Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.
1043 - 1048
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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.
Authorsvan Rheenen, W; Shatunov, A; Dekker, AM; McLaughlin, RL; Diekstra, FP; Pulit, SL; van der Spek, RA; Võsa, U; de Jong, S; Robinson, MR; Yang, J; Fogh, I; van Doormaal, PT; Tazelaar, GH; 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, CA; Saker-Delye, S; Dürr, A; Wood, NW; Tittmann, L; Lieb, W; Franke, A; Rietschel, M; Cichon, S; Nöthen, MM; Amouyel, P; Tzourio, C; Dartigues, JF; Uitterlinden, AG; Rivadeneira, F; Estrada, K; Hofman, A; Curtis, C; Blauw, HM; van der Kooi, AJ; et al.
- College Publications