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SCIENCE CHINA Life Sciences, Volume 62, Issue 4: 517-525(2019) https://doi.org/10.1007/s11427-018-9453-x

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

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  • ReceivedSep 20, 2018
  • AcceptedOct 12, 2018
  • PublishedMar 7, 2019

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.


Funded by

the funding of the National Natural Science Foundation of China(81371394)

the National Key Research and Development Program of China(2016YFC0901504)


Acknowledgment

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).


Interest statement

The author(s) declare that they have no conflict of interest.


Supplement

SUPPORTING INFORMATION

Table S1 The mutation frequencies of common causative genes in Chinese ALS patients from included studies

The supporting information is available online at http://life.scichina.com and http://link.springer.com. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.


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  • Figure 1

    Flow diagram showing the studies selected for literature review.

  • Figure 2

    Genetic architecture of FALS and SALS in Chinese population. FALS, familial amyotrophic lateral sclerosis; SALS, sporadic amyotrophic lateral sclerosis.

  • Table 1   Mutation frequencies of common causative genes in Chinese ALS patients

    Genes

    FALS

    SALS

    Studies

    N

    N (mutation)

    %

    Studies

    N

    N (mutation)

    %

    SOD1

    11

    250

    64

    25.6

    6

    1,476

    24

    1.6

    FUS

    6

    154

    9

    5.8

    4

    847

    11

    1.3

    TRADBP

    9

    154

    9

    5.8

    9

    1,705

    5

    0.3

    C9

    7

    173

    6

    3.5

    7

    3,051

    16

    0.5

    SQSTM1

    3

    73

    0

    0

    3

    873

    9

    1

    ATXN2

    4

    71

    2

    2.8

    5

    234

    1

    0.4

    CHCHD10

    4

    123

    0

    0

    4

    1,332

    3

    0.2

    TBK1

    2

    55

    0

    0

    2

    446

    3

    0.7

    PFN1

    5

    88

    0

    0

    4

    1,229

    1

    0.1

    ANG

    5

    94

    0

    0

    2

    558

    1

    0.1

    VCP

    4

    78

    0

    0

    3

    689

    0

    0

    VAPB

    4

    83

    1

    1.2

    1

    234

    0

    0

    OPTN

    3

    58

    1

    1.7

    3

    876

    8

    0.9

    UBQLN2

    3

    58

    1

    1.7

    3

    880

    1

    0.1

    DCTN1

    2

    28

    1

    3.6

    2

    744

    5

    0.7

    MATR3

    1

    32

    0

    0

    2

    684

    2

    0.3

    CCNF

    2

    54

    0

    0

    2

    382

    3

    0.8

    TUBA4A

    1

    80

    0

    0

    1

    500

    0

    0

    TIA1

    3

    63

    0

    0

    3

    1,493

    4

    0.3

    ARHGEF28

    1

    25

    0

    0

    2

    464

    3

    0.6

    GLE1

    1

    20

    0

    0

    1

    230

    0

    0

    ANXA11

    2

    30

    1

    3.3

    2

    573

    8

    1.4

    KIF5A

    0

    1

    960

    4

    0.4

    Total (%)

    55.0

    11.7

    Unknown

    42.7

    87.4

  • Table 2   Summary of single nucleotide polymorphisms studies conducted in Chinese ALS patients

    Genes

    Polymorphism

    Authors

    Samples

    Results

    SREBF1

    Rs11868035

    Yuan et al. (2018)

    833 sALS, 814 HCs

    The minor allele “G”

    Reduced risk for EOALS and female ALS

    RTN4R

    Rs854971

    Xu et al. (2018)

    499 sALS, 503 HCs

    (–)

    RTN4R

    Rs887765

    Xu et al. (2018)

    499 sALS, 503 HCs

    (–)

    RTN4R

    Rs696880

    Xu et al. (2018)

    499 sALS, 503 HCs

    The minor allele “A” , Risk

    RTN4R

    Rs1567871

    Xu et al. (2018)

