@article {7920, title = {Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 Nov 01}, pages = {691-706}, abstract = {

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~{\texttimes} 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.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.09.009}, author = {Ligthart, Symen and Vaez, Ahmad and V{\~o}sa, Urmo and Stathopoulou, Maria G and de Vries, Paul S and Prins, Bram P and van der Most, Peter J and Tanaka, Toshiko and Naderi, Elnaz and Rose, Lynda M and Wu, Ying and Karlsson, Robert and Barbalic, Maja and Lin, Honghuang and Pool, Rene and Zhu, Gu and Mace, Aurelien and Sidore, Carlo and Trompet, Stella and Mangino, Massimo and Sabater-Lleal, Maria and Kemp, John P and Abbasi, Ali and Kacprowski, Tim and Verweij, Niek and Smith, Albert V and Huang, Tao and Marzi, Carola and Feitosa, Mary F and Lohman, Kurt K and Kleber, Marcus E and Milaneschi, Yuri and Mueller, Christian and Huq, Mahmudul and Vlachopoulou, Efthymia and Lyytik{\"a}inen, Leo-Pekka and Oldmeadow, Christopher and Deelen, Joris and Perola, Markus and Zhao, Jing Hua and Feenstra, Bjarke and Amini, Marzyeh and Lahti, Jari and Schraut, Katharina E and Fornage, Myriam and Suktitipat, Bhoom and Chen, Wei-Min and Li, Xiaohui and Nutile, Teresa and Malerba, Giovanni and Luan, Jian{\textquoteright}an and Bak, Tom and Schork, Nicholas and del Greco M, Fabiola and Thiering, Elisabeth and Mahajan, Anubha and Marioni, Riccardo E and Mihailov, Evelin and Eriksson, Joel and Ozel, Ayse Bilge and Zhang, Weihua and Nethander, Maria and Cheng, Yu-Ching and Aslibekyan, Stella and Ang, Wei and Gandin, Ilaria and Yengo, Loic and Portas, Laura and Kooperberg, Charles and Hofer, Edith and Rajan, Kumar B and Schurmann, Claudia and den Hollander, Wouter and Ahluwalia, Tarunveer S and Zhao, Jing and Draisma, Harmen H M and Ford, Ian and Timpson, Nicholas and Teumer, Alexander and Huang, Hongyan and Wahl, Simone and Liu, Yongmei and Huang, Jie and Uh, Hae-Won and Geller, Frank and Joshi, Peter K and Yanek, Lisa R and Trabetti, Elisabetta and Lehne, Benjamin and Vozzi, Diego and Verbanck, Marie and Biino, Ginevra and Saba, Yasaman and Meulenbelt, Ingrid and O{\textquoteright}Connell, Jeff R and Laakso, Markku and Giulianini, Franco and Magnusson, Patrik K E and Ballantyne, Christie M and Hottenga, Jouke Jan and Montgomery, Grant W and Rivadineira, Fernando and Rueedi, Rico and Steri, Maristella and Herzig, Karl-Heinz and Stott, David J and Menni, Cristina and Fr{\r a}nberg, Mattias and St Pourcain, Beate and Felix, Stephan B and Pers, Tune H and Bakker, Stephan J L and Kraft, Peter and Peters, Annette and Vaidya, Dhananjay and Delgado, Graciela and Smit, Johannes H and Gro{\ss}mann, Vera and Sinisalo, Juha and Sepp{\"a}l{\"a}, Ilkka and Williams, Stephen R and Holliday, Elizabeth G and Moed, Matthijs and Langenberg, Claudia and R{\"a}ikk{\"o}nen, Katri and Ding, Jingzhong and Campbell, Harry and Sale, Mich{\`e}le M and Chen, Yii-der I and James, Alan L and Ruggiero, Daniela and Soranzo, Nicole and Hartman, Catharina A and Smith, Erin N and Berenson, Gerald S and Fuchsberger, Christian and Hernandez, Dena and Tiesler, Carla M T and Giedraitis, Vilmantas and Liewald, David and Fischer, Krista and Mellstr{\"o}m, Dan and Larsson, Anders and Wang, Yunmei and Scott, William R and Lorentzon, Matthias and Beilby, John and Ryan, Kathleen A and Pennell, Craig E and Vuckovic, Dragana and Balkau, Beverly and Concas, Maria Pina and Schmidt, Reinhold and Mendes de Leon, Carlos F and Bottinger, Erwin P and Kloppenburg, Margreet and Paternoster, Lavinia and Boehnke, Michael and Musk, A W and Willemsen, Gonneke and Evans, David M and Madden, Pamela A F and K{\"a}h{\"o}nen, Mika and Kutalik, Zolt{\'a}n and Zoledziewska, Magdalena and Karhunen, Ville and Kritchevsky, Stephen B and Sattar, Naveed and Lachance, Genevieve and Clarke, Robert and Harris, Tamara B and Raitakari, Olli T and Attia, John R and van Heemst, Diana and Kajantie, Eero and Sorice, Rossella and Gambaro, Giovanni and Scott, Robert A and Hicks, Andrew A and Ferrucci, Luigi and Standl, Marie and Lindgren, Cecilia M and Starr, John M and Karlsson, Magnus and Lind, Lars and Li, Jun Z and Chambers, John C and Mori, Trevor A and de Geus, Eco J C N and Heath, Andrew C and Martin, Nicholas G and Auvinen, Juha and Buckley, Brendan M and de Craen, Anton J M and Waldenberger, Melanie and Strauch, Konstantin and Meitinger, Thomas and Scott, Rodney J and McEvoy, Mark and Beekman, Marian and Bombieri, Cristina and Ridker, Paul M and Mohlke, Karen L and Pedersen, Nancy L and Morrison, Alanna C and Boomsma, Dorret I and Whitfield, John B and Strachan, David P and Hofman, Albert and Vollenweider, Peter and Cucca, Francesco and Jarvelin, Marjo-Riitta and Jukema, J Wouter and Spector, Tim D and Hamsten, Anders and Zeller, Tanja and Uitterlinden, Andr{\'e} G and Nauck, Matthias and Gudnason, Vilmundur and Qi, Lu and Grallert, Harald and Borecki, Ingrid B and Rotter, Jerome I and M{\"a}rz, Winfried and Wild, Philipp S and Lokki, Marja-Liisa and Boyle, Michael and Salomaa, Veikko and Melbye, Mads and Eriksson, Johan G and Wilson, James F and Penninx, Brenda W J H and Becker, Diane M and Worrall, Bradford B and Gibson, Greg and Krauss, Ronald M and Ciullo, Marina and Zaza, Gianluigi and Wareham, Nicholas J and Oldehinkel, Albertine J and Palmer, Lyle J and Murray, Sarah S and Pramstaller, Peter P and Bandinelli, Stefania and Heinrich, Joachim and Ingelsson, Erik and Deary, Ian J and M{\"a}gi, Reedik and Vandenput, Liesbeth and van der Harst, Pim and Desch, Karl C and Kooner, Jaspal S and Ohlsson, Claes and Hayward, Caroline and Lehtim{\"a}ki, Terho and Shuldiner, Alan R and Arnett, Donna K and Beilin, Lawrence J and Robino, Antonietta and Froguel, Philippe and Pirastu, Mario and Jess, Tine and Koenig, Wolfgang and Loos, Ruth J F and Evans, Denis A and Schmidt, Helena and Smith, George Davey and Slagboom, P Eline and Eiriksdottir, Gudny and Morris, Andrew P and Psaty, Bruce M and Tracy, Russell P and Nolte, Ilja M and Boerwinkle, Eric and Visvikis-Siest, Sophie and Reiner, Alex P and Gross, Myron and Bis, Joshua C and Franke, Lude and Franco, Oscar H and Benjamin, Emelia J and Chasman, Daniel I and Dupuis, Jos{\'e}e and Snieder, Harold and Dehghan, Abbas and Alizadeh, Behrooz Z} } @article {7792, title = {Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0198166}, abstract = {

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.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0198166}, author = {Feitosa, Mary F and Kraja, Aldi T and Chasman, Daniel I and Sung, Yun J and Winkler, Thomas W and Ntalla, Ioanna and Guo, Xiuqing and Franceschini, Nora and Cheng, Ching-Yu and Sim, Xueling and Vojinovic, Dina and Marten, Jonathan and Musani, Solomon K and Li, Changwei and Bentley, Amy R and Brown, Michael R and Schwander, Karen and Richard, Melissa A and Noordam, Raymond and Aschard, Hugues and Bartz, Traci M and Bielak, Lawrence F and Dorajoo, Rajkumar and Fisher, Virginia and Hartwig, Fernando P and Horimoto, Andrea R V R and Lohman, Kurt K and Manning, Alisa K and Rankinen, Tuomo and Smith, Albert V and Tajuddin, Salman M and Wojczynski, Mary K and Alver, Maris and Boissel, Mathilde and Cai, Qiuyin and Campbell, Archie and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Gao, Chuan and Goel, Anuj and Hagemeijer, Yanick and Harris, Sarah E and He, Meian and Hsu, Fang-Chi and Jackson, Anne U and K{\"a}h{\"o}nen, Mika and Kasturiratne, Anuradhani and Komulainen, Pirjo and Kuhnel, Brigitte and Laguzzi, Federica and Luan, Jian{\textquoteright}an and Matoba, Nana and Nolte, Ilja M and Padmanabhan, Sandosh and Riaz, Muhammad and Rueedi, Rico and Robino, Antonietta and Said, M Abdullah and Scott, Robert A and Sofer, Tamar and Stan{\v c}{\'a}kov{\'a}, Alena and Takeuchi, Fumihiko and Tayo, Bamidele O and van der Most, Peter J and Varga, Tibor V and Vitart, Veronique and Wang, Yajuan and Ware, Erin B and Warren, Helen R and Weiss, Stefan and Wen, Wanqing and Yanek, Lisa R and Zhang, Weihua and Zhao, Jing Hua and Afaq, Saima and Amin, Najaf and Amini, Marzyeh and Arking, Dan E and Aung, Tin and Boerwinkle, Eric and Borecki, Ingrid and Broeckel, Ulrich and Brown, Morris and Brumat, Marco and Burke, Gregory L and Canouil, Micka{\"e}l and Chakravarti, Aravinda and Charumathi, Sabanayagam and Ida Chen, Yii-Der and Connell, John M and Correa, Adolfo and de Las Fuentes, Lisa and de Mutsert, Ren{\'e}e and de Silva, H Janaka and Deng, Xuan and Ding, Jingzhong and Duan, Qing and Eaton, Charles B and Ehret, Georg and Eppinga, Ruben N and Evangelou, Evangelos and Faul, Jessica D and Felix, Stephan B and Forouhi, Nita G and Forrester, Terrence and Franco, Oscar H and Friedlander, Yechiel and Gandin, Ilaria and Gao, He and Ghanbari, Mohsen and Gigante, Bruna and Gu, C Charles and Gu, Dongfeng and Hagenaars, Saskia P and Hallmans, G{\"o}ran and Harris, Tamara B and He, Jiang and Heikkinen, Sami and Heng, Chew-Kiat and Hirata, Makoto and Howard, Barbara V and Ikram, M Arfan and John, Ulrich and Katsuya, Tomohiro and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Krieger, Jose E and Kritchevsky, Stephen B and Kubo, Michiaki and Kuusisto, Johanna and Lakka, Timo A and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lehne, Benjamin and Lewis, Cora E and Li, Yize and Lin, Shiow and Liu, Jianjun and Liu, Jingmin and Loh, Marie and Louie, Tin and M{\"a}gi, Reedik and McKenzie, Colin A and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Milani, Lili and Mohlke, Karen L and Momozawa, Yukihide and Nalls, Mike A and Nelson, Christopher P and Sotoodehnia, Nona and Norris, Jill M and O{\textquoteright}Connell, Jeff R and Palmer, Nicholette D and Perls, Thomas and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Poulter, Neil and Raffel, Leslie J and Raitakari, Olli T and Roll, Kathryn and Rose, Lynda M and Rosendaal, Frits R and Rotter, Jerome I and Schmidt, Carsten O and Schreiner, Pamela J and Schupf, Nicole and Scott, William R and Sever, Peter S and Shi, Yuan and Sidney, Stephen and Sims, Mario and Sitlani, Colleen M and Smith, Jennifer A and Snieder, Harold and Starr, John M and Strauch, Konstantin and Stringham, Heather M and Tan, Nicholas Y Q and Tang, Hua and Taylor, Kent D and Teo, Yik Ying and Tham, Yih Chung and Turner, Stephen T and Uitterlinden, Andr{\'e} G and Vollenweider, Peter and Waldenberger, Melanie and Wang, Lihua and Wang, Ya Xing and Wei, Wen Bin and Williams, Christine and Yao, Jie and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Zonderman, Alan B and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and Chambers, John C and Deary, Ian J and Esko, T{\~o}nu and Farrall, Martin and Franks, Paul W and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Jonas, Jost Bruno and Kamatani, Yoichiro and Kato, Norihiro and Kooner, Jaspal S and Kutalik, Zolt{\'a}n and Laakso, Markku and Laurie, Cathy C and Leander, Karin and Lehtim{\"a}ki, Terho and Study, Lifelines Cohort and Magnusson, Patrik K E and Oldehinkel, Albertine J and Penninx, Brenda W J H and Polasek, Ozren and Porteous, David J and Rauramaa, Rainer and Samani, Nilesh J and Scott, James and Shu, Xiao-Ou and van der Harst, Pim and Wagenknecht, Lynne E and Wareham, Nicholas J and Watkins, Hugh and Weir, David R and Wickremasinghe, Ananda R and Wu, Tangchun and Zheng, Wei and Bouchard, Claude and Christensen, Kaare and Evans, Michele K and Gudnason, Vilmundur and Horta, Bernardo L and Kardia, Sharon L R and Liu, Yongmei and Pereira, Alexandre C and Psaty, Bruce M and Ridker, Paul M and van Dam, Rob M and Gauderman, W James and Zhu, Xiaofeng and Mook-Kanamori, Dennis O and Fornage, Myriam and Rotimi, Charles N and Cupples, L Adrienne and Kelly, Tanika N and Fox, Ervin R and Hayward, Caroline and van Duijn, Cornelia M and Tai, E Shyong and Wong, Tien Yin and Kooperberg, Charles and Palmas, Walter and Rice, Kenneth and Morrison, Alanna C and Elliott, Paul and Caulfield, Mark J and Munroe, Patricia B and Rao, Dabeeru C and Province, Michael A and Levy, Daniel} } @article {8109, title = {A catalog of genetic loci associated with kidney function from analyses of a million individuals.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 06}, pages = {957-972}, abstract = {

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.

}, keywords = {Chromosome Mapping, European Continental Ancestry Group, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Inheritance Patterns, Kidney Function Tests, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, Renal Insufficiency, Chronic, Uromodulin}, issn = {1546-1718}, doi = {10.1038/s41588-019-0407-x}, author = {Wuttke, Matthias and Li, Yong and Li, Man and Sieber, Karsten B and Feitosa, Mary F and Gorski, Mathias and Tin, Adrienne and Wang, Lihua and Chu, Audrey Y and Hoppmann, Anselm and Kirsten, Holger and Giri, Ayush and Chai, Jin-Fang and Sveinbjornsson, Gardar and Tayo, Bamidele O and Nutile, Teresa and Fuchsberger, Christian and Marten, Jonathan and Cocca, Massimiliano and Ghasemi, Sahar and Xu, Yizhe and Horn, Katrin and Noce, Damia and van der Most, Peter J and Sedaghat, Sanaz and Yu, Zhi and Akiyama, Masato and Afaq, Saima and Ahluwalia, Tarunveer S and Almgren, Peter and Amin, Najaf and Arnl{\"o}v, Johan and Bakker, Stephan J L and Bansal, Nisha and Baptista, Daniela and Bergmann, Sven and Biggs, Mary L and Biino, Ginevra and Boehnke, Michael and Boerwinkle, Eric and Boissel, Mathilde and Bottinger, Erwin P and Boutin, Thibaud S and Brenner, Hermann and Brumat, Marco and Burkhardt, Ralph and Butterworth, Adam S and Campana, Eric and Campbell, Archie and Campbell, Harry and Canouil, Micka{\"e}l and Carroll, Robert J and Catamo, Eulalia and Chambers, John C and Chee, Miao-Ling and Chee, Miao-Li and Chen, Xu and Cheng, Ching-Yu and Cheng, Yurong and Christensen, Kaare and Cifkova, Renata and Ciullo, Marina and Concas, Maria Pina and Cook, James P and Coresh, Josef and Corre, Tanguy and Sala, Cinzia Felicita and Cusi, Daniele and Danesh, John and Daw, E Warwick and de Borst, Martin H and De Grandi, Alessandro and de Mutsert, Ren{\'e}e and de Vries, Aiko P J and Degenhardt, Frauke and Delgado, Graciela and Demirkan, Ayse and Di Angelantonio, Emanuele and Dittrich, Katalin and Divers, Jasmin and Dorajoo, Rajkumar and Eckardt, Kai-Uwe and Ehret, Georg and Elliott, Paul and Endlich, Karlhans and Evans, Michele K and Felix, Janine F and Foo, Valencia Hui Xian and Franco, Oscar H and Franke, Andre and Freedman, Barry I and Freitag-Wolf, Sandra and Friedlander, Yechiel and Froguel, Philippe and Gansevoort, Ron T and Gao, He and Gasparini, Paolo and Gaziano, J Michael and Giedraitis, Vilmantas and Gieger, Christian and Girotto, Giorgia and Giulianini, Franco and G{\"o}gele, Martin and Gordon, Scott D and Gudbjartsson, Daniel F and Gudnason, Vilmundur and Haller, Toomas and Hamet, Pavel and Harris, Tamara B and Hartman, Catharina A and Hayward, Caroline and Hellwege, Jacklyn N and Heng, Chew-Kiat and Hicks, Andrew A and Hofer, Edith and Huang, Wei and Hutri-K{\"a}h{\"o}nen, Nina and Hwang, Shih-Jen and Ikram, M Arfan and Indridason, Olafur S and Ingelsson, Erik and Ising, Marcus and Jaddoe, Vincent W V and Jakobsdottir, Johanna and Jonas, Jost B and Joshi, Peter K and Josyula, Navya Shilpa and Jung, Bettina and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kammerer, Candace M and Kanai, Masahiro and Kastarinen, Mika and Kerr, Shona M and Khor, Chiea-Chuen and Kiess, Wieland and Kleber, Marcus E and Koenig, Wolfgang and Kooner, Jaspal S and K{\"o}rner, Antje and Kovacs, Peter and Kraja, Aldi T and Krajcoviechova, Alena and Kramer, Holly and Kr{\"a}mer, Bernhard K and Kronenberg, Florian and Kubo, Michiaki and Kuhnel, Brigitte and Kuokkanen, Mikko and Kuusisto, Johanna and La Bianca, Martina and Laakso, Markku and Lange, Leslie A and Langefeld, Carl D and Lee, Jeannette Jen-Mai and Lehne, Benjamin and Lehtim{\"a}ki, Terho and Lieb, Wolfgang and Lim, Su-Chi and Lind, Lars and Lindgren, Cecilia M and Liu, Jun and Liu, Jianjun and Loeffler, Markus and Loos, Ruth J F and Lucae, Susanne and Lukas, Mary Ann and Lyytik{\"a}inen, Leo-Pekka and M{\"a}gi, Reedik and Magnusson, Patrik K E and Mahajan, Anubha and Martin, Nicholas G and Martins, Jade and M{\"a}rz, Winfried and Mascalzoni, Deborah and Matsuda, Koichi and Meisinger, Christa and Meitinger, Thomas and Melander, Olle and Metspalu, Andres and Mikaelsdottir, Evgenia K and Milaneschi, Yuri and Miliku, Kozeta and Mishra, Pashupati P and Mohlke, Karen L and Mononen, Nina and Montgomery, Grant W and Mook-Kanamori, Dennis O and Mychaleckyj, Josyf C and Nadkarni, Girish N and Nalls, Mike A and Nauck, Matthias and Nikus, Kjell and Ning, Boting and Nolte, Ilja M and Noordam, Raymond and O{\textquoteright}Connell, Jeffrey and O{\textquoteright}Donoghue, Michelle L and Olafsson, Isleifur and Oldehinkel, Albertine J and Orho-Melander, Marju and Ouwehand, Willem H and Padmanabhan, Sandosh and Palmer, Nicholette D and Palsson, Runolfur and Penninx, Brenda W J H and Perls, Thomas and Perola, Markus and Pirastu, Mario and Pirastu, Nicola and Pistis, Giorgio and Podgornaia, Anna I and Polasek, Ozren and Ponte, Belen and Porteous, David J and Poulain, Tanja and Pramstaller, Peter P and Preuss, Michael H and Prins, Bram P and Province, Michael A and Rabelink, Ton J and Raffield, Laura M and Raitakari, Olli T and Reilly, Dermot F and Rettig, Rainer and Rheinberger, Myriam and Rice, Kenneth M and Ridker, Paul M and Rivadeneira, Fernando and Rizzi, Federica and Roberts, David J and Robino, Antonietta and Rossing, Peter and Rudan, Igor and Rueedi, Rico and Ruggiero, Daniela and Ryan, Kathleen A and Saba, Yasaman and Sabanayagam, Charumathi and Salomaa, Veikko and Salvi, Erika and Saum, Kai-Uwe and Schmidt, Helena and Schmidt, Reinhold and Sch{\"o}ttker, Ben and Schulz, Christina-Alexandra and Schupf, Nicole and Shaffer, Christian M and Shi, Yuan and Smith, Albert V and Smith, Blair H and Soranzo, Nicole and Spracklen, Cassandra N and Strauch, Konstantin and Stringham, Heather M and Stumvoll, Michael and Svensson, Per O and Szymczak, Silke and Tai, E-Shyong and Tajuddin, Salman M and Tan, Nicholas Y Q and Taylor, Kent D and Teren, Andrej and Tham, Yih-Chung and Thiery, Joachim and Thio, Chris H L and Thomsen, Hauke and Thorleifsson, Gudmar and Toniolo, Daniela and T{\"o}njes, Anke and Tremblay, Johanne and Tzoulaki, Ioanna and Uitterlinden, Andr{\'e} G and Vaccargiu, Simona and van Dam, Rob M and van der Harst, Pim and van Duijn, Cornelia M and Velez Edward, Digna R and Verweij, Niek and Vogelezang, Suzanne and V{\"o}lker, Uwe and Vollenweider, Peter and Waeber, G{\'e}rard and Waldenberger, Melanie and Wallentin, Lars and Wang, Ya Xing and Wang, Chaolong and Waterworth, Dawn M and Bin Wei, Wen and White, Harvey and Whitfield, John B and Wild, Sarah H and Wilson, James F and Wojczynski, Mary K and Wong, Charlene and Wong, Tien-Yin and Xu, Liang and Yang, Qiong and Yasuda, Masayuki and Yerges-Armstrong, Laura M and Zhang, Weihua and Zonderman, Alan B and Rotter, Jerome I and Bochud, Murielle and Psaty, Bruce M and Vitart, Veronique and Wilson, James G and Dehghan, Abbas and Parsa, Afshin and Chasman, Daniel I and Ho, Kevin and Morris, Andrew P and Devuyst, Olivier and Akilesh, Shreeram and Pendergrass, Sarah A and Sim, Xueling and B{\"o}ger, Carsten A and Okada, Yukinori and Edwards, Todd L and Snieder, Harold and Stefansson, Kari and Hung, Adriana M and Heid, Iris M and Scholz, Markus and Teumer, Alexander and K{\"o}ttgen, Anna and Pattaro, Cristian} } @article {7976, title = {Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 01 22}, pages = {376}, abstract = {

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.

