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The Potential Mutation of GAK Gene in the Typical Sporadic Parkinson’s Disease from the Han Population of Chinese Mainland

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Abstract

The genetic factors about the pathogenesis of sporadic Parkinson’s disease (sPD) is not completely clear at present; therefore, we performed a genome-wide association study, high-throughput sequencing analysis (HTPSA) of all cyclin G-associated kinase (GAK) exons, loss-of-function assessment, and sorting intolerant from tolerant analysis of HTPSA data in 250 typical sPD and 250 controls, which found 55 candidate single nucleotide polymorphisms (SNPs). To further explore these SNPs, we sequenced the 30 most strongly associated SNPs in the 460 typical sPD cases and the 525 controls. All subjects were from the Han population of Chinese mainland and excluded the toxic exposure, the heavy coffee drinking, and the early- and late-onset sPD. The minor allele frequencies (MAFs) at c.3824T>G, c.3794T>C, and c.3819G>A were higher in the control. The TG of c.3824T>G, the TC of c.3794T>C, and the AG of c.3819G>A were associated with the decreased risk of sPD. The subjects carrying the minor C allele of c.3794T>C or the minor A allele of c.3819G>A exhibited a decreased risk of sPD. c.3824T>G negatively affected the binding affinity of heat shock protein 70 (HSP70). c.3794T>C increased the surface area exposed to substrates. c.3819G>A most likely reduced the expression level of GAK. Our data suggest that the multiple SNPs of GAK synergistically participate in the pathogenesis of sPD through multiple pathways.

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Abbreviations

sPD:

Sporadic Parkinson’s disease

GAK:

Cyclin G-associated kinase

HPCM:

Han population from Chinese mainland

GWAS:

Genome-wide association study

HTPSA:

High-throughput sequencing analysis

LoF:

Loss-of-function assessment

SIFT:

Sorting intolerant from tolerant

SNPs:

Single nucleotide polymorphisms

MAFs:

Minor allele frequencies

OR:

Odds ratio

HSP70:

Heat shock protein 70

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Acknowledgments

We are grateful to the PD patients who generously contributed their time and materials for this study, and also thank GFK biotech Inc. of Shanghai for performing the analysis of structure modeling and synonymous functional prediction.

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    Authors and Affiliations

    1. Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China

      Jie Zhang, Hanyi Zeng, Lei Zhu, Xin Fang, Xia Deng, Huiting Liang, Chunyan Tang, Yi Lu, Jiao Li & Renshi Xu

    2. Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Nanchang University, Nanchang, 330006, Jiangxi, China

      Jie Zhang

    3. Department of Human Genetics, Institute of Translational Medicine, Nanchang University, Nanchang, 330006, Jiangxi, China

      Libing Deng

    4. Department of Neurology, The Affiliated Union Hospital of Huazhong Technological University, Wuhan, 430006, Hubei, China

      Xuebing Cao

    5. Department of Biochemistry and Molecular Biology, the First Clinical Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China

      Xiao Ren & Wenjie Zuo

    6. Department of Neurology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Neuroscience Institute, Guangzhou, 510080, Guangdong, China

      Xiong Zhang

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    1. Jie Zhang
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    Correspondence to Xiong Zhang or Renshi Xu.

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    The authors declare no competing interests

    Funding

    The work was funded by National Natural Science Foundation of China (grant number 30560042, 81160161, 81360198), Education Department of Jiangxi Province of China (grant number GJJ13198), and Jiangxi provincial department of science and technology (grant number [2014]-47).

    Authors’ contributions

    All authors contributed significantly to this research and preparation of the manuscript. Xu R, Zhang J, Zeng H, and Zhang X conceived and designed the experiments and wrote the manuscript. Zhang J, Zeng H, Zhu L, Deng L, Fang X, Deng X, Liang H, Tang C, Lu Y, Li J, Ren X, and Zuo W performed the experiments and analyzed the data. Cao X and Zhang X contributed some materials. JZ and HZ are the first authors and contributed equally to the work. Xu R and Zhang X are the corresponding authors. All authors have been involved in the drafting, critical revision, and final approval of the manuscript for publication. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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    Jie Zhang and Hanyi Zeng contributed equally to this work.

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    Figure S1

    Research approach. (TIF 418 kb)

    Figure S2

    Procedure of ion torrent sequence. (TIF 138 kb)

    Table S1

    34 loci within GAK gene possibly associated with sPD of HPCM in our GWAS result. (DOC 116 kb)

    Table S2

    Results of a high-throughput sequencing analysis (HTPSA) of all exons in the GAK gene demonstrated that 994 SNPs in GAK gene exons were significantly associated with sPD from HPCM. (DOC 3666 kb)

    Table S3

    The loss-of-function (LoF) assessment analysis of HTPSA data revealed that 129 SNPs might be associated with the pathogenesis of sPD. (DOC 164 kb)

    Table S4

    The sorting intolerant from tolerant (SIFT) analysis of HTPSA data showed that 55 SNPs might be associated with the pathogenesis of sPD from HPCM. (DOC 98 kb)

    Table S5

    The top 30 most likely candidate SNPs for further analysis by sequencing. (DOC 64 kb)

    Table S6

    Primers used to amplify exons of GAK gene. (DOC 47 kb)

    Table S7

    General codon usage for human genome. (DOC 45 kb)

    Table S8

    The codon usage was calculated using all CDS sequences for GAK. (DOC 47 kb)

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    Zhang, J., Zeng, H., Zhu, L. et al. The Potential Mutation of GAK Gene in the Typical Sporadic Parkinson’s Disease from the Han Population of Chinese Mainland. Mol Neurobiol 53, 7119–7136 (2016). https://doi.org/10.1007/s12035-015-9595-2

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