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1. Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder

Author

Nievergelt, Caroline M., Maihofer, Adam X., Atkinson, Elizabeth G., Chen, Chia-Yen, Choi, Karmel W., Coleman, Jonathan R. I., Daskalakis, Nikolaos P., Duncan, Laramie E., Polimanti, Renato, Aaronson, Cindy, Amstadter, Ananda B., Andersen, Soren B., Andreassen, Ole A., Arbisi, Paul A., Ashley-Koch, Allison E., Austin, S. Bryn, Avdibegoviç, Esmina, Babić, Dragan, Bacanu, Silviu-Alin, Baker, Dewleen G., Batzler, Anthony, Beckham, Jean C., Belangero, Sintia, Benjet, Corina, Bergner, Carisa, Bierer, Linda M., Biernacka, Joanna M., Bierut, Laura J., Bisson, Jonathan I., Boks, Marco P., Bolger, Elizabeth A., Brandolino, Amber, Breen, Gerome, Bressan, Rodrigo Affonseca, Bryant, Richard A., Bustamante, Angela C., Bybjerg-Grauholm, Jonas, Bækvad-Hansen, Marie, Børglum, Anders D., Børte, Sigrid, Cahn, Leah, Calabrese, Joseph R., Caldas-de-Almeida, Jose Miguel, Chatzinakos, Chris, Cheema, Sheraz, Clouston, Sean A. P., Colodro-Conde, Lucía, Coombes, Brandon J., Cruz-Fuentes, Carlos S., Dale, Anders M., Dalvie, Shareefa, Davis, Lea K., Deckert, Jürgen, Delahanty, Douglas L., Dennis, Michelle F., Desarnaud, Frank, DiPietro, Christopher P., Disner, Seth G., Docherty, Anna R., Domschke, Katharina, Dyb, Grete, Kulenović, Alma Džubur, Edenberg, Howard J., Evans, Alexandra, Fabbri, Chiara, Fani, Negar, Farrer, Lindsay A., Feder, Adriana, Feeny, Norah C., Flory, Janine D., Forbes, David, Franz, Carol E., Galea, Sandro, Garrett, Melanie E., Gelaye, Bizu, Gelernter, Joel, Geuze, Elbert, Gillespie, Charles F., Goleva, Slavina B., Gordon, Scott D., Goçi, Aferdita, Grasser, Lana Ruvolo, Guindalini, Camila, Haas, Magali, Hagenaars, Saskia, Hauser, Michael A., Heath, Andrew C., Hemmings, Sian M. J., Hesselbrock, Victor, Hickie, Ian B., Hogan, Kelleigh, Hougaard, David Michael, Huang, Hailiang, Huckins, Laura M., Hveem, Kristian, Jakovljević, Miro, Javanbakht, Arash, Jenkins, Gregory D., Johnson, Jessica, Jones, Ian, Jovanovic, Tanja, Karstoft, Karen-Inge, Kaufman, Milissa L., Kennedy, James L., Kessler, Ronald C., Khan, Alaptagin, Kimbrel, Nathan A., King, Anthony P., Koen, Nastassja, Kotov, Roman, Kranzler, Henry R., Krebs, Kristi, Kremen, William S., Kuan, Pei-Fen, Lawford, Bruce R., Lebois, Lauren A. M., Lehto, Kelli, Levey, Daniel F., Lewis, Catrin, Liberzon, Israel, Linnstaedt, Sarah D., Logue, Mark W., Lori, Adriana, Lu, Yi, Luft, Benjamin J., Lupton, Michelle K., Luykx, Jurjen J., Makotkine, Iouri, Maples-Keller, Jessica L., Marchese, Shelby, Marmar, Charles, Martin, Nicholas G., Martínez-Levy, Gabriela A., McAloney, Kerrie, McFarlane, Alexander, McLaughlin, Katie A., McLean, Samuel A., Medland, Sarah E., Mehta, Divya, Meyers, Jacquelyn, Michopoulos, Vasiliki, Mikita, Elizabeth A., Milani, Lili, Milberg, William, Miller, Mark W., Morey, Rajendra A., Morris, Charles Phillip, Mors, Ole, Mortensen, Preben Bo, Mufford, Mary S., Nelson, Elliot C., Nordentoft, Merete, Norman, Sonya B., Nugent, Nicole R., O’Donnell, Meaghan, Orcutt, Holly K., Pan, Pedro M., Panizzon, Matthew S., Pathak, Gita A., Peters, Edward S., Peterson, Alan L., Peverill, Matthew, Pietrzak, Robert H., Polusny, Melissa A., Porjesz, Bernice, Powers, Abigail, Qin, Xue-Jun, Ratanatharathorn, Andrew, Risbrough, Victoria B., Roberts, Andrea L., Rothbaum, Alex O., Rothbaum, Barbara O., Roy-Byrne, Peter, Ruggiero, Kenneth J., Rung, Ariane, Runz, Heiko, Rutten, Bart P. F., de Viteri, Stacey Saenz, Salum, Giovanni Abrahão, Sampson, Laura, Sanchez, Sixto E., Santoro, Marcos, Seah, Carina, Seedat, Soraya, Seng, Julia S., Shabalin, Andrey, Sheerin, Christina M., Silove, Derrick, Smith, Alicia K., Smoller, Jordan W., Sponheim, Scott R., Stein, Dan J., Stensland, Synne, Stevens, Jennifer S., Sumner, Jennifer A., Teicher, Martin H., Thompson, Wesley K., Tiwari, Arun K., Trapido, Edward, Uddin, Monica, Ursano, Robert J., Valdimarsdóttir, Unnur, Van Hooff, Miranda, Vermetten, Eric, Vinkers, Christiaan H., Voisey, Joanne, Wang, Yunpeng, Wang, Zhewu, Waszczuk, Monika, Weber, Heike, Wendt, Frank R., Werge, Thomas, Williams, Michelle A., Williamson, Douglas E., Winsvold, Bendik S., Winternitz, Sherry, Wolf, Christiane, Wolf, Erika J., Xia, Yan, Xiong, Ying, Yehuda, Rachel, Young, Keith A., Young, Ross McD, Zai, Clement C., Zai, Gwyneth C., Zervas, Mark, Zhao, Hongyu, Zoellner, Lori A., Zwart, John-Anker, deRoon-Cassini, Terri, van Rooij, Sanne J. H., van den Heuvel, Leigh L., Stein, Murray B., Ressler, Kerry J., and Koenen, Karestan C.

Published
2024
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2. Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits

