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1. Transcriptome-wide association analysis identifies candidate susceptibility genes for prostate-specific antigen levels in men without prostate cancer.

Author

Chen, Dorothy, Dong, Ruocheng, Kachuri, Linda, Hoffmann, Thomas, Jiang, Yu, Berndt, Sonja, Shelley, John, Schaffer, Kerry, Machiela, Mitchell, Freedman, Neal, Huang, Wen-Yi, Li, Shengchao, Lilja, Hans, Justice, Amy, Madduri, Ravi, Rodriguez, Alex, Van Den Eeden, Stephen, Chanock, Stephen, Haiman, Christopher, Conti, David, Klein, Robert, Mosley, Jonathan, Witte, John, and Graff, Rebecca

Subjects
gene expression, genetics, prostate cancer, prostate-specific antigen, screening, transcriptome-wide association study, Humans, Male, Prostate-Specific Antigen, Genome-Wide Association Study, Prostatic Neoplasms, Genetic Predisposition to Disease, Transcriptome, Gene Expression Profiling, Polymorphism, Single Nucleotide
Abstract

Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility for prostate cancer (PCa) screening. Using genome-wide association study (GWAS) summary statistics from 95,768 PCa-free men, we conducted a transcriptome-wide association study (TWAS) to examine impacts of genetically predicted gene expression on PSA. Analyses identified 41 statistically significant (p 0.5: CCNA2 and HIST1H2BN. Six of the 20 identified genes are not known to impact PCa risk. Fine-mapping based on whole blood and prostate tissue revealed five protein-coding genes with evidence of causal relationships with PSA levels. Of these five genes, four exhibited evidence of colocalization and one was conditionally independent of previous GWAS findings. These results yield hypotheses that should be further explored to improve understanding of genetic factors underlying PSA levels.

Published
2024

2. Clinical associations with a polygenic predisposition to benign lower white blood cell counts

Author

Mosley, Jonathan D., Shelley, John P., Dickson, Alyson L., Zanussi, Jacy, Daniel, Laura L., Zheng, Neil S., Bastarache, Lisa, Wei, Wei-Qi, Shi, Mingjian, Jarvik, Gail P., Rosenthal, Elisabeth A., Khan, Atlas, Sherafati, Alborz, Kullo, Iftikhar J., Walunas, Theresa L., Glessner, Joseph, Hakonarson, Hakon, Cox, Nancy J., Roden, Dan M., Frangakis, Stephan G., Vanderwerff, Brett, Stein, C. Michael, Van Driest, Sara L., Borinstein, Scott C., Shu, Xiao-Ou, Zawistowski, Matthew, Chung, Cecilia P., and Kawai, Vivian K.

Published
2024
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3. Clinical consequences of a genetic predisposition toward higher benign prostate-specific antigen levels.

Author

Shi, Mingjian, Shelley, John, Schaffer, Kerry, Tosoian, Jeffrey, Bagheri, Minoo, Kachuri, Linda, Mosley, Jonathan, and Witte, John

Subjects
Associations, Cox proportional hazards regression, Polygenic score (PGS), Prostate cancer, Prostate specific antigen (PSA)
Abstract

BACKGROUND: Prostate-specific antigen (PSA) levels are influenced by genetic variation unrelated to prostate cancer risk. Whether a genetic predisposition to a higher PSA level predisposes to a diagnostic work-up for prostate cancer is not known. METHODS: Participants were 3110 men of African and European ancestries ages 45-70, without prostate cancer and with a baseline PSA < 4 ng/mL, undergoing routine clinical PSA screening. The exposure was a polygenic score (PGS) comprising 111 single nucleotide polymorphisms associated with PSA level, but not prostate cancer. We tested whether the PGS was associated with a: 1) PSA value > 4 ng/mL, 2) International Classification of Diseases (ICD) code for an elevated PSA, 3) encounter with a urologist, or 4) prostate biopsy. Multivariable Cox proportional hazards models were adjusted for age and genetic principal components. Analyses were stratified by age (45-59 years, and 60-70 years old). Association estimates are per standard deviation change in the PGS. FINDINGS: The median age was 56.6 years, and 2118 (68%) participants were 45-59 years. The median (IQR) baseline PSA level was 1.0 (0.6-1.7) ng/mL. Among men ages 45-59, the PGS was associated with a PSA > 4 (hazard ratio [HR] = 1.35 [95% CI, 1.17-1.57], p = 4.5 × 10-5), an ICD code for elevated PSA (HR = 1.30 [1.12-1.52], p = 8.0 × 10-4), a urological evaluation (HR = 1.34 [1.14-1.57], p = 4.8 × 10-4), and undergoing a prostate biopsy (HR = 1.35 [1.11-1.64], p = 0.002). Among men ages 60-70, association effect sizes were smaller and not significant. INTERPRETATION: A predisposition toward higher PSA levels was associated with clinical evaluations of an elevated PSA among men ages 45-59 years. FUNDING: National Institutes of Health (NIH).

Published
2023

4. Genetically adjusted PSA levels for prostate cancer screening.

Author

Kachuri, Linda, Hoffmann, Thomas J, Jiang, Yu, Berndt, Sonja I, Shelley, John P, Schaffer, Kerry R, Machiela, Mitchell J, Freedman, Neal D, Huang, Wen-Yi, Li, Shengchao A, Easterlin, Ryder, Goodman, Phyllis J, Till, Cathee, Thompson, Ian, Lilja, Hans, Van Den Eeden, Stephen K, Chanock, Stephen J, Haiman, Christopher A, Conti, David V, Klein, Robert J, Mosley, Jonathan D, Graff, Rebecca E, and Witte, John S

Subjects
Humans, Prostatic Neoplasms, Prostate-Specific Antigen, Biopsy, Male, Early Detection of Cancer, Neoplasm Grading, Aging, Prevention, Cancer, Urologic Diseases, Prostate Cancer, Genetics, Good Health and Well Being, Medical and Health Sciences, Immunology
Abstract

Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting for genetic determinants of constitutive, non-cancer-related PSA variation has potential to improve screening utility. In this study, we discovered 128 genome-wide significant associations (P

Published
2023

6. Transcriptome-wide association analysis identifies candidate susceptibility genes for prostate-specific antigen levels in men without prostate cancer

Author

Chen, Dorothy M., Dong, Ruocheng, Kachuri, Linda, Hoffmann, Thomas J., Jiang, Yu, Berndt, Sonja I., Shelley, John P., Schaffer, Kerry R., Machiela, Mitchell J., Freedman, Neal D., Huang, Wen-Yi, Li, Shengchao A., Lilja, Hans, Justice, Amy C., Madduri, Ravi K., Rodriguez, Alex A., Van Den Eeden, Stephen K., Chanock, Stephen J., Haiman, Christopher A., Conti, David V., Klein, Robert J., Mosley, Jonathan D., Witte, John S., and Graff, Rebecca E.

Published
2024
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7. Returning integrated genomic risk and clinical recommendations: The eMERGE study

