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

Gratten, Jacob, Zhao, Qiongyi, Benyamin, Beben, Garton, Fleur, He, Ji, Leo, Paul J., Mangelsdorf, Marie, Anderson, Lisa, Zhang, Zong-Hong, Chen, Lu, Chen, Xiang-Ding, Cremin, Katie, Deng, Hong-Weng, Edson, Janette, Han, Ying-Ying, Harris, Jessica, Henders, Anjali K., Jin, Zi-Bing, Li, Zhongshan, Lin, Yong, Liu, Xiaolu, Marshall, Mhairi, Mowry, Bryan J., Ran, Shu, Reutens, David C., Song, Sharon, Tan, Li-Jun, Tang, Lu, Wallace, Robyn H., Wheeler, Lawrie, Wu, Jinyu, Yang, Jian, Xu, Huji, Visscher, Peter M., Bartlett, Perry F., Brown, Matthew A., Wray, Naomi R. and Fan, Dongsheng (2017) Whole-exome sequencing in amyotrophic lateral sclerosis suggests NEK1 is a risk gene in Chinese. Genome Medicine, 9 97: 97. doi:10.1186/s13073-017-0487-0

Author Gratten, Jacob
Zhao, Qiongyi
Benyamin, Beben
Garton, Fleur
He, Ji
Leo, Paul J.
Mangelsdorf, Marie
Anderson, Lisa
Zhang, Zong-Hong
Chen, Lu
Chen, Xiang-Ding
Cremin, Katie
Deng, Hong-Weng
Edson, Janette
Han, Ying-Ying
Harris, Jessica
Henders, Anjali K.
Jin, Zi-Bing
Li, Zhongshan
Lin, Yong
Liu, Xiaolu
Marshall, Mhairi
Mowry, Bryan J.
Ran, Shu
Reutens, David C.
Song, Sharon
Tan, Li-Jun
Tang, Lu
Wallace, Robyn H.
Wheeler, Lawrie
Wu, Jinyu
Yang, Jian
Xu, Huji
Visscher, Peter M.
Bartlett, Perry F.
Brown, Matthew A.
Wray, Naomi R.
Fan, Dongsheng
Title Whole-exome sequencing in amyotrophic lateral sclerosis suggests NEK1 is a risk gene in Chinese
Journal name Genome Medicine   Check publisher's open access policy
ISSN 1756-994X
Publication date 2017-11-17
Year available 2017
Sub-type Article (original research)
DOI 10.1186/s13073-017-0487-0
Open Access Status DOI
Volume 9
Issue 97
Start page 97
Total pages 9
Place of publication London, United Kingdom
Publisher BioMed Central
Language eng
Subject 1313 Molecular Medicine
1312 Molecular Biology
1311 Genetics
2716 Genetics (clinical)
Abstract 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.

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.

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).

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.
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID Ross Maclean Senior Research Fellowships
R01 AR069055
U19 AG055373
Linkage Grant
Ross Maclean Senior Research Fellowship
Institutional Status UQ

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Created: Wed, 29 Nov 2017, 12:03:03 EST