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Pathway analysis of genome-wide association studies for Parkinson’s disease

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Abstract

The study was done to identify the candidate causal single nucleotide polymorphisms (SNPs) and candidate causal mechanisms that contribute to Parkinson’s disease (PD) susceptibility and to generate a SNP to ene to pathway hypothesis using an analytical pathway-based approach. We used a PD genome-wide association study (GWAS) meta-analysis data of the genotypes of 2,525,705 SNPs in 4,238 PD cases and 4,239 controls. Identify candidate Causal SNPs and Pathways (ICSNPathway) analysis was applied to the PD GWAS dataset. The first stage involved the pre-selection of candidate causal SNPs by linkage disequilibrium analysis and the functional SNP annotation of the most significant SNPs found. The second stage involved the annotation of biological mechanisms for the pre-selected candidate causal SNPs using improved-gene set enrichment analysis. ICSNPathway analysis identified three candidate SNPs, two genes, twenty-one pathways, and three hypothetical biological mechanisms: (1) rs17651549 to microtubule-associated protein tau (MAPT) to protein domain specific binding (nominal p < 0.001, false discovery rate (FDR) < 0.001), neurogenesis (nominal p < 0.001, FDR < 0.001), regulation of neurogenesis (nominal p < 0.001, FDR = 0.001), positive regulation of axonogenesis (nominal p < 0.001, FDR = 0.001), regulation of protein polymerization (nominal p < 0.001, FDR = 0.004), negative regulation of organelle organization (nominal p < 0.001, FDR = 0.004), hsa01510 (nominal p < 0.001, FDR = 0.005), neuron differentiation (nominal p < 0.001, FDR = 0.009), and axonogenesis (nominal p < 0.001, FDR = 0.009); (2) rs10445337 to MAPT to protein domain specific binding (nominal p < 0.001, FDR < 0.001), neurogenesis (nominal p < 0.001, FDR < 0.001), regulation of neurogenesis (nominal p < 0.001, FDR = 0.001), and positive regulation of axonogenesis (nominal p < 0.001, FDR = 0.001); (3) rs9938550 to HSD3B7 to hsa00363 (nominal p < 0.001, FDR = 0.004), bile acid metabolic process (nominal p = 0.005, FDR = 0.019), and steroid metabolic process (nominal p = 0.010, FDR = 0.039). By applying the ICSNPathway analysis to PD GWAS meta-analysis data, three candidate SNPs, two genes (MAPT and HSD3B7), and 21 pathways involving protein domain specific binding and neurogenesis were identified, which may contribute to PD susceptibility.

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References

  1. Lill CM, Roehr JT, McQueen MB, Kavvoura FK, Bagade S, Schjeide BM, Schjeide LM, Meissner E, Zauft U, Allen NC, Liu T, Schilling M, Anderson KJ, Beecham G, Berg D, Biernacka JM, Brice A, DeStefano AL, Do CB, Eriksson N, Factor SA, Farrer MJ, Foroud T, Gasser T, Hamza T, Hardy JA, Heutink P, Hill-Burns EM, Klein C, Latourelle JC, Maraganore DM, Martin ER, Martinez M, Myers RH, Nalls MA, Pankratz N, Payami H, Satake W, Scott WK, Sharma M, Singleton AB, Stefansson K, Toda T, Tung JY, Vance J, Wood NW, Zabetian CP, Young P, Tanzi RE, Khoury MJ, Zipp F, Lehrach H, Ioannidis JP, Bertram L (2012) Comprehensive research synopsis and systematic meta-analyses in Parkinson’s disease genetics: the PDGene database. PLoS Genet 8:e1002548

    Article  PubMed  CAS  Google Scholar 

  2. Harley JB, Alarcon-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL, Tsao BP, Vyse TJ, Langefeld CD, Nath SK, Guthridge JM, Cobb BL, Mirel DB, Marion MC, Williams AH, Divers J, Wang W, Frank SG, Namjou B, Gabriel SB, Lee AT, Gregersen PK, Behrens TW, Taylor KE, Fernando M, Zidovetzki R, Gaffney PM, Edberg JC, Rioux JD, Ojwang JO, James JA, Merrill JT, Gilkeson GS, Seldin MF, Yin H, Baechler EC, Li QZ, Wakeland EK, Bruner GR, Kaufman KM, Kelly JA (2008) Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 40:204–210

