Abstract
Continual discoveries of new genes and unraveling the genetic etiology in amyotrophic lateral sclerosis (ALS) have provided greater insight into the underlying pathogenesis in motor neuron degeneration, as well as facilitating the disease modeling and the testing of targeted therapeutics. While, the genetic etiology accounted for two-thirds of FALS and approximately 11% of SALS in Caucasians. However, the contributions of these causative genes to ALS vary among different populations. Furthermore, the prominent difference between Chinese population and other ethnics remains a source of ongoing debate. We systemically reviewed genetics literature of Chinese ALS populations and updated the mutation frequencies of the main ALS-implicated genes aiming to determine the genetic features of ALS in Chinese population. We also reviewed the associations between ALS-implicated single nucleotide polymorphisms (SNPs) and the risk of ALS in Chinese population. A total of 116 studies were included in this analysis (86 gene mutation study articles and 30 SNPs study articles). The results showed that the overall gene mutation rates of ALS-related causative genes were 55.0% in familial ALS (FALS) and 11.7% in sporadic ALS (SALS) in Chinese population. In Chinese FALS, the highest mutation frequency was found in SOD1 gene (25.6%), followed by FUS (5.8%), TARDBP (5.8%), DCTN1 (3.6%) and C9orf72 (3.5%). In Chinese SALS, the highest mutation frequency was also identified in SOD1 gene (1.6%), followed by ANXA11 (1.4%), FUS (1.3%), SQSTM1 (1.0%), OPTN (0.9%) and CCNF (0.8%). The associations between several SNPs and risk of ALS were also reported in Chinese population. The genetic features of ALS in Chinese population are significantly different from those in Caucasian population, indicating an association between genetic susceptibility and origin of population. Further explorations are required to understand the gene complexity of ALS, including the contribution of most minor genes and the molecular mechanisms in ALS pathologies.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Benyamin, B., He, J., Zhao, Q., Gratten, J., Garton, F., Leo, P.J., Liu, Z., Mangelsdorf, M., Al-Chalabi, A., Anderson, L., et al. (2017). Crossethnic meta-analysis identifies association of the GPX3-TNIP1 locus with amyotrophic lateral sclerosis. Nat Commun 8, 611.
Brown, R.H., and Al-Chalabi, A. (2017). Amyotrophic lateral sclerosis. N Engl J Med 377, 162–172.
Byrne, S., Bede, P., Elamin, M., Kenna, K., Lynch, C., McLaughlin, R., and Hardiman, O. (2011). Proposed criteria for familial amyotrophic lateral sclerosis. Amyotroph Lateral Scler 12, 157–159.
Caballero-Hernandez, D., Toscano, M.G., Cejudo-Guillen, M., Garcia-Martin, M.L., Lopez, S., Franco, J.M., Quintana, F.J., Roodveldt, C., and Pozo, D. (2016). The ‘Omics’ of amyotrophic lateral sclerosis. Trends Mol Med 22, 53–67.
Chen, A., Oakley, A.E., Monteiro, M., Tuomela, K., Allan, L.M., Mukaetova-Ladinska, E.B., O’Brien, J.T., and Kalaria, R.N. (2016). Multiplex analyte assays to characterize different dementias: brain inflammatory cytokines in poststroke and other dementias. Neurobiol Aging 38, 56–67.
Chiò, A., Traynor, B.J., Lombardo, F., Fimognari, M., Calvo, A., Ghiglione, P., Mutani, R., and Restagno, G. (2008). Prevalence of SOD1 mutations in the Italian ALS population. Neurology 70, 533–537.
Huynh, W., and Kiernan, M.C. (2015). A unique account of ALS in China: exploring ethnic heterogeneity. J Neurol Neurosurg Psych 86, 1051–1052.
Iida, A., Kamei, T., Sano, M., Oshima, S., Tokuda, T., Nakamura, Y., and Ikegawa, S. (2012). Large-scale screening of TARDBP mutation in amyotrophic lateral sclerosis in Japanese. Neurobiol Aging 33, 786–790.
Ji, A.L., Zhang, X., Chen, W.W., and Huang, W.J. (2017). Genetics insight into the amyotrophic lateral sclerosis/frontotemporal dementia spectrum. J Med Genet 54, 145–154.
Kenna, K.P., McLaughlin, R.L., Byrne, S., Elamin, M., Heverin, M., Kenny, E.M., Cormican, P., Morris, D.W., Donaghy, C.G., Bradley, D. G., et al. (2013). Delineating the genetic heterogeneity of ALS using targeted high-throughput sequencing. J Med Genet 50, 776–783.
