Welcome to the ALS Variant Server (AVS)
The goal of the ALS Variant Server is to provide researchers with a database of variants identified from exome sequencing of ALS cases. It is our hope that these results will increase the efficiency of researchers to identify ALS-associated genes and reduce false-positives.
This web site was conceived and developed by researchers at the University of Massachusetts Medical School (Worcester, MA) and the IRCCS Istituto Auxologico Italiano - Università degli Studi di Milano (Milan, Italy).
Additional assistance and data was provided by:
- Fondazione IRRCS Istituto Neurologico 'Carlo Besta' (Milan, Italy)
- Stanford University (Stanford, CA)
- Worcester Polytechnic Institute (Worcester, MA)
This design and layout of this website is strongly modeled from the NHLBI Exome Sequencing Project. We would like to thank the contributors of this project for their excellent work.
About
In order to increase the speed in which the scientific community identifies ALS-associated genes, we have taken the step to create this publicly available database of exome sequences from ALS samples. Researchers identify candidate genes for ALS by a variety of methods (e.g. expression analysis). However, to further investigate these genes, researchers often have to obtain a large number of ALS samples and then sequence these candidate genes. This approach can be extremely expensive and thus cost-prohibitive to the advancement of ALS genetic research. This does not take into account the time and labor needed to investigate such genes. Furthermore, there is an inherent redundancy for the scientific community with this approach that ends up wasting research money. By creating a public database of ALS samples, researchers can now investigate their gene of interest within minutes at no cost whatsoever. This will allow researchers to focus on those genes with the greatest promise and not waste money, time and labor on potential false leads. The current version of the ALS Variant Server consists of 277 sporadic ALS cases and over 1,000 familial ALS cases.
SALS browser
The SALS browser provides a user interface to search and download details of variants detected by whole exome sequencing of 277 sporadic ALS cases from the United States and Italy.
FALS browser
The FALS browser provides a user interface to search and download details of variants detected by whole exome sequencing of 1,138 familial ALS cases. Extended details of the FALS cohort are reported in the following publications:
- Kenna, K.P.*, van Doormaal, P.T.C.*, Dekker, A.M.*, Ticozzi, N.*, Kenna, B.J., Diekstra, F.P., van Rheenen, W., van Eijk, K.R., Jones, A.R., Keagle, P., Shatunov, A., Sproviero, W., Smith, B.N., van Es, M.A., Topp, S.D., Kenna, A., Miller, J.W., Fallini, C., Tiloca, C., McLaughlin, R.L., Vance, C., Troakes, C., Colombrita, C., Mora, G., Calvo, A., Verde, F., Al-Sarraj, S., King, A., Calini, D., de Belleroche, J., Baas, F., van der Kooi, A.J., de Visser, M., Ten Asbroek, A.L.M.A., Sapp, P.C., McKenna-Yasek, D., Polak, M., Asress, S., Muñoz-Blanco, J.L., Strom, T.M., Meitinger, T., Morrison, K.E., SLAGEN Consortium, Lauria, G., Williams, K.L., Leigh, P.N., Nicholson, G.A., Blair, I.P., Leblond, C.S., Dion, P.A., Rouleau, G.A., Pall, H., Shaw, P.J., Turner, M.R., Talbot, K., Taroni, F., Boylan, K.B., Van Blitterswijk, M., Rademakers, R., Esteban-Pérez, J., García-Redondo, A., Van Damme, P., Robberecht, W., Chio, A., Gellera, C., Drepper, C., Sendtner, M., Ratti, A., Glass, J.D., Mora, J.S., Basak, N.A., Hardiman, O., Ludolph, A.C., Andersen, P.M., Weishaupt, J.H., Brown, R.H., Al-Chalabi, A., Silani, V.*, Shaw, C.E.*, van den Berg, L.H.*, Veldink, J.H.*, Landers, J.E.*, 2016. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. Nat. Genet. 48, 1037–1042. https://doi.org/10.1038/ng.3626
