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Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions
de Vries, Paul S; Brown, Michael R; Bentley, Amy R; Sung, Yun J; Winkler, Thomas W; Ntalla, Ioanna; Schwander, Karen; Kraja, Aldi T; Guo, Xiuqing; Franceschini, Nora; Cheng, Ching-Yu; Sim, Xueling; Vojinovic, Dina; Huffman, Jennifer E; Musani, Solomon K; Li, Changwei; Feitosa, Mary F; Richard, Melissa A; Noordam, Raymond; Aschard, Hugues; Bartz, Traci M; Bielak, Lawrence F; Deng, Xuan; Dorajoo, Rajkumar; Lohman, Kurt K; Manning, Alisa K; Rankinen, Tuomo; Smith, Albert V; Tajuddin, Salman M; Evangelou, Evangelos; Graff, Mariaelisa; Alver, Maris; Boissel, Mathilde; Chai, Jin Fang; Chen, Xu; Divers, Jasmin; Gandin, Ilaria; Gao, Chuan; Goel, Anuj; Hagemeijer, Yanick; Harris, Sarah E; Hartwig, Fernando P; He, Meian; Horimoto, Andrea R V R; Hsu, Fang-Chi; Jackson, Anne U; Kasturiratne, Anuradhani; Komulainen, Pirjo; Kühnel, Brigitte; Laguzzi, Federica; Lee, Joseph H; Luan, Jian'an; Lyytikäinen, Leo-Pekka; Matoba, Nana; Nolte, Ilja M; Pietzner, Maik; Riaz, Muhammad; Said, M Abdullah; Scott, Robert A; Sofer, Tamar; StanÄáková, Alena; Takeuchi, Fumihiko; Tayo, Bamidele O; van der Most, Peter J; Varga, Tibor V; Wang, Yajuan; Ware, Erin B; Wen, Wanqing; Yanek, Lisa R; Zhang, Weihua; Zhao, Jing Hua; Afaq, Saima; Amin, Najaf; Amini, Marzyeh; Arking, Dan E; Aung, Tin; Ballantyne, Christie; Boerwinkle, Eric; Broeckel, Ulrich; Campbell, Archie; Canouil, Mickaël; Charumathi, Sabanayagam; Chen, Yii-Der Ida; Connell, John M; de Faire, Ulf; de Las Fuentes, Lisa; de Mutsert, Renée; de Silva, H Janaka; Ding, Jingzhong; Dominiczak, Anna F; Duan, Qing; Eaton, Charles B; Eppinga, Ruben N; Faul, Jessica D; Fisher, Virginia; Forrester, Terrence; Franco, Oscar H; Friedlander, Yechiel; Ghanbari, Mohsen; Giulianini, Franco; Grabe, Hans J; Grove, Megan L; Gu, C Charles; Harris, Tamara B; Heikkinen, Sami; Heng, Chew-Kiat; Hirata, Makoto; Hixson, James E; Howard, Barbara V; Ikram, M Arfan; Jacobs, David R; Johnson, Craig; Jonas, Jost Bruno; Kammerer, Candace M; Katsuya, Tomohiro; Khor, Chiea Chuen; Kilpeläinen, Tuomas O; Koh, Woon-Puay; Koistinen, Heikki A; Kolcic, Ivana; Kooperberg, Charles; Krieger, Jose E; Kritchevsky, Steve B; Kubo, Michiaki; Kuusisto, Johanna; Lakka, Timo A; Langefeld, Carl D; Langenberg, Claudia; Launer, Lenore J; Lehne, Benjamin; Lemaitre, Rozenn N; Li, Yize; Liang, Jingjing; Liu, Jianjun; Liu, Kiang; Loh, Marie; Louie, Tin; Mägi, Reedik; Manichaikul, Ani W; McKenzie, Colin A; Meitinger, Thomas; Metspalu, Andres; Milaneschi, Yuri; Milani, Lili; Mohlke, Karen L; Mosley, Thomas H; Mukamal, Kenneth J; Nalls, Mike A; Nauck, Matthias; Nelson, Christopher P; Sotoodehnia, Nona; O'Connell, Jeff R; Palmer, Nicholette D; Pazoki, Raha; Pedersen, Nancy L; Peters, Annette; Peyser, Patricia A; Polasek, Ozren; Poulter, Neil; Raffel, Leslie J; Raitakari, Olli T; Reiner, Alex P; Rice, Treva K; Rich, Stephen S; Robino, Antonietta; Robinson, Jennifer G; Rose, Lynda M; Rudan, Igor; Schmidt, Carsten O; Schreiner, Pamela J; Scott, William R; Sever, Peter; Shi, Yuan; Sidney, Stephen; Sims, Mario; Smith, Blair H; Smith, Jennifer A; Snieder, Harold; Starr, John M; Strauch, Konstantin; Tan, Nicholas; Taylor, Kent D; Teo, Yik Ying; Tham, Yih Chung; Uitterlinden, André G; van Heemst, Diana; Vuckovic, Dragana; Waldenberger, Melanie; Wang, Lihua; Wang, Yujie; Wang, Zhe; Wei, Wen Bin; Williams, Christine; Wilson, Gregory; Wojczynski, Mary K; Yao, Jie; Yu, Bing; Yu, Caizheng; Yuan, Jian-Min; Zhao, Wei; Zonderman, Alan B; Becker, Diane M; Boehnke, Michael; Bowden, Donald W; Chambers, John C; Deary, Ian J; Esko, Tõnu; Farrall, Martin; Franks, Paul W; Freedman, Barry I; Froguel, Philippe; Gasparini, Paolo; Gieger, Christian; Horta, Bernardo L; Kamatani, Yoichiro; Kato, Norihiro; Kooner, Jaspal S; Laakso, Markku; Leander, Karin; Lehtimäki, Terho; Magnusson, Patrik K E; Penninx, Brenda; Pereira, Alexandre C; Rauramaa, Rainer; Samani, Nilesh J; Scott, James; Shu, Xiao-Ou; van der Harst, Pim; Wagenknecht, Lynne E; Wang, Ya Xing; Wareham, Nicholas J; Watkins, Hugh; Weir, David R; Wickremasinghe, Ananda R; Zheng, Wei; Elliott, Paul; North, Kari E; Bouchard, Claude; Evans, Michele K; Gudnason, Vilmundur; Liu, Ching-Ti; Liu, Yongmei; Psaty, Bruce M; Ridker, Paul M; van Dam, Rob M; Kardia, Sharon L R; Zhu, Xiaofeng; Rotimi, Charles N; Mook-Kanamori, Dennis O; Fornage, Myriam; Kelly, Tanika N; Fox, Ervin R; Hayward, Caroline; van Duijn, Cornelia M; Tai, E Shyong; Wong, Tien Yin; Liu, Jingmin; Rotter, Jerome I; Gauderman, W James; Province, Michael A; Munroe, Patricia B; Rice, Kenneth; Chasman, Daniel I; Cupples, L Adrienne; Rao, Dabeeru C; Morrison, Alanna C
A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.
