A genome-wide association study identifies the GPM6A locus associated with age at onset in ALS.
Nakamura R, Tohnai G, Atsuta N et al.
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Amyotrophic lateral sclerosis (ALS) exhibits considerable clinical variability, such as differences in age at onset (AAO). Multiple factors, including genetic factors, may underlie this variability; however, the specific determinants remain unclear. To identify genes affecting AAO, we have conducted a genome-wide association study in Japanese patients with ALS (discovery cohort: n = 1808; replication cohort: n = 207). Here, we show that the minor A allele of rs113161727 at the ADAM29-GPM6A locus is associated with a younger AAO in the discovery cohort (effect, -4.27 years; p = 4.60 × 10-8); this finding has been confirmed in the replication cohort (p = 0.0068) and meta-analysis (p = 1.08 × 10-9). Among 65 ALS patients with a SOD1 mutation, the AAO has been found to be 10.2 years younger in those with the A allele than in those without it (p = 0.002). This variant correlates with GPM6A upregulation in iPSC-derived motor neurons, suggesting GPM6A as a candidate AAO modifier. Overall, our study highlights the impact of genetic modifiers on ALS heterogeneity and provides a potential target for delaying disease onset.
2,015 Japanese ancestry cases
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