Abstract
Linkage and association of Tourette Syndrome (TS) and Attention-Deficit/Hyperactivity Disorder (ADHD) have previously been reported in the 11q24 chromosomal region. To identify the risk gene within the region we studied the potassium inwardly-rectifying channel J5 (KCNJ5) gene in a sample of 170 nuclear families with TS. We genotyped eight markers across the gene and observed biased transmission of haplotypes from parents to probands in this sample. We then tested these markers in an independent sample of 242 nuclear families with ADHD and found the same haplotype was significantly over transmitted to ADHD probands. Screening of the coding region of KCNJ5 in 48 probands with TS did not identify any variation that could explain the association of the haplotype. We also genotyped two microsatellite markers, one in the promoter and the other in the 3' region and found no evidence for association for either marker for TS, however, we found significant evidence for association with the 3' repeat and ADHD. A small gene (c11orf45) of unknown function lies within the first intron of KCNJ5 that is transcribed in the opposite orientation and this gene may regulate the expression of KCNJ5. We studied the correlation of the expression of KCNJ5 and the antisense transcript in brain tissues from control individuals and found that the antisense transcript and the short KCNJ5 isoform are co-expressed in three brain regions. The results of this study indicate that KCNJ5 is associated with TS and ADHD in our samples, however, the functional variant(s) remain to be identified.
Highlights
Linkage and association of Tourette Syndrome (TS) and Attention-Deficit/Hyperactivity Disorder (ADHD) have previously been reported in the 11q24 chromosomal region
On the basis of this association finding, and because of the previous linkage findings for ADHD to this region (Arcos-Burgos et al 2004; Ogdie et al 2003), we examined a subset of the markers for association to ADHD in an independent sample of 242 nuclear families with 277 children diagnosed with ADHD
Transmission disequilibrium test (TDT) analysis showed no significant association for any of the single single nucleotide polymorphism (SNP) tested in this sample (Table 1)
Summary
Linkage and association of Tourette Syndrome (TS) and Attention-Deficit/Hyperactivity Disorder (ADHD) have previously been reported in the 11q24 chromosomal region. To identify the risk gene within the region we studied the potassium inwardly-rectifying channel J5 (KCNJ5) gene in a sample of 170 nuclear families with TS. Linkage and association studies of TS have suggested a risk locus in the 11q24 chromosomal region (Barr 2005) We note that this region was originally identified as 11q23, the current genome annotation (hg19) indicates the location of these markers as 11q24. One of the markers in the linked region (D11S933) is located 7 cM from the marker D11S912 (11q24.3) that resulted in a LOD score greater than 1 in the first Tourette Syndrome Association (TSA) linkage genome scan (The Tourette Syndrome Association International Consortium for Genetics 1999) This region has been implicated by studies using independent TS samples using association (case–control and family based controls) and linkage. We found they were co-expressed in the three brain regions examined
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