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New genetic loci link adipose and insulin biology to body fat distribution
Open accessAbstract
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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“Interestingly, although Gao et al. use the most up-to-date BMI GWAS data, 20 they do not do the same for WHR, despite the most recent GWAS for WHR adjusted for BMI identifying 33 additional variants (as well as confirming the 14 used here from the earlier GWAS) and being published around the same time as the most up-to-date BMI GWAS.”
From Commentary: Two-sample Mendelian randomization: opportunities and challenges (2016) · cites this paper as [21]
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“In both GWAS, the results of the per allele effect of the genetic instrument on WHR adjusted for BMI is notably stronger in females than males.”
From Commentary: Two-sample Mendelian randomization: opportunities and challenges (2016) · cites this paper as [21]
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“Seven of the 14 WHR adjusted for BMI variants used by Gao and colleagues were stronger in females compared with males ( Table 2 ), with 19 of the 44 variants in the more up-to-date GWAS being stronger in females (and one stronger in males).”
From Commentary: Two-sample Mendelian randomization: opportunities and challenges (2016) · cites this paper as [21]
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“Large GWAS have revealed many genetic loci associated with BMI or adiposity in adults (9-13).”
BackgroundSelf-citationCalcium Homeostasis and Organelle Function in the Pathogenesis of Obesity and Diabetes
Arruda, A. P., & Hotamışlıgil, G. S. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.06.010 · Cited by 352
“The role of Ca2+ flux through the IP3R in human metabolic disease has been suggested by a recent GWAS meta-analysis that identified a SNP in the IP3R2 locus associated with alterations in the waist-to-hip ratio adjusted for BMI (Shungin et al., 2015).”
ResultGenetic mapping of cell type specificity for complex traits
Watanabe, K., Mirkov, M. U., de Leeuw, C., van den Heuvel, M. P., & Posthuma, D. (2019) · Nature Communications · doi:10.1038/s41467-019-11181-1 · Cited by 329
Chronic tissue inflammation and metabolic diseasePreprint
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“, WWOX, MAP8IP1, IFNGR1, ST6GAL1, JAZF1, MAP3K1, MACROD1, NFE2L3, and TLR4) are also associated with the incidence of T2DM (Waeber et al. 2000; Kooner et al. 2011; Cho et al. 2012; Manning et al. 2012; Locke et al. 2015; Shungin et al. 2015; Flannick et al. 2019; Liao et al. 2019; Diedisheim et al. 2020).”
BackgroundLittle Fish, Big Data: Zebrafish as a Model for Cardiovascular and Metabolic Disease
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Genome-wide physical activity interactions in adiposity ― A meta-analysis of 200,452 adults
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“To evaluate the effect of PA adjustment on the results for the 11 novel loci, we performed a look-up in published GIANT consortium meta-analyses for BMI, WCadjBMI, and WHRadjBMI that did not adjust for PA [17, 18] (S22 Table).”
BackgroundMethodSelf-citationZengini, E., Hatzikotoulas, K., Tachmazidou, I., Steinberg, J., Hartwig, F. P., Southam, L., Hackinger, S., Boer, C. G., Styrkársdóttir, U., Gilly, A., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0079-y · Cited by 323
Self-citationDiagnosis of obesity and use of obesity biomarkers in science and clinical medicine
Nimptsch, K., Konigorski, S., & Pischon, T. (2018) · Metabolism · doi:10.1016/j.metabol.2018.12.006 · Cited by 333
Genetic contributions to NAFLD: leveraging shared genetics to uncover systems biology
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Frank, A. P., Santos, R. D. S., Palmer, B. F., & Clegg, D. J. (2018) · Journal of Lipid Research · doi:10.1194/jlr.r086975 · Cited by 333
Zebrafish as a Model for Obesity and Diabetes
Zang, L., Maddison, L. A., & Chen, W. (2018) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2018.00091 · Cited by 325
“PLEXIN D1 is one of the 67 genes identified in GWAS analyses in humans to be associated with visceral fat mass (Shungin et al., 2015), but the function of PLEXIN D1 in the distribution of fat mass was unknown.”
BackgroundGenome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging
McCartney, D. L., Min, J. L., Richmond, R. C., Lu, A. T.-H., Sobczyk, M., Davies, G., Broer, L., Guo, X., Jeong, A., Jung, J., et al. (2021) · Genome biology · doi:10.1186/s13059-021-02398-9 · Cited by 310
Self-citationGenetics and Pathogenesis of Inflammatory Bowel Disease
Liu, T.-C., & Stappenbeck, T. S. (2016) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-012615-044152 · Cited by 289
“In humans, genetics appear to account for only a small part of the increase in body mass index (∼5%) (73, 74).”
BackgroundGenetic Basis for Sex Differences in Obesity and Lipid Metabolism
Link, J. C., & Reue, K. (2017) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071816-064827 · Cited by 305
“Concordant with these findings, another large meta-analysis of nearly 225,000 individuals reported 49 loci associated with waist-hip ratio adjusted for body mass index, and 20 of these 49 loci had significant sexual dimorphism (103).”
ResultNew loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
Lu, Y., Day, F. R., Gustafsson, S., Buchkovich, M. L., Na, J., Bataille, V. A., Cousminer, D. L., Dastani, Z., Drong, A., Esko, T., et al. (2016) · Nature Communications · doi:10.1038/ncomms10495 · Cited by 294
Self-citationIdentification of nine new susceptibility loci for endometrial cancer
O’Mara, T. A., Glubb, D. M., Amant, F. C., Annibali, D., Ashton, K. A., Attia, J., Auer, P. L., Beckmann, M. W., Black, A., Bolla, M. K., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05427-7 · Cited by 286
Self-citationInsights into modifiable risk factors of cholelithiasis: A Mendelian randomization study
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“[15] For waist circumference, hip circumference, and waist- to- hip ratio genome- wide association studies (GWASs), the participants were 210,088 Europeans and the researchers adjusted for age, age square, and study- specific covariates if necessary.[16] In our MR analysis, we included GWASs adjusting for BMI and not…”
BackgroundSelf-citationFranzén, O., Ermel, R., Cohain, A., Akers, N. K., Di Narzo, A., Talukdar, H. A., Foroughi-Asl, H., Giambartolomei, C., Fullard, J. F., Sukhavasi, K., et al. (2016) · Science · doi:10.1126/science.aad6970 · Cited by 288
“/ 4 established by GWAS for CAD, CMDs and Alzheimer’s disease (AD) (3-16, 24) (figs.”
InfluentialSelf-citationDeciphering the cellular interplays underlying obesity-induced adipose tissue fibrosis
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“Moreover, a GWAS analysis revealed a link between angiogenesis gene loci and insulin resistance markers, supporting the notion that suboptimal vascularization could be of importance in maintaining insulin resistance in obesity (57).”
BackgroundMachine Learning in Genomic Medicine: A Review of Computational Problems and Data Sets
Leung, M. K. K., Delong, A., Alipanahi, B., & Frey, B. J. (2015) · Proceedings of the IEEE · doi:10.1109/jproc.2015.2494198 · Cited by 284
“[230] D.”
Zhao, W., Rasheed, A., Tikkanen, E., Lee, J., Butterworth, A. S., Howson, J. M. M., Assimes, T. L., Chowdhury, R., Orho‐Melander, M., Damrauer, S. M., et al. (2017) · Nature Genetics · doi:10.1038/ng.3943 · Cited by 263
“The region around CCDC92 segregates numerous cardiometabolic trait associations, including T2D (rs1727313) 9 , HDL-C (rs4759375, rs838880), triglycerides (rs4765127) 17 , and waist-hip ratio adjusted for body mass index (rs4765219) 18 .”
InfluentialSelf-citationPei, Y., Liu, Y., Yang, X., Zhang, H., Feng, G.-J., Wei, X., & Zhang, L. (2020) · Communications Biology · doi:10.1038/s42003-020-01334-0 · Cited by 273
Self-citationConservation, acquisition, and functional impact of sex-biased gene expression in mammals
Naqvi, S., Godfrey, A. K., Hughes, J. F., Goodheart, M. L., Mitchell, R. N., & Page, D. C. (2019) · Science · doi:10.1126/science.aaw7317 · Cited by 261
Carreras‐Torres, R., Johansson, M., Gaborieau, V., Haycock, P., Wade, K. H., Relton, C. L., Martin, R. M., Smith, G. D., & Brennan, P. (2017) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djx012 · Cited by 273
“Results from the Genetic Investigation of ANthropometric Traits (GIANT) consortium were used to identify genetic proxies for height (26), BMI (27), and waist-to-hip ratio (28).”
MethodSex differences in obesity, lipid metabolism, and inflammation—A role for the sex chromosomes?
Zore, T., Palafox, M., & Reue, K. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.04.003 · Cited by 239
“For example, a meta-analysis of more than 50 GWAS studies with waist-to-hip ratio (adjusted for total fat) in more than 200,000 individuals identified 49 loci, 20 of which showed sex-specific effects, with 19 of these having stronger effects in women [28].”
BackgroundGenetic correlates of social stratification in Great Britain
Abdellaoui, A., Hugh-Jones, D., Yengo, L., Kemper, K. E., Nivard, M. G., Veul, L., Holtz, Y., Zietsch, B. P., Frayling, T. M., Wray, N. R., et al. (2019) · Nature Human Behaviour · doi:10.1038/s41562-019-0757-5 · Cited by 261
Self-citationSumHer better estimates the SNP heritability of complex traits from summary statistics
Speed, D., & Balding, D. J. (2019) · Nature Genetics · doi:10.1038/s41588-018-0279-5 · Cited by 254
Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels
Emdin, C. A., Khera, A. V., Natarajan, P., Klarin, D., Won, H.-H., Peloso, G. M., Stitziel, N. O., Nomura, A., Zekavat, S. M., Bick, A. G., et al. (2016) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2016.10.033 · Cited by 244
“GIANT (37,38) Waist-to-hip ratio Waist circumference Hip circumference Body mass index Up to 322,154 individuals Various arrays, imputation to 2.”
BackgroundSelf-citationAssociations of Fitness, Physical Activity, Strength, and Genetic Risk With Cardiovascular Disease
Tikkanen, E., Gustafsson, S., & Ingelsson, E. (2018) · Circulation · doi:10.1161/circulationaha.117.032432 · Cited by 265
Self-citationEpigenetic prediction of complex traits and death
McCartney, D. L., Hillary, R. F., Stevenson, A. J., Ritchie, S. J., Walker, R. M., Zhang, Q., Morris, S. W., Bermingham, M. L., Campbell, A., Murray, A. D., et al. (2018) · Genome biology · doi:10.1186/s13059-018-1514-1 · Cited by 249
Self-citationHughes, D. A., Bacigalupe, R., Wang, J., Rühlemann, M. C., Tito, R. Y., Falony, G., Joossens, M., Vieira‐Silva, S., Henckaerts, L., Rymenans, L., et al. (2020) · Nature Microbiology · doi:10.1038/s41564-020-0743-8 · Cited by 247
Qasim, A., Turcotte, M., de Souza, R. J., Samaan, M. C., Champredon, D., Dushoff, J., Speakman, J. R., & Meyre, D. (2018) · Obesity Reviews · doi:10.1111/obr.12625 · Cited by 241
Metadata
- Authors
- The ADIPOGen Consortium, Shungin, D., The CARDIOGRAMplusC4D Consortium, The CKDGen Consortium, The GEFOS Consortium, The GENIE Consortium, The, G. L. G. C., The, I. C. B. P., The International Endogene Consortium, Study, T. L. C., The MAGIC Investigators, The MuTHER Consortium, The PAGE Consortium, The ReproGen Consortium, Winkler, T. W., Croteau-Chonka, D. C., Ferreira, T., Locke, A. E., Mägi, R., Strawbridge, R. J., Pers, T. H., Fischer, K., Justice, A. E., Workalemahu, T., Wu, J. M. W., Buchkovich, M. L., Heard-Costa, N. L., Roman, T. S., Drong, A. W., Song, C., Gustafsson, S., Day, F. R., Esko, T., Fall, T., Kutalik, Z., Luan, J., Randall, J. C., Scherag, A., Vedantam, S., Wood, A. R., Chen, J., Fehrmann, R., Karjalainen, J., Kahali, B., Liu, C.-T., Schmidt, E. M., Absher, D., Amin, N., Anderson, D., Beekman, M., Bragg-Gresham, J. L., Buyske, S., Demirkan, A., Ehret, G. B., Feitosa, M. F., Goel, A., Jackson, A. U., Johnson, T., Kleber, M. E., Kristiansson, K., Mangino, M., Mateo Leach, I., Medina-Gomez, C., Palmer, C. D., Pasko, D., Pechlivanis, S., Peters, M. J., Prokopenko, I., Stančáková, A., Ju Sung, Y., Tanaka, T., Teumer, A., Van Vliet-Ostaptchouk, J. V., Yengo, L., Zhang, W., Albrecht, E., Ärnlöv, J., Arscott, G. M., Bandinelli, S., Barrett, A., Bellis, C., Bennett, A. J., Berne, C., Blüher, M., Böhringer, S., Bonnet, F., Böttcher, Y., Bruinenberg, M., Carba, D. B., Caspersen, I. H., Clarke, R., Warwick Daw, E., Deelen, J., Deelman, E., Delgado, G., Doney, A. S. F., Eklund, N., Erdos, M. R., Estrada, K., Eury, E., Friedrich, N., Garcia, M. E., Giedraitis, V., Gigante, B., Go, A. S., Golay, A., Grallert, H., Grammer, T. B., Gräßler, J., Grewal, J., Groves, C. J., Haller, T., Hallmans, G., Hartman, C. A., Hassinen, M., Hayward, C., Heikkilä, K., Herzig, K.-H., Helmer, Q., Hillege, H. L., Holmen, O., Hunt, S. C., Isaacs, A., Ittermann, T., James, A. L., Johansson, I., Juliusdottir, T., Kalafati, I.