%0 Journal Article %J Am J Hum Genet %D 2018 %T Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. %A Ligthart, Symen %A Vaez, Ahmad %A Võsa, Urmo %A Stathopoulou, Maria G %A de Vries, Paul S %A Prins, Bram P %A van der Most, Peter J %A Tanaka, Toshiko %A Naderi, Elnaz %A Rose, Lynda M %A Wu, Ying %A Karlsson, Robert %A Barbalic, Maja %A Lin, Honghuang %A Pool, Rene %A Zhu, Gu %A Mace, Aurelien %A Sidore, Carlo %A Trompet, Stella %A Mangino, Massimo %A Sabater-Lleal, Maria %A Kemp, John P %A Abbasi, Ali %A Kacprowski, Tim %A Verweij, Niek %A Smith, Albert V %A Huang, Tao %A Marzi, Carola %A Feitosa, Mary F %A Lohman, Kurt K %A Kleber, Marcus E %A Milaneschi, Yuri %A Mueller, Christian %A Huq, Mahmudul %A Vlachopoulou, Efthymia %A Lyytikäinen, Leo-Pekka %A Oldmeadow, Christopher %A Deelen, Joris %A Perola, Markus %A Zhao, Jing Hua %A Feenstra, Bjarke %A Amini, Marzyeh %A Lahti, Jari %A Schraut, Katharina E %A Fornage, Myriam %A Suktitipat, Bhoom %A Chen, Wei-Min %A Li, Xiaohui %A Nutile, Teresa %A Malerba, Giovanni %A Luan, Jian'an %A Bak, Tom %A Schork, Nicholas %A del Greco M, Fabiola %A Thiering, Elisabeth %A Mahajan, Anubha %A Marioni, Riccardo E %A Mihailov, Evelin %A Eriksson, Joel %A Ozel, Ayse Bilge %A Zhang, Weihua %A Nethander, Maria %A Cheng, Yu-Ching %A Aslibekyan, Stella %A Ang, Wei %A Gandin, Ilaria %A Yengo, Loic %A Portas, Laura %A Kooperberg, Charles %A Hofer, Edith %A Rajan, Kumar B %A Schurmann, Claudia %A den Hollander, Wouter %A Ahluwalia, Tarunveer S %A Zhao, Jing %A Draisma, Harmen H M %A Ford, Ian %A Timpson, Nicholas %A Teumer, Alexander %A Huang, Hongyan %A Wahl, Simone %A Liu, Yongmei %A Huang, Jie %A Uh, Hae-Won %A Geller, Frank %A Joshi, Peter K %A Yanek, Lisa R %A Trabetti, Elisabetta %A Lehne, Benjamin %A Vozzi, Diego %A Verbanck, Marie %A Biino, Ginevra %A Saba, Yasaman %A Meulenbelt, Ingrid %A O'Connell, Jeff R %A Laakso, Markku %A Giulianini, Franco %A Magnusson, Patrik K E %A Ballantyne, Christie M %A Hottenga, Jouke Jan %A Montgomery, Grant W %A Rivadineira, Fernando %A Rueedi, Rico %A Steri, Maristella %A Herzig, Karl-Heinz %A Stott, David J %A Menni, Cristina %A Frånberg, Mattias %A St Pourcain, Beate %A Felix, Stephan B %A Pers, Tune H %A Bakker, Stephan J L %A Kraft, Peter %A Peters, Annette %A Vaidya, Dhananjay %A Delgado, Graciela %A Smit, Johannes H %A Großmann, Vera %A Sinisalo, Juha %A Seppälä, Ilkka %A Williams, Stephen R %A Holliday, Elizabeth G %A Moed, Matthijs %A Langenberg, Claudia %A Räikkönen, Katri %A Ding, Jingzhong %A Campbell, Harry %A Sale, Michèle M %A Chen, Yii-der I %A James, Alan L %A Ruggiero, Daniela %A Soranzo, Nicole %A Hartman, Catharina A %A Smith, Erin N %A Berenson, Gerald S %A Fuchsberger, Christian %A Hernandez, Dena %A Tiesler, Carla M T %A Giedraitis, Vilmantas %A Liewald, David %A Fischer, Krista %A Mellström, Dan %A Larsson, Anders %A Wang, Yunmei %A Scott, William R %A Lorentzon, Matthias %A Beilby, John %A Ryan, Kathleen A %A Pennell, Craig E %A Vuckovic, Dragana %A Balkau, Beverly %A Concas, Maria Pina %A Schmidt, Reinhold %A Mendes de Leon, Carlos F %A Bottinger, Erwin P %A Kloppenburg, Margreet %A Paternoster, Lavinia %A Boehnke, Michael %A Musk, A W %A Willemsen, Gonneke %A Evans, David M %A Madden, Pamela A F %A Kähönen, Mika %A Kutalik, Zoltán %A Zoledziewska, Magdalena %A Karhunen, Ville %A Kritchevsky, Stephen B %A Sattar, Naveed %A Lachance, Genevieve %A Clarke, Robert %A Harris, Tamara B %A Raitakari, Olli T %A Attia, John R %A van Heemst, Diana %A Kajantie, Eero %A Sorice, Rossella %A Gambaro, Giovanni %A Scott, Robert A %A Hicks, Andrew A %A Ferrucci, Luigi %A Standl, Marie %A Lindgren, Cecilia M %A Starr, John M %A Karlsson, Magnus %A Lind, Lars %A Li, Jun Z %A Chambers, John C %A Mori, Trevor A %A de Geus, Eco J C N %A Heath, Andrew C %A Martin, Nicholas G %A Auvinen, Juha %A Buckley, Brendan M %A de Craen, Anton J M %A Waldenberger, Melanie %A Strauch, Konstantin %A Meitinger, Thomas %A Scott, Rodney J %A McEvoy, Mark %A Beekman, Marian %A Bombieri, Cristina %A Ridker, Paul M %A Mohlke, Karen L %A Pedersen, Nancy L %A Morrison, Alanna C %A Boomsma, Dorret I %A Whitfield, John B %A Strachan, David P %A Hofman, Albert %A Vollenweider, Peter %A Cucca, Francesco %A Jarvelin, Marjo-Riitta %A Jukema, J Wouter %A Spector, Tim D %A Hamsten, Anders %A Zeller, Tanja %A Uitterlinden, André G %A Nauck, Matthias %A Gudnason, Vilmundur %A Qi, Lu %A Grallert, Harald %A Borecki, Ingrid B %A Rotter, Jerome I %A März, Winfried %A Wild, Philipp S %A Lokki, Marja-Liisa %A Boyle, Michael %A Salomaa, Veikko %A Melbye, Mads %A Eriksson, Johan G %A Wilson, James F %A Penninx, Brenda W J H %A Becker, Diane M %A Worrall, Bradford B %A Gibson, Greg %A Krauss, Ronald M %A Ciullo, Marina %A Zaza, Gianluigi %A Wareham, Nicholas J %A Oldehinkel, Albertine J %A Palmer, Lyle J %A Murray, Sarah S %A Pramstaller, Peter P %A Bandinelli, Stefania %A Heinrich, Joachim %A Ingelsson, Erik %A Deary, Ian J %A Mägi, Reedik %A Vandenput, Liesbeth %A van der Harst, Pim %A Desch, Karl C %A Kooner, Jaspal S %A Ohlsson, Claes %A Hayward, Caroline %A Lehtimäki, Terho %A Shuldiner, Alan R %A Arnett, Donna K %A Beilin, Lawrence J %A Robino, Antonietta %A Froguel, Philippe %A Pirastu, Mario %A Jess, Tine %A Koenig, Wolfgang %A Loos, Ruth J F %A Evans, Denis A %A Schmidt, Helena %A Smith, George Davey %A Slagboom, P Eline %A Eiriksdottir, Gudny %A Morris, Andrew P %A Psaty, Bruce M %A Tracy, Russell P %A Nolte, Ilja M %A Boerwinkle, Eric %A Visvikis-Siest, Sophie %A Reiner, Alex P %A Gross, Myron %A Bis, Joshua C %A Franke, Lude %A Franco, Oscar H %A Benjamin, Emelia J %A Chasman, Daniel I %A Dupuis, Josée %A Snieder, Harold %A Dehghan, Abbas %A Alizadeh, Behrooz Z %X