PMCID:6545280
PMID: 30698716
ISSN: 1476-6256
CID: 4318852
A catalog of genetic loci associated with kidney function from analyses of a million individuals
Wuttke, Matthias; Li, Yong; Li, Man; Sieber, Karsten B; Feitosa, Mary F; Gorski, Mathias; Tin, Adrienne; Wang, Lihua; Chu, Audrey Y; Hoppmann, Anselm; Kirsten, Holger; Giri, Ayush; Chai, Jin-Fang; Sveinbjornsson, Gardar; Tayo, Bamidele O; Nutile, Teresa; Fuchsberger, Christian; Marten, Jonathan; Cocca, Massimiliano; Ghasemi, Sahar; Xu, Yizhe; Horn, Katrin; Noce, Damia; van der Most, Peter J; Sedaghat, Sanaz; Yu, Zhi; Akiyama, Masato; Afaq, Saima; Ahluwalia, Tarunveer S; Almgren, Peter; Amin, Najaf; Ärnlöv, Johan; Bakker, Stephan J L; Bansal, Nisha; Baptista, Daniela; Bergmann, Sven; Biggs, Mary L; Biino, Ginevra; Boehnke, Michael; Boerwinkle, Eric; Boissel, Mathilde; Bottinger, Erwin P; Boutin, Thibaud S; Brenner, Hermann; Brumat, Marco; Burkhardt, Ralph; Butterworth, Adam S; Campana, Eric; Campbell, Archie; Campbell, Harry; Canouil, Mickaël; Carroll, Robert J; Catamo, Eulalia; Chambers, John C; Chee, Miao-Ling; Chee, Miao-Li; Chen, Xu; Cheng, Ching-Yu; Cheng, Yurong; Christensen, Kaare; Cifkova, Renata; Ciullo, Marina; Concas, Maria Pina; Cook, James P; Coresh, Josef; Corre, Tanguy; Sala, Cinzia Felicita; Cusi, Daniele; Danesh, John; Daw, E Warwick; de Borst, Martin H; De Grandi, Alessandro; de Mutsert, Renée; de Vries, Aiko P J; Degenhardt, Frauke; Delgado, Graciela; Demirkan, Ayse; Di Angelantonio, Emanuele; Dittrich, Katalin; Divers, Jasmin; Dorajoo, Rajkumar; Eckardt, Kai-Uwe; Ehret, Georg; Elliott, Paul; Endlich, Karlhans; Evans, Michele K; Felix, Janine F; Foo, Valencia Hui Xian; Franco, Oscar H; Franke, Andre; Freedman, Barry I; Freitag-Wolf, Sandra; Friedlander, Yechiel; Froguel, Philippe; Gansevoort, Ron T; Gao, He; Gasparini, Paolo; Gaziano, J Michael; Giedraitis, Vilmantas; Gieger, Christian; Girotto, Giorgia; Giulianini, Franco; Gögele, Martin; Gordon, Scott D; Gudbjartsson, Daniel F; Gudnason, Vilmundur; Haller, Toomas; Hamet, Pavel; Harris, Tamara B; Hartman, Catharina A; Hayward, Caroline; Hellwege, Jacklyn N; Heng, Chew-Kiat; Hicks, Andrew A; Hofer, Edith; Huang, Wei; Hutri-Kähönen, Nina; Hwang, Shih-Jen; Ikram, M Arfan; Indridason, Olafur S; Ingelsson, Erik; Ising, Marcus; Jaddoe, Vincent W V; Jakobsdottir, Johanna; Jonas, Jost B; Joshi, Peter K; Josyula, Navya Shilpa; Jung, Bettina; Kähönen, Mika; Kamatani, Yoichiro; Kammerer, Candace M; Kanai, Masahiro; Kastarinen, Mika; Kerr, Shona M; Khor, Chiea-Chuen; Kiess, Wieland; Kleber, Marcus E; Koenig, Wolfgang; Kooner, Jaspal S; Körner, Antje; Kovacs, Peter; Kraja, Aldi T; Krajcoviechova, Alena; Kramer, Holly; Krämer, Bernhard K; Kronenberg, Florian; Kubo, Michiaki; Kühnel, Brigitte; Kuokkanen, Mikko; Kuusisto, Johanna; La Bianca, Martina; Laakso, Markku; Lange, Leslie A; Langefeld, Carl D; Lee, Jeannette Jen-Mai; Lehne, Benjamin; Lehtimäki, Terho; Lieb, Wolfgang; Lim, Su-Chi; Lind, Lars; Lindgren, Cecilia M; Liu, Jun; Liu, Jianjun; Loeffler, Markus; Loos, Ruth J F; Lucae, Susanne; Lukas, Mary Ann; Lyytikäinen, Leo-Pekka; Mägi, Reedik; Magnusson, Patrik K E; Mahajan, Anubha; Martin, Nicholas G; Martins, Jade; März, Winfried; Mascalzoni, Deborah; Matsuda, Koichi; Meisinger, Christa; Meitinger, Thomas; Melander, Olle; Metspalu, Andres; Mikaelsdottir, Evgenia K; Milaneschi, Yuri; Miliku, Kozeta; Mishra, Pashupati P; Mohlke, Karen L; Mononen, Nina; Montgomery, Grant W; Mook-Kanamori, Dennis O; Mychaleckyj, Josyf C; Nadkarni, Girish N; Nalls, Mike A; Nauck, Matthias; Nikus, Kjell; Ning, Boting; Nolte, Ilja M; Noordam, Raymond; O'Connell, Jeffrey; O'Donoghue, Michelle L; Olafsson, Isleifur; Oldehinkel, Albertine J; Orho-Melander, Marju; Ouwehand, Willem H; Padmanabhan, Sandosh; Palmer, Nicholette D; Palsson, Runolfur; Penninx, Brenda W J H; Perls, Thomas; Perola, Markus; Pirastu, Mario; Pirastu, Nicola; Pistis, Giorgio; Podgornaia, Anna I; Polasek, Ozren; Ponte, Belen; Porteous, David J; Poulain, Tanja; Pramstaller, Peter P; Preuss, Michael H; Prins, Bram P; Province, Michael A; Rabelink, Ton J; Raffield, Laura M; Raitakari, Olli