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Genome-wide association study in essential tremor identifies three new loci.

ABSTRACT: We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two 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.

SUBMITTER: Muller SH

PROVIDER: S-EPMC5382938 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Genome-wide association study in essential tremor identifies three new loci.

Müller Stefanie H SH Girard Simon L SL Hopfner Franziska F Merner Nancy D ND Bourassa Cynthia V CV Lorenz Delia D Clark Lorraine N LN Tittmann Lukas L Soto-Ortolaza Alexandra I AI Klebe Stephan S Hallett Mark M Schneider Susanne A SA Hodgkinson Colin A CA Lieb Wolfgang W Wszolek Zbigniew K ZK Pendziwiat Manuela M Lorenzo-Betancor Oswaldo O Poewe Werner W Ortega-Cubero Sara S Seppi Klaus K Rajput Alex A Hussl Anna A Rajput Ali H AH Berg Daniela D Dion Patrick A PA Wurster Isabel I Shulman Joshua M JM Srulijes Karin K Haubenberger Dietrich D Pastor Pau P Vilariño-Güell Carles C Postuma Ronald B RB Bernard Geneviève G Ladwig Karl-Heinz KH Dupré Nicolas N Jankovic Joseph J Strauch Konstantin K Panisset Michel M Winkelmann Juliane J Testa Claudia M CM Reischl Eva E Zeuner Kirsten E KE Ross Owen A OA Arzberger Thomas T Chouinard Sylvain S Deuschl Günther G Louis Elan D ED Kuhlenbäumer Gregor G Rouleau Guy A GA

Brain : a journal of neurology 20161020 Pt 12

We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discover ...[more]

PMID: 27797806

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Project description:ImportanceEssential tremor (ET) is one of the most common movement disorders, affecting 5% of the general population older than 65 years. Common variants are thought to contribute toward susceptibility to ET, but no variants have been robustly identified.ObjectiveTo identify common genetic factors associated with risk of ET.Design, setting, and participantsCase-control genome-wide association study. Inverse-variance meta-analysis was used to combine cohorts. Multicenter samples collected from European populations were collected from January 2010 to September 2019 as part of an ongoing study. Included patients were clinically diagnosed with or reported having ET. Control individuals were not diagnosed with or reported to have ET. Of 485 250 individuals, data for 483 054 passed data quality control and were used.Main outcomes and measuresGenotypes of common variants associated with risk of ET.ResultsOf the 483 054 individuals included, there were 7177 with ET (3693 [51.46%] female; mean [SD] age, 62.66 [15.12] years), and 475 877 control individuals (253 785 [53.33%] female; mean [SD] age, 56.40 [17.6] years). Five independent genome-wide significant loci and were identified and were associated with approximately 18% of ET heritability. Functional analyses found significant enrichment in the cerebellar hemisphere, cerebellum, and axonogenesis pathways. Genetic correlation (r), which measures the degree of genetic overlap, revealed significant common variant overlap with Parkinson disease (r, 0.28; P = 2.38 × 10-8) and depression (r, 0.12; P = 9.78 × 10-4). A separate fine-mapping of transcriptome-wide association hits identified genes such as BACE2, LRRN2, DHRS13, and LINC00323 in disease-relevant brain regions, such as the cerebellum.Conclusions and relevanceThe results of this genome-wide association study suggest that a portion of ET heritability can be explained by common genetic variation and can help identify new common genetic risk factors for ET.

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Genome-wide association study in essential tremor identifies three new loci.

Publications

Genome-wide association study in essential tremor identifies three new loci.

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