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

%B Am J Hum Genet %V 103 %P 691-706 %8 2018 Nov 01 %G eng %N 5 %R 10.1016/j.ajhg.2018.09.009 %0 Journal Article %J PLoS One %D 2018 %T Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries. %A Feitosa, Mary F %A Kraja, Aldi T %A Chasman, Daniel I %A Sung, Yun J %A Winkler, Thomas W %A Ntalla, Ioanna %A Guo, Xiuqing %A Franceschini, Nora %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Marten, Jonathan %A Musani, Solomon K %A Li, Changwei %A Bentley, Amy R %A Brown, Michael R %A Schwander, Karen %A Richard, Melissa A %A Noordam, Raymond %A Aschard, Hugues %A Bartz, Traci M %A Bielak, Lawrence F %A Dorajoo, Rajkumar %A Fisher, Virginia %A Hartwig, Fernando P %A Horimoto, Andrea R V R %A Lohman, Kurt K %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert V %A Tajuddin, Salman M %A Wojczynski, Mary K %A Alver, Maris %A Boissel, Mathilde %A Cai, Qiuyin %A Campbell, Archie %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Gao, Chuan %A Goel, Anuj %A Hagemeijer, Yanick %A Harris, Sarah E %A He, Meian %A Hsu, Fang-Chi %A Jackson, Anne U %A Kähönen, Mika %A Kasturiratne, Anuradhani %A Komulainen, Pirjo %A Kuhnel, Brigitte %A Laguzzi, Federica %A Luan, Jian'an %A Matoba, Nana %A Nolte, Ilja M %A Padmanabhan, Sandosh %A Riaz, Muhammad %A Rueedi, Rico %A Robino, Antonietta %A Said, M Abdullah %A Scott, Robert A %A Sofer, Tamar %A Stančáková, Alena %A Takeuchi, Fumihiko %A Tayo, Bamidele O %A van der Most, Peter J %A Varga, Tibor V %A Vitart, Veronique %A Wang, Yajuan %A Ware, Erin B %A Warren, Helen R %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Afaq, Saima %A Amin, Najaf %A Amini, Marzyeh %A Arking, Dan E %A Aung, Tin %A Boerwinkle, Eric %A Borecki, Ingrid %A Broeckel, Ulrich %A Brown, Morris %A Brumat, Marco %A Burke, Gregory L %A Canouil, Mickaël %A Chakravarti, Aravinda %A Charumathi, Sabanayagam %A Ida Chen, Yii-Der %A Connell, John M %A Correa, Adolfo %A de Las Fuentes, Lisa %A de Mutsert, Renée %A de Silva, H Janaka %A Deng, Xuan %A Ding, Jingzhong %A Duan, Qing %A Eaton, Charles B %A Ehret, Georg %A Eppinga, Ruben N %A Evangelou, Evangelos %A Faul, Jessica D %A Felix, Stephan B %A Forouhi, Nita G %A Forrester, Terrence %A Franco, Oscar H %A Friedlander, Yechiel %A Gandin, Ilaria %A Gao, He %A Ghanbari, Mohsen %A Gigante, Bruna %A Gu, C Charles %A Gu, Dongfeng %A Hagenaars, Saskia P %A Hallmans, Göran %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Howard, Barbara V %A Ikram, M Arfan %A John, Ulrich %A Katsuya, Tomohiro %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Krieger, Jose E %A Kritchevsky, Stephen B %A Kubo, Michiaki %A Kuusisto, Johanna %A Lakka, Timo A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lewis, Cora E %A Li, Yize %A Lin, Shiow %A Liu, Jianjun %A Liu, Jingmin %A Loh, Marie %A Louie, Tin %A Mägi, Reedik %A McKenzie, Colin A %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Milani, Lili %A Mohlke, Karen L %A Momozawa, Yukihide %A Nalls, Mike A %A Nelson, Christopher P %A Sotoodehnia, Nona %A Norris, Jill M %A O'Connell, Jeff R %A Palmer, Nicholette D %A Perls, Thomas %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Poulter, Neil %A Raffel, Leslie J %A Raitakari, Olli T %A Roll, Kathryn %A Rose, Lynda M %A Rosendaal, Frits R %A Rotter, Jerome I %A Schmidt, Carsten O %A Schreiner, Pamela J %A Schupf, Nicole %A Scott, William R %A Sever, Peter S %A Shi, Yuan %A Sidney, Stephen %A Sims, Mario %A Sitlani, Colleen M %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Stringham, Heather M %A Tan, Nicholas Y Q %A Tang, Hua %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Turner, Stephen T %A Uitterlinden, André G %A Vollenweider, Peter %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya Xing %A Wei, Wen Bin %A Williams, Christine %A Yao, Jie %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Jonas, Jost Bruno %A Kamatani, Yoichiro %A Kato, Norihiro %A Kooner, Jaspal S %A Kutalik, Zoltán %A Laakso, Markku %A Laurie, Cathy C %A Leander, Karin %A Lehtimäki, Terho %A Study, Lifelines Cohort %A Magnusson, Patrik K E %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Polasek, Ozren %A Porteous, David J %A Rauramaa, Rainer %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Zheng, Wei %A Bouchard, Claude %A Christensen, Kaare %A Evans, Michele K %A Gudnason, Vilmundur %A Horta, Bernardo L %A Kardia, Sharon L R %A Liu, Yongmei %A Pereira, Alexandre C %A Psaty, Bruce M %A Ridker, Paul M %A van Dam, Rob M %A Gauderman, W James %A Zhu, Xiaofeng %A Mook-Kanamori, Dennis O %A Fornage, Myriam %A Rotimi, Charles N %A Cupples, L Adrienne %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Kooperberg, Charles %A Palmas, Walter %A Rice, Kenneth %A Morrison, Alanna C %A Elliott, Paul %A Caulfield, Mark J %A Munroe, Patricia B %A Rao, Dabeeru C %A Province, Michael A %A Levy, Daniel %X

