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

Research output: Contribution to journalArticle

86 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)401-408
Number of pages8
JournalNeurogenetics
Volume11
Issue number4
DOIs
StatePublished - Oct 2010
Externally publishedYes

Keywords

  • Essential tremor
  • Genetic association
  • LINGO1
  • LINGO2
  • Parkinson disease

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Cellular and Molecular Neuroscience

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    Vilariño-Güell, C., Wider, C., Ross, O. A., Jasinska-Myga, B., Kachergus, J., Cobb, S. A., Soto-Ortolaza, A. I., Behrouz, B., Heckman, M. G., Diehl, N. N., Testa, C. M., Wszolek, Z. K., Uitti, R. J., Jankovic, J., Louis, E. D., Clark, L. N., Rajput, A., & Farrer, M. J. (2010). LINGO1 and LINGO2 variants are associated with essential tremor and Parkinson disease. Neurogenetics, 11(4), 401-408. https://doi.org/10.1007/s10048-010-0241-x