}, keywords = {Adolescent, Adult, African Continental Ancestry Group, Aged, Aged, 80 and over, Asian Continental Ancestry Group, Brazil, Calcium-Binding Proteins, Cholesterol, Cholesterol, HDL, Cholesterol, LDL, European Continental Ancestry Group, Exercise, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Hispanic Americans, Humans, LIM-Homeodomain Proteins, Lipid Metabolism, Lipids, Male, Membrane Proteins, Microtubule-Associated Proteins, Middle Aged, Muscle Proteins, Nerve Tissue Proteins, Transcription Factors, Triglycerides, Young Adult}, issn = {2041-1723}, doi = {10.1038/s41467-018-08008-w}, author = {Kilpel{\"a}inen, Tuomas O and Bentley, Amy R and Noordam, Raymond and Sung, Yun Ju and Schwander, Karen and Winkler, Thomas W and Jakupovi{\'c}, Hermina and Chasman, Daniel I and Manning, Alisa and Ntalla, Ioanna and Aschard, Hugues and Brown, Michael R and de Las Fuentes, Lisa and Franceschini, Nora and Guo, Xiuqing and Vojinovic, Dina and Aslibekyan, Stella and Feitosa, Mary F and Kho, Minjung and Musani, Solomon K and Richard, Melissa and Wang, Heming and Wang, Zhe and Bartz, Traci M and Bielak, Lawrence F and Campbell, Archie and Dorajoo, Rajkumar and Fisher, Virginia and Hartwig, Fernando P and Horimoto, Andrea R V R and Li, Changwei and Lohman, Kurt K and Marten, Jonathan and Sim, Xueling and Smith, Albert V and Tajuddin, Salman M and Alver, Maris and Amini, Marzyeh and Boissel, Mathilde and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Evangelou, Evangelos and Gao, Chuan and Graff, Mariaelisa and Harris, Sarah E and He, Meian and Hsu, Fang-Chi and Jackson, Anne U and Zhao, Jing Hua and Kraja, Aldi T and Kuhnel, Brigitte and Laguzzi, Federica and Lyytik{\"a}inen, Leo-Pekka and Nolte, Ilja M and Rauramaa, Rainer and Riaz, Muhammad and Robino, Antonietta and Rueedi, Rico and Stringham, Heather M and Takeuchi, Fumihiko and van der Most, Peter J and Varga, Tibor V and Verweij, Niek and Ware, Erin B and Wen, Wanqing and Li, Xiaoyin and Yanek, Lisa R and Amin, Najaf and Arnett, Donna K and Boerwinkle, Eric and Brumat, Marco and Cade, Brian and Canouil, Micka{\"e}l and Chen, Yii-Der Ida and Concas, Maria Pina and Connell, John and de Mutsert, Ren{\'e}e and de Silva, H Janaka and de Vries, Paul S and Demirkan, Ayse and Ding, Jingzhong and Eaton, Charles B and Faul, Jessica D and Friedlander, Yechiel and Gabriel, Kelley P and Ghanbari, Mohsen and Giulianini, Franco and Gu, Chi Charles and Gu, Dongfeng and Harris, Tamara B and He, Jiang and Heikkinen, Sami and Heng, Chew-Kiat and Hunt, Steven C and Ikram, M Arfan and Jonas, Jost B and Koh, Woon-Puay and Komulainen, Pirjo and Krieger, Jose E and Kritchevsky, Stephen B and Kutalik, Zolt{\'a}n and Kuusisto, Johanna and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Leander, Karin and Lemaitre, Rozenn N and Lewis, Cora E and Liang, Jingjing and Liu, Jianjun and M{\"a}gi, Reedik and Manichaikul, Ani and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Mohlke, Karen L and Mosley, Thomas H and Murray, Alison D and Nalls, Mike A and Nang, Ei-Ei Khaing and Nelson, Christopher P and Nona, Sotoodehnia and Norris, Jill M and Nwuba, Chiamaka Vivian and O{\textquoteright}Connell, Jeff and Palmer, Nicholette D and Papanicolau, George J and Pazoki, Raha and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Polasek, Ozren and Porteous, David J and Poveda, Alaitz and Raitakari, Olli T and Rich, Stephen S and Risch, Neil and Robinson, Jennifer G and Rose, Lynda M and Rudan, Igor and Schreiner, Pamela J and Scott, Robert A and Sidney, Stephen S and Sims, Mario and Smith, Jennifer A and Snieder, Harold and Sofer, Tamar and Starr, John M and Sternfeld, Barbara and Strauch, Konstantin and Tang, Hua and Taylor, Kent D and Tsai, Michael Y and Tuomilehto, Jaakko and Uitterlinden, Andr{\'e} G and van der Ende, M Yldau and van Heemst, Diana and Voortman, Trudy and Waldenberger, Melanie and Wennberg, Patrik and Wilson, Gregory and Xiang, Yong-Bing and Yao, Jie and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Zonderman, Alan B and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and de Faire, Ulf and Deary, Ian J and Elliott, Paul and Esko, T{\~o}nu and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Kato, Norihiro and Laakso, Markku and Lakka, Timo A and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and Oldehinkel, Albertine J and Penninx, Brenda W J H and Samani, Nilesh J and Shu, Xiao-Ou and van der Harst, Pim and van Vliet-Ostaptchouk, Jana V and Vollenweider, Peter and Wagenknecht, Lynne E and Wang, Ya X and Wareham, Nicholas J and Weir, David R and Wu, Tangchun and Zheng, Wei and Zhu, Xiaofeng and Evans, Michele K and Franks, Paul W and Gudnason, Vilmundur and Hayward, Caroline and Horta, Bernardo L and Kelly, Tanika N and Liu, Yongmei and North, Kari E and Pereira, Alexandre C and Ridker, Paul M and Tai, E Shyong and van Dam, Rob M and Fox, Ervin R and Kardia, Sharon L R and Liu, Ching-Ti and Mook-Kanamori, Dennis O and Province, Michael A and Redline, Susan and van Duijn, Cornelia M and Rotter, Jerome I and Kooperberg, Charles B and Gauderman, W James and Psaty, Bruce M and Rice, Kenneth and Munroe, Patricia B and Fornage, Myriam and Cupples, L Adrienne and Rotimi, Charles N and Morrison, Alanna C and Rao, Dabeeru C and Loos, Ruth J F} } @article {8207, title = {Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 Oct}, pages = {1459-1474}, abstract = {

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.

