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. 2013 Jan;34(1):357.e7-19.
doi: 10.1016/j.neurobiolaging.2012.07.017. Epub 2012 Sep 5.

Age of onset of amyotrophic lateral sclerosis is modulated by a locus on 1p34.1

Kreshnik B Ahmeti, Senda Ajroud-Driss, Ammar Al-Chalabi, Peter M Andersen, Jennifer Armstrong, Anne Birve, Hylke M Blauw, Robert H Brown, Lucie Bruijn, Wenjie Chen, Adriano Chio, Mary C Comeau, Simon Cronin, Frank P Diekstra, Athina Soraya Gkazi, Jonathan D Glass, Josh D Grab, Ewout J Groen, Jonathan L Haines, Orla Hardiman, Scott Heller, Jie Huang, Wu-Yen Hung; ITALSGEN consortium; James M Jaworski, Ashley Jones, Humaira Khan, John E Landers, Carl D Langefeld, P Nigel Leigh, Miranda C Marion, Russell L McLaughlin, Vincent Meininger, Judith Melki, Jack W Miller, Gabriele Mora, Margaret A Pericak-Vance, Evadnie Rampersaud, Wim Robberecht, Laurie P Russell, Francois Salachas, Christiaan G Saris, Aleksey Shatunov, Christopher E Shaw, Nailah Siddique, Teepu Siddique, Bradley N Smith, Robert Sufit, Simon Topp, Bryan J Traynor, Caroline Vance, Philip van Damme, Leonard H van den Berg, Michael A van Es, Paul W van Vught, Jan H Veldink, Yi Yang, J G Zheng; ALSGEN Consortium
Collaborators

Age of onset of amyotrophic lateral sclerosis is modulated by a locus on 1p34.1

Kreshnik B Ahmeti et al. Neurobiol Aging. 2013 Jan.

Abstract

Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. Individuals with ALS rapidly progress to paralysis and die from respiratory failure within 3 to 5 years after symptom onset. Epidemiological factors explain only a modest amount of the risk for ALS. However, there is growing evidence of a strong genetic component to both familial and sporadic ALS risk. The International Consortium on Amyotrophic Lateral Sclerosis Genetics was established to bring together existing genome-wide association cohorts and identify sporadic ALS susceptibility and age at symptom onset loci. Here, we report the results of a meta-analysis of the International Consortium on Amyotrophic Lateral Sclerosis Genetics genome-wide association samples, consisting of 4243 ALS cases and 5112 controls from 13 European ancestry cohorts from across the United States and Europe. Eight genomic regions provided evidence of association with ALS, including 9p21.2 (rs3849942, odds ratio [OR] = 1.21; p = 4.41 × 10(-7)), 17p11.2 (rs7477, OR = 1.30; p = 2.89 × 10(-7)), and 19p13 (rs12608932, OR = 1.37, p = 1.29 × 10(-7)). Six genomic regions were associated with age at onset of ALS. The strongest evidence for an age of onset locus was observed at 1p34.1, with comparable evidence at rs3011225 (R(2)(partial) = 0.0061; p = 6.59 × 10(-8)) and rs803675 (R(2)(partial) = 0.0060; p = 6.96 × 10(-8)). These associations were consistent across all 13 cohorts. For rs3011225, individuals with at least 1 copy of the minor allele had an earlier average age of onset of over 2 years. Identifying the underlying pathways influencing susceptibility to and age at onset of ALS may provide insight into the pathogenic mechanisms and motivate new pharmacologic targets for this fatal neurodegenerative disease.

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Figures

Fig. 1
Fig. 1
Results of the genome-wide association analysis contrasting amyotrophic lateral sclerosis (ALS) cases versus controls (joint analysis).
Fig. 2
Fig. 2
Results of the genome-wide association analysis for age of amyotrophic lateral sclerosis (ALS) onset (joint analysis).
Fig. 3
Fig. 3
Chromosome 1 top hit from age of onset, joint analysis.
Fig. 4
Fig. 4
Age of onset chromosome 1p34.1 region (dominant model p values).
See this image and copyright information in PMC

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