Author

Keaton, Jacob M., Kamali, Zoha, Xie, Tian, Vaez, Ahmad, Williams, Ariel, Goleva, Slavina B., Ani, Alireza, Evangelou, Evangelos, Hellwege, Jacklyn N., Yengo, Loic, Young, William J., Traylor, Matthew, Giri, Ayush, Zheng, Zhili, Zeng, Jian, Chasman, Daniel I., Morris, Andrew P., Caulfield, Mark J., Hwang, Shih-Jen, Kooner, Jaspal S., Conen, David, Attia, John R., Morrison, Alanna C., Loos, Ruth J. F., Kristiansson, Kati, Schmidt, Reinhold, Hicks, Andrew A., Pramstaller, Peter P., Nelson, Christopher P., Samani, Nilesh J., Risch, Lorenz, Gyllensten, Ulf, Melander, Olle, Riese, Harriette, Wilson, James F., Campbell, Harry, Rich, Stephen S., Psaty, Bruce M., Lu, Yingchang, Rotter, Jerome I., Guo, Xiuqing, Rice, Kenneth M., Vollenweider, Peter, Sundström, Johan, Langenberg, Claudia, Tobin, Martin D., Giedraitis, Vilmantas, Luan, Jian’an, Tuomilehto, Jaakko, Kutalik, Zoltan, Ripatti, Samuli, Salomaa, Veikko, Girotto, Giorgia, Trompet, Stella, Jukema, J. Wouter, van der Harst, Pim, Ridker, Paul M., Giulianini, Franco, Vitart, Veronique, Goel, Anuj, Watkins, Hugh, Harris, Sarah E., Deary, Ian J., van der Most, Peter J., Oldehinkel, Albertine J., Keavney, Bernard D., Hayward, Caroline, Campbell, Archie, Boehnke, Michael, Scott, Laura J., Boutin, Thibaud, Mamasoula, Chrysovalanto, Järvelin, Marjo-Riitta, Peters, Annette, Gieger, Christian, Lakatta, Edward G., Cucca, Francesco, Hui, Jennie, Knekt, Paul, Enroth, Stefan, De Borst, Martin H., Polašek, Ozren, Concas, Maria Pina, Catamo, Eulalia, Cocca, Massimiliano, Li-Gao, Ruifang, Hofer, Edith, Schmidt, Helena, Spedicati, Beatrice, Waldenberger, Melanie, Strachan, David P., Laan, Maris, Teumer, Alexander, Dörr, Marcus, Gudnason, Vilmundur, Cook, James P., Ruggiero, Daniela, Kolcic, Ivana, Boerwinkle, Eric, Traglia, Michela, Lehtimäki, Terho, Raitakari, Olli T., Johnson, Andrew D., Newton-Cheh, Christopher, Brown, Morris J., Dominiczak, Anna F., Sever, Peter J., Poulter, Neil, Chambers, John C., Elosua, Roberto, Siscovick, David, Esko, Tõnu, Metspalu, Andres, Strawbridge, Rona J., Laakso, Markku, Hamsten, Anders, Hottenga, Jouke-Jan, de Geus, Eco, Morris, Andrew D., Palmer, Colin N. A., Nolte, Ilja M., Milaneschi, Yuri, Marten, Jonathan, Wright, Alan, Zeggini, Eleftheria, Howson, Joanna M. M., O’Donnell, Christopher J., Spector, Tim, Nalls, Mike A., Simonsick, Eleanor M., Liu, Yongmei, van Duijn, Cornelia M., Butterworth, Adam S., Danesh, John N., Menni, Cristina, Wareham, Nicholas J., Khaw, Kay-Tee, Sun, Yan V., Wilson, Peter W. F., Cho, Kelly, Visscher, Peter M., Denny, Joshua C., Levy, Daniel, Edwards, Todd L., Munroe, Patricia B., Snieder, Harold, and Warren, Helen R.

Published
2024
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3. Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits.

Author

Martin, Joanna, Khramtsova, Ekaterina A, Goleva, Slavina B, Blokland, Gabriëlla AM, Traglia, Michela, Walters, Raymond K, Hübel, Christopher, Coleman, Jonathan RI, Breen, Gerome, Børglum, Anders D, Demontis, Ditte, Grove, Jakob, Werge, Thomas, Bralten, Janita, Bulik, Cynthia M, Lee, Phil H, Mathews, Carol A, Peterson, Roseann E, Winham, Stacey J, Wray, Naomi, Edenberg, Howard J, Guo, Wei, Yao, Yin, Neale, Benjamin M, Faraone, Stephen V, Petryshen, Tracey L, Weiss, Lauren A, Duncan, Laramie E, Goldstein, Jill M, Smoller, Jordan W, Stranger, Barbara E, Davis, Lea K, and Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium

Subjects
Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium, Humans, Sex Characteristics, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide, Female, Male, Genome-Wide Association Study, Behavioral, GWAS, Genetic correlation, Heritability, Psychiatric, Sex differences, Prevention, Genetics, Mental Health, Human Genome, Biotechnology, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

BackgroundThe origin of sex differences in prevalence and presentation of neuropsychiatric and behavioral traits is largely unknown. Given established genetic contributions and correlations, we tested for a sex-differentiated genetic architecture within and between traits.MethodsUsing European ancestry genome-wide association summary statistics for 20 neuropsychiatric and behavioral traits, we tested for sex differences in single nucleotide polymorphism (SNP)-based heritability and genetic correlation (rg < 1). For each trait, we computed per-SNP z scores from sex-stratified regression coefficients and identified genes with sex-differentiated effects using a gene-based approach. We calculated correlation coefficients between z scores to test for shared sex-differentiated effects. Finally, we tested for sex differences in across-trait genetic correlations.ResultsWe observed no consistent sex differences in SNP-based heritability. Between-sex, within-trait genetic correlations were high, although

Published
2021

5. Polygenic burden in focal and generalized epilepsies

Author

Leu, Costin, Stevelink, Remi, Smith, Alexander W, Goleva, Slavina B, Kanai, Masahiro, Ferguson, Lisa, Campbell, Ciaran, Kamatani, Yoichiro, Okada, Yukinori, Sisodiya, Sanjay M, Cavalleri, Gianpiero L, Koeleman, Bobby PC, Lerche, Holger, Jehi, Lara, Davis, Lea K, Najm, Imad M, Palotie, Aarno, Daly, Mark J, Busch, Robyn M, Consortium, Epi25, and Lal, Dennis

Subjects
Biomedical and Clinical Sciences, Clinical Research, Neurosciences, Brain Disorders, Neurodegenerative, Epilepsy, Genetics, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Cohort Studies, Cost of Illness, Databases, Factual, Epilepsies, Partial, Epilepsy, Generalized, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Polymorphism, Single Nucleotide, White People, Epi25 Consortium, common variant risk, epilepsy, genetic generalized epilepsy, genetics, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10-15; Cleveland: P = 2.85×10-4; Finnish-ancestry Epi25: P = 1.80×10-4) or population controls (Epi25: P = 2.35×10-70; Cleveland: P = 1.43×10-7; Finnish-ancestry Epi25: P = 3.11×10-4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10-4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10-19; Cleveland: P = 1.69×10-6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10-15; Cleveland: P = 1.39×10-2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls-in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment.

Published
2019

8. Systematic replication of smoking disease associations using survey responses and EHR data in the All of Us Research Program

Author

Schlueter, David J, primary, Sulieman, Lina, additional, Mo, Huan, additional, Keaton, Jacob M, additional, Ferrara, Tracey M, additional, Williams, Ariel, additional, Qian, Jun, additional, Stubblefield, Onajia, additional, Zeng, Chenjie, additional, Tran, Tam C, additional, Bastarache, Lisa, additional, Dai, Jian, additional, Babbar, Anav, additional, Ramirez, Andrea, additional, Goleva, Slavina B, additional, and Denny, Joshua C, additional

Published
2023
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10. Systematic replication of smoking disease associations using survey responses and EHR data in the All of Us Research Program.

Author

Schlueter, David J, Sulieman, Lina, Mo, Huan, Keaton, Jacob M, Ferrara, Tracey M, Williams, Ariel, Qian, Jun, Stubblefield, Onajia, Zeng, Chenjie, Tran, Tam C, Bastarache, Lisa, Dai, Jian, Babbar, Anav, Ramirez, Andrea, Goleva, Slavina B, and Denny, Joshua C

Abstract

Objective The All of Us Research Program (All of Us) aims to recruit over a million participants to further precision medicine. Essential to the verification of biobanks is a replication of known associations to establish validity. Here, we evaluated how well All of Us data replicated known cigarette smoking associations. Materials and Methods We defined smoking exposure as follows: (1) an EHR Smoking exposure that used International Classification of Disease codes; (2) participant provided information (PPI) Ever Smoking; and, (3) PPI Current Smoking, both from the lifestyle survey. We performed a phenome-wide association study (PheWAS) for each smoking exposure measurement type. For each, we compared the effect sizes derived from the PheWAS to published meta-analyses that studied cigarette smoking from PubMed. We defined two levels of replication of meta-analyses: (1) nominally replicated: which required agreement of direction of effect size, and (2) fully replicated: which required overlap of confidence intervals. Results PheWASes with EHR Smoking, PPI Ever Smoking, and PPI Current Smoking revealed 736, 492, and 639 phenome-wide significant associations, respectively. We identified 165 meta-analyses representing 99 distinct phenotypes that could be matched to EHR phenotypes. At P  < .05, 74 were nominally replicated and 55 were fully replicated. At P  < 2.68 × 10−5 (Bonferroni threshold), 58 were nominally replicated and 40 were fully replicated. Discussion Most phenotypes found in published meta-analyses associated with smoking were nominally replicated in All of Us. Both survey and EHR definitions for smoking produced similar results. Conclusion This study demonstrated the feasibility of studying common exposures using All of Us data. [ABSTRACT FROM AUTHOR]

Published
2024
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12. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author

