Indications of linkage and association of Gilles de la Tourette syndrome in two independent family samples: 17q25 is a putative susceptibility region.
Gilles de la Tourette syndrome (GTS) is characterized by multiple motor and phonic tics and high comorbidity rates with other neurobehavioral disorders. It is hypothesized that frontal-subcortical pathways and a complex genetic background are involved in the etiopathogenesis of the disorder. The genetic basis of GTS remains elusive. However, several genomic regions have been implicated. Among them, 17q25 appears to be of special interest, as suggested by various independent investigators. In the present study, we explored the possibility that 17q25 contributes to the genetic component of GTS. The initial scan of chromosome 17 performed on two large pedigrees provided a nonparametric LOD score of 2.41 near D17S928. Fine mapping with 17 additional microsatellite markers increased the peak to 2.61 (P=.002). The original families, as well as two additional pedigrees, were genotyped for 25 single-nucleotide polymorphisms (SNPs), with a focus on three genes in the indicated region that could play a role in the development of GTS, on the basis of their function and expression profile. Multiple three-marker haplotypes spanning all three genes studied provided highly significant association results (P<.001). An independent sample of 96 small families with one or two children affected with GTS was also studied. Of the 25 SNPs, 3 were associated with GTS at a statistically significant level. The transmission/disequilibrium test for a three-site haplotype moving window again provided multiple positive results. The background linkage disequilibrium (LD) of the region was studied in eight populations of European origin. A complicated pattern was revealed, with the pairwise tests producing unexpectedly high LD values at the telomeric TBCD gene. In conclusion, our findings warrant the further investigation of 17q25 as a candidate susceptibility region for GTS.
Paschou
P
P
Department of Genetics, Yale University School of Medicine, New Haven, CT 06520-8005, USA. peristera.paschou@yale.edu
Feng
Y
Y
Pakstis
A J
AJ
Speed
W C
WC
DeMille
M M
MM
Kidd
J R
JR
Jaghori
B
B
Kurlan
R
R
Pauls
D L
DL
Sandor
P
P
Barr
C L
CL
Kidd
K K
KK
D002097:C-Reactive Protein / Q000235:genetics; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008126:Lod Score; D018895:Microsatellite Repeats / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D005879:Tourette Syndrome / Q000235:genetics*; D044465:White People / Q000235:genetics; D000099153:Pentraxins
D002097:C-Reactive Protein; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D000099153:Pentraxins; C119539:BAIAP2 protein, human; C418662:TBCD protein, human