Author

Gordon, Adam, Sobowale, Agboade, Allworth, Aimee, Patel, Akshar, DiVietro, Alanna, Strong, Alanna, Sherafati, Alborz, Sherfati, Alborz, Bick, Alex, Miller, Alexandra, Chandel, Alka, Rosenthal, Alyssa, Khera, Amit, Kontorovich, Amy, Beck, Andrew, Beck, Andy, Espinoza, Angelica, Lewis, Anna, Prince, Anya, Khan, Atlas, Iverson, Ayuko, Khales, Bahram Namjou, Benoit, Barbara, Hernan, Becca, Kallman, Ben, Kerman, Ben, Shoemaker, Ben, Satterfield, Benjamin, Devine, Beth, Etheridge, Bethany, Goff, Blake, Freimuth, Bob, Grundmeier, Bob, Collier, Brenae, Mutai, Brenda, Harnett, Brett, Chang, Brian, Piening, Brian, Davis, Brittney, Korf, Bruce, Patterson, Candace, Demetriou, Carmen, Ta, Casey, Hammack, Catherine, Nelson, Catrina, Gascoigne, Caytie, Dorn, Chad, Moretz, Chad, Kachulis, Chris, Hoell, Christie, Cowles, Christine, Lange, Christoph, Weng, Chunhua, Prows, Cindy, Brokamp, Cole, Liu, Cong, Scherr, Courtney, Gonzalez, Crystal, Ramirez, Cynthia, Shimbo, Daichi, Roden, Dan, Schaid, Daniel, Kaufman, Dave, Crosslin, David, Kochan, David, Veenstra, David, Singh, Davinder, Karavite, Dean, Abrams, Debbie, Absher, Devin, Edwards, Digna Velez, Haverfield, Eden, Morales, Eduardo, Esplin, Edward, Malolepsza, Edyta, Alipour, Ehsan, Kenny, Eimear, Rosenthal, Elisabeth, Duvall, Eliza, McNally, Elizabeth, Bhoj, Elizabeth, Cohn, Elizabeth, Hibler, Elizabeth, Karlson, Elizabeth, Clayton, Ellen, Chesnut, Emily, DeFranco, Emily, Gallagher, Emily, Soper, Emily, Perez, Emma, Cash, Erin, Berner, Eta, Wang, Fei, Wehbe, Firas, Ricci, Francisco, Mentch, Frank, Shaibi, Gabriel, Jarvik, Gail, Hahn, George, Hripcsak, George, Wiesner, Georgia, Belbin, Gillian, Davogustto, Gio, Nadkarni, Girish, Qiu, Haijun, Hakonarson, Hakon, Bangash, Hana, Beasley, Hannah, Liu, Hao, Aungst, Heide, Tiwari, Hemant, Duckham, Hillary, Thomas, Hope, Kullo, Iftikhar, Holm, Ingrid, Allen, Isabelle, Ionita-Laza, Iuliana, Hellwege, Jacklyn, Petrzelka, Jacob, Odgis, Jacqueline, Narula, Jahnavi, Petrzelka, Jake, Patel, Jalpa, Cimino, James, Meigs, James, Snyder, James, Olson, Janet, Zahner, Janet, Pennington, Jeff, Pacheco, Jen, Pacheco, Jennifer Allen, Morse, Jennifer, Corsmo, Jeremy, Thayer, Jeritt, Cimino, Jim, Chen, Jingheng, Fournier, Jocelyn, Jackson, Jodell, Glessner, Joe, Pacyna, Joel, Smith, Johanna, Connolly, John, Lynch, John, Shelley, John, Mosley, Jonathan, Nestor, Jordan, Smoller, Jordan, Alsip, Jorge, Kannry, Joseph, Sutton, Joseph, Peterson, Josh, Smith, Joshua, Galasso, Julia, Smith, Julia, Wynn, Julia, Gundelach, Justin, Starren, Justin, Choi, Karmel, Mittendorf, Kate, Anderson, Katherine, Bonini, Katherine, Leppig, Kathleen, Muenzen, Kathleen, Larkin, Katie, Stuttgen, Kelsey, Wiley, Ken, Nguyen, Kenny, Dufendach, Kevin, Atkins, Kiley, Sawicki, Konrad, Norland, Kristjan, Kiryluk, Krzysztof, Beskow, Laura, Rasmussen-Torvik, Laura, Kottyan, Leah, Hsu, Li, Tian, Lifeng, Mahanta, Lisa, Martin, Lisa, Wang, Lisa, Gomez, Lizbeth, Thompson, Lorenzo, Orlando, Lori, Richter, Lucas, Rasmussen, Luke, Petukhova, Lynn, Seabolt, Lynn, O’Brien, Madison, Harden, Maegan, Fullerton, Malia, Harr, Margaret, Beasley, Mark, Guindo, Marta, Horike, Martha, Horike-Pyne, Martha, Abdalla, Marwah, Hamed, Marwan, Terry, Mary Beth, Maradik, Mary, Wyatt, Matt, Davis, Matthew, Lebo, Matthew, Smith, Maureen, Rosario, Maya del, Sabatello, Maya, Behr, Meckenzie, Roy-Puckelwartz, Meg, Habrat, Mel, Myers, Melanie, Yetisgen, Meliha, Iris, Merve, DaSilva, Michael, Preuss, Michael, McGowan, Michelle, Shi, Mingjian, Perera, Minoli, Thomas, Minta, Elkind, Mitch, Abbass, Mohammad, Saadatagah, Mohammad, Hess, Molly, Maradik, Molly, Vaitinadin, Nataraja “RJ”, Vaitinadin, Nataraja, Muthu, Naveen, Netherly, Neil, Lennon, Niall, Shang, Ning, Limdi, Nita, Forrest, Noah, Romero, Noheli, Robinson, Nora, Abul-Husn, Noura, Elsekaily, Omar, Dikilitas, Ozan, Kovatch, Patricia, Davis, Patrick, Appelbaum, Paul, Francaviglia, Paul, O’Reilly, Paul, Chandler, Paulette, Caraballo, Pedro, Tarczy-Hornoch, Peter, Shum, Pierre, Marathe, Priya, Murali, Priyanka, Feng, Qiping, Wells, Quinn, Atchley, Rachel, Narla, Radhika, Barton, Rene, Sterling, Rene, Chisholm, Rex, Green, Richard, Sharp, Richard, Peters, Riki, Kukafka, Rita, Rowley, Robb, Freimuth, Robert, Green, Robert, Winter, Robert, Mueller, Roger, Loos, Ruth, Irvin, Ryan, Suckiel, Sabrina, Hussain, Sajjad, Sharba, Samer, Aronson, Sandy, Jones, Sarah, Knerr, Sarah, Nigbur, Scott, Weiss, Scott, Mooney, Sean, Terek, Shannon, Aufox, Sharon, Nirenberg, Sharon, Murphy, Shawn, O’Byrne, Sheila, Wang (Sam) Choi, Shing, Aguilar, Sienna, Bland, S.T., Rodrigues, Stefanie, Ledbetter, Stephanie, Rutledge, Stephanie, Booth, Stuart James, Xian, Su, Trinidad, Susan Brown, Bakken, Suzanne, Schmidlen, Tara, Rakhra-Burris, Tejinder, Manolio, Teri, Mersha, Tesfaye, Walunas, Theresa, Chandereng, Thevaa, May, Thomas, Ge, Tian, Edwards, Todd, Kaszemacher, Tom, Hernandez, Valentina, Willis, Valerie, Desai, Vemi, Desai, Vimi, Lorenzi, Virginia, Gainer, Vivian, Wei, Wei-Qi, Chung, Wendy, Su, Wu-Chen, Chang, Xiao, Zhao, Yiqing, Luo, Yuan, Shen, Yufeng, Linder, Jodell E., Bland, Harris T., Caraballo, Pedro J., Chisholm, Rex L., Clayton, Ellen Wright, Crosslin, David R., Esplin, Edward D., Forman, Sophie, Freimuth, Robert R., Gordon, Adam S., Harden, Maegan V., Holm, Ingrid A., Jarvik, Gail P., Karlson, Elizabeth W., Labrecque, Sofia, Lennon, Niall J., Limdi, Nita A., Mittendorf, Kathleen F., Murphy, Shawn N., Prows, Cynthia A., Rasmussen, Luke V., Sawicki, Konrad Teodor, Velez Edwards, Digna R., Abul-Husn, Noura S., Below, Jennifer E., Berner, Eta S., Booth, James, Chung, Wendy K., Cimino, James J., Fullerton, Stephanie M., Guiducci, Candace, Habrat, Melissa L., Hain, Heather, Hoell, Christin, Irvin, Marguerite R., Kachulis, Christopher, Kenny, Eimear E., Kullo, Iftikhar J., Manolio, Teri A., McNally, Elizabeth M., Mooney, Sean D., Namjou, Bahram, Perez, Emma F., Puckelwartz, Megan J., Roden, Dan M., Rosenthal, Elisabeth A., Saadatagah, Seyedmohammad, Schaid, Dan J., Schultz, Baergen, Shaibi, Gabriel Q., Sharp, Richard R., Shirts, Brian, Smith, Maureen E., Smoller, Jordan W., Suckiel, Sabrina A., Tiwari, Hemant K., Trinidad, Susan B., Wells, Quinn S., Wiesner, Georgia L., and Peterson, Josh F.

Published
2023
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10. Sexual Trauma, Polygenic Scores, and Mental Health Diagnoses and Outcomes.

Author

Lake, Allison M., Zhou, Yu, Wang, Bo, Actkins, Ky'Era V., Zhang, Yingzhe, Shelley, John P., Rajamani, Anindita, Steigman, Michael, Kennedy, Chris J., Smoller, Jordan W., Choi, Karmel W., Khankari, Nikhil K., and Davis, Lea K.

Subjects
SEXUAL trauma, MENTAL depression, BIPOLAR disorder, MENTAL illness, ACADEMIC medical centers
Abstract

Key Points: Question: What are the independent, joint, and interacting contributions of sexual trauma history and polygenic liability to the risk of schizophrenia, bipolar disorder, and major depressive disorder diagnoses? Findings: This genetic association study identified associations between sexual trauma and mental health diagnoses in 96 002 patients from 2 geographically distinct academic medical center settings, with both sexual trauma history and polygenic scores showing significant independent and joint associations with schizophrenia and major depressive disorder across all analyses. In a cross-site meta-analysis, polygenic scores for schizophrenia and bipolar disorder demonstrated an interaction with sexual trauma disclosures in which the association between each polygenic score and its respective diagnosis was weaker among individuals reporting sexual trauma. Meaning: Sexual trauma and polygenic scores were independently and jointly important risk factors for mental health conditions, yet the associations of polygenic scores generated using existing methods may be less impactful than the mental health risk conferred by sexual trauma among patients with this history. Importance: Leveraging real-world clinical biobanks to investigate the associations between genetic and environmental risk factors for mental illness may help direct clinical screening efforts and evaluate the portability of polygenic scores across environmental contexts. Objective: To examine the associations between sexual trauma, polygenic liability to mental health outcomes, and clinical diagnoses of schizophrenia, bipolar disorder, and major depressive disorder in a clinical biobank setting. Design, Setting, and Participants: This genetic association study was conducted using clinical and genotyping data from 96 002 participants across hospital-linked biobanks located at Vanderbilt University Medical Center (VUMC), Nashville, Tennessee (including 58 262 individuals with high genetic similarity to the 1000 Genomes Project [1KG] Northern European from Utah reference population [1KG-EU-clustered] and 11 047 with high genetic similarity to the 1KG African-ancestry reference population of Yoruba in Ibadan, Nigeria [1KG-YRI-clustered]), and Mass General Brigham (MGB), Boston, Massachusetts (26 693 individuals with high genetic similarity to the combined European-ancestry superpopulation [1KG-EU-clustered]). Clinical data analyzed included diagnostic billing codes and clinical notes spanning from 1976 to 2023. Data analysis was performed from 2022 to 2024. Exposures: Clinically documented sexual trauma disclosures and polygenic scores for schizophrenia, bipolar disorder, and major depressive disorder. Main Outcomes and Measures: Diagnoses of schizophrenia, bipolar disorder, and major depressive disorder, determined by aggregating related diagnostic billing codes, were the dependent variables in logistic regression models including sexual trauma disclosure status, polygenic scores, and their interactions as the independent variables. Results: Across the VUMC and MGB biobanks, 96 002 individuals were included in analyses (VUMC 1KG-EU-clustered: 33 011 [56.7%] female; median [range] age, 56.8 [10.0 to >89] years; MGB 1KG-EU-clustered: 14 647 [54.9%] female; median [range] age, 58.0 [10.0 to >89] years; VUMC 1KG-YRI-clustered: 6961 [63.0%] female; median [range] age, 44.6 [10.1 to >89] years). Sexual trauma history was associated with all mental health conditions across institutions (ORs ranged from 8.83 [95% CI, 5.50-14.18] for schizophrenia in the VUMC 1KG-YRI-clustered cohort to 17.65 [95% CI, 12.77-24.40] for schizophrenia in the VUMC 1KG-EU-clustered cohort). Sexual trauma history and polygenic scores jointly explained 3.8% to 8.8% of mental health phenotypic variance. Schizophrenia and bipolar disorder polygenic scores had greater associations with mental health outcomes in individuals with no documented disclosures of sexual trauma (schizophrenia interaction: OR, 0.70 [95% CI, 0.56-0.88]; bipolar disorder interaction: OR, 0.83 [95% CI, 0.74-0.94]). Conclusions and Relevance: Sexual trauma and mental health polygenic scores, while correlated with one another, were independent and joint risk factors for severe mental illness in a large, diverse hospital biobank population. Furthermore, associations of schizophrenia and bipolar disorder polygenic scores with respective diagnoses were greater in those without disclosures, suggesting that genetic predisposition to mental illness as measured by polygenic scores may be less impactful in the presence of this severe environmental risk factor. This genetic association study examined the associations between sexual trauma, polygenic liability to mental health outcomes, and clinical diagnoses of schizophrenia, bipolar disorder, and major depressive disorder in a clinical biobank setting. [ABSTRACT FROM AUTHOR]

Published
2025
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13. Calculating Apparent pKaValues of Ionizable Lipids in Lipid Nanoparticles

Author

Hamilton, Nicholas B., Arns, Steve, Shelley, Mee, Bechis, Irene, and Shelley, John C.

