Abstract
Body fat distribution is a heritable risk factor for a range of adverse health consequences, including hyperlipidemia and type 2 diabetes. To identify protein-coding variants associated with body fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, we analyzed 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries for discovery and 132,177 independent European-ancestry individuals for validation. We identified 15 common (minor allele frequency, MAF ≥ 5%) and 9 low frequency or rare (MAF < 5%) coding variants that have not been reported previously. Pathway/gene set enrichment analyses of all associated variants highlight lipid particle, adiponectin level, abnormal white adipose tissue physiology, and bone development and morphology as processes affecting fat distribution and body shape. Furthermore, the cross-trait associations and the analyses of variant and gene function highlight a strong connection to lipids, cardiovascular traits, and type 2 diabetes. In functional follow-up analyses, specifically in Drosophila RNAi-knockdown crosses, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). By examining variants often poorly tagged or entirely missed by genome-wide association studies, we implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
| Original language | English (US) |
|---|---|
| Journal | Unknown Journal |
| DOIs | |
| State | Published - Jun 30 2018 |
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Agricultural and Biological Sciences(all)
- Immunology and Microbiology(all)
- Neuroscience(all)
- Pharmacology, Toxicology and Pharmaceutics(all)
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Protein-coding variants implicate novel genes related to Lipid homeostasis contributing to body fat distribution. / 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, 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; de Denus, Simon; de Mutsert, Renée; 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.; Kees Hovingh, G.; Howson, Joanna M.M.; Hu, Yao; Hung, Yi Jen; Hveem, Kristian; Arfan Ikram, M.; 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, 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 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'Connel, Jeffrey R.; Owen, Katharine R.; Pedersen, Oluf; Peloso, Gina M.; Pennell, Craig E.; Perola, Markus; Perry, James A.; Perry, John R.B.; Pers, Tune H.; Pirie, 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 P.; 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; Betina, H. Thuesen; 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.; Ntalla, 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; Deloukas, Panos; Frayling, Timothy M.; Lettre, Guillaume; Mohlke, Karen L.; Rotter, Jerome I.; Kutalik, Zoltán; Hirschhorn, Joel N.; Adrienne Cupples, L.; Loos, Ruth J.F.; North, Kari E.; Lindgren, Cecilia M.
In: Unknown Journal, 30.06.2018.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Protein-coding variants implicate novel genes related to Lipid homeostasis contributing to body fat distribution
AU - Justice, Anne E.
AU - Karaderi, Tugce
AU - Highland, Heather M.
AU - Young, Kristin L.
AU - Graff, Mariaelisa
AU - Lu, Yingchang
AU - Turcot, Valérie
AU - Auer, Paul L.
AU - Fine, Rebecca S.
AU - Guo, Xiuqing
AU - Schurmann, Claudia
AU - Lempradl, Adelheid
AU - Marouli, Eirini
AU - Mahajan, Anubha
AU - Winkler, Thomas W.
AU - Locke, Adam E.
AU - Medina-Gomez, Carolina
AU - Esko, Tõnu
AU - Vedantam, Sailaja
AU - Giri, Ayush
AU - Lo, Ken Sin
AU - Alfred, Tamuno
AU - Mudgal, Poorva
AU - Ng, Maggie C.Y.
AU - Heard-Costa, Nancy L.
AU - Feitosa, Mary F.
AU - Manning, Alisa K.
AU - Willems, Sara M.
AU - Sivapalaratnam, Suthesh
AU - Abecasis, Goncalo
AU - Alam, Dewan S.
AU - Allison, Matthew
AU - Amouyel, Philippe
AU - Arzumanyan, Zorayr
AU - Balkau, Beverley
AU - Bastarache, Lisa
AU - Bergmann, Sven
AU - Bielak, Lawrence F.
AU - Blüher, Matthias
AU - Boehnke, Michael
AU - Boeing, Heiner
AU - Boerwinkle, Eric
AU - Böger, Carsten A.
AU - Bork-Jensen, Jette
AU - Bottinger, Erwin P.
AU - Bowden, Donald W.
AU - Brandslund, Ivan
AU - Broer, Linda
AU - Burt, Amber A.
AU - Butterworth, Adam S.
AU - Caulfield, Mark J.
AU - Cesana, Giancarlo
AU - Chambers, John C.
AU - Chasman, Daniel I.
AU - Chen, Yii Der Ida
AU - Chowdhury, Rajiv
AU - Christensen, Cramer
AU - Chu, Audrey Y.
AU - Collins, Francis S.
AU - Cook, James P.
AU - Cox, Amanda J.
AU - Crosslin, David S.
AU - Danesh, John
AU - de Bakker, Paul IW
AU - de Denus, Simon
AU - de Mutsert, Renée
AU - Dedoussis, George
AU - Demerath, Ellen W.