Blokland, Gabriëlla A.M., primary, Grove, Jakob, additional, Chen, Chia-Yen, additional, Cotsapas, Chris, additional, Tobet, Stuart, additional, Handa, Robert, additional, St Clair, David, additional, Lencz, Todd, additional, Mowry, Bryan J., additional, Periyasamy, Sathish, additional, Cairns, Murray J., additional, Tooney, Paul A., additional, Wu, Jing Qin, additional, Kelly, Brian, additional, Kirov, George, additional, Sullivan, Patrick F., additional, Corvin, Aiden, additional, Riley, Brien P., additional, Esko, Tõnu, additional, Milani, Lili, additional, Jönsson, Erik G., additional, Palotie, Aarno, additional, Ehrenreich, Hannelore, additional, Begemann, Martin, additional, Steixner-Kumar, Agnes, additional, Sham, Pak C., additional, Iwata, Nakao, additional, Weinberger, Daniel R., additional, Gejman, Pablo V., additional, Sanders, Alan R., additional, Buxbaum, Joseph D., additional, Rujescu, Dan, additional, Giegling, Ina, additional, Konte, Bettina, additional, Hartmann, Annette M., additional, Bramon, Elvira, additional, Murray, Robin M., additional, Pato, Michele T., additional, Lee, Jimmy, additional, Melle, Ingrid, additional, Molden, Espen, additional, Ophoff, Roel A., additional, McQuillin, Andrew, additional, Bass, Nicholas J., additional, Adolfsson, Rolf, additional, Malhotra, Anil K., additional, Martin, Nicholas G., additional, Fullerton, Janice M., additional, Mitchell, Philip B., additional, Schofield, Peter R., additional, Forstner, Andreas J., additional, Degenhardt, Franziska, additional, Schaupp, Sabrina, additional, Comes, Ashley L., additional, Kogevinas, Manolis, additional, Guzman-Parra, José, additional, Reif, Andreas, additional, Streit, Fabian, additional, Sirignano, Lea, additional, Cichon, Sven, additional, Grigoroiu-Serbanescu, Maria, additional, Hauser, Joanna, additional, Lissowska, Jolanta, additional, Mayoral, Fermin, additional, Müller-Myhsok, Bertram, additional, Świątkowska, Beata, additional, Schulze, Thomas G., additional, Nöthen, Markus M., additional, Rietschel, Marcella, additional, Kelsoe, John, additional, Leboyer, Marion, additional, Jamain, Stéphane, additional, Etain, Bruno, additional, Bellivier, Frank, additional, Vincent, John B., additional, Alda, Martin, additional, O’Donovan, Claire, additional, Cervantes, Pablo, additional, Biernacka, Joanna M., additional, Frye, Mark, additional, McElroy, Susan L., additional, Scott, Laura J., additional, Stahl, Eli A., additional, Landén, Mikael, additional, Hamshere, Marian L., additional, Smeland, Olav B., additional, Djurovic, Srdjan, additional, Vaaler, Arne E., additional, Andreassen, Ole A., additional, Baune, Bernhard T., additional, Air, Tracy, additional, Preisig, Martin, additional, Uher, Rudolf, additional, Levinson, Douglas F., additional, Weissman, Myrna M., additional, Potash, James B., additional, Shi, Jianxin, additional, Knowles, James A., additional, Perlis, Roy H., additional, Lucae, Susanne, additional, Boomsma, Dorret I., additional, Penninx, Brenda W.J.H., additional, Hottenga, Jouke-Jan, additional, de Geus, Eco J.C., additional, Willemsen, Gonneke, additional, Milaneschi, Yuri, additional, Tiemeier, Henning, additional, Grabe, Hans J., additional, Teumer, Alexander, additional, Van der Auwera, Sandra, additional, Völker, Uwe, additional, Hamilton, Steven P., additional, Magnusson, Patrik K.E., additional, Viktorin, Alexander, additional, Mehta, Divya, additional, Mullins, Niamh, additional, Adams, Mark J., additional, Breen, Gerome, additional, McIntosh, Andrew M., additional, Lewis, Cathryn M., additional, Hougaard, David M., additional, Nordentoft, Merete, additional, Mors, Ole, additional, Mortensen, Preben B., additional, Werge, Thomas, additional, Als, Thomas D., additional, Børglum, Anders D., additional, Petryshen, Tracey L., additional, Smoller, Jordan W., additional, Goldstein, Jill M., additional, Ripke, Stephan, additional, Neale, Benjamin M., additional, Walters, James T.R., additional, Farh, Kai-How, additional, Holmans, Peter A., additional, Lee, Phil, additional, Bulik-Sullivan, Brendan, additional, Collier, David A., additional, Huang, Hailiang, additional, Pers, Tune H., additional, Agartz, Ingrid, additional, Agerbo, Esben, additional, Albus, Margot, additional, Alexander, Madeline, additional, Amin, Farooq, additional, Bacanu, Silviu A., additional, Belliveau, Richard A., additional, Bene, Judit, additional, Bergen, Sarah E., additional, Bevilacqua, Elizabeth, additional, Bigdeli, Tim B., additional, Black, Donald W., additional, Bruggeman, Richard, additional, Buccola, Nancy G., additional, Buckner, Randy L., additional, Byerley, William, additional, Cahn, Wiepke, additional, Cai, Guiqing, additional, Campion, Dominique, additional, Cantor, Rita M., additional, Carr, Vaughan J., additional, Carrera, Noa, additional, Catts, Stanley V., additional, Chambert, Kimberly D., additional, Chan, Raymond C.K., additional, Chen, Ronald Y.L., additional, Chen, Eric Y.H., additional, Cheng, Wei, additional, Cheung, Eric F.C., additional, Chong, Siow Ann, additional, Cloninger, C. Robert, additional, Cohen, David, additional, Cohen, Nadine, additional, Cormican, Paul, additional, Craddock, Nick, additional, Crowley, James J., additional, Curtis, David, additional, Davidson, Michael, additional, Davis, Kenneth L., additional, Del Favero, Jurgen, additional, Demontis, Ditte, additional, Dikeos, Dimitris, additional, Dinan, Timothy, additional, Donohoe, Gary, additional, Drapeau, Elodie, additional, Duan, Jubao, additional, Dudbridge, Frank, additional, Durmishi, Naser, additional, Eichhammer, Peter, additional, Eriksson, Johan, additional, Escott-Price, Valentina, additional, Essioux, Laurent, additional, Fanous, Ayman H., additional, Farrell, Martilias S., additional, Frank, Josef, additional, Franke, Lude, additional, Freedman, Robert, additional, Freimer, Nelson B., additional, Friedl, Marion, additional, Friedman, Joseph I., additional, Fromer, Menachem, additional, Genovese, Giulio, additional, Georgieva, Lyudmila, additional, Giusti-Rodríguez, Paola, additional, Godard, Stephanie, additional, Goldstein, Jacqueline I., additional, Golimbet, Vera, additional, Gopal, Srihari, additional, Gratten, Jacob, additional, de Haan, Lieuwe, additional, Hammer, Christian, additional, Hansen, Mark, additional, Hansen, Thomas, additional, Haroutunian, Vahram, additional, Henskens, Frans A., additional, Herms, Stefan, additional, Hirschhorn, Joel N., additional, Hoffmann, Per, additional, Hofman, Andrea, additional, Hollegaard, Mads V., additional, Ikeda, Masashi, additional, Joa, Inge, additional, Julià, Antonio, additional, Kahn, René S., additional, Kalaydjieva, Luba, additional, Karachanak-Yankova, Sena, additional, Karjalainen, Juha, additional, Kavanagh, David, additional, Keller, Matthew C., additional, Kennedy, James L., additional, Khrunin, Andrey, additional, Kim, Yunjung, additional, Klovins, Janis, additional, Kucinskas, Vaidutis, additional, Kucinskiene, Zita Ausrele, additional, Kuzelova-Ptackova, Hana, additional, Kähler, Anna K., additional, Laurent, Claudine, additional, Lee Chee Keong, Jimmy, additional, Lee, S. Hong, additional, Legge, Sophie E., additional, Lerer, Bernard, additional, Li, Miaoxin, additional, Li, Tao, additional, Liang, Kung-Yee, additional, Lieberman, Jeffrey, additional, Limborska, Svetlana, additional, Loughland, Carmel M., additional, Lubinski, Jan, additional, Lönnqvist, Jouko, additional, Macek, Milan, additional, Maher, Brion S., additional, Maier, Wolfgang, additional, Mallet, Jacques, additional, Marsal, Sara, additional, Mattheisen, Manuel, additional, Mattingsdal, Morten, additional, McCarley, Robert W., additional, McDonald, Colm, additional, Meier, Sandra, additional, Meijer, Carin J., additional, Melegh, Bela, additional, Mesholam-Gately, Raquelle I., additional, Metspalu, Andres, additional, Michie, Patricia T., additional, Milanova, Vihra, additional, Mokrab, Younes, additional, Morris, Derek W., additional, Murphy, Kieran C., additional, Myin-Germeys, Inez, additional, Nelis, Mari, additional, Nenadic, Igor, additional, Nertney, Deborah A., additional, Nestadt, Gerald, additional, Nicodemus, Kristin K., additional, Nikitina-Zake, Liene, additional, Nisenbaum, Laura, additional, Nordin, Annelie, additional, O’Callaghan, Eadbhard, additional, O’Dushlaine, Colm, additional, O’Neill, F. Anthony, additional, Oh, Sang-Yun, additional, Olincy, Ann, additional, Olsen, Line, additional, Van Os, Jim, additional, Pantelis, Christos, additional, Papadimitriou, George N., additional, Papiol, Sergi, additional, Parkhomenko, Elena, additional, Paunio, Tiina, additional, Pejovic-Milovancevic, Milica, additional, Perkins, Diana O., additional, Pietiläinen, Olli, additional, Pimm, Jonathan, additional, Pocklington, Andrew J., additional, Powell, John, additional, Price, Alkes, additional, Pulver, Ann E., additional, Purcell, Shaun M., additional, Quested, Digby, additional, Rasmussen, Henrik B., additional, Reichenberg, Abraham, additional, Reimers, Mark A., additional, Richards, Alexander L., additional, Roffman, Joshua L., additional, Roussos, Panos, additional, Ruderfer, Douglas M., additional, Salomaa, Veikko, additional, Schall, Ulrich, additional, Schubert, Christian R., additional, Schwab, Sibylle G., additional, Scolnick, Edward M., additional, Scott, Rodney J., additional, Seidman, Larry J., additional, Sigurdsson, Engilbert, additional, Silagadze, Teimuraz, additional, Silverman, Jeremy M., additional, Sim, Kang, additional, Slominsky, Petr, additional, So, Hon-Cheong, additional, Spencer, Chris C.A., additional, Stefansson, Hreinn, additional, Steinberg, Stacy, additional, Stogmann, Elisabeth, additional, Straub, Richard E., additional, Strengman, Eric, additional, Strohmaier, Jana, additional, Stroup, T. Scott, additional, Subramaniam, Mythily, additional, Suvisaari, Jaana, additional, Svrakic, Dragan M., additional, Szatkiewicz, Jin P., additional, Söderman, Erik, additional, Thirumalai, Srinivas, additional, Toncheva, Draga, additional, Tosato, Sarah, additional, Veijola, Juha, additional, Waddington, John, additional, Walsh, Dermot, additional, Wang, Dai, additional, Wang, Qiang, additional, Webb, Bradley T., additional, Weiser, Mark, additional, Wildenauer, Dieter B., additional, Williams, Nigel M., additional, Williams, Stephanie, additional, Witt, Stephanie H., additional, Wolen, Aaron R., additional, Wong, Emily H.M., additional, Wormley, Brandon K., additional, Xi, Hualin Simon, additional, Zai, Clement C., additional, Zheng, Xuebin, additional, Zimprich, Fritz, additional, Wray, Naomi R., additional, Stefansson, Kari, additional, Visscher, Peter M., additional, Blackwood, Douglas