@article {7845, title = {Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Oct}, pages = {1412-1425}, abstract = {

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0205-x}, author = {Evangelou, Evangelos and Warren, Helen R and Mosen-Ansorena, David and Mifsud, Borbala and Pazoki, Raha and Gao, He and Ntritsos, Georgios and Dimou, Niki and Cabrera, Claudia P and Karaman, Ibrahim and Ng, Fu Liang and Evangelou, Marina and Witkowska, Katarzyna and Tzanis, Evan and Hellwege, Jacklyn N and Giri, Ayush and Velez Edwards, Digna R and Sun, Yan V and Cho, Kelly and Gaziano, J Michael and Wilson, Peter W F and Tsao, Philip S and Kovesdy, Csaba P and Esko, T{\~o}nu and M{\"a}gi, Reedik and Milani, Lili and Almgren, Peter and Boutin, Thibaud and Debette, Stephanie and Ding, Jun and Giulianini, Franco and Holliday, Elizabeth G and Jackson, Anne U and Li-Gao, Ruifang and Lin, Wei-Yu and Luan, Jian{\textquoteright}an and Mangino, Massimo and Oldmeadow, Christopher and Prins, Bram Peter and Qian, Yong and Sargurupremraj, Muralidharan and Shah, Nabi and Surendran, Praveen and Th{\'e}riault, S{\'e}bastien and Verweij, Niek and Willems, Sara M and Zhao, Jing-Hua and Amouyel, Philippe and Connell, John and de Mutsert, Ren{\'e}e and Doney, Alex S F and Farrall, Martin and Menni, Cristina and Morris, Andrew D and Noordam, Raymond and Par{\'e}, Guillaume and Poulter, Neil R and Shields, Denis C and Stanton, Alice and Thom, Simon and Abecasis, Goncalo and Amin, Najaf and Arking, Dan E and Ayers, Kristin L and Barbieri, Caterina M and Batini, Chiara and Bis, Joshua C and Blake, Tineka and Bochud, Murielle and Boehnke, Michael and Boerwinkle, Eric and Boomsma, Dorret I and Bottinger, Erwin P and Braund, Peter S and Brumat, Marco and Campbell, Archie and Campbell, Harry and Chakravarti, Aravinda and Chambers, John C and Chauhan, Ganesh and Ciullo, Marina and Cocca, Massimiliano and Collins, Francis and Cordell, Heather J and Davies, Gail and Borst, Martin H de and Geus, Eco J de and Deary, Ian J and Deelen, Joris and del Greco M, Fabiola and Demirkale, Cumhur Yusuf and D{\"o}rr, Marcus and Ehret, Georg B and Elosua, Roberto and Enroth, Stefan and Erzurumluoglu, A Mesut and Ferreira, Teresa and Fr{\r a}nberg, Mattias and Franco, Oscar H and Gandin, Ilaria and Gasparini, Paolo and Giedraitis, Vilmantas and Gieger, Christian and Girotto, Giorgia and Goel, Anuj and Gow, Alan J and Gudnason, Vilmundur and Guo, Xiuqing and Gyllensten, Ulf and Hamsten, Anders and Harris, Tamara B and Harris, Sarah E and Hartman, Catharina A and Havulinna, Aki S and Hicks, Andrew A and Hofer, Edith and Hofman, Albert and Hottenga, Jouke-Jan and Huffman, Jennifer E and Hwang, Shih-Jen and Ingelsson, Erik and James, Alan and Jansen, Rick and Jarvelin, Marjo-Riitta and Joehanes, Roby and Johansson, Asa and Johnson, Andrew D and Joshi, Peter K and Jousilahti, Pekka and Jukema, J Wouter and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kathiresan, Sekar and Keavney, Bernard D and Khaw, Kay-Tee and Knekt, Paul and Knight, Joanne and Kolcic, Ivana and Kooner, Jaspal S and Koskinen, Seppo and Kristiansson, Kati and Kutalik, Zolt{\'a}n and