T; Reilly, Dermot F; Rettig, Rainer; Rheinberger, Myriam; Rice, Kenneth M; Ridker, Paul M; Rivadeneira, Fernando; Rizzi, Federica; Roberts, David J; Robino, Antonietta; Rossing, Peter; Rudan, Igor; Rueedi, Rico; Ruggiero, Daniela; Ryan, Kathleen A; Saba, Yasaman; Sabanayagam, Charumathi; Salomaa, Veikko; Salvi, Erika; Saum, Kai-Uwe; Schmidt, Helena; Schmidt, Reinhold; Schöttker, Ben; Schulz, Christina-Alexandra; Schupf, Nicole; Shaffer, Christian M; Shi, Yuan; Smith, Albert V; Smith, Blair H; Soranzo, Nicole; Spracklen, Cassandra N; Strauch, Konstantin; Stringham, Heather M; Stumvoll, Michael; Svensson, Per O; Szymczak, Silke; Tai, E-Shyong; Tajuddin, Salman M; Tan, Nicholas Y Q; Taylor, Kent D; Teren, Andrej; Tham, Yih-Chung; Thiery, Joachim; Thio, Chris H L; Thomsen, Hauke; Thorleifsson, Gudmar; Toniolo, Daniela; Tönjes, Anke; Tremblay, Johanne; Tzoulaki, Ioanna; Uitterlinden, André G; Vaccargiu, Simona; van Dam, Rob M; van der Harst, Pim; van Duijn, Cornelia M; Velez Edward, Digna R; Verweij, Niek; Vogelezang, Suzanne; Völker, Uwe; Vollenweider, Peter; Waeber, Gerard; Waldenberger, Melanie; Wallentin, Lars; Wang, Ya Xing; Wang, Chaolong; Waterworth, Dawn M; Bin Wei, Wen; White, Harvey; Whitfield, John B; Wild, Sarah H; Wilson, James F; Wojczynski, Mary K; Wong, Charlene; Wong, Tien-Yin; Xu, Liang; Yang, Qiong; Yasuda, Masayuki; Yerges-Armstrong, Laura M; Zhang, Weihua; Zonderman, Alan B; Rotter, Jerome I; Bochud, Murielle; Psaty, Bruce M; Vitart, Veronique; Wilson, James G; Dehghan, Abbas; Parsa, Afshin; Chasman, Daniel I; Ho, Kevin; Morris, Andrew P; Devuyst, Olivier; Akilesh, Shreeram; Pendergrass, Sarah A; Sim, Xueling; Böger, Carsten A; Okada, Yukinori; Edwards, Todd L; Snieder, Harold; Stefansson, Kari; Hung, Adriana M; Heid, Iris M; Scholz, Markus; Teumer, Alexander; Köttgen, Anna; Pattaro, Cristian
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
PMID: 31152163
ISSN: 1546-1718
CID: 3936112
A randomized pilot study comparing graft-first to fistula-first strategies in older patients with incident end-stage kidney disease: Clinical rationale and study design
Murea, Mariana; Geary, Randolph L; Edwards, Matthew S; Moossavi, Shahriar; Davis, Ross P; Goldman, Matthew P; Hurie, Justin; Williams, Timothy K; Velazquez-Ramirez, Gabriela; Robinson, Todd W; Bagwell, Benjamin; Tuttle, Audrey B; Callahan, Kathryn E; Rocco, Michael V; Houston, Denise K; Pajewski, Nicholas M; Divers, Jasmin; Freedman, Barry I; Williamson, Jeff D
Timely placement of an arteriovenous (AV) vascular access (native AV fistula [AVF] or prosthetic AV graft [AVG]) is necessary to limit the use of tunneled central venous catheters (TCVC) in patients with end-stage kidney disease (ESKD) treated with hemodialysis (HD). National guidelines recommend placement of AVF as the AV access of first choice in all patients to improve patient survival. The benefits of AVF over AVG are less certain in the older adults, as age-related biological changes independently modulate patient outcomes. This manuscript describes the rationale, study design and protocol for a randomized controlled pilot study of the feasibility and effects of AVG-first access placement in older adults with no prior AV access surgery. Fifty patients age ≥65 years, with incident ESKD on HD via TCVC or advanced kidney disease facing imminent HD initiation, and suitable upper extremity vasculature for initial placement of an AVF or AVG, will be randomly assigned to receive either an upper extremity AVG-first (intervention) or AVF-first (comparator) access. The study will establish feasibility of randomizing older adults to the two types of AV access surgery, evaluate relationships between measurements of preoperative physical function and vascular access development, compare vascular access outcomes between groups, and gather longitudinal assessments of upper extremity muscle strength, gait speed, performance of activities of daily living, and patient satisfaction with their vascular access and quality of life. Results will assist with the planning of a larger, multicenter trial assessing patient-centered outcomes.