Abstract

Creating new ionizable lipids for use in lipid nanoparticles (LNPs) is an active field of research. One of the critical properties for selecting suitable ionizable lipids is the apparent pKavalue of the lipid as formulated in an LNP. We have developed a structure-based, computational methodology for the prediction of the apparent pKavalue of ionizable lipids within LNPs and have tested it using the lipid formulations in the mRNA LNP COVID-19 vaccines COMIRNATY and Spikevax, and the siRNA LNP therapeutic Onpattro. The calculation was also applied to Lipid A, a variant of the ionizable lipid used in COMIRNATY.

Published
2025
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16. Predicting the Release Mechanism of Amorphous Solid Dispersions: A Combination of Thermodynamic Modeling and In Silico Molecular Simulation.

Author

Walter, Stefanie, Mileo, Paulo G. M., Afzal, Mohammad Atif Faiz, Kyeremateng, Samuel O., Degenhardt, Matthias, Browning, Andrea R., and Shelley, John C.

Subjects
TERNARY phase diagrams, THERMODYNAMIC molecular model, PHASE transitions, AMORPHOUS substances, THERMODYNAMIC potentials, PHASE separation
Abstract

Background: During the dissolution of amorphous solid dispersion (ASD) formulations, the drug load (DL) often impacts the release mechanism and the occurrence of loss of release (LoR). The ASD/water interfacial gel layer and its specific phase behavior in connection with DL strongly dictate the release mechanism and LoR of ASDs, as reported in the literature. Thermodynamically driven liquid-liquid phase separation (LLPS) and/or drug crystallization at the interface are the key phase transformations that drive LoR. Methods: In this study, a combination of Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) thermodynamic modeling and in silico molecular simulation was applied to investigate the release mechanism and the occurrence LoR of an ASD formulation consisting of ritonavir as the active pharmaceutical ingredient (API) and the polymer, polyvinylpyrrolidone-co-vinyl acetate (PVPVA64). A thermodynamically modeled ternary phase diagram of ritonavir (PVPVA64) and water was applied to predict DL-dependent LLPS in the ASD/water interfacial gel layer. Microscopic Erosion Time Testing (METT) was used to experimentally validate the phase diagram predictions. Additionally, in silico molecular simulation was applied to provide further insights into the phase separation, the release mechanism, and aggregation behavior on a molecular level. Results: Thermodynamic modeling, molecular simulation, and experimental results were consistent and complementary, providing evidence that ASD/water interactions and phase separation are essential factors driving the dissolution behavior and LoR at 40 wt% DL of the investigated ritonavir/PVPVA64 ASD system, consistent with previous studies. Conclusions: This study provides insights into the potential of blending thermodynamic modeling, molecular simulation, and experimental research to comprehensively understand ASD formulations. Such a combined approach can be leveraged as a computational framework to gain insights into the ASD dissolution mechanism, thereby facilitating in silico screening, designing, and optimization of formulations with the benefit of significantly reducing the number of experimental tests. [ABSTRACT FROM AUTHOR]

Published
2024
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19. Coarse-Grained Simulation of mRNA-Loaded Lipid Nanoparticle Self-Assembly

Author

Grzetic, Douglas J., Hamilton, Nicholas B., and Shelley, John C.

Abstract

Ionizable lipid-containing lipid nanoparticles (LNPs) have enabled the delivery of RNA for a range of therapeutic applications. In order to optimize safe, targeted, and effective LNP-based RNA delivery platforms, an understanding of the role of composition and pH in their structural properties and self-assembly is crucial, yet there have been few computational studies of such phenomena. Here we present a coarse-grained model of ionizable lipid and mRNA-containing LNPs. Our model allows access to the large length- and time-scales necessary for LNP self-assembly and is mapped and parametrized with reference to all-atom structures and simulations of the corresponding components at compositions typical of LNPs used for mRNA delivery. Our simulations reveal insights into the dynamics of self-assembly of such mRNA-encapsulating LNPs, as well as the subsequent pH change-driven LNP morphology and release of mRNA.

Published
2024
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24. Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves cross-ancestry prediction

Author

Hoffmann, Thomas J, primary, Graff, Rebecca E, additional, Madduri, Ravi K, additional, Rodriguez, Alex A, additional, Cario, Clint L, additional, Feng, Karen, additional, Jiang, Yu, additional, Wang, Anqi, additional, Klein, Robert J, additional, Pierce, Brandon L, additional, Eggener, Scott, additional, Tong, Lin, additional, Blot, William, additional, Long, Jirong, additional, Rebbeck, Timothy, additional, Lachance, Joseph, additional, Andrews, Caroline, additional, Adebiyi, Akindele O, additional, Adusei, Ben, additional, Aisuodionoe-Shadrach, Oseremen I, additional, Fernandez, Pedro W, additional, Jalloh, Mohamed, additional, Janivara, Rohini, additional, Chen, Wenlong C, additional, Mensah, James E, additional, Agalliu, Ilir, additional, Berndt, Sonja I, additional, Shelley, John P, additional, Schaffer, Kerry, additional, Machiela, Mitchell J, additional, Freedman, Neal D, additional, Huang, Wen-Yi, additional, Li, Shengchao A, additional, Goodman, Phyllis J, additional, Till, Cathee, additional, Thompson, Ian, additional, Lilja, Hans, additional, Van Den Eeden, Stephen K, additional, Chanock, Stephen J, additional, Mosley, Jonathan D, additional, Conti, David V, additional, Haiman, Christopher A, additional, Justice, Amy C, additional, Kachuri, Linda, additional, and Witte, John S, additional