Laan, Maris and Larson, Marty and Launer, Lenore J and Lehne, Benjamin and Lehtim{\"a}ki, Terho and Liewald, David C M and Lin, Li and Lind, Lars and Lindgren, Cecilia M and Liu, Yongmei and Loos, Ruth J F and Lopez, Lorna M and Lu, Yingchang and Lyytik{\"a}inen, Leo-Pekka and Mahajan, Anubha and Mamasoula, Chrysovalanto and Marrugat, Jaume and Marten, Jonathan and Milaneschi, Yuri and Morgan, Anna and Morris, Andrew P and Morrison, Alanna C and Munson, Peter J and Nalls, Mike A and Nandakumar, Priyanka and Nelson, Christopher P and Niiranen, Teemu and Nolte, Ilja M and Nutile, Teresa and Oldehinkel, Albertine J and Oostra, Ben A and O{\textquoteright}Reilly, Paul F and Org, Elin and Padmanabhan, Sandosh and Palmas, Walter and Palotie, Aarno and Pattie, Alison and Penninx, Brenda W J H and Perola, Markus and Peters, Annette and Polasek, Ozren and Pramstaller, Peter P and Nguyen, Quang Tri and Raitakari, Olli T and Ren, Meixia and Rettig, Rainer and Rice, Kenneth and Ridker, Paul M and Ried, Janina S and Riese, Harri{\"e}tte and Ripatti, Samuli and Robino, Antonietta and Rose, Lynda M and Rotter, Jerome I and Rudan, Igor and Ruggiero, Daniela and Saba, Yasaman and Sala, Cinzia F and Salomaa, Veikko and Samani, Nilesh J and Sarin, Antti-Pekka and Schmidt, Reinhold and Schmidt, Helena and Shrine, Nick and Siscovick, David and Smith, Albert V and Snieder, Harold and S{\~o}ber, Siim and Sorice, Rossella and Starr, John M and Stott, David J and Strachan, David P and Strawbridge, Rona J and Sundstr{\"o}m, Johan and Swertz, Morris A and Taylor, Kent D and Teumer, Alexander and Tobin, Martin D and Tomaszewski, Maciej and Toniolo, Daniela and Traglia, Michela and Trompet, Stella and Tuomilehto, Jaakko and Tzourio, Christophe and Uitterlinden, Andr{\'e} G and Vaez, Ahmad and van der Most, Peter J and van Duijn, Cornelia M and Vergnaud, Anne-Claire and Verwoert, Germaine C and Vitart, Veronique and V{\"o}lker, Uwe and Vollenweider, Peter and Vuckovic, Dragana and Watkins, Hugh and Wild, Sarah H and Willemsen, Gonneke and Wilson, James F and Wright, Alan F and Yao, Jie and Zemunik, Tatijana and Zhang, Weihua and Attia, John R and Butterworth, Adam S and Chasman, Daniel I and Conen, David and Cucca, Francesco and Danesh, John and Hayward, Caroline and Howson, Joanna M M and Laakso, Markku and Lakatta, Edward G and Langenberg, Claudia and Melander, Olle and Mook-Kanamori, Dennis O and Palmer, Colin N A and Risch, Lorenz and Scott, Robert A and Scott, Rodney J and Sever, Peter and Spector, Tim D and van der Harst, Pim and Wareham, Nicholas J and Zeggini, Eleftheria and Levy, Daniel and Munroe, Patricia B and Newton-Cheh, Christopher and Brown, Morris J and Metspalu, Andres and Hung, Adriana M and O{\textquoteright}Donnell, Christopher J and Edwards, Todd L and Psaty, Bruce M and Tzoulaki, Ioanna and Barnes, Michael R and Wain, Louise V and Elliott, Paul and Caulfield, Mark J} } @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 {9372, title = {Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group.}, journal = {Am J Hypertens}, volume = {32}, year = {2019}, month = {2019 Nov 15}, pages = {1146-1153}, abstract = {

