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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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InfluentialGenome-wide association study identifies genetic risk loci for adiposity in a Taiwanese population
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“A genome-wide association study (GWAS) meta-analyses of traits related to waist and hip circumferences in 224,459 people identified a list of genes suspected to be involved in body fat distribution; these include familiar genes such as SMAD6, BMP2, BCL2, PPARG, and VEGFA, which are known to be involved in carcinogenes…”
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“Further sensitivity analysis was conducted after excluding 9 SNPs that were nominally ( P 0.001) associated with BMI 32 (44-SNPs).”
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Self-citationGenetic Variation at the Sulfonylurea Receptor, Type 2 Diabetes, and Coronary Heart Disease
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The heritability of body composition
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“These inconsistencies might be due to the relative small sample size of subjects available here (n = approximately 750 compared to the reported n = 210,000 [6]), the enrichment for obese subjects in the here analysed study population, or the relative numbers of men and women (n = 202 and n = 587 respectively).”
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“Age and BMI wer e c hosen especiall y due to their known shared associations with multiple traits as previously documented by Shungin and collea gues [ 48 ], whic h could lead to confounding biases in the downstr eam inter pr etation of phenotypic r elationships.”
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Self-citationA cellular model for the investigation of depot specific human adipocyte biology
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“A high WHR is generally more closely associated with obesity-related metabolic disease risk than measures of overall obesity, i.e. body mass index (BMI).3-5 By comparison, fat accumulation in the lower-body (gluteal, femoral) is paradoxically associated with reduced cardiometabolic risk after adjustment for BMI and co…”
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“WHRadjBMI was calculated as the residual of WHR adjusted for age, age2, and BMI, for men and women separately, and then transformed by the inverse standard normal function [21].”
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Genetic Determinants of Clustering of Cardiometabolic Risk Factors in U.K. Biobank
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Genetic liability to multiple factors and uterine leiomyoma risk: a Mendelian randomization study
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“For waist circumference, hip circumference, and waist-to-hip ratio, the GWAS included 210,088 Europeans and adjusted for age, age square, and study-specific covariates if necessary (22).”
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Self-citationRelationship of Fat Mass Ratio, a Biomarker for Lipodystrophy, With Cardiometabolic Traits
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“trait (Lu & Loos, 2013) and new loci are still being identified (Locke et al. 2015; Shungin et al., 2015).”
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“These genetic variants discovered though GWAS explain <5% of genetic variation in obesity (29, 30), <15% in lipid traits (36, 37), and <11% in T2DM related traits (34).”
BackgroundA genome-wide association study of severe asthma exacerbations in Latino children and adolescents
Yan, Q., Forno, E., Luis, E. H., Pino-Yanes, M. D. M., Qi, C., Rios, R., Han, Y., Kim, S., Oh, S. S., Acosta‐Pérez, E., et al. (2020) · European Respiratory Journal · doi:10.1183/13993003.02693-2020 · Cited by 25
“body mass index (BMI) and waist-to-hip ratio [39, 40], which have been associated with worse asthma outcomes in children and adults.”
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“The summary-level data for WHRadjBMI, WCadjBMI, and HCadjBMI were obtained from a previous large-scale GWAS including individuals of European descent.((19)) A total of 49, 28, and 7 SNPs associatedwithWHRadjBMI,WCadjBMI, and HCadjBMI were used in the present study, respectively.”
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“Meanwhile, hippocampal atrophy is the pathogenesis of drug-resistant epilepsy (28).”
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“This locus has been associated with WHR, with a stronger effect in women than in men [32, 37, 38].”
BackgroundDiscovering metabolic disease gene interactions by correlated effects on cellular morphology
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“Three genes (DNLZ, VAR2, and TSPAN15) were identified in T2D associated loci [26e28] and two (COL4A3BP and USP37) from BMI associated loci [12,13] (Figure 2A).”
BackgroundDaghlas, I., Richmond, R. C., Lane, J. M., Dashti, H. S., Ollila, H. M., Schernhammer, E. S., Smith, G. D., Rutter, M. K., Saxena, R., & Vetter, C. (2021) · International Journal of Epidemiology · doi:10.1093/ije/dyab031 · Cited by 22
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Adiposity and the risk of dementia: mediating effects from inflammation and lipid levels
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Self-citationPolygenic scores of diabetes-related traits in subgroups of type 2 diabetes in India: a cohort study
Yajnik, C. S., Wagh, R. S. H., Kunte, P. S., Asplund, O., Ahlqvist, E., Bhat, D., Shukla, S., & Prasad, R. B. (2023) · The Lancet Regional Health - Southeast Asia · doi:10.1016/j.lansea.2023.100182 · Cited by 24
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“Betas and standard errors obtained from a GWAS of the GIANT consortium [8] and downloaded from http://portals.”