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

%B PLoS One %V 13 %P e0198166 %8 2018 %G eng %N 6 %R 10.1371/journal.pone.0198166 %0 Journal Article %J Nat Genet %D 2019 %T A catalog of genetic loci associated with kidney function from analyses of a million individuals. %A Wuttke, Matthias %A Li, Yong %A Li, Man %A Sieber, Karsten B %A Feitosa, Mary F %A Gorski, Mathias %A Tin, Adrienne %A Wang, Lihua %A Chu, Audrey Y %A Hoppmann, Anselm %A Kirsten, Holger %A Giri, Ayush %A Chai, Jin-Fang %A Sveinbjornsson, Gardar %A Tayo, Bamidele O %A Nutile, Teresa %A Fuchsberger, Christian %A Marten, Jonathan %A Cocca, Massimiliano %A Ghasemi, Sahar %A Xu, Yizhe %A Horn, Katrin %A Noce, Damia %A van der Most, Peter J %A Sedaghat, Sanaz %A Yu, Zhi %A Akiyama, Masato %A Afaq, Saima %A Ahluwalia, Tarunveer S %A Almgren, Peter %A Amin, Najaf %A Arnlöv, Johan %A Bakker, Stephan J L %A Bansal, Nisha %A Baptista, Daniela %A Bergmann, Sven %A Biggs, Mary L %A Biino, Ginevra %A Boehnke, Michael %A Boerwinkle, Eric %A Boissel, Mathilde %A Bottinger, Erwin P %A Boutin, Thibaud S %A Brenner, Hermann %A Brumat, Marco %A Burkhardt, Ralph %A Butterworth, Adam S %A Campana, Eric %A Campbell, Archie %A Campbell, Harry %A Canouil, Mickaël %A Carroll, Robert J %A Catamo, Eulalia %A Chambers, John C %A Chee, Miao-Ling %A Chee, Miao-Li %A Chen, Xu %A Cheng, Ching-Yu %A Cheng, Yurong %A Christensen, Kaare %A Cifkova, Renata %A Ciullo, Marina %A Concas, Maria Pina %A Cook, James P %A Coresh, Josef %A Corre, Tanguy %A Sala, Cinzia Felicita %A Cusi, Daniele %A Danesh, John %A Daw, E Warwick %A de Borst, Martin H %A De Grandi, Alessandro %A de Mutsert, Renée %A de Vries, Aiko P J %A Degenhardt, Frauke %A Delgado, Graciela %A Demirkan, Ayse %A Di Angelantonio, Emanuele %A Dittrich, Katalin %A Divers, Jasmin %A Dorajoo, Rajkumar %A Eckardt, Kai-Uwe %A Ehret, Georg %A Elliott, Paul %A Endlich, Karlhans %A Evans, Michele K %A Felix, Janine F %A Foo, Valencia Hui Xian %A Franco, Oscar H %A Franke, Andre %A Freedman, Barry I %A Freitag-Wolf, Sandra %A Friedlander, Yechiel %A Froguel, Philippe %A Gansevoort, Ron T %A Gao, He %A Gasparini, Paolo %A Gaziano, J Michael %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Giulianini, Franco %A Gögele, Martin %A Gordon, Scott D %A Gudbjartsson, Daniel F %A Gudnason, Vilmundur %A Haller, Toomas %A Hamet, Pavel %A Harris, Tamara B %A Hartman, Catharina A %A Hayward, Caroline %A Hellwege, Jacklyn N %A Heng, Chew-Kiat %A Hicks, Andrew A %A Hofer, Edith %A Huang, Wei %A Hutri-Kähönen, Nina %A Hwang, Shih-Jen %A Ikram, M Arfan %A Indridason, Olafur S %A Ingelsson, Erik %A Ising, Marcus %A Jaddoe, Vincent W V %A Jakobsdottir, Johanna %A Jonas, Jost B %A Joshi, Peter K %A Josyula, Navya Shilpa %A Jung, Bettina %A Kähönen, Mika %A Kamatani, Yoichiro %A Kammerer, Candace M %A Kanai, Masahiro %A Kastarinen, Mika %A Kerr, Shona M %A Khor, Chiea-Chuen %A Kiess, Wieland %A Kleber, Marcus E %A Koenig, Wolfgang %A Kooner, Jaspal S %A Körner, Antje %A Kovacs, Peter %A Kraja, Aldi T %A Krajcoviechova, Alena %A Kramer, Holly %A Krämer, Bernhard K %A Kronenberg, Florian %A Kubo, Michiaki %A Kuhnel, Brigitte %A Kuokkanen, Mikko %A Kuusisto, Johanna %A La Bianca, Martina %A Laakso, Markku %A Lange, Leslie A %A Langefeld, Carl D %A Lee, Jeannette Jen-Mai %A Lehne, Benjamin %A Lehtimäki, Terho %A Lieb, Wolfgang %A Lim, Su-Chi %A Lind, Lars %A Lindgren, Cecilia M %A Liu, Jun %A Liu, Jianjun %A Loeffler, Markus %A Loos, Ruth J F %A Lucae, Susanne %A Lukas, Mary Ann %A Lyytikäinen, Leo-Pekka %A Mägi, Reedik %A Magnusson, Patrik K E %A Mahajan, Anubha %A Martin, Nicholas G %A Martins, Jade %A März, Winfried %A Mascalzoni, Deborah %A Matsuda, Koichi %A Meisinger, Christa %A Meitinger, Thomas %A Melander, Olle %A Metspalu, Andres %A Mikaelsdottir, Evgenia K %A Milaneschi, Yuri %A Miliku, Kozeta %A Mishra, Pashupati P %A Mohlke, Karen L %A Mononen, Nina %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Mychaleckyj, Josyf C %A Nadkarni, Girish N %A Nalls, Mike A %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A Noordam, Raymond %A O'Connell, Jeffrey %A O'Donoghue, Michelle L %A Olafsson, Isleifur %A Oldehinkel, Albertine J %A Orho-Melander, Marju %A Ouwehand, Willem H %A Padmanabhan, Sandosh %A Palmer, Nicholette D %A Palsson, Runolfur %A Penninx, Brenda W J H %A Perls, Thomas %A Perola, Markus %A Pirastu, Mario %A Pirastu, Nicola %A Pistis, Giorgio %A Podgornaia, Anna I %A Polasek, Ozren %A Ponte, Belen %A Porteous, David J %A Poulain, Tanja %A Pramstaller, Peter P %A Preuss, Michael H %A Prins, Bram P %A Province, Michael A %A Rabelink, Ton J %A Raffield, Laura M %A Raitakari, Olli T %A Reilly, Dermot F %A Rettig, Rainer %A Rheinberger, Myriam %A Rice, Kenneth M %A Ridker, Paul M %A Rivadeneira, Fernando %A Rizzi, Federica %A Roberts, David J %A Robino, Antonietta %A Rossing, Peter %A Rudan, Igor %A Rueedi, Rico %A Ruggiero, Daniela %A Ryan, Kathleen A %A Saba, Yasaman %A Sabanayagam, Charumathi %A Salomaa, Veikko %A Salvi, Erika %A Saum, Kai-Uwe %A Schmidt, Helena %A Schmidt, Reinhold %A Schöttker, Ben %A Schulz, Christina-Alexandra %A Schupf, Nicole %A Shaffer, Christian M %A Shi, Yuan %A Smith, Albert V %A Smith, Blair H %A Soranzo, Nicole %A Spracklen, Cassandra N %A Strauch, Konstantin %A Stringham, Heather M %A Stumvoll, Michael %A Svensson, Per O %A Szymczak, Silke %A Tai, E-Shyong %A Tajuddin, Salman M %A Tan, Nicholas Y Q %A Taylor, Kent D %A Teren, Andrej %A Tham, Yih-Chung %A Thiery, Joachim %A Thio, Chris H L %A Thomsen, Hauke %A Thorleifsson, Gudmar %A Toniolo, Daniela %A Tönjes, Anke %A Tremblay, Johanne %A Tzoulaki, Ioanna %A Uitterlinden, André G %A Vaccargiu, Simona %A van Dam, Rob M %A van der Harst, Pim %A van Duijn, Cornelia M %A Velez Edward, Digna R %A Verweij, Niek %A Vogelezang, Suzanne %A Völker, Uwe %A Vollenweider, Peter %A Waeber, Gérard %A Waldenberger, Melanie %A Wallentin, Lars %A Wang, Ya Xing %A Wang, Chaolong %A Waterworth, Dawn M %A Bin Wei, Wen %A White, Harvey %A Whitfield, John B %A Wild, Sarah H %A Wilson, James F %A Wojczynski, Mary K %A Wong, Charlene %A Wong, Tien-Yin %A Xu, Liang %A Yang, Qiong %A Yasuda, Masayuki %A Yerges-Armstrong, Laura M %A Zhang, Weihua %A Zonderman, Alan B %A Rotter, Jerome I %A Bochud, Murielle %A Psaty, Bruce M %A Vitart, Veronique %A Wilson, James G %A Dehghan, Abbas %A Parsa, Afshin %A Chasman, Daniel I %A Ho, Kevin %A Morris, Andrew P %A Devuyst, Olivier %A Akilesh, Shreeram %A Pendergrass, Sarah A %A Sim, Xueling %A Böger, Carsten A %A Okada, Yukinori %A Edwards, Todd L %A Snieder, Harold %A Stefansson, Kari %A Hung, Adriana M %A Heid, Iris M %A Scholz, Markus %A Teumer, Alexander %A Köttgen, Anna %A Pattaro, Cristian %K Chromosome Mapping %K European Continental Ancestry Group %K Genetic Association Studies %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Inheritance Patterns %K Kidney Function Tests %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Quantitative Trait, Heritable %K Renal Insufficiency, Chronic %K Uromodulin %X