BACKGROUND: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.

METHODS: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP >= 140 mm Hg and/or diastolic BP >= 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL.

RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 {\texttimes} 10-8) and in the race-combined analysis (P = 1.5 {\texttimes} 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95\% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls.

CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.

}, keywords = {Aged, Antihypertensive Agents, Black or African American, Blood Pressure, Case-Control Studies, DNA (Cytosine-5-)-Methyltransferases, DNA Methyltransferase 3A, DNA-Binding Proteins, Drug Resistance, Dystrophin-Associated Proteins, Europe, Female, Genetic Loci, Genome-Wide Association Study, Humans, Hypertension, Male, Middle Aged, Myosin Heavy Chains, Myosin Type V, Neuropeptides, Pharmacogenetics, Pharmacogenomic Variants, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Transcription Factors, United States, White People}, issn = {1941-7225}, doi = {10.1093/ajh/hpz150}, author = {Irvin, Marguerite R and Sitlani, Colleen M and Floyd, James S and Psaty, Bruce M and Bis, Joshua C and Wiggins, Kerri L and Whitsel, Eric A and St{\"u}rmer, Til and Stewart, James and Raffield, Laura and Sun, Fangui and Liu, Ching-Ti and Xu, Hanfei and Cupples, Adrienne L and Tanner, Rikki M and Rossing, Peter and Smith, Albert and Zilh{\~a}o, Nuno R and Launer, Lenore J and Noordam, Raymond and Rotter, Jerome I and Yao, Jie and Li, Xiaohui and Guo, Xiuqing and Limdi, Nita and Sundaresan, Aishwarya and Lange, Leslie and Correa, Adolfo and Stott, David J and Ford, Ian and Jukema, J Wouter and Gudnason, Vilmundur and Mook-Kanamori, Dennis O and Trompet, Stella and Palmas, Walter and Warren, Helen R and Hellwege, Jacklyn N and Giri, Ayush and O{\textquoteright}donnell, Christopher and Hung, Adriana M and Edwards, Todd L and Ahluwalia, Tarunveer S and Arnett, Donna K and Avery, Christy L} } @article {7914, title = {Trans-ethnic association study of blood pressure determinants in over 750,000 individuals.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 Jan}, pages = {51-62}, abstract = {

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0303-9}, author = {Giri, Ayush and Hellwege, Jacklyn N and Keaton, Jacob M and Park, Jihwan and Qiu, Chengxiang and Warren, Helen R and Torstenson, Eric S and Kovesdy, Csaba P and Sun, Yan V and Wilson, Otis D and Robinson-Cohen, Cassianne and Roumie, Christianne L and Chung, Cecilia P and Birdwell, Kelly A and Damrauer, Scott M and DuVall, Scott L and Klarin, Derek and Cho, Kelly and Wang, Yu and Evangelou, Evangelos and Cabrera, Claudia P and Wain, Louise V and Shrestha, Rojesh and Mautz, Brian S and Akwo, Elvis A and Sargurupremraj, Muralidharan and Debette, Stephanie and Boehnke, Michael and Scott, Laura J and Luan, Jian{\textquoteright}an and Zhao, Jing-Hua and Willems, Sara M and Th{\'e}riault, S{\'e}bastien and Shah, Nabi and Oldmeadow, Christopher and Almgren, Peter and Li-Gao, Ruifang and Verweij, Niek and Boutin, Thibaud S and Mangino, Massimo and Ntalla, Ioanna and Feofanova, Elena and Surendran, Praveen and Cook, James P and Karthikeyan, Savita and Lahrouchi, Najim and Liu, Chunyu and Sep{\'u}lveda, Nuno and Richardson, Tom G and Kraja, Aldi and Amouyel, Philippe and Farrall, Martin and Poulter, Neil R and Laakso, Markku and Zeggini, Eleftheria and Sever, Peter and Scott, Robert A and Langenberg, Claudia and Wareham, Nicholas J and Conen, David and Palmer, Colin Neil Alexander and Attia, John and Chasman, Daniel I and Ridker, Paul M and Melander, Olle and Mook-Kanamori, Dennis Owen and Harst, Pim van der and Cucca, Francesco and Schlessinger, David and Hayward, Caroline and Spector, Tim D and Jarvelin, Marjo-Riitta and Hennig, Branwen J and Timpson, Nicholas J and Wei, Wei-Qi and Smith, Joshua C and Xu, Yaomin and Matheny, Michael E and Siew, Edward E and Lindgren, Cecilia and Herzig, Karl-Heinz and Dedoussis, George and Denny, Joshua C and Psaty, Bruce M and Howson, Joanna M M and Munroe, Patricia B and Newton-Cheh, Christopher and Caulfield, Mark J and Elliott, Paul and Gaziano, J Michael and Concato, John and Wilson, Peter W F and Tsao, Philip S and Velez Edwards, Digna R and Susztak, Katalin and O{\textquoteright}Donnell, Christopher J and Hung, Adriana M and Edwards, Todd L} } @article {9099, title = {Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension.}, journal = {Hypertension}, year = {2022}, month = {2022 Jun 02}, pages = {101161HYPERTENSIONAHA12219324}, abstract = {

