Whole genome sequencing identifies candidate genes for familial essential tremor and reveals biological pathways implicated in essential tremor aetiology
Lorraine N. Clark,
Yizhe Gao,
Gao T. Wang,
Nora Hernandez,
Allison Ashley-Koch,
Joseph Jankovic,
Ruth Ottman,
Suzanne M. Leal,
Sandra M. Barral Rodriguez,
Elan D. Louis
Affiliations
Lorraine N. Clark
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; Corresponding author at: Pathology and Cell Biology, Department of Pathology and Cell Biology, Taub Institute, Columbia University Irving Medical Center, New York, NY, USA.
Yizhe Gao
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
Gao T. Wang
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
Nora Hernandez
Department of Neurology, University of Texas Southwestern Medical Center, Dallas TX, USA
Allison Ashley-Koch
Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA
Joseph Jankovic
Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston TX, USA
Ruth Ottman
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
Suzanne M. Leal
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
Sandra M. Barral Rodriguez
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; Corresponding author at: Neurogenetics, Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
Elan D. Louis
Department of Neurology, University of Texas Southwestern Medical Center, Dallas TX, USA; Corresponding author at: Linda and Mitch Hart Distinguished Chair in Neurology, Chair, Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Summary: 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).
