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.
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Carles
authors.initials: C
authors.lastname: Vilariño-Güell
authors.forename: Christian
authors.initials: C
authors.lastname: Wider
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.forename: Barbara
authors.initials: B
authors.lastname: Jasinska-Myga
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kachergus
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Cobb
authors.forename: Alexandra I
authors.initials: AI
authors.lastname: Soto-Ortolaza
authors.forename: Bahareh
authors.initials: B
authors.lastname: Behrouz
authors.forename: Michael G
authors.initials: MG
authors.lastname: Heckman
authors.forename: Nancy N
authors.initials: NN
authors.lastname: Diehl
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Testa
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Uitti
authors.forename: Joseph
authors.initials: J
authors.lastname: Jankovic
authors.forename: Elan D
authors.initials: ED
authors.lastname: Louis
authors.forename: Lorraine N
authors.initials: LN
authors.lastname: Clark
authors.forename: Alex
authors.initials: A
authors.lastname: Rajput
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Farrer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020329:Essential Tremor / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008957:Models, Genetic; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016017:Odds Ratio; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: C482293:LINGO1 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins