Fig 1.
SNPs in the previously reported celiac disease associated regions.
Manhattan plot of P-values on the −log10 scale for SNPs (±400kb) previously associated with celiac disease (A) and persistent tissue transglutaminase autoantibody (tTGA) positivity (B). HRs and p-values are calculated using three possible genotypes and adjusted for family history of celiac disease, HLA-DR-DQ genotype, gender, HLA-DPB1, population stratification (ancestral heterogeneity) and country of residence (as strata). The red dashed line represents p = 1x10−4. Kaplan-Meier plots of the three most significant SNPs associated with celiac disease (C) and tTGA (D) are plotted by dividing the subjects in two groups: (i) Major homozygous (black curves) and (ii) Heterozygous combined with minor homozygous (red curves).
Table 1.
Associations with celiac disease or tissue transglutaminase autoantibody (tTGA) positivity (p<10−4), mapped to previously known regions.
Fig 2.
Associations with risk of celiac disease and risk of persistent tissue transglutaminase autoantibody (tTGA) positivity.
Manhattan plot of 133,620 SNPs with MAF>0.01, displaying the P-values on the −log10 scale for SNP associations with celiac disease (A) and persistent tTGA positivity (B). HRs and p-values are calculated using three possible genotypes and adjusted for family history of celiac disease, HLA-DR-DQ genotype, gender, HLA-DPB1, population stratification (ancestral heterogeneity) and country of residence (as strata). The red dashed line represents p = 1x10−4, the red solid line represents Bonferroni correction threshold. Kaplan-Meier plots of selected SNPs associated with celiac disease (C) and persistent tTGA (D) are plotted by dividing the subjects in two groups: (i) Major homozygous (black curves) and (ii) Heterozygous combined with minor homozygous (red curves).
Table 2.
Novel associations with celiac disease or tissue transglutaminase autoantibody (tTGA) positivity (p<10−4).
Fig 3.
Associations with risk of celiac disease in the Swedish population.
A: Manhattan plot of 133620 SNPs with MAF>0.01, displaying the P-values on the −log10 scale for the SNPs associated with celiac disease in the Swedish TEDDY population. B: Regional association plots at the PKIA locus generated by LocusZoom, showing the significance of association and the recombination rate. Colors represent HapMap CEU linkage disequilibrium r2 values with the most significantly associated SNP (rs117128341; shown in purple). C: Pairwise LD plot for five SNPs in the region of PKIA. The five most significant SNPs from this region are in high LD with each other.
Fig 4.
Country-specific associations with risk of celiac disease.
Kaplan-Meier plots of five SNPs mapped to the PKIA region and one SNP mapped to the PFKFB3 region, in the Swedish TEDDY population (A) and in the other TEDDY countries (B). Kaplan-Meier plots clearly indicate country-specific differences. HRs and p-values are calculated using three possible genotypes and adjusted for family history of celiac disease, HLA-DR-DQ genotype, gender, HLA-DPB1 and population stratification (ancestral heterogeneity).
Table 3.
Six SNPs from two genomic regions significantly associated with celiac disease in Sweden.
Five SNPs mapped to PKIA region and one SNP mapped PFKFB3 region.
Fig 5.
Flow chart of study participants.
The Environmental Determinants of Diabetes in the Young (TEDDY) is an international multicenter study that screened over 420,000 newborns from the general population in four different countries. The present study genotyped 195,806 SNPs on ImmunoChip in 6,010 TEDDY children to identify potential genetic factors responsible for the development of CD and country-specific differences in genetic predisposition. As shown in flow chart, a total of 6,010 subjects were included in the analysis of time-to-CD, and 5379 subjects were included in the analysis of time-to-tTGA.