BACKGROUND: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.

METHODS: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.

RESULTS: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (<5{\texttimes}10). Among them, a rare intergenic variant at novel locus, , was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; =4.99{\texttimes}10) but not stage-2 analysis (=0.11). Furthermore, a novel common variant at the known locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; =4.18{\texttimes}10) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; =7.28{\texttimes}10). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (<1{\texttimes}10 and <1{\texttimes}10, respectively).

DISCUSSION: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.

}, issn = {1524-4563}, doi = {10.1161/HYPERTENSIONAHA.122.19324}, author = {Kelly, Tanika N and Sun, Xiao and He, Karen Y and Brown, Michael R and Taliun, Sarah A Gagliano and Hellwege, Jacklyn N and Irvin, Marguerite R and Mi, Xuenan and Brody, Jennifer A and Franceschini, Nora and Guo, Xiuqing and Hwang, Shih-Jen and de Vries, Paul S and Gao, Yan and Moscati, Arden and Nadkarni, Girish N and Yanek, Lisa R and Elfassy, Tali and Smith, Jennifer A and Chung, Ren-Hua and Beitelshees, Amber L and Patki, Amit and Aslibekyan, Stella and Blobner, Brandon M and Peralta, Juan M and Assimes, Themistocles L and Palmas, Walter R and Liu, Chunyu and Bress, Adam P and Huang, Zhijie and Becker, Lewis C and Hwa, Chii-Min and O{\textquoteright}Connell, Jeffrey R and Carlson, Jenna C and Warren, Helen R and Das, Sayantan and Giri, Ayush and Martin, Lisa W and Craig Johnson, W and Fox, Ervin R and Bottinger, Erwin P and Razavi, Alexander C and Vaidya, Dhananjay and Chuang, Lee-Ming and Chang, Yen-Pei C and Naseri, Take and Jain, Deepti and Kang, Hyun Min and Hung, Adriana M and Srinivasasainagendra, Vinodh and Snively, Beverly M and Gu, Dongfeng and Montasser, May E and Reupena, Muagututi{\textquoteright}a Sefuiva and Heavner, Benjamin D and LeFaive, Jonathon and Hixson, James E and Rice, Kenneth M and Wang, Fei Fei and Nielsen, Jonas B and Huang, Jianfeng and Khan, Alyna T and Zhou, Wei and Nierenberg, Jovia L and Laurie, Cathy C and Armstrong, Nicole D and Shi, Mengyao and Pan, Yang and Stilp, Adrienne M and Emery, Leslie and Wong, Quenna and Hawley, Nicola L and Minster, Ryan L and Curran, Joanne E and Munroe, Patricia B and Weeks, Daniel E and North, Kari E and Tracy, Russell P and Kenny, Eimear E and Shimbo, Daichi and Chakravarti, Aravinda and Rich, Stephen S and Reiner, Alex P and Blangero, John and Redline, Susan and Mitchell, Braxton D and Rao, Dabeeru C and Ida Chen, Yii-Der and Kardia, Sharon L R and Kaplan, Robert C and Mathias, Rasika A and He, Jiang and Psaty, Bruce M and Fornage, Myriam and Loos, Ruth J F and Correa, Adolfo and Boerwinkle, Eric and Rotter, Jerome I and Kooperberg, Charles and Edwards, Todd L and Abecasis, Goncalo R and Zhu, Xiaofeng and Levy, Daniel and Arnett, Donna K and Morrison, Alanna C} } @article {9581, title = {Whole genome sequence analysis of apparent treatment resistant hypertension status in participants from the Trans-Omics for Precision Medicine program.}, journal = {Front Genet}, volume = {14}, year = {2023}, month = {2023}, pages = {1278215}, abstract = {

Apparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive (AHT) classes to achieve blood pressure (BP) control. In the current study, we conducted single-variant and gene-based analyses of aTRH among individuals from 12 Trans-Omics for Precision Medicine cohorts with whole-genome sequencing data. Cases were defined as individuals treated for hypertension (HTN) taking three different AHT classes, with average systolic BP >= 140 or diastolic BP >= 90~mmHg, or four or more medications regardless of BP ( = 1,705). A normotensive control group was defined as individuals with BP < 140/90~mmHg ( = 22,079), not on AHT medication. A second control group comprised individuals who were treatment responsive on one AHT medication with BP < 140/ 90~mmHg ( = 5,424). Logistic regression with kinship adjustment using the Scalable and Accurate Implementation of Generalized mixed models (SAIGE) was performed, adjusting for age, sex, and genetic ancestry. We assessed variants using SKAT-O in rare-variant analyses. Single-variant and gene-based tests were conducted in a pooled multi-ethnicity stratum, as well as self-reported ethnic/racial strata (European and African American). One variant in the known HTN locus, , was a top finding in the multi-ethnic analysis ( = 8.23E-07) for the normotensive control group [rs12476527, odds ratio (95\% confidence interval) = 0.80 (0.74-0.88)]. This variant was replicated in the Vanderbilt University Medical Center{\textquoteright}s DNA repository data. Aggregate gene-based signals included the genes and . Additional work validating these loci in larger, more diverse populations, is warranted to determine whether these regions influence the pathobiology of aTRH.

}, issn = {1664-8021}, doi = {10.3389/fgene.2023.1278215}, author = {Armstrong, Nicole D and Srinivasasainagendra, Vinodh and Ammous, Farah and Assimes, Themistocles L and Beitelshees, Amber L and Brody, Jennifer and Cade, Brian E and Ida Chen, Yii-Der and Chen, Han and de Vries, Paul S and Floyd, James S and Franceschini, Nora and Guo, Xiuqing and Hellwege, Jacklyn N and House, John S and Hwu, Chii-Min and Kardia, Sharon L R and Lange, Ethan M and Lange, Leslie A and McDonough, Caitrin W and Montasser, May E and O{\textquoteright}Connell, Jeffrey R and Shuey, Megan M and Sun, Xiao and Tanner, Rikki M and Wang, Zhe and Zhao, Wei and Carson, April P and Edwards, Todd L and Kelly, Tanika N and Kenny, Eimear E and Kooperberg, Charles and Loos, Ruth J F and Morrison, Alanna C and Motsinger-Reif, Alison and Psaty, Bruce M and Rao, Dabeeru C and Redline, Susan and Rich, Stephen S and Rotter, Jerome I and Smith, Jennifer A and Smith, Albert V and Irvin, Marguerite R and Arnett, Donna K} } @article {9666, title = {Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits.}, journal = {Nat Genet}, year = {2024}, month = {2024 Apr 30}, abstract = {

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 {\texttimes} 10) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60\% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95\% CI, 15.5-18.2 mmHg, P = 2.22 {\texttimes} 10) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95\% CI, 5.54-9.70; P = 4.13 {\texttimes} 10) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95\% CI, 0.781-0.801) to 0.826 (95\% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 {\texttimes} 10). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

