Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps
Open accessAbstract
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.
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Genome-wide association studies have expanded the list of associated loci in type 2 diabetes to more than 250 with 400 independent signals.
“since the turn of the century, increasing size and depth of genome-wide association studies have rapidly expanded the list of associated loci in type 2 diabetes to more than 250 with 400 independent signals79.”
From 100 years of insulin: celebrating the past, present and future of diabetes therapy (2021) · cites this paper as [79]
The Results section, “Multiple association signals at T2D susceptibility loci” (page not provided), reports 403 significant T2D-association signals, supporting the approximate 400-signal figure. It reports 243 associated loci, however, not more than 250. (LLM, conf=0.92)
Experimental — accuracy not yet measuredDespite the large number of associated loci, their individual contributions to overall risk are moderate, explaining just under 20% of heritability and highlighting missing heritability.
“Despite the large number of associated loci, their individual contributions to overall risk are moderate, explaining just under 20% of heritability and highlighting the proportion of ‘missing heritability’ that is still to be fully elucidated.”
From 100 years of insulin: celebrating the past, present and future of diabetes therapy (2021) · cites this paper as [79]
The Results section ('The contribution of lower-frequency variants'; page unavailable) says most associated variants have modest effects and reports that common and lower-frequency signals explain 16.3% and 1.13% of T2D phenotypic variance, respectively. The separate 'Heritability estimates' section estimates chip heritability at 18%, about half the estimate from family studies. The claim conflates variance explained by associated signals with the proportion of heritability they explain; the paper does not say those loci explain just under 20% of heritability. (LLM, conf=0.88)
Experimental — accuracy not yet measuredGenome-wide association studies have identified more than 30 genetic factors, which increase the risk for type 2 diabetes.
“Genome-wide association studies have identified more than 30 genetic factors, which increase the risk for type 2 diabetes (394,395).”
From Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus (2023) · cites this paper as [394]
Trait-specific consortia formed to accelerate genetic discovery through aggregation and meta-analysis of data from multiple GWAS studies.
“A host of trait-specific consortia formed, covering diverse dichotomous and quantitative phenotypes, to accelerate genetic discovery through the aggregation and meta-analysis of data from multiple GWAS studies41–43.”
From A brief history of human disease genetics (2020) · cites this paper as [41]
Common diseases are not simply aggregations of related Mendelian conditions; for most complex traits, genetic predisposition is shared across thousands of mostly common variants with individually modest effects on population risk.
“Common diseases are not simply aggregations of related Mendelian conditions: for most complex traits, genetic predisposition is shared across thousands of mostly common variants with individually modest effects on population risk41,43.”
From A brief history of human disease genetics (2020) · cites this paper as [41]
SCD5 has not been reported as a cell-type-specific marker for beta cells, but in a GWAS study, a novel loci for T2D susceptibility was fine-mapped to a coding variant of SCD.
“For instance, SCD5 hasn't been reported as a cell-type-specific marker for beta cells, but in a GWAS study, a novel loci for T2D susceptibility was fine-mapped to a coding variant of SCD 42 .”
