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

ABSTRACT: 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.

SUBMITTER: van Rheenen W

PROVIDER: S-EPMC5556360 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

van Rheenen Wouter W Shatunov Aleksey A Dekker Annelot M AM McLaughlin Russell L RL Diekstra Frank P FP Pulit Sara L SL van der Spek Rick A A RA Võsa Urmo U de Jong Simone S Robinson Matthew R MR Yang Jian J Fogh Isabella I van Doormaal Perry Tc PT Tazelaar Gijs H P GH Koppers Max M Blokhuis Anna M AM Sproviero William W Jones Ashley R AR Kenna Kevin P KP van Eijk Kristel R KR Harschnitz Oliver O Schellevis Raymond D RD Brands William J WJ Medic Jelena J Menelaou Androniki A Vajda Alice A Ticozzi Nicola N Lin Kuang K Rogelj Boris B Vrabec Katarina K Ravnik-Glavač Metka M Koritnik Blaž B Zidar Janez J Leonardis Lea L Grošelj Leja Dolenc LD Millecamps Stéphanie S Salachas François F Meininger Vincent V de Carvalho Mamede M Pinto Susana S Mora Jesus S JS Rojas-García Ricardo R Polak Meraida M Chandran Siddharthan S Colville Shuna S Swingler Robert R Morrison Karen E KE Shaw Pamela J PJ Hardy John J Orrell Richard W RW Pittman Alan A Sidle Katie K Fratta Pietro P Fratta Pietro P Malaspina Andrea A Topp Simon S Petri Susanne S Abdulla Susanne S Drepper Carsten C Sendtner Michael M Meyer Thomas T Ophoff Roel A RA Staats Kim A KA Staats Kim A KA Wiedau-Pazos Martina M Lomen-Hoerth Catherine C Van Deerlin Vivianna M VM Trojanowski John Q JQ Elman Lauren L McCluskey Leo L Basak A Nazli AN Tunca Ceren C Hamzeiy Hamid H Parman Yesim Y Meitinger Thomas T Lichtner Peter P Radivojkov-Blagojevic Milena M Andres Christian R CR Maurel Cindy C Bensimon Gilbert G Landwehrmeyer Bernhard B Brice Alexis A Payan Christine A M CA Saker-Delye Safaa S Dürr Alexandra A Wood Nicholas W NW Tittmann Lukas L Lieb Wolfgang W Franke Andre A Rietschel Marcella M Cichon Sven S Nöthen Markus M MM Amouyel Philippe P Tzourio Christophe C Dartigues Jean-François JF Uitterlinden Andre G AG Rivadeneira Fernando F Estrada Karol K Hofman Albert A Curtis Charles C Blauw Hylke M HM van der Kooi Anneke J AJ de Visser Marianne M Goris An A Weber Markus M Shaw Christopher E CE Smith Bradley N BN Pansarasa Orietta O Cereda Cristina C Del Bo Roberto R Comi Giacomo P GP D'Alfonso Sandra S Bertolin Cinzia C Sorarù Gianni G Mazzini Letizia L Pensato Viviana V Gellera Cinzia C Tiloca Cinzia C Ratti Antonia A Calvo Andrea A Moglia Cristina C Brunetti Maura M Arcuti Simona S Capozzo Rosa R Zecca Chiara C Lunetta Christian C Penco Silvana S Riva Nilo N Padovani Alessandro A Filosto Massimiliano M Muller Bernard B Stuit Robbert Jan RJ Blair Ian I Zhang Katharine K McCann Emily P EP Fifita Jennifer A JA Nicholson Garth A GA Rowe Dominic B DB Pamphlett Roger R Kiernan Matthew C MC Grosskreutz Julian J Witte Otto W OW Ringer Thomas T Prell Tino T Stubendorff Beatrice B Kurth Ingo I Hübner Christian A CA Leigh P Nigel PN Casale Federico F Chio Adriano A Beghi Ettore E Pupillo Elisabetta E Tortelli Rosanna R Logroscino Giancarlo G Powell John J Ludolph Albert C AC Weishaupt Jochen H JH Robberecht Wim W Van Damme Philip P Franke Lude L Pers Tune H TH Brown Robert H RH Glass Jonathan D JD Landers John E JE Hardiman Orla O Andersen Peter M PM Corcia Philippe P Vourc'h Patrick P Silani Vincenzo V Wray Naomi R NR Visscher Peter M PM de Bakker Paul I W PI van Es Michael A MA Pasterkamp R Jeroen RJ Lewis Cathryn M CM Breen Gerome G Al-Chalabi Ammar A van den Berg Leonard H LH Veldink Jan H JH

Nature genetics 20160725 9

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 ...[more]

PMID: 27455348

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Project description:Therapy of motoneuron diseases entered a new phase with the use of intrathecal antisense oligonucleotide therapies treating patients with specific gene mutations predominantly in the context of familial amyotrophic lateral sclerosis. With the majority of cases being sporadic, we conducted a cohort study to describe the mutational landscape of sporadic amyotrophic lateral sclerosis. We analysed genetic variants in amyotrophic lateral sclerosis-associated genes to assess and potentially increase the number of patients eligible for gene-specific therapies. We screened 2340 sporadic amyotrophic lateral sclerosis patients from the German Network for motor neuron diseases for variants in 36 amyotrophic lateral sclerosis-associated genes using targeted next-generation sequencing and for the C9orf72 hexanucleotide repeat expansion. The genetic analysis could be completed on 2267 patients. Clinical data included age at onset, disease progression rate and survival. In this study, we found 79 likely pathogenic Class 4 variants and 10 pathogenic Class 5 variants (without the C9orf72 hexanucleotide repeat expansion) according to the American College of Medical Genetics and Genomics guidelines, of which 31 variants are novel. Thus, including C9orf72 hexanucleotide repeat expansion, Class 4, and Class 5 variants, 296 patients, corresponding to ∼13% of our cohort, could be genetically resolved. We detected 437 variants of unknown significance of which 103 are novel. Corroborating the theory of oligogenic causation in amyotrophic lateral sclerosis, we found a co-occurrence of pathogenic variants in 10 patients (0.4%) with 7 being C9orf72 hexanucleotide repeat expansion carriers. In a gene-wise survival analysis, we found a higher hazard ratio of 1.47 (95% confidence interval 1.02-2.1) for death from any cause for patients with the C9orf72 hexanucleotide repeat expansion and a lower hazard ratio of 0.33 (95% confidence interval 0.12-0.9) for patients with pathogenic SOD1 variants than for patients without a causal gene mutation. In summary, the high yield of 296 patients (∼13%) harbouring a pathogenic variant and oncoming gene-specific therapies for SOD1/FUS/C9orf72, which would apply to 227 patients (∼10%) in this cohort, corroborates that genetic testing should be made available to all sporadic amyotrophic lateral sclerosis patients after respective counselling.

Project description:BackgroundEpidemiological and clinical studies have suggested comorbidity between amyotrophic lateral sclerosis (ALS) and autoimmune disorders. However, little is known about their shared genetic architecture.MethodsTo examine the relation between ALS and 10 autoimmune diseases, including asthma, celiac disease (CeD), Crohn's disease (CD), inflammatory bowel disease (IBD), multiple sclerosis (MS), psoriasis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), and ulcerative colitis (UC), and identify shared risk loci, we first estimated the genetic correlation using summary statistics from genome-wide association studies, and then analyzed the genetic enrichment leveraging the conditional false discovery rate statistical method.ResultsWe identified a significant positive genetic correlation between ALS and CeD, MS, RA, and SLE, as well as a significant negative genetic correlation between ALS and IBD, UC, and CD. Robust genetic enrichment was observed between ALS and CeD and MS, and moderate enrichment was found between ALS and UC and T1D. Thirteen shared genetic loci were identified, among which five were suggestively significant in another ALS GWAS, namely rs3828599 (GPX3), rs3849943 (C9orf72), rs7154847 (G2E3), rs6571361 (SCFD1), and rs9903355 (GGNBP2). By integrating cis-expression quantitative trait loci analyses in Braineac and GTEx, we further identified GGNBP2, ATXN3, and SLC9A8 as novel ALS risk genes. Functional enrichment analysis indicated that the shared risk genes were involved in four pathways including membrane trafficking, vesicle-mediated transport, ER to Golgi anterograde transport, and transport to the Golgi and subsequent modification.ConclusionsOur findings demonstrate a specific genetic correlation between ALS and autoimmune diseases and identify shared risk loci, including three novel ALS risk genes. These results provide a better understanding for the pleiotropy of ALS and have implications for future therapeutic trials.

Project description:Abstract Increasing genetic evidence supports the hypothesis that variants in the annexin A11 gene (ANXA11) contribute to amyotrophic lateral sclerosis pathogenesis. Therefore, we studied the clinical aspects of sporadic amyotrophic lateral sclerosis patients carrying ANXA11 variants. We also implemented functional experiments to verify the pathogenicity of the hotspot variants associated with amyotrophic lateral sclerosis-frontotemporal dementia. Korean patients diagnosed with amyotrophic lateral sclerosis (n = 882) underwent genetic evaluations through next-generation sequencing, which identified 16 ANXA11 variants in 26 patients. We analysed their clinical features, such as the age of onset, progression rate, initial symptoms and cognitive status. To evaluate the functional significance of the ANXA11 variants in amyotrophic lateral sclerosis-frontotemporal dementia pathology, we additionally utilized patient fibroblasts carrying frontotemporal dementia-linked ANXA11 variants (p.P36R and p.D40G) to perform a series of in vitro studies, including calcium imaging, stress granule dynamics and protein translation. The frequency of the pathogenic or likely pathogenic variants of ANXA11 was 0.3% and the frequency of variants classified as variants of unknown significance was 2.6%. The patients with variants in the low-complexity domain presented unique clinical features, including late-onset, a high prevalence of amyotrophic lateral sclerosis-frontotemporal dementia, a fast initial progression rate and a high tendency for bulbar-onset compared with patients carrying variants in the C-terminal repeated annexin homology domains. In addition, functional studies using amyotrophic lateral sclerosis-frontotemporal dementia patient fibroblasts revealed that the ANXA11 variants p.P36R and p.D40G impaired intracellular calcium homeostasis, stress granule disassembly and protein translation. This study suggests that the clinical manifestations of amyotrophic lateral sclerosis and amyotrophic lateral sclerosis-frontotemporal dementia spectrum patients with ANXA11 variants could be distinctively characterized depending upon the location of the variant. This study investigated the clinical aspects of sporadic amyotrophic lateral sclerosis patients carrying ANXA11 variants and verified the pathogenicity of the hotspot variants associated with amyotrophic lateral sclerosis-frontotemporal dementia. Sung et al. reported unique clinical features of the patients with variants in the low-complexity domain with in vitro study results. Graphical Abstract Graphical abstract

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

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

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