neurogenetics

, Volume 11, Issue 4, pp 401–408 | Cite as

LINGO1 and LINGO2 variants are associated with essential tremor and Parkinson disease

  • Carles Vilariño-Güell
  • Christian Wider
  • Owen A. Ross
  • Barbara Jasinska-Myga
  • Jennifer Kachergus
  • Stephanie A. Cobb
  • Alexandra I. Soto-Ortolaza
  • Bahareh Behrouz
  • Michael G. Heckman
  • Nancy N. Diehl
  • Claudia M. Testa
  • Zbigniew K. Wszolek
  • Ryan J. Uitti
  • Joseph Jankovic
  • Elan D. Louis
  • Lorraine N. Clark
  • Alex Rajput
  • Matthew J. Farrer
ORIGINAL ARTICLE

Abstract

Genetic variation in the leucine-rich repeat and Ig domain containing 1 gene (LINGO1) was recently associated with an increased risk of developing essential tremor (ET) and Parkinson disease (PD). Herein, we performed a comprehensive study of LINGO1 and its paralog LINGO2 in ET and PD by sequencing both genes in patients (ET, n = 95; PD, n = 96) and by examining haplotype-tagging single-nucleotide polymorphisms (tSNPs) in a multicenter North American series of patients (ET, n = 1,247; PD, n = 633) and controls (n = 642). The sequencing study identified six novel coding variants in LINGO1 (p.S4C, p.V107M, p.A277T, p.R423R, p.G537A, p.D610D) and three in LINGO2 (p.D135D, p.P217P, p.V565V), however segregation analysis did not support pathogenicity. The association study employed 16 tSNPs at the LINGO1 locus and 21 at the LINGO2 locus. One variant in LINGO1 (rs9652490) displayed evidence of an association with ET (odds ratio (OR) = 0.63; P = 0.026) and PD (OR = 0.54; P = 0.016). Additionally, four other tSNPs in LINGO1 and one in LINGO2 were associated with ET and one tSNP in LINGO2 associated with PD (P < 0.05). Further analysis identified one tSNP in LINGO1 and two in LINGO2 which influenced age at onset of ET and two tSNPs in LINGO1 which altered age at onset of PD (P < 0.05). Our results support a role for LINGO1 and LINGO2 in determining risk for and perhaps age at onset of ET and PD. Further studies are warranted to confirm these findings and to determine the pathogenic mechanisms involved.

Keywords

Essential tremor Parkinson disease LINGO1 LINGO2 Genetic association 

Supplementary material

10048_2010_241_MOESM1_ESM.doc (89 kb)
Supplemental Table 1Genotype frequencies (DOC 89 kb)
10048_2010_241_MOESM2_ESM.doc (84 kb)
Supplemental Table 2Association with age at onset using tagging SNPs. Significant P values, with corresponding regression coefficients (RC) and 95% confident intervals (CI) are given in bold. Regression coefficients result from linear regression models adjusted for gender and are interpreted as the increase in mean age at onset given the presence of at least one minor allele (dominant models) or two minor alleles (recessive models). MA minor allele. (DOC 84 kb)

