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Genome-wide association study in essential tremor identifies three new loci

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ABSTRACT

Essential tremor has a high heritability, but its molecular genetic determinants remain unknown. Müller et al. conduct a genome-wide association study in more than 2800 patients with essential tremor and more than 6800 controls of European descent, and identify three new loci associated with the disease.

No MeSH data available.


Fine mapping of 500 kb windows centred around each of the three essential tremor-associated loci.Top to bottom: Chromosome ideogram followed by genes (horizontal line) and their coding regions (vertical bars), negative logarithmic P-values of all markers for the discovery stage (left y-axis) against chromosomal position (x-axis) and recombination rates for the genomic positions (right y-axis) in pink. Bottom: Heatmap indicating LD. Saturated red indicating high LD, white indicating no LD. (A) STK32B; (B) PPARGC1A; and (C) CTNNA3.
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aww242-F1: Fine mapping of 500 kb windows centred around each of the three essential tremor-associated loci.Top to bottom: Chromosome ideogram followed by genes (horizontal line) and their coding regions (vertical bars), negative logarithmic P-values of all markers for the discovery stage (left y-axis) against chromosomal position (x-axis) and recombination rates for the genomic positions (right y-axis) in pink. Bottom: Heatmap indicating LD. Saturated red indicating high LD, white indicating no LD. (A) STK32B; (B) PPARGC1A; and (C) CTNNA3.

Mentions: In the replication stage we genotyped an independent cohort of 1029 patients with essential tremor and 1065 control samples for 59 best markers selected from all three analyses (PLINK, GEMMA, GEMMA imputed data). We applied logistic regression analysis (PLINK) in the replication stage and in a combined analysis of both stages. Two variants, both selected from the GEMMA first stage analysis, met a Bonferroni-corrected significance threshold of P = 8.47 × 10−4 (Tables 1 and 2). The first variant rs10937625 [P = 7.36 × 10−4, OR = 0.77, 95% confidence interval (CI) 0.66–0.90] locates to an intronic region of STK32B (Fig. 1A), coding for a serine/threonine kinase. The second variant rs17590046 [P = 6.81 × 10−4, OR = 0.75 (95% CI 0.64–0.89)] lies in an intron of PPARGC1A (Fig. 1B), a transcriptional coactivator. LD analysis showed no additional associated markers in neighbouring genes (Fig. 1A and B). None of the SNPs chosen based on the PLINK analysis of the discovery stage or the imputed data was successfully replicated. Therefore, we do not report any imputed data. Combined analysis of first and second stage data revealed a region on chromosome 10q21.3 containing variants with small P-values in PLINK as well as GEMMA analysis, including three intronic variants in the adhesion molecule gene CTNNA3[rs7903491, P = 2.49 × 10−7, OR = 1.10 (95% CI 1.03–1.18); rs12764057, P = 1.19 × 10−8, OR = 1.17 (95% CI 1.09–1.26) and rs10822974, 1.65 × 10−7, OR = 1.16 (95% CI 1.08–1.24)] (Fig. 1C). The variants are located close to each other but are not in strong LD (r2 < 0.8) and testing for independent haplotypic effects using PLINK showed no correlation (Fig. 1C). Association results for individual stages and combined analysis of the 20 most significant markers are summarized in Supplementary Table 4. The minor allele frequencies of successfully replicated markers rs10937652 and rs1750046 were highly consistent between different recruiting centres and discovery/replication samples while higher deviations between stages were observed for markers in CTNNA3 (Supplementary Table 5 and Supplementary Fig. 5). Heterogeneity metrics of associated markers between different stages and recruitment sites are displayed in Table 1 and forest plots in Supplementary Figs 6–10. In many studies, including this one, the age at onset data follow a bimodal distribution (Supplementary Fig. 11). Stratification into early (<25 years) and late (>50 years) age at onset groups did not reveal large differences in the allele frequencies of the top 20 markers between both groups (Supplementary Table 6 and Supplementary Fig. 12). We do not present subgroup analyses because these did not provide additional insights.Figure 1