H.R., additional, Darvasi, Ariel, additional, Domenici, Enrico, additional, Gill, Michael, additional, Gurling, Hugh, additional, Hultman, Christina M., additional, Jablensky, Assen V., additional, Kendler, Kenneth S., additional, Knight, Jo, additional, Li, Qingqin S., additional, Liu, Jianjun, additional, McCarroll, Steven A., additional, Moran, Jennifer L., additional, Owen, Michael J., additional, Pato, Carlos N., additional, Posthuma, Danielle, additional, Sklar, Pamela, additional, Wendland, Jens R., additional, Daly, Mark J., additional, O’Donovan, Michael C., additional, Donnelly, Peter, additional, Barroso, Ines, additional, Blackwell, Jenefer M., additional, Brown, Matthew A., additional, Casas, Juan P., additional, Deloukas, Panos, additional, Duncanson, Audrey, additional, Jankowski, Janusz, additional, Markus, Hugh S., additional, Mathew, Christopher G., additional, Palmer, Colin N.A., additional, Plomin, Robert, additional, Rautanen, Anna, additional, Sawcer, Stephen J., additional, Trembath, Richard C., additional, Viswanathan, Ananth C., additional, Wood, Nicholas W., additional, Band, Gavin, additional, Bellenguez, Céline, additional, Freeman, Colin, additional, Giannoulatou, Eleni, additional, Hellenthal, Garrett, additional, Pearson, Richard, additional, Pirinen, Matti, additional, Strange, Amy, additional, Su, Zhan, additional, Vukcevic, Damjan, additional, Langford, Cordelia, additional, Blackburn, Hannah, additional, Bumpstead, Suzannah J., additional, Dronov, Serge, additional, Edkins, Sarah, additional, Gillman, Matthew, additional, Gray, Emma, additional, Gwilliam, Rhian, additional, Hammond, Naomi, additional, Hunt, Sarah E., additional, Jayakumar, Alagurevathi, additional, Liddle, Jennifer, additional, McCann, Owen T., additional, Potter, Simon C., additional, Ravindrarajah, Radhi, additional, Ricketts, Michelle, additional, Tashakkori-Ghanbaria, Avazeh, additional, Waller, Matthew, additional, Weston, Paul, additional, Whittaker, Pamela, additional, Widaa, Sara, additional, McCarthy, Mark I., additional, Arranz, Maria J., additional, Bakker, Steven, additional, Bender, Stephan, additional, Crespo-Facorro, Benedicto, additional, Hall, Jeremy, additional, Iyegbe, Conrad, additional, Lawrie, Stephen, additional, Lin, Kuang, additional, Linszen, Don H., additional, Mata, Ignacio, additional, Walshe, Muriel, additional, Weisbrod, Matthias, additional, Wiersma, Durk, additional, Trubetskoy, Vassily, additional, Wang, Yunpeng, additional, Coleman, Jonathan R.I., additional, Gaspar, Héléna A., additional, de Leeuw, Christiaan A., additional, Whitehead Pavlides, Jennifer M., additional, Trzaskowski, Maciej, additional, Byrne, Enda M., additional, Abbott, Liam, additional, Akil, Huda, additional, Albani, Diego, additional, Alliey-Rodriguez, Ney, additional, Anjorin, Adebayo, additional, Antilla, Verneri, additional, Awasthi, Swapnil, additional, Badner, Judith A., additional, Bækvad-Hansen, Marie, additional, Barchas, Jack D., additional, Bass, Nicholas, additional, Bauer, Michael, additional, Belliveau, Richard, additional, Pedersen, Carsten Bøcker, additional, Bøen, Erlend, additional, Boks, Marco P., additional, Boocock, James, additional, Budde, Monika, additional, Bunney, William, additional, Burmeister, Margit, additional, Bybjerg-Grauholm, Jonas, additional, Casas, Miquel, additional, Cerrato, Felecia, additional, Chambert, Kimberly, additional, Charney, Alexander W., additional, Chen, Danfeng, additional, Churchhouse, Claire, additional, Clarke, Toni-Kim, additional, Coryell, William, additional, Craig, David W., additional, Cruceanu, Cristiana, additional, Czerski, Piotr M., additional, Dale, Anders M., additional, de Jong, Simone, additional, Del-Favero, Jurgen, additional, DePaulo, J. Raymond, additional, Dobbyn, Amanda L., additional, Dumont, Ashley, additional, Elvsåshagen, Torbjørn, additional, Fan, Chun Chieh, additional, Fischer, Sascha B., additional, Flickinger, Matthew, additional, Foroud, Tatiana M., additional, Forty, Liz, additional, Fraser, Christine, additional, Gade, Katrin, additional, Gage, Diane, additional, Garnham, Julie, additional, Giambartolomei, Claudia, additional, Pedersen, Marianne Giørtz, additional, Goldstein, Jaqueline, additional, Gordon, Scott D., additional, Gordon-Smith, Katherine, additional, Green, Elaine K., additional, Green, Melissa J., additional, Greenwood, Tiffany A., additional, Guan, Weihua, additional, Hautzinger, Martin, additional, Heilbronner, Urs, additional, Hipolito, Maria, additional, Holland, Dominic, additional, Huckins, Laura, additional, Johnson, Jessica S., additional, Kandaswamy, Radhika, additional, Karlsson, Robert, additional, Kittel-Schneider, Sarah, additional, Koller, Anna C., additional, Kupka, Ralph, additional, Lavebratt, Catharina, additional, Lawrence, Jacob, additional, Lawson, William B., additional, Leber, Markus, additional, Lee, Phil H., additional, Levy, Shawn E., additional, Li, Jun Z., additional, Liu, Chunyu, additional, Maaser, Anna, additional, MacIntyre, Donald J., additional, Mahon, Pamela B., additional, Martinsson, Lina, additional, McCarroll, Steve, additional, McGuffin, Peter, additional, McInnis, Melvin G., additional, McKay, James D., additional, Medeiros, Helena, additional, Medland, Sarah E., additional, Meng, Fan, additional, Montgomery, Grant W., additional, Mühleisen, Thomas W., additional, Nguyen, Hoang, additional, Nievergelt, Caroline M., additional, Adolfsson, Annelie Nordin, additional, Nwulia, Evaristus A., additional, O'Donovan, Claire, additional, Olde Loohuis, Loes M., additional, Ori, Anil P.S., additional, Oruc, Lilijana, additional, Ösby, Urban, additional, Perry, Amy, additional, Pfennig, Andrea, additional, Regeer, Eline J., additional, Reinbold, Céline S., additional, Rice, John P., additional, Rivas, Fabio, additional, Rivera, Margarita, additional, Ryu, Euijung, additional, Sánchez-Mora, Cristina, additional, Schatzberg, Alan F., additional, Scheftner, William A., additional, Schork, Nicholas J., additional, Weickert, Cynthia Shannon, additional, Shehktman, Tatyana, additional, Shilling, Paul D., additional, Slaney, Claire, additional, Sobell, Janet L., additional, Hansen, Christine Søholm, additional, Spijker, Anne T., additional, Steffens, Michael, additional, Strauss, John S., additional, Szelinger, Szabolcs, additional, Thompson, Robert C., additional, Thorgeirsson, Thorgeir E., additional, Treutlein, Jens, additional, Vedder, Helmut, additional, Wang, Weiqing, additional, Watson, Stanley J., additional, Weickert, Thomas W., additional, Xi, Simon, additional, Xu, Wei, additional, Young, Allan H., additional, Zandi, Peter, additional, Zhang, Peng, additional, Zöllner, Sebastian, additional, Abdellaoui, Abdel, additional, Air, Tracy M., additional, Andlauer, Till F.M., additional, Bacanu, Silviu-Alin, additional, Beekman, Aartjan T.F., additional, Binder, Elisabeth B., additional, Bryois, Julien, additional, Buttenschøn, Henriette N., additional, Cai, Na, additional, Castelao, Enrique, additional, Christensen, Jane Hvarregaard, additional, Colodro-Conde, Lucía, additional, Couvy-Duchesne, Baptiste, additional, Crawford, Gregory E., additional, Davies, Gail, additional, Deary, Ian J., additional, Derks, Eske M., additional, Direk, Nese, additional, Dolan, Conor V., additional, Dunn, Erin C., additional, Eley, Thalia C., additional, Hassan Kiadeh, Farnush Farhadi, additional, Finucane, Hilary K., additional, Foo, Jerome C., additional, Goes, Fernando S., additional, Hall, Lynsey S., additional, Hansen, Thomas F., additional, Hickie, Ian B., additional, Homuth, Georg, additional, Horn, Carsten, additional, Howard, David M., additional, Ising, Marcus, additional, Jansen, Rick, additional, Jones, Ian, additional, Jones, Lisa A., additional, Jorgenson, Eric, additional, Kohane, Isaac S., additional, Kraft, Julia, additional, Kretzschmar, Warren W., additional, Kutalik, Zoltán, additional, Li, Yihan, additional, Lind, Penelope A., additional, MacKinnon, Dean F., additional, Maier, Robert M., additional, Marchini, Jonathan, additional, Mbarek, Hamdi, additional, McGrath, Patrick, additional, Middeldorp, Christel M., additional, Mihailov, Evelin, additional, Mondimore, Francis M., additional, Mostafavi, Sara, additional, Nauck, Matthias, additional, Ng, Bernard, additional, Nivard, Michel G., additional, Nyholt, Dale R., additional, O'Reilly, Paul F., additional, Oskarsson, Hogni, additional, Painter, Jodie N., additional, Peterson, Roseann E., additional, Peyrot, Wouter J., additional, Pistis, Giorgio, additional, Quiroz, Jorge A., additional, Qvist, Per, additional, Mirza, Saira Saeed, additional, Schoevers, Robert, additional, Schulte, Eva C., additional, Shen, Ling, additional, Shyn, Stanley I., additional, Sinnamon, Grant C.B., additional, Smit, Johannes H., additional, Smith, Daniel J., additional, Tansey, Katherine E., additional, Teismann, Henning, additional, Thompson, Wesley, additional, Thomson, Pippa A., additional, Traylor, Matthew, additional, Uitterlinden, André G., additional, Umbricht, Daniel, additional, van Hemert, Albert M., additional, Weinsheimer, Shantel Marie, additional, Wellmann, Jürgen, additional, Wu, Yang, additional, Xi, Hualin S., additional, Yang, Jian, additional, Zhang, Futao, additional, Arolt, Volker, additional, Berger, Klaus, additional, Dannlowski, Udo, additional, Domschke, Katharina, additional, Hayward, Caroline, additional, Heath, Andrew C., additional, Kloiber, Stefan, additional, Lewis, Glyn, additional, Madden, Pamela AF., additional, Magnusson, Patrik K., additional, Mortensen, Preben Bo, additional, O'Donovan, Michael C., additional, Paciga, Sara A., additional, Pedersen, Nancy L., additional, Porteous, David J., additional, Schaefer, Catherine, additional, Völzke, Henry, additional, Blokland, Gabriëlla A.M., additional, Bortolato, Marco, additional, Bralten, Janita, additional, Bulik, Cynthia M., additional, Burton, Christie L., additional, Carey, Caitlin E., additional, Davis, Lea K., additional, Duncan, Laramie E., additional, Edenberg, Howard J., additional, Erdman, Lauren, additional, Faraone, Stephen V., additional, Goleva, Slavina B., additional, Guo, Wei, additional, Hübel, Christopher, additional, Huckins, Laura M., additional, Khramtsova, Ekaterina A., additional, Martin, Joanna, additional, Mathews, Carol A., additional, Robinson, Elise, additional, Stahl, Eli, additional, Stranger, Barbara E., additional, Traglia, Michela, additional, Walters, Raymond K., additional, Weiss, Lauren A., additional, Winham, Stacey J., additional, Yao, Yin, additional, Skajaa, Kristjar, additional, Nöthen, Markus, additional, Owen, Michael, additional, Yolken, Robert H., additional, Plath, Niels, additional, Mill, Jonathan, additional, and Geschwind, Daniel, additional

