Journal Article

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

Luan, Jian’an, Payne, Anthony J., Läll, Kristi, Scott, Robert A., Thurner, Matthias, Morris, Andrew D., Pedersen, Oluf, Lyssenko, Valeriya, Bowden, Donald W., Yengo, Loïc, Locke, Adam E., Jørgensen, Torben, Mohlke, Karen L., Kriebel, Jennifer, Loos, Ruth J. F., Below, Jennifer E., Hattersley, Andrew T., Lindgren, Cecilia M., Taliun, Daniel, Stefansson, Kari, Kim, Young Jin, Peters, Annette, Prins, Bram Peter, Ikram, M. Arfan, Thorand, Barbara, Peyser, Patricia A., Canouil, Mickaël, Ligthart, Symen, Palmer, Colin N. A., Sim, Xueling, Bork-Jensen, Jette, Brummett, Chad M., Rayner, N. William, Mägi, Reedik, Jørgensen, Marit E., Grarup, Niels, Liu, Ching-Ti, Nano, Jana, Jukema, J. Wouter, Taylor, Kent D., Langenberg, Claudia, Linneberg, Allan, Dehghan, Abbas, Schmidt, Ellen M., Lind, Lars, Frayling, Timothy M., Gieger, Christian, Köttgen, Anna, Kronenberg, Florian, Bennett, Amanda J., Sattar, Naveed, Franco, Oscar H., Christensen, Cramer, Herder, Christian, Kuusisto, Johanna, Meigs, James B., Thorleifsson, Gudmar, Morris, Andrew P., Cook, James P., Mamakou, Vasiliki, Zeggini, Eleftheria, Collins, Francis S., Sc

2018

Overview

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). Combining 32 genome-wide association studies with high-density imputation provides a comprehensive view of the genetic contribution to type 2 diabetes in individuals of European ancestry with respect to locus discovery, causal-variant resolution, and mechanistic insight.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45 / 45/43 / 631/208/191 / 631/208/205/2138 / Agriculture / Alleles / Analysis / Animal Genetics and Genomics / Annotations / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Body Mass Index / Cancer Research / Case-Control Studies / Chromosome Mapping - methods / Conditional probability / Density / Diabetes / Diabetes mellitus / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 2 - epidemiology / Diabetes Mellitus, Type 2 - genetics / Diabetes Mellitus, Type 2 - pathology / Epigenesis, Genetic / Female / Females / Gene expression / Gene Frequency / Gene Function / Gene mapping / Genes / Genetic Loci - genetics / Genetic Predisposition to Disease / Genome, Human - genetics / Genome-Wide Association Study / Genomes / Genomics / Haplotypes / Heritability / High-Throughput Screening Assays - methods / Human Genetics / Humans / Islets of Langerhans - metabolism / Islets of Langerhans - pathology / Life Sciences / Linkage Disequilibrium / Loci / Male / Mapping / Medical schools / Meta-Analysis as Topic / Obesity / Polymorphism, Single Nucleotide / Risk / Sex Factors / Therapeutic applications / Translation (Genetics) / Type 2 diabetes / White People - genetics