}, issn = {1546-1718}, doi = {10.1038/s41588-024-01714-w}, author = {Keaton, Jacob M and Kamali, Zoha and Xie, Tian and Vaez, Ahmad and Williams, Ariel and Goleva, Slavina B and Ani, Alireza and Evangelou, Evangelos and Hellwege, Jacklyn N and Yengo, Loic and Young, William J and Traylor, Matthew and Giri, Ayush and Zheng, Zhili and Zeng, Jian and Chasman, Daniel I and Morris, Andrew P and Caulfield, Mark J and Hwang, Shih-Jen and Kooner, Jaspal S and Conen, David and Attia, John R and Morrison, Alanna C and Loos, Ruth J F and Kristiansson, Kati and Schmidt, Reinhold and Hicks, Andrew A and Pramstaller, Peter P and Nelson, Christopher P and Samani, Nilesh J and Risch, Lorenz and Gyllensten, Ulf and Melander, Olle and Riese, Harri{\"e}tte and Wilson, James F and Campbell, Harry and Rich, Stephen S and Psaty, Bruce M and Lu, Yingchang and Rotter, Jerome I and Guo, Xiuqing and Rice, Kenneth M and Vollenweider, Peter and Sundstr{\"o}m, Johan and Langenberg, Claudia and Tobin, Martin D and Giedraitis, Vilmantas and Luan, Jian{\textquoteright}an and Tuomilehto, Jaakko and Kutalik, Zolt{\'a}n and Ripatti, Samuli and Salomaa, Veikko and Girotto, Giorgia and Trompet, Stella and Jukema, J Wouter and van der Harst, Pim and Ridker, Paul M and Giulianini, Franco and Vitart, Veronique and Goel, Anuj and Watkins, Hugh and Harris, Sarah E and Deary, Ian J and van der Most, Peter J and Oldehinkel, Albertine J and Keavney, Bernard D and Hayward, Caroline and Campbell, Archie and Boehnke, Michael and Scott, Laura J and Boutin, Thibaud and Mamasoula, Chrysovalanto and Jarvelin, Marjo-Riitta and Peters, Annette and Gieger, Christian and Lakatta, Edward G and Cucca, Francesco and Hui, Jennie and Knekt, Paul and Enroth, Stefan and de Borst, Martin H and Polasek, Ozren and Concas, Maria Pina and Catamo, Eulalia and Cocca, Massimiliano and Li-Gao, Ruifang and Hofer, Edith and Schmidt, Helena and Spedicati, Beatrice and Waldenberger, Melanie and Strachan, David P and Laan, Maris and Teumer, Alexander and D{\"o}rr, Marcus and Gudnason, Vilmundur and Cook, James P and Ruggiero, Daniela and Kolcic, Ivana and Boerwinkle, Eric and Traglia, Michela and Lehtim{\"a}ki, Terho and Raitakari, Olli T and Johnson, Andrew D and Newton-Cheh, Christopher and Brown, Morris J and Dominiczak, Anna F and Sever, Peter J and Poulter, Neil and Chambers, John C and Elosua, Roberto and Siscovick, David and Esko, T{\~o}nu and Metspalu, Andres and Strawbridge, Rona J and Laakso, Markku and Hamsten, Anders and Hottenga, Jouke-Jan and de Geus, Eco and Morris, Andrew D and Palmer, Colin N A and Nolte, Ilja M and Milaneschi, Yuri and Marten, Jonathan and Wright, Alan and Zeggini, Eleftheria and Howson, Joanna M M and O{\textquoteright}Donnell, Christopher J and Spector, Tim and Nalls, Mike A and Simonsick, Eleanor M and Liu, Yongmei and van Duijn, Cornelia M and Butterworth, Adam S and Danesh, John N and Menni, Cristina and Wareham, Nicholas J and Khaw, Kay-Tee and Sun, Yan V and Wilson, Peter W F and Cho, Kelly and Visscher, Peter M and Denny, Joshua C and Levy, Daniel and Edwards, Todd L and Munroe, Patricia B and Snieder, Harold and Warren, Helen R} } @article {9579, title = {X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements.}, journal = {Nat Commun}, volume = {15}, year = {2024}, month = {2024 Jan 18}, pages = {586}, abstract = {

