Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Lagou, V. et al. (2021) Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability. Nature Communications, 12, 24. (doi: 10.1038/s41467-020-19366-9) (PMID:33402679) (PMCID:PMC7785747)

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Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.

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Glasgow Author(s) Enlighten ID:Johnson, Dr Paul and Ford, Professor Ian and Sattar, Professor Naveed and Strawbridge, Dr Rona
Authors: Lagou, V., Mägi, R., Hottenga, J.- J., Grallert, H., Perry, J. R. B., Bouatia-Naji, N., Marullo, L., Rybin, D., Jansen, R., Min, J. L., Dimas, A. S., Ulrich, A., Zudina, L., Gådin, J. R., Jiang, L., Faggian, A., Bonnefond, A., Fadista, J., Stathopoulou, M. G., Isaacs, A., Willems, S. M., Navarro, P., Tanaka, T., Jackson, A. U., Montasser, M. E., O’Connell, J. R., Bielak, L. F., Webster, R. J., Saxena, R., Stafford, J. M., Pourcain, B. S., Timpson, N. J., Salo, P., Shin, S.-Y., Amin, N., Smith, A. V., Li, G., Verweij, N., Goel, A., Ford, I., Johnson, P. C.D., Johnson, T., Kapur, K., Thorleifsson, G., Strawbridge, R. J., Rasmussen-Torvik, L. J., Esko, T., Mihailov, E., Fall, T., Fraser, R. M., Mahajan, A., Kanoni, S., Giedraitis, V., Kleber, M. E., Silbernagel, G., Meyer, J., Müller-Nurasyid, M., Ganna, A., Sarin, A.-P., Yengo, L., Shungin, D., Luan, J.’a., Horikoshi, M., An, P., Sanna, S., Boettcher, Y., Rayner, N. W., Nolte, I. M., Zemunik, T., Iperen, E. v., Kovacs, P., Hastie, N. D., Wild, S. H., McLachlan, S., Campbell, S., Polasek, O., Carlson, O., Egan, J., Kiess, W., Willemsen, G., Kuusisto, J., Laakso, M., Dimitriou, M., Hicks, A. A., Rauramaa, R., Bandinelli, S., Thorand, B., Liu, Y., Miljkovic, I., Lind, L., Doney, A., Perola, M., Hingorani, A., Kivimaki, M., Kumari, M., Bennett, A. J., Groves, C. J., Herder, C., Koistinen, H. A., Kinnunen, L., Faire, U. d., Bakker, S. J. L., Uusitupa, M., Palmer, C. N. A., Jukema, J. W., Sattar, N., Pouta, A., Snieder, H., Boerwinkle, E., Pankow, J. S., Magnusson, P. K., Krus, U., Scapoli, C., de Geus, E. J. C. N., Blüher, M., Wolffenbuttel, B. H. R., Province, M. A., Abecasis, G. R., Meigs, J. B., Hovingh, G. K., Lindström, J., Wilson, J. F., Wright, A. F., Dedoussis, G. V., Bornstein, S. R., Schwarz, P. E. H., Tönjes, A., Winkelmann, B. R., Boehm, B. O., März, W., Metspalu, A., Price, J. F., Deloukas, P., Körner, A., Lakka, T. A., Keinanen-Kiukaanniemi, S. M., Saaristo, T. E., Bergman, R. N., Tuomilehto, J., Wareham, N. J., Langenberg, C., Männistö, S., Franks, P. W., Hayward, C., Vitart, V., Kaprio, J., Visvikis-Siest, S., Balkau, B., Altshuler, D., Rudan, I., Stumvoll, M., Campbell, H., van Duijn, C. M., Gieger, C., Illig, T., Ferrucci, L., Pedersen, N. L., Pramstaller, P. P., Boehnke, M., Frayling, T. M., Shuldiner, A. R., Peyser, P. A., Kardia, S. L. R., Palmer, L. J., Penninx, B. W., Meneton, P., Harris, T. B., Navis, G., Harst, P. v. d., Smith, G. D., Forouhi, N. G., Loos, R. J. F., Salomaa, V., Soranzo, N., Boomsma, D. I., Groop, L., Tuomi, T., Hofman, A., Munroe, P. B., Gudnason, V., Siscovick, D. S., Watkins, H., Lecoeur, C., Vollenweider, P., Franco-Cereceda, A., Eriksson, P., Jarvelin, M.-R., Stefansson, K., Hamsten, A., Nicholson, G., Karpe, F., Dermitzakis, E. T., Lindgren, C. M., McCarthy, M. I., Froguel, P., Kaakinen, M. A., Lyssenko, V., Watanabe, R. M., Ingelsson, E., Florez, J. C., Dupuis, J., Barroso, I., Morris, A. P., and Prokopenko, I.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Mental Health and Wellbeing
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
Journal Name:Nature Communications
Publisher:Nature Research
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Nature Communications 12: 24
Publisher Policy:Reproduced under a Creative Commons License
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