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.

%B Nat Genet %V 51 %P 957-972 %8 2019 06 %G eng %N 6 %R 10.1038/s41588-019-0407-x %0 Journal Article %J Nat Commun %D 2019 %T Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity. %A Kilpeläinen, Tuomas O %A Bentley, Amy R %A Noordam, Raymond %A Sung, Yun Ju %A Schwander, Karen %A Winkler, Thomas W %A Jakupović, Hermina %A Chasman, Daniel I %A Manning, Alisa %A Ntalla, Ioanna %A Aschard, Hugues %A Brown, Michael R %A de Las Fuentes, Lisa %A Franceschini, Nora %A Guo, Xiuqing %A Vojinovic, Dina %A Aslibekyan, Stella %A Feitosa, Mary F %A Kho, Minjung %A Musani, Solomon K %A Richard, Melissa %A Wang, Heming %A Wang, Zhe %A Bartz, Traci M %A Bielak, Lawrence F %A Campbell, Archie %A Dorajoo, Rajkumar %A Fisher, Virginia %A Hartwig, Fernando P %A Horimoto, Andrea R V R %A Li, Changwei %A Lohman, Kurt K %A Marten, Jonathan %A Sim, Xueling %A Smith, Albert V %A Tajuddin, Salman M %A Alver, Maris %A Amini, Marzyeh %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Evangelou, Evangelos %A Gao, Chuan %A Graff, Mariaelisa %A Harris, Sarah E %A He, Meian %A Hsu, Fang-Chi %A Jackson, Anne U %A Zhao, Jing Hua %A Kraja, Aldi T %A Kuhnel, Brigitte %A Laguzzi, Federica %A Lyytikäinen, Leo-Pekka %A Nolte, Ilja M %A Rauramaa, Rainer %A Riaz, Muhammad %A Robino, Antonietta %A Rueedi, Rico %A Stringham, Heather M %A Takeuchi, Fumihiko %A van der Most, Peter J %A Varga, Tibor V %A Verweij, Niek %A Ware, Erin B %A Wen, Wanqing %A Li, Xiaoyin %A Yanek, Lisa R %A Amin, Najaf %A Arnett, Donna K %A Boerwinkle, Eric %A Brumat, Marco %A Cade, Brian %A Canouil, Mickaël %A Chen, Yii-Der Ida %A Concas, Maria Pina %A Connell, John %A de Mutsert, Renée %A de Silva, H Janaka %A de Vries, Paul S %A Demirkan, Ayse %A Ding, Jingzhong %A Eaton, Charles B %A Faul, Jessica D %A Friedlander, Yechiel %A Gabriel, Kelley P %A Ghanbari, Mohsen %A Giulianini, Franco %A Gu, Chi Charles %A Gu, Dongfeng %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hunt, Steven C %A Ikram, M Arfan %A Jonas, Jost B %A Koh, Woon-Puay %A Komulainen, Pirjo %A Krieger, Jose E %A Kritchevsky, Stephen B %A Kutalik, Zoltán %A Kuusisto, Johanna %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Leander, Karin %A Lemaitre, Rozenn N %A Lewis, Cora E %A Liang, Jingjing %A Liu, Jianjun %A Mägi, Reedik %A Manichaikul, Ani %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Mohlke, Karen L %A Mosley, Thomas H %A Murray, Alison D %A Nalls, Mike A %A Nang, Ei-Ei Khaing %A Nelson, Christopher P %A Nona, Sotoodehnia %A Norris, Jill M %A Nwuba, Chiamaka Vivian %A O'Connell, Jeff %A Palmer, Nicholette D %A Papanicolau, George J %A Pazoki, Raha %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Porteous, David J %A Poveda, Alaitz %A Raitakari, Olli T %A Rich, Stephen S %A Risch, Neil %A Robinson, Jennifer G %A Rose, Lynda M %A Rudan, Igor %A Schreiner, Pamela J %A Scott, Robert A %A Sidney, Stephen S %A Sims, Mario %A Smith, Jennifer A %A Snieder, Harold %A Sofer, Tamar %A Starr, John M %A Sternfeld, Barbara %A Strauch, Konstantin %A Tang, Hua %A Taylor, Kent D %A Tsai, Michael Y %A Tuomilehto, Jaakko %A Uitterlinden, André G %A van der Ende, M Yldau %A van Heemst, Diana %A Voortman, Trudy %A Waldenberger, Melanie %A Wennberg, Patrik %A Wilson, Gregory %A Xiang, Yong-Bing %A Yao, Jie %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A de Faire, Ulf %A Deary, Ian J %A Elliott, Paul %A Esko, Tõnu %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Kato, Norihiro %A Laakso, Markku %A Lakka, Timo A %A Lehtimäki, Terho %A Magnusson, Patrik K E %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Samani, Nilesh J %A Shu, Xiao-Ou %A van der Harst, Pim %A van Vliet-Ostaptchouk, Jana V %A Vollenweider, Peter %A Wagenknecht, Lynne E %A Wang, Ya X %A Wareham, Nicholas J %A Weir, David R %A Wu, Tangchun %A Zheng, Wei %A Zhu, Xiaofeng %A Evans, Michele K %A Franks, Paul W %A Gudnason, Vilmundur %A Hayward, Caroline %A Horta, Bernardo L %A Kelly, Tanika N %A Liu, Yongmei %A North, Kari E %A Pereira, Alexandre C %A Ridker, Paul M %A Tai, E Shyong %A van Dam, Rob M %A Fox, Ervin R %A Kardia, Sharon L R %A Liu, Ching-Ti %A Mook-Kanamori, Dennis O %A Province, Michael A %A Redline, Susan %A van Duijn, Cornelia M %A Rotter, Jerome I %A Kooperberg, Charles B %A Gauderman, W James %A Psaty, Bruce M %A Rice, Kenneth %A Munroe, Patricia B %A Fornage, Myriam %A Cupples, L Adrienne %A Rotimi, Charles N %A Morrison, Alanna C %A Rao, Dabeeru C %A Loos, Ruth J F %K Adolescent %K Adult %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K Asian Continental Ancestry Group %K Brazil %K Calcium-Binding Proteins %K Cholesterol %K Cholesterol, HDL %K Cholesterol, LDL %K European Continental Ancestry Group %K Exercise %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Hispanic Americans %K Humans %K LIM-Homeodomain Proteins %K Lipid Metabolism %K Lipids %K Male %K Membrane Proteins %K Microtubule-Associated Proteins %K Middle Aged %K Muscle Proteins %K Nerve Tissue Proteins %K Transcription Factors %K Triglycerides %K Young Adult %X

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.