Published
2023
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27. Clinical consequences of a polygenic predisposition to benign lower white blood cell counts

Author

Mosley, Jonathan D., primary, Shelley, John, additional, Dickson, Alyson L., additional, Zanussi, Jacy, additional, Daniel, Laura, additional, Zheng, Neil S, additional, Bastarache, Lisa, additional, Wei, Wei-Qi, additional, Shi, Mingjian, additional, Jarvik, Gail P, additional, Rosenthal, Elisabeth A, additional, Khan, Atlas, additional, Sherafati, Alborz, additional, Kullo, Iftikhar, additional, Walunas, Theresa, additional, Glessner, Joe, additional, Hakonarson, Hakon, additional, Cox, Nancy J, additional, Roden, Dan M., additional, Frangakis, Stephan G., additional, Vanderwerff, Brett, additional, Stein, C. Michael, additional, Van Driest, Sara L., additional, Borinstein, Scott C., additional, Zawistowski, Matthew, additional, Shu, Xiao-Ou, additional, Chung, Cecilia, additional, and Kawai, Vivian K., additional

Published
2023
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33. Flavobacterium covaeis the predominant species of columnaris‐causing bacteria impacting the Channel Catfish industry in the southeastern United States

Author

LaFrentz, Benjamin R., Khoo, Lester H., Lawrence, Mark L., Petrie‐Hanson, Lora, Hanson, Larry A., Baumgartner, Wes A., Hemstreet, William G., Kelly, Anita M., García, Julio C., Shelley, John P., Johnston, Amber E., Bruce, Timothy J., and Griffin, Matt J.

Abstract

Columnaris disease is a leading cause of disease‐related losses in the catfish industry of the southeastern United States. The term “columnaris‐causing bacteria” (CCB) has been coined in reference to the four described species that cause columnaris disease: Flavobacterium columnare, F. covae, F. davisii, and F. oreochromis. Historically, F. columnare, F. covae, and F. davisiihave been isolated from columnaris disease cases in the catfish industry; however, there is a lack of knowledge of which CCB species are most prevalent in farm‐raised catfish. The current research objectives were to (1) sample columnaris disease cases from the U.S. catfish industry and identify the species of CCB involved and (2) determine the virulence of the four CCB species in Channel Catfish Ictalurus punctatusin controlled laboratory challenges. Bacterial isolates or swabs of external lesions from catfish were collected from 259 columnaris disease cases in Mississippi and Alabama during 2015–2019. The DNA extracted from the samples was analyzed using a CCB‐specific multiplex polymerase chain reaction to identify the CCB present in each diagnostic case. Channel Catfish were challenged by immersion with isolates belonging to each CCB species to determine virulence at ~28°C and 20°C. Flavobacterium covaewas identified as the predominant CCB species impacting the U.S. catfish industry, as it was present in 94.2% (n= 244) of diagnostic case submissions. Challenge experiments demonstrated that F. covaeand F. oreochromiswere highly virulent to Channel Catfish, with most isolates resulting in near 100% mortality. In contrast, F. columnareand F. davisiiwere less virulent, with most isolates resulting in less than 40% mortality. Collectively, these results demonstrate that F. covaeis the predominant CCB in the U.S. catfish industry, and research aimed at developing new control and prevention strategies should target this bacterial species. The methods described herein can be used to continue monitoring the prevalence of CCB in the catfish industry and can be easily applied to other industries to identify which Flavobacteriumspecies have the greatest impact. Impact statementColumnaris disease is a leading cause of disease‐related losses in the southeastern U.S. catfish industry. Recently, four species of columnaris‐causing bacteria (CCB) have been described, but their prevalence in the industry was unknown. In this research, Flavobacterium covaewas identified as the predominant species of CCB impacting the industry and was demonstrated to be highly virulent in Channel Catfish. Research aimed at developing new control and prevention strategies should target this bacterial species. Columnaris disease is a leading cause of disease‐related losses in the southeastern U.S. catfish industry. Recently, four species of columnaris‐causing bacteria (CCB) have been described, but their prevalence in the industry was unknown. In this research, Flavobacterium covaewas identified as the predominant species of CCB impacting the industry and was demonstrated to be highly virulent in Channel Catfish. Research aimed at developing new control and prevention strategies should target this bacterial species.