AU - Dennis, Joe G.
AU - Denny, Josh C.
AU - Angelantonio, Emanuele Di
AU - Dörr, Marcus
AU - Drenos, Fotios
AU - Dubé, Marie Pierre
AU - Dunning, Alison M.
AU - Easton, Douglas F.
AU - Elliott, Paul
AU - Evangelou, Evangelos
AU - Farmaki, Aliki Eleni
AU - Feng, Shuang
AU - Ferrannini, Ele
AU - Ferrieres, Jean
AU - Florez, Jose C.
AU - Fornage, Myriam
AU - Fox, Caroline S.
AU - Franks, Paul W.
AU - Friedrich, Nele
AU - Gan, Wei
AU - Gandin, Ilaria
AU - Gasparini, Paolo
AU - Giedraitis, Vilmantas
AU - Girotto, Giorgia
AU - Gorski, Mathias
AU - Grallert, Harald
AU - Grarup, Niels
AU - Grove, Megan L.
AU - Gustafsson, Stefan
AU - Haessler, Jeff
AU - Hansen, Torben
AU - Hattersley, Andrew T.
AU - Hayward, Caroline
AU - Heid, Iris M.
AU - Holmen, Oddgeir L.
AU - Kees Hovingh, G.
AU - Howson, Joanna M.M.
AU - Hu, Yao
AU - Hung, Yi Jen
AU - Hveem, Kristian
AU - Arfan Ikram, M.
AU - Ingelsson, Erik
AU - Jackson, Anne U.
AU - Jarvik, Gail P.
AU - Jia, Yucheng
AU - Jørgensen, Torben
AU - Jousilahti, Pekka
AU - Justesen, Johanne M.
AU - Kahali, Bratati
AU - Karaleftheri, Maria
AU - Kardia, Sharon L.R.
AU - Karpe, Fredrik
AU - Kee, Frank
AU - Kitajima, Hidetoshi
AU - Komulainen, Pirjo
AU - Kooner, Jaspal S.
AU - Kovacs, Peter
AU - Krämer, Bernhard K.
AU - Kuulasmaa, Kari
AU - Kuusisto, Johanna
AU - Laakso, Markku
AU - Lakka, Timo A.
AU - Lamparter, David
AU - Lange, Leslie A.
AU - Langenberg, Claudia
AU - Larson, Eric B.
AU - Lee, Nanette R.
AU - Lee, Wen Jane
AU - Lehtimäki, Terho
AU - Lewis, Cora E.
AU - Li, Huaixing
AU - Li, Jin
AU - Li-Gao, Ruifang
AU - Lin, Li An
AU - Lin, Xu
AU - Lind, Lars
AU - Lindström, Jaana
AU - Linneberg, Allan
AU - Liu, Ching Ti
AU - Liu, Dajiang J.
AU - Luan, Jian'an
AU - Lyytikäinen, Leo Pekka
AU - MacGregor, Stuart
AU - Mägi, Reedik
AU - Männistö, Satu
AU - Marenne, Gaëlle
AU - Marten, Jonathan
AU - Masca, Nicholas G.D.
AU - McCarthy, Mark I.
AU - Meidtner, Karina
AU - Mihailov, Evelin
AU - Moilanen, Leena
AU - Moitry, Marie
AU - Mook-Kanamori, Dennis O.
AU - Morgan, Anna
AU - Morris, Andrew P.
AU - Müller-Nurasyid, Martina
AU - Munroe, Patricia B.
AU - Narisu, Narisu
AU - Nelson, Christopher P.
AU - Neville, Matt
AU - Ntalla, Ioanna
AU - O'Connel, Jeffrey R.
AU - Owen, Katharine R.
AU - Pedersen, Oluf
AU - Peloso, Gina M.
AU - Pennell, Craig E.
AU - Perola, Markus
AU - Perry, James A.
AU - Perry, John R.B.
AU - Pers, Tune H.
AU - Pirie, Ailith
AU - Polasek, Ozren
AU - Raitakari, Olli T.
AU - Rasheed, Asif
AU - Raulerson, Chelsea K.
AU - Rauramaa, Rainer
AU - Reilly, Dermot F.
AU - Reiner, Alex P.
AU - Ridker, Paul M.
AU - Rivas, Manuel A.
AU - Robertson, Neil R.
AU - Robino, Antonietta
AU - Rudan, Igor
AU - Ruth, Katherine S.
AU - Saleheen, Danish
AU - Salomaa, Veikko
AU - Samani, Nilesh J.
AU - Schreiner, Pamela J.
AU - Schulze, Matthias B.
AU - Scott, Robert A.
AU - Segura-Lepe, Marcelo P.
AU - Sim, Xueling
AU - Slater, Andrew J.
AU - Small, Kerrin S.
AU - Smith, Blair H.
AU - Smith, Jennifer A.
