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

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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.

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Acknowledgements

The authors wish to thank the patients and families who participated in the study. This work was supported by the Parkinson’s Disease Foundation (International Research Project Grant awarded to CW), the Morris K. Udall Center, National Institute of Neurological Disorders and Stroke P50 NS40256 and The Mayo Foundation Research Committee, Essential Tremor: Clinical and Molecular Genetic Studies (CR program). CW was also supported by the Swiss National Science Foundation/FSBMB (PASMP3-123268/1). ZKW is also partially funded by P01 AG017216, R01 NS057567, R01 AG015866 and CIHR 121849. EDL was funded by R01 NS042859 and R01 NS039422. MJF and ZKW are also partially funded by P01 AG017216 and the Pacific Alzheimer Research Foundation.

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Authors and Affiliations

  1. Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Carles Vilariño-Güell, Christian Wider, Owen A. Ross, Barbara Jasinska-Myga, Jennifer Kachergus, Stephanie A. Cobb, Alexandra I. Soto-Ortolaza, Bahareh Behrouz & Matthew J. Farrer

  2. Department of Neurology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

    Christian Wider

  3. Department of Neurology, Medical University of Silesia, Katowice, Poland

    Barbara Jasinska-Myga

  4. Biostatistics Unit, Mayo Clinic, Jacksonville, FL, USA

    Michael G. Heckman & Nancy N. Diehl

  5. Emory Department of Neurology and Center for Neurodegenerative Diseases, Whitehead Biomedical Research Building, Atlanta, GA, USA

    Claudia M. Testa

  6. Department of Neurology, Mayo Clinic, Jacksonville, FL, USA

    Zbigniew K. Wszolek & Ryan J. Uitti

  7. Department of Neurology, Parkinson’s Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, TX, USA

    Joseph Jankovic

  8. GH Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Elan D. Louis

  9. Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Elan D. Louis

  10. Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Elan D. Louis & Lorraine N. Clark

  11. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA

    Elan D. Louis

  12. Division of Neurology, Royal University Hospital, University of Saskatchewan, Saskatoon, SK, Canada

    Alex Rajput

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  1. Carles Vilariño-Güell
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Corresponding author

Correspondence to Matthew J. Farrer.

Additional information

Carles Vilariño-Güell and Christian Wider have contributed equally to this work.

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Supplemental Table 1

Genotype frequencies (DOC 89 kb)

Supplemental Table 2

Association 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)

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Vilariño-Güell, C., Wider, C., Ross, O.A. et al. LINGO1 and LINGO2 variants are associated with essential tremor and Parkinson disease. Neurogenetics 11, 401–408 (2010). https://doi.org/10.1007/s10048-010-0241-x

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