}, issn = {1546-1718}, doi = {10.1038/s41588-019-0504-x}, author = {Tin, Adrienne and Marten, Jonathan and Halperin Kuhns, Victoria L and Li, Yong and Wuttke, Matthias and Kirsten, Holger and Sieber, Karsten B and Qiu, Chengxiang and Gorski, Mathias and Yu, Zhi and Giri, Ayush and Sveinbjornsson, Gardar and Li, Man and Chu, Audrey Y and Hoppmann, Anselm and O{\textquoteright}Connor, Luke J and Prins, Bram and Nutile, Teresa and Noce, Damia and Akiyama, Masato and Cocca, Massimiliano and Ghasemi, Sahar and van der Most, Peter J and Horn, Katrin and Xu, Yizhe and Fuchsberger, Christian and Sedaghat, Sanaz and Afaq, Saima and Amin, Najaf and Arnl{\"o}v, Johan and Bakker, Stephan J L and Bansal, Nisha and Baptista, Daniela and Bergmann, Sven and Biggs, Mary L and Biino, Ginevra and Boerwinkle, Eric and Bottinger, Erwin P and Boutin, Thibaud S and Brumat, Marco and Burkhardt, Ralph and Campana, Eric and Campbell, Archie and Campbell, Harry and Carroll, Robert J and Catamo, Eulalia and Chambers, John C and Ciullo, Marina and Concas, Maria Pina and Coresh, Josef and Corre, Tanguy and Cusi, Daniele and Felicita, Sala Cinzia and de Borst, Martin H and De Grandi, Alessandro and de Mutsert, Ren{\'e}e and de Vries, Aiko P J and Delgado, Graciela and Demirkan, Ayse and Devuyst, Olivier and Dittrich, Katalin and Eckardt, Kai-Uwe and Ehret, Georg and Endlich, Karlhans and Evans, Michele K and Gansevoort, Ron T and Gasparini, Paolo and Giedraitis, Vilmantas and Gieger, Christian and Girotto, Giorgia and G{\"o}gele, Martin and Gordon, Scott D and Gudbjartsson, Daniel F and Gudnason, Vilmundur and Haller, Toomas and Hamet, Pavel and Harris, Tamara B and Hayward, Caroline and Hicks, Andrew A and Hofer, Edith and Holm, Hilma and Huang, Wei and Hutri-K{\"a}h{\"o}nen, Nina and Hwang, Shih-Jen and Ikram, M Arfan and Lewis, Raychel M and Ingelsson, Erik and Jakobsdottir, Johanna and Jonsdottir, Ingileif and Jonsson, Helgi and Joshi, Peter K and Josyula, Navya Shilpa and Jung, Bettina and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kanai, Masahiro and Kerr, Shona M and Kiess, Wieland and Kleber, Marcus E and Koenig, Wolfgang and Kooner, Jaspal S and K{\"o}rner, Antje and Kovacs, Peter and Kr{\"a}mer, Bernhard K and Kronenberg, Florian and Kubo, Michiaki and Kuhnel, Brigitte and La Bianca, Martina and Lange, Leslie A and Lehne, Benjamin and Lehtim{\"a}ki, Terho and Liu, Jun and Loeffler, Markus and Loos, Ruth J F and Lyytik{\"a}inen, Leo-Pekka and M{\"a}gi, Reedik and Mahajan, Anubha and Martin, Nicholas G and M{\"a}rz, Winfried and Mascalzoni, Deborah and Matsuda, Koichi and Meisinger, Christa and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and O{\textquoteright}Donnell, Christopher J and Wilson, Otis D and Gaziano, J Michael and Mishra, Pashupati P and Mohlke, Karen L and Mononen, Nina and Montgomery, Grant W and Mook-Kanamori, Dennis O and M{\"u}ller-Nurasyid, Martina and Nadkarni, Girish N and Nalls, Mike A and Nauck, Matthias and Nikus, Kjell and Ning, Boting and Nolte, Ilja M and Noordam, Raymond and O{\textquoteright}Connell, Jeffrey R and Olafsson, Isleifur and Padmanabhan, Sandosh and Penninx, Brenda W J H and Perls, Thomas and Peters, Annette and Pirastu, Mario and Pirastu, Nicola and Pistis, Giorgio and Polasek, Ozren and Ponte, Belen and Porteous, David J and Poulain, Tanja and Preuss, Michael H and Rabelink, Ton J and Raffield, Laura M and Raitakari, Olli T and Rettig, Rainer and Rheinberger, Myriam and Rice, Kenneth M and Rizzi, Federica and Robino, Antonietta and Rudan, Igor and Krajcoviechova, Alena and Cifkova, Renata and Rueedi, Rico and Ruggiero, Daniela and Ryan, Kathleen A and Saba, Yasaman and Salvi, Erika and Schmidt, Helena and Schmidt, Reinhold and Shaffer, Christian M and Smith, Albert V and Smith, Blair H and Spracklen, Cassandra N and Strauch, Konstantin and Stumvoll, Michael and Sulem, Patrick and Tajuddin, Salman M and Teren, Andrej and Thiery, Joachim and Thio, Chris H L and Thorsteinsdottir, Unnur and Toniolo, Daniela and T{\"o}njes, Anke and Tremblay, Johanne and Uitterlinden, Andr{\'e} G and Vaccargiu, Simona and van der Harst, Pim and van Duijn, Cornelia M and Verweij, Niek and V{\"o}lker, Uwe and Vollenweider, Peter and Waeber, G{\'e}rard and Waldenberger, Melanie and Whitfield, John B and Wild, Sarah H and Wilson, James F and Yang, Qiong and Zhang, Weihua and Zonderman, Alan B and Bochud, Murielle and Wilson, James G and Pendergrass, Sarah A and Ho, Kevin and Parsa, Afshin and Pramstaller, Peter P and Psaty, Bruce M and B{\"o}ger, Carsten A and Snieder, Harold and Butterworth, Adam S and Okada, Yukinori and Edwards, Todd L and Stefansson, Kari and Susztak, Katalin and Scholz, Markus and Heid, Iris M and Hung, Adriana M and Teumer, Alexander and Pattaro, Cristian and Woodward, Owen M and Vitart, Veronique and K{\"o}ttgen, Anna} } @article {8381, title = {Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.}, journal = {Mol Psychiatry}, year = {2020}, month = {2020 May 05}, abstract = {

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 {\texttimes} 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.