-P., Kinnunen, L., Koenig, W., Kooner, I. K., Kratzer, W., Lamina, C., Leander, K., Lee, N. R., Lichtner, P., Lind, L., Lindström, J., Lobbens, S., Lorentzon, M., Mach, F., Magnusson, P. K. E., Mahajan, A., McArdle, W. L., Menni, C., Merger, S., Mihailov, E., Milani, L., Mills, R., Moayyeri, A., Monda, K. L., Mooijaart, S. P., Mühleisen, T. W., Mulas, A., Müller, G., Müller-Nurasyid, M., Nagaraja, R., Nalls, M. A., Narisu, N., Glorioso, N., Nolte, I. M., Olden, M., Rayner, N. W., Renstrom, F., Ried, J. S., Robertson, N. R., Rose, L. M., Sanna, S., Scharnagl, H., Scholtens, S., Sennblad, B., Seufferlein, T., Sitlani, C. M., Vernon Smith, A., Stirrups, K., Stringham, H. M., Sundström, J., Swertz, M. A., Swift, A. J., Syvänen, A.-C., Tayo, B. O., Thorand, B., Thorleifsson, G., Tomaschitz, A., Troffa, C., van Oort, F. V. A., Verweij, N., Vonk, J. M., Waite, L. L., Wennauer, R., Wilsgaard, T., Wojczynski, M. K., Wong, A., Zhang, Q., Hua Zhao, J., Brennan, E. P., Choi, M., Eriksson, P., Folkersen, L., Franco-Cereceda, A., Gharavi, A. G., Hedman, Å. K., Hivert, M.-F., Huang, J., Kanoni, S., Karpe, F., Keildson, S., Kiryluk, K., Liang, L., Lifton, R. P., Ma, B., McKnight, A. J., McPherson, R., Metspalu, A., Min, J. L., Moffatt, M. F., Montgomery, G. W., Murabito, J. M., Nicholson, G., Nyholt, D. R., Olsson, C., Perry, J. R. B., Reinmaa, E., Salem, R. M., Sandholm, N., Schadt, E. E., Scott, R. A., Stolk, L., Vallejo, E. E., Westra, H.-J., Zondervan, K. T., Amouyel, P., Arveiler, D., Bakker, S. J. L., Beilby, J., Bergman, R. N., Blangero, J., Brown, M. J., Burnier, M., Campbell, H., Chakravarti, A., Chines, P. S., Claudi-Boehm, S., Collins, F. S., Crawford, D. C., Danesh, J., de Faire, U., de Geus, E. J. C., Dörr, M., Erbel, R., Eriksson, J. G., Farrall, M., Ferrannini, E., Ferrières, J., Forouhi, N. G., Forrester, T., Franco, O. H., Gansevoort, R. T., Gieger, C., Gudnason, V., Haiman, C. A., Harris, T. B., Hattersley, A. T., Heliövaara, M., Hicks, A. A., Hingorani, A. D., Hoffmann, W., Hofman, A., Homuth, G., Humphries, S. E., Hyppönen, E., Illig, T., Jarvelin, M.-R., Johansen, B., Jousilahti, P., Jula, A. M., Kaprio, J., Kee, F., Keinanen-Kiukaanniemi, S. M., Kooner, J. S., Kooperberg, C., Kovacs, P., Kraja, A. T., Kumari, M., Kuulasmaa, K., Kuusisto, J., Lakka, T. A., Langenberg, C., Le Marchand, L., Lehtimäki, T., Lyssenko, V., Männistö, S., Marette, A., Matise, T. C., McKenzie, C. A., McKnight, B., Musk, A. W., Möhlenkamp, S., Morris, A. D., Nelis, M., Ohlsson, C., Oldehinkel, A. J., Ong, K. K., Palmer, L. J., Penninx, B. W., Peters, A., Pramstaller, P. P., Raitakari, O. T., Rankinen, T., Rao, D. C., Rice, T. K., Ridker, P. M., Ritchie, M. D., Rudan, I., Salomaa, V., Samani, N. J., Saramies, J., Sarzynski, M. A., Schwarz, P. E. H., Shuldiner, A. R., Staessen, J. A., Steinthorsdottir, V., Stolk, R. P., Strauch, K., Tönjes, A., Tremblay, A., Tremoli, E., Vohl, M.-C., Völker, U., Vollenweider, P., Wilson, J. F., Witteman, J. C., Adair, L. S., Bochud, M., Boehm, B. O., Bornstein, S. R., Bouchard, C., Cauchi, S., Caulfield, M. J., Chambers, J. C., Chasman, D. I., Cooper, R. S., Dedoussis, G., Ferrucci, L., Froguel, P., Grabe, H.-J., Hamsten, A., Hui, J., Hveem, K., Jöckel, K.-H., Kivimaki, M., Kuh, D., Laakso, M., Liu, Y., März, W., Munroe, P. B., Njølstad, I., Oostra, B. A., Palmer, C. N. A., Pedersen, N. L., Perola, M., Pérusse, L., Peters, U., Power, C., Quertermous, T., Rauramaa, R., Rivadeneira, F., Saaristo, T. E., Saleheen, D., Sinisalo, J., Eline Slagboom, P., Snieder, H., Spector, T. D., Thorsteinsdottir, U., Stumvoll, M., Tuomilehto, J., Uitterlinden, A. G., Uusitupa, M., van der Harst, P., Veronesi, G., Walker, M., Wareham, N. J., Watkins, H., Wichmann, H.-E., Abecasis, G. R., Assimes, T. L., Berndt, S. I., Boehnke, M., Borecki, I. B., Deloukas, P., Franke, L., Frayling, T. M., Groop, L. C., Hunter, D. J., Kaplan, R. C., O’Connell, J. R., Qi, L., Schlessinger, D., Strachan, D. P., Stefansson, K., van Duijn, C. M., Willer, C. J., Visscher, P. M., Yang, J., Hirschhorn, J. N., Carola Zillikens, M., McCarthy, M. I., Speliotes, E. K., North, K. E., Fox, C. S., Barroso, I., Franks, P. W., Ingelsson, E., Heid, I. M., Loos, R. J. F., Cupples, L. A., Morris, A. P., Lindgren, C. M., & Mohlke, K. L.