MethodSelf-citationVillalobos‐Comparán, M., Antuna-Puente, B. P., Villarreal-Molina, M. T., Canizales‐Quinteros, S., Velázquez‐Cruz, R., León‐Mimila, P., Villamil‐Ramírez, H., González-Barrios, J. A., Merino-García, J. L., Thompson-Bonilla, M. R., et al. (2017) · BMC Medical Genetics · doi:10.1186/s12881-017-0410-y · Cited by 23
“However, previous evidence supports the role of ABCA1 in body fat distribution both in the Mexican population [8], and in a recent multi-ethnic metaanalysis that identified ABCA1 rs10991437 as a variant associated with higher waist-hip ratio adjusted for BMI [15].”
ResultXiao, L., Yuan, Z., Jin, S., Wang, T., Huang, S., & Zeng, P. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.587243 · Cited by 23
“, 2019) and waist circumference adjusted for body mass index (Shungin et al., 2015; Graff et al., 2017; Justice et al., 2017), which are in turn believed to be relevant to the development of ALS (Desport et al.”
BackgroundSun, J., Zhang, H., Zhang, Y., Wang, L., Sun, B., Gao, F., & Liu, G. (2021) · Clinical Nutrition · doi:10.1016/j.clnu.2021.03.012 · Cited by 24
Detection and interpretation of shared genetic influences on 40 human traitsPreprint
Pickrell, J. K., Berisa, T., Ségurel, L., Tung, J. Y., & Hinds, D. A. (2015) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/019885 · Cited by 24
“, 2015] 30 240 Waist-hip ratio WHR [Shungin et al., 2015] 13 143 Low-density lipoproteins LDL [Teslovich et al.”
Garitazelaia, A., Rueda-Martínez, A., Arauzo, R., de Miguel, J., Cilleros-Portet, A., Marí, S., Bilbao, J. R., Fernandez-Jimenez, N., & García-Santisteban, I. (2021) · Life · doi:10.3390/life11010024 · Cited by 22
“Multiple sclerosis (MS) GCST005531 38,589 161,311 24076602 [24] No (14,498/24,091) Anthropometric traits Weight ieu-a-107 73,137 2,747,007 23754948 [25] Yes Height ieu-a-97 73,137 2,748,546 23754948 [25] Yes Body Mass Index (BMI) ieu-a-974 171,977 2,494,613 25673413 [26] Yes Waist-To-Hip ratio (WTH) ieu-a-75 118,003 2…”
Szendrei, B., González‐Lamuño, D., Amigo, T., Wang, G., Pitsiladis, Y. P., Benito, P. J., Gómez‐Candela, C., Calderón, F. J., Cupeiro, R., & PRONAF Study Group (2015) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/apnm-2015-0425 · Cited by 22
Proteomic Profiles of Body Mass Index and Waist-to-Hip Ratio and Their Role in Incidence of Diabetes
Bao, X., Xu, B., Yin, S., Pan, J., Nilsson, P. M., Nilsson, J. Å., Melander, O., Orho‐Melander, M., & Engström, G. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac140 · Cited by 21
The relationship between central obesity and bone mineral density: a Mendelian randomization study
Du, D., Jing, Z., Zhang, G., Dang, X., Liu, R., & Song, J. (2022) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-022-00840-x · Cited by 22
“For the central obesity dataset, the anthropometric summary statistic datasets for WC, WCadjBMI, HC, HCadjBMI, WHR, and WHRadjBMI from individuals included in the genetic investigation of anthropometric traits (GIANT) consortium (224,459 samples, European ancestry) were used [13].”
MethodWang, C., Zhu, Y., Liu, Z., Long, H., Ruan, Z., & Zhao, S. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1011896 · Cited by 24
“Summary-level GWAS data for waist to hip ratio (n = 224452), waist circumference (n = 134593), and hip circumference (n = 127997) were acquired from a metaanalysis of 224459 individuals of European ancestry from the GIANT consortium (20).”
BackgroundLiu, J., Xu, H., Cupples, L. A., O’Connor, G. T., & Liu, C. (2023) · Annals of Human Genetics · doi:10.1111/ahg.12506 · Cited by 24
Self-citationBauzá-Thorbrügge, M., Vujičić, M., Chanclón, B., Pálsdóttir, V., Pillon, N. J., Benrick, A., & Asterholm, I. W. (2023) · Metabolism · doi:10.1016/j.metabol.2023.155716 · Cited by 22
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“It is located in the 3’-UTR region of the tryptophanyl TRNA synthetase 2 mitochondrial gene (WARS2) and has been previously reported to be associated with WHR (11).”
InfluentialSelf-citationDisparity in Adiposity among Adults with Normal Body Mass Index and Waist-to-Height Ratio
Dybala, M. P., Brady, M., & Hara, M. (2019) · iScience · doi:10.1016/j.isci.2019.10.062 · Cited by 22
FAM13A Represses AMPK Activity and Regulates Hepatic Glucose and Lipid Metabolism
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“In human studies, a locus near PEMT was associated with abdominal obesity and insulin resistance [31].”
