Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology.

Publication

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology.

Journal Paper/Review - Dec 6, 2021

van Rheenen Wouter, van der Spek Rick A A, Bakker Mark K, Farei-Campagna Jan Marino, Hop Paul J, Zwamborn Ramona A J, de Klein Niek, Westra Harm-Jan, Bakker Olivier B, Deelen Patrick, Shireby Gemma, Hannon Eilis, Moisse Matthieu, Baird Denis, Restuadi Restuadi, Dolzhenko Egor, Dekker Annelot M, Gawor Klara, Westeneng Henk-Jan, Tazelaar Gijs H P, van Eijk Kristel R, Kooyman Maarten, Byrne Ross P, Doherty Mark, Heverin Mark, Al Khleifat Ahmad, Iacoangeli Alfredo, Shatunov Aleksey, Ticozzi Nicola, Cooper-Knock Johnathan, Smith Bradley N, Gromicho Marta, Chandran Siddharthan, Pal Suvankar, Morrison Karen E, Openshaw Peter J M, Hardy John, Orrell Richard W, Sendtner Michael, Meyer Thomas, Başak Nazli A, van der Kooi Anneke J, Ratti Antonia, Fogh Isabella, Gellera Cinzia, Lauria Giuseppe, Corti Stefania, Cereda Cristina, Sproviero Daisy, D'Alfonso Sandra, Sorarù Gianni, Siciliano Gabriele, Filosto Massimiliano, Padovani Alessandro, Chio Adriano, Calvo Andrea, Moglia Cristina, Brunetti Maura, Canosa Antonio, Grassano Maurizio, Beghi Ettore, Pupillo Elisabetta, Logroscino Giancarlo, Nefussy Beatrice, Osmanovic Alma, Nordin Angelica, Lerner Yossef, Zabari Michal, Gotkine Marc, Baloh Robert H, Bell Shaughn, Vourc'h Patrick, Corcia Philippe, Couratier Philippe, Millecamps Stéphanie, Meininger Vincent, Salachas François, Mora Jesus S, Assialioui Abdelilah, Rojas-García Ricardo, Dion Patrick A, Ross Jay P, Ludolph Albert C., Weishaupt Jochen H, Brenner David, Freischmidt Axel, Bensimon Gilbert, Brice Alexis, Dürr Alexandra, Payan Christine A M, Saker-Delye Safaa, Wood Nicholas W, Topp Simon, Rademakers Rosa, Tittmann Lukas, Lieb Wolfgang, Klein-Franke Andreas, Ripke Stephan, Braun Alice, Kraft Julia, Whiteman David C, Olsen Catherine M, Uitterlinden André G, Hofman Albert, Rietschel Marcella, Cichon Sven, Nöthen Markus M, Amouyel Philippe, SLALOM Consortium, PARALS Consortium, SLAGEN Consortium, SLAP Consortium, Traynor Bryan J, Singleton Andrew B, Mitne Neto Miguel, Cauchi Ruben J, Ophoff Roel A, Wiedau-Pazos Martina, Lomen-Hoerth Catherine, Van Deerlin Vivianna M, Grosskreutz Julian, Roediger Annekathrin, Gaur Nayana, Jörk Alexander, Barthel Tabea, Theele Erik, Ilse Benjamin, Stubendorff Beatrice, Witte Otto W, Steinbach Robert, Hübner Christian A, Graff Caroline, Brylev Lev, Fominykh Vera, Demeshonok Vera, Ataulina Anastasia, Rogelj Boris, Koritnik Blaž, Zidar Janez, Ravnik-Glavač Metka, Glavač Damjan, Stević Zorica, Drory Vivian E, Povedano Monica, Blair Ian P, Kiernan Matthew C, Benyamin Beben, Henderson Robert D, Furlong Sarah, Mathers Susan, McCombe Pamela A, Needham Merrilee, Ngo Shyuan T, Nicholson Garth A, Pamphlett Roger, Rowe Dominic B, Steyn Frederik J, Williams Kelly L, Mather Karen A, Sachdev Perminder S, Henders Anjali K, Wallace Leanne, de Carvalho Mamede, Pinto Susana, Petri Susanne, Weber Markus, Rouleau Guy A, Silani Vincenzo, Curtis Charles J, Breen Gerome, Glass Jonathan D, Brown Robert H, Landers John E, Shaw Christopher E, Andersen Peter Munch, Groen Ewout J N, van Es Michael A, Pasterkamp R Jeroen, Fan Dongsheng, Garton Fleur C, McRae Allan F, Davey Smith George, Gaunt Tom R, Eberle Michael A, Mill Jonathan, McLaughlin Russell L, Hardiman Orla, Kenna Kevin P, Wray Naomi R, Tsai Ellen, Runz Heiko, Franke Lude, Al-Chalabi Ammar, Van Damme Philip, van den Berg Leonard H, Veldink Jan H

