Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.
van Rheenen W., Shatunov A., Dekker AM., McLaughlin RL., Diekstra FP., Pulit SL., van der Spek RAA., Võsa U., de Jong S., Robinson MR., Yang J., Fogh I., van Doormaal PT., Tazelaar GHP., Koppers M., Blokhuis AM., Sproviero W., Jones AR., Kenna KP., van Eijk KR., Harschnitz O., Schellevis RD., Brands WJ., Medic J., Menelaou A., Vajda A., Ticozzi N., Lin K., Rogelj B., Vrabec K., Ravnik-Glavač M., Koritnik B., Zidar J., Leonardis L., Grošelj LD., Millecamps S., Salachas F., Meininger V., de Carvalho M., Pinto S., Mora JS., Rojas-García R., Polak M., Chandran S., Colville S., Swingler R., Morrison KE., Shaw PJ., Hardy J., Orrell RW., Pittman A., Sidle K., Fratta P., Malaspina A., Topp S., Petri S., Abdulla S., Drepper C., Sendtner M., Meyer T., Ophoff RA., Staats KA., Wiedau-Pazos M., Lomen-Hoerth C., Van Deerlin VM., Trojanowski JQ., Elman L., McCluskey L., Basak AN., Tunca C., Hamzeiy H., Parman Y., Meitinger T., Lichtner P., Radivojkov-Blagojevic M., Andres CR., Maurel C., Bensimon G., Landwehrmeyer B., Brice A., Payan CAM., Saker-Delye S., Dürr A., Wood NW., Tittmann L., Lieb W., Franke A., Rietschel M., Cichon S., Nöthen MM., Amouyel P., Tzourio C., Dartigues J-F., Uitterlinden AG., Rivadeneira F., Estrada K., Hofman A., Curtis C., Blauw HM., van der Kooi AJ., de Visser M., Goris A., Weber M., Shaw CE., Smith BN., Pansarasa O., Cereda C., Del Bo R., Comi GP., D'Alfonso S., Bertolin C., Sorarù G., Mazzini L., Pensato V., Gellera C., Tiloca C., Ratti A., Calvo A., Moglia C., Brunetti M., Arcuti S., Capozzo R., Zecca C., Lunetta C., Penco S., Riva N., Padovani A., Filosto M., Muller B., Stuit RJ., PARALS Registry None., SLALOM Group None., SLAP Registry None., FALS Sequencing Consortium None., SLAGEN Consortium None., NNIPPS Study Group None., Blair I., Zhang K., McCann EP., Fifita JA., Nicholson GA., Rowe DB., Pamphlett R., Kiernan MC., Grosskreutz J., Witte OW., Ringer T., Prell T., Stubendorff B., Kurth I., Hübner CA., Leigh PN., Casale F., Chio A., Beghi E., Pupillo E., Tortelli R., Logroscino G., Powell J., Ludolph AC., Weishaupt JH., Robberecht W., Van Damme P., Franke L., Pers TH., Brown RH., Glass JD., Landers JE., Hardiman O., Andersen PM., Corcia P., Vourc'h P., Silani V., Wray NR., Visscher PM., de Bakker PIW., van Es MA., Pasterkamp RJ., Lewis CM., Breen G., Al-Chalabi A., van den Berg LH., Veldink JH.
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.