Whole-exome sequencing in amyotrophic lateral sclerosis suggests NEK1 is a risk gene in Chinese

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease characterised by the degeneration of motor neurons, which are responsible for voluntary movement. There remains limited understanding of disease aetiology, with median survival of ALS of three years and no effective treatment. Identifying genes that contribute to ALS susceptibility is an important step towards understanding aetiology. The vast majority of published human genetic studies, including for ALS, have used samples of European ancestry. The importance of trans-ethnic studies in human genetic studies is widely recognised, yet a dearth of studies of non-European ancestries remains. Here, we report analyses of novel whole-exome sequencing (WES) data from Chinese ALS and control individuals. METHODS: WES data were generated for 610 ALS cases and 460 controls drawn from Chinese populations. We assessed evidence for an excess of rare damaging mutations at the gene level and the gene set level, considering only singleton variants filtered to have allele frequency less than 5 × 10(–5) in reference databases. To meta-analyse our results with a published study of European ancestry, we used a Cochran–Mantel–Haenszel test to compare gene-level variant counts in cases vs controls. RESULTS: No gene passed the genome-wide significance threshold with ALS in Chinese samples alone. Combining rare variant counts in Chinese with those from the largest WES study of European ancestry resulted in three genes surpassing genome-wide significance: TBK1 (p = 8.3 × 10(–12)), SOD1 (p = 8.9 × 10(–9)) and NEK1 (p = 1.1 × 10(–9)). In the Chinese data alone, SOD1 and NEK1 were nominally significantly associated with ALS (p = 0.04 and p = 7 × 10(–3), respectively) and the case/control frequencies of rare coding variants in these genes were similar in Chinese and Europeans (SOD1: 1.5%/0.2% vs 0.9%/0.1%, NEK1 1.8%/0.4% vs 1.9%/0.8%). This was also true for TBK1 (1.2%/0.2% vs 1.4%/0.4%), but the association with ALS in Chinese was not significant (p = 0.14). CONCLUSIONS: While SOD1 is already recognised as an ALS-associated gene in Chinese, we provide novel evidence for association of NEK1 with ALS in Chinese, reporting variants in these genes not previously found in Europeans. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13073-017-0487-0) contains supplementary material, which is available to authorized users.