AU - Southam, Lorraine
AU - Spector, Timothy D.
AU - Speliotes, Elizabeth K.
AU - Stefansson, Kari
AU - Steinthorsdottir, Valgerdur
AU - Stirrups, Kathleen E.
AU - Strauch, Konstantin
AU - Stringham, Heather M.
AU - Stumvoll, Michael
AU - Sun, Liang
AU - Surendran, Praveen
AU - Swart, Karin M.A.
AU - Tardif, Jean Claude
AU - Taylor, Kent D.
AU - Teumer, Alexander
AU - Thompson, Deborah J.
AU - Thorleifsson, Gudmar
AU - Thorsteinsdottir, Unnur
AU - Betina, H. Thuesen
AU - Tönjes, Anke
AU - Torres, Mina
AU - Tsafantakis, Emmanouil
AU - Tuomilehto, Jaakko
AU - Uitterlinden, André G.
AU - Uusitupa, Matti
AU - van Duijn, Cornelia M.
AU - Vanhala, Mauno
AU - Varma, Rohit
AU - Vermeulen, Sita H.
AU - Vestergaard, Henrik
AU - Vitart, Veronique
AU - Vogt, Thomas F.
AU - Ntalla, Dragana
AU - Wagenknecht, Lynne E.
AU - Walker, Mark
AU - Wallentin, Lars
AU - Wang, Feijie
AU - Wang, Carol A.
AU - Wang, Shuai
AU - Wareham, Nicholas J.
AU - Warren, Helen R.
AU - Waterworth, Dawn M.
AU - Wessel, Jennifer
AU - White, Harvey D.
AU - Willer, Cristen J.
AU - Wilson, James G.
AU - Wood, Andrew R.
AU - Wu, Ying
AU - Yaghootkar, Hanieh
AU - Yao, Jie
AU - Yerges-Armstrong, Laura M.
AU - Young, Robin
AU - Zeggini, Eleftheria
AU - Zhan, Xiaowei
AU - Zhang, Weihua
AU - Zhao, Jing Hua
AU - Zhao, Wei
AU - Zheng, He
AU - Zhou, Wei
AU - Deloukas, Panos
AU - Frayling, Timothy M.
AU - Lettre, Guillaume
AU - Mohlke, Karen L.
AU - Rotter, Jerome I.
AU - Kutalik, Zoltán
AU - Hirschhorn, Joel N.
AU - Adrienne Cupples, L.
AU - Loos, Ruth J.F.
AU - North, Kari E.
AU - Lindgren, Cecilia M.
N1 - Publisher Copyright: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2018/6/30
Y1 - 2018/6/30
N2 - Body fat distribution is a heritable risk factor for a range of adverse health consequences, including hyperlipidemia and type 2 diabetes. To identify protein-coding variants associated with body fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, we analyzed 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries for discovery and 132,177 independent European-ancestry individuals for validation. We identified 15 common (minor allele frequency, MAF ≥ 5%) and 9 low frequency or rare (MAF < 5%) coding variants that have not been reported previously. Pathway/gene set enrichment analyses of all associated variants highlight lipid particle, adiponectin level, abnormal white adipose tissue physiology, and bone development and morphology as processes affecting fat distribution and body shape. Furthermore, the cross-trait associations and the analyses of variant and gene function highlight a strong connection to lipids, cardiovascular traits, and type 2 diabetes. In functional follow-up analyses, specifically in Drosophila RNAi-knockdown crosses, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). By examining variants often poorly tagged or entirely missed by genome-wide association studies, we implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
AB - Body fat distribution is a heritable risk factor for a range of adverse health consequences, including hyperlipidemia and type 2 diabetes. To identify protein-coding variants associated with body fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, we analyzed 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries for discovery and 132,177 independent European-ancestry individuals for validation. We identified 15 common (minor allele frequency, MAF ≥ 5%) and 9 low frequency or rare (MAF < 5%) coding variants that have not been reported previously. Pathway/gene set enrichment analyses of all associated variants highlight lipid particle, adiponectin level, abnormal white adipose tissue physiology, and bone development and morphology as processes affecting fat distribution and body shape. Furthermore, the cross-trait associations and the analyses of variant and gene function highlight a strong connection to lipids, cardiovascular traits, and type 2 diabetes. In functional follow-up analyses, specifically in Drosophila RNAi-knockdown crosses, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). By examining variants often poorly tagged or entirely missed by genome-wide association studies, we implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
UR - http://www.scopus.com/inward/record.url?scp=85095661173&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85095661173&partnerID=8YFLogxK
U2 - 10.1101/352674
DO - 10.1101/352674
M3 - Article
AN - SCOPUS:85095661173
JO - Seminars in Fetal and Neonatal Medicine
JF - Seminars in Fetal and Neonatal Medicine
SN - 1744-165X
ER -