Konno, T., Shiga, A., Tsujino, A., Sugai, A., Kato, T., Kanai, K., Yokoseki, A., Eguchi, H., Kuwabara, S., Nishizawa, M., et al. (2013). Japanese amyotrophic lateral sclerosis patients with GGGGCC hexanucleotide repeat expansion in C9ORF72. J Neurol Neurosurg Psych 84, 398–401.
Li, C., Ji, Y., Tang, L., Zhang, N., He, J., Ye, S., Liu, X., and Fan, D. (2015). Optineurin mutations in patients with sporadic amyotrophic lateral sclerosis in China. Amyotroph Lateral Scler Frontotemp Degener 16, 485–489.
Lin, A.L., Zhang, W., Gao, X., and Watts, L. (2015). Caloric restriction increases ketone bodies metabolism and preserves blood flow in aging brain. Neurobiol Aging 36, 2296–2303.
Liu, X., He, J., Gao, F.B., Gitler, A.D., and Fan, D. (2018). The epidemiology and genetics of amyotrophic lateral sclerosis in China. Brain Res 1693, 121–126.
Liu, Z.J., Lin, H.X., Liu, G.L., Tao, Q.Q., Ni, W., Xiao, B.G., and Wu, Z.Y. (2017). The investigation of genetic and clinical features in Chinese patients with juvenile amyotrophic lateral sclerosis. Clin Genet 92, 267–273.
Lu, H.P., Gan, S.R., Chen, S., Li, H.F., Liu, Z.J., Ni, W., Wang, N., and Wu, Z.Y. (2015). Intermediate-length polyglutamine in ATXN2 is a possible risk factor among Eastern Chinese patients with amyotrophic lateral sclerosis. Neurobiol Aging 36, 1603.e11–1603.e14.
Mitchell, J., and Borasio, G. (2007). Amyotrophic lateral sclerosis. Lancet 369, 2031–2041.
Nakamura, R., Sone, J., Atsuta, N., Tohnai, G., Watanabe, H., Yokoi, D., Nakatochi, M., Watanabe, H., Ito, M., Senda, J., et al. (2016). Nextgeneration sequencing of 28 ALS-related genes in a Japanese ALS cohort. Neurobiol Aging 39, 219.e1–219.e8.
Rosenberg, N.A., Huang, L., Jewett, E.M., Szpiech, Z.A., Jankovic, I., and Boehnke, M. (2010). Genome-wide association studies in diverse populations. Nat Rev Genet 11, 356–366.
Shahrizaila, N., Sobue, G., Kuwabara, S., Kim, S.H., Birks, C., Fan, D.S., Bae, J.S., Hu, C.J., Gourie-Devi, M., Noto, Y., et al. (2016). Amyotrophic lateral sclerosis and motor neuron syndromes in Asia. J Neurol Neurosurg Psych 87, 821–830.
Tsai, P.C., Liao, Y.C., Jih, K.Y., Soong, B.W., Lin, K.P., and Lee, Y.C. (2018). Genetic analysis of ANXA11 variants in a Han Chinese cohort with amyotrophic lateral sclerosis in Taiwan. Neurobiol Aging 72, 188. e1–188.e2.
Tsai, C.P., Soong, B.W., Lin, K.P., Tu, P.H., Lin, J.L., and Lee, Y.C. (2011). FUS, TARDBP, and SOD1 mutations in a Taiwanese cohort with familial ALS. Neurobiol Aging 32, 553.e13–553.e21.
Tsai, C.P., Soong, B.W., Tu, P.H., Lin, K.P., Fuh, J.L., Tsai, P.C., Lu, Y.C., Lee, I.H., and Lee, Y.C. (2012). A hexanucleotide repeat expansion in C9ORF72 causes familial and sporadic ALS in Taiwan. Neurobiol Aging 33, 2232.e11–2232.e18.
Tsai, P.C., Liao, Y.C., Chen, P.L., Guo, Y.C., Chen, Y.H., Jih, K.Y., Lin, K. P., Soong, B.W., Tsai, C.P., and Lee, Y.C. (2018). Investigating CCNF mutations in a Taiwanese cohort with amyotrophic lateral sclerosis. Neurobiol Aging 62, 243.e1–243.e6.