    499 sALS, 503 HCs

    (–)

    CTSD

    Rs17571

    Xi et al. (2018)

    301 sALS, 474 HCs

    (–)

    SCFD1

    Rs10139154

    Chen et al. (2018)

    1074 sALS, 927 HCs

    (–)

    HNMT and

    Thr105Ile

    Chen et al. (2018)

    850 sALS, 836 HCs

    (–)

    STK39

    Rs2390669

    Chen et al. (2018)

    850 sALS, 836 HCs

    (–)

    NMD3

    Rs34016896

    Chen et al. (2018)

    850 sALS, 836 HCs

    (–)

    HLA-DRA/HLA-DRB5

    Rs9268877

    Yang et al. (2017)

    400 sALS, 634 HCs

    (–)

    HLA-DRA/HLA-DRB5

    Rs9268856

    Yang et al. (2017)

    400 sALS, 634 HCs

    AA genotype, Risk

    BTNL2

    Rs1980493

    Yang et al. (2017)

    400 sALS, 634 HCs

    (–)

    RAB38/CTSC

    Rs302668

    Yang et al. (2017)

    400 sALS, 634 HCs

    (–)

    BDNF

    Rs6265

    Xu et al. (2017)

    499 sALS, 634 HCs

    (–)

    BDNF

    Rs56164415

    Xu et al. (2017)

    499 sALS, 634 HCs

    CT genotype and T allele, Risk

    VMAT2

    Rs363371

    Hu et al. (2017)

    863 sALS, 829 HCs

    GG, Risk

    VMAT2

    Rs363324

    Hu et al. (2017)

    863 sALS, 829 HCs

    (–)

    TMEM106B

    Rs1990622

    Hu et al. (2017)

    863 sALS, 829 HCs

    (–)

    TMEM106B

    Rs3173615

    Hu et al. (2017)

    863 sALS, 829 HCs

    (–)

    DISC1

    Rs3737597

    Deng et al. (2017)

    500 sALS, 500 HCs

    Closely associated

    P4HB

    Rs876016

    Yang et al. (2016)

    322 sALS, 265 HCs

    The minor allele “C” , Risk

    P4HB

    Rs2070872

    Yang et al. (2016)

    322 sALS, 265 HCs

    The minor allele “G”, Risk

    GPNMB

    Rs156429

    Xu et al. (2016)

    876 sALS, 829 HCs

    (–)

    SLC1A2

    Rs3794087

    Xu et al. (2016)

    513 sALS, 437 HCs

    (–)

    ZNF512B

    Rs2275294

    Yang et al. (2015)

    301 sALS, 457 HCs

    CC genotype and C, Risk

    ZNF512B

    Rs2275294

    Ju et al. (2015)

    953 sALS, 1039 HCs

    (–)

    SNCA

    Rs3775444

    Chen et al. (2015)

    885 sALS, 846 HCs

    (–)

    SNCA

    Rs3822086

    Chen et al. (2015)

    885 sALS, 846 HCs

    (–)

    SNCA

    Rs11931074

    Chen et al. (2015)

    885 sALS, 846 HCs

    (–)

    TREM2

    Rs75932628

    Chen et al. (2015)

    868 sALS, 869 HCs

    (–)

    KRT18P55

    Rs34517613

    Chen et al. (2015)

    869 sALS,871 HCs

    (–)

    C9orf72

    Rs3849942

    Chen et al. (2015)

    869 sALS, 871 HCs

    (–)

    KRT18P55

    Rs34517613

    An et al. (2015)

    298 sALS, 486 HCs

    (–)

    C9orf72

    Rs3849943

    An et al. (2015)

    298 sALS, 486 HCs

    (–)

    SUSD2

    Rs8141797

    An et al. (2015)

    298 sALS, 486 HCs

    (–)

    CAMK1G

    Rs6703183

    An et al. (2015)

    298 sALS, 486 HCs

    (–)