From scBERT as a Large-scale Pretrained Deep Language Model for Cell Type Annotation of Single-cell RNA-seq Data (2021) · cites this paper as [42]
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References 76 · Cited by 1,744
- Authors
- Mahajan, A., Taliun, D., Thurner, M., Robertson, N. R., Torres, J. M., Rayner, N. W., Payne, A. J., Steinthorsdottir, V., Scott, R. A., Grarup, N., Cook, J. P., Schmidt, E. M., Wuttke, M., Sarnowski, C., Mägi, R., Nano, J., Gieger, C., Trompet, S., Lecoeur, C., Preuss, M. H., Prins, B. P., Guo, X., Bielak, L. F., Below, J. E., Bowden, D. W., Chambers, J. C., Kim, Y. J., Ng, M. C. Y., Petty, L. E., Sim, X., Zhang, W., Bennett, A. J., Bork-Jensen, J., Brummett, C. M., Canouil, M., Ec kardt, K.-U., Fischer, K., Kardia, S. L. R., Kronenberg, F., Läll, K., Liu, C.-T., Locke, A. E., Luan, J., Ntalla, I., Nylander, V., Schönherr, S., Schurmann, C., Yengo, L., Bottinger, E. P., Brandslund, I., Christensen, C., Dedoussis, G., Florez, J. C., Ford, I., Franco, O. H., Frayling, T. M., Giedraitis, V., Hackinger, S., Hattersley, A. T., Herder, C., Ikram, M. A., Ingelsson, M., Jørgensen, M. E., Jørgensen, T., Kriebel, J., Kuusisto, J., Ligthart, S., Lindgren, C. M., Linneberg, A., Lyssenko, V., Mamakou, V., Meitinger, T., Mohlke, K. L., Morris, A. D., Nadkarni, G., Pankow, J. S., Peters, A., Sattar, N., Stančáková, A., Strauch, K., Taylor, K. D., Thorand, B., Thorleifsson, G., Thorsteinsdottir, U., Tuomilehto, J., Witte, D. R., Dupuis, J., Peyser, P. A., Zeggini, E., Loos, R. J. F., Froguel, P., Ingelsson, E., Lind, L., Groop, L., Laakso, M., Collins, F. S., Jukema, J. W., Palmer, C. N. A., Grallert, H., Metspalu, A., Dehghan, A., Köttgen, A., Abecasis, G. R., Meigs, J. B., Rotter, J. I., Marchini, J., Pedersen, O., Hansen, T., Langenberg, C., Wareham, N. J., Stefansson, K., Gloyn, A. L., Morris, A. P., Boehnke, M., & McCarthy, M. I.
- Affiliations
- Centre for Human Genetics (GB)
- University of Michigan (US)
- University of Cambridge (GB)
- University of Copenhagen (DK)
- University of Liverpool (GB)
- University of Freiburg (DE)
- Boston University (US)
- University of Tartu (EE)
- Erasmus MC (NL)
- Helmholtz Munich (DE)
- Leiden University Medical Center (NL)
- Icahn School of Medicine at Mount Sinai (US)
- Wellcome Sanger Institute (GB)
- Harbor–UCLA Medical Center (US)
- Vanderbilt University Medical Center (US)
- Wake Forest University Health Sciences (US)
- Imperial College Healthcare NHS Trust (GB)
- Korea National Institute of Health (KR)
- National University of Singapore (SG)
- Ealing Hospital (GB)
- University of Oxford (GB)
- Centre National de la Recherche Scientifique (FR)
- Innsbruck Medical University (AT)
- Washington University in St. Louis (US)
- University of Southern Denmark (DK)
- Vejle Sygehus (DK)
- Harokopio University of Athens (GR)
- University of Glasgow (GB)
- University of Exeter (GB)
- Uppsala University (SE)
- Deutsches Diabetes-Zentrum e.V. (DE)
- University of Eastern Finland (FI)
- Broad Institute (US)
- Lund University (SE)
- National and Kapodistrian University of Athens (GR)
- University of North Carolina at Chapel Hill (US)
- University of Minnesota (US)
- Universität für Weiterbildung Krems (AT)
- Aarhus University (DK)
- University of Helsinki (FI)
- National Institutes of Health (US)
- University of Dundee (GB)
- Corresponding author
- Mahajan, Anubha
- McCarthy, Mark I.
- ORCID
- Mahajan, Anubha
- Taliun, Daniel
- Thurner, Matthias
- Torres, Jason M.
- Rayner, N. William
- Payne, Anthony J.
- Grarup, Niels
- Cook, James P.
- Schmidt, Ellen M.
- Wuttke, Matthias
- Sarnowski, Chloé
- Mägi, Reedik
- Nano, Jana
- Gieger, Christian
- Trompet, Stella
- Preuss, Michael H.
- Prins, Bram Peter
- Guo, Xiuqing
- Bielak, Lawrence F.
- Below, Jennifer E.
- Bowden, Donald W.
- Chambers, John Campbell
- Kim, Young Jin
- Ng, Maggie C. Y.
- Petty, Lauren E.
- Sim, Xueling
- Zhang, Weihua
- Bennett, Amanda J.
- Brummett, Chad M.
- Canouil, Mickaël
- Fischer, Krista
- Kardia, Sharon L. R.
- Kronenberg, Florian
- Läll, Kristi
- Liu, Ching-Ti
- Locke, Adam E.
