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

Abstract

BackgroundAmyotrophic 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.MethodsWES 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.ResultsNo 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).ConclusionsWhile 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 materialThe online version of this article (doi:10.1186/s13073-017-0487-0) contains supplementary material, which is available to authorized users.

The epidemiology and genetics of Amyotrophic lateral sclerosis in China

“…Afterwards, it was identified that a significant association of rs10463311 spanning GPX3-TNIP1 with ALS in the meta analysis of GWAS data from Chinese and European cohorts (Benyamin et al, 2017). Recently, NEK1 was reported a risk ALS gene based on the meta-analysis of WES data from large cohorts of Chinese and European ancestry (Gratten et al, 2017), which was consistent with the two studies from several European countries (Brenner et al, 2016; Kenna et al, 2016) and considered the first study to define a new gene with WES data in Chinese ALS.…”

Checking NEKs: Overcoming a Bottleneck in Human Diseases

“…In a rare variant burden (RVB) analysis of a whole-exome from index FALS cases, a higher mutation profile of NEK1 was found in FALS and SALS cases [41]. Similarly, in a sample of Chinese patients, whole-exome analysis contributed to European evidence showing that NEK1 is an ALS gene as well as reporting new variants [43]. Furthermore, given the few studies endorsing NEK1 as an ALS gene and the ethnic heterogeneity of genes from ALS patients, Shu et al [44] published a mutation screening of NEK1 from Chinese ALS patients by Polymerase Chain Reaction (PCR)-sanger sequencing, which led to the identification of coherent data of risk variants of NEK1 and, in total, three novel heterozygous loss-of-function mutations were identified.…”

New molecular diagnostic trends and biomarkers for amyotrophic lateral sclerosis

“…Among the new genes, the FTO genomic variants are founder mutations for the Greek population (Mitropoulos, Katsila, Patrinos, & Pampalakis, 2018). NEK1 pathogenic variants constitute a risk factor in the Chinese population (Gratten et al, 2017). This knowledge may be applied in the designing of new genetic testing based on the population under study.…”