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

}, keywords = {Androgens, Chromosomes, Human, X, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Kidney, Male, Polymorphism, Single Nucleotide, Response Elements, Tetraspanins}, issn = {2041-1723}, doi = {10.1038/s41467-024-44709-1}, author = {Scholz, Markus and Horn, Katrin and Pott, Janne and Wuttke, Matthias and K{\"u}hnapfel, Andreas and Nasr, M Kamal and Kirsten, Holger and Li, Yong and Hoppmann, Anselm and Gorski, Mathias and Ghasemi, Sahar and Li, Man and Tin, Adrienne and Chai, Jin-Fang and Cocca, Massimiliano and Wang, Judy and Nutile, Teresa and Akiyama, Masato and {\r A}svold, Bj{\o}rn Olav and Bansal, Nisha and Biggs, Mary L and Boutin, Thibaud and Brenner, Hermann and Brumpton, Ben and Burkhardt, Ralph and Cai, Jianwen and Campbell, Archie and Campbell, Harry and Chalmers, John and Chasman, Daniel I and Chee, Miao Ling and Chee, Miao Li and Chen, Xu and Cheng, Ching-Yu and Cifkova, Renata and Daviglus, Martha and Delgado, Graciela and Dittrich, Katalin and Edwards, Todd L and Endlich, Karlhans and Michael Gaziano, J and Giri, Ayush and Giulianini, Franco and Gordon, Scott D and Gudbjartsson, Daniel F and Hallan, Stein and Hamet, Pavel and Hartman, Catharina A and Hayward, Caroline and Heid, Iris M and Hellwege, Jacklyn N and Holleczek, Bernd and Holm, Hilma and Hutri-K{\"a}h{\"o}nen, Nina and Hveem, Kristian and Isermann, Berend and Jonas, Jost B and Joshi, Peter K and Kamatani, Yoichiro and Kanai, Masahiro and Kastarinen, Mika and Khor, Chiea Chuen and Kiess, Wieland and Kleber, Marcus E and K{\"o}rner, Antje and Kovacs, Peter and Krajcoviechova, Alena and Kramer, Holly and Kr{\"a}mer, Bernhard K and Kuokkanen, Mikko and K{\"a}h{\"o}nen, Mika and Lange, Leslie A and Lash, James P and Lehtim{\"a}ki, Terho and Li, Hengtong and Lin, Bridget M and Liu, Jianjun and Loeffler, Markus and Lyytik{\"a}inen, Leo-Pekka and Magnusson, Patrik K E and Martin, Nicholas G and Matsuda, Koichi and Milaneschi, Yuri and Mishra, Pashupati P and Mononen, Nina and Montgomery, Grant W and Mook-Kanamori, Dennis O and Mychaleckyj, Josyf C and M{\"a}rz, Winfried and Nauck, Matthias and Nikus, Kjell and Nolte, Ilja M and Noordam, Raymond and Okada, Yukinori and Olafsson, Isleifur and Oldehinkel, Albertine J and Penninx, Brenda W J H and Perola, Markus and Pirastu, Nicola and Polasek, Ozren and Porteous, David J and Poulain, Tanja and Psaty, Bruce M and Rabelink, Ton J and Raffield, Laura M and Raitakari, Olli T and Rasheed, Humaira and Reilly, Dermot F and Rice, Kenneth M and Richmond, Anne and Ridker, Paul M and Rotter, Jerome I and Rudan, Igor and Sabanayagam, Charumathi and Salomaa, Veikko and Schneiderman, Neil and Sch{\"o}ttker, Ben and Sims, Mario and Snieder, Harold and Stark, Klaus J and Stefansson, Kari and Stocker, Hannah and Stumvoll, Michael and Sulem, Patrick and Sveinbjornsson, Gardar and Svensson, Per O and Tai, E-Shyong and Taylor, Kent D and Tayo, Bamidele O and Teren, Andrej and Tham, Yih-Chung and Thiery, Joachim and Thio, Chris H L and Thomas, Laurent F and Tremblay, Johanne and T{\"o}njes, Anke and van der Most, Peter J and Vitart, Veronique and V{\"o}lker, Uwe and Wang, Ya Xing and Wang, Chaolong and Wei, Wen Bin and Whitfield, John B and Wild, Sarah H and Wilson, James F and Winkler, Thomas W and Wong, Tien-Yin and Woodward, Mark and Sim, Xueling and Chu, Audrey Y and Feitosa, Mary F and Thorsteinsdottir, Unnur and Hung, Adriana M and Teumer, Alexander and Franceschini, Nora and Parsa, Afshin and K{\"o}ttgen, Anna and Schlosser, Pascal and Pattaro, Cristian} }