Large-scale whole-genome sequence data sets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole-genome sequence data from the UK10K and 1000 Genomes Project into 35,981 study participants of European ancestry, followed by association analysis with 20 quantitative cardiometabolic and hematological traits. We describe 17 new associations, including 6 rare (minor allele frequency (MAF) < 1%) or low-frequency (1% < MAF < 5%) variants with platelet count (PLT), red blood cell indices (MCH and MCV) and HDL cholesterol. Applying fine-mapping analysis to 233 known and new loci associated with the 20 traits, we resolve the associations of 59 loci to credible sets of 20 or fewer variants and describe trait enrichments within regions of predicted regulatory function. These findings improve understanding of the allelic architecture of risk factors for cardiometabolic and hematological diseases and provide additional functional insights with the identification of potentially novel biological targets.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Causal associations of circulating adiponectin with cardiometabolic diseases and osteoporotic fracture
Scientific Reports Open Access 23 April 2022
Communications Biology Open Access 08 June 2021
Scientific Reports Open Access 18 March 2021
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Cohen, J.C. et al. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305, 869–872 (2004).
Johansen, C.T. et al. Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia. Nat. Genet. 42, 684–687 (2010).
Auer, P.L. et al. Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits. Nat. Genet. 46, 629–634 (2014).
Willer, C.J. et al. Discovery and refinement of loci associated with lipid levels. Nat. Genet. 45, 1274–1283 (2013).
Huyghe, J.R. et al. Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion. Nat. Genet. 45, 197–201 (2013).
Morris, A.P. et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat. Genet. 44, 981–990 (2012).
Peloso, G.M. et al. Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. Am. J. Hum. Genet. 94, 223–232 (2014).
van der Harst, P. et al. Seventy-five genetic loci influencing the human red blood cell. Nature 492, 369–375 (2012).
Auer, P.L. et al. Imputation of exome sequence variants into population-based samples and blood-cell-trait-associated loci in African Americans: NHLBI GO Exome Sequencing Project. Am. J. Hum. Genet. 91, 794–808 (2012).
Steinthorsdottir, V. et al. Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes. Nat. Genet. 46, 294–298 (2014).
Surakka, I. et al. The impact of low-frequency and rare variants on lipid levels. Nat. Genet. 47, 589–597 (2015).
Moayyeri, A., Hammond, C.J., Hart, D.J. & Spector, T.D. Effects of age on genetic influence on bone loss over 17 years in women: the Healthy Ageing Twin Study (HATS). J. Bone Miner. Res. 27, 2170–2178 (2012).
Boyd, A. et al. Cohort profile: the 'children of the 90s'—the index offspring of the Avon Longitudinal Study of Parents and Children. Int. J. Epidemiol. 42, 111–127 (2013).
Walter, K. et al. The UK10K project identifies rare variants in health and disease. Nature 526, 82–90 (2015).
Timpson, N.J. et al. A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans. Nat. Commun. 5, 4871 (2014).
Taylor, P.N. et al. Whole-genome sequence-based analysis of thyroid function. Nat. Commun. 6, 5681 (2015).
Huang, J. et al. Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel. Nat. Commun. 6, 8111 (2015).
Genome of the Netherlands Consortium. Whole-genome sequence variation, population structure and demographic history of the Dutch population. Nat. Genet. 46, 818–825 (2014).
Do, R. et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat. Genet. 45, 1345–1352 (2013).
Okada, Y. et al. Meta-analysis identifies multiple loci associated with kidney function–related traits in east Asian populations. Nat. Genet. 44, 904–909 (2012).
Meyer, T.E. et al. Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six loci influencing serum magnesium levels. PLoS Genet. 6, e1001045 (2010).
Polfus, L.M. et al. Whole-exome sequencing identifies loci associated with blood cell traits and reveals a role for alternative GFI1B splice variants in human hematopoiesis. Am. J. Hum. Genet. 99, 481–488 (2016).
Service, S.K. et al. Re-sequencing expands our understanding of the phenotypic impact of variants at GWAS loci. PLoS Genet. 10, e1004147 (2014).
Maller, J.B. et al. Bayesian refinement of association signals for 14 loci in 3 common diseases. Nat. Genet. 44, 1294–1301 (2012).
Benner, C. et al. FINEMAP: efficient variable selection using summary data from genome-wide association studies. Bioinformatics 32, 1493–1501 (2016).
Hormozdiari, F., Kostem, E., Kang, E.Y., Pasaniuc, B. & Eskin, E. Identifying causal variants at loci with multiple signals of association. Genetics 198, 497–508 (2014).
Lee, D. et al. A method to predict the impact of regulatory variants from DNA sequence. Nat. Genet. 47, 955–961 (2015).
Maurano, M.T. et al. Large-scale identification of sequence variants influencing human transcription factor occupancy in vivo. Nat. Genet. 47, 1393–1401 (2015).
Douvris, A. et al. Functional analysis of the TRIB1 associated locus linked to plasma triglycerides and coronary artery disease. J. Am. Heart Assoc. 3, e000884 (2014).
Iwamoto, S. et al. The role of TRIB1 in lipid metabolism; from genetics to pathways. Biochem. Soc. Trans. 43, 1063–1068 (2015).
Baerenwald, D.A. et al. Multiple functional polymorphisms in the G6PC2 gene contribute to the association with higher fasting plasma glucose levels. Diabetologia 56, 1306–1316 (2013).
Duan, Q., Liu, E.Y., Croteau-Chonka, D.C., Mohlke, K.L. & Li, Y. A comprehensive SNP and indel imputability database. Bioinformatics 29, 528–531 (2013).
Lappalainen, T. et al. Transcriptome and genome sequencing uncovers functional variation in humans. Nature 501, 506–511 (2013).
Möröy, T., Vassen, L., Wilkes, B. & Khandanpour, C. From cytopenia to leukemia: the role of Gfi1 and Gfi1b in blood formation. Blood 126, 2561–2569 (2015).
Laurent, B. et al. A short Gfi-1B isoform controls erythroid differentiation by recruiting the LSD1-CoREST complex through the dimethylation of its SNAG domain. J. Cell Sci. 125, 993–1002 (2012).
Danjou, F. et al. Genome-wide association analyses based on whole-genome sequencing in Sardinia provide insights into regulation of hemoglobin levels. Nat. Genet. 47, 1264–1271 (2015).
Sankaran, V.G. et al. Cyclin D3 coordinates the cell cycle during differentiation to regulate erythrocyte size and number. Genes Dev. 26, 2075–2087 (2012).
Ono, Y. et al. Induction of functional platelets from mouse and human fibroblasts by p45NF-E2/Maf. Blood 120, 3812–3821 (2012).
Shavit, J.A. et al. Impaired megakaryopoiesis and behavioral defects in mafG-null mutant mice. Genes Dev. 12, 2164–2174 (1998).
Stevenson, W.S. et al. GFI1B mutation causes a bleeding disorder with abnormal platelet function. J. Thromb. Haemost. 11, 2039–2047 (2013).
Monteferrario, D. et al. A dominant-negative GFI1B mutation in the gray platelet syndrome. N. Engl. J. Med. 370, 245–253 (2014).
Wiestner, A., Schlemper, R.J., van der Maas, A.P. & Skoda, R.C. An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia. Nat. Genet. 18, 49–52 (1998).
Ghilardi, N., Wiestner, A., Kikuchi, M., Ohsaka, A. & Skoda, R.C. Hereditary thrombocythaemia in a Japanese family is caused by a novel point mutation in the thrombopoietin gene. Br. J. Haematol. 107, 310–316 (1999).
Kondo, T. et al. Familial essential thrombocythemia associated with one-base deletion in the 5′-untranslated region of the thrombopoietin gene. Blood 92, 1091–1096 (1998).