References

  1. 1.
    de Rijk MC, Launer LJ, Berger K, Breteler MM, Dartigues JF, Baldereschi M, Fratiglioni L, Lobo A, Martinez-Lage J, Trenkwalder C, Hofman A (2000) Prevalence of Parkinson’s disease in Europe: a collaborative study of population-based cohorts. Neurologic diseases in the elderly research group. Neurology 54:S21–S23PubMedGoogle Scholar
  2. 2.
    Louis ED, Thawani SP, Andrews HF (2009) Prevalence of essential tremor in a multiethnic, community-based study in northern Manhattan, New York, NY. Neuroepidemiology 32:208–214CrossRefPubMedGoogle Scholar
  3. 3.
    Rajput AH, Birdi S (1997) Epidemiology of Parkinson’s disease. Parkinsonism Relat Disord 3:175–186CrossRefPubMedGoogle Scholar
  4. 4.
    Sur H, Ilhan S, Erdogan H, Ozturk E, Tasdemir M, Boru UT (2009) Prevalence of essential tremor: a door-to-door survey in Sile, Istanbul, Turkey. Parkinsonism Relat Disord 15:101–104CrossRefPubMedGoogle Scholar
  5. 5.
    Louis ED, Faust PL, Vonsattel JP, Honig LS, Rajput A, Robinson CA, Pahwa R, Lyons KE, Ross GW, Borden S, Moskowitz CB, Lawton A, Hernandez N (2007) Neuropathological changes in essential tremor: 33 cases compared with 21 controls. Brain 130:3297–3307CrossRefPubMedGoogle Scholar
  6. 6.
    Dickson DW (2001) Alpha-synuclein and the Lewy body disorders. Curr Opin Neurol 14:423–432CrossRefPubMedGoogle Scholar
  7. 7.
    Benito-Leon J, Louis ED, Bermejo-Pareja F (2009) Risk of incident Parkinson’s disease and parkinsonism in essential tremor: a population based study. J Neurol Neurosurg Psychiatry 80:423–425CrossRefPubMedGoogle Scholar
  8. 8.
    Isaias IU, Canesi M, Benti R, Gerundini P, Cilia R, Pezzoli G, Antonini A (2008) Striatal dopamine transporter abnormalities in patients with essential tremor. Nucl Med Commun 29:349–353CrossRefPubMedGoogle Scholar
  9. 9.
    Vilarino-Guell C, Ross OA, Wider C, Jasinska-Myga B, Cobb SA, Soto-Ortolaza AI, Kachergus JM, Keeling BH, Dachsel JC, Melrose HL, Behrouz B, Wszolek ZK, Uitti RJ, Aasly JO, Rajput A, Farrer MJ (2009) LINGO1 rs9652490 is associated with essential tremor and Parkinson disease. Parkinsonism Relat Disord. doi:10.1016/j.parkreldis.2009.08.006, EpubGoogle Scholar
  10. 10.
    Inoue H, Lin L, Lee X, Shao Z, Mendes S, Snodgrass-Belt P, Sweigard H, Engber T, Pepinsky B, Yang L, Beal MF, Mi S, Isacson O (2007) Inhibition of the leucine-rich repeat protein LINGO-1 enhances survival, structure, and function of dopaminergic neurons in Parkinson’s disease models. Proc Natl Acad Sci USA 104:14430–14435CrossRefPubMedGoogle Scholar
  11. 11.
    Mi S, Lee X, Shao Z, Thill G, Ji B, Relton J, Levesque M, Allaire N, Perrin S, Sands B, Crowell T, Cate RL, McCoy JM, Pepinsky RB (2004) LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nat Neurosci 7:221–228CrossRefPubMedGoogle Scholar
  12. 12.
    Mi S, Miller RH, Lee X, Scott ML, Shulag-Morskaya S, Shao Z, Chang J, Thill G, Levesque M, Zhang M, Hession C, Sah D, Trapp B, He Z, Jung V, McCoy JM, Pepinsky RB (2005) LINGO-1 negatively regulates myelination by oligodendrocytes. Nat Neurosci 8:745–751CrossRefPubMedGoogle Scholar
  13. 13.
    Li W, Walus L, Rabacchi SA, Jirik A, Chang E, Schauer J, Zheng BH, Benedetti NJ, Liu BP, Choi E, Worley D, Silvian L, Mo W, Mullen C, Yang W, Strittmatter SM, Sah DW, Pepinsky B, Lee DH (2004) A neutralizing anti-Nogo66 receptor monoclonal antibody reverses inhibition of neurite outgrowth by central nervous system myelin. J Biol Chem 279:43780–43788CrossRefPubMedGoogle Scholar