- Affiliations
- Lund University (SE)
- University of Regensburg (DE)
- Brigham and Women's Hospital (US)
- University Medical Center Groningen (NL)
- University of Michigan (US)
- Centre for Human Genetics (GB)
- Boston Children's Hospital (US)
- University of North Carolina at Chapel Hill (US)
- Harvard University (US)
- Broad Institute (US)
- Boston University (US)
- Uppsala University (SE)
- University of Cambridge (GB)
- SIB Swiss Institute of Bioinformatics (CH)
- University of Exeter (GB)
- Rutgers, The State University of New Jersey (US)
- The Kids Research Institute Australia (AU)
- Johns Hopkins University (US)
- Washington University in St. Louis (US)
- King's College London (GB)
- Heidelberg University (DE)
- University of Eastern Finland (FI)
- Erasmus MC (NL)
- National Institute on Aging (US)
- Universitätsmedizin Greifswald (DE)
- Centre National de la Recherche Scientifique (FR)
- Azienda Sanitaria di Firenze (IT)
- Helmholtz Munich (DE)
- Dalarna University (SE)
- University of Oxford (GB)
- Texas Biomedical Research Institute (US)
- Inserm (FR)
- Leiden University Medical Center (NL)
- University of Southern California (US)
- University of Helsinki (FI)
- National Institutes of Health (US)
- Kaiser Permanente (US)
- University Hospital of Geneva (CH)
- University Hospital Carl Gustav Carus (DE)
- Western General Hospital (GB)
- University of Utah (US)
- Norwegian University of Science and Technology (NO)
- The University of Western Australia (AU)
- University Hospital Ulm (DE)
- Harokopio University of Athens (GR)
- Innsbruck Medical University (AT)
- Ealing Hospital NHS Trust (GB)
- Karolinska Institutet (SE)
- University of Bristol (GB)
- University of Bonn (DE)
- University of Sassari (IT)
- Medical University of Graz (AT)
- Institute of Genetic and Biomedical Research (IT)
- University of Washington (US)
- Science for Life Laboratory (SE)
- MRC Unit for Lifelong Health and Ageing (GB)
- University College Dublin (IE)
- Seoul National University (KR)
- Shanghai Jiao Tong University (CN)
- Queen Mary University of London (GB)
- Howard Hughes Medical Institute (US)
- Queen's University Belfast (GB)
- QIMR Berghofer Medical Research Institute (AU)
- National Heart, Lung, and Blood Institute (US)
- Helsinki University Hospital (FI)
- Université de Strasbourg (FR)
- Cedars-Sinai Medical Center (US)
- Centre Hospitalier Universitaire Vaudois (CH)
- Vanderbilt University (US)
- University of Pisa (IT)
- Essen University Hospital (DE)
- University of the West Indies (JM)
- University of Iceland (IS)
- Eurac Research (IT)
- University College London (GB)
- University of South Australia (AU)
- Finnish Institute for Health and Welfare (FI)
- Imperial College Healthcare NHS Trust (GB)
- Tampere University (FI)
- Steno Diabetes Centers (DK)
- Sir Charles Gairdner Hospital (AU)
- University of Dundee (GB)
- University of Toronto (CA)
- Vrije Universiteit Amsterdam (NL)
- Ontario Institute for Cancer Research (CA)
- Pennington Biomedical Research Center (US)
- Pennsylvania State University (US)
- University of Maryland, Baltimore (US)
- Maastricht University (NL)
- University of Milan (IT)
- Nanyang Technological University (SG)
- Université de Lille (FR)
- University of London (GB)
- Loyola University Chicago (US)
- Institut für Medizinische Informatik, Biometrie und Epidemiologie (DE)
- Wake Forest University Health Sciences (US)
- Finnish Diabetes Association (FI)
- deCODE Genetics (Iceland) (IS)
- University of Insubria (IT)
- Albert Einstein College of Medicine (US)
- The University of Queensland (AU)
- Corresponding author
- Lindgren, Cecilia M.
