1. Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
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Justice, Anne E, Karaderi, Tugce, Highland, Heather M, Young, Kristin L, Graff, Mariaelisa, Lu, Yingchang, Turcot, Valérie, Auer, Paul L, Fine, Rebecca S, Guo, Xiuqing, Schurmann, Claudia, Lempradl, Adelheid, Marouli, Eirini, Mahajan, Anubha, Winkler, Thomas W, Locke, Adam E, Medina-Gomez, Carolina, Esko, Tõnu, Vedantam, Sailaja, Giri, Ayush, Lo, Ken Sin, Alfred, Tamuno, Mudgal, Poorva, Ng, Maggie CY, Heard-Costa, Nancy L, Feitosa, Mary F, Manning, Alisa K, Willems, Sara M, Sivapalaratnam, Suthesh, Abecasis, Goncalo, Alam, Dewan S, Allison, Matthew, Amouyel, Philippe, Arzumanyan, Zorayr, Balkau, Beverley, Bastarache, Lisa, Bergmann, Sven, Bielak, Lawrence F, Blüher, Matthias, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A, Bork-Jensen, Jette, Bottinger, Erwin P, Bowden, Donald W, Brandslund, Ivan, Broer, Linda, Burt, Amber A, Butterworth, Adam S, Caulfield, Mark J, Cesana, Giancarlo, Chambers, John C, Chasman, Daniel I, Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y, Collins, Francis S, Cook, James P, Cox, Amanda J, Crosslin, David S, Danesh, John, de Bakker, Paul IW, Denus, Simon de, Mutsert, Renée de, Dedoussis, George, Demerath, Ellen W, Dennis, Joe G, Denny, Josh C, Angelantonio, Emanuele Di, Dörr, Marcus, Drenos, Fotios, Dubé, Marie-Pierre, Dunning, Alison M, Easton, Douglas F, Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C, Fornage, Myriam, Fox, Caroline S, Franks, Paul W, Friedrich, Nele, Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmantas, Girotto, Giorgia, Gorski, Mathias, Grallert, Harald, Grarup, Niels, Grove, Megan L, Gustafsson, Stefan, Haessler, Jeff, Hansen, Torben, Hattersley, Andrew T, Hayward, Caroline, Heid, Iris M, Holmen, Oddgeir L, Hovingh, G Kees, Howson, Joanna MM, Hu, Yao, Hung, Yi-Jen, Hveem, Kristian, Ikram, M Arfan, Ingelsson, Erik, Jackson, Anne U, Jarvik, Gail P, Jia, Yucheng, Jørgensen, Torben, Jousilahti, Pekka, Justesen, Johanne M, Kahali, Bratati, Karaleftheri, Maria, Kardia, Sharon LR, Karpe, Fredrik, Kee, Frank, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S, Kovacs, Peter, Krämer, Bernhard K, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A, Lamparter, David, Lange, Leslie A, Langenberg, Claudia, Larson, Eric B, Lee, Nanette R, Lee, Wen-Jane, Lehtimäki, Terho, Lewis, Cora E, Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Li-An, Lin, Xu, Lind, Lars, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J, Luan, Jian'an, Lyytikäinen, Leo-Pekka, MacGregor, Stuart, Mägi, Reedik, Männistö, Satu, Marenne, Gaëlle, Marten, Jonathan, Masca, Nicholas GD, McCarthy, Mark I, Meidtner, Karina, Mihailov, Evelin, Moilanen, Leena, Moitry, Marie, Mook-Kanamori, Dennis O, Morgan, Anna, Morris, Andrew P, Müller-Nurasyid, Martina, Munroe, Patricia B, Narisu, Narisu, Nelson, Christopher P, Neville, Matt, Ntalla, Ioanna, O'Connell, Jeffrey R, Owen, Katharine R, Pedersen, Oluf, Peloso, Gina M, Pennell, Craig E, Perola, Markus, Perry, James A, Perry, John RB, Pers, Tune H, Ewing, Ailith, Polasek, Ozren, Raitakari, Olli T, Rasheed, Asif, Raulerson, Chelsea K, Rauramaa, Rainer, Reilly, Dermot F, Reiner, Alex P, Ridker, Paul M, Rivas, Manuel A, Robertson, Neil R, Robino, Antonietta, Rudan, Igor, Ruth, Katherine S, Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J, Schreiner, Pamela J, Schulze, Matthias B, Scott, Robert A, Segura-Lepe, Marcelo, Sim, Xueling, Slater, Andrew J, Small, Kerrin S, Smith, Blair H, Smith, Jennifer A, Southam, Lorraine, Spector, Timothy D, Speliotes, Elizabeth K, Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E, Strauch, Konstantin, Stringham, Heather M, Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swart, Karin MA, Tardif, Jean-Claude, Taylor, Kent D, Teumer, Alexander, Thompson, Deborah J, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H, Tönjes, Anke, Torres, Mina, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, van Duijn, Cornelia M, Vanhala, Mauno, Varma, Rohit, Vermeulen, Sita H, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F, Vuckovic, Dragana, Wagenknecht, Lynne E, Walker, Mark, Wallentin, Lars, Wang, Feijie, Wang, Carol A, Wang, Shuai, Wareham, Nicholas J, Warren, Helen R, Waterworth, Dawn M, Wessel, Jennifer, White, Harvey D, Willer, Cristen J, Wilson, James G, Wood, Andrew R, Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yerges-Armstrong, Laura M, Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zheng, He, Zhou, Wei, Zillikens, M Carola, CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CH, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Rivadeneira, Fernando, Borecki, Ingrid B, Pospisilik, J Andrew, Deloukas, Panos, Frayling, Timothy M, Lettre, Guillaume, Mohlke, Karen L, Rotter, Jerome I, Kutalik, Zoltán, Hirschhorn, Joel N, Cupples, L Adrienne, Loos, Ruth JF, North, Kari E, Lindgren, Cecilia M, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Radiology & Nuclear Medicine, CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Institute for Molecular Medicine Finland, Research Programs Unit, Diabetes and Obesity Research Program, University of Helsinki, Young, Kristin L [0000-0003-0070-6145], Mahajan, Anubha [0000-0001-5585-3420], Winkler, Thomas W [0000-0003-0292-5421], Locke, Adam E [0000-0001-6227-198X], Medina-Gomez, Carolina [0000-0001-7999-5538], Giri, Ayush [0000-0002-7786-4670], Ng, Maggie CY [0000-0002-4133-2007], Heard-Costa, Nancy L [0000-0001-9730-0306], Manning, Alisa K [0000-0003-0247-902X], Alam, Dewan S [0000-0002-2051-3837], Amouyel, Philippe [0000-0001-9088-234X], Bergmann, Sven [0000-0002-6785-9034], Boehnke, Michael [0000-0002-6442-7754], Butterworth, Adam S [0000-0002-6915-9015], Caulfield, Mark J [0000-0001-9295-3594], Collins, Francis S [0000-0002-1023-7410], de Bakker, Paul IW [0000-0001-7735-7858], Dennis, Joe G [0000-0003-4591-1214], Easton, Douglas F [0000-0003-2444-3247], Elliott, Paul [0000-0002-7511-5684], Evangelou, Evangelos [0000-0002-5488-2999], Giedraitis, Vilmantas [0000-0003-3423-2021], Girotto, Giorgia [0000-0003-4507-6589], Grarup, Niels [0000-0001-5526-1070], Gustafsson, Stefan [0000-0001-5894-0351], Hansen, Torben [0000-0001-8748-3831], Hayward, Caroline [0000-0002-9405-9550], Howson, Joanna MM [0000-0001-7618-0050], Ikram, M Arfan [0000-0003-0372-8585], Jackson, Anne U [0000-0002-9672-2547], Justesen, Johanne M [0000-0002-0484-8522], Kovacs, Peter [0000-0002-0290-5423], Kuulasmaa, Kari [0000-0003-2165-1411], Langenberg, Claudia [0000-0002-5017-7344], Lin, Li-An [0000-0003-2731-1346], Linneberg, Allan [0000-0002-0994-0184], Liu, Ching-Ti [0000-0002-0703-0742], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], MacGregor, Stuart [0000-0001-6731-8142], McCarthy, Mark I [0000-0002-4393-0510], Morgan, Anna [0000-0001-6290-445X], Müller-Nurasyid, Martina [0000-0003-3793-5910], Munroe, Patricia B [0000-0002-4176-2947], Narisu, Narisu [0000-0002-8483-1156], Neville, Matt [0000-0002-6004-5433], Reilly, Dermot F [0000-0002-9456-1364], Rudan, Igor [0000-0001-6993-6884], Saleheen, Danish [0000-0001-6193-020X], Salomaa, Veikko [0000-0001-7563-5324], Sim, Xueling [0000-0002-1233-7642], Small, Kerrin S [0000-0003-4566-0005], Smith, Blair H [0000-0002-5362-9430], Smith, Jennifer A [0000-0002-3575-5468], Southam, Lorraine [0000-0002-7546-9650], Stefansson, Kari [0000-0003-1676-864X], Stirrups, Kathleen E [0000-0002-6823-3252], Stringham, Heather M [0000-0002-2991-6392], Teumer, Alexander [0000-0002-8309-094X], Thompson, Deborah J [0000-0003-1465-5799], Vestergaard, Henrik [0000-0003-3090-269X], Vitart, Veronique [0000-0002-4991-3797], Wang, Carol A [0000-0002-4301-3974], Wessel, Jennifer [0000-0002-7031-0085], Willer, Cristen J [0000-0001-5645-4966], Zeggini, Eleftheria [0000-0003-4238-659X], Rivadeneira, Fernando [0000-0001-9435-9441], Pospisilik, J Andrew [0000-0002-9745-0977], Deloukas, Panos [0000-0001-9251-070X], Mohlke, Karen L [0000-0001-6721-153X], Kutalik, Zoltán [0000-0001-8285-7523], Loos, Ruth JF [0000-0002-8532-5087], Lindgren, Cecilia M [0000-0002-4903-9374], Apollo - University of Cambridge Repository, Home Office, Medical Research Council (MRC), National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, UK DRI Ltd, Medical and Clinical Psychology, Justice, Anne E., Karaderi, Tugce, Highland, Heather M., Young, Kristin L., Graff, Mariaelisa, Lu, Yingchang, Turcot, Valérie, Auer, Paul L., Fine, Rebecca S., Guo, Xiuqing, Schurmann, Claudia, Lempradl, Adelheid, Marouli, Eirini, Mahajan, Anubha, Winkler, Thomas W., Locke, Adam E., Medina-Gomez, Carolina, Esko, Tõnu, Vedantam, Sailaja, Giri, Ayush, Lo, Ken Sin, Alfred, Tamuno, Mudgal, Poorva, Ng, Maggie C. Y., Heard-Costa, Nancy L., Feitosa, Mary F., Manning, Alisa K., Willems, Sara M., Sivapalaratnam, Suthesh, Abecasis, Goncalo, Alam, Dewan S., Allison, Matthew, Amouyel, Philippe, Arzumanyan, Zorayr, Balkau, Beverley, Bastarache, Lisa, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthia, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A., Bork-Jensen, Jette, Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Broer, Linda, Burt, Amber A., Butterworth, Adam S., Caulfield, Mark J., Cesana, Giancarlo, Chambers, John C., Chasman, Daniel I., Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Collins, Francis S., Cook, James P., Cox, Amanda J., Crosslin, David S., Danesh, John, de Bakker, Paul I. W., Denus, Simon de, Mutsert, Renée de, Dedoussis, George, Demerath, Ellen W., Dennis, Joe G., Denny, Josh C., Angelantonio, Emanuele Di, Dörr, Marcu, Drenos, Fotio, Dubé, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Elliott, Paul, Evangelou, Evangelo, Farmaki, Aliki-Eleni, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C., Fornage, Myriam, Fox, Caroline S., Franks, Paul W., Friedrich, Nele, Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmanta, Girotto, Giorgia, Gorski, Mathia, Grallert, Harald, Grarup, Niel, Grove, Megan L., Gustafsson, Stefan, Haessler, Jeff, Hansen, Torben, Hattersley, Andrew T., Hayward, Caroline, Heid, Iris M., Holmen, Oddgeir L., Hovingh, G. Kee, Howson, Joanna M. M., Hu, Yao, Hung, Yi-Jen, Hveem, Kristian, Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jarvik, Gail P., Jia, Yucheng, Jørgensen, Torben, Jousilahti, Pekka, Justesen, Johanne M., Kahali, Bratati, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kee, Frank, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S., Kovacs, Peter, Krämer, Bernhard K., Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, Lange, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lee, Wen-Jane, Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Li-An, Lin, Xu, Lind, Lar, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Luan, Jian’An, Lyytikäinen, Leo-Pekka, Macgregor, Stuart, Mägi, Reedik, Männistö, Satu, Marenne, Gaëlle, Marten, Jonathan, Masca, Nicholas G. D., Mccarthy, Mark I., Meidtner, Karina, Mihailov, Evelin, Moilanen, Leena, Moitry, Marie, Mook-Kanamori, Dennis O., Morgan, Anna, Morris, Andrew P., Müller-Nurasyid, Martina, Munroe, Patricia B., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Ntalla, Ioanna, O’Connell, Jeffrey R., Owen, Katharine R., Pedersen, Oluf, Peloso, Gina M., Pennell, Craig E., Perola, Marku, Perry, James A., Perry, John R. B., Pers, Tune H., Ewing, Ailith, Polasek, Ozren, Raitakari, Olli T., Rasheed, Asif, Raulerson, Chelsea K., Rauramaa, Rainer, Reilly, Dermot F., Reiner, Alex P., Ridker, Paul M., Rivas, Manuel A., Robertson, Neil R., Robino, Antonietta, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo, Sim, Xueling, Slater, Andrew J., Small, Kerrin S., Smith, Blair H., Smith, Jennifer A., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swart, Karin M. A., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H., Tönjes, Anke, Torres, Mina, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Uitterlinden, André G., Uusitupa, Matti, van Duijn, Cornelia M., Vanhala, Mauno, Varma, Rohit, Vermeulen, Sita H., Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Vuckovic, Dragana, Wagenknecht, Lynne E., Walker, Mark, Wallentin, Lar, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wareham, Nicholas J., Warren, Helen R., Waterworth, Dawn M., Wessel, Jennifer, White, Harvey D., Willer, Cristen J., Wilson, James G., Wood, Andrew R., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zheng, He, Zhou, Wei, Zillikens, M. Carola, Rivadeneira, Fernando, Borecki, Ingrid B., Pospisilik, J. Andrew, Deloukas, Pano, Frayling, Timothy M., Lettre, Guillaume, Mohlke, Karen L., Rotter, Jerome I., Kutalik, Zoltán, Hirschhorn, Joel N., Cupples, L. Adrienne, Loos, Ruth J. F., North, Kari E., Lindgren, Cecilia M., APH - Societal Participation & Health, APH - Health Behaviors & Chronic Diseases, APH - Aging & Later Life, Epidemiology and Data Science, and VU University medical center
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Exome/genetics ,Male ,ReproGen Consortium ,Adipose tissue ,Genome-wide association study ,Type 2 diabetes ,White adipose tissue ,Body Mass Index ,Animals ,Body Fat Distribution ,Case-Control Studies ,Drosophila ,Exome ,Female ,Gene Frequency ,Genetic Predisposition to Disease ,Genetic Variation ,Genome-Wide Association Study ,Homeostasis ,Humans ,Lipids ,Proteins ,Risk Factors ,Waist-Hip Ratio ,0302 clinical medicine ,Hyperlipidemia ,Body fat distribution ,2. Zero hunger ,Genetics ,0303 health sciences ,INSULIN-RESISTANCE ,ADIPOCYTE DIFFERENTIATION ,CHD Exome+ Consortium ,Genetic Predisposition to Disease/genetics ,Drosophila/genetics ,RS11209026 POLYMORPHISM ,KINASE 7 ,1184 Genetics, developmental biology, physiology ,T2D-Genes Consortium ,11 Medical And Health Sciences ,Body Fat Distribution/methods ,RECEPTOR ALK7 ,ADIPOSE-TISSUE ,Gene Frequency/genetics ,Genetic Variation/genetics ,InterAct ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,genetic association study ,RNA splicing ,Proteins/genetics ,Genome-Wide Association Study/methods ,Lipid particle ,ExomeBP Consortium ,WAIST CIRCUMFERENCE ,Waist-Hip Ratio/methods ,Biology ,EPIC-CVD Consortium ,Article ,MAGIC Investigators ,03 medical and health sciences ,Homeostasis/genetics ,Lipids/genetics ,All institutes and research themes of the Radboud University Medical Center ,medicine ,Global Lipids Genetic Consortium ,Risk factor ,GENOME-WIDE ASSOCIATION ,ABDOMINAL ADIPOSITY ,Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium ,Gene ,030304 developmental biology ,06 Biological Sciences ,medicine.disease ,Minor allele frequency ,GoT2D Genes Consortium ,genetics research ,TYPE-2 DIABETES SUSCEPTIBILITY ,3111 Biomedicine ,Body mass index ,030217 neurology & neurosurgery ,Developmental Biology - 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 9 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., Editorial summary: A trans-ethnic exome-wide association study for body fat distribution identifies protein-coding variants that are significantly associated with waist-to-hip ratio adjusted for body mass index.
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