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Meta-Analysis
. 2021 Oct 12;37(2):109807.
doi: 10.1016/j.celrep.2021.109807.

TIGER: The gene expression regulatory variation landscape of human pancreatic islets

Lorena Alonso  1 , Anthony Piron  2 , Ignasi Morán  1 , Marta Guindo-Martínez  1 , Sílvia Bonàs-Guarch  3 , Goutham Atla  3 , Irene Miguel-Escalada  3 , Romina Royo  1 , Montserrat Puiggròs  1 , Xavier Garcia-Hurtado  3 , Mara Suleiman  4 , Lorella Marselli  4 , Jonathan L S Esguerra  5 , Jean-Valéry Turatsinze  6 , Jason M Torres  7 , Vibe Nylander  8 , Ji Chen  9 , Lena Eliasson  5 , Matthieu Defrance  6 , Ramon Amela  1 ; MAGIC; Hindrik Mulder  10 , Anna L Gloyn  11 , Leif Groop  12 , Piero Marchetti  4 , Decio L Eizirik  13 , Jorge Ferrer  14 , Josep M Mercader  15 , Miriam Cnop  16 , David Torrents  17
Affiliations
Meta-Analysis

TIGER: The gene expression regulatory variation landscape of human pancreatic islets

Lorena Alonso et al. Cell Rep. .

Abstract

Genome-wide association studies (GWASs) identified hundreds of signals associated with type 2 diabetes (T2D). To gain insight into their underlying molecular mechanisms, we have created the translational human pancreatic islet genotype tissue-expression resource (TIGER), aggregating >500 human islet genomic datasets from five cohorts in the Horizon 2020 consortium T2DSystems. We impute genotypes using four reference panels and meta-analyze cohorts to improve the coverage of expression quantitative trait loci (eQTL) and develop a method to combine allele-specific expression across samples (cASE). We identify >1 million islet eQTLs, 53 of which colocalize with T2D signals. Among them, a low-frequency allele that reduces T2D risk by half increases CCND2 expression. We identify eight cASE colocalizations, among which we found a T2D-associated SLC30A8 variant. We make all data available through the TIGER portal (http://tiger.bsc.es), which represents a comprehensive human islet genomic data resource to elucidate how genetic variation affects islet function and translates into therapeutic insight and precision medicine for T2D.

Keywords: RNA-seq; allele-specific expression; beta cell; epigenomics; expression quantitative trait locus (eQTL); genome-wide association study (GWAS); pancreatic islets; regulatory variation; transcriptome; type 2 diabetes.

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Conflict of interest statement

Declaration of interests A.L.G.’s spouse is an employee of Genentech and holds stock options in Roche.

Figures

Figure 1.
Figure 1.. Project overview and genotype imputation
(A) Overview of the TIGER data portal. (B) Datasets of the T2DSystems Consortium and project workflow. (C and D) Multi-panel genotype imputation identified 13.1–15.7 million autosomal variants (top) and 550,000–700,000 chrX variants (bottom) (C), with (D) a large proportion of low-frequency (minor allele frequency [MAF] 1%–5%) and rare (<1%) variants, with 10.2% of structural variants (SVs), including small indels and large SVs.
Figure 2.
Figure 2.. cis-eQTL meta-analysis in human pancreatic islets
(A) Overview of the meta-analysis. (B) Manhattan plot of all eQTLs, including chrX, analyzed with female-only (F) or male-only (M) samples, and jointly (X). (C) Fold enrichment over controls of significant eQTL variants, in islet regulatory chromatin regions. p values for 1% FDR eQTL enrichments are shown. (D) Proportion of exclusive eQTLs in TIGER human islets (green) and previously found in GTEx project: tissues related to T2D etiology (orange), other tissues (blue); means in dashed lines. Right panel restricted to low MAF variants only. (E) Gene Ontology analysis of the genes of TIGER-specific eQTLs.
Figure 3.
Figure 3.. Examples of colocalization of pancreatic islet eQTLs with T2D GWAS
(A) Boxplots representing expression of CPLX1 across different genotypes of variant rs1531583 in each of the cohorts and final meta-analysis results. (B) rs1531583 was not significant in GTEx whole pancreas for CPLX1, but instead it was for PCGF3 (bottom). (C) LocusZoom plots of islet eQTL (top) and T2D GWAS (bottom) signals for rs1531583-CPLX1, and their co-localization (right). ABF, approximate Bayes factor, PP, posterior probability. (D) An islet enhancer overlaps with rs73221115 and rs73221116, part of the CPLX1 credible set of SNPs. (E) Two human islet samples heterozygous for rs73221115 and rs73221116 showed allelic imbalance in their H3K27ac enhancer chromatin marks. (F) eQTL meta-analysis of CCND2 and the low-frequency cis-regulatory variant rs76895963. (G) Co-localization plots for rs76895963-CCND2, as in (B).
Figure 4.
Figure 4.. Combined ASE analysis in human islets
(A) Overview of the cASE analysis, with IAPP as example of a gene with an imbalanced reporter variant, rs12826421. (B) Manhattan plot of cASE, positive values refer to reference-biased genes, negative to alternate. (C) Significant cASE genes are enriched for islet-specific expression and proximity to islet-regulatory regions. p values for 1% FDR eQTL enrichments are shown. (D) Gene Ontology analysis of cASE significant genes. (E) In genes with significant cASE, the proportion of those also identified as eGenes grew with increasing cASE magnitude. (F) Total number of cis-regulated genes (top) and of islet-specific expressed (bottom), identified only by the eQTL analysis (green), cASE (purple), and both (orange).
Figure 5.
Figure 5.. Identification of cis-regulatory variants in combined ASE
(A) Overview of the analysis. (B) An example of cis-regulatory variant analysis; the samples Het for the candidate variant (green) have a higher cASE Z score for the reporter SNP, while samples that are Hom for the candidate (yellow) do not show significant imbalance for the reporter SNP. (C) Candidate variants often have stronger Z scores than the reporters, including some reporter variants that were non-significant by themselves (orange). (D) Fold enrichment over controls of significant cASE candidate cis-regulatory variants, in islet regulatory chromatin regions. p values for 1% FDR cASE enrichments. (E) Total number of candidate cis-regulatory variants (top) and low-frequency variants (bottom) identified by only the eQTL analysis (green), cASE (purple), and both (orange). (F) cASE analysis for SLC30A8, its best reporter SNP (top), and best candidate variant (bottom). (G) LocusZoom plots of islet cASE (top) and T2D GWAS (bottom) signals for rs3802177-SLC30A8, and their colocalization (right).
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