- Mohlke, Karen L
- ORCID
- Shungin, Dmitry
- Winkler, Thomas W.
- Ferreira, Teresa
- Locke, Adam E.
- Mägi, Reedik
- Strawbridge, Rona J.
- Pers, Tune H.
- Fischer, Krista
- Justice, Anne E.
- Workalemahu, Tsegaselassie
- Wu, Joseph M. W.
- Buchkovich, Martin L.
- Roman, Tamara S.
- Song, Ci
- Gustafsson, Stefan
- Day, Felix R.
- Fall, Tove
- Kutalik, Zoltán
- Luan, Jian’an
- Scherag, André
- Vedantam, Sailaja
- Wood, Andrew R.
- Fehrmann, Rudolf
- Karjalainen, Juha
- Kahali, Bratati
- Schmidt, Ellen M.
- Amin, Najaf
- Anderson, Denise
- Beekman, Marian
- Buyske, Steven
- Ehret, Georg B.
- Feitosa, Mary F.
- Goel, Anuj
- Jackson, Anne U.
- Johnson, Toby
- Kleber, Marcus E.
- Kristiansson, Kati
- Mangino, Massimo
- Palmer, Cameron D.
- Pechlivanis, Sonali
- Peters, Marjolein J.
- Prokopenko, Inga
- Tanaka, Toshiko
- Teumer, Alexander
- Yengo, Loïc
- Zhang, Weihua
- Ärnlöv, Johan
- Arscott, Gillian M.
- Bandinelli, Stefania
- Bellis, Claire
- Bennett, Amanda J.
- Blüher, Matthias
- Böhringer, Stefan
- Bonnet, Fabrice
- Böttcher, Yvonne
- Carba, Delia B.
- Caspersen, Ida H.
- Deelen, Joris
- Deelman, Ewa
- Doney, Alex S. F.
- Erdos, Michael R.
- Estrada, Karol
- Giedraitis, Vilmantas
- Gigante, Bruna
- Go, Alan S.
- Golay, Alain
- Grallert, Harald
- Grewal, Jagvir
- Groves, Christopher J.
- Haller, Toomas
- Hartman, Catharina A.
- Hayward, Caroline
- Herzig, Karl-Heinz
- Hillege, Hans L.
- Hunt, Steven C.
- Isaacs, Aaron
- Ittermann, Till
- Johansson, Ingegerd
- Kalafati, Ioanna-Panagiota
- Kinnunen, Leena
- Kratzer, Wolfgang
- Lamina, Claudia
- Leander, Karin
- Lichtner, Peter
- Lind, Lars
- Lindström, Jaana
- Lorentzon, Mattias
- Mach, François
- Magnusson, Patrik K. E.
- Mahajan, Anubha
- Menni, Cristina
- Merger, Sigrun
- Milani, Lili
- Mills, Rebecca
- Moayyeri, Alireza
- Mooijaart, Simon P.
- Mulas, Antonella
- Müller, Gabriele
- Nagaraja, Ramaiah
- Narisu, Narisu
- Nolte, Ilja M.
- Olden, Matthias
- Rayner, Nigel W.
- Rose, Lynda M.
- Sanna, Serena
- Scharnagl, Hubert
- Scholtens, Salome
- Sennblad, Bengt
- Seufferlein, Thomas
- Sitlani, Colleen M.
- Stirrups, Kathleen
- Stringham, Heather M.
- Sundström, Johan
- Swertz, Morris A.
- Tayo, Bamidele O.
- Thorand, Barbara
- Tomaschitz, Andreas
- Verweij, Niek
- Vonk, Judith M.
- Wilsgaard, Tom
- Wojczynski, Mary K.
- Wong, Andrew
- Brennan, Eoin P.
- Choi, Murim
- Eriksson, Per
- Folkersen, Lasse
- Gharavi, Ali G.
- Hedman, Åsa K.
- Hivert, Marie-France
- Huang, Jinyan
- Kanoni, Stavroula
- Karpe, Fredrik
- Kiryluk, Krzysztof
- Liang, Liming
- Lifton, Richard P.
- Ma, Baoshan
- McKnight, Amy J.
- McPherson, Ruth
- Metspalu, Andres
- Min, Josine L.
- Moffatt, Miriam F.
- Montgomery, Grant W.
- Murabito, Joanne M.
- Nyholt, Dale R.
- Olsson, Christian
- Perry, John R. B.
- Salem, Rany M.