%B Nat Commun %V 10 %P 376 %8 2019 01 22 %G eng %N 1 %R 10.1038/s41467-018-08008-w %0 Journal Article %J Nat Genet %D 2019 %T Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels. %A Tin, Adrienne %A Marten, Jonathan %A Halperin Kuhns, Victoria L %A Li, Yong %A Wuttke, Matthias %A Kirsten, Holger %A Sieber, Karsten B %A Qiu, Chengxiang %A Gorski, Mathias %A Yu, Zhi %A Giri, Ayush %A Sveinbjornsson, Gardar %A Li, Man %A Chu, Audrey Y %A Hoppmann, Anselm %A O'Connor, Luke J %A Prins, Bram %A Nutile, Teresa %A Noce, Damia %A Akiyama, Masato %A Cocca, Massimiliano %A Ghasemi, Sahar %A van der Most, Peter J %A Horn, Katrin %A Xu, Yizhe %A Fuchsberger, Christian %A Sedaghat, Sanaz %A Afaq, Saima %A Amin, Najaf %A Arnlöv, Johan %A Bakker, Stephan J L %A Bansal, Nisha %A Baptista, Daniela %A Bergmann, Sven %A Biggs, Mary L %A Biino, Ginevra %A Boerwinkle, Eric %A Bottinger, Erwin P %A Boutin, Thibaud S %A Brumat, Marco %A Burkhardt, Ralph %A Campana, Eric %A Campbell, Archie %A Campbell, Harry %A Carroll, Robert J %A Catamo, Eulalia %A Chambers, John C %A Ciullo, Marina %A Concas, Maria Pina %A Coresh, Josef %A Corre, Tanguy %A Cusi, Daniele %A Felicita, Sala Cinzia %A de Borst, Martin H %A De Grandi, Alessandro %A de Mutsert, Renée %A de Vries, Aiko P J %A Delgado, Graciela %A Demirkan, Ayse %A Devuyst, Olivier %A Dittrich, Katalin %A Eckardt, Kai-Uwe %A Ehret, Georg %A Endlich, Karlhans %A Evans, Michele K %A Gansevoort, Ron T %A Gasparini, Paolo %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Gögele, Martin %A Gordon, Scott D %A Gudbjartsson, Daniel F %A Gudnason, Vilmundur %A Haller, Toomas %A Hamet, Pavel %A Harris, Tamara B %A Hayward, Caroline %A Hicks, Andrew A %A Hofer, Edith %A Holm, Hilma %A Huang, Wei %A Hutri-Kähönen, Nina %A Hwang, Shih-Jen %A Ikram, M Arfan %A Lewis, Raychel M %A Ingelsson, Erik %A Jakobsdottir, Johanna %A Jonsdottir, Ingileif %A Jonsson, Helgi %A Joshi, Peter K %A Josyula, Navya Shilpa %A Jung, Bettina %A Kähönen, Mika %A Kamatani, Yoichiro %A Kanai, Masahiro %A Kerr, Shona M %A Kiess, Wieland %A Kleber, Marcus E %A Koenig, Wolfgang %A Kooner, Jaspal S %A Körner, Antje %A Kovacs, Peter %A Krämer, Bernhard K %A Kronenberg, Florian %A Kubo, Michiaki %A Kuhnel, Brigitte %A La Bianca, Martina %A Lange, Leslie A %A Lehne, Benjamin %A Lehtimäki, Terho %A Liu, Jun %A Loeffler, Markus %A Loos, Ruth J F %A Lyytikäinen, Leo-Pekka %A Mägi, Reedik %A Mahajan, Anubha %A Martin, Nicholas G %A März, Winfried %A Mascalzoni, Deborah %A Matsuda, Koichi %A Meisinger, Christa %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A O'Donnell, Christopher J %A Wilson, Otis D %A Gaziano, J Michael %A Mishra, Pashupati P %A Mohlke, Karen L %A Mononen, Nina %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Müller-Nurasyid, Martina %A Nadkarni, Girish N %A Nalls, Mike A %A Nauck, Matthias %A Nikus, Kjell %A Ning, Boting %A Nolte, Ilja M %A Noordam, Raymond %A O'Connell, Jeffrey R %A Olafsson, Isleifur %A Padmanabhan, Sandosh %A Penninx, Brenda W J H %A Perls, Thomas %A Peters, Annette %A Pirastu, Mario %A Pirastu, Nicola %A Pistis, Giorgio %A Polasek, Ozren %A Ponte, Belen %A Porteous, David J %A Poulain, Tanja %A Preuss, Michael H %A Rabelink, Ton J %A Raffield, Laura M %A Raitakari, Olli T %A Rettig, Rainer %A Rheinberger, Myriam %A Rice, Kenneth M %A Rizzi, Federica %A Robino, Antonietta %A Rudan, Igor %A Krajcoviechova, Alena %A Cifkova, Renata %A Rueedi, Rico %A Ruggiero, Daniela %A Ryan, Kathleen A %A Saba, Yasaman %A Salvi, Erika %A Schmidt, Helena %A Schmidt, Reinhold %A Shaffer, Christian M %A Smith, Albert V %A Smith, Blair H %A Spracklen, Cassandra N %A Strauch, Konstantin %A Stumvoll, Michael %A Sulem, Patrick %A Tajuddin, Salman M %A Teren, Andrej %A Thiery, Joachim %A Thio, Chris H L %A Thorsteinsdottir, Unnur %A Toniolo, Daniela %A Tönjes, Anke %A Tremblay, Johanne %A Uitterlinden, André G %A Vaccargiu, Simona %A van der Harst, Pim %A van Duijn, Cornelia M %A Verweij, Niek %A Völker, Uwe %A Vollenweider, Peter %A Waeber, Gérard %A Waldenberger, Melanie %A Whitfield, John B %A Wild, Sarah H %A Wilson, James F %A Yang, Qiong %A Zhang, Weihua %A Zonderman, Alan B %A Bochud, Murielle %A Wilson, James G %A Pendergrass, Sarah A %A Ho, Kevin %A Parsa, Afshin %A Pramstaller, Peter P %A Psaty, Bruce M %A Böger, Carsten A %A Snieder, Harold %A Butterworth, Adam S %A Okada, Yukinori %A Edwards, Todd L %A Stefansson, Kari %A Susztak, Katalin %A Scholz, Markus %A Heid, Iris M %A Hung, Adriana M %A Teumer, Alexander %A Pattaro, Cristian %A Woodward, Owen M %A Vitart, Veronique %A Köttgen, Anna %X