PMCID:6475715
PMID: 31016270
ISSN: 2451-8654
CID: 4318902
Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids
Bentley, Amy R; Sung, Yun J; Brown, Michael R; Winkler, Thomas W; Kraja, Aldi T; Ntalla, Ioanna; Schwander, Karen; Chasman, Daniel I; Lim, Elise; Deng, Xuan; Guo, Xiuqing; Liu, Jingmin; Lu, Yingchang; Cheng, Ching-Yu; Sim, Xueling; Vojinovic, Dina; Huffman, Jennifer E; Musani, Solomon K; Li, Changwei; Feitosa, Mary F; Richard, Melissa A; Noordam, Raymond; Baker, Jenna; Chen, Guanjie; Aschard, Hugues; Bartz, Traci M; Ding, Jingzhong; Dorajoo, Rajkumar; Manning, Alisa K; Rankinen, Tuomo; Smith, Albert V; Tajuddin, Salman M; Zhao, Wei; Graff, Mariaelisa; Alver, Maris; Boissel, Mathilde; Chai, Jin Fang; Chen, Xu; Divers, Jasmin; Evangelou, Evangelos; Gao, Chuan; Goel, Anuj; Hagemeijer, Yanick; Harris, Sarah E; Hartwig, Fernando P; He, Meian; Horimoto, Andrea R V R; Hsu, Fang-Chi; Hung, Yi-Jen; Jackson, Anne U; Kasturiratne, Anuradhani; Komulainen, Pirjo; Kühnel, Brigitte; Leander, Karin; Lin, Keng-Hung; Luan, Jian'an; Lyytikäinen, Leo-Pekka; Matoba, Nana; Nolte, Ilja M; Pietzner, Maik; Prins, Bram; Riaz, Muhammad; Robino, Antonietta; Said, M Abdullah; Schupf, Nicole; Scott, Robert A; Sofer, Tamar; Stancáková, Alena; Takeuchi, Fumihiko; Tayo, Bamidele O; van der Most, Peter J; Varga, Tibor V; Wang, Tzung-Dau; Wang, Yajuan; Ware, Erin B; Wen, Wanqing; Xiang, Yong-Bing; Yanek, Lisa R; Zhang, Weihua; Zhao, Jing Hua; Adeyemo, Adebowale; Afaq, Saima; Amin, Najaf; Amini, Marzyeh; Arking, Dan E; Arzumanyan, Zorayr; Aung, Tin; Ballantyne, Christie; Barr, R Graham; Bielak, Lawrence F; Boerwinkle, Eric; Bottinger, Erwin P; Broeckel, Ulrich; Brown, Morris; Cade, Brian E; Campbell, Archie; Canouil, Mickaël; Charumathi, Sabanayagam; Chen, Yii-Der Ida; Christensen, Kaare; Concas, Maria Pina; Connell, John M; de Las Fuentes, Lisa; de Silva, H Janaka; de Vries, Paul S; Doumatey, Ayo; Duan, Qing; Eaton, Charles B; Eppinga, Ruben N; Faul, Jessica D; Floyd, James S; Forouhi, Nita G; Forrester, Terrence; Friedlander, Yechiel; Gandin, Ilaria; Gao, He; Ghanbari, Mohsen; Gharib, Sina A; Gigante, Bruna; Giulianini, Franco; Grabe, Hans J; Gu, C Charles; Harris, Tamara B; Heikkinen, Sami; Heng, Chew-Kiat; Hirata, Makoto; Hixson, James E; Ikram, M Arfan; Jia, Yucheng; Joehanes, Roby; Johnson, Craig; Jonas, Jost Bruno; Justice, Anne E; Katsuya, Tomohiro; Khor, Chiea Chuen; Kilpeläinen, Tuomas O; Koh, Woon-Puay; Kolcic, Ivana; Kooperberg, Charles; Krieger, Jose E; Kritchevsky, Stephen B; Kubo, Michiaki; Kuusisto, Johanna; Lakka, Timo A; Langefeld, Carl D; Langenberg, Claudia; Launer, Lenore J; Lehne, Benjamin; Lewis, Cora E; Li, Yize; Liang, Jingjing; Lin, Shiow; Liu, Ching-Ti; Liu, Jianjun; Liu, Kiang; Loh, Marie; Lohman, Kurt K; Louie, Tin; Luzzi, Anna; Mägi, Reedik; Mahajan, Anubha; Manichaikul, Ani W; McKenzie, Colin A; Meitinger, Thomas; Metspalu, Andres; Milaneschi, Yuri; Milani, Lili; Mohlke, Karen L; Momozawa, Yukihide; Morris, Andrew P; Murray, Alison D; Nalls, Mike A; Nauck, Matthias; Nelson, Christopher P; North, Kari E; O'Connell, Jeffrey R; Palmer, Nicholette D; Papanicolau, George J; Pedersen, Nancy L; Peters, Annette; Peyser, Patricia A; Polasek, Ozren; Poulter, Neil; Raitakari, Olli T; Reiner, Alex P; Renström, Frida; Rice, Treva K; Rich, Stephen S; Robinson, Jennifer G; Rose, Lynda M; Rosendaal, Frits R; Rudan, Igor; Schmidt, Carsten O; Schreiner, Pamela J; Scott, William R; Sever, Peter; Shi, Yuan; Sidney, Stephen; Sims, Mario; Smith, Jennifer A; Snieder, Harold; Starr, John M; Strauch, Konstantin; Stringham, Heather M; Tan, Nicholas Y Q; Tang, Hua; Taylor, Kent D; Teo, Yik Ying; Tham, Yih Chung; Tiemeier, Henning; Turner, Stephen T; Uitterlinden, André G; van Heemst, Diana; Waldenberger, Melanie; Wang, Heming; Wang, Lan; Wang, Lihua; Wei, Wen Bin; Williams, Christine A; Wilson, Gregory; Wojczynski, Mary K; Yao, Jie; Young, Kristin; Yu, Caizheng; Yuan, Jian-Min; Zhou, Jie; Zonderman, Alan B; Becker, Diane M; Boehnke, Michael; Bowden, Donald W; Chambers, John C; Cooper, Richard S; de Faire, Ulf; Deary, Ian J; Elliott, Paul; Esko, Tõnu; Farrall, Martin; Franks, Paul W; Freedman, Barry I; Froguel, Philippe; Gasparini, Paolo; Gieger, Christian; Horta, Bernardo L; Juang, Jyh-Ming Jimmy; Kamatani, Yoichiro; Kammerer, Candace M; Kato, Norihiro; Kooner, Jaspal S; Laakso, Markku; Laurie, Cathy C; Lee, I-Te; Lehtimäki, Terho; Magnusson, Patrik K E; Oldehinkel, Albertine J; Penninx, Brenda W J H; Pereira, Alexandre C; Rauramaa, Rainer; Redline, Susan; Samani, Nilesh J; Scott, James; Shu, Xiao-Ou; van der Harst, Pim; Wagenknecht, Lynne E; Wang, Jun-Sing; Wang, Ya Xing; Wareham, Nicholas J; Watkins, Hugh; Weir, David R; Wickremasinghe, Ananda R; Wu, Tangchun; Zeggini, Eleftheria; Zheng, Wei; Bouchard, Claude; Evans, Michele K; Gudnason, Vilmundur; Kardia, Sharon L R; Liu, Yongmei; Psaty, Bruce M; Ridker, Paul M; van Dam, Rob M; Mook-Kanamori, Dennis O; Fornage, Myriam; Province, Michael A; Kelly, Tanika N; Fox, Ervin R; Hayward, Caroline; van Duijn, Cornelia M; Tai, E Shyong; Wong, Tien Yin; Loos, Ruth J F; Franceschini, Nora; Rotter, Jerome I; Zhu, Xiaofeng; Bierut, Laura J; Gauderman, W James; Rice, Kenneth; Munroe, Patricia B; Morrison, Alanna C; Rao, Dabeeru C; Rotimi, Charles N; Cupples, L Adrienne
The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.
PMCID:6467258
PMID: 30926973
ISSN: 1546-1718
CID: 4094682
Occurrence of severe hypoglycaemic events among US youth and young adults with type 1 or type 2 diabetes
Saydah, Sharon; Imperatore, Giuseppina; Divers, Jasmin; Bell, Ronny; Henkin, Leora; Mayer-Davis, Elizabeth; Zhong, Victor W; Dabelea, Dana; Lawrence, Jean M; Pihoker, Catherine
Objective/UNASSIGNED:Although severe hypoglycaemia (SH) can lead to adverse health outcomes, little is known about its occurrence and re-occurrence among youth with type 1 or type 2 diabetes. Methods/UNASSIGNED:This study included 2740 participants aged <20Â years at diabetes diagnosis and 5-14Â years diabetes duration from the SEARCH for Diabetes in Youth Cohort Study. Participants reported SH events in the past 6Â months. Differences in SH events by demographic and clinical factors were tested using logistic regression models. Results/UNASSIGNED:Â <Â 0.002). The median number of SH events per youth who had at least one SH event in the past 6Â months was 1 for both type 1 type 2 diabetes. For youth with type 1 diabetes, those who reported SH events were older, were more likely to have obesity or to be physically active, and had lower HbA1c. After adjustments, one unit increase in HbA1c was associated with 16% lower likelihood (OR 0.84, 95% CI 0.75, 0.94) and being physically active was associated with an 87% higher likelihood (OR 1.87, 95% CI 1.23, 2.86) of reporting a SH event. There were too few SH events among youth with type 2 diabetes to analyse further. Conclusions/UNASSIGNED:In youth with diabetes, SH was common even within a short 6-month window. Better understanding the causes of SH may help prevent them from occurring.
