Support of the Histaminergic Hypothesis in Tourette Syndrome
Support of the Histaminergic Hypothesis in Tourette Syndrome
Genotyping results for all SNPs conformed to Hardy–Weinberg equilibrium proportions and Mendelian transmission within families. Rare allele frequencies for each analysed sample are shown in online supplementary figure S1. Since the transmission disequilibrium test (TDT) is robust to population stratification, we were able to perform analysis for the complete sample that was available to us, as well as families within each individual population. Single SNP analysis for association with the TS phenotype in the complete sample (520 families) produced strong results of overtransmission of alleles for SNP rs854150 and rs1894236 (Table 1). These results remained statistically significant after performing 1000 permutations of the data. Using the Gabriel et al criteria for the combined sample, four haplotype blocks were defined across the studied region. The first of the two TS-associated SNPs in our analysis (rs854150) resides within a two-SNP haplotype block, which is also significantly associated with the TS phenotype, both for the protective and the susceptibility alleles (Table 1). Significant association is also found with the haplotype block that carries the second TS-associated SNP in our analysis (rs1894236). This is a five-SNP haplotype spanning 9.2 Kb (SNPs rs854151, rs2070596, rs2070595, rs2853766 and rs1894236). The rs1894236 allele that is overtransmitted to TS patients is found on four different haplotypes. On the other hand, the undertransmitted, and thus, protective allele, is only found on a single haplotype at a frequency of 0.21%, which is also significantly undertransmitted to TS patients (permutation p=0.04) (Table 1).
(Enlarge Image)
Figure 1.
Linkage disequilibrium structure of studied region covering the L-histidine decarboxylase (HDC) gene (chromosome 15: 48 316 000–48 356 000 NCBI build 36). Unrelated individuals from a sample of 520 nuclear families were analysed using Haploview and haplotype blocks were defined using the Gabriel et al16 criteria and visualised with the software Haplot. HDC variants found in individuals with Gilles de la Tourette Syndrome (TS) in previous studies are also shown. The triangle indicates the position of the originally described mutation that led to a premature termination codon (p. W317*, c.951G>A) in a family with TS,7 and the stars indicate the position of variants described in Chinese Han patients with TS (not predicted to result in amino acid changes).9 Access the article online to view this figure in colour.
Individual population analysis also revealed interesting results that further support a possible role for HDC in TS aetiology (see online supplementary tables S3 and S4). In our combined sample of German origin (our largest individual population sample with 165 trios), SNP rs854150 retained a trend of overtransmission to TS patients (uncorrected p value of 0.04), which, however, did not withstand permutation testing. Nevertheless, an additional association signal was found, including the haplotype block of the two SNPs most distal to our studied region (rs9920021 and rs1365503) with a permutation p value of 0.048. Interestingly, in our Canadian sample (150 families), these two same SNPs produced the strongest signals of association with permutation p values of 0.001 for rs1365503 and 0.021 for rs9920021. SNP rs1894236 was also significantly associated with TS in the Canadian sample. In the Italian population (50 trios), SNP rs7182203 was associated with the TS phenotype (permutation p value of 0.043), as well as a three-site haplotype including this SNP as well as rs854158 and rs854163. Individual analysis of the remaining samples did not produce any remarkable results, which could be due to small individual sample size. We should also note that analysis of the Canadian, German and Italian samples revealed an identical haplotype block structure, while a slightly different structure was observed for the remaining populations that we analysed.
Results
Genotyping results for all SNPs conformed to Hardy–Weinberg equilibrium proportions and Mendelian transmission within families. Rare allele frequencies for each analysed sample are shown in online supplementary figure S1. Since the transmission disequilibrium test (TDT) is robust to population stratification, we were able to perform analysis for the complete sample that was available to us, as well as families within each individual population. Single SNP analysis for association with the TS phenotype in the complete sample (520 families) produced strong results of overtransmission of alleles for SNP rs854150 and rs1894236 (Table 1). These results remained statistically significant after performing 1000 permutations of the data. Using the Gabriel et al criteria for the combined sample, four haplotype blocks were defined across the studied region. The first of the two TS-associated SNPs in our analysis (rs854150) resides within a two-SNP haplotype block, which is also significantly associated with the TS phenotype, both for the protective and the susceptibility alleles (Table 1). Significant association is also found with the haplotype block that carries the second TS-associated SNP in our analysis (rs1894236). This is a five-SNP haplotype spanning 9.2 Kb (SNPs rs854151, rs2070596, rs2070595, rs2853766 and rs1894236). The rs1894236 allele that is overtransmitted to TS patients is found on four different haplotypes. On the other hand, the undertransmitted, and thus, protective allele, is only found on a single haplotype at a frequency of 0.21%, which is also significantly undertransmitted to TS patients (permutation p=0.04) (Table 1).
(Enlarge Image)
Figure 1.
Linkage disequilibrium structure of studied region covering the L-histidine decarboxylase (HDC) gene (chromosome 15: 48 316 000–48 356 000 NCBI build 36). Unrelated individuals from a sample of 520 nuclear families were analysed using Haploview and haplotype blocks were defined using the Gabriel et al16 criteria and visualised with the software Haplot. HDC variants found in individuals with Gilles de la Tourette Syndrome (TS) in previous studies are also shown. The triangle indicates the position of the originally described mutation that led to a premature termination codon (p. W317*, c.951G>A) in a family with TS,7 and the stars indicate the position of variants described in Chinese Han patients with TS (not predicted to result in amino acid changes).9 Access the article online to view this figure in colour.
Individual population analysis also revealed interesting results that further support a possible role for HDC in TS aetiology (see online supplementary tables S3 and S4). In our combined sample of German origin (our largest individual population sample with 165 trios), SNP rs854150 retained a trend of overtransmission to TS patients (uncorrected p value of 0.04), which, however, did not withstand permutation testing. Nevertheless, an additional association signal was found, including the haplotype block of the two SNPs most distal to our studied region (rs9920021 and rs1365503) with a permutation p value of 0.048. Interestingly, in our Canadian sample (150 families), these two same SNPs produced the strongest signals of association with permutation p values of 0.001 for rs1365503 and 0.021 for rs9920021. SNP rs1894236 was also significantly associated with TS in the Canadian sample. In the Italian population (50 trios), SNP rs7182203 was associated with the TS phenotype (permutation p value of 0.043), as well as a three-site haplotype including this SNP as well as rs854158 and rs854163. Individual analysis of the remaining samples did not produce any remarkable results, which could be due to small individual sample size. We should also note that analysis of the Canadian, German and Italian samples revealed an identical haplotype block structure, while a slightly different structure was observed for the remaining populations that we analysed.
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