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Neurotoxicity Research

, Volume 35, Issue 1, pp 41–48 | Cite as

A Genome-Wide Association Study of α-Synuclein Levels in Cerebrospinal Fluid

  • Xiao-ling Zhong
  • Jie-Qiong Li
  • Li Sun
  • Ya-Qing Li
  • Hui-Fu Wang
  • Xi-Peng Cao
  • Chen-Chen Tan
  • Ling Wang
  • Lan Tan
  • Jin-Tai Yu
  • Alzheimer’s Disease Neuroimaging Initiative
ORIGINAL ARTICLE

Abstract

α-Synuclein is a 140-amino acid protein produced predominantly by neurons in the brain which plays a role in the regulation of neurotransmitter release, synaptic function, and plasticity, thus making it the focus in understanding the etiology of a group of neurodegenerative diseases. We conducted genome-wide association studies (GWAS) of α-synuclein levels in cerebrospinal fluid (CSF) with 209 non-Hispanic white participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI-1) cohort using a linear regression model to identify novel variants associated with α-synuclein concentration. The minor allele (T) of rs7072338 in the long intergenic non-protein coding RNA 1515 (LINC01515) and the minor allele (T) of rs17794023 in clusterin-associated protein 1 (CLUAP1) were associated with higher CSF α-synuclein levels at genome-wide significance (P = 4.167 × 10–9 and 9.56 × 10–9, respectively). In addition, single nucleotide polymorphisms (SNPs) near amyloid beta precursor protein (APP) (rs1394839) (P = 2.31 × 10–7), Rap guanine nucleotide exchange factor 1 (RAPGEF1) (rs10901091) (P = 8.07 × 10–7), and two intergenic loci on chromosome 2 and 14 (rs11687064 P = 2.50 × 10–7and rs7147386 P = 4.05 × 10–7) were identified as suggestive loci associated with CSF α-synuclein levels. We have identified significantly associated SNPs for CSF α-synuclein. These associations have important implications for a better understanding of α-synuclein regulation and allow researchers to further explore the relationships between these SNPs and α-synuclein-related neurodegenerative disorders.

Keywords

α-Synuclein Cerebrospinal fluid Endophenotype Genome-wide association studies 

Notes

Funding

Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. This work was supported by grants from the Taishan Scholars Program of Shandong Province (ts201511109 and tsqn20161079), Qingdao Key Health Discipline Development Fund, Qingdao Outstanding Health Professional Development Fund, and Qingdao Innovation and Entrepreneurship Leading Talent Program.

Compliance with Ethical Standards

The study procedures were approved by the institutional review boards of all participating centers (https://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf). Ethics approval was obtained from the institutional review boards of each institution involved: Oregon Health and Science University; University of Southern California; University of California—San Diego; University of Michigan; Mayo Clinic, Rochester; Baylor College of Medicine; Columbia University Medical Center; Washington University, St. Louis; University of Alabama at Birmingham; Mount Sinai School of Medicine; Rush University Medical Center; Wien Center; Johns Hopkins University; New York University; Duke University Medical Center; University of Pennsylvania; University of Kentucky; University of Pittsburgh; University of Rochester Medical Center; University of California, Irvine; University of Texas Southwestern Medical School; Emory University; University of Kansas, Medical Center; University of California, Los Angeles; Mayo Clinic, Jacksonville; Indiana University; Yale University School of Medicine; McGill University, Montreal-Jewish General Hospital; Sunnybrook Health Sciences, Ontario; U.B.C.Clinic for AD & Related Disorders; Cognitive Neurology—St. Joseph’s, Ontario; Cleveland Clinic Lou Ruvo Center for Brain Health; Northwestern University; Premiere Research Inst (Palm Beach Neurology); Georgetown University Medical Center; Brigham and Women’s Hospital; Stanford University; Banner Sun Health Research Institute; Boston University; Howard University; Case Western Reserve University; University of California, Davis—Sacramento; Neurological Care of CNY; Parkwood Hospital; University of Wisconsin; University of California, Irvine—BIC; Banner Alzheimer’s Institute; Dent Neurologic Institute; Ohio State University; Albany Medical College; Hartford Hospital, Olin Neuropsychiatry Research Center; Dartmouth-Hitchcock Medical Center; Wake Forest University Health Sciences; Rhode Island Hospital; Butler Hospital; UC San Francisco; Medical University South Carolina; St. Joseph’s Health Care Nathan Kline Institute; University of Iowa College of Medicine; Cornell University; and University of South Florida: USF Health Byrd Alzheimer’s Institute.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Informed Consent

Informed consent was obtained from all participants or their authorized representatives.

Supplementary material

12640_2018_9922_MOESM1_ESM.xlsx (13 kb)
Supplementary Table 1 Title: Association results for CSF α-synuclein in ADNI; Description: Abbreviations: CHR = Chromosome; SNP=Single nucleotide polymorphism; BP = base pair location in release 19, build 135 of the human genome in the dbSNP database; A1 = The minor allele; MAF = Minor allele frequency in ADNI; SNP.Type = Type of SNP; BETA = Change CSF α-synuclein per copy of the minor allele, in which positive numbers indicate more rapid decline and negative numbers indicate slower decline; P = relationship between SNPs and CSF α-synuclein using multiple linear regression model adjust for educational years, APOE ε4 status and baseline disease status. (XLSX 12 kb)
12640_2018_9922_MOESM2_ESM.pdf (588 kb)
Supplementary Fig.1 Title: Linkage disequilibrium surrounding rs7072338 in both the ADNI cohort and the 1000 Genomes cohort; Description: Abbreviations: BP = base pair location in release 19, build 135 of the human genome in the dbSNP database. (pdf 588 kb). (PDF 588 kb)
12640_2018_9922_MOESM3_ESM.pdf (111 kb)
Supplementary Fig.2 Multiple linear regression models were used to estimate possible correlation between genotypes of rs7072338 and CSF α-synuclein concentration (PDF 111 kb)
12640_2018_9922_MOESM4_ESM.pdf (113 kb)
Supplementary Fig.3 Multiple linear regression models were used to estimate possible correlation between genotypes of rs17794023 and CSF α-synuclein concentration (PDF 112 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Xiao-ling Zhong
    • 1
  • Jie-Qiong Li
    • 2
  • Li Sun
    • 1
  • Ya-Qing Li
    • 3
  • Hui-Fu Wang
    • 2
    • 4
  • Xi-Peng Cao
    • 4
  • Chen-Chen Tan
    • 2
  • Ling Wang
    • 1
  • Lan Tan
    • 2
    • 4
  • Jin-Tai Yu
    • 2
    • 4
    • 5
  • Alzheimer’s Disease Neuroimaging Initiative
  1. 1.Department of Neurology, Qingdao Central HospitalQingdao UniversityQingdaoChina
  2. 2.Department of Neurology, Qingdao Municipal HospitalQingdao UniversityQingdaoChina
  3. 3.Department of Neurology, Zhongnan HospitalWuhan UniversityWuhanChina
  4. 4.Clinical Research Center, Qingdao Municipal HospitalQingdao UniversityQingdaoChina
  5. 5.Department of NeurologyUniversity of California, San FranciscoSan FranciscoUSA

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