PMCID:6458461
PMID: 31008365
ISSN: 2398-9238
CID: 4318892
Mechanisms of Injury in APOL1-associated Kidney Disease
Ma, Lijun; Divers, Jasmin; Freedman, Barry I
BACKGROUND:An improved understanding of the pathogenesis in apolipoprotein L1 (APOL1) gene-associated chronic kidney disease (CKD) arose from observations in kidney transplantation. APOL1 genotyping could soon improve the safety of living kidney donation in individuals with recent African ancestry and alter the allocation of deceased donor kidneys. METHODS:This article reviews the potential mechanisms that underlie development of APOL1-associated nephropathy. Roles for circulating APOL1 protein versus intrinsic renal expression of APOL1 are discussed, as well as the requirement for modifying genetic and/or environmental factors. RESULTS:Abundant evidence supports local kidney production of APOL1 renal-risk variant protein in the development of nephropathy; this is true in both native kidney disease and after renal transplantation. Only a minority of kidneys from individuals with APOL1 high-risk genotypes will develop CKD or manifest shorter renal allograft survival after transplantation. Therefore, modifying factors that explain why only a subset of kidneys develops nephropathy remain critical to identify. It appears likely that environmental exposures, as opposed to major APOL1-second gene interactions, will prove to be stronger modifiers of the risk for nephropathy. CONCLUSIONS:The evolving understanding of the pathogenesis in APOL1-associated nephropathy will identify biomarkers predicting nephropathy in individuals at high genetic risk and lead to novel therapies to prevent or slow native CKD progression and prolong survival of transplanted kidneys. In the interim, the National Institutes of Health-sponsored "APOL1 Long-term Kidney Transplantation Outcomes" Network will determine whether APOL1 genotyping in individuals with recent African ancestry improves outcomes and safety in kidney transplantation.
PMCID:6226011
PMID: 30371607
ISSN: 1534-6080
CID: 4318832
Type 1 Diabetes Risk in African-Ancestry Participants and Utility of an Ancestry-Specific Genetic Risk Score
Onengut-Gumuscu, Suna; Chen, Wei-Min; Robertson, Catherine C; Bonnie, Jessica K; Farber, Emily; Zhu, Zhennan; Oksenberg, Jorge R; Brant, Steven R; Bridges, S Louis; Edberg, Jeffrey C; Kimberly, Robert P; Gregersen, Peter K; Rewers, Marian J; Steck, Andrea K; Black, Mary H; Dabelea, Dana; Pihoker, Catherine; Atkinson, Mark A; Wagenknecht, Lynne E; Divers, Jasmin; Bell, Ronny A; Erlich, Henry A; Concannon, Patrick; Rich, Stephen S
OBJECTIVE:Genetic risk scores (GRS) have been developed that differentiate individuals with type 1 diabetes from those with other forms of diabetes and are starting to be used for population screening; however, most studies were conducted in European-ancestry populations. This study identifies novel genetic variants associated with type 1 diabetes risk in African-ancestry participants and develops an African-specific GRS. RESEARCH DESIGN AND METHODS/METHODS:). RESULTS:*03:02) were significantly associated with type 1 diabetes risk. Among European-ancestry defined non-HLA risk loci, six risk loci were significantly associated with type 1 diabetes in subjects of African ancestry. An African-specific GRS provided strong prediction of type 1 diabetes risk (area under the curve 0.871), performing significantly better than a European-based GRS and two polygenic risk scores in independent discovery and validation cohorts. CONCLUSIONS:Genetic risk of type 1 diabetes includes ancestry-specific, disease-associated variants. The GRS developed here provides improved prediction of type 1 diabetes in African-ancestry subjects and a means to identify groups of individuals who would benefit from immune monitoring for early detection of islet autoimmunity.