  14. 14.
    Mi S, Hu B, Hahm K, Luo Y, Kam Hui ES, Yuan Q, Wong WM, Wang L, Su H, Chu TH, Guo J, Zhang W, So KF, Pepinsky B, Shao Z, Graff C, Garber E, Jung V, Wu EX, Wu W (2007) LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis. Nat Med 13:1228–1233CrossRefPubMedGoogle Scholar
  15. 15.
    Shao Z, Browning JL, Lee X, Scott ML, Shulga-Morskaya S, Allaire N, Thill G, Levesque M, Sah D, McCoy JM, Murray B, Jung V, Pepinsky RB, Mi S (2005) TAJ/TROY, an orphan TNF receptor family member, binds Nogo-66 receptor 1 and regulates axonal regeneration. Neuron 45:353–359CrossRefPubMedGoogle Scholar
  16. 16.
    Carim-Todd L, Escarceller M, Estivill X, Sumoy L (2003) LRRN6A/LERN1 (leucine-rich repeat neuronal protein 1), a novel gene with enriched expression in limbic system and neocortex. Eur J NeuroSci 18:3167–3182CrossRefPubMedGoogle Scholar
  17. 17.
    Ji B, Li M, Wu WT, Yick LW, Lee X, Shao Z, Wang J, So KF, McCoy JM, Pepinsky RB, Mi S, Relton JK (2006) LINGO-1 antagonist promotes functional recovery and axonal sprouting after spinal cord injury. Mol Cell Neurosci 33:311–320CrossRefPubMedGoogle Scholar
  18. 18.
    Mi S, Sandrock A, Miller RH (2008) LINGO-1 and its role in CNS repair. Int J Biochem Cell Biol 40:1971–1978CrossRefPubMedGoogle Scholar
  19. 19.
    Stefansson H, Steinberg S, Petursson H, Gustafsson O, Gudjonsdottir IH, Jonsdottir GA, Palsson ST, Jonsson T, Saemundsdottir J, Bjornsdottir G, Bottcher Y, Thorlacius T, Haubenberger D, Zimprich A, Auff E, Hotzy C, Testa CM, Miyatake LA, Rosen AR, Kristleifsson K, Rye D, Asmus F, Schols L, Dichgans M, Jakobsson F, Benedikz J, Thorsteinsdottir U, Gulcher J, Kong A, Stefansson K (2009) Variant in the sequence of the LINGO1 gene confers risk of essential tremor. Nat Genet 41:277–279CrossRefPubMedGoogle Scholar
  20. 20.
    Tan EK, Teo YY, Prakash KM, Li R, Lim HQ, Angeles D, Tan LC, Au WL, Yih Y, Zhao Y (2009) LINGO1 variant increases risk of familial essential tremor. Neurology 73:1161–1162CrossRefPubMedGoogle Scholar
  21. 21.
    Haines BP, Rigby PW (2008) Expression of the Lingo/LERN gene family during mouse embryogenesis. Gene Expr Patterns 8:79–86CrossRefPubMedGoogle Scholar
  22. 22.
    Homma S, Shimada T, Hikake T, Yaginuma H (2009) Expression pattern of LRR and Ig domain-containing protein (LRRIG protein) in the early mouse embryo. Gene Expr Patterns 9:1–26CrossRefPubMedGoogle Scholar
  23. 23.
    Gelb DJ, Oliver E, Gilman S (1999) Diagnostic criteria for Parkinson disease. Arch Neurol 56:33–39CrossRefPubMedGoogle Scholar
  24. 24.
    Louis ED, Ford B, Lee H, Andrews H, Cameron G (1998) Diagnostic criteria for essential tremor: a population perspective. Arch Neurol 55:823–828CrossRefPubMedGoogle Scholar
  25. 25.
    Mata IF, Kachergus JM, Taylor JP, Lincoln S, Aasly J, Lynch T, Hulihan MM, Cobb SA, Wu RM, Lu CS, Lahoz C, Wszolek ZK, Farrer MJ (2005) Lrrk2 pathogenic substitutions in Parkinson’s disease. Neurogenetics 6:171–177CrossRefPubMedGoogle Scholar
  26. 26.
    Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265CrossRefPubMedGoogle Scholar
  27. 27.
