Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
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Publication date
2016-09
Authors
van Rheenen, Wouter
Shatunov, Aleksey
Dekker, Annelot
McLaughlin, Russell L.
Diekstra, Frank P.
Pulit, Sara
van der Spek, Rick
Võsa, Urmo
de Jong, Simone
Robinson, Matthew R
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Advisors
Supervisors
Document Type
Letter
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taverne
Abstract
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.
Keywords
Taverne, Journal Article, Comparative Study
Citation
van Rheenen, W, Shatunov, A, Dekker, A M, McLaughlin, R L, Diekstra, F P, Pulit, S L, van der Spek, R A A, Võsa, U, de Jong, S, Robinson, M R, Yang, J, Fogh, I, van Doormaal, P T, Tazelaar, G H P, Koppers, M, Blokhuis, A M, Sproviero, W, Jones, A R, Kenna, K P, van Eijk, K R, Harschnitz, O, Schellevis, R D, Brands, W J, Medic, J, Menelaou, A, Vajda, A, Ticozzi, N, Lin, K, Rogelj, B, Vrabec, K, Ravnik-Glavač, M, Koritnik, B, Zidar, J, Leonardis, L, Grošelj, L D, Millecamps, S, Salachas, F, Meininger, V, de Carvalho, M, Pinto, S, Mora, J S, Rojas-García, R, Polak, M, Ophoff, R A, Blauw, H M, de Bakker, P I W, van Es, M A, Pasterkamp, R J, van den Berg, L H, Veldink, J H & PARALS Registry 2016, 'Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis', Nature Genetics, vol. 48, no. 9, pp. 1043–1048. https://doi.org/10.1038/ng.3622