PMID: 30659077
ISSN: 1935-5548
CID: 3682642
Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity
Kilpeläinen, Tuomas O; Bentley, Amy R; Noordam, Raymond; Sung, Yun Ju; Schwander, Karen; Winkler, Thomas W; Jakupović, Hermina; Chasman, Daniel I; Manning, Alisa; Ntalla, Ioanna; Aschard, Hugues; Brown, Michael R; de Las Fuentes, Lisa; Franceschini, Nora; Guo, Xiuqing; Vojinovic, Dina; Aslibekyan, Stella; Feitosa, Mary F; Kho, Minjung; Musani, Solomon K; Richard, Melissa; Wang, Heming; Wang, Zhe; Bartz, Traci M; Bielak, Lawrence F; Campbell, Archie; Dorajoo, Rajkumar; Fisher, Virginia; Hartwig, Fernando P; Horimoto, Andrea R V R; Li, Changwei; Lohman, Kurt K; Marten, Jonathan; Sim, Xueling; Smith, Albert V; Tajuddin, Salman M; Alver, Maris; Amini, Marzyeh; Boissel, Mathilde; Chai, Jin Fang; Chen, Xu; Divers, Jasmin; Evangelou, Evangelos; Gao, Chuan; Graff, Mariaelisa; Harris, Sarah E; He, Meian; Hsu, Fang-Chi; Jackson, Anne U; Zhao, Jing Hua; Kraja, Aldi T; Kühnel, Brigitte; Laguzzi, Federica; Lyytikäinen, Leo-Pekka; Nolte, Ilja M; Rauramaa, Rainer; Riaz, Muhammad; Robino, Antonietta; Rueedi, Rico; Stringham, Heather M; Takeuchi, Fumihiko; van der Most, Peter J; Varga, Tibor V; Verweij, Niek; Ware, Erin B; Wen, Wanqing; Li, Xiaoyin; Yanek, Lisa R; Amin, Najaf; Arnett, Donna K; Boerwinkle, Eric; Brumat, Marco; Cade, Brian; Canouil, Mickaël; Chen, Yii-Der Ida; Concas, Maria Pina; Connell, John; de Mutsert, Renée; de Silva, H Janaka; de Vries, Paul S; Demirkan, AyÅŸe; Ding, Jingzhong; Eaton, Charles B; Faul, Jessica D; Friedlander, Yechiel; Gabriel, Kelley P; Ghanbari, Mohsen; Giulianini, Franco; Gu, Chi Charles; Gu, Dongfeng; Harris, Tamara B; He, Jiang; Heikkinen, Sami; Heng, Chew-Kiat; Hunt, Steven C; Ikram, M Arfan; Jonas, Jost B; Koh, Woon-Puay; Komulainen, Pirjo; Krieger, Jose E; Kritchevsky, Stephen B; Kutalik, Zoltán; Kuusisto, Johanna; Langefeld, Carl D; Langenberg, Claudia; Launer, Lenore J; Leander, Karin; Lemaitre, Rozenn N; Lewis, Cora E; Liang, Jingjing; Liu, Jianjun; Mägi, Reedik; Manichaikul, Ani; Meitinger, Thomas; Metspalu, Andres; Milaneschi, Yuri; Mohlke, Karen L; Mosley, Thomas H; Murray, Alison D; Nalls, Mike A; Nang, Ei-Ei Khaing; Nelson, Christopher P; Nona, Sotoodehnia; Norris, Jill M; Nwuba, Chiamaka Vivian; O'Connell, Jeff; Palmer, Nicholette D; Papanicolau, George J; Pazoki, Raha; Pedersen, Nancy L; Peters, Annette; Peyser, Patricia A; Polasek, Ozren; Porteous, David J; Poveda, Alaitz; Raitakari, Olli T; Rich, Stephen S; Risch, Neil; Robinson, Jennifer G; Rose, Lynda M; Rudan, Igor; Schreiner, Pamela J; Scott, Robert A; Sidney, Stephen S; Sims, Mario; Smith, Jennifer A; Snieder, Harold; Sofer, Tamar; Starr, John M; Sternfeld, Barbara; Strauch, Konstantin; Tang, Hua; Taylor, Kent D; Tsai, Michael Y; Tuomilehto, Jaakko; Uitterlinden, André G; van der Ende, M Yldau; van Heemst, Diana; Voortman, Trudy; Waldenberger, Melanie; Wennberg, Patrik; Wilson, Gregory; Xiang, Yong-Bing; Yao, Jie; Yu, Caizheng; Yuan, Jian-Min; Zhao, Wei; Zonderman, Alan B; Becker, Diane M; Boehnke, Michael; Bowden, Donald W; de Faire, Ulf; Deary, Ian J; Elliott, Paul; Esko, Tõnu; Freedman, Barry I; Froguel, Philippe; Gasparini, Paolo; Gieger, Christian; Kato, Norihiro; Laakso, Markku; Lakka, Timo A; Lehtimäki, Terho; Magnusson, Patrik K E; Oldehinkel, Albertine J; Penninx, Brenda W J H; Samani, Nilesh J; Shu, Xiao-Ou; van der Harst, Pim; Van Vliet-Ostaptchouk, Jana V; Vollenweider, Peter; Wagenknecht, Lynne E; Wang, Ya X; Wareham, Nicholas J; Weir, David R; Wu, Tangchun; Zheng, Wei; Zhu, Xiaofeng; Evans, Michele K; Franks, Paul W; Gudnason, Vilmundur; Hayward, Caroline; Horta, Bernardo L; Kelly, Tanika N; Liu, Yongmei; North, Kari E; Pereira, Alexandre C; Ridker, Paul M; Tai, E Shyong; van Dam, Rob M; Fox, Ervin R; Kardia, Sharon L R; Liu, Ching-Ti; Mook-Kanamori, Dennis O; Province, Michael A; Redline, Susan; van Duijn, Cornelia M; Rotter, Jerome I; Kooperberg, Charles B; Gauderman, W James; Psaty, Bruce M; Rice, Kenneth; Munroe, Patricia B; Fornage, Myriam; Cupples, L Adrienne; Rotimi, Charles N; Morrison, Alanna C; Rao, Dabeeru C; Loos, Ruth J F
Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.