}, issn = {1476-5578}, doi = {10.1038/s41380-020-0719-3}, author = {de Las Fuentes, Lisa and Sung, Yun Ju and Noordam, Raymond and Winkler, Thomas and Feitosa, Mary F and Schwander, Karen and Bentley, Amy R and Brown, Michael R and Guo, Xiuqing and Manning, Alisa and Chasman, Daniel I and Aschard, Hugues and Bartz, Traci M and Bielak, Lawrence F and Campbell, Archie and Cheng, Ching-Yu and Dorajoo, Rajkumar and Hartwig, Fernando P and Horimoto, A R V R and Li, Changwei and Li-Gao, Ruifang and Liu, Yongmei and Marten, Jonathan and Musani, Solomon K and Ntalla, Ioanna and Rankinen, Tuomo and Richard, Melissa and Sim, Xueling and Smith, Albert V and Tajuddin, Salman M and Tayo, Bamidele O and Vojinovic, Dina and Warren, Helen R and Xuan, Deng and Alver, Maris and Boissel, Mathilde and Chai, Jin-Fang and Chen, Xu and Christensen, Kaare and Divers, Jasmin and Evangelou, Evangelos and Gao, Chuan and Girotto, Giorgia and Harris, Sarah E and He, Meian and Hsu, Fang-Chi and Kuhnel, Brigitte and Laguzzi, Federica and Li, Xiaoyin and Lyytik{\"a}inen, Leo-Pekka and Nolte, Ilja M and Poveda, Alaitz and Rauramaa, Rainer and Riaz, Muhammad and Rueedi, Rico and Shu, Xiao-Ou and Snieder, Harold and Sofer, Tamar and Takeuchi, Fumihiko and Verweij, Niek and Ware, Erin B and Weiss, Stefan and Yanek, Lisa R and Amin, Najaf and Arking, Dan E and Arnett, Donna K and Bergmann, Sven and Boerwinkle, Eric and Brody, Jennifer A and Broeckel, Ulrich and Brumat, Marco and Burke, Gregory and Cabrera, Claudia P and Canouil, Micka{\"e}l and Chee, Miao Li and Chen, Yii-Der Ida and Cocca, Massimiliano and Connell, John and de Silva, H Janaka and de Vries, Paul S and Eiriksdottir, Gudny and Faul, Jessica D and Fisher, Virginia and Forrester, Terrence and Fox, Ervin F and Friedlander, Yechiel and Gao, He and Gigante, Bruna and Giulianini, Franco and Gu, Chi Charles and Gu, Dongfeng and Harris, Tamara B and He, Jiang and Heikkinen, Sami and Heng, Chew-Kiat and Hunt, Steven and Ikram, M Arfan and Irvin, Marguerite R and K{\"a}h{\"o}nen, Mika and Kavousi, Maryam and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Komulainen, Pirjo and Kraja, Aldi T and Krieger, J E and Langefeld, Carl D and Li, Yize and Liang, Jingjing and Liewald, David C M and Liu, Ching-Ti and Liu, Jianjun and Lohman, Kurt K and M{\"a}gi, Reedik and McKenzie, Colin A and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Milani, Lili and Mook-Kanamori, Dennis O and Nalls, Mike A and Nelson, Christopher P and Norris, Jill M and O{\textquoteright}Connell, Jeff and Ogunniyi, Adesola and Padmanabhan, Sandosh and Palmer, Nicholette D and Pedersen, Nancy L and Perls, Thomas and Peters, Annette and Petersmann, Astrid and Peyser, Patricia A and Polasek, Ozren and Porteous, David J and Raffel, Leslie J and Rice, Treva K and Rotter, Jerome I and Rudan, Igor and Rueda-Ochoa, Oscar-Leonel and Sabanayagam, Charumathi and Salako, Babatunde L and Schreiner, Pamela J and Shikany, James M and Sidney, Stephen S and Sims, Mario and Sitlani, Colleen M and Smith, Jennifer A and Starr, John M and Strauch, Konstantin and Swertz, Morris A and Teumer, Alexander and Tham, Yih Chung and Uitterlinden, Andr{\'e} G and Vaidya, Dhananjay and van der Ende, M Yldau and Waldenberger, Melanie and Wang, Lihua and Wang, Ya-Xing and Wei, Wen-Bin and Weir, David R and Wen, Wanqing and Yao, Jie and Yu, Bing and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Zonderman, Alan B and Becker, Diane M and Bowden, Donald W and Deary, Ian J and D{\"o}rr, Marcus and Esko, T{\~o}nu and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Jonas, Jost Bruno and Kammerer, Candace M and Kato, Norihiro and Lakka, Timo A and Leander, Karin and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and Marques-Vidal, Pedro and Penninx, Brenda W J H and Samani, Nilesh J and van der Harst, Pim and Wagenknecht, Lynne E and Wu, Tangchun and Zheng, Wei and Zhu, Xiaofeng and Bouchard, Claude and Cooper, Richard S and Correa, Adolfo and Evans, Michele K and Gudnason, Vilmundur and Hayward, Caroline and Horta, Bernardo L and Kelly, Tanika N and Kritchevsky, Stephen B and Levy, Daniel and Palmas, Walter R and Pereira, A C and Province, Michael M and Psaty, Bruce M and Ridker, Paul M and Rotimi, Charles N and Tai, E Shyong and van Dam, Rob M and van Duijn, Cornelia M and Wong, Tien Yin and Rice, Kenneth and Gauderman, W James and Morrison, Alanna C and North, Kari E and Kardia, Sharon L R and Caulfield, Mark J and Elliott, Paul and Munroe, Patricia B and Franks, Paul W and Rao, Dabeeru C and Fornage, Myriam} } @article {8835, title = {Genetic insights into biological mechanisms governing human ovarian ageing.}, journal = {Nature}, volume = {596}, year = {2021}, month = {2021 Aug}, pages = {393-397}, abstract = {

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.

