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 #
2R01NS073872-04A1
Application #
8964978
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Gwinn, Katrina
Project Start
2011-09-15
Project End
2020-05-31
Budget Start
2015-08-01
Budget End
2016-05-31
Support Year
4
Fiscal Year
2015
Total Cost
$1,247,110
Indirect Cost
$154,679
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Louis, Elan D; Meyers, James H; Cristal, Ashley D et al. (2018) Unaffected first-degree relatives of essential tremor cases have more imbalance than age-matched control subjects. Parkinsonism Relat Disord 52:24-29
Cristal, Ashley D; Chen, Karen P; Hernandez, Nora Cristina et al. (2018) Knowledge about Essential Tremor: A Study of Essential Tremor Families. Front Neurol 9:27
Louis, Elan D; Kuo, Sheng-Han; Tate, William J et al. (2018) Heterotopic Purkinje Cells: a Comparative Postmortem Study of Essential Tremor and Spinocerebellar Ataxias 1, 2, 3, and 6. Cerebellum 17:104-110
Naranjo, Kelly V; Park, Jemin; Chen, Karen P et al. (2018) Genetic Testing Preferences of Individuals in Families with Essential Tremor. Tremor Other Hyperkinet Mov (N Y) 8:545
Louis, Elan D (2018) Essential tremor then and now: How views of the most common tremor diathesis have changed over time. Parkinsonism Relat Disord 46 Suppl 1:S70-S74
Louis, Elan D (2018) The evolving definition of essential tremor: What are we dealing with? Parkinsonism Relat Disord 46 Suppl 1:S87-S91
Ottman, Ruth; Freyer, Catharine; Mefford, Heather C et al. (2018) Return of individual results in epilepsy genomic research: A view from the field. Epilepsia 59:1635-1642
Smith, Philip; Arias, Ronald; Sonti, Shilpa et al. (2018) A Drosophila Model of Essential Tremor. Sci Rep 8:7664
Clark, Lorraine N; Louis, Elan D (2018) Essential tremor. Handb Clin Neurol 147:229-239
Louis, Elan D; Meyers, James H; Cristal, Ashley D et al. (2018) Transient, Isolated Head Tremor in ""Unaffected"" Individuals: Is Essential Tremor an Even More Prevalent Disease Than We Suppose? Front Neurol 9:570

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