Essential tremor (ET) is among the most common neurological diseases, with a prevalence (age >40 years) estimated to be 4.0% and prevalence in advanced age (>90 years) exceeding 20%. The underlying pathogenesis remains poorly understood and, as a consequence, current medications are empiric and of limited efficacy. There are only two front-line medications, a situation that has not changed in more than 30 years, and one in two patients simply stops these medications due to poor efficacy. The foremost obstacle to the study of pathogenesis is the absence of an animal (genetic) model for this disease. ET (often referred to as familial tremor), is generally regarded as a highly-geneti disorder, with physicians commonly seeing families with affecteds over multiple generations, and twin studies showing high concordance among monozygotes. Despite its extraordinarily high prevalence, we still know almost nothing about genes that predispose individuals to develop ET. During the current funding period of R01 NS073872 (9/30/11 - 8/31/14), our linkage scan in 52 `pure' ET families, which used a stringent phenotype definition (definite and probable ET), provides evidence for linkage to the short arm of chromosome 6 (6p24)(LOD score 3.013). There are also several additional promising leads in analyses that used slightly less stringent phenotype definition, with evidence of linkage (LOD>3) detected in five additional chromosomal regions. Analysis of WES data using pVAAST from 52 early onset ET families has also identified candidate ET genes that are genome wide significant and that are located within linkage intervals with significant LOD scores (>3.0). Despite a limited 3- year funding window (9/30/11 - 8/31/14), at the 3.2 year point, we have completed the aims and have identified ET candidate genes. Our experience with these families has served to further our appreciation of the complexity of the clinical material and to underscore the prime importance of painstaking clinical phenotyping as well as alternative approaches to data analysis, each of which is critical to a successful endeavor. In this A1 resubmission of the competing continuation of R01 NS073872, we have made several substantive changes. We have tripled the size of both the family-based discovery and replication datasets, thereby using all of the available resources of the ET community and all of the academic centers who collect ET families to arrive at the unprecedented sample size of 1,500 subjects. We will carefully standardize phenotyping across all sites and employ innovative methods including whole genome sequencing together with linkage analysis and novel analytic methods. We propose three Specific Aims:
AIM 1 : To greatly increase the sample size of `pure' ET families in the discovery dataset, and rephenotype and recruit new `pure' ET families in the replication dataset.
Aim 2 : To perform genetic analyses of 150 ET families to confirm and replicate ET genetic loci in addition to identifying new ET genes.
AIM 3 : To replicate and validate findings in an independent family-based replicate sample, and to perform genotype-phenotype correlations in the entire sample.

Public Health Relevance

Essential tremor (ET), a highly genetic disorder, is the most common cause of tremor in humans, affecting large numbers of individuals worldwide. Often referred to as 'familial tremor', ET is generally regarded as a highly-genetic disorder, yet we stil know almost nothing about genes that predispose individuals to develop ET. Gene discovery would have a major impact on the ET field, and the current proposal, brings with it an unprecedented sample size, a multi-site collaborative effort, a thoughtful and meticulous approach to phenotyping, and a variety of innovative genetic and analytic methods in order to tackle the problem.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS073872-06
Application #
9276822
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Sieber, Beth-Anne
Project Start
2011-09-15
Project End
2020-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Louis, Elan D; Badejo, Funmi M; Cristal, Ashley D et al. (2017) Early Head Tremor in Essential Tremor: A Case Series and Commentary. Tremor Other Hyperkinet Mov (N Y) 7:453
Louis, Elan D; Hernandez, Nora; Chen, Karen P et al. (2017) Familial Aggregation of the Cerebellar Signs in Familial Essential Tremor. Tremor Other Hyperkinet Mov (N Y) 7:439
Louis, Elan D; Kuo, Sheng-Han; Tate, William J et al. (2017) Cerebellar pathology in childhood-onset vs. adult-onset essential tremor. Neurosci Lett 659:69-74
Lenka, Abhishek; Pal, Pramod Kumar; Bhatti, Danish Ejaz et al. (2017) Pathogenesis of Primary Orthostatic Tremor: Current Concepts and Controversies. Tremor Other Hyperkinet Mov (N Y) 7:513
Louis, Elan D; Patel, Amar; Gerrard, Jason L (2017) What is the pathway forward for the surgical management of essential tremor? Ann Neurol 81:351-353
Serrano, J Ignacio; Romero, Juan P; Castillo, Ma Dolores Del et al. (2017) A data mining approach using cortical thickness for diagnosis and characterization of essential tremor. Sci Rep 7:2190
Lenka, Abhishek; Benito-León, Julian; Louis, Elan D (2017) Is there a Premotor Phase of Essential Tremor? Tremor Other Hyperkinet Mov (N Y) 7:498
Kuo, Sheng-Han; Wang, Jie; Tate, William J et al. (2017) Cerebellar Pathology in Early Onset and Late Onset Essential Tremor. Cerebellum 16:473-482
Kuo, Sheng-Han; Lin, Chi-Ying; Wang, Jie et al. (2017) Climbing fiber-Purkinje cell synaptic pathology in tremor and cerebellar degenerative diseases. Acta Neuropathol 133:121-138

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