Whole genome sequencing identifies candidate genes for familial essential tremor and reveals biological pathways implicated in essential tremor aetiology

Affiliations

¹ Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; The Taub Institute for Research on Alzheimer's Disease and The Aging Brain, Columbia University Irving Medical Center, New York, NY, USA. Electronic address: lc654@cumc.columbia.edu.
² The G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; The Center for Statistical Genetics, Columbia University Irving Medical Center, New York, NY, USA.
³ Department of Neurology, University of Texas Southwestern Medical Center, Dallas TX, USA.
⁴ Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
⁵ Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston TX, USA.
⁶ The G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY, USA; Division of Translational Epidemiology, New York State Psychiatric Institute, New York, NY, USA.
⁷ The Taub Institute for Research on Alzheimer's Disease and The Aging Brain, Columbia University Irving Medical Center, New York, NY, USA; The G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; The Center for Statistical Genetics, Columbia University Irving Medical Center, New York, NY, USA.
⁸ The Taub Institute for Research on Alzheimer's Disease and The Aging Brain, Columbia University Irving Medical Center, New York, NY, USA; The G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. Electronic address: smb2174@cumc.columbia.edu.
⁹ Department of Neurology, University of Texas Southwestern Medical Center, Dallas TX, USA. Electronic address: Elan.Louis@UTSouthwestern.edu.

PMID: 36183486
PMCID: PMC9525816
DOI: 10.1016/j.ebiom.2022.104290

Whole genome sequencing identifies candidate genes for familial essential tremor and reveals biological pathways implicated in essential tremor aetiology

Lorraine N Clark et al. EBioMedicine. 2022 Nov.

. 2022 Nov:85:104290.

doi: 10.1016/j.ebiom.2022.104290. Epub 2022 Sep 29.

Authors

Affiliations

¹ Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; The Taub Institute for Research on Alzheimer's Disease and The Aging Brain, Columbia University Irving Medical Center, New York, NY, USA. Electronic address: lc654@cumc.columbia.edu.
² The G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; The Center for Statistical Genetics, Columbia University Irving Medical Center, New York, NY, USA.
³ Department of Neurology, University of Texas Southwestern Medical Center, Dallas TX, USA.
⁴ Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
⁵ Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston TX, USA.
⁶ The G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY, USA; Division of Translational Epidemiology, New York State Psychiatric Institute, New York, NY, USA.
⁷ The Taub Institute for Research on Alzheimer's Disease and The Aging Brain, Columbia University Irving Medical Center, New York, NY, USA; The G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; The Center for Statistical Genetics, Columbia University Irving Medical Center, New York, NY, USA.
⁸ The Taub Institute for Research on Alzheimer's Disease and The Aging Brain, Columbia University Irving Medical Center, New York, NY, USA; The G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. Electronic address: smb2174@cumc.columbia.edu.
⁹ Department of Neurology, University of Texas Southwestern Medical Center, Dallas TX, USA. Electronic address: Elan.Louis@UTSouthwestern.edu.

PMID: 36183486
PMCID: PMC9525816
DOI: 10.1016/j.ebiom.2022.104290

Abstract

Background: Essential tremor (ET), one of the most common neurological disorders, has a phenotypically heterogeneous presentation characterized by bilateral kinetic tremor of the arms and, in some patients, tremor involving other body regions (e.g., head, voice). Genetic studies suggest that ET is genetically heterogeneous.

Methods: We analyzed whole genome sequence data (WGS) generated on 104 multi-generational white families with European ancestry affected by ET. Genome-wide parametric linkage and association scans were analyzed using adjusted logistic regression models through the application of the Pseudomarker software. To investigate the additional contribution of rare variants in familial ET, we also performed an aggregate variant non-parametric linkage (NPL) analysis using the collapsed haplotype method implemented in CHP-NPL software.

Findings: Parametric linkage analysis of common variants identified several loci with significant evidence of linkage (HLOD ≥3.6). Among the gene regions within the strongest ET linkage peaks were BTC (4q13.3, HLOD=4.53), N6AMT1 (21q21.3, HLOD=4.31), PCDH9 (13q21.32, HLOD=4.21), EYA1 (8q13.3, HLOD=4.04), RBFOX1 (16p13.3, HLOD=4.02), MAPT (17q21.31, HLOD=3.99) and SCARB2 (4q21.1, HLOD=3.65). CHP-NPL analysis identified fifteen additional genes with evidence of significant linkage (LOD ≥3.8). These genes include TUBB2A, VPS33B, STEAP1B, SPINK5, ZRANB1, TBC1D3C, PDPR, NPY4R, ETS2, ZNF736, SPATA21, ARL17A, PZP, BLK and CCDC94. In one ET family contributing to the linkage peak on chromosome 16p13.3, we identified a likely pathogenic heterozygous canonical splice acceptor variant in exon 2 of RBFOX1 (ENST00000547372; c.4-2A>G), that co-segregated with the ET phenotype in the family.

Interpretation: Linkage and association analyses of WGS identified several novel ET candidate genes, which are implicated in four major pathways that include 1) the epidermal growth factor receptor-phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha-AKT serine/threonine kinase 1 (EGFR-PI3K-AKT) and Mitogen-activated protein Kinase 1 (ERK) pathways, 2) Reactive oxygen species (ROS) and DNA repair, 3) gamma-aminobutyric acid-ergic (GABAergic) system and 4) RNA binding and regulation of RNA processes. Our study provides evidence for a possible overlap in the genetic architecture of ET, neurological disease, cancer and aging. The genes and pathways identified can be prioritized in future genetic and functional studies.

Funding: National Institutes of Health, NINDS, NS073872 (USA) and NIA AG058131(USA).

Keywords: Essential tremor; Genome-wide linkage analysis; Multi-generation ET families; Whole genome sequencing.

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Conflict of interest statement

Declaration of interests The authors have no conflict of interest.

Figures

**Figure 1**
Workflow of Genome-Wide linkage scan using Pseudomarker and RV NPL in 104 ET families.

See this image and copyright information in PMC

References

1. Louis ED. Clinical practice. Essential tremor. N Engl J Med. 2001;345(12):887–891. - PubMed
1. Louis ED. The primary type of tremor in essential tremor is kinetic rather than postural: cross-sectional observation of tremor phenomenology in 369 cases. Eur J Neurol. 2013;20(4):725–727. - PMC - PubMed
1. Louis ED, LSt Dure, Pullman S. Essential tremor in childhood: a series of nineteen cases. Mov Disord. 2001;16(5):921–923. - PubMed
1. Louis ED, Ferreira JJ. How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor. Mov Disord. 2010;25(5):534–541. - PubMed
1. Louis ED, M M. How common is essential tremor? Update on the worldwide prevalence of essential tremor. Tremor Other Hyperkinet Mov (N Y) 2021 - PMC - PubMed

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Whole genome sequencing identifies candidate genes for familial essential tremor and reveals biological pathways implicated in essential tremor aetiology

Affiliations

Whole genome sequencing identifies candidate genes for familial essential tremor and reveals biological pathways implicated in essential tremor aetiology

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous