Skip to main content
[Preprint]. 2024 Aug 6:2024.08.03.606460. [Version 1] doi: 10.1101/2024.08.03.606460

Figure 4. Enrichment of disease risk in changes in gene regulation associated with phenotype and genotype.

Figure 4.

a) Enrichment of SNPs in the T2D credible set that overlap cREs associated with age, BMI, HbA1c and sex, in the six largest cell types. Nominally significant enrichments (pval<.05) are indicated with °. b) Example of a BMI-associated cRE in beta cells which contains T2D risk variants at the TCF7L2 locus. Top: locus plot showing the cRE chr10:112998372–112998672 that contains T2D risk SNPs, and it’s predicted target gene TCF7L2. Bottom left: association between donor BMI and the accessibility of the cRE in beta cells per donor. Bottom right: T2D summary statistics in the TCF7L2 locus. The grey box indicates the cRE, and the blue dot and line indicates the SNP that overlaps the cRE. c) Enrichment of SNPs in the glycemic trait, T1D and T2D credible set that overlap cREs that have a significant caQTL in each cell type. FDR significant enrichments (FDR<.1) are indicated with * and nominally significant enrichments (pval<.05) are indicated with °. d) Summary of the number of statistically significant (PIP>0.8) colocalizations between cell type caQTLs and summary statistics for glycemic traits, T1D, and T2D. e) The PIP for each T2D colocalized cRE across all cell types. Non-significant colocalizations are colored in blue and significant colocalizations are colored in green. Row names indicate the nearest credible set to the cRE that overlaps T2D risk. The vertical color bar indicates the cell type classifications of caQTLs based on mashR results, with Misc referring to anything not covered by the other categories. f-h) Example colocalizations between T2D, T1D, or glycemic trait association and beta cell caQTLs predicted to regulate (f) CAMK1D, (g) DEUP1, and (h) DYRK3. Top: locus plot showing the cRE with colocalized caQTLs (grey box), and predicted target gene links. Bottom left: caQTL and GWAS summary statistics for the region around the cRE. Middle right: box plots for a representative SNP that is a caQTL for the cRE and directly overlaps a GWAS variant. Bottom right: Motif created by the example caQTL with the caQTL created base highlighted in blue.