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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease characterised by the degeneration of motor neurons, which are responsible for voluntary movement
Amyotrophic lateral sclerosis (ALS) is a progressing motor neuron disease characterised by loss of function (LOF) of motor neurons, which are essential for controlling voluntary muscle activity such as walking, breathing and speaking
When we meta-analysed per-gene case-control counts of rare functional mutations in our Chinese sample with those from the largest whole-exome sequencing (WES) study of European ancestry [9] (Additional file 1: Table S6), three genes surpassed genome-wide significance for association with ALS with smaller p values than in the European ancestry samples alone: TBK1; NEK1;and SOD1 (Table 1; Fig. 1). Both NEK1 and SOD1 were nominally significant in our Chinese sample, while TBK1 was not significant (Table 1), and the case-control frequencies of rare coding variants were similar to Europeans (NEK1 1.8%/0.4% vs 1.9%/0.8%; SOD1: 1.5%/0.2% vs 0.9%/0.1%; TBK1: 1.2%/0.2% vs 1.4%/0.4%)
Summary
Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease characterised by the degeneration of motor neurons, which are responsible for voluntary movement. Amyotrophic lateral sclerosis (ALS) is a progressing motor neuron disease characterised by loss of function (LOF) of motor neurons, which are essential for controlling voluntary muscle activity such as walking, breathing and speaking This condition leads to premature death with a median survival of about two to three years. Highly penetrant identified mutations still only account for up to 10% of cases [6, 7] and more work needs to be done Identification of both causal and risk genes will help build a more complete picture of the underlying mechanisms and pathways for disease and any new ALS molecule is potentially a new therapeutic target [8]
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