    Article  PubMed  CAS  Google Scholar 

  3. Manolio TA (2010) Genomewide association studies and assessment of the risk of disease. N Engl J Med 363:166–176

    Article  PubMed  CAS  Google Scholar 

  4. Johnson AD, O’Donnell CJ (2009) An open access database of genome-wide association results. BMC Med Genet 10:6

    Article  PubMed  Google Scholar 

  5. Hom G, Graham RR, Modrek B, Taylor KE, Ortmann W, Garnier S, Lee AT, Chung SA, Ferreira RC, Pant PV, Ballinger DG, Kosoy R, Demirci FY, Kamboh MI, Kao AH, Tian C, Gunnarsson I, Bengtsson AA, Rantapaa-Dahlqvist S, Petri M, Manzi S, Seldin MF, Ronnblom L, Syvanen AC, Criswell LA, Gregersen PK, Behrens TW (2008) Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med 358:900–909

    Article  PubMed  CAS  Google Scholar 

  6. Schadt EE (2009) Molecular networks as sensors and drivers of common human diseases. Nature 461:218–223

    Article  PubMed  CAS  Google Scholar 

  7. Wang K, Li M, Hakonarson H (2010) Analysing biological pathways in genome-wide association studies. Nat Rev Genet 11:843–854

    Article  PubMed  CAS  Google Scholar 

  8. Zhang K, Chang S, Cui S, Guo L, Zhang L, Wang J (2011) ICSNPathway: identify candidate causal SNPs and pathways from genome-wide association study by one analytical framework. Nucleic Acids Res 39:W437–W443

    Article  PubMed  CAS  Google Scholar 

  9. Pankratz N, Beecham GW, DeStefano AL, Dawson TM, Doheny KF, Factor SA, Hamza TH, Hung AY, Hyman BT, Ivinson AJ, Krainc D, Latourelle JC, Clark LN, Marder K, Martin ER, Mayeux R, Ross OA, Scherzer CR, Simon DK, Tanner C, Vance JM, Wszolek ZK, Zabetian CP, Myers RH, Payami H, Scott WK, Foroud T (2012) Meta-analysis of Parkinson’s disease: identification of a novel locus, RIT2. Ann Neurol 71:370–384

    Article  PubMed  CAS  Google Scholar 

  10. Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55:181–184

    Article  PubMed  CAS  Google Scholar 

  11. Kanehisa M, Goto S, Furumichi M, Tanabe M, Hirakawa M (2010) KEGG for representation and analysis of molecular networks involving diseases and drugs. Nucleic Acids Res 38:D355–D360

    Article  PubMed  CAS  Google Scholar 

  12. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G (2000) Gene ontology: tool for the unification of biology. The gene ontology consortium. Nat Genet 25:25–29

    Article  PubMed  CAS  Google Scholar 

  13. Johnson AD, Handsaker RE, Pulit SL, Nizzari MM, O’Donnell CJ, de Bakker PI (2008) SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 24:2938–2939

    Article  PubMed  CAS  Google Scholar 

  14. Lei SF, Jiang H, Deng FY, Deng HW (2007) Searching for genes underlying susceptibility to osteoporotic fracture: current progress and future prospect. Osteoporos Int 18:1157–1175

    Article  PubMed  Google Scholar 

  15. Rademakers R, Cruts M, van Broeckhoven C (2004) The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum Mutat 24:277–295

    Article  PubMed  CAS  Google Scholar 

  16. Persson B, Kallberg Y, Bray JE, Bruford E, Dellaporta SL, Favia AD, Duarte RG, Jornvall H, Kavanagh KL, Kedishvili N, Kisiela M, Maser E, Mindnich R, Orchard S, Penning TM, Thornton JM, Adamski J, Oppermann U (2009) The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative. Chem Biol Interact 178:94–98

    Article  PubMed  CAS  Google Scholar 

  17. Edwards YJ, Beecham GW, Scott WK, Khuri S, Bademci G, Tekin D, Martin ER, Jiang Z, Mash DC, ffrench-Mullen J, Pericak-Vance MA, Tsinoremas N, Vance JM (2011) Identifying consensus disease pathways in Parkinson’s disease using an integrative systems biology approach. PLoS One 6:e16917