}, issn = {1476-4687}, doi = {10.1038/s41586-021-03779-7}, author = {Ruth, Katherine S and Day, Felix R and Hussain, Jazib and Mart{\'\i}nez-Marchal, Ana and Aiken, Catherine E and Azad, Ajuna and Thompson, Deborah J and Knoblochova, Lucie and Abe, Hironori and Tarry-Adkins, Jane L and Gonzalez, Javier Martin and Fontanillas, Pierre and Claringbould, Annique and Bakker, Olivier B and Sulem, Patrick and Walters, Robin G and Terao, Chikashi and Turon, Sandra and Horikoshi, Momoko and Lin, Kuang and Onland-Moret, N Charlotte and Sankar, Aditya and Hertz, Emil Peter Thrane and Timshel, Pascal N and Shukla, Vallari and Borup, Rehannah and Olsen, Kristina W and Aguilera, Paula and Ferrer-Roda, M{\`o}nica and Huang, Yan and Stankovic, Stasa and Timmers, Paul R H J and Ahearn, Thomas U and Alizadeh, Behrooz Z and Naderi, Elnaz and Andrulis, Irene L and Arnold, Alice M and Aronson, Kristan J and Augustinsson, Annelie and Bandinelli, Stefania and Barbieri, Caterina M and Beaumont, Robin N and Becher, Heiko and Beckmann, Matthias W and Benonisdottir, Stefania and Bergmann, Sven and Bochud, Murielle and Boerwinkle, Eric and Bojesen, Stig E and Bolla, Manjeet K and Boomsma, Dorret I and Bowker, Nicholas and Brody, Jennifer A and Broer, Linda and Buring, Julie E and Campbell, Archie and Campbell, Harry and Castelao, Jose E and Catamo, Eulalia and Chanock, Stephen J and Chenevix-Trench, Georgia and Ciullo, Marina and Corre, Tanguy and Couch, Fergus J and Cox, Angela and Crisponi, Laura and Cross, Simon S and Cucca, Francesco and Czene, Kamila and Smith, George Davey and de Geus, Eco J C N and de Mutsert, Ren{\'e}e and De Vivo, Immaculata and Demerath, Ellen W and Dennis, Joe and Dunning, Alison M and Dwek, Miriam and Eriksson, Mikael and Esko, T{\~o}nu and Fasching, Peter A and Faul, Jessica D and Ferrucci, Luigi and Franceschini, Nora and Frayling, Timothy M and Gago-Dominguez, Manuela and Mezzavilla, Massimo and Garc{\'\i}a-Closas, Montserrat and Gieger, Christian and Giles, Graham G and Grallert, Harald and Gudbjartsson, Daniel F and Gudnason, Vilmundur and Gu{\'e}nel, Pascal and Haiman, Christopher A and H{\r a}kansson, Niclas and Hall, Per and Hayward, Caroline and He, Chunyan and He, Wei and Heiss, Gerardo and H{\o}ffding, Miya K and Hopper, John L and Hottenga, Jouke J and Hu, Frank and Hunter, David and Ikram, Mohammad A and Jackson, Rebecca D and Joaquim, Micaella D R and John, Esther M and Joshi, Peter K and Karasik, David and Kardia, Sharon L R and Kartsonaki, Christiana and Karlsson, Robert and Kitahara, Cari M and Kolcic, Ivana and Kooperberg, Charles and Kraft, Peter and Kurian, Allison W and Kutalik, Zolt{\'a}n and La Bianca, Martina and Lachance, Genevieve and Langenberg, Claudia and Launer, Lenore J and Laven, Joop S E and Lawlor, Deborah A and Le Marchand, Lo{\"\i}c and Li, Jingmei and Lindblom, Annika and Lindstr{\"o}m, Sara and Lindstrom, Tricia and Linet, Martha and Liu, Yongmei and Liu, Simin and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Magnusson, Patrik K E and Mangino, Massimo and Mannermaa, Arto and Marco, Brumat and Marten, Jonathan and Martin, Nicholas G and Mbarek, Hamdi and McKnight, Barbara and Medland, Sarah E and Meisinger, Christa and Meitinger, Thomas and Menni, Cristina and Metspalu, Andres and Milani, Lili and Milne, Roger L and Montgomery, Grant W and Mook-Kanamori, Dennis O and Mulas, Antonella and Mulligan, Anna M and Murray, Alison and Nalls, Mike A and Newman, Anne and Noordam, Raymond and Nutile, Teresa and Nyholt, Dale R and Olshan, Andrew F and Olsson, H{\r a}kan and Painter, Jodie N and Patel, Alpa V and Pedersen, Nancy L and Perjakova, Natalia and Peters, Annette and Peters, Ulrike and Pharoah, Paul D P and Polasek, Ozren and Porcu, Eleonora and Psaty, Bruce M and Rahman, Iffat and Rennert, Gad and Rennert, Hedy S and Ridker, Paul M and Ring, Susan M and Robino, Antonietta and Rose, Lynda M and Rosendaal, Frits R and Rossouw, Jacques and Rudan, Igor and Rueedi, Rico and Ruggiero, Daniela and Sala, Cinzia F and Saloustros, Emmanouil and Sandler, Dale P and Sanna, Serena and Sawyer, Elinor J and Sarnowski, Chloe and Schlessinger, David and Schmidt, Marjanka K and Schoemaker, Minouk J and Schraut, Katharina E and Scott, Christopher and Shekari, Saleh and Shrikhande, Amruta and Smith, Albert V and Smith, Blair H and Smith, Jennifer A and Sorice, Rossella and Southey, Melissa C and Spector, Tim D and Spinelli, John J and Stampfer, Meir and St{\"o}ckl, Doris and van Meurs, Joyce B J and Strauch, Konstantin and Styrkarsdottir, Unnur and Swerdlow, Anthony J and Tanaka, Toshiko and Teras, Lauren R and Teumer, Alexander and {\TH}orsteinsdottir, Unnur and Timpson, Nicholas J and Toniolo, Daniela and Traglia, Michela and Troester, Melissa A and Truong, Th{\'e}r{\`e}se and Tyrrell, Jessica and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and Vachon, Celine M and Vitart, Veronique and V{\"o}lker, Uwe and Vollenweider, Peter and V{\"o}lzke, Henry and Wang, Qin and Wareham, Nicholas J and Weinberg, Clarice R and Weir, David R and Wilcox, Amber N and van Dijk, Ko Willems and Willemsen, Gonneke and Wilson, James F and Wolffenbuttel, Bruce H R and Wolk, Alicja and Wood, Andrew R and Zhao, Wei and Zygmunt, Marek and Chen, Zhengming and Li, Liming and Franke, Lude and Burgess, Stephen and Deelen, Patrick and Pers, Tune H and Gr{\o}ndahl, Marie Louise and Andersen, Claus Yding and Pujol, Anna and Lopez-Contreras, Andres J and Daniel, Jeremy A and Stefansson, Kari and Chang-Claude, Jenny and van der Schouw, Yvonne T and Lunetta, Kathryn L and Chasman, Daniel I and Easton, Douglas F and Visser, Jenny A and Ozanne, Susan E and Namekawa, Satoshi H and Solc, Petr and Murabito, Joanne M and Ong, Ken K and Hoffmann, Eva R and Murray, Anna and Roig, Ignasi and Perry, John R B} } @article {9112, title = {Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals.}, journal = {Commun Biol}, volume = {5}, year = {2022}, month = {2022 Jun 13}, pages = {580}, abstract = {

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.