PMCID:6342931
PMID: 30670697
ISSN: 2041-1723
CID: 4318842
Co-occurrence of early diabetes-related complications in adolescents and young adults with type 1 diabetes: an observational cohort study
Sauder, Katherine A; Stafford, Jeanette M; Mayer-Davis, Elizabeth J; Jensen, Elizabeth T; Saydah, Sharon; Mottl, Amy; Dolan, Lawrence M; Hamman, Richard F; Lawrence, Jean M; Pihoker, Catherine; Marcovina, Santica; D'Agostino, Ralph B; Dabelea, Dana; [Divers, Jasmin]
BACKGROUND:One in three adolescents and young adults with type 1 diabetes have at least one early diabetes-related complication or comorbidity. We aimed to examine the prevalence and pattern of co-occurring complications in this population, as well as the related risk factors. METHODS:This observational cohort study includes data from individuals diagnosed with type 1 diabetes before age 20 years who participated in the SEARCH for Diabetes in Youth Study across five sites in the USA. We assessed sociodemographic and metabolic risk factors at baseline and at follow-up, and diabetes complications at follow-up. A frequency analysis was done to examine the difference in observed versus expected prevalence (calculated using a contingency table assuming independence across cells) of co-occurring complications or comorbidities. A cluster analysis was done to identify unique clusters of participants based on demographic characteristics and metabolic risk factors. FINDINGS/RESULTS:1327 participants who completed the follow-up visit were included in the frequency analysis. The mean age was 10·1 (SD 3·9) years at the time of type 1 diabetes diagnosis and 18·0 (4·1) years at follow-up. At a mean diabetes duration of 7·8 [SD 1·9] years, co-occurrence of any two or more complications was observed in 78 (5·9%) participants, more frequently than expected by chance alone (58 [4·4%], p=0·015). Specifically, the complications that co-occurred more frequently than expected were retinopathy and diabetic kidney disease (11 [0·8%] vs three [0·2%]; p=0·0007), retinopathy and arterial stiffness (13 [1·0%] vs four [0·3%]; p=0·0016), and arterial stiffness and cardiovascular autonomic neuropathy (24 [1·8%] vs 13 [1·0%]; p=0·015). We identified four unique clusters characterised by progressively worsening metabolic risk factor profiles (longer duration of diabetes and higher glycated haemoglobin, non-HDL cholesterol, and waist-to-height ratio). The prevalence of at least two complications increased across the clusters (six [2·3%] of 261 in the low-risk cluster, 32 [6·3%] of 509 in the moderate-risk cluster, 28 [8%] of 348 in the high-risk cluster, and five [20·8%] of 24 in the highest-risk cluster). Compared with the low-risk and moderate-risk clusters, the high-risk and highest-risk clusters were characterised by a lower proportion of participants who were non-Hispanic white, and a higher proportion of participants who had a household income below US$50 000 and did not have private health insurance. INTERPRETATION/CONCLUSIONS:Early complications co-occur in adolescents and young adults with type 1 diabetes more frequently than expected. Identification of individuals with adverse risk factors could enable targeted behavioural or medical interventions that reduce the likelihood of early development of lifelong diabetes-related morbidity. FUNDING/BACKGROUND:US Centers for Disease Control and Prevention, US National Institutes of Health.
PMCID:6295346
PMID: 30409691
ISSN: 2352-4650
CID: 4325142
Genetic Architecture of Primary Open Angle Glaucoma in Individuals of African Descent: The African Descent & Glaucoma Evaluation Study (ADAGES) III
Taylor, Kent D; Guo, Xiuqing; Zangwill, Linda M; Liebmann, Jeffrey M; Girkin, Christopher A; Feldman, Robert M; Dubiner, Harvey; Hai, Yang; Samuels, Brian C; Panarelli, Joseph F; Mitchell, John P; Al-Aswad, Lama A; Park, Sung Chul; Tello, Celso; Cotliar, Jeremy; Bansal, Rajendra; Sidoti, Paul A; Cioffi, George A; Blumberg, Dana; Ritch, Robert; Bell, Nicholas P; Blieden, Lauren S; Davis, Garvin; Medeiros, Felipe A; Das, Swapan K; Divers, Jasmin; Langefeld, Carl D; Palmer, Nicholette D; Freedman, Barry I; Bowden, Donald W; Ng, Maggie C Y; Ida Chen, Yii-Der; Ayyagari, Radha; Rotter, Jerome I; Weinreb, Robert N
OBJECTIVE:Find genetic contributions to glaucoma in African Americans. DESIGN/METHODS:Cross-sectional, case-control study. PARTICIPANTS/METHODS:1875 POAG cases and 1709 controls, self-identified as African Descent (AD), from the African Descent and Glaucoma Evaluation Study (ADAGESIII) and Wake Forest School of Medicine. METHODS:MegaChip genotypes were imputed to Thousand Genomes data. Association of SNPs with POAG and advanced POAG was tested by linear mixed model correcting for relatedness and population stratification. Genetic risk scores were tested by Receiver Operator Characteristics (ROC-AUC). MAIN OUTCOME/RESULTS:POAG defined by visual field loss without other non-ocular conditions (N=1875). Advanced POAG was defined by age-based mean deviation of visual field (N=946). RESULTS:) was observed, not in LD with the previously reported ED SNP. Additional previously identified loci associated with POAG in AD were: 8q22, AFAP1, TMCO1. An AUC of 0.62 was observed with an unweighted genetic risk score composed of 11 SNPs in candidate genes. Two additional risk scores were studied by using a penalized matrix decomposition with cross-validation; risk scores of 50 and 400 SNPs were identified with ROC of AUC=0.74 and AUC=0.94, respectively. CONCLUSIONS:A novel association with advanced POAG in the ENO4 locus was putatively identified in subjects of African descent. In addition to this finding, this GWAS in AD POAG subjects contributes to POAG genetics by identification of novel signals in prior loci (9p21), as well as advancing the fine-mapping of regions due to shorter average linkage disequilibrium (FNDC3B). While not useful without confirmation and clinical trials, the use of genetic risk scores demonstrated that considerable AD-specific genetic information remains in these data.
PMID: 30352225
ISSN: 1549-4713
CID: 3384612
