Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution

Justice, A. E. et al. (2019) Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. Nature Genetics, 51(3), pp. 452-469. (doi: 10.1038/s41588-018-0334-2) (PMID:30778226)

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Abstract

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

Item Type:Articles
Additional Information:This work was primarily supported through funding from the National Institute of Health (NIH): 1K99HL130580, R01-DK089256, 2R01HD057194, U01HG007416, R01DK101855, T32 HL007055, KL2TR001109; and the American Heart Association (AHA): 13POST16500011 and 13GRNT16490017.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Young, Dr Robin
Authors: Justice, A. E., Karaderi, T., Highland, H. M., Young, K. L., Graff, M., Lu, Y., Turcot, V., Auer, P. L., Fine, R. S., Guo, X., Schurmann, C., Lempradl, A., Marouli, E., Mahajan, A., Winkler, T. W., Locke, A. E., Medina-Gomez, C., Esko, T., Vedantam, S., Giri, A., Lo, K. S., Alfred, T., Mudgal, P., Ng, M. C. Y., Heard-Costa, N. L., Feitosa, M. F., Manning, A. K., Willems, S. M., Sivapalaratnam, S., Abecasis, G., Alam, D. S., Allison, M., Amouyel, P., Arzumanyan, Z., Balkau, B., Bastarache, L., Bergmann, S., Bielak, L. F., Blüher, M., Boehnke, M., Boeing, H., Boerwinkle, E., Böger, C. A., Bork-Jensen, J., Bottinger, E. P., Bowden, D. W., Brandslund, I., Broer, L., Burt, A. A., Butterworth, A. S., Caulfield, M. J., Cesana, G., Chambers, J. C., Chasman, D. I., Chen, Y.-D. I., Chowdhury, R., Christensen, C., Chu, A. Y., Collins, F. S., Cook, J. P., Cox, A. J., Crosslin, D. S., Danesh, J., de Bakker, P. I. W., Denus, S. d., Mutsert, R. d., Dedoussis, G., Demerath, E. W., Dennis, J. G., Denny, J. C., Angelantonio, E. D., Dörr, M., Drenos, F., Dubé, M.-P., Dunning, A. M., Easton, D. F., Elliott, P., Evangelou, E., Farmaki, A.-E., Feng, S., Ferrannini, E., Ferrieres, J., Florez, J. C., Fornage, M., Fox, C. S., Franks, P. W., Friedrich, N., Gan, W., Gandin, I., Gasparini, P., Giedraitis, V., Girotto, G., Gorski, M., Grallert, H., Grarup, N., Grove, M. L., Gustafsson, S., Haessler, J., Hansen, T., Hattersley, A. T., Hayward, C., Heid, I. M., Holmen, O. L., Hovingh, G. K., Howson, J. M. M., Hu, Y., Hung, Y.-J., Hveem, K., Ikram, M. A., Ingelsson, E., Jackson, A. U., Jarvik, G. P., Jia, Y., Jørgensen, T., Jousilahti, P., Justesen, J. M., Kahali, B., Karaleftheri, M., Kardia, S. L. R., Karpe, F., Kee, F., Kitajima, H., Komulainen, P., Kooner, J. S., Kovacs, P., Krämer, B. K., Kuulasmaa, K., Kuusisto, J., Laakso, M., Lakka, T. A., Lamparter, D., Lange, L. A., Langenberg, C., Larson, E. B., Lee, N. R., Lee, W.-J., Lehtimäki, T., Lewis, C. E., Li, H., Li, J., Li-Gao, R., Lin, L.-A., Lin, X., Lind, L., Lindström, J., Linneberg, A., Liu, C.-T., Liu, D. J., Luan, J.'a., Lyytikäinen, L.-P., MacGregor, S., Mägi, R., Männistö, S., Marenne, G., Marten, J., Masca, N. G. D., McCarthy, M. I., Meidtner, K., Mihailov, E., Moilanen, L., Moitry, M., Mook-Kanamori, D. O., Morgan, A., Morris, A. P., Müller-Nurasyid, M., Munroe, P. B., Narisu, N., Nelson, C. P., Neville, M., Ntalla, I., O'Connell, J. R., Owen, K. R., Pedersen, O., Peloso, G. M., Pennell, C. E., Perola, M., Perry, J. A., Perry, J. R. B., Pers, T. H., Ewing, A., Polasek, O., Raitakari, O. T., Rasheed, A., Raulerson, C. K., Rauramaa, R., Reilly, D. F., Reiner, A. P., Ridker, P. M., Rivas, M. A., Robertson, N. R., Robino, A., Rudan, I., Ruth, K. S., Saleheen, D., Salomaa, V., Samani, N. J., Schreiner, P. J., Schulze, M. B., Scott, R. A., Segura-Lepe, M., Sim, X., Slater, A. J., Small, K. S., Smith, B. H., Smith, J. A., Southam, L., Spector, T. D., Speliotes, E. K., Stefansson, K., Steinthorsdottir, V., Stirrups, K. E., Strauch, K., Stringham, H. M., Stumvoll, M., Sun, L., Surendran, P., Swart, K. M. A., Tardif, J.-C., Taylor, K. D., Teumer, A., Thompson, D. J., Thorleifsson, G., Thorsteinsdottir, U., Thuesen, B. H., Tönjes, A., Torres, M., Tsafantakis, E., Tuomilehto, J., Uitterlinden, A. G., Uusitupa, M., van Duijn, C. M., Vanhala, M., Varma, R., Vermeulen, S. H., Vestergaard, H., Vitart, V., Vogt, T. F., Vuckovic, D., Wagenknecht, L. E., Walker, M., Wallentin, L., Wang, F., Wang, C. A., Wang, S., Wareham, N. J., Warren, H. R., Waterworth, D. M., Wessel, J., White, H. D., Willer, C. J., Wilson, J. G., Wood, A. R., Wu, Y., Yaghootkar, H., Yao, J., Yerges-Armstrong, L. M., Young, R., Zeggini, E., Zhan, X., Zhang, W., Zhao, J. H., Zhao, W., Zheng, H., Zhou, W., Zillikens, M. C., Rivadeneira, F., Borecki, I. B., Pospisilik, J. A., Deloukas, P., Frayling, T. M., Lettre, G., Mohlke, K. L., Rotter, J. I., Kutalik, Z., Hirschhorn, J. N., Cupples, L. A., Loos, R. J. F., North, K. E., and Lindgren, C. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
Journal Name:Nature Genetics
Publisher:Nature Research
ISSN:1061-4036
ISSN (Online):1546-1718
Published Online:18 February 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Nature Genetics 51(3): 452-469
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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