Brain Advance Access originally published online on May 15, 2006
Brain 2006 129(9):2318-2331; doi:10.1093/brain/awl120
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Genomewide scans in North American families reveal genetic linkage of essential tremor to a region on chromosome 6p23
1 National Institute of Neurological Disorders and Stroke, National Institutes of Health Bethesda, MD, USA 2 National Institute of Aging, National Institutes of Health Bethesda, MD, USA 3 Biotech Research Labs, Gaithersburg MD, USA 4 Department of Neurology, Baylor College of Medicine Houston, TX, USA 5 Southern Illinois University School of Medicine Springfield, IL, USA 6 Center for Genome Information, University of Cincinnati College of Medicine Cincinnati, OH, USA 7 Children's Hospital Boston, Harvard Medical School Boston, MA, USA
Correspondence to: Lev G. Goldfarb, MD, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 5625 Fishers Lane, Room 4S06, Bethesda, MD 20892-9404, USAE-mail: GoldfarbL{at}ninds.nih.gov
Essential tremor (ET) is the most prevalent adult-onset movement disorder showing evidence of non-random accumulation in some families. ET has previously been mapped to genetic loci on chromosomes 2p and 3q, but no causative genes identified. We conducted genomewide linkage screening with subsequent fine mapping in seven large North American families comprising a total of 325 genotyped individuals that included 65 patients diagnosed as definite ET. Linkage analysis was based on methodology implemented in SimWalk2 and LINKAGE programs. A multigenerational family revealed suggestive linkage to a locus on chromosome 6p23 with maximal nonparametric linkage (NPL) multipoint score 3.281 (P = 0.0005) and parametric multipoint log of the odds (LOD) score 2.983. A second family showed positive linkage to the same 6p23 region with a maximal NPL score 2.125 (P = 0.0075) and LOD score 1.265. Haplotype analysis led to the identification of a 600 kb interval shared by both families. Sequencing of coding regions of 15 genes located in the linked region detected numerous sequence variants, some of them predicting a change of the encoded amino acid, but each was also found in controls. Our findings provide evidence for linkage to a novel susceptibility locus on chromosome 6p23. Analysis of additional ET-affected families is needed to confirm linkage and identify the underlying gene.
Key Words: essential tremor; focal dystonia; linkage mapping; chromosome 6p
Abbreviations: ET, essential tremor; LOD, log of the odds; NPL, nonparametric linkage
Received December 28, 2005. Revised March 31, 2006. Accepted April 4, 2006.
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