P.T.C.v.D., G.H.P.T., M.K., A.M.B., W.S., A.R.J., K.P.K., I.F., A.V., N.T., R.D.S., W.J.B., A.V., K.V., M.R.-G., B.K., L.L., S. Abdulla, K.S., E.P., F.P.D., J.M., C. Curtis, G. Breen, A.A.-C. and J.H.V. prepared DNA and performed SNP array hybridizations. W.v.R., S.L.P., K.P.K., K.L., A.M.D., P.T.C.v.D., G.H.P.T., K.R.v.E., P.I.W.d.B. and J.H.V. were involved in the next-generation sequencing analyses. W.v.R., K.R.v.E., A. Menelaou, P.I.W.d.B., A.A.-C. and J.H.V. performed the imputation. W.v.R., A.S., F.P.D., R.L.M., S.L.P., S.d.J., I.F., N.T., W.S., A.R.J., K.P.K., K.R.v.E., K.S., H.M.B., P.I.W.d.B., M.A.v.E., C.M.L., G. Breen, A.A.-C., L.H.v.d.B. and J.H.V. performed GWAS analyses. W.v.R., A.M.D., R.A.A.v.d.S., R.L.M., C.R.A., M.K., A.M.B., R.D.S., E.P.M., J.A.F., C. Tunca, H.H., K.Z., P.C., P.V. and J.H.V. performed the replication analyses. W.v.R., A.S., R.L.M., M.R.R., J.Y., N.R.W., P.M.V., C.M.L., A.A.-C. and J.H.V. performed polygenic risk scoring and heritability analyses. S.d.J., U.V., L.F., T.H.P., W.v.R., O. Harschnitz, G. Breen, R.J.P. and J.H.V. performed biological pathway analyses. U.V., L.F., W.v.R. and J.H.V. performed eQTL analyses. W.v.R., A.S., A.A.-C., L.H.v.d.B. and J.H.V. prepared the manuscript with contributions from all authors. A.A.-C., L.H.v.d.B. and J.H.V. directed the study.
Corresponding authors
Correspondence toAmmar Al-Chalabi or Jan H Veldink.
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The authors declare no competing financial interests.
Additional information
A list of members appears in the Supplementary Note.
A list of members appears in the Supplementary Note.
A list of members appears in the Supplementary Note.
A list of members appears in the Supplementary Note.
A list of members appears in the Supplementary Note.
A list of members appears in the Supplementary Note.
Integrated supplementary information
Supplementary Figure 1 Coverage distribution for reference panel.
(a) Average coverage for all non-reference bases for all samples in the custom reference panel. An average coverage of 43.7 reads per base was achieved. (b) Percentage of non-reference bases covered by at least 5 (blue), 10 (yellow) or 20 (red) reads. Histograms include all individuals, before quality control.
Supplementary Figure 2 Comparison between meta-analysis and linear mixed-model results.
Regressing the –log10 (P values) derived from the linear mixed model on the meta-analysis P values yielded a slope below the diagonal (β = 0.86), implying no overall inflation of the test statistic. Strongly associated SNPs, however, deviated from the regression line representing the increased power of a linear mixed model in comparison to a meta-analysis for association testing.
Supplementary Figure 3 Quantile–quantile plots.
(a,b) Meta-analysis (a) and linear mixed model (b). For presentation purposes, P values <5 × 10−8 are plotted at 5 × 10−8.
Supplementary Figure 4 Replication results.
Forest plot for the inverse-variance-weighted, fixed-effect meta-analysis of the discovery phase and replication cohorts. OR, odds ratio; CI, confidence interval.
Supplementary Figure 5 Fine-mapping of the C21orf2 locus.
(a) Associations for all SNPs analyzed in the GWAS in the C21orf2 locus where only rs75087725 reaches genome-wide significance. (b) LD as defined by |_D_′| (absolute _D_-prime value) for all variants obtained from whole-genome sequencing data of the custom reference panel. Possible causal variants for driving factors of the GWAS association were considered when they met the following criteria: (i) risk allele frequency difference between cases and controls exceeding 0.4% (risk allele frequency difference for rs75087725 = 0.8%), (ii) rs75087725 as the best genotyped GWAS tag for the variant and (iii) minor allele with a risk-increasing effect on ALS. (c) No such variant was in LD with rs75087725. (d) LD defined by _R_2 is very sparse. (e) C21orf2 is the only gene in this locus with an increased burden of rare nonsynonymous variants in the sequencing data of our custom reference panel, indicating that C21orf2 is indeed the ALS risk gene.
Supplementary Figure 6 C21orf2 rare variant burden.
Summary of the rare (MAF < 0.05) nonsynonymous and loss-of-function mutations in the canonical transcript of C21orf2. Conditioning on the SNP found to be associated in the GWAS (rs75087725, p.V58L; gray), there was an increased burden of nonsynonymous and loss-of-function mutations among ALS cases (_P_T5 = 9.2 × 10−5, _P_T1 = 0.01). Odds ratios (calculated by counting alleles in cases and controls per stratum, unadjusted for principal components, combined in a Cochran–Mantel–Haenszel test) are 1.63 and 1.48 for T5 and T1 burden, respectively. The two loss-of-function mutations observed in cases are colored red.
Supplementary Figure 7 _cis_-eQTL regional plots for six genome-wide-significant loci.
Highlighted are _cis_-eQTLs acquired from several resources (genes in green) and brain _cis_-eQTLs (genes in black). Stranded RNA-seq data for one fetal brain (3,000-bp sliding window) are shown on a separate track. For the MOBP region, there was an eQTL effect for MOBP (P = 7.12 × 10−18), but the effect SNP, rs1707953, did not show any association with ALS in our GWAS (P = 0.74). Further details of highlighted brain _cis_-eQTLs and non-brain _cis_-eQTLs are given in Supplementary Table 10 and the Supplementary Data Set. eQTL annotation and LD data are shown only for SNPs present in the 1000 Genomes Project p1v3 CEU population.
Supplementary Figure 8 Polygenic risk scores.
(a) Polygenic risk score analyses where nine cohorts were used as targets. Best predictions were made when including the six genome-wide-significant SNPs from the C9orf72 and UNC13A loci only. (b) Polygenic risk score analyses excluding all variants on chromosome 9. Increased polygenic risk score predictions were made when including more variants by lowering the _P_-value threshold. Note that the overall prediction accuracy is lower than when SNPs on chromosome 9 were included.
Supplementary Figure 9 Partitioned heritability excluding candidate loci.
(a) SNPs in the C9orf72 locus (within 1 Mb of rs3849943 and _r_2 >0.2) were excluded from heritability estimates. (b) SNPs within 1 Mb of the top associated SNP and _r_2 >0.2 for all loci exceeding genome-wide significance were excluded for heritability estimates. In both instances, most heritability was explained by low-frequency variants (MAF < 0.1).
Supplementary Figure 10 DEPICT biological pathway analysis.
The top ten terms from Gene Ontology, KEGG and Reactome pathways that are most enriched for genes tagged by SNPs in the GWAS are displayed. Different thresholds of significance were used to select SNPs for the DEPICT analyses. The lengths of the bars correspond to the nominal significance levels, the black line indicates the _P_-value threshold of 0.05 and color corresponds to FDR, determined by 200 permutations. When all SNPs with a P value <1 × 10−4 in the linear mixed-model analysis were included, it identifies the Gene Ontology category SNAP receptor (SNARE) activity as the only significantly enriched term after correction for multiple testing.
Supplementary Figure 11 Population outlier removal.
(a) Example of stratum sNL2 projected onto the first two principal components calculated on HapMap 3 individuals. Individuals of non-European ancestry (±10 s.d. from the HapMap CEU mean on PC1–PC4) were removed. (b) Subsequent removal of samples deviating by more than 4 s.d. from the stratum mean eigenvalues on PC1 and PC2 (HapMap 3). (c,d) Individuals remaining after removing population outliers resulting in a homogenous European sample where the Scandinavian individuals (mainly Finnish), as expected, depart from the other strata.
Supplementary Figure 12 Population structure of the custom reference panel.
Individuals projected onto the first two principal components calculated on HapMap 3 individuals. NL, Netherlands; Ir, Ireland; It, Italy; No, Norway; Sp, Spain; Sw, Sweden; US, United States.
Supplementary Figure 13 C21orf2 rare variant analysis quality control.
Quantile–quantile plots for the single-SNV regression of chromosome 21 including the first ten principal components as covariates are displayed on the left. Principal-components plots for each stratum are shown on the right. Population stratification was successfully corrected for, resulting in well-behaved burden tests without evidence for overall inflation of the test statistic.
Supplementary Figure 14 Genetic relationship matrix distribution.
(a) Diagonal values of the SNP-based GRM. (b) Distribution of the off-diagonal values representing the relatedness between samples. Pairs of individuals whose relatedness exceeded 0.05 were excluded from the heritability estimations. GRM, genetic relationship matrix.
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van Rheenen, W., Shatunov, A., Dekker, A. et al. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.Nat Genet 48, 1043–1048 (2016). https://doi.org/10.1038/ng.3622
- Received: 07 January 2016
- Accepted: 20 June 2016
- Published: 25 July 2016
- Issue Date: September 2016
- DOI: https://doi.org/10.1038/ng.3622