Turner, M.R., Hardiman, O., Benatar, M., Brooks, B.R., Chio, A., de Carvalho, M., Ince, P.G., Lin, C., Miller, R.G., Mitsumoto, H., et al. (2013). Controversies and priorities in amyotrophic lateral sclerosis. Lancet Neurol 12, 310–322.
van der Zee, J., Gijselinck, I., Dillen, L., Van Langenhove, T., Theuns, J., Engelborghs, S., Philtjens, S., Vandenbulcke, M., Sleegers, K., Sieben, A., et al. (2013). A pan-European study of the C9orf72 repeat associated with FTLD: Geographic prevalence, genomic instability, and intermediate repeats. Hum Mutat 34, 363–373.
Wei, Q., Chen, X., Zheng, Z., Huang, R., Guo, X., Cao, B., Zhao, B., and Shang, H. (2015). Clinical features of amyotrophic lateral sclerosis in south-west China. Amyotroph Lateral Scler Frontotemp Degener 16, 512–519.
Wei, Q.Q., Zhou, Q.Q., Chen, Y.P., Ou, R.W., Cao, B., Xu, Y.Q., Yang, J., and Shang, H.F. (2017). Analysis of SOD1 mutations in a Chinese population with amyotrophic lateral sclerosis: a case-control study and literature review. Sci Rep 7, 44606.
Wingo, T.S., Cutler, D.J., Yarab, N., Kelly, C.M., and Glass, J.D. (2011). The heritability of amyotrophic lateral sclerosis in a clinically ascertained United States research registry. PLoS ONE 6, e27985.
Xie, T., Deng, L., Mei, P., Zhou, Y., Wang, B., Zhang, J., Lin, J., Wei, Y., Zhang, X., and Xu, R. (2014). A genome-wide association study combining pathway analysis for typical sporadic amyotrophic lateral sclerosis in Chinese Han populations. Neurobiol Aging 35, 1778.e9–1778.e23.
Xu, L., Tian, D., Li, J., Chen, L., Tang, L., and Fan, D. (2017). The analysis of two BDNF polymorphisms G196A/C270T in Chinese sporadic amyotrophic lateral sclerosis. Front Aging Neurosci 9, 135.
Xu, L., Li, J., Tian, D., Chen, L., Tang, L., and Fan, D. (2018). The rs696880 polymorphism in the Nogo-A receptor gene (RTN4R) is associated with susceptibility to sporadic amyotrophic lateral sclerosis in the Chinese population. Front Aging Neurosci 10, 108.
Yang, X., Zheng, J.H., Tian, S., Chen, Y., An, R., Zhao, Q., and Xu, Y. (2017). HLA-DRA/HLA-DRB5 polymorphism affects risk of sporadic ALS and survival in a southwest Chinese cohort. J Neurol Sci 373, 124–128.
Yang, Y., and Fan, D. (2014). To screen for SQSTM1/p62 gene in Chinese patients with familial amyotrophic lateral sclerosis carrying superoxide dismutase 1 mutation. Zhonghua Nei Ke Za Zhi 53, 957–960.
Yuan, X.Q., Cao, B., Wu, Y., Chen, Y.P., Wei, Q.Q., Ou, R.W., Yang, J., Chen, X.P., Zhao, B., Song, W., et al. (2018). Association analysis of SNP rs11868035 in SREBF1 with sporadic Parkinson’s disease, sporadic amyotrophic lateral sclerosis and multiple system atrophy in a Chinese population. Neurosci Lett 664, 128–132.
Zhang, K., Liu, Q., Liu, K., Shen, D., Tai, H., Shu, S., Ding, Q., Fu, H., Liu, S., Wang, Z., et al. (2018). ANXA11 mutations prevail in Chinese ALS patients with and without cognitive dementia. Neurol Genet 4, e237.
Zou, Z.Y., Liu, M.S., Li, X.G., and Cui, L.Y. (2013). Screening of VCP mutations in Chinese amyotrophic lateral sclerosis patients. Neurobiol Aging 34, 1519.e3–1519.e4.
Zou, Z.Y., Liu, M.S., Li, X.G., and Cui, L.Y. (2016). The distinctive genetic architecture of ALS in mainland China. J Neurol Neurosurg Psych 87, 906–907.
Zou, Z.Y., Zhou, Z.R., Che, C.H., Liu, C.Y., He, R.L., and Huang, H.P. (2017). Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psych 88, 540–549.
Acknowledgements
This study was supported by the funding of the National Natural Science Foundation of China (81371394) and the National Key Research and Development Program of China (2016YFC0901504).
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Wei, Q., Chen, X., Chen, Y. et al. Unique characteristics of the genetics epidemiology of amyotrophic lateral sclerosis in China. Sci. China Life Sci. 62, 517–525 (2019). https://doi.org/10.1007/s11427-018-9453-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11427-018-9453-x