- Sandholm, Niina
- Vallejo, Edgar E.
- Westra, Harm-Jan
- Zondervan, Krina T.
- Amouyel, Philippe
- Bakker, Stephan J. L.
- Beilby, John
- Bergman, Richard N.
- Blangero, John
- Brown, Morris J.
- Burnier, Michel
- Chakravarti, Aravinda
- Collins, Francis S.
- Crawford, Dana C.
- Danesh, John
- Dörr, Marcus
- Eriksson, Johan G.
- Farrall, Martin
- Ferrannini, Ele
- Ferrières, Jean
- Forouhi, Nita G.
- Franco, Oscar H.
- Gansevoort, Ron T.
- Gieger, Christian
- Gudnason, Vilmundur
- Haiman, Christopher A.
- Harris, Tamara B.
- Hattersley, Andrew T.
- Hicks, Andrew A.
- Hingorani, Aroon D.
- Hoffmann, Wolfgang
- Homuth, Georg
- Humphries, Steve E.
- Hyppönen, Elina
- Johansen, Berit
- Kaprio, Jaakko
- Kee, Frank
- Keinanen-Kiukaanniemi, Sirkka M.
- Kooner, Jaspal S.
- Kooperberg, Charles
- Kovacs, Peter
- Kuulasmaa, Kari
- Lakka, Timo A.
- Langenberg, Claudia
- Lehtimäki, Terho
- Lyssenko, Valeriya
- Männistö, Satu
- Marette, André
- Matise, Tara C.
- Musk, Arthur W.
- Morris, Andrew D.
- Nelis, Mari
- Ohlsson, Claes
- Oldehinkel, Albertine J.
- Ong, Ken K.
- Palmer, Lyle J.
- Penninx, Brenda W.
- Peters, Annette
- Pramstaller, Peter P.
- Raitakari, Olli T.
- Rao, D. C.
- Rice, Treva K.
- Ridker, Paul M.
- Ritchie, Marylyn D.
- Rudan, Igor
- Salomaa, Veikko
- Samani, Nilesh J.
- Sarzynski, Mark A.
- Schwarz, Peter E. H.
- Shuldiner, Alan R.
- Staessen, Jan A.
- Stolk, Ronald P.
- Strauch, Konstantin
- Tönjes, Anke
- Tremblay, Angelo
- Tremoli, Elena
- Vohl, Marie-Claude
- Völker, Uwe
- Wilson, James F.
- Adair, Linda S.
- Bochud, Murielle
- Boehm, Bernhard O.
- Bornstein, Stefan R.
- Bouchard, Claude
- Cauchi, Stéphane
- Caulfield, Mark J.
- Chambers, John C.
- Chasman, Daniel I.
- Cooper, Richard S.
- Dedoussis, George
- Ferrucci, Luigi
- Froguel, Philippe
- Grabe, Hans-Jörgen
- Hamsten, Anders
- Hui, Jennie
- Hveem, Kristian
- Jöckel, Karl-Heinz
- Kuh, Diana
- Laakso, Markku
- März, Winfried
- Munroe, Patricia B.
- Njølstad, Inger
- Pedersen, Nancy L.
- Perola, Markus
- Peters, Ulrike
- Power, Chris
- Quertermous, Thomas
- Rivadeneira, Fernando
- Saleheen, Danish
- Sinisalo, Juha
- Snieder, Harold
- Spector, Tim D.
- Tuomilehto, Jaakko
- Uitterlinden, André G.
- Uusitupa, Matti
- Veronesi, Giovanni
- Walker, Mark
- Wareham, Nicholas J.
- Watkins, Hugh
- Wichmann, H-Erich
- Assimes, Themistocles L.
- Berndt, Sonja I.
- Boehnke, Michael
- Borecki, Ingrid B.
- Deloukas, Panos
- Franke, Lude
- Frayling, Timothy M.
- Kaplan, Robert C.
- O’Connell, Jeffrey R.
- Qi, Lu
- Strachan, David P.
- Willer, Cristen J.
- Visscher, Peter M.
- Yang, Jian
- Hirschhorn, Joel N.
- McCarthy, Mark I.
- Speliotes, Elizabeth K.
- North, Kari E.
- Fox, Caroline S.
- Barroso, Inês
- Franks, Paul W.
- Ingelsson, Erik
- Heid, Iris M.
- Loos, Ruth J. F.
- Cupples, L. Adrienne
- Morris, Andrew P.
- Lindgren, Cecilia M.
