Science China Life Sciences

, Volume 62, Issue 4, pp 517–525 | Cite as

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

  • Qianqian Wei
  • Xueping Chen
  • Yongping Chen
  • Ruwei Ou
  • Bei Cao
  • Yanbing Hou
  • Lingyu Zhang
  • Hui-Fang ShangEmail author
Research Paper


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.


amyotrophic lateral sclerosis gene mutation single nucleotide polymorphisms 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.



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).

Supplementary material

11427_2018_9453_MOESM1_ESM.docx (26 kb)
Supplementary table 1 The mutation frequencies of common causative genes in Chinese ALS patients from included studies.


  1. 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.CrossRefGoogle Scholar
  2. Brown, R.H., and Al-Chalabi, A. (2017). Amyotrophic lateral sclerosis. N Engl J Med 377, 162–172.CrossRefGoogle Scholar
  3. 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.CrossRefGoogle Scholar
  4. 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.CrossRefGoogle Scholar
  5. 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.CrossRefGoogle Scholar
  6. 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.CrossRefGoogle Scholar
  7. Huynh, W., and Kiernan, M.C. (2015). A unique account of ALS in China: exploring ethnic heterogeneity. J Neurol Neurosurg Psych 86, 1051–1052.CrossRefGoogle Scholar
  8. 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.CrossRefGoogle Scholar
  9. 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.CrossRefGoogle Scholar
  10. 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.CrossRefGoogle Scholar
  11. 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.CrossRefGoogle Scholar
  12. 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.CrossRefGoogle Scholar
  13. 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.CrossRefGoogle Scholar
  14. 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.CrossRefGoogle Scholar
  15. 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.CrossRefGoogle Scholar
  16. 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.CrossRefGoogle Scholar
  17. Mitchell, J., and Borasio, G. (2007). Amyotrophic lateral sclerosis. Lancet 369, 2031–2041.CrossRefGoogle Scholar
  18. 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.CrossRefGoogle Scholar
  19. 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.CrossRefGoogle Scholar
  20. 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.CrossRefGoogle Scholar
  21. 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.CrossRefGoogle Scholar
  22. 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.CrossRefGoogle Scholar
  23. 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.CrossRefGoogle Scholar
  24. 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.CrossRefGoogle Scholar
  25. 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.CrossRefGoogle Scholar
  26. 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.CrossRefGoogle Scholar
  27. 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.CrossRefGoogle Scholar
  28. 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.CrossRefGoogle Scholar
  29. 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.CrossRefGoogle Scholar
  30. 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.CrossRefGoogle Scholar
  31. 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.CrossRefGoogle Scholar
  32. 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.CrossRefGoogle Scholar
  33. 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.CrossRefGoogle Scholar
  34. 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.Google Scholar
  35. 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.CrossRefGoogle Scholar
  36. 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.CrossRefGoogle Scholar
  37. 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.Google Scholar
  38. 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.CrossRefGoogle Scholar
  39. 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.CrossRefGoogle Scholar

Copyright information

© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Qianqian Wei
    • 1
  • Xueping Chen
    • 1
  • Yongping Chen
    • 1
  • Ruwei Ou
    • 1
  • Bei Cao
    • 1
  • Yanbing Hou
    • 1
  • Lingyu Zhang
    • 1
  • Hui-Fang Shang
    • 1
    Email author
  1. 1.Department of Neurology and Rare Disease Center of West China HospitalSichuan UniversityChengduChina

Personalised recommendations