The emerging concept of ET as a possible neurodegenerative disorder, better understanding of associated biochemical changes, including alterations in the γ-aminobutyric acid (GABA)-ergic system and gap junctions, and the identification of the role of the leucine-rich repeat and immunoglobulin-like domain-containing 1 (LINGO-1) gene in ET pathogenesis suggest new avenues for more targeted therapies.
Recent discoveries linking LINGO1, FUS and TENM4 to essential tremor have been met with cautious optimism since reproducibility and pathogenicity have been contentious in previously implicated genes.
Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.
Before planning trials with ET patients, refinement on the genetic link between LINGO1 and ET, and a detailed genetic and phenotypic assessment of ET patients to be enrolled, should be carried out.
Two genome-wide association studies demonstrated association between variants in the LINGO1 gene (leucine-rich repeat and Ig domain containing 1) and the SLC1A2 gene (solute carrier family 1 member 2) and ET, respectively.
In the recent years, leucine-rich repeat (LRR) and immunoglobulin (Ig) domain-containing Nogo receptor-interacting proteins 1 and 2 (LINGO1 and LINGO2, respectively) have been increasingly regarded as possible ET modulators due to emerging genetic association studies linking LINGO with ET.
To explore whether the LINGO1 gene plays a role in ET susceptibility, we performed a systematic genetic analysis of the coding region in the LINGO1 gene.
In addition, we also investigated the variant in patients with Parkinson disease (PD) because the GWAS LINGO1 variant has been implicated in both ET and PD and etiologic links between the conditions have been suggested.(6.)
Recently, the first genome-wide association study in ET followed by replication studies conducted in diverse populations identified a significant association between the leucine-rich repeat and Ig domain containing 1 gene (LINGO1) SNP rs9652490 and risk for ET Although further novel variants were indentified in LINGO1 and its paralog LINGO2 that may be associated with risk for ET, the pathogenic mechanisms involved remain elusive.
The results of the meta-analysis suggest a relationship between LINGO1rs11856808 polymorphism and the risk for ET and for familial ET, while rs9652490 polymorphism was only related with the risk for familial ET.
To explore whether the LINGO4 gene (a homologous gene of the LINGO1 and the LINGO2 genes) plays a role in ET susceptibility, we performed genetic analysis of coding region of the LINGO4 gene in 100 patients with ET from Mainland China.
Here, we review published reports of the LINGO1 variants in ET and PD in an attempt to better understand the molecular and pathogenic relationship of LINGO1 to the two disorders.
The first genome-wide association study in ET showed a significant association with the rs9652490 SNP of the leucine-rich repeat and Ig domain containing 1 (LINGO1) gene.
Within the last two years, genome-wide association (GWA) analyses have revealed a number of novel low-risk susceptibility variants for Parkinson's disease, among them HLA-DRB5, BST1, ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R) and have confirmed LINGO1 as risk factor for essential tremor.
OBJECTIVE - Genome-wide association study (GWAS) has identified a variant in LINGO1 (rs9652490) that increases the risk of essential tremor (ET) among Caucasians.
A large genome-wide association study has shown that the "leucine-rich repeat (LRR) and immunoglobulin (Ig) domain-containing, Nogo receptor-interacting protein-1 (LINGO1) gene" is associated with an increased risk for essential tremor (ET) recently.
Our results indicate that the LINGO1 variants analyzed are not a major risk factor for developing familial ET in our population, which suggests the existence of other unknown genetic risk factors responsible for familial ET in the Spanish population.
Our study independently confirms that the LINGO1 gene is a risk factor for ET in a Caucasian population in North America, and further shows that those with early-onset ET are likely to be at high risk.
Finally, association studies have nominated genetic variation in the leucine-rich repeat and Ig containing 1 gene (LINGO1) as a risk for both Parkinson disease and essential tremor, providing the first genetic evidence of a link between the two conditions.
Our study demonstrates a significant association between LINGO1rs9652490 and essential tremor (P = 0.014) and Parkinson disease (P = 0.0003), thus providing the first evidence of a genetic link between both diseases.