- Aude Nicolas*, Kevin P. Kenna*, Alan E. Renton*, Nicola Ticozzi*, Faraz Faghri*, Ruth Chia*, Janice A. Dominov, Brendan J.Kenna, Mike A. Nalls, Pamela Keagle, Alberto M. Rivera, Wouter van Rheenen, Natalie A. Murphy, Joke J.F.A. van Vugt, Joshua T. Geiger, Rick A. Van der Spek, Hannah A. Pliner, Shankaracharya, Bradley N.Smith, GiuseppeMarangi, Simon D.Topp, Yevgeniya Abramzon, Athina Soragia Gkazi, John D. Eicher, Aoife Kenna, ITALSGEN Consortium, Gabriele Mora, Andrea Calvo, Letizia Mazzini, Nilo Riva, Jessica Mandrioli, Claudia Caponnetto, Stefania Battistini, Paolo Volanti, Vincenzo La Bella, Francesca L. Conforti, Giuseppe Borghero, Sonia Messina, Isabella L. Simone, Francesca Trojsi, Fabrizio Salvi, Francesco O. Logullo, Sandra D’Alfonso, Lucia Corrado, Margherita Capasso, LuigiFerrucci, Genomic Translation for ALS Care (GTAC) Consortium, Cristiane de Araujo Martins Moreno, Sitharthan Kamalakaran, David B. Goldstein, The ALS Sequencing Consortium, Aaron D. Gitler, Tim Harris, Richard M. Myers, NYGC ALS Consortium, Hemali Phatnani, Rajeeva Lochan Musunuri, Uday Shankar Evani, Avinash Abhyankar, Michael Charles Zody, Answer ALS Foundation, Julia Kaye, Steven Finkbeiner, Stacia Wyman, AlexanderLenail, Leandro Lima, Ernest Fraenkel, CliveN.Svendsen, Leslie M.Thompson, Jennifer E.Van Eyk, James D.Berry, Timothy M.Miller, Stephen J.Kolb, Merit Cudkowicz, Emily Baxi, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe)Consortium, Michael Benatar, J. Paul Taylor, Evadnie Rampersaud, Gang Wu, Joanne Wuu, SLAGEN Consortium, Giuseppe Lauria, Federico Verde, Isabella Fogh, Cinzia Tiloca, Giacomo P. Comi, Gianni Sorarù, Cristina Cereda, French ALS Consortium, Philippe Corcia, Hannu Laaksovirta, Liisa Myllykangas, Lilja Jansson, Miko Valori, John Ealing, Hesham Hamdallah, Sara Rollinson, Stuart Pickering-Brown, Richard W. Orrell, Katie C. Sidle, Andrea Malaspina, John Hardy,Andrew B. Singleton, Janel O. Johnson, Sampath Arepalli, Peter C.Sapp, Diane McKenna-Yasek, Meraida Polak, Seneshaw Asress, Safa Al-Sarraj, Andrew King, Claire Troakes, Caroline Vance, Jacqueline de Belleroche, Frank Baas, Anneloor LMA ten Asbroek, José Luis Muñoz-Blanco, Dena G. Hernandez, Jinhui Ding, J. Raphael Gibbs, Sonja W. Scholz, Mary Kay Floeter, Roy H.Campbell, Francesco Landi, Robert Bowser, Stefan M. Pulst, John M. Ravits, Daniel J.L. MacGowan, Janine Kirby, Erik Pioro, Roger Pamphlett, James Broach, Glenn Gerhard, Travis L. Dunckley, Christopher B. Brady, Neil W. Kowall, Juan C. Troncoso, Isabelle LE BER, Kevin Mouzat, Serge Lumbroso, Terry D. Heiman-Patterson, Freya Kamel, Ludo Van Den Bosch, Robert H. Baloh, Tim M. Strom, Thomas Meitinger, Aleksey Shatunov, Kristel R. Van Eijk, Mamede de Carvalho, Maarten Kooyman, Bas Middelkoop, Matthieu Moisse, Russell L. McLaughlin, Michael A. Van Es, Markus Weber, Kevin B.Boylan, Marka Van Blitterswijk, Rosa Rademakers, Karen E. Morrison, A. Nazli Basak, Jesús S.Mora, Vivian E.Drory, Pamela J.Shaw, Martin