Published
2024
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35. Transcriptome-Wide Association Analysis Identifies Novel Candidate Susceptibility Genes for Prostate-Specific Antigen Levels in Men Without Prostate Cancer

Author

Chen, Dorothy, primary, Dong, Ruocheng, additional, Kachuri, Linda, additional, Hoffmann, Thomas, additional, Jiang, Yu, additional, Berndt, Sonja I, additional, Shelley, John P, additional, Schaffer, Kerry R, additional, Machiela, Mitchell J, additional, Freedman, Neal D, additional, Huang, Wen-Yi, additional, Li, Shengchao A, additional, Lilja, Hans, additional, Van Den Eeden, Stephen K, additional, Chanock, Stephen, additional, Haiman, Christopher A, additional, Conti, David V, additional, Klein, Robert J, additional, Mosley, Jonathan D, additional, Witte, John S, additional, and Graff, Rebecca E, additional

Published
2023
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36. Epik: pKa and Protonation State Prediction through Machine Learning

Author

Johnston, Ryne C., primary, Yao, Kun, additional, Kaplan, Zachary, additional, Chelliah, Monica, additional, Leswing, Karl, additional, Seekins, Sean, additional, Watts, Shawn, additional, Calkins, David, additional, Chief Elk, Jackson, additional, Jerome, Steven V., additional, Repasky, Matthew P., additional, and Shelley, John C., additional

Published
2023
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38. Returning integrated genomic risk and clinical recommendations: The eMERGE study

