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

doi:10.1007/s10048-010-0241-x

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

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92 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 language	English (US)
Pages (from-to)	401-408
Number of pages	8
Journal	Neurogenetics
Volume	11
Issue number	4
DOIs	https://doi.org/10.1007/s10048-010-0241-x
State	Published - Oct 2010

Keywords

Essential tremor
Genetic association
LINGO1
LINGO2
Parkinson disease

ASJC Scopus subject areas

Genetics
Genetics(clinical)
Cellular and Molecular Neuroscience

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10.1007/s10048-010-0241-x

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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

Vilariño-Güell, C, Wider, C, Ross, OA, Jasinska-Myga, B, Kachergus, J, Cobb, SA, Soto-Ortolaza, AI, Behrouz, B, Heckman, MG, Diehl, NN, Testa, CM, Wszolek, ZK, Uitti, RJ, Jankovic, J, Louis, ED, Clark, LN, Rajput, A & Farrer, MJ 2010, 'LINGO1 and LINGO2 variants are associated with essential tremor and Parkinson disease', Neurogenetics, vol. 11, no. 4, pp. 401-408. https://doi.org/10.1007/s10048-010-0241-x

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title = "LINGO1 and LINGO2 variants are associated with essential tremor and Parkinson disease",

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, Genetic association, LINGO1, LINGO2, Parkinson disease",

author = "Carles Vilari{\~n}o-G{\"u}ell and Christian Wider and Ross, {Owen A.} and Barbara Jasinska-Myga and Jennifer Kachergus and Cobb, {Stephanie A.} and Soto-Ortolaza, {Alexandra I.} and Bahareh Behrouz and Heckman, {Michael G.} and Diehl, {Nancy N.} and Testa, {Claudia M.} and Wszolek, {Zbigniew K.} and Uitti, {Ryan J.} and Joseph Jankovic and Louis, {Elan D.} and Clark, {Lorraine N.} and Alex Rajput and Farrer, {Matthew J.}",

note = "Funding Information: The authors wish to thank the patients and families who participated in the study. This work was supported by the Parkinson{\textquoteright}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.",

year = "2010",

month = oct,

doi = "10.1007/s10048-010-0241-x",

language = "English (US)",

volume = "11",

pages = "401--408",

journal = "Neurogenetics",

issn = "1364-6745",

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T1 - LINGO1 and LINGO2 variants are associated with essential tremor and Parkinson disease

AU - Vilariño-Güell, Carles

AU - Wider, Christian

AU - Ross, Owen A.

AU - Jasinska-Myga, Barbara

AU - Kachergus, Jennifer

AU - Cobb, Stephanie A.

AU - Soto-Ortolaza, Alexandra I.

AU - Behrouz, Bahareh

AU - Heckman, Michael G.

AU - Diehl, Nancy N.

AU - Testa, Claudia M.

AU - Wszolek, Zbigniew K.

AU - Uitti, Ryan J.

AU - Jankovic, Joseph

AU - Louis, Elan D.

AU - Clark, Lorraine N.

AU - Rajput, Alex

AU - Farrer, Matthew J.

N1 - Funding Information: 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.

PY - 2010/10

Y1 - 2010/10

N2 - 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.

AB - 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.

KW - Essential tremor

KW - Genetic association

KW - LINGO1

KW - LINGO2

KW - Parkinson disease

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ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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