    RAB7L1

    Rs1572931

    Guo et al. (2014)

    778 sALS, 516 HCs

    (–)

    SNCA

    Rs2736990

    Guo et al. (2014)

    778 sALS, 721 HCs

    (–)

    SNCA

    Rs356220

    Guo et al. (2014)

    778 sALS, 721 HCs

    (–)

    9p21

    Rs2814707

    Chen et al. (2014)

    397 sALS, 287 HCs

    (–)

    UNC13A

    Rs12608932

    Chen et al. (2014)

    397 sALS, 287 HCs

    (–)

    TIMA1

    Rs13048019

    Chen et al. (2014)

    397 sALS, 287 HCs

    (–)

    SCNN1A

    Rs2228576

    Chen et al. (2014)

    397 sALS, 287 HCs

    (–)

    FGGY

    Rs6700125

    Cai et al. (2014)

    397 sALS, 287 HCs

    (–)

    FGGY

    Rs6690993

    Cai et al. (2014)

    397 sALS, 287 HCs

    (–)

    MMP–9

    C(–1562)T

    He et al. (2013)

    226 sALS, 351 HCs

    Risk

    ITPR2

    Rs2306677

    Chen et al. (2012)

    395 sALS, 288 HCs

    (–)

    KIFAP3

    Rs1541160

    Chen et al. (2012)

    395 sALS, 288 HCs

    (–)

    FLJ10986

    Rs6690993

    Chen et al. (2012)

    395 sALS, 288 HCs

    (–)

    FLJ10986

    Rs6700125

    Chen et al. (2012)

    395 sALS, 288 HCs

    (–)

    DPP6

    Rs10260404

    Chen et al. (2012)

    395 sALS, 288 HCs

    (–)

    PON1

    Rs662

    Chen et al. (2012)

    373 sALS, 248 HCs

    (–)

    PON1

    Rs705381

    Chen et al. (2012)

    373 sALS, 248 HCs

    (–)

    PON1

    Rs705382

    Chen et al. (2012)

    373 sALS, 248 HCs

    (–)

    PON1

    Rs854548

    Chen et al. (2012)

    373 sALS, 248 HCs

    (–)

    PON1

    Rs854560

    Chen et al. (2012)

    373 sALS, 248 HCs

    (–)

    PON2

    Rs7493

    Chen et al. (2012)

    373 sALS, 248 HCs

    (–)

    PON2

    Rs11981433

    Chen et al. (2012)

    373 sALS, 248 HCs

    (–)

    PON3

    Rs757158

    Chen et al. (2012)

    373 sALS, 248 HCs

    (–)

    PON3

    Rs10487132

    Chen et al. (2012)

    373 sALS, 248 HCs

    (–)

    9p21.2

    Rs2814707

    Iida et al. (2011)

    684 sALS, 830 HCs

    (–)

    19p13.3

    Rs12608932

    Iida et al. (2011)

    684 sALS, 830 HCs

    (–)

    HFE

    H63D

    He et al. (2011)

    195 sALS, 405 HCs

    Risk

    DPP6

    Rs10260404

    Li et al. (2009)

    58 sALS, 52 HCs

    (–)

    FLJ10986

    Rs10493256

    Fang et al. (2009)

    57 sALS, 100 HCs

    Risk

    FLJ10986

    Rs1470407

    Fang et al. (2009)

    57 sALS, 100 HCs

    (–)

    FLJ10986

    Rs6587852

    Fang et al. (2009)

    57 sALS, 100 HCs

    (–)

    FLJ10986

    Rs333662

    Fang et al. (2009)

    57 sALS, 100 HCs

    (–)

    FLJ10986

    Rs6700125

    Fang et al. (2009)

    57 sALS, 100 HCs

    (–)

    FLJ10986

    Rs6690993

    Fang et al. (2009)

    57 sALS, 100 HCs

    (–)

    VEGF

    C2578A

    Zhang et al. (2006)

    115 sALS, 200 HCs

    (–)

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