Published
2022
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14. Additional file 3 of Clinical laboratory test-wide association scan of polygenic scores identifies biomarkers of complex disease

Author

Dennis, Jessica K., Sealock, Julia M., Straub, Peter, Younga H. Lee, Hucks, Donald, Ky’Era Actkins, Faucon, Annika, Yen-Chen Anne Feng, Ge, Tian, Goleva, Slavina B., Niarchou, Maria, Kritika Singh, Morley, Theodore, Smoller, Jordan W., Ruderfer, Douglas M., Mosley, Jonathan D., Guanhua Chen, and Davis, Lea K.

Abstract

Additional file 3: Contains all supplementary figures. Figure S1. QualityLab data visualizations. Figure S2. Manhattan and QQ plots from GWAS of BioVU lipids. Figure S3.. Predictive abilities of different polygenic scoring methods. Figure S4. Lipids levels by genetic ancestry. Figure S5. Histogram of BioVU lab heritability estimates. Figure S6. LDL genetic correlation sensitivity analyses. Figure S7. LabWAS Manhattan of CAD diagnosis. Figure S8. LabWAS of Lipids PGS in MGBB. Figure S9. LabWAS of CAD PGS in MGBB.

Published
2021
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15. Additional file 1 of Clinical laboratory test-wide association scan of polygenic scores identifies biomarkers of complex disease

Author

Dennis, Jessica K., Sealock, Julia M., Straub, Peter, Younga H. Lee, Hucks, Donald, Ky’Era Actkins, Faucon, Annika, Yen-Chen Anne Feng, Ge, Tian, Goleva, Slavina B., Niarchou, Maria, Kritika Singh, Morley, Theodore, Smoller, Jordan W., Ruderfer, Douglas M., Mosley, Jonathan D., Guanhua Chen, and Davis, Lea K.

Abstract

Additional file 1. Contains supplementary methods information on genotyping and quality control, definition of coronary artery disease and lipids lowering mediation, and polygenic scoring methods.

Published
2021
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17. Potential positive and negative consequences of ZnT8 inhibition

Author

Syring, Kristen E, primary, Bosma, Karin J, additional, Goleva, Slavina B, additional, Singh, Kritika, additional, Oeser, James K, additional, Lopez, Christopher A, additional, Skaar, Eric P, additional, McGuinness, Owen P, additional, Davis, Lea K, additional, Powell, David R, additional, and O’Brien, Richard M, additional

Published
2020
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18. Pancreatic islet beta cell-specific deletion of G6pc2 reduces fasting blood glucose

Author

Bosma, Karin J, primary, Rahim, Mohsin, additional, Singh, Kritika, additional, Goleva, Slavina B, additional, Wall, Martha L, additional, Xia, Jing, additional, Syring, Kristen E, additional, Oeser, James K, additional, Poffenberger, Greg, additional, McGuinness, Owen P, additional, Means, Anna L, additional, Powers, Alvin C, additional, Li, Wen-hong, additional, Davis, Lea K, additional, Young, Jamey D, additional, and O’Brien, Richard M, additional

Published
2020
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19. Lab-wide association scan of polygenic scores identifies biomarkers of complex disease

Author

Dennis, Jessica K, primary, Sealock, Julia M, additional, Straub, Peter, additional, Hucks, Donald, additional, Actkins, Ky’Era, additional, Faucon, Annika, additional, Goleva, Slavina B, additional, Nirachou, Maria, additional, Singh, Kritika, additional, Morley, Theodore, additional, Ruderfer, Douglas M., additional, Mosley, Jonathan D, additional, Chen, Guanhua, additional, and Davis, Lea K, additional

Published
2020
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20. An antisense oligonucleotide leads to suppressed transcriptional elongation ofHdac2and long-term memory enhancement

Author

Poplawski, Shane G., primary, Garbett, Krassimira A., additional, McMahan, Rebekah L., additional, Kordasiewicz, Holly B., additional, Zhao, Hien, additional, Kennedy, Andrew J., additional, Goleva, Slavina B., additional, Sanders, Teresa H., additional, Motley, S. Timothy, additional, Swayze, Eric E., additional, Ecker, David J., additional, Sweatt, J. David, additional, Michael, Todd P., additional, and Greer, Celeste B., additional

Published
2019
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22. A salt-sensing kinase in T lymphocytes, SGK1, drives hypertension and hypertensive end-organ damage

Author

Norlander, Allison E., primary, Saleh, Mohamed A., additional, Pandey, Arvind K., additional, Itani, Hana A., additional, Wu, Jing, additional, Xiao, Liang, additional, Kang, Jooeun, additional, Dale, Bethany L., additional, Goleva, Slavina B., additional, Laroumanie, Fanny, additional, Du, Liping, additional, Harrison, David G., additional, and Madhur, Meena S., additional

Published
2017
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26. Clinical laboratory test-wide association scan of polygenic scores identifies biomarkers of complex disease

Author

Dennis, Jessica K, Sealock, Julia M, Straub, Peter, Lee, Younga H, Hucks, Donald, Actkins, Ky’Era, Faucon, Annika, Feng, Yen-Chen A, Ge, Tian, Goleva, Slavina B, Niarchou, Maria, Singh, Kritika, Morley, Theodore, Smoller, Jordan W, Ruderfer, Douglas M, Mosley, Jonathan D, Chen, Guanhua, and Davis, Lea K

Subjects
3. Good health
Abstract

Background: Clinical laboratory (lab) tests are used in clinical practice to diagnose, treat, and monitor disease conditions. Test results are stored in electronic health records (EHRs), and a growing number of EHRs are linked to patient DNA, offering unprecedented opportunities to query relationships between genetic risk for complex disease and quantitative physiological measurements collected on large populations. Methods: A total of 3075 quantitative lab tests were extracted from Vanderbilt University Medical Center’s (VUMC) EHR system and cleaned for population-level analysis according to our QualityLab protocol. Lab values extracted from BioVU were compared with previous population studies using heritability and genetic correlation analyses. We then tested the hypothesis that polygenic risk scores for biomarkers and complex disease are associated with biomarkers of disease extracted from the EHR. In a proof of concept analyses, we focused on lipids and coronary artery disease (CAD). We cleaned lab traits extracted from the EHR performed lab-wide association scans (LabWAS) of the lipids and CAD polygenic risk scores across 315 heritable lab tests then replicated the pipeline and analyses in the Massachusetts General Brigham Biobank. Results: Heritability estimates of lipid values (after cleaning with QualityLab) were comparable to previous reports and polygenic scores for lipids were strongly associated with their referent lipid in a LabWAS. LabWAS of the polygenic score for CAD recapitulated canonical heart disease biomarker profiles including decreased HDL, increased pre-medication LDL, triglycerides, blood glucose, and glycated hemoglobin (HgbA1C) in European and African descent populations. Notably, many of these associations remained even after adjusting for the presence of cardiovascular disease and were replicated in the MGBB. Conclusions: Polygenic risk scores can be used to identify biomarkers of complex disease in large-scale EHR-based genomic analyses, providing new avenues for discovery of novel biomarkers and deeper understanding of disease trajectories in pre-symptomatic individuals. We present two methods and associated software, QualityLab and LabWAS, to clean and analyze EHR labs at scale and perform a Lab-Wide Association Scan.

27. Abstract 219.

Author

Rhoads, Megan K, Goleva, Slavina B, Beierschmitt, Amy, and Osborn, Jeffrey L

Abstract

Current models of essential hypertension are limited in comparisons to human pathophysiology due to distinct differences in postural positioning, circadian rhythmicity, and genetic variation. We have identified a unique non-human primate model of spontaneous, essential hypertension in Chlorocebus aethiops sabaeus, the African Green, or vervet, monkey. Using forearm plethysmography under light ketamine sedation (~15mg/kg), adult vervets were categorized as hypertensive (HT; SBP >140mmHg), borderline hypertensive (BHT; 120mmHg < SBP < 140mmHg), or normotensive (NT; SBP < 120 mmHg). Of the 168 males phenotyped, 32% (53 of 168) were HT (average SBP = 168.79±3.29mmHg), 27% (45 of 168) were BHT (average SBP = 129.58±0.88mmHg), and 41% (70 of 168) were NT (average SBP = 100.21±1.65mmHg). In a smaller study of 18 adult females, 1 was found to be HT (SBP = 156mmHg), 2 were BHT (average SBP = 134±2.0mmHg), and 15 were NT (average SBP = 98.06±4.32mmHg). Fixed paraffin-embedded histological sections of vervet cardiac (H&E) and renal (periodic acid Schiff) tissues were digitized and analyzed. Wall/lumen ratios of renal arterioles (average diameter 33.01±0.5μm) were greater in HT (0.33±0.03) compared to NT (0.24±0.01) male monkeys. Bowman’s capsule space was increased in HT (43.14±3.98% area) glomeruli compared to NT (29.92±2.42% area) glomeruli (p<0.05). Indicative of left ventricular hypertrophy, left ventricular cells were decreased in HT (1833.33±65.48 cells/mm2) compared to NT monkeys (2223.61±59.72 cells/mm2; p<0.05). The increased wall/lumen ratios and Bowman’s capsular spaces indicate that renal vascular hypertrophy and glomerular damage occur in this non-human primate model of essential hypertension. Left ventricular hypertrophy combined with renal glomerular and vascular dysfunction provides strong evidence for using this non-human primate model as a translational experimental species. [ABSTRACT FROM AUTHOR]

Published
2014

29. Racial and Ethnic Disparities in Antihypertensive Medication Prescribing Patterns and Effectiveness.

Author

Goleva SB, Williams A, Schlueter DJ, Keaton JM, Tran TC, Waxse BJ, Ferrara TM, Cassini T, Mo H, and Denny JC

Abstract

Variability in drug effectiveness and provider prescribing patterns have been reported in different racial and ethnic populations. We sought to evaluate antihypertensive drug effectiveness and prescribing patterns among self-identified Hispanic/Latino (Hispanic), Non-Hispanic Black (Black), and Non-Hispanic White (White) populations that enrolled in the NIH All of Us Research Program, a US longitudinal cohort. We employed a self-controlled case study method using electronic health record and survey data from 17,718 White, Hispanic, and Black participants who were diagnosed with essential hypertension and prescribed at least one of 19 commonly used antihypertensive medications. Effectiveness was determined by calculating the reduction in systolic blood pressure measurements after 28 or more days of drug exposure. Starting systolic blood pressure and effectiveness for each medication were compared for self-reported Black, Hispanic, and White participants using adjusted linear regressions. Black and Hispanic participants were started on antihypertensive medications at significantly higher SBP than White participants in 13 and 7 out of 19 medications, respectively. More Black participants were prescribed multiple antihypertensive medications (58.46%) than White (52.35%) or Hispanic (49.9%) participants. First-line HTN medications differed by race and ethnicity. Following the 2017 American College of Cardiology and the American Heart Association High Blood Pressure Guideline release, around 64% of Black participants were prescribed a recommended first-line antihypertensive drug compared with 76% of White and 82% of Hispanic participants. Effect sizes suggested that most antihypertensive drugs were less effective in Hispanic and Black, compared with White, participants, and statistical significance was reached in 6 out of 19 drugs. These results indicate that Black and Hispanic populations may benefit from earlier intervention and screening and highlight the potential benefits of personalizing first-line medications., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Published
2024
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30. Discovery of 95 PTSD loci provides insight into genetic architecture and neurobiology of trauma and stress-related disorders.