Liu, K. et al. A de novo splice donor mutation in the thrombopoietin gene causes hereditary thrombocythemia in a Polish family. Haematologica 93, 706–714 (2008).
Dasouki, M.J. et al. Exome sequencing reveals a thrombopoietin ligand mutation in a Micronesian family with autosomal recessive aplastic anemia. Blood 122, 3440–3449 (2013).
Giannakopoulos, B. & Krilis, S.A. The pathogenesis of the antiphospholipid syndrome. N. Engl. J. Med. 368, 1033–1044 (2013).
De Groot, P.G., Meijers, J.C. & Urbanus, R.T. Recent developments in our understanding of the antiphospholipid syndrome. Int. J. Lab. Hematol. 34, 223–231 (2012).
Sanghera, D.K., Wagenknecht, D.R., McIntyre, J.A. & Kamboh, M.I. Identification of structural mutations in the fifth domain of apolipoprotein H (β2-glycoprotein I) which affect phospholipid binding. Hum. Mol. Genet. 6, 311–316 (1997).
Korporaal, S.J. et al. Binding of low density lipoprotein to platelet apolipoprotein E receptor 2′ results in phosphorylation of p38MAPK. J. Biol. Chem. 279, 52526–52534 (2004).
Lutters, B.C. et al. Dimers of β2-glycoprotein I increase platelet deposition to collagen via interaction with phospholipids and the apolipoprotein E receptor 2′. J. Biol. Chem. 278, 33831–33838 (2003).
Adams, D. et al. BLUEPRINT to decode the epigenetic signature written in blood. Nat. Biotechnol. 30, 224–226 (2012).
Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013).
Khan, A. & Zhang, X. dbSUPER: a database of super-enhancers in mouse and human genome. Nucleic Acids Res. 44, D1, D164–D171 (2016).
Xu, J. et al. Combinatorial assembly of developmental stage-specific enhancers controls gene expression programs during human erythropoiesis. Dev. Cell 23, 796–811 (2012).
ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).
GTEx Consortium. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648–660 (2015).
Kundaje, A. et al. Integrative analysis of 111 reference human epigenomes. Nature 518, 317–330 (2015).
Kiryluk, K. et al. Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens. Nat. Genet. 46, 1187–1196 (2014).
Keller, M.F. et al. Trans-ethnic meta-analysis of white blood cell phenotypes. Hum. Mol. Genet. 23, 6944–6960 (2014).
Vijai, J. et al. A genome-wide association study of marginal zone lymphoma shows association to the HLA region. Nat. Commun. 6, 5751 (2015).
Gieger, C. et al. New gene functions in megakaryopoiesis and platelet formation. Nature 480, 201–208 (2011).
Menicanin, D., Bartold, P.M., Zannettino, A.C. & Gronthos, S. Identification of a common gene expression signature associated with immature clonal mesenchymal cell populations derived from bone marrow and dental tissues. Stem Cells Dev. 19, 1501–1510 (2010).
Konopatskaya, O. et al. PKCα regulates platelet granule secretion and thrombus formation in mice. J. Clin. Invest. 119, 399–407 (2009).
Williams, C.M., Harper, M.T. & Poole, A.W. PKCα negatively regulates in vitro proplatelet formation and in vivo platelet production in mice. Platelets 25, 62–68 (2014).
Kong, Y., Wang, H., Lin, T. & Wang, S. Sphingosine-1-phosphate/S1P receptors signaling modulates cell migration in human bone marrow–derived mesenchymal stem cells. Mediators Inflamm. 2014, 565369 (2014).
Yang, L. et al. Sphingosine 1-phosphate receptor 2 and 3 mediate bone marrow–derived monocyte/macrophage motility in cholestatic liver injury in mice. Sci. Rep. 5, 13423 (2015).
Westra, H.J. et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat. Genet. 45, 1238–1243 (2013).
Hildebrand, J.D. Shroom regulates epithelial cell shape via the apical positioning of an actomyosin network. J. Cell Sci. 118, 5191–5203 (2005).