R.Turner, Kevin Talbot, Orla Hardiman, Kelly L Williams, Jennifer A.Fifita, Garth A.Nicholson, Ian P.Blair, Guy A.Rouleau, Jesús Esteban-Pérez, Alberto García-Redondo, Ammar Al-Chalabi, Project MinE ALS Sequencing Consortium,Ekaterina Rogaeva, Lorne Zinman, Lyle Ostrow, Nicholas J. Maragakis, Jeffrey D. Rothstein, Zachary Simmons, Johnathan Cooper-Knock, Alexis Brice, Stephen A. Goutman, Eva L. Feldman, Summer B. Gibson, Franco Taroni, Antonia Ratti, Cinzia Gellera, Philip Van Damme, Wim Robberecht, Pietro Fratta, Mario Sabatelli, Christian Lunetta, Albert C.Ludolph, Peter M.Andersen, Jochen H.Weishaupt, William Camu, John Q Trojanowski, Vivianna M.Van Deerlin, Robert H.Brown, Jr., Leonard H. van den Berg, Jan H. Veldink, Matthew B. Harms, Jonathan D. Glass, David J. Stone*, Pentti Tienari*, Vincenzo Silani*, Adriano Chiò*, Christopher E.Shaw*, Bryan J.Traynor*, John E.Landers*, 2018. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron. https://doi.org/10.1016/j.neuron.2018.02.027
Using Gene Browsers
Data from the AVS may only be searched at the gene level at this time. Enter the gene name of interest in the text box and click "search". Output columns may be sorted by clicking the appropriate column header. Rows are coloured based on the general variant type. The output may also be exported to a tab-delimited file.
Annotation Descriptions
Variant annotations were generated by GATK or imported from dbNSFP, dbNSFPsc and snpEFF. Full details of dbNSFP annotations can be found in the dbNSFP documentation.
| Annotation | Description |
|---|---|
| Chromosome | Chromosome |
| Genomic Pos. | Genomic position (GRCh37) |
| Ref | Reference allele |
| Alt | Alternate allele |
| Gene Name | HGNC symbol |
| AA Ref | Amino acid reference allele |
| AA Pos | Amino acid position |
| AA Alt | Amino acid alternate allele |
| Pred Splicing | Variant is predicted to disrupt splcing |
| FALS het | FALS samples genotyped as heterozygous |
| FALS homAlt | FALS samples genotyped as homozygous for alternate allele |
| FALS homRef | FALS samples genotyped as homozygous for reference allele |
| QUAL | Variant quality score |
| QD | Variant quality by depth score |
| VQSR | Variant quality score log odds (VQSLOD) generated during GATK variant quality score recalibration |
| dbSNP | dbSNP id |
| Ensembl Gene ID | Ensembl gene identifier |
| Ensembl Transcript ID | Ensembl transcript identifier |
| SIFT | Variant impact prediction using SIFT |
| PolyPhen2 HDIV | Variant impact prediction using PolyPhen HDIV |
| PolyPhen2 HVAR | Variant impact prediction using PolyPhen HVAR |
| LRT | Variant impact prediction using LRT |
| Mutation Taster | Variant impact prediction using MutationTaster |
| Mutation Assessor | Variant impact prediction using MutationAssessor |
| FATHMM | Variant impact prediction using FATHMM |
| PROVEAN | Variant impact prediction using PROVEAN |
| CADD | Phred scaled score from variant impact prediction using CADD |
| Meta SVM | Variant impact prediction using MetaSVM |
| Meta LR | Variant impact prediction using MetaLR |
| GERP | GERP "Neutral rate" conservartion score |
| phyloP | PhyloP conservation score |
| SiPhy | SiPhy stationary distribution score. |
| ADA | Splice prediction score from dbNSFPsc. |
| RF | Splice prediction score from dbNSFPsc. |
Data Usage and Release
We request that any data obtained from this website be cited in publications.
Citation
ALS Variant Server, Worcester, MA (URL: http://als.umassmed.edu/) [date (month, yr) accessed].
Acknowledgement for Publication
The authors would like to thank the ALS Variant Server (als.umassmed.edu) which is supported by funds from NIH/NINDS (1R01NS065847), AriSLA (EXOMEFALS, NOVALS), the ALS Association, and the Motor Neurone Disease Association.
Permission and Terms of Use
This web site is intended to provide results from exome sequencing data of ALS samples. The contents of the AVS is intended strictly for educational and research purposes. The data derived from this website may not be used for any commercial purpose. The data from this website may not be replicated on any other website.
Meta-analysis summary statistics from GWAS of 20,806 ALS cases vs 59,804 controls
Aude Nicolas*, Kevin P. Kenna*, Alan E. Renton*, Nicola Ticozzi*, Faraz Faghri*, Ruth Chia*, Janice A. Dominov, Brendan J.Kenna, Mike A. Nalls, Pamela Keagle, Alberto M. Rivera, Wouter van Rheenen, Natalie A. Murphy, Joke J.F.A. van Vugt, Joshua T. Geiger, Rick A. Van der Spek, Hannah A. Pliner, Shankaracharya, Bradley N.Smith, GiuseppeMarangi, Simon D.Topp, Yevgeniya Abramzon, Athina Soragia Gkazi, John D. Eicher, Aoife Kenna, ITALSGEN Consortium, Gabriele Mora, Andrea Calvo, Letizia Mazzini, Nilo Riva, Jessica Mandrioli, Claudia Caponnetto, Stefania Battistini, Paolo Volanti, Vincenzo La Bella, Francesca L. Conforti, Giuseppe Borghero, Sonia Messina, Isabella L. Simone, Francesca Trojsi, Fabrizio Salvi, Francesco O. Logullo, Sandra D’Alfonso, Lucia Corrado, Margherita Capasso, LuigiFerrucci, Genomic Translation for ALS Care (GTAC) Consortium, Cristiane de Araujo Martins Moreno, Sitharthan Kamalakaran, David B. Goldstein, The ALS Sequencing Consortium, Aaron D. Gitler, Tim Harris, Richard M. Myers, NYGC ALS Consortium, Hemali Phatnani, Rajeeva Lochan Musunuri, Uday Shankar Evani, Avinash Abhyankar, Michael Charles Zody, Answer ALS Foundation, Julia Kaye, Steven Finkbeiner, Stacia Wyman, AlexanderLenail, Leandro Lima, Ernest Fraenkel, CliveN.Svendsen, Leslie M.Thompson, Jennifer E.Van Eyk, James D.Berry, Timothy M.Miller, Stephen J.Kolb, Merit Cudkowicz, Emily Baxi, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe)Consortium, Michael Benatar, J. Paul Taylor, Evadnie Rampersaud, Gang Wu, Joanne Wuu, SLAGEN Consortium, Giuseppe Lauria, Federico Verde, Isabella Fogh, Cinzia Tiloca, Giacomo P. Comi, Gianni Sorarù, Cristina Cereda, French ALS Consortium, Philippe Corcia, Hannu Laaksovirta, Liisa Myllykangas, Lilja Jansson, Miko Valori, John Ealing, Hesham Hamdallah, Sara Rollinson, Stuart Pickering-Brown, Richard W. Orrell, Katie C. Sidle, Andrea Malaspina, John Hardy,Andrew B. Singleton, Janel O. Johnson, Sampath Arepalli, Peter C.Sapp, Diane McKenna-Yasek, Meraida Polak, Seneshaw Asress, Safa Al-Sarraj, Andrew King, Claire Troakes, Caroline Vance, Jacqueline de Belleroche, Frank Baas, Anneloor LMA ten Asbroek, José Luis Muñoz-Blanco, Dena G. Hernandez, Jinhui Ding, J. Raphael Gibbs, Sonja W. Scholz, Mary Kay Floeter, Roy H.Campbell, Francesco Landi, Robert Bowser, Stefan M. Pulst, John M. Ravits, Daniel J.L. MacGowan, Janine Kirby, Erik Pioro, Roger Pamphlett, James Broach, Glenn Gerhard, Travis L. Dunckley, Christopher B. Brady, Neil W. Kowall, Juan C. Troncoso, Isabelle LE BER, Kevin Mouzat, Serge Lumbroso, Terry D. Heiman-Patterson, Freya Kamel, Ludo Van Den Bosch, Robert H. Baloh, Tim M. Strom, Thomas Meitinger, Aleksey Shatunov, Kristel R. Van Eijk, Mamede de Carvalho, Maarten Kooyman, Bas Middelkoop, Matthieu Moisse, Russell L. McLaughlin, Michael A. Van Es, Markus Weber, Kevin B.Boylan, Marka Van Blitterswijk, Rosa Rademakers, Karen E. Morrison, A. Nazli Basak, Jesús S.Mora, Vivian E.Drory, Pamela J.Shaw, Martin R.Turner, Kevin Talbot, Orla Hardiman, Kelly L Williams, Jennifer A.Fifita, Garth A.Nicholson, Ian P.Blair, Guy A.Rouleau, Jesús Esteban-Pérez, Alberto García-Redondo, Ammar Al-Chalabi, Project MinE ALS Sequencing Consortium,Ekaterina Rogaeva, Lorne Zinman, Lyle Ostrow, Nicholas J. Maragakis, Jeffrey D. Rothstein, Zachary Simmons, Johnathan Cooper-Knock, Alexis Brice, Stephen A. Goutman, Eva L. Feldman, Summer B. Gibson, Franco Taroni, Antonia Ratti, Cinzia Gellera, Philip Van Damme, Wim Robberecht, Pietro Fratta, Mario Sabatelli, Christian Lunetta, Albert C.Ludolph, Peter M.Andersen, Jochen H.Weishaupt, William Camu, John Q Trojanowski, Vivianna M.Van Deerlin, Robert H.Brown, Jr., Leonard H. van den Berg, Jan H. Veldink, Matthew B. Harms, Jonathan D. Glass, David J. Stone*, Pentti Tienari*, Vincenzo Silani*, Adriano Chiò*, Christopher E.Shaw*, Bryan J.Traynor*, John E.Landers*, 2018. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron. https://doi.org/10.1016/j.neuron.2018.02.027
Contact and FAQ
Contributors
- John E. Landers
- Nicola Ticozzi
- Vincenzo Silani
- Cinzia Gellera
- Aaron Gitler
- Robert Brown
Database/Website Design and Data Analysis
- Kevin Kenna
- Jason Kost
- Aoife Kenna
- Neil Pomerleau
- Pamela Keagle
- Shankaracharya
Sample Preparation
- Pamela Keagle
- Cinzia Tiloca
If you have questions concerning the AVS, please read the FAQs below. If you have additional questions, please contact john.landers@umassmed.edu.
Are INDELs included in the AVS?
At the present time, we have elected to not include INDELs in the AVS and focus strictly on single nucleotide polymorphisms. This is due to the reduced accuracy associated with indel calling from exome sequencing.
What methods were used to generate the data present on the AVS?
Sequence reads were aligned to human reference GRCh37 using BWA (Burrows-Wheeler Aligner) and processed according to recommended Genome Analysis Toolkit’s (GATK) best practices. Joint variant detection and genotyping of all samples were performed using the GATK HaplotypeCaller. Variant quality control was performed using the GATK variant quality score recalibration method with default filters. A minimum variant quality by depth (QD) score of 2 was also imposed and all genotypes associated with genotype quality (GQ) scores below 20 were reset to missing.
I would like to contribute sample DNA or data to your project. Who should I contact?
Please contact us at john.landers@umassmed.edu.