}, keywords = {Creatinine, Diabetes Mellitus, Diabetic Nephropathies, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney}, issn = {2399-3642}, doi = {10.1038/s42003-022-03448-z}, author = {Winkler, Thomas W and Rasheed, Humaira and Teumer, Alexander and Gorski, Mathias and Rowan, Bryce X and Stanzick, Kira J and Thomas, Laurent F and Tin, Adrienne and Hoppmann, Anselm and Chu, Audrey Y and Tayo, Bamidele and Thio, Chris H L and Cusi, Daniele and Chai, Jin-Fang and Sieber, Karsten B and Horn, Katrin and Li, Man and Scholz, Markus and Cocca, Massimiliano and Wuttke, Matthias and van der Most, Peter J and Yang, Qiong and Ghasemi, Sahar and Nutile, Teresa and Li, Yong and Pontali, Giulia and G{\"u}nther, Felix and Dehghan, Abbas and Correa, Adolfo and Parsa, Afshin and Feresin, Agnese and de Vries, Aiko P J and Zonderman, Alan B and Smith, Albert V and Oldehinkel, Albertine J and De Grandi, Alessandro and Rosenkranz, Alexander R and Franke, Andre and Teren, Andrej and Metspalu, Andres and Hicks, Andrew A and Morris, Andrew P and T{\"o}njes, Anke and Morgan, Anna and Podgornaia, Anna I and Peters, Annette and K{\"o}rner, Antje and Mahajan, Anubha and Campbell, Archie and Freedman, Barry I and Spedicati, Beatrice and Ponte, Belen and Sch{\"o}ttker, Ben and Brumpton, Ben and Banas, Bernhard and Kr{\"a}mer, Bernhard K and Jung, Bettina and {\r A}svold, Bj{\o}rn Olav and Smith, Blair H and Ning, Boting and Penninx, Brenda W J H and Vanderwerff, Brett R and Psaty, Bruce M and Kammerer, Candace M and Langefeld, Carl D and Hayward, Caroline and Spracklen, Cassandra N and Robinson-Cohen, Cassianne and Hartman, Catharina A and Lindgren, Cecilia M and Wang, Chaolong and Sabanayagam, Charumathi and Heng, Chew-Kiat and Lanzani, Chiara and Khor, Chiea-Chuen and Cheng, Ching-Yu and Fuchsberger, Christian and Gieger, Christian and Shaffer, Christian M and Schulz, Christina-Alexandra and Willer, Cristen J and Chasman, Daniel I and Gudbjartsson, Daniel F and Ruggiero, Daniela and Toniolo, Daniela and Czamara, Darina and Porteous, David J and Waterworth, Dawn M and Mascalzoni, Deborah and Mook-Kanamori, Dennis O and Reilly, Dermot F and Daw, E Warwick and Hofer, Edith and Boerwinkle, Eric and Salvi, Erika and Bottinger, Erwin P and Tai, E-Shyong and Catamo, Eulalia and Rizzi, Federica and Guo, Feng and Rivadeneira, Fernando and Guilianini, Franco and Sveinbjornsson, Gardar and Ehret, Georg and Waeber, G{\'e}rard and Biino, Ginevra and Girotto, Giorgia and Pistis, Giorgio and Nadkarni, Girish N and Delgado, Graciela E and Montgomery, Grant W and Snieder, Harold and Campbell, Harry and White, Harvey D and Gao, He and Stringham, Heather M and Schmidt, Helena and Li, Hengtong and Brenner, Hermann and Holm, Hilma and Kirsten, Holgen and Kramer, Holly and Rudan, Igor and Nolte, Ilja M and Tzoulaki, Ioanna and Olafsson, Isleifur and Martins, Jade and Cook, James P and Wilson, James F and Halbritter, Jan and Felix, Janine F and Divers, Jasmin and Kooner, Jaspal S and Lee, Jeannette Jen-Mai and O{\textquoteright}Connell, Jeffrey and Rotter, Jerome I and Liu, Jianjun and Xu, Jie and Thiery, Joachim and Arnl{\"o}v, Johan and Kuusisto, Johanna and Jakobsdottir, Johanna and Tremblay, Johanne and Chambers, John C and Whitfield, John B and Gaziano, John M and Marten, Jonathan and Coresh, Josef and Jonas, Jost B and Mychaleckyj, Josyf C and Christensen, Kaare and Eckardt, Kai-Uwe and Mohlke, Karen L and Endlich, Karlhans and Dittrich, Katalin and Ryan, Kathleen A and Rice, Kenneth M and Taylor, Kent D and Ho, Kevin and Nikus, Kjell and Matsuda, Koichi and Strauch, Konstantin and Miliku, Kozeta and Hveem, Kristian and Lind, Lars and Wallentin, Lars and Yerges-Armstrong, Laura M and Raffield, Laura M and Phillips, Lawrence S and Launer, Lenore J and Lyytik{\"a}inen, Leo-Pekka and Lange, Leslie A and Citterio, Lorena and Klaric, Lucija and Ikram, M Arfan and Ising, Marcus and Kleber, Marcus E and Francescatto, Margherita and Concas, Maria Pina and Ciullo, Marina and Piratsu, Mario and Orho-Melander, Marju and Laakso, Markku and Loeffler, Markus and Perola, Markus and de Borst, Martin H and G{\"o}gele, Martin and Bianca, Martina La and Lukas, Mary Ann and Feitosa, Mary F and Biggs, Mary L and Wojczynski, Mary K and Kavousi, Maryam and Kanai, Masahiro and Akiyama, Masato and Yasuda, Masayuki and Nauck, Matthias and Waldenberger, Melanie and Chee, Miao-Li and Chee, Miao-Ling and Boehnke, Michael and Preuss, Michael H and Stumvoll, Michael and Province, Michael A and Evans, Michele K and O{\textquoteright}Donoghue, Michelle L and Kubo, Michiaki and K{\"a}h{\"o}nen, Mika and Kastarinen, Mika and Nalls, Mike A and Kuokkanen, Mikko and Ghanbari, Mohsen and Bochud, Murielle and Josyula, Navya Shilpa and Martin, Nicholas G and Tan, Nicholas Y Q and Palmer, Nicholette D and Pirastu, Nicola and Schupf, Nicole and Verweij, Niek and Hutri-K{\"a}h{\"o}nen, Nina and Mononen, Nina and Bansal, Nisha and Devuyst, Olivier and Melander, Olle and Raitakari, Olli T and Polasek, Ozren and Manunta, Paolo and Gasparini, Paolo and Mishra, Pashupati P and Sulem, Patrick and Magnusson, Patrik K E and Elliott, Paul and Ridker, Paul M and Hamet, Pavel and Svensson, Per O and Joshi, Peter K and Kovacs, Peter and Pramstaller, Peter P and Rossing, Peter and Vollenweider, Peter and van der Harst, Pim and Dorajoo, Rajkumar and Sim, Ralene Z H and Burkhardt, Ralph and Tao, Ran and Noordam, Raymond and M{\"a}gi, Reedik and Schmidt, Reinhold and de Mutsert, Ren{\'e}e and Rueedi, Rico and van Dam, Rob M and Carroll, Robert J and Gansevoort, Ron T and Loos, Ruth J F and Felicita, Sala Cinzia and Sedaghat, Sanaz and Padmanabhan, Sandosh and Freitag-Wolf, Sandra and Pendergrass, Sarah A and Graham, Sarah E and Gordon, Scott D and Hwang, Shih-Jen and Kerr, Shona M and Vaccargiu, Simona and Patil, Snehal B and Hallan, Stein and Bakker, Stephan J L and Lim, Su-Chi and Lucae, Susanne and Vogelezang, Suzanne and Bergmann, Sven and Corre, Tanguy and Ahluwalia, Tarunveer S and Lehtim{\"a}ki, Terho and Boutin, Thibaud S and Meitinger, Thomas and Wong, Tien-Yin and Bergler, Tobias and Rabelink, Ton J and Esko, T{\~o}nu and Haller, Toomas and Thorsteinsdottir, Unnur and V{\"o}lker, Uwe and Foo, Valencia Hui Xian and Salomaa, Veikko and Vitart, Veronique and Giedraitis, Vilmantas and Gudnason, Vilmundur and Jaddoe, Vincent W V and Huang, Wei and Zhang, Weihua and Wei, Wen Bin and Kiess, Wieland and M{\"a}rz, Winfried and Koenig, Wolfgang and Lieb, Wolfgang and G{\`a}o, Xin and Sim, Xueling and Wang, Ya Xing and Friedlander, Yechiel and Tham, Yih-Chung and Kamatani, Yoichiro and Okada, Yukinori and Milaneschi, Yuri and Yu, Zhi and Stark, Klaus J and Stefansson, Kari and B{\"o}ger, Carsten A and Hung, Adriana M and Kronenberg, Florian and K{\"o}ttgen, Anna and Pattaro, Cristian and Heid, Iris M} }