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

%B Nat Genet %V 51 %P 1459-1474 %8 2019 Oct %G eng %N 10 %R 10.1038/s41588-019-0504-x %0 Journal Article %J Mol Psychiatry %D 2020 %T Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci. %A de Las Fuentes, Lisa %A Sung, Yun Ju %A Noordam, Raymond %A Winkler, Thomas %A Feitosa, Mary F %A Schwander, Karen %A Bentley, Amy R %A Brown, Michael R %A Guo, Xiuqing %A Manning, Alisa %A Chasman, Daniel I %A Aschard, Hugues %A Bartz, Traci M %A Bielak, Lawrence F %A Campbell, Archie %A Cheng, Ching-Yu %A Dorajoo, Rajkumar %A Hartwig, Fernando P %A Horimoto, A R V R %A Li, Changwei %A Li-Gao, Ruifang %A Liu, Yongmei %A Marten, Jonathan %A Musani, Solomon K %A Ntalla, Ioanna %A Rankinen, Tuomo %A Richard, Melissa %A Sim, Xueling %A Smith, Albert V %A Tajuddin, Salman M %A Tayo, Bamidele O %A Vojinovic, Dina %A Warren, Helen R %A Xuan, Deng %A Alver, Maris %A Boissel, Mathilde %A Chai, Jin-Fang %A Chen, Xu %A Christensen, Kaare %A Divers, Jasmin %A Evangelou, Evangelos %A Gao, Chuan %A Girotto, Giorgia %A Harris, Sarah E %A He, Meian %A Hsu, Fang-Chi %A Kuhnel, Brigitte %A Laguzzi, Federica %A Li, Xiaoyin %A Lyytikäinen, Leo-Pekka %A Nolte, Ilja M %A Poveda, Alaitz %A Rauramaa, Rainer %A Riaz, Muhammad %A Rueedi, Rico %A Shu, Xiao-Ou %A Snieder, Harold %A Sofer, Tamar %A Takeuchi, Fumihiko %A Verweij, Niek %A Ware, Erin B %A Weiss, Stefan %A Yanek, Lisa R %A Amin, Najaf %A Arking, Dan E %A Arnett, Donna K %A Bergmann, Sven %A Boerwinkle, Eric %A Brody, Jennifer A %A Broeckel, Ulrich %A Brumat, Marco %A Burke, Gregory %A Cabrera, Claudia P %A Canouil, Mickaël %A Chee, Miao Li %A Chen, Yii-Der Ida %A Cocca, Massimiliano %A Connell, John %A de Silva, H Janaka %A de Vries, Paul S %A Eiriksdottir, Gudny %A Faul, Jessica D %A Fisher, Virginia %A Forrester, Terrence %A Fox, Ervin F %A Friedlander, Yechiel %A Gao, He %A Gigante, Bruna %A Giulianini, Franco %A Gu, Chi Charles %A Gu, Dongfeng %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hunt, Steven %A Ikram, M Arfan %A Irvin, Marguerite R %A Kähönen, Mika %A Kavousi, Maryam %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Komulainen, Pirjo %A Kraja, Aldi T %A Krieger, J E %A Langefeld, Carl D %A Li, Yize %A Liang, Jingjing %A Liewald, David C M %A Liu, Ching-Ti %A Liu, Jianjun %A Lohman, Kurt K %A Mägi, Reedik %A McKenzie, Colin A %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Milani, Lili %A Mook-Kanamori, Dennis O %A Nalls, Mike A %A Nelson, Christopher P %A Norris, Jill M %A O'Connell, Jeff %A Ogunniyi, Adesola %A Padmanabhan, Sandosh %A Palmer, Nicholette D %A Pedersen, Nancy L %A Perls, Thomas %A Peters, Annette %A Petersmann, Astrid %A Peyser, Patricia A %A Polasek, Ozren %A Porteous, David J %A Raffel, Leslie J %A Rice, Treva K %A Rotter, Jerome I %A Rudan, Igor %A Rueda-Ochoa, Oscar-Leonel %A Sabanayagam, Charumathi %A Salako, Babatunde L %A Schreiner, Pamela J %A Shikany, James M %A Sidney, Stephen S %A Sims, Mario %A Sitlani, Colleen M %A Smith, Jennifer A %A Starr, John M %A Strauch, Konstantin %A Swertz, Morris A %A Teumer, Alexander %A Tham, Yih Chung %A Uitterlinden, André G %A Vaidya, Dhananjay %A van der Ende, M Yldau %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya-Xing %A Wei, Wen-Bin %A Weir, David R %A Wen, Wanqing %A Yao, Jie %A Yu, Bing %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Zonderman, Alan B %A Becker, Diane M %A Bowden, Donald W %A Deary, Ian J %A Dörr, Marcus %A Esko, Tõnu %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Jonas, Jost Bruno %A Kammerer, Candace M %A Kato, Norihiro %A Lakka, Timo A %A Leander, Karin %A Lehtimäki, Terho %A Magnusson, Patrik K E %A Marques-Vidal, Pedro %A Penninx, Brenda W J H %A Samani, Nilesh J %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wu, Tangchun %A Zheng, Wei %A Zhu, Xiaofeng %A Bouchard, Claude %A Cooper, Richard S %A Correa, Adolfo %A Evans, Michele K %A Gudnason, Vilmundur %A Hayward, Caroline %A Horta, Bernardo L %A Kelly, Tanika N %A Kritchevsky, Stephen B %A Levy, Daniel %A Palmas, Walter R %A Pereira, A C %A Province, Michael M %A Psaty, Bruce M %A Ridker, Paul M %A Rotimi, Charles N %A Tai, E Shyong %A van Dam, Rob M %A van Duijn, Cornelia M %A Wong, Tien Yin %A Rice, Kenneth %A Gauderman, W James %A Morrison, Alanna C %A North, Kari E %A Kardia, Sharon L R %A Caulfield, Mark J %A Elliott, Paul %A Munroe, Patricia B %A Franks, Paul W %A Rao, Dabeeru C %A Fornage, Myriam %X