- Mohlke, Karen L
- Venue
- Nature
- Published
- 2015-02-11
- Volume
- 518
- Issue
- 7538
- Pages
- 187-196
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4338562
- OpenAlex
- W2047783882
- Cited by
- 1,580
- References
- 101
- Citations by year
- 2026: 56 · 2025: 120 · 2024: 129 · 2023: 177 · 2022: 158 · 2021: 167 · 2020: 122 · 2019: 142 · 2018: 161 · 2017: 156 · 2016: 118 · 2015: 71
- FWCI
- 21.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Research Explorer (The University of Manchester) (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
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- VU Research Portal (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- IRIS (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Civil War Book Review (submittedVersion)
- ScholarWorks @ UTRGV (The University of Texas Rio Grande Valley) (submittedVersion)
- UNSWorks (UNSW Sydney) (submittedVersion, cc-by-nc-nd)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- HAL (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion)
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- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Digital Access to Libraries (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- DR-NTU (Nanyang Technological University) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- IrInSubria (University of Insubria) (submittedVersion)
- UnissResearch (Università degli Studi di Sassari) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
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- Open Research Exeter (University of Exeter) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
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- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- McKnight Foundation
- Pennsylvania State University (16802)
- Wellcome Trust (098017, 098381, 098498, 085235, 097117, WT098017, 100574, 084766, WT098381, WT100574, WT097117, WT084766, WT098498, WT085235)
- Cancer Research UK (CRUK_14136, 14136)
- National Institute for Health and Care Research (NF-SI-0512-10165, NF-SI-0513-10109, NF-SI-0611-10170, NF-SI-0512-10113, NF-SI-0508-10082, NF-SI-0507-10380, NF-SI-0611-10099, NF-SI-0512-10114, NF-SI-0611-10219, NF-SI-0513-10085, NF-SI-0514-10027, NF-SI-0512-10135)
- British Heart Foundation (BHF_FS/14/55/30806, FS/14/55/30806, BHF_RG/13/2/30098, RG/08/008/25291, BHF_RG/10/12/28456, BHF_RG/08/008/25291, RG/10/12/28456, BHF_RG/08/014/24067, RG/13/2/30098, RG/07/008/23674, RG/08/014/24067)
- Diabetes UK (DUK_12/0004470, 12/0004470)
- University of Leicester
- University of Warwick
- European Commission (259679)
- Vrije Universiteit Amsterdam
- Bundesministerium für Bildung und Forschung (01EO1001)
- Lundbeckfonden (R190 2014-3904)
- Turun Yliopisto
- Novo Nordisk Fonden (NNF14OC0010513, NNF12OC1016467, NNF13OC0005785, NNF15OC0016416, NNF14OC0011039, NNF13OC0005781, NNF12OC1016167, NNF11OC1014855)
- Turun Yliopistollinen Keskussairaala
- National Institutes of Health (1r01hl120393-01a1)
- Medical Research Council (MC_U106179472, MR/K013351/1, MR/K006584/1, MC_UU_12015/5, MR/N01104X/1, MC_PC_U127561128, MR/L003120/1, MR/K011480/1, MC_UP_A100_1003, MC_UU_12015/2, G0601261, MC_UP_A620_1014, G0601463, MC_UU_12011/1, MC_UU_12015/1, G1000143, G1001799)
- Economic and Social Research Council (ES/J023299/1, ES/F02679X/1)
- National Institute on Aging (U01AG049505, R01AG025941, R01AG033193, R01AG041517)
- National Heart, Lung, and Blood Institute (R00HL094535, R01-HL120393, R01HL105756, K01HL116770, R01HL117078, R01HL117626, T32HL069768, T32HL007055, R01HL109946)
- National Institute on Drug Abuse (R21DA027040)
- National Human Genome Research Institute (Z01HG000024, U01HG007416, U01HG007417, U01HG007419, U01HG007376)
- National Cancer Institute (UM1CA182913, UM1CA182910, P30CA071789)
- National Institute of General Medical Sciences (T32GM007092, T32GM067553, P30GM103341)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK078150, R01DK072193, R01DK089256, U01DK062370, R01DK107437, K23DK080145, P30DK079637, P30DK072488, P60DK020541, R01DK075787, P30DK020572, P30DK056341, R01DK093757, P30DK020541, P30DK040561, R01DK062370)
- NIH Clinical Center
- National Institute on Minority Health and Health Disparities (P20MD006899)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083211)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
- Keywords
- body fat distribution, waist-to-hip ratio, waist circumference, hip circumference, genetic loci, adipose tissue, adipogenesis, angiogenesis, insulin resistance, transcriptional regulation, sexual dimorphism, abdominal fat, cardiometabolic traits, regulatory elements
- MeSH terms
- Adipose Tissue, Age Factors, Europe, Female, Humans, Insulin, Insulin Resistance, Male, Models, Biological, Obesity, Sex Characteristics, Transcription, Genetic, Genome, Human, Body Mass Index, Adipocytes, Neovascularization, Physiologic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Epigenesis, Genetic, Racial Groups, Waist-Hip Ratio, Adipogenesis, Body Fat Distribution, Genome-Wide Association Study
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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