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

Objective: Sporadic, genetically complex essential tremor (ET) is one of the most common movement disorders and may lead to severe impairment of the quality of life. Despite high heritability, the genetic determinants of ET are largely unknown. We performed the second genome-wide association study (GWAS) for ET to elucidate genetic risk factors of ET. Methods:Using the Affymetrix Genome-Wide SNP Array 6.0 (1000K) we conducted a two-stage GWAS in a total of 990 subjects and 1,537 control subjects from Europe to identify genetic variants associated with ET. Results:We discovered association of an intronic variant of the main glial glutamate transporter (SLC1A2) gene with ET in the first-stage sample (rs3794087, p ϭ 6.95 ϫ 10 Ϫ5 , odds ratio [OR] ϭ 1.46). We verified the association of rs3794087 with ET in a second-stage sample (p ϭ 1.25 ϫ 10 Ϫ3 , OR ϭ 1.38). In the subgroup analysis of patients classified as definite ET, rs3794087obtained genome-wide significance (p ϭ 3.44 ϫ 10 Ϫ10 , OR ϭ 1.59) in the combined first-and second-stage sample. Genetic fine mapping using nonsynonymous single nucleotide polymorphisms (SNPs) and SNPs in high linkage disequilibrium with rs3794087 did not reveal any SNP with a stronger association with ET than rs3794087. Conclusions:We identified SLC1A2 encoding the major glial high-affinity glutamate reuptake transporter in the brain as a potential ET susceptibility gene. Acute and chronic glutamatergic overexcitation is implied in the pathogenesis of ET. SLC1A2 is therefore a good functional candidate gene for ET. Neurology Sporadic, genetically complex essential tremor (ET) is one of the most frequent neurologic disorders with a prevalence between 0.9% and 4.6% in the population older than 65 years. 1The clinical hallmark of the disease is a postural or kinetic tremor of the upper extremities. Severe ET not only causes permanent disability but often also social stigmatization. In a large proportion of patients, ET can be acutely alleviated by moderate doses of ethanol. 2,3 The diagnosis of ET is based on the clinical examination because no biomarker or specific diagnostic test exists. The most stringent research diagnostic criteria for ET are the consensus criteria proposed by the Tremor Investigation Group (TRIG).1 Family history studies and twin studies demonstrated high heritability with concordance rates of up to 95% in monozygotic vs 29% in

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“…6 This finding was confirmed by several but not all other groups attempting replication. [7][8][9] Here, we present the second GWAS for ET.…”

mentioning

confidence: 99%

Polymorphisms in the glial glutamate transporter SLC1A2 are associated with essential tremor

Thier¹,

Lorenz²,

Nothnagel³

et al. 2012

Neurology

106

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“…In addition, using the RegulomeDB website, rs10813121 in chromosome 9 was found to bind to seven proteins, among them STAT3 and Nrf-2, a key transcription factor that regulates antioxidant defense in macrophages and epithelial cells (35). The leucine-rich repeat and Ig domaincontaining 2 gene (LINGO2) is expressed in neuronal tissue, and variants have been associated with essential tremor and Parkinson's disease as well as obesity (36)(37)(38). The function of LINGO2 is currently unclear, and further investigation is needed to understand its potential role in the pathogenesis of airway responsiveness.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease

Hansel¹,

Paré

Rafaels

et al. 2015

Am J Respir Cell Mol Biol

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Increased airway responsiveness is linked to lung function decline and mortality in subjects with chronic obstructive pulmonary disease (COPD); however, the genetic contribution to airway responsiveness remains largely unknown. A genome-wide association study (GWAS) was performed using the Illumina (San Diego, CA) Human660W-Quad BeadChip on European Americans with COPD from the Lung Health Study. Linear regression models with correlated meta-analyses, including data from baseline (n = 2,814) and Year 5 (n = 2,657), were used to test for common genetic variants associated with airway responsiveness. Genotypic imputation was performed using reference 1000 Genomes Project data. Expression quantitative trait loci (eQTL) analyses in lung tissues were assessed for the top 10 markers identified, and immunohistochemistry assays assessed protein staining for SGCD and MYH15. Four genes were identified within the top 10 associations with airway responsiveness. Markers on chromosome 9p21.2 flanked by LINGO2 met a predetermined threshold of genome-wide significance (P , 9.57 3 10 28 ). Markers on chromosomes 3q13.1 (flanked by MYH15), 5q33 (SGCD), and 6q21 (PDSS2) yielded suggestive evidence of association (9.57 3 10 28 , P < 4.6 3 10 26 ). Gene expression studies in lung tissue showed single nucleotide polymorphisms on chromosomes 5 and 3 to act as eQTL for SGCD (P = 2.57 3 10 29 ) and MYH15 (P = 1.62 3 10 26 ), respectively. Immunohistochemistry confirmed localization of SGCD protein to airway smooth muscle and vessels and MYH15 to airway epithelium, vascular endothelium, and inflammatory cells. We identified novel loci associated with airway responsiveness in a GWAS among smokers with COPD. Risk alleles on chromosomes 5 and 3 acted as eQTLs for SGCD and MYH15 messenger RNA, and these proteins were expressed in lung cells relevant to the development of airway responsiveness.Keywords: COPD; airway reactivity; bronchial responsiveness; eQTL; d-sarcoglycan

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“…A large genome-wide association study has shown that the "leucine-rich repeat (LRR) and immunoglobulin (lg) domaincontaining, Nogo receptor-interacting protein-I (LINGO 1) gene" which has a role in pathogenesis of essential tremor could be equally be associated with PD [216].…”

Section: Llngo1 and Llngo2mentioning

confidence: 99%

Mechanisms Implicated in Parkinson Disease from Genetic Perspective

Popescu¹

2016

Med Clin Rev

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Parkinson's disease (PD) etiology is based upon interactions between genetic susceptibility and the environmental exposure. Multiple environmental factors inducing oxidative stress, mitochondrial damage, impairment of the neuroprotective and autophagic mechanisms are responsible for dopaminergic neurons death. Defining the contributions of genetic and environmental factors, may have important implications for understanding the pathogenesis of PD. The linkage analysis in Mendelian forms of PD especially in multiplex highly penetrant families is essential to elucidate biological mechanisms for PD susceptibility. Concerning the monogenic forms of PD were found mutations in 7 genes of AD transmission (SNCA, LRRK2, GIGYF2, VPS35, EIF4G1, HTRA2, TMEM230) and even more in those of AR transmission. This review aims to give an overview of the existing evidence of multiples molecular pathways involving cytoplasmic organelles' function, neurodevelopmental mechanisms, synaptic vesicles endocytosis and trafficking, maintaining the integrity of the cytoskeleton and axonal transport in neurons. Understanding the molecular mechanisms following the identification of genes mutations and low-penetrance susceptibility alleles in familial and sporadic PD patients by genotyping technology and functional studies represent an essential step for the development of adequate biomarkers and potent therapies.

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

Cited by 123 publications

References 30 publications

Polymorphisms in the glial glutamate transporter SLC1A2 are associated with essential tremor

Polymorphisms in the glial glutamate transporter SLC1A2 are associated with essential tremor

Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease

Mechanisms Implicated in Parkinson Disease from Genetic Perspective

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