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. 2017 Nov 17;9(1):97.
doi: 10.1186/s13073-017-0487-0.

Whole-exome Sequencing in Amyotrophic Lateral Sclerosis Suggests NEK1 Is a Risk Gene in Chinese

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Free PMC article

Whole-exome Sequencing in Amyotrophic Lateral Sclerosis Suggests NEK1 Is a Risk Gene in Chinese

Jacob Gratten et al. Genome Med. .
Free PMC article

Abstract

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.

Conflict of interest statement

Ethics approval and consent to participate

ALS patients were from the ALS specialty clinic at the Department of Neurology of the Peking University Third Hospital, Beijing, China. Control samples were from individuals who attended the same hospital, Shanghai Changzheng Hospital, Hunan Normal University, the University of Shanghai for Science and Technology and Wenzhou Medical University. All cases and controls provided written informed consent to participate in the research. Sample collections were approved by the human research ethics committees of the Peking University Third Hospital, Shanghai Changzheng Hospital, the University of Shanghai for Science and Technology and Wenzhou Medical University Eye Hospital (KYK-2015-18) and by the Hunan University Ethics Committee in their Department of Research Administration. Analyses conducted at the University of Queensland were approved by the University human research ethics committee (Approval no. 2011001173). The study conformed to the principles of the Declaration of Helsinki.

Consent for publication

N/A. Our manuscript does not include any individual person’s data in any form.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Quantile–quantile plots of the analysis of rare variant counts in combined Chinese and European data (up to 4797 cases and 9236 controls). The Cochran–Mantel–Haenszel test was applied to qualifying variants under three models: (L) dominant coding; (R) dominant not benign; and dominant LOF (Additional file 2: Figure S1). Test statistics are provided for the genes with the top ten associations (blue = increased risk, grey = reduced risk; *no qualifying variants were observed in controls for gene S100A2, so the OR was estimated by adding 0.5 to each cell of the largest cohort). The Bonferroni-corrected significance threshold was p ≤ 1.9 × 10–6, based on 26,214 tests across 18,117 genes. The genomic inflation factor, lambda (λ), was 1.069 for the dominant coding analysis and 1.067 for the dominant not benign analysisrecognised in our Chinese sample
Fig. 2
Fig. 2
Summary of rare variants in Chinese WES sample comprising 597 sporadic (sALS) and 13 familial (fALS) cases. The screening of WES data of Chinese ALS cases identified ~ 5% with previously reported likely causal variants. Variants previously reported for ALS but now found to have population frequency (0.00005 ≤ freq < 0.01) are classified as ‘unlikely causal’. For variants identified in cases only, a number of putatively damaging, rare (MAF < 0.00005 dominant or < 0.01 recessive) variants in a predefined set of known ALS-priority genes (n = 32 cases) and ALS-relevant genes (n = 89 cases) were identified, but these have uncertain significance. Considering only fALS probands (n = 13), WES identified previously reported likely causal variants in five cases (1 DCTN1, 2 FUS, 1 SOD1, 1 TARDBP) with uncertain significance variants (damaging rare in ALS-relevant genes) in four others. Four percent of cases (24/610) and 3% of controls (13/460) were identified to be carrying one or more rare variants in ALS genes (from any category; causal, risk, candidate) and/or similar disease genes (Additional file 1: Table S10), but no individual harboured more than one likely causal variant. The number of cases are defined in the legend and expressed a percentage of total ALS case exomes screened (n = 610)

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References

    1. Marangi G, Traynor BJ. Genetic causes of amyotrophic lateral sclerosis: New genetic analysis methodologies entailing new opportunities and challenges. Brain Res. 1607;2015:75–93. - PMC - PubMed
    1. Renton AE, Chiò A, Traynor BJ, Cirulli ET, Lasseigne BN, Petrovski S, et al. State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci. 2014;17:17–23. doi: 10.1038/nn.3584. - DOI - PMC - PubMed
    1. He J, Mangelsdorf M, Fan D, Bartlett P, Brown MA. Amyotrophic lateral sclerosis genetic studies. Neurosci. 2015;21:599–615. - PubMed
    1. Fang F, Quinlan P, Ye W, Barber MK, Umbach DM, Sandler DP, et al. Workplace exposures and the risk of amyotrophic lateral sclerosis. Environ Health Perspect. 2009;117:1387–92. doi: 10.1289/ehp.0900580. - DOI - PMC - PubMed
    1. Taylor JP, Brown RH, Cleveland DW. Decoding ALS: from genes to mechanism. Nature. 2016;539:197–206. doi: 10.1038/nature20413. - DOI - PMC - PubMed

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