Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps



Mahajan, Anubha, Taliun, Daniel, Thurner, Matthias, Robertson, Neil R, Torres, Jason M, Rayner, N William, Payne, Anthony J, Steinthorsdottir, Valgerdur, Scott, Robert A, Grarup, Niels
et al (show 105 more authors) (2018) Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. NATURE GENETICS, 50 (11). pp. 1505-1513.

[thumbnail of Main text NG-A47886R final.pdf] Text
Main text NG-A47886R final.pdf - Author Accepted Manuscript

Download (1MB)
[thumbnail of 3. Integrated Supplementary Figures.pdf] Text
3. Integrated Supplementary Figures.pdf - Author Accepted Manuscript

Download (1MB)
[thumbnail of 4. Supplementary Notes.pdf] Text
4. Supplementary Notes.pdf - Author Accepted Manuscript

Download (555kB)
[thumbnail of 4. Supplementary Tables NG-A47886R.xlsx] Spreadsheet
4. Supplementary Tables NG-A47886R.xlsx - Author Accepted Manuscript

Download (252kB)
[thumbnail of Figure 1.pdf] Text
Figure 1.pdf - Author Accepted Manuscript

Download (291kB)
[thumbnail of Figure 2.pdf] Text
Figure 2.pdf - Author Accepted Manuscript

Download (130kB)
[thumbnail of Figure 3.pdf] Text
Figure 3.pdf - Author Accepted Manuscript

Download (89kB)
[thumbnail of Figure 4.pdf] Text
Figure 4.pdf - Author Accepted Manuscript

Download (39kB)
[thumbnail of Figure 5.pdf] Text
Figure 5.pdf - Author Accepted Manuscript

Download (64kB)
[thumbnail of Figure 6.pdf] Text
Figure 6.pdf - Author Accepted Manuscript

Download (730kB)

Abstract

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%, 14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).

Item Type: Article
Uncontrolled Keywords: Islets of Langerhans, Humans, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Body Mass Index, Case-Control Studies, Chromosome Mapping, Sex Factors, Epigenesis, Genetic, Gene Frequency, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Genome, Human, Female, Male, Meta-Analysis as Topic, Genome-Wide Association Study, Genetic Loci, High-Throughput Screening Assays, White People
Depositing User: Symplectic Admin
Date Deposited: 15 Oct 2018 14:27
Last Modified: 19 Jan 2023 01:14
DOI: 10.1038/s41588-018-0241-6
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3027479