Skip to main content
SpringerLink
Log in

Unique characteristics of the genetics epidemiology of amyotrophic lateral sclerosis in China

  • Research Paper
  • Published:
Science China Life Sciences Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brown, R.H., and Al-Chalabi, A. (2017). Amyotrophic lateral sclerosis. N Engl J Med 377, 162–172.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • Huynh, W., and Kiernan, M.C. (2015). A unique account of ALS in China: exploring ethnic heterogeneity. J Neurol Neurosurg Psych 86, 1051–1052.

    Article  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Mitchell, J., and Borasio, G. (2007). Amyotrophic lateral sclerosis. Lancet 369, 2031–2041.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  Google Scholar 

Download references

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

  1. Department of Neurology and Rare Disease Center of West China Hospital, Sichuan University, Chengdu, 610041, China

    Qianqian Wei, Xueping Chen, Yongping Chen, Ruwei Ou, Bei Cao, Yanbing Hou, Lingyu Zhang & Hui-Fang Shang

Authors
  1. Qianqian Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xueping Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yongping Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ruwei Ou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bei Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yanbing Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lingyu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hui-Fang Shang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hui-Fang Shang.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11427-018-9453-x

Keywords

Search

Navigation