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

%B Mol Psychiatry %8 2020 May 05 %G eng %R 10.1038/s41380-020-0719-3 %0 Journal Article %J Nature %D 2021 %T Genetic insights into biological mechanisms governing human ovarian ageing. %A Ruth, Katherine S %A Day, Felix R %A Hussain, Jazib %A Martínez-Marchal, Ana %A Aiken, Catherine E %A Azad, Ajuna %A Thompson, Deborah J %A Knoblochova, Lucie %A Abe, Hironori %A Tarry-Adkins, Jane L %A Gonzalez, Javier Martin %A Fontanillas, Pierre %A Claringbould, Annique %A Bakker, Olivier B %A Sulem, Patrick %A Walters, Robin G %A Terao, Chikashi %A Turon, Sandra %A Horikoshi, Momoko %A Lin, Kuang %A Onland-Moret, N Charlotte %A Sankar, Aditya %A Hertz, Emil Peter Thrane %A Timshel, Pascal N %A Shukla, Vallari %A Borup, Rehannah %A Olsen, Kristina W %A Aguilera, Paula %A Ferrer-Roda, Mònica %A Huang, Yan %A Stankovic, Stasa %A Timmers, Paul R H J %A Ahearn, Thomas U %A Alizadeh, Behrooz Z %A Naderi, Elnaz %A Andrulis, Irene L %A Arnold, Alice M %A Aronson, Kristan J %A Augustinsson, Annelie %A Bandinelli, Stefania %A Barbieri, Caterina M %A Beaumont, Robin N %A Becher, Heiko %A Beckmann, Matthias W %A Benonisdottir, Stefania %A Bergmann, Sven %A Bochud, Murielle %A Boerwinkle, Eric %A Bojesen, Stig E %A Bolla, Manjeet K %A Boomsma, Dorret I %A Bowker, Nicholas %A Brody, Jennifer A %A Broer, Linda %A Buring, Julie E %A Campbell, Archie %A Campbell, Harry %A Castelao, Jose E %A Catamo, Eulalia %A Chanock, Stephen J %A Chenevix-Trench, Georgia %A Ciullo, Marina %A Corre, Tanguy %A Couch, Fergus J %A Cox, Angela %A Crisponi, Laura %A Cross, Simon S %A Cucca, Francesco %A Czene, Kamila %A Smith, George Davey %A de Geus, Eco J C N %A de Mutsert, Renée %A De Vivo, Immaculata %A Demerath, Ellen W %A Dennis, Joe %A Dunning, Alison M %A Dwek, Miriam %A Eriksson, Mikael %A Esko, Tõnu %A Fasching, Peter A %A Faul, Jessica D %A Ferrucci, Luigi %A Franceschini, Nora %A Frayling, Timothy M %A Gago-Dominguez, Manuela %A Mezzavilla, Massimo %A García-Closas, Montserrat %A Gieger, Christian %A Giles, Graham G %A Grallert, Harald %A Gudbjartsson, Daniel F %A Gudnason, Vilmundur %A Guénel, Pascal %A Haiman, Christopher A %A Håkansson, Niclas %A Hall, Per %A Hayward, Caroline %A He, Chunyan %A He, Wei %A Heiss, Gerardo %A Høffding, Miya K %A Hopper, John L %A Hottenga, Jouke J %A Hu, Frank %A Hunter, David %A Ikram, Mohammad A %A Jackson, Rebecca D %A Joaquim, Micaella D R %A John, Esther M %A Joshi, Peter K %A Karasik, David %A Kardia, Sharon L R %A Kartsonaki, Christiana %A Karlsson, Robert %A Kitahara, Cari M %A Kolcic, Ivana %A Kooperberg, Charles %A Kraft, Peter %A Kurian, Allison W %A Kutalik, Zoltán %A La Bianca, Martina %A Lachance, Genevieve %A Langenberg, Claudia %A Launer, Lenore J %A Laven, Joop S E %A Lawlor, Deborah A %A Le Marchand, Loïc %A Li, Jingmei %A Lindblom, Annika %A Lindström, Sara %A Lindstrom, Tricia %A Linet, Martha %A Liu, Yongmei %A Liu, Simin %A Luan, Jian'an %A Mägi, Reedik %A Magnusson, Patrik K E %A Mangino, Massimo %A Mannermaa, Arto %A Marco, Brumat %A Marten, Jonathan %A Martin, Nicholas G %A Mbarek, Hamdi %A McKnight, Barbara %A Medland, Sarah E %A Meisinger, Christa %A Meitinger, Thomas %A Menni, Cristina %A Metspalu, Andres %A Milani, Lili %A Milne, Roger L %A Montgomery, Grant W %A Mook-Kanamori, Dennis O %A Mulas, Antonella %A Mulligan, Anna M %A Murray, Alison %A Nalls, Mike A %A Newman, Anne %A Noordam, Raymond %A Nutile, Teresa %A Nyholt, Dale R %A Olshan, Andrew F %A Olsson, Håkan %A Painter, Jodie N %A Patel, Alpa V %A Pedersen, Nancy L %A Perjakova, Natalia %A Peters, Annette %A Peters, Ulrike %A Pharoah, Paul D P %A Polasek, Ozren %A Porcu, Eleonora %A Psaty, Bruce M %A Rahman, Iffat %A Rennert, Gad %A Rennert, Hedy S %A Ridker, Paul M %A Ring, Susan M %A Robino, Antonietta %A Rose, Lynda M %A Rosendaal, Frits R %A Rossouw, Jacques %A Rudan, Igor %A Rueedi, Rico %A Ruggiero, Daniela %A Sala, Cinzia F %A Saloustros, Emmanouil %A Sandler, Dale P %A Sanna, Serena %A Sawyer, Elinor J %A Sarnowski, Chloe %A Schlessinger, David %A Schmidt, Marjanka K %A Schoemaker, Minouk J %A Schraut, Katharina E %A Scott, Christopher %A Shekari, Saleh %A Shrikhande, Amruta %A Smith, Albert V %A Smith, Blair H %A Smith, Jennifer A %A Sorice, Rossella %A Southey, Melissa C %A Spector, Tim D %A Spinelli, John J %A Stampfer, Meir %A Stöckl, Doris %A van Meurs, Joyce B J %A Strauch, Konstantin %A Styrkarsdottir, Unnur %A Swerdlow, Anthony J %A Tanaka, Toshiko %A Teras, Lauren R %A Teumer, Alexander %A Þorsteinsdottir, Unnur %A Timpson, Nicholas J %A Toniolo, Daniela %A Traglia, Michela %A Troester, Melissa A %A Truong, Thérèse %A Tyrrell, Jessica %A Uitterlinden, André G %A Ulivi, Sheila %A Vachon, Celine M %A Vitart, Veronique %A Völker, Uwe %A Vollenweider, Peter %A Völzke, Henry %A Wang, Qin %A Wareham, Nicholas J %A Weinberg, Clarice R %A Weir, David R %A Wilcox, Amber N %A van Dijk, Ko Willems %A Willemsen, Gonneke %A Wilson, James F %A Wolffenbuttel, Bruce H R %A Wolk, Alicja %A Wood, Andrew R %A Zhao, Wei %A Zygmunt, Marek %A Chen, Zhengming %A Li, Liming %A Franke, Lude %A Burgess, Stephen %A Deelen, Patrick %A Pers, Tune H %A Grøndahl, Marie Louise %A Andersen, Claus Yding %A Pujol, Anna %A Lopez-Contreras, Andres J %A Daniel, Jeremy A %A Stefansson, Kari %A Chang-Claude, Jenny %A van der Schouw, Yvonne T %A Lunetta, Kathryn L %A Chasman, Daniel I %A Easton, Douglas F %A Visser, Jenny A %A Ozanne, Susan E %A Namekawa, Satoshi H %A Solc, Petr %A Murabito, Joanne M %A Ong, Ken K %A Hoffmann, Eva R %A Murray, Anna %A Roig, Ignasi %A Perry, John R B %X