- Luan, Jian’an
- Nylander, Vibe
- Schönherr, Sebastian
- Schurmann, Claudia
- Yengo, Loïc
- Brandslund, Ivan
- Dedoussis, George
- Ford, Ian
- Franco, Oscar H.
- Frayling, Timothy M.
- Giedraitis, Vilmantas
- Hackinger, Sophie
- Hattersley, Andrew T.
- Herder, Christian
- Ikram, M. Arfan
- Ingelsson, Martin
- Jørgensen, Marit E.
- Jørgensen, Torben
- Kriebel, Jennifer
- Lindgren, Cecilia M.
- Linneberg, Allan
- Lyssenko, Valeriya
- Mamakou, Vasiliki
- Meitinger, Thomas
- Mohlke, Karen L.
- Morris, Andrew D.
- Nadkarni, Girish
- Pankow, James S.
- Peters, Annette
- Sattar, Naveed
- Strauch, Konstantin
- Taylor, Kent D.
- Thorand, Barbara
- Tuomilehto, Jaakko
- Witte, Daniel R.
- Dupuis, Josée
- Peyser, Patricia A.
- Zeggini, Eleftheria
- Loos, Ruth J. F.
- Froguel, Philippe
- Ingelsson, Erik
- Lind, Lars
- Groop, Leif
- Laakso, Markku
- Collins, Francis S.
- Jukema, J. Wouter
- Grallert, Harald
- Metspalu, Andres
- Dehghan, Abbas
- Köttgen, Anna
- Meigs, James B.
- Rotter, Jerome I.
- Marchini, Jonathan
- Pedersen, Oluf
- Hansen, Torben
- Langenberg, Claudia
- Wareham, Nicholas J.
- Gloyn, Anna L.
- Morris, Andrew P.
- Boehnke, Michael
- McCarthy, Mark I.
- Venue
- Nature Genetics
- Published
- 2018-10-08
- Volume
- 50
- Issue
- 11
- Pages
- 1505-1513
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6287706
- OpenAlex
- W2894662039
- Semantic Scholar
- a4e0977a148e9f09838dd5cb52d93e435b9879ee
- Cited by
- 1,744
- References
- 76
- Citations by year
- 2026: 111 · 2025: 164 · 2024: 227 · 2023: 271 · 2022: 317 · 2021: 271 · 2020: 239 · 2019: 124 · 2018: 17
- FWCI
- 99.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
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- PubMed (publishedVersion)
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- Research Explorer (The University of Manchester) (acceptedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- Leiden Repository (Leiden University) (submittedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, cc-by-nc-nd)
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- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
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- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Site cant be reached (submittedVersion, other-oa)
- Spiral (Imperial College London) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Funders
- Eli Lilly and Company
- Pfizer
- Sanofi
- University of Michigan
- Wellcome Trust (098381, 098395/Z/12/Z, 200837/Z/16/Z)
- Steno Diabetes Center Copenhagen (SDCC 3. B Epidemiology)
- National Institute for Health and Care Research (NF-SI-0611-10099, NF-SI-0611-10219, NF-SI-0616-10080, NF-SI-0512-10135, NF-SI-0617-10149, NF-SI-0617-10090)
- Lundbeckfonden (R16-2007-1691)
- Novo Nordisk Fonden (NNF15OC0016416)
- Nestec
- College of Pharmacy, University of Michigan
- Medical Research Council (MC_PC_13046, MC_PC_13048, MC_UU_12015/1)
- National Institute on Aging (K99AG066849)
- National Heart, Lung, and Blood Institute (R01HL119443, R01HL105756)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK072193, U01DK062370, R01DK066358, U01DK105556, U01DK105535, R01DK078616, K24DK080140, U01DK078616, R01DK087914, P30DK020572, R01DK093757, P30DK116074)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- type 2 diabetes, genetic susceptibility loci, fine mapping, causal variant identification, polygenic risk score, therapeutic target, European ancestry
- MeSH terms
- Chromosome Mapping, Diabetes Mellitus, Type 2, Female, Gene Frequency, Humans, Islets of Langerhans, Male, Sex Factors, Meta-Analysis as Topic, Linkage Disequilibrium, Genome, Human, Body Mass Index, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Epigenesis, Genetic, White People, Genome-Wide Association Study, Genetic Loci, High-Throughput Screening Assays
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