Author

Nievergelt CM, Maihofer AX, Atkinson EG, Chen CY, Choi KW, Coleman JR, Daskalakis NP, Duncan LE, Polimanti R, Aaronson C, Amstadter AB, Andersen SB, Andreassen OA, Arbisi PA, Ashley-Koch AE, Austin SB, Avdibegoviç E, Babic D, Bacanu SA, Baker DG, Batzler A, Beckham JC, Belangero S, Benjet C, Bergner C, Bierer LM, Biernacka JM, Bierut LJ, Bisson JI, Boks MP, Bolger EA, Brandolino A, Breen G, Bressan RA, Bryant RA, Bustamante AC, Bybjerg-Grauholm J, Bækvad-Hansen M, Børglum AD, Børte S, Cahn L, Calabrese JR, Caldas-de-Almeida JM, Chatzinakos C, Cheema S, Clouston SAP, Colodro-Conde L, Coombes BJ, Cruz-Fuentes CS, Dale AM, Dalvie S, Davis LK, Deckert J, Delahanty DL, Dennis MF, deRoon-Cassini T, Desarnaud F, DiPietro CP, Disner SG, Docherty AR, Domschke K, Dyb G, Kulenovic AD, Edenberg HJ, Evans A, Fabbri C, Fani N, Farrer LA, Feder A, Feeny NC, Flory JD, Forbes D, Franz CE, Galea S, Garrett ME, Gelaye B, Gelernter J, Geuze E, Gillespie CF, Goci A, Goleva SB, Gordon SD, Grasser LR, Guindalini C, Haas M, Hagenaars S, Hauser MA, Heath AC, Hemmings SM, Hesselbrock V, Hickie IB, Hogan K, Hougaard DM, Huang H, Huckins LM, Hveem K, Jakovljevic M, Javanbakht A, Jenkins GD, Johnson J, Jones I, Jovanovic T, Karstoft KI, Kaufman ML, Kennedy JL, Kessler RC, Khan A, Kimbrel NA, King AP, Koen N, Kotov R, Kranzler HR, Krebs K, Kremen WS, Kuan PF, Lawford BR, Lebois LAM, Lehto K, Levey DF, Lewis C, Liberzon I, Linnstaedt SD, Logue MW, Lori A, Lu Y, Luft BJ, Lupton MK, Luykx JJ, Makotkine I, Maples-Keller JL, Marchese S, Marmar C, Martin NG, MartÍnez-Levy GA, McAloney K, McFarlane A, McLaughlin KA, McLean SA, Medland SE, Mehta D, Meyers J, Michopoulos V, Mikita EA, Milani L, Milberg W, Miller MW, Morey RA, Morris CP, Mors O, Mortensen PB, Mufford MS, Nelson EC, Nordentoft M, Norman SB, Nugent NR, O'Donnell M, Orcutt HK, Pan PM, Panizzon MS, Pathak GA, Peters ES, Peterson AL, Peverill M, Pietrzak RH, Polusny MA, Porjesz B, Powers A, Qin XJ, Ratanatharathorn A, Risbrough VB, Roberts AL, Rothbaum BO, Rothbaum AO, Roy-Byrne P, Ruggiero KJ, Rung A, Runz H, Rutten BPF, de Viteri SS, Salum GA, Sampson L, Sanchez SE, Santoro M, Seah C, Seedat S, Seng JS, Shabalin A, Sheerin CM, Silove D, Smith AK, Smoller JW, Sponheim SR, Stein DJ, Stensland S, Stevens JS, Sumner JA, Teicher MH, Thompson WK, Tiwari AK, Trapido E, Uddin M, Ursano RJ, Valdimarsdóttir U, van den Heuvel LL, Van Hooff M, van Rooij SJ, Vermetten E, Vinkers CH, Voisey J, Wang Z, Wang Y, Waszczuk M, Weber H, Wendt FR, Werge T, Williams MA, Williamson DE, Winsvold BS, Winternitz S, Wolf EJ, Wolf C, Xia Y, Xiong Y, Yehuda R, Young RM, Young KA, Zai CC, Zai GC, Zervas M, Zhao H, Zoellner LA, Zwart JA, Stein MB, Ressler KJ, and Koenen KC

Abstract

Posttraumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 novel). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (e.g., GRIA1, GRM8, CACNA1E ), developmental, axon guidance, and transcription factors (e.g., FOXP2, EFNA5, DCC ), synaptic structure and function genes (e.g., PCLO, NCAM1, PDE4B ), and endocrine or immune regulators (e.g., ESR1, TRAF3, TANK ). Additional top genes influence stress, immune, fear, and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

Published
2023
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31. Sex Differences in Health Conditions Associated with Sexual Assault in a Large Hospital Population.

Author

Lake AM, Goleva SB, Samuels LR, Carpenter LM, and Davis LK

Abstract

Introduction: Sexual assault is an urgent public health concern with both immediate and long-lasting health consequences, affecting 44% of women and 25% of men during their lifetimes. Large studies are needed to understand the unique healthcare needs of this patient population., Methods: We mined clinical notes to identify patients with a history of sexual assault in the electronic health record (EHR) at Vanderbilt University Medical Center (VUMC), a large university hospital in the Southeastern USA, from 1989 to 2021 ( N = 3,376,424). Using a phenome-wide case-control study, we identified diagnoses co-occurring with disclosures of sexual assault. We performed interaction tests to examine whether sex modified any of these associations. Association analyses were restricted to a subset of patients receiving regular care at VUMC ( N = 833,185)., Results: The phenotyping approach identified 14,496 individuals (0.43%) across the VUMC-EHR with documentation of sexual assault and achieved a positive predictive value of 93.0% (95% confidence interval = 85.6-97.0%), determined by manual patient chart review. Out of 1,703 clinical diagnoses tested across all subgroup analyses, 465 were associated with sexual assault. Sex-by-trauma interaction analysis revealed 55 sex-differential associations and demonstrated increased odds of psychiatric diagnoses in male survivors., Discussion: This case-control study identified associations between disclosures of sexual assault and hundreds of health conditions, many of which demonstrated sex-differential effects. The findings of this study suggest that patients who have experienced sexual assault are at risk for developing wide-ranging medical and psychiatric comorbidities and that male survivors may be particularly vulnerable to developing mental illness., Competing Interests: The authors have declared no conflicts of interest., (The Author(s). Published by S. Karger AG, Basel.)

Published
2023
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32. Renal vascular and glomerular pathologies associated with spontaneous hypertension in the nonhuman primate Chlorocebus aethiops sabaeus .

Author

Rhoads MK, Goleva SB, Beierwaltes WH, and Osborn JL

Subjects
Animals, Female, Humans, Hypertension, Renovascular etiology, Male, Renal Artery Obstruction complications, Chlorocebus aethiops physiology, Disease Models, Animal, Hypertension, Renovascular physiopathology, Kidney Glomerulus pathology, Kidney Glomerulus physiopathology, Renal Artery Obstruction physiopathology
Abstract

Hypertension is a complex, multifactorial disease affecting an estimated 78 million adults in the United States. Despite scientific gains, the etiology of human essential hypertension is unknown and current experimental models do not recapitulate all the behavioral and physiological characteristics of the pathology. Researchers should assess the translational capacity of these models and look to other animal models for the discovery of new therapies. Chlorocebus aethiops sabaeus , the African Green Monkey (AGM), is a nonhuman primate that develops spontaneous hypertension and may provide a novel translational model for the study of hypertension and associated diseases. In a randomly selected group of 424 adult AGMs, 37% (157/424) exhibited systolic blood pressures (SBP) >140 mmHg (SBP: 172.0 ± 2.2 mmHg) and were characterized as hypertensive (HT). 44% (187/424) were characterized as normotensive with SBP <120 mmHg (NT, SBP: 99.6 ± 1.0 mmHg) and the remaining 18% (80/424) as borderline hypertensive (BHT, SBP: 130.6 ± 0.6 mmHg). When compared with NT animals, HT AGMs are older (8.7 ± 0.6 vs. 12.4 ± 0.7 yr, P < 0.05) with elevated heart rates (125.7 ± 2.0 vs. 137.7 ± 2.2 beats/min, P < 0.05). BHT animals had average heart rates of 138.2 ± 3.1 beats/min ( P < 0.05 compared with NT) and were 11.00 ± 0.9 yr old. NT and HT animals had similar levels of angiotensinogen gene expression, plasma renin activity, and renal cortical renin content ( P > 0.05). HT monkeys exhibit renal vascular remodeling (wall-to-lumen ratio NT 0.11 ± 0.01 vs. HT 0.15 ± 0.02, P < 0.05) and altered glomerular morphology (Bowman's capsular space: NT 30.9 ± 1.9% vs. HT 44.4 ± 3.1%, P < 0.05). The hypertensive AGM provides a large animal model that is highly similar to humans and should be studied to identify novel, more effective targets for the treatment of hypertension., (Copyright © 2017 the American Physiological Society.)

Published
2017
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