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Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps
- Publisher :
- Springer Science and Business Media LLC
-
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 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).
- Subjects :
- Male
endocrine system diseases
Genome, Human
Chromosome Mapping
Polymorphism, Single Nucleotide
Linkage Disequilibrium
White People
3. Good health
Body Mass Index
Epigenesis, Genetic
High-Throughput Screening Assays
Islets of Langerhans
Sex Factors
Diabetes Mellitus, Type 2
Gene Frequency
Meta-Analysis as Topic
Genetic Loci
Case-Control Studies
Humans
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Subjects
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi...........88ad77ecfa6a7e416644d5de3cbc5c13