BackgroundFat biology and metabolic balance: On the significance of sex
Pan, R., & Chen, Y. (2021) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2021.111336 · Cited by 23
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“Guidance for this study design came from the suspected roles of adipocyte differentiation in obesity put forward by many previous investigations, including pathway analyses of obesity GWAS (83).”
BackgroundSelf-citationAhmad, S., Hammar, U., Kennedy, B., Salihović, S., Ganna, A., Lind, L., Sundström, J., Ärnlöv, J., Berne, C., Risérus, U., et al. (2021) · Diabetes · doi:10.2337/db20-1120 · Cited by 21
Self-citationGenetically predicted frailty index and risk of stroke and Alzheimer's disease
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“Genetic variants for BMI and WHR were obtained from the GIANT consortium [27,28].”
MethodSelf-citationHuang, N., Zhuang, Z., Liu, Z., & Huang, T. (2022) · Nutrients · doi:10.3390/nu14112273 · Cited by 23
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“Although genome-wide association studies (GWAS) have identified many diabetes risk variants [6, 7, 11–13], the underlying mechanisms remain elusive.”
BackgroundMinchin, J. E. N., Scahill, C. M., Staudt, N. D., Busch‐Nentwich, E. M., & Rawls, J. F. (2018) · Journal of Lipid Research · doi:10.1194/jlr.d084525 · Cited by 21
Grarup, N., Moltke, I., Andersen, M. K., Bjerregaard, P., Larsen, C. V. L., Dahl‐Petersen, I. K., Jørsboe, E., Tiwari, H. K., Hopkins, S. E., Wiener, H. W., et al. (2018) · Diabetologia · doi:10.1007/s00125-018-4659-2 · Cited by 20
Increased Diet Quality is Associated with Long‐Term Reduction of Abdominal and Pericardial Fat
Hennein, R., Liu, C., McKeown, N. M., Hoffmann, U., Long, M. T., Levy, D. A., & Ma, J. (2019) · Obesity · doi:10.1002/oby.22427 · Cited by 21
“In two large meta-analyses of genome-wide association studies (GWAS), 97 and 49 genetic loci were associated with BMI and waist to hip ratio (WHR), respectively, suggesting that genetic factors play an important role in determining the interindividual variation in adiposity (9,10).”
Self-citationGenome-wide association study reveals sex-specific genetic architecture of facial attractiveness
Hu, B., Shen, N., Li, J. J., Kang, H., Hong, J., Fletcher, J. M., Greenberg, J. S., Seltzer, M. M., & Lu, Q. (2019) · PLoS Genetics · doi:10.1371/journal.pgen.1007973 · Cited by 21
“8e-4 for MC-AS) and is known to associate with waist-hip ratio across populations [45, 51].”
The Association Between Adiposity and Inpatient Hospital Costs in the UK Biobank Cohort
Dixon, P., Smith, G. D., & Hollingworth, W. (2018) · Applied Health Economics and Health Policy · doi:10.1007/s40258-018-0450-2 · Cited by 21
Benonisdottir, S., Straub, V. J., Kong, A., & Mills, M. C. (2024) · Nature Aging · doi:10.1038/s43587-024-00733-w · Cited by 23
“In fact, 21 of the genes that have a role in obesity were also associated with human infertility and reproduction 75 , and the GWAS locus near LEKR1 and CCNL1 is common to waist-to-hip ratio 76 and birth weight 77 .”
Tang, J., Zhou, H., Sahay, K., Xu, W., Yang, J., Zhang, W., & Chen, W. (2018) · International Journal of Obesity · doi:10.1038/s41366-018-0222-y · Cited by 20
Self-citationHeianza, Y., Zhou, T., Yuhang, C., Huang, T., Willett, W. C., Hu, F. B., Bray, G. A., Sacks, F. M., & Qi, L. (2020) · Diabetes · doi:10.2337/db19-1257 · Cited by 20
Self-citationProtein Glycosylation in Diabetes
Štambuk, T., & Gornik, O. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-70115-4_14 · Cited by 20
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Self-citationManagement of BMI Is a Potential New Approach for the Prevention of Idiopathic Pulmonary Fibrosis
Ma, Y., Feng, C., Tang, H., Deng, P., Li, Y., Wang, J., Zhu, S., & Zhu, L. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.821029 · Cited by 20
“, 2015), and 35 SNPs for WHR (adjusted for BMI) (Shungin et al., 2015) as IVs to perform MR analyses.”
BackgroundMethodKulyté, A., Aman, A., Strawbridge, R. J., Arner, P., & Dahlman, I. A. (2022) · Diabetes · doi:10.2337/db21-0804 · Cited by 21
Self-citationKong, L., Ye, C., Wang, Y., Zheng, J., Zhao, Z., Li, M., Xu, Y., Lu, J., Chen, Y., Xu, M., et al. (2023) · Liver International · doi:10.1111/liv.15532 · Cited by 22
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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- Pure Amsterdam UMC (submittedVersion, other-oa)
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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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