Cross-ethnic meta-analysis identifies association of the GPX3-TNIP1 locus with amyotrophic lateral sclerosis.
Benyamin B., He J., Zhao Q., Gratten J., Garton F., Leo PJ., Liu Z., Mangelsdorf M., Al-Chalabi A., Anderson L., Butler TJ., Chen L., Chen X-D., Cremin K., Deng H-W., Devine M., Edson J., Fifita JA., Furlong S., Han Y-Y., Harris J., Henders AK., Jeffree RL., Jin Z-B., Li Z., Li T., Li M., Lin Y., Liu X., Marshall M., McCann EP., Mowry BJ., Ngo ST., Pamphlett R., Ran S., Reutens DC., Rowe DB., Sachdev P., Shah S., Song S., Tan L-J., Tang L., van den Berg LH., van Rheenen W., Veldink JH., Wallace RH., Wheeler L., Williams KL., Wu J., Wu X., Yang J., Yue W., Zhang Z-H., Zhang D., Noakes PG., Blair IP., Henderson RD., McCombe PA., Visscher PM., Xu H., Bartlett PF., Brown MA., Wray NR., Fan D.
Cross-ethnic genetic studies can leverage power from differences in disease epidemiology and population-specific genetic architecture. In particular, the differences in linkage disequilibrium and allele frequency patterns across ethnic groups may increase gene-mapping resolution. Here we use cross-ethnic genetic data in sporadic amyotrophic lateral sclerosis (ALS), an adult-onset, rapidly progressing neurodegenerative disease. We report analyses of novel genome-wide association study data of 1,234 ALS cases and 2,850 controls. We find a significant association of rs10463311 spanning GPX3-TNIP1 with ALS (p = 1.3 × 10-8), with replication support from two independent Australian samples (combined 576 cases and 683 controls, p = 1.7 × 10-3). Both GPX3 and TNIP1 interact with other known ALS genes (SOD1 and OPTN, respectively). In addition, GGNBP2 was identified using gene-based analysis and summary statistics-based Mendelian randomization analysis, although further replication is needed to confirm this result. Our results increase our understanding of genetic aetiology of ALS.Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease. Here, Wray and colleagues identify association of the GPX3-TNIP1 locus with ALS using cross-ethnic meta-analyses.