    Article  PubMed  CAS  Google Scholar 

  18. Hong MG, Pawitan Y, Magnusson PK, Prince JA (2009) Strategies and issues in the detection of pathway enrichment in genome-wide association studies. Hum Genet 126:289–301

    Article  PubMed  CAS  Google Scholar 

  19. Eleftherohorinou H, Hoggart CJ, Wright VJ, Levin M, Coin LJ (2011) Pathway-driven gene stability selection of two rheumatoid arthritis GWAS identifies and validates new susceptibility genes in receptor mediated signalling pathways. Hum Mol Genet 20:3494–3506

    Article  PubMed  CAS  Google Scholar 

  20. Elbers CC, van Eijk KR, Franke L, Mulder F, van der Schouw YT, Wijmenga C, Onland-Moret NC (2009) Using genome-wide pathway analysis to unravel the etiology of complex diseases. Genet Epidemiol 33:419–431

    Article  PubMed  Google Scholar 

  21. Kim HR, Park MK, Cho ML, Kim KW, Oh HJ, Park JS, Heo YM, Lee SH, Kim HY, Park SH (2010) Induction of macrophage migration inhibitory factor in ConA-stimulated rheumatoid arthritis synovial fibroblasts through the P38 map kinase-dependent signaling pathway. Korean J Intern Med 25:317–326

    Article  PubMed  Google Scholar 

  22. Pankratz N, Wilk JB, Latourelle JC, DeStefano AL, Halter C, Pugh EW, Doheny KF, Gusella JF, Nichols WC, Foroud T, Myers RH, Psg P, GenePD Investigators Coordinators and Molecular Genetic Laboratories (2009) Genomewide association study for susceptibility genes contributing to familial Parkinson disease. Hum Genet 124:593–605

    Article  PubMed  CAS  Google Scholar 

  23. Fung HC, Scholz S, Matarin M, Simon-Sanchez J, Hernandez D, Britton A, Gibbs JR, Langefeld C, Stiegert ML, Schymick J, Okun MS, Mandel RJ, Fernandez HH, Foote KD, Rodriguez RL, Peckham E, De Vrieze FW, Gwinn-Hardy K, Hardy JA, Singleton A (2006) Genome-wide genotyping in Parkinson’s disease and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol 5:911–916

    Article  PubMed  CAS  Google Scholar 

  24. Simon-Sanchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, Paisan-Ruiz C, Lichtner P, Scholz SW, Hernandez DG, Kruger R, Federoff M, Klein C, Goate A, Perlmutter J, Bonin M, Nalls MA, Illig T, Gieger C, Houlden H, Steffens M, Okun MS, Racette BA, Cookson MR, Foote KD, Fernandez HH, Traynor BJ, Schreiber S, Arepalli S, Zonozi R, Gwinn K, van der Brug M, Lopez G, Chanock SJ, Schatzkin A, Park Y, Hollenbeck A, Gao J, Huang X, Wood NW, Lorenz D, Deuschl G, Chen H, Riess O, Hardy JA, Singleton AB, Gasser T (2009) Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 41:1308–1312

    Article  PubMed  CAS  Google Scholar 

  25. Edwards TL, Scott WK, Almonte C, Burt A, Powell EH, Beecham GW, Wang L, Zuchner S, Konidari I, Wang G, Singer C, Nahab F, Scott B, Stajich JM, Pericak-Vance M, Haines J, Vance JM, Martin ER (2010) Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann Hum Genet 74:97–109

    Article  PubMed  CAS  Google Scholar 

  26. Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, Yearout D, Kay DM, Doheny KF, Paschall J, Pugh E, Kusel VI, Collura R, Roberts J, Griffith A, Samii A, Scott WK, Nutt J, Factor SA, Payami H (2010) Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Genet 42:781–785

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors gratefully acknowledge investigators for sharing their valuable GWAS data.

Conflict of interest

The authors declare that they have no vested interest that could be construed to have inappropriately influenced this study.

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  1. Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul, 136-705, Korea

    Gwan Gyu Song & Young Ho Lee

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  1. Gwan Gyu Song
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Correspondence to Young Ho Lee.

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Song, G.G., Lee, Y.H. Pathway analysis of genome-wide association studies for Parkinson’s disease. Mol Biol Rep 40, 2599–2607 (2013). https://doi.org/10.1007/s11033-012-2346-9

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