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

%B Nature %V 596 %P 393-397 %8 2021 Aug %G eng %N 7872 %R 10.1038/s41586-021-03779-7 %0 Journal Article %J Commun Biol %D 2022 %T Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals. %A Winkler, Thomas W %A Rasheed, Humaira %A Teumer, Alexander %A Gorski, Mathias %A Rowan, Bryce X %A Stanzick, Kira J %A Thomas, Laurent F %A Tin, Adrienne %A Hoppmann, Anselm %A Chu, Audrey Y %A Tayo, Bamidele %A Thio, Chris H L %A Cusi, Daniele %A Chai, Jin-Fang %A Sieber, Karsten B %A Horn, Katrin %A Li, Man %A Scholz, Markus %A Cocca, Massimiliano %A Wuttke, Matthias %A van der Most, Peter J %A Yang, Qiong %A Ghasemi, Sahar %A Nutile, Teresa %A Li, Yong %A Pontali, Giulia %A Günther, Felix %A Dehghan, Abbas %A Correa, Adolfo %A Parsa, Afshin %A Feresin, Agnese %A de Vries, Aiko P J %A Zonderman, Alan B %A Smith, Albert V %A Oldehinkel, Albertine J %A De Grandi, Alessandro %A Rosenkranz, Alexander R %A Franke, Andre %A Teren, Andrej %A Metspalu, Andres %A Hicks, Andrew A %A Morris, Andrew P %A Tönjes, Anke %A Morgan, Anna %A Podgornaia, Anna I %A Peters, Annette %A Körner, Antje %A Mahajan, Anubha %A Campbell, Archie %A Freedman, Barry I %A Spedicati, Beatrice %A Ponte, Belen %A Schöttker, Ben %A Brumpton, Ben %A Banas, Bernhard %A Krämer, Bernhard K %A Jung, Bettina %A Åsvold, Bjørn Olav %A Smith, Blair H %A Ning, Boting %A Penninx, Brenda W J H %A Vanderwerff, Brett R %A Psaty, Bruce M %A Kammerer, Candace M %A Langefeld, Carl D %A Hayward, Caroline %A Spracklen, Cassandra N %A Robinson-Cohen, Cassianne %A Hartman, Catharina A %A Lindgren, Cecilia M %A Wang, Chaolong %A Sabanayagam, Charumathi %A Heng, Chew-Kiat %A Lanzani, Chiara %A Khor, Chiea-Chuen %A Cheng, Ching-Yu %A Fuchsberger, Christian %A Gieger, Christian %A Shaffer, Christian M %A Schulz, Christina-Alexandra %A Willer, Cristen J %A Chasman, Daniel I %A Gudbjartsson, Daniel F %A Ruggiero, Daniela %A Toniolo, Daniela %A Czamara, Darina %A Porteous, David J %A Waterworth, Dawn M %A Mascalzoni, Deborah %A Mook-Kanamori, Dennis O %A Reilly, Dermot F %A Daw, E Warwick %A Hofer, Edith %A Boerwinkle, Eric %A Salvi, Erika %A Bottinger, Erwin P %A Tai, E-Shyong %A Catamo, Eulalia %A Rizzi, Federica %A Guo, Feng %A Rivadeneira, Fernando %A Guilianini, Franco %A Sveinbjornsson, Gardar %A Ehret, Georg %A Waeber, Gérard %A Biino, Ginevra %A Girotto, Giorgia %A Pistis, Giorgio %A Nadkarni, Girish N %A Delgado, Graciela E %A Montgomery, Grant W %A Snieder, Harold %A Campbell, Harry %A White, Harvey D %A Gao, He %A Stringham, Heather M %A Schmidt, Helena %A Li, Hengtong %A Brenner, Hermann %A Holm, Hilma %A Kirsten, Holgen %A Kramer, Holly %A Rudan, Igor %A Nolte, Ilja M %A Tzoulaki, Ioanna %A Olafsson, Isleifur %A Martins, Jade %A Cook, James P %A Wilson, James F %A Halbritter, Jan %A Felix, Janine F %A Divers, Jasmin %A Kooner, Jaspal S %A Lee, Jeannette Jen-Mai %A O'Connell, Jeffrey %A Rotter, Jerome I %A Liu, Jianjun %A Xu, Jie %A Thiery, Joachim %A Arnlöv, Johan %A Kuusisto, Johanna %A Jakobsdottir, Johanna %A Tremblay, Johanne %A Chambers, John C %A Whitfield, John B %A Gaziano, John M %A Marten, Jonathan %A Coresh, Josef %A Jonas, Jost B %A Mychaleckyj, Josyf C %A Christensen, Kaare %A Eckardt, Kai-Uwe %A Mohlke, Karen L %A Endlich, Karlhans %A Dittrich, Katalin %A Ryan, Kathleen A %A Rice, Kenneth M %A Taylor, Kent D %A Ho, Kevin %A Nikus, Kjell %A Matsuda, Koichi %A Strauch, Konstantin %A Miliku, Kozeta %A Hveem, Kristian %A Lind, Lars %A Wallentin, Lars %A Yerges-Armstrong, Laura M %A Raffield, Laura M %A Phillips, Lawrence S %A Launer, Lenore J %A Lyytikäinen, Leo-Pekka %A Lange, Leslie A %A Citterio, Lorena %A Klaric, Lucija %A Ikram, M Arfan %A Ising, Marcus %A Kleber, Marcus E %A Francescatto, Margherita %A Concas, Maria Pina %A Ciullo, Marina %A Piratsu, Mario %A Orho-Melander, Marju %A Laakso, Markku %A Loeffler, Markus %A Perola, Markus %A de Borst, Martin H %A Gögele, Martin %A Bianca, Martina La %A Lukas, Mary Ann %A Feitosa, Mary F %A Biggs, Mary L %A Wojczynski, Mary K %A Kavousi, Maryam %A Kanai, Masahiro %A Akiyama, Masato %A Yasuda, Masayuki %A Nauck, Matthias %A Waldenberger, Melanie %A Chee, Miao-Li %A Chee, Miao-Ling %A Boehnke, Michael %A Preuss, Michael H %A Stumvoll, Michael %A Province, Michael A %A Evans, Michele K %A O'Donoghue, Michelle L %A Kubo, Michiaki %A Kähönen, Mika %A Kastarinen, Mika %A Nalls, Mike A %A Kuokkanen, Mikko %A Ghanbari, Mohsen %A Bochud, Murielle %A Josyula, Navya Shilpa %A Martin, Nicholas G %A Tan, Nicholas Y Q %A Palmer, Nicholette D %A Pirastu, Nicola %A Schupf, Nicole %A Verweij, Niek %A Hutri-Kähönen, Nina %A Mononen, Nina %A Bansal, Nisha %A Devuyst, Olivier %A Melander, Olle %A Raitakari, Olli T %A Polasek, Ozren %A Manunta, Paolo %A Gasparini, Paolo %A Mishra, Pashupati P %A Sulem, Patrick %A Magnusson, Patrik K E %A Elliott, Paul %A Ridker, Paul M %A Hamet, Pavel %A Svensson, Per O %A Joshi, Peter K %A Kovacs, Peter %A Pramstaller, Peter P %A Rossing, Peter %A Vollenweider, Peter %A van der Harst, Pim %A Dorajoo, Rajkumar %A Sim, Ralene Z H %A Burkhardt, Ralph %A Tao, Ran %A Noordam, Raymond %A Mägi, Reedik %A Schmidt, Reinhold %A de Mutsert, Renée %A Rueedi, Rico %A van Dam, Rob M %A Carroll, Robert J %A Gansevoort, Ron T %A Loos, Ruth J F %A Felicita, Sala Cinzia %A Sedaghat, Sanaz %A Padmanabhan, Sandosh %A Freitag-Wolf, Sandra %A Pendergrass, Sarah A %A Graham, Sarah E %A Gordon, Scott D %A Hwang, Shih-Jen %A Kerr, Shona M %A Vaccargiu, Simona %A Patil, Snehal B %A Hallan, Stein %A Bakker, Stephan J L %A Lim, Su-Chi %A Lucae, Susanne %A Vogelezang, Suzanne %A Bergmann, Sven %A Corre, Tanguy %A Ahluwalia, Tarunveer S %A Lehtimäki, Terho %A Boutin, Thibaud S %A Meitinger, Thomas %A Wong, Tien-Yin %A Bergler, Tobias %A Rabelink, Ton J %A Esko, Tõnu %A Haller, Toomas %A Thorsteinsdottir, Unnur %A Völker, Uwe %A Foo, Valencia Hui Xian %A Salomaa, Veikko %A Vitart, Veronique %A Giedraitis, Vilmantas %A Gudnason, Vilmundur %A Jaddoe, Vincent W V %A Huang, Wei %A Zhang, Weihua %A Wei, Wen Bin %A Kiess, Wieland %A März, Winfried %A Koenig, Wolfgang %A Lieb, Wolfgang %A Gào, Xīn %A Sim, Xueling %A Wang, Ya Xing %A Friedlander, Yechiel %A Tham, Yih-Chung %A Kamatani, Yoichiro %A Okada, Yukinori %A Milaneschi, Yuri %A Yu, Zhi %A Stark, Klaus J %A Stefansson, Kari %A Böger, Carsten A %A Hung, Adriana M %A Kronenberg, Florian %A Köttgen, Anna %A Pattaro, Cristian %A Heid, Iris M %K Creatinine %K Diabetes Mellitus %K Diabetic Nephropathies %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Kidney %X

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (n = 178,691, n = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.

%B Commun Biol %V 5 %P 580 %8 2022 Jun 13 %G eng %N 1 %R 10.1038/s42003-022-03448-z