    Lin PI, Vance JM, Pericak-Vance MA, Martin ER (2007) No gene is an island: the flip-flop phenomenon. Am J Hum Genet 80:531–538CrossRefPubMedGoogle Scholar
  28. 28.
    Goris A, Williams-Gray CH, Clark GR, Foltynie T, Lewis SJ, Brown J, Ban M, Spillantini MG, Compston A, Burn DJ, Chinnery PF, Barker RA, Sawcer SJ (2007) Tau and alpha-synuclein in susceptibility to, and dementia in, Parkinson’s disease. Ann Neurol 62:145–153CrossRefPubMedGoogle Scholar
  29. 29.
    Wider C, Vilarino-Guell C, Jasinska-Myga B, Heckman M, Soto-Ortolaza AI, Cobb SA, Aasly JO, Gibson JM, Lynch T, Uitti RJ, Wszolek ZK, Farrer MJ, Ross OA (2009) Association of the MAPT locus with Parkinson's disease. Eur J Neurol. doi:10.1111/j.1468-1331.2009.02847.x, EpubGoogle Scholar
  30. 30.
    Peuralinna T, Oinas M, Polvikoski T, Paetau A, Sulkava R, Niinisto L, Kalimo H, Hernandez D, Hardy J, Singleton A, Tienari PJ, Myllykangas L (2008) Neurofibrillary tau pathology modulated by genetic variation of alpha-synuclein. Ann Neurol 64:348–352CrossRefPubMedGoogle Scholar
  31. 31.
    Scholz SW, Houlden H, Schulte C, Sharma M, Li A, Berg D, Melchers A, Paudel R, Gibbs JR, Simon-Sanchez J, Paisan-Ruiz C, Bras J, Ding J, Chen H, Traynor BJ, Arepalli S, Zonozi RR, Revesz T, Holton J, Wood N, Lees A, Oertel W, Wullner U, Goldwurm S, Pellecchia MT, Illig T, Riess O, Fernandez HH, Rodriguez RL, Okun MS, Poewe W, Wenning GK, Hardy JA, Singleton AB, Gasser T (2009) SNCA variants are associated with increased risk for multiple system atrophy. Ann Neurol 65:610–614CrossRefPubMedGoogle Scholar
  32. 32.
    Farrer MJ (2006) Genetics of Parkinson disease: paradigm shifts and future prospects. Nat Rev Genet 7:306–318CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Carles Vilariño-Güell
    • 1
  • Christian Wider
    • 1
    • 2
  • Owen A. Ross
    • 1
  • Barbara Jasinska-Myga
    • 1
    • 3
  • Jennifer Kachergus
    • 1
  • Stephanie A. Cobb
    • 1
  • Alexandra I. Soto-Ortolaza
    • 1
  • Bahareh Behrouz
    • 1
  • Michael G. Heckman
    • 4
  • Nancy N. Diehl
    • 4
  • Claudia M. Testa
    • 5
  • Zbigniew K. Wszolek
    • 6
  • Ryan J. Uitti
    • 6
  • Joseph Jankovic
    • 7
  • Elan D. Louis
    • 8
    • 9
    • 10
    • 11
  • Lorraine N. Clark
    • 10
  • Alex Rajput
    • 12
  • Matthew J. Farrer
    • 1
  1. 1.Department of NeuroscienceMayo ClinicJacksonvilleUSA
  2. 2.Department of NeurologyCentre Hospitalier Universitaire Vaudois (CHUV)LausanneSwitzerland
  3. 3.Department of NeurologyMedical University of SilesiaKatowicePoland
  4. 4.Biostatistics UnitMayo ClinicJacksonvilleUSA
  5. 5.Emory Department of Neurology and Center for Neurodegenerative DiseasesWhitehead Biomedical Research BuildingAtlantaUSA
  6. 6.Department of NeurologyMayo ClinicJacksonvilleUSA
  7. 7.Department of Neurology, Parkinson’s Disease Center and Movement Disorders ClinicBaylor College of MedicineHoustonUSA
  8. 8.GH Sergievsky Center, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA
  9. 9.Department of Neurology, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA
  10. 10.Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA
  11. 11.Department of Epidemiology, Mailman School of Public HealthColumbia UniversityNew YorkUSA
  12. 12.Division of NeurologyRoyal University Hospital, University of SaskatchewanSaskatoonCanada

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