Citation

van Rheenen W, van der Spek R, Bakker M, Farei-Campagna J, Hop P, Zwamborn R, de Klein N, Westra H, Bakker O, Deelen P, Shireby G, Hannon E, Moisse M, Baird D, Restuadi R, Dolzhenko E, Dekker A, Gawor K, Westeneng H, Tazelaar G, van Eijk K, Kooyman M, Byrne R, Doherty M, Heverin M, Al Khleifat A, Iacoangeli A, Shatunov A, Ticozzi N, Cooper-Knock J, Smith B, Gromicho M, Chandran S, Pal S, Morrison K, Openshaw P, Hardy J, Orrell R, Sendtner M, Meyer T, Başak N, van der Kooi A, Ratti A, Fogh I, Gellera C, Lauria G, Corti S, Cereda C, Sproviero D, D'Alfonso S, Sorarù G, Siciliano G, Filosto M, Padovani A, Chio A, Calvo A, Moglia C, Brunetti M, Canosa A, Grassano M, Beghi E, Pupillo E, Logroscino G, Nefussy B, Osmanovic A, Nordin A, Lerner Y, Zabari M, Gotkine M, Baloh R, Bell S, Vourc'h P, Corcia P, Couratier P, Millecamps S, Meininger V, Salachas F, Mora J, Assialioui A, Rojas-García R, Dion P, Ross J, Ludolph A, Weishaupt J, Brenner D, Freischmidt A, Bensimon G, Brice A, Dürr A, Payan C, Saker-Delye S, Wood N, Topp S, Rademakers R, Tittmann L, Lieb W, Klein-Franke A, Ripke S, Braun A, Kraft J, Whiteman D, Olsen C, Uitterlinden A, Hofman A, Rietschel M, Cichon S, Nöthen M, Amouyel P, SLALOM Consortium, PARALS Consortium, SLAGEN Consortium, SLAP Consortium, Traynor B, Singleton A, Mitne Neto M, Cauchi R, Ophoff R, Wiedau-Pazos M, Lomen-Hoerth C, Van Deerlin V, Grosskreutz J, Roediger A, Gaur N, Jörk A, Barthel T, Theele E, Ilse B, Stubendorff B, Witte O, Steinbach R, Hübner C, Graff C, Brylev L, Fominykh V, Demeshonok V, Ataulina A, Rogelj B, Koritnik B, Zidar J, Ravnik-Glavač M, Glavač D, Stević Z, Drory V, Povedano M, Blair I, Kiernan M, Benyamin B, Henderson R, Furlong S, Mathers S, McCombe P, Needham M, Ngo S, Nicholson G, Pamphlett R, Rowe D, Steyn F, Williams K, Mather K, Sachdev P, Henders A, Wallace L, de Carvalho M, Pinto S, Petri S, Weber M, Rouleau G, Silani V, Curtis C, Breen G, Glass J, Brown R, Landers J, Shaw C, Andersen P, Groen E, van Es M, Pasterkamp R, Fan D, Garton F, McRae A, Davey Smith G, Gaunt T, Eberle M, Mill J, McLaughlin R, Hardiman O, Kenna K, Wray N, Tsai E, Runz H, Franke L, Al-Chalabi A, Van Damme P, van den Berg L, Veldink J. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nat Genet 2021; 53:1636-1648.

Type

Journal Paper/Review (English)

Journal

Nat Genet 2021; 53

Publication Date

Dec 6, 2021

Issn Electronic

1546-1718

Pages

1636-1648

Brief description/objective

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.