Menon, M.C. et al. Intronic locus determines SHROOM3 expression and potentiates renal allograft fibrosis. J. Clin. Invest. 125, 208–221 (2015).
Teslovich, T.M. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–713 (2010).
Grand, F.H. et al. p53-binding protein 1 is fused to the platelet-derived growth factor receptor β in a patient with a t(5;15)(q33;q22) and an imatinib-responsive eosinophilic myeloproliferative disorder. Cancer Res. 64, 7216–7219 (2004).
Caulfield, M.J. et al. SLC2A9 is a high-capacity urate transporter in humans. PLoS Med. 5, e197 (2008).
Köttgen, A. et al. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat. Genet. 45, 145–154 (2013).
Delaneau, O., Marchini, J. & Zagury, J.F. A linear complexity phasing method for thousands of genomes. Nat. Methods 9, 179–181 (2011).
Danecek, P. et al. The variant call format and VCFtools. Bioinformatics 27, 2156–2158 (2011).
Howie, B., Fuchsberger, C., Stephens, M., Marchini, J. & Abecasis, G.R. Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat. Genet. 44, 955–959 (2012).
Mägi, R. & Morris, A.P. GWAMA: software for genome-wide association meta-analysis. BMC Bioinformatics 11, 288 (2010).
Wakefield, J. Bayes factors for genome-wide association studies: comparison with P-values. Genet. Epidemiol. 33, 79–86 (2009).
Chen, W. et al. Fine mapping causal variants with an approximate Bayesian method using marginal test statistics. Genetics 200, 719–736 (2015).
Thurman, R.E. et al. The accessible chromatin landscape of the human genome. Nature 489, 75–82 (2012).
This study makes use of data generated by the UK10K Consortium, derived from samples from the ALSPAC and TwinsUK data sets. A full list of the investigators who contributed to the generation of the data is available from http://www.UK10K.org/. Funding for UK10K was provided by the Wellcome Trust under award WT091310. The research of N.S. is supported by the Wellcome Trust (grants WT098051 and WT091310), the European Union Framework Programme 7 (EPIGENESYS grant 257082 and BLUEPRINT grant HEALTH-F5-2011-282510) and the National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge in partnership with NHS Blood and Transplant (NHSBT). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health or NHSBT. P.L.A. was supported by NHLBI R21 HL121422-02. A full list of grant support and acknowledgements can be found in the Supplementary Note and ref. 14.
The authors declare no competing financial interests.
A list of consortium members and affiliations can be found at http://www.uk10k.org/.
Supplementary Note and Supplementary Figures 1–4. (PDF 8534 kb)
Study descriptives. (XLSX 117 kb)
Phenotype preparation protocols. (XLSX 73 kb)
Association statistics for new loci in discovery and replication. (XLSX 131 kb)
GENCODE, ENCODE and Roadmap Epigenomics annotations used for enrichment analysis with software GARFIELD. (XLSX 106 kb)
Enrichment of cardiometabolic traits in 1,005 GENCODE, ENCODE and Roadmap Epigenomics annotations at 1 × 10−5 and 1 × 10−8 GWAS significance thresholds. (XLSX 202 kb)
Fine-mapping results. (XLSX 231 kb)
FINEMAP analysis with a relaxed assumption of multiple causal variants per locus. (XLSX 41 kb)
About this article
Cite this article
Iotchkova, V., Huang, J., Morris, J. et al. Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps. Nat Genet 48, 1303–1312 (2016). https://doi.org/10.1038/ng.3668
This article is cited by
Causal associations of circulating adiponectin with cardiometabolic diseases and osteoporotic fracture
Scientific Reports (2022)
Admixture mapping of anthropometric traits in the Black Women’s Health Study: evidence of a shared African ancestry component with birth weight and type 2 diabetes
Journal of Human Genetics (2022)
Scientific Reports (2021)
Communications Biology (2021)
Nature Communications (2021)