Author

Linder, Jodell E., primary, Allworth, Aimee, additional, Bland, Sarah T., additional, Caraballo, Pedro J., additional, Chisholm, Rex L., additional, Clayton, Ellen Wright, additional, Crosslin, David R., additional, Dikilitas, Ozan, additional, DiVietro, Alanna, additional, Esplin, Edward D., additional, Forman, Sophie, additional, Freimuth, Robert R., additional, Gordon, Adam S., additional, Green, Richard, additional, Harden, Maegan V., additional, Holm, Ingrid A., additional, Jarvik, Gail P., additional, Karlson, Elizabeth W., additional, Labrecque, Sofia, additional, Lennon, Niall J., additional, Limdi, Nita A., additional, Mittendorf, Kathleen F., additional, Murphy, Shawn N., additional, Orlando, Lori, additional, Prows, Cynthia A., additional, Rasmussen, Luke V., additional, Rasmussen-Torvik, Laura, additional, Rowley, Robb, additional, Sawicki, Konrad Teodor, additional, Schmidlen, Tara, additional, Terek, Shannon, additional, Veenstra, David, additional, Velez Edwards, Digna R., additional, Absher, Devin, additional, Abul-Husn, Noura S., additional, Alsip, Jorge, additional, Bangash, Hana, additional, Beasley, Mark, additional, Below, Jennifer E., additional, Berner, Eta S., additional, Booth, James, additional, Chung, Wendy K., additional, Cimino, James J., additional, Connolly, John, additional, Davis, Patrick, additional, Devine, Beth, additional, Fullerton, Stephanie M., additional, Guiducci, Candace, additional, Habrat, Melissa L., additional, Hain, Heather, additional, Hakonarson, Hakon, additional, Harr, Margaret, additional, Haverfield, Eden, additional, Hernandez, Valentina, additional, Hoell, Christin, additional, Horike-Pyne, Martha, additional, Hripcsak, George, additional, Irvin, Marguerite R., additional, Kachulis, Christopher, additional, Karavite, Dean, additional, Kenny, Eimear E., additional, Khan, Atlas, additional, Kiryluk, Krzysztof, additional, Korf, Bruce, additional, Kottyan, Leah, additional, Kullo, Iftikhar J., additional, Larkin, Katie, additional, Liu, Cong, additional, Malolepsza, Edyta, additional, Manolio, Teri A., additional, May, Thomas, additional, McNally, Elizabeth M., additional, Mentch, Frank, additional, Miller, Alexandra, additional, Mooney, Sean D., additional, Murali, Priyanka, additional, Mutai, Brenda, additional, Muthu, Naveen, additional, Namjou, Bahram, additional, Perez, Emma F., additional, Puckelwartz, Megan J., additional, Rakhra-Burris, Tejinder, additional, Roden, Dan M., additional, Rosenthal, Elisabeth A., additional, Saadatagah, Seyedmohammad, additional, Sabatello, Maya, additional, Schaid, Dan J., additional, Schultz, Baergen, additional, Seabolt, Lynn, additional, Shaibi, Gabriel Q., additional, Sharp, Richard R., additional, Shirts, Brian, additional, Smith, Maureen E., additional, Smoller, Jordan W., additional, Sterling, Rene, additional, Suckiel, Sabrina A., additional, Thayer, Jeritt, additional, Tiwari, Hemant K., additional, Trinidad, Susan B., additional, Walunas, Theresa, additional, Wei, Wei-Qi, additional, Wells, Quinn S., additional, Weng, Chunhua, additional, Wiesner, Georgia L., additional, Wiley, Ken, additional, Peterson, Josh F., additional, Gordon, Adam, additional, Sobowale, Agboade, additional, Patel, Akshar, additional, Strong, Alanna, additional, Sherafati, Alborz, additional, Sherfati, Alborz, additional, Bick, Alex, additional, Chandel, Alka, additional, Rosenthal, Alyssa, additional, Khera, Amit, additional, Kontorovich, Amy, additional, Beck, Andrew, additional, Beck, Andy, additional, Espinoza, Angelica, additional, Lewis, Anna, additional, Prince, Anya, additional, Iverson, Ayuko, additional, Khales, Bahram Namjou, additional, Benoit, Barbara, additional, Hernan, Becca, additional, Kallman, Ben, additional, Kerman, Ben, additional, Shoemaker, Ben, additional, Satterfield, Benjamin, additional, Etheridge, Bethany, additional, Goff, Blake, additional, Freimuth, Bob, additional, Grundmeier, Bob, additional, Collier, Brenae, additional, Harnett, Brett, additional, Chang, Brian, additional, Piening, Brian, additional, Davis, Brittney, additional, Patterson, Candace, additional, Demetriou, Carmen, additional, Ta, Casey, additional, Hammack, Catherine, additional, Nelson, Catrina, additional, Gascoigne, Caytie, additional, Dorn, Chad, additional, Moretz, Chad, additional, Kachulis, Chris, additional, Hoell, Christie, additional, Cowles, Christine, additional, Lange, Christoph, additional, Prows, Cindy, additional, Brokamp, Cole, additional, Scherr, Courtney, additional, Gonzalez, Crystal, additional, Ramirez, Cynthia, additional, Shimbo, Daichi, additional, Roden, Dan, additional, Schaid, Daniel, additional, Kaufman, Dave, additional, Crosslin, David, additional, Kochan, David, additional, Singh, Davinder, additional, Abrams, Debbie, additional, Edwards, Digna Velez, additional, Morales, Eduardo, additional, Esplin, Edward, additional, Alipour, Ehsan, additional, Kenny, Eimear, additional, Rosenthal, Elisabeth, additional, Duvall, Eliza, additional, McNally, Elizabeth, additional, Bhoj, Elizabeth, additional, Cohn, Elizabeth, additional, Hibler, Elizabeth, additional, Karlson, Elizabeth, additional, Clayton, Ellen, additional, Chesnut, Emily, additional, DeFranco, Emily, additional, Gallagher, Emily, additional, Soper, Emily, additional, Perez, Emma, additional, Cash, Erin, additional, Berner, Eta, additional, Wang, Fei, additional, Wehbe, Firas, additional, Ricci, Francisco, additional, Shaibi, Gabriel, additional, Jarvik, Gail, additional, Hahn, George, additional, Wiesner, Georgia, additional, Belbin, Gillian, additional, Davogustto, Gio, additional, Nadkarni, Girish, additional, Qiu, Haijun, additional, Beasley, Hannah, additional, Liu, Hao, additional, Aungst, Heide, additional, Tiwari, Hemant, additional, Duckham, Hillary, additional, Thomas, Hope, additional, Kullo, Iftikhar, additional, Holm, Ingrid, additional, Allen, Isabelle, additional, Ionita-Laza, Iuliana, additional, Hellwege, Jacklyn, additional, Petrzelka, Jacob, additional, Odgis, Jacqueline, additional, Narula, Jahnavi, additional, Petrzelka, Jake, additional, Patel, Jalpa, additional, Cimino, James, additional, Meigs, James, additional, Snyder, James, additional, Olson, Janet, additional, Zahner, Janet, additional, Pennington, Jeff, additional, Pacheco, Jen, additional, Pacheco, Jennifer Allen, additional, Morse, Jennifer, additional, Corsmo, Jeremy, additional, Cimino, Jim, additional, Chen, Jingheng, additional, Fournier, Jocelyn, additional, Jackson, Jodell, additional, Glessner, Joe, additional, Pacyna, Joel, additional, Smith, Johanna, additional, Lynch, John, additional, Shelley, John, additional, Mosley, Jonathan, additional, Nestor, Jordan, additional, Smoller, Jordan, additional, Kannry, Joseph, additional, Sutton, Joseph, additional, Peterson, Josh, additional, Smith, Joshua, additional, Galasso, Julia, additional, Smith, Julia, additional, Wynn, Julia, additional, Gundelach, Justin, additional, Starren, Justin, additional, Choi, Karmel, additional, Mittendorf, Kate, additional, Anderson, Katherine, additional, Bonini, Katherine, additional, Leppig, Kathleen, additional, Muenzen, Kathleen, additional, Stuttgen, Kelsey, additional, Nguyen, Kenny, additional, Dufendach, Kevin, additional, Atkins, Kiley, additional, Sawicki, Konrad, additional, Norland, Kristjan, additional, Beskow, Laura, additional, Hsu, Li, additional, Tian, Lifeng, additional, Mahanta, Lisa, additional, Martin, Lisa, additional, Wang, Lisa, additional, Gomez, Lizbeth, additional, Thompson, Lorenzo, additional, Richter, Lucas, additional, Rasmussen, Luke, additional, Petukhova, Lynn, additional, O’Brien, Madison, additional, Harden, Maegan, additional, Fullerton, Malia, additional, Guindo, Marta, additional, Horike, Martha, additional, Abdalla, Marwah, additional, Hamed, Marwan, additional, Terry, Mary Beth, additional, Maradik, Mary, additional, Wyatt, Matt, additional, Davis, Matthew, additional, Lebo, Matthew, additional, Smith, Maureen, additional, Rosario, Maya del, additional, Behr, Meckenzie, additional, Roy-Puckelwartz, Meg, additional, Habrat, Mel, additional, Myers, Melanie, additional, Yetisgen, Meliha, additional, Iris, Merve, additional, DaSilva, Michael, additional, Preuss, Michael, additional, McGowