Genomewide scans in North American families reveal genetic linkage of essential tremor to a region on chromosome 6p23

TY - JOUR

T1 - Genomewide scans in North American families reveal genetic linkage of essential tremor to a region on chromosome 6p23

AU - Shatunov, Alexey

AU - Sambuughin, Nyamkhishig

AU - Jankovic, Joseph

AU - Elble, Rodger

AU - Lee, Hee Suk

AU - Singleton, Andrew B

AU - Dagvadorj, Ayush

AU - Ji, Jay

AU - Zhang, Yiping

AU - Kimonis, Virginia E

AU - Hardy, John

AU - Hallett, Mark

AU - Goldfarb, Lev G

PY - 2006/9

Y1 - 2006/9

N2 - 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.

AB - 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.

KW - Adult

KW - Age of Onset

KW - Chromosome Mapping

KW - Chromosomes, Human, Pair 6

KW - DNA Mutational Analysis

KW - Dystonia

KW - Family Health

KW - Female

KW - Genetic Linkage

KW - Genetic Markers

KW - Genetic Predisposition to Disease

KW - Genotype

KW - Haplotypes

KW - Humans

KW - Male

KW - Microsatellite Repeats

KW - Middle Aged

KW - Pedigree

KW - Phenotype

KW - Tremor

KW - United States

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, N.I.H., Intramural

U2 - 10.1093/brain/awl120

DO - 10.1093/brain/awl120

M3 - Article

C2 - 16702189

SN - 0006-8950

VL - 129

SP - 2318

EP - 2331

JO - Brain : a journal of neurology

JF - Brain : a journal of neurology

IS - Pt 9

ER -