Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
van Rheenen W., van der Spek RAA., Bakker MK., van Vugt JJFA., Hop PJ., Zwamborn RAJ., de Klein N., Westra H-J., Bakker OB., Deelen P., Shireby G., Hannon E., Moisse M., Baird D., Restuadi R., Dolzhenko E., Dekker AM., Gawor K., Westeneng H-J., Tazelaar GHP., van Eijk KR., Kooyman M., Byrne RP., Doherty M., Heverin M., Al Khleifat A., Iacoangeli A., Shatunov A., Ticozzi N., Cooper-Knock J., Smith BN., Gromicho M., Chandran S., Pal S., Morrison KE., Shaw PJ., Hardy J., Orrell RW., Sendtner M., Meyer T., Başak N., van der Kooi AJ., 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., Chiò 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 RH., Bell S., Vourc’h P., Corcia P., Couratier P., Millecamps S., Meininger V., Salachas F., Mora Pardina JS., Assialioui A., Rojas-García R., Dion PA., Ross JP., Ludolph AC., Weishaupt JH., Brenner D., Freischmidt A., Bensimon G., Brice A., Durr A., Payan CAM., Saker-Delye S., Wood NW., Topp S., Rademakers R., Tittmann L., Lieb W., Franke A., Ripke S., Braun A., Kraft J., Whiteman DC., Olsen CM., Uitterlinden AG., Hofman A., Rietschel M., Cichon S., Nöthen MM., Amouyel P., Comi G., Riva N., Lunetta C., Gerardi F., Cotelli MS., Rinaldi F., Chiveri L., Guaita MC., Perrone P., Ceroni M., Diamanti L., Ferrarese C., Tremolizzo L., Delodovici ML., Bono G., Canosa A., Manera U., Vasta R., Bombaci A., Casale F., Fuda G., Salamone P., Iazzolino B., Peotta L., Cugnasco P., De Marco G., Torrieri MC., Palumbo F., Gallone S., Barberis M., Sbaiz L., Gentile S., Mauro A., Mazzini L., De Marchi F., Corrado L., D’Alfonso S., Bertolotto A., Gionco M., Leotta D., Odddenino E., Imperiale D., Cavallo R., Pignatta P., De Mattei M., Geda C., Papurello DM., Gusmaroli G., Comi C., Labate C., Ruiz L., Ferrandi D., Rota E., Aguggia M., Di Vito N., Meineri P., Ghiglione P., Launaro N., Dotta M., Di Sapio A., Giardini G., Tiloca C., Peverelli S., Taroni F., Pensato V., Castellotti B., Comi GP., Del Bo R., Ceroni M., Gagliardi S., Corrado L., Mazzini L., Raggi F., Simoncini C., Lo Gerfo A., Inghilleri M., Ferlini A., Simone IL., Passarella B., Guerra V., Zoccolella S., Nozzoli C., Mundi C., Leone M., Zarrelli M., Tamma F., Valluzzi F., Calabrese G., Boero G., Rini A., Traynor BJ., Singleton AB., Mitne Neto M., Cauchi RJ., Ophoff RA., Wiedau-Pazos M., Lomen-Hoerth C., van Deerlin VM., Grosskreutz J., Roediger A., Gaur N., Jörk A., Barthel T., Theele E., Ilse B., Stubendorff B., Witte OW., Steinbach R., Hübner CA., 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 IP., Kiernan MC., Benyamin B., Henderson RD., Furlong S., Mathers S., McCombe PA., Needham M., Ngo ST., Nicholson GA., Pamphlett R., Rowe DB., Steyn FJ., Williams KL., Mather KA., Sachdev PS., Henders AK., Wallace L., de Carvalho M., Pinto S., Petri S., Weber M., Rouleau GA., Silani V., Curtis CJ., Breen G., Glass JD., Brown RH., Landers JE., Shaw CE., Andersen PM., Groen EJN., van Es MA., Pasterkamp RJ., Fan D., Garton FC., McRae AF., Davey Smith G., Gaunt TR., Eberle MA., Mill J., McLaughlin RL., Hardiman O., Kenna KP., Wray NR., Tsai E., Runz H., Franke L., Al-Chalabi A., Van Damme P., van den Berg LH., Veldink JH.
AbstractAmyotrophic 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.