Genome-wide association study in essential tremor identifies three new loci
Fine mapping of 500 kb windows centred around each of the three essential tremor-associated loci.Top to bottom: Chromosome ideogram followed by genes (horizontal line) and their coding regions (vertical bars), negative logarithmic P-values of all markers for the discovery stage (left y-axis) against chromosomal position (x-axis) and recombination rates for the genomic positions (right y-axis) in pink. Bottom: Heatmap indicating LD. Saturated red indicating high LD, white indicating no LD. (A) STK32B; (B) PPARGC1A; and (C) CTNNA3.
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Related In: Results  -  Collection

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aww242-F1: Fine mapping of 500 kb windows centred around each of the three essential tremor-associated loci.Top to bottom: Chromosome ideogram followed by genes (horizontal line) and their coding regions (vertical bars), negative logarithmic P-values of all markers for the discovery stage (left y-axis) against chromosomal position (x-axis) and recombination rates for the genomic positions (right y-axis) in pink. Bottom: Heatmap indicating LD. Saturated red indicating high LD, white indicating no LD. (A) STK32B; (B) PPARGC1A; and (C) CTNNA3.
Mentions: In the replication stage we genotyped an independent cohort of 1029 patients with essential tremor and 1065 control samples for 59 best markers selected from all three analyses (PLINK, GEMMA, GEMMA imputed data). We applied logistic regression analysis (PLINK) in the replication stage and in a combined analysis of both stages. Two variants, both selected from the GEMMA first stage analysis, met a Bonferroni-corrected significance threshold of P = 8.47 × 10−4 (Tables 1 and 2). The first variant rs10937625 [P = 7.36 × 10−4, OR = 0.77, 95% confidence interval (CI) 0.66–0.90] locates to an intronic region of STK32B (Fig. 1A), coding for a serine/threonine kinase. The second variant rs17590046 [P = 6.81 × 10−4, OR = 0.75 (95% CI 0.64–0.89)] lies in an intron of PPARGC1A (Fig. 1B), a transcriptional coactivator. LD analysis showed no additional associated markers in neighbouring genes (Fig. 1A and B). None of the SNPs chosen based on the PLINK analysis of the discovery stage or the imputed data was successfully replicated. Therefore, we do not report any imputed data. Combined analysis of first and second stage data revealed a region on chromosome 10q21.3 containing variants with small P-values in PLINK as well as GEMMA analysis, including three intronic variants in the adhesion molecule gene CTNNA3[rs7903491, P = 2.49 × 10−7, OR = 1.10 (95% CI 1.03–1.18); rs12764057, P = 1.19 × 10−8, OR = 1.17 (95% CI 1.09–1.26) and rs10822974, 1.65 × 10−7, OR = 1.16 (95% CI 1.08–1.24)] (Fig. 1C). The variants are located close to each other but are not in strong LD (r2 < 0.8) and testing for independent haplotypic effects using PLINK showed no correlation (Fig. 1C). Association results for individual stages and combined analysis of the 20 most significant markers are summarized in Supplementary Table 4. The minor allele frequencies of successfully replicated markers rs10937652 and rs1750046 were highly consistent between different recruiting centres and discovery/replication samples while higher deviations between stages were observed for markers in CTNNA3 (Supplementary Table 5 and Supplementary Fig. 5). Heterogeneity metrics of associated markers between different stages and recruitment sites are displayed in Table 1 and forest plots in Supplementary Figs 6–10. In many studies, including this one, the age at onset data follow a bimodal distribution (Supplementary Fig. 11). Stratification into early (<25 years) and late (>50 years) age at onset groups did not reveal large differences in the allele frequencies of the top 20 markers between both groups (Supplementary Table 6 and Supplementary Fig. 12). We do not present subgroup analyses because these did not provide additional insights.Figure 1

View Article: PubMed Central - PubMed

ABSTRACT

Essential tremor has a high heritability, but its molecular genetic determinants remain unknown. M&uuml;ller et al. conduct a genome-wide association study in more than 2800 patients with essential tremor and more than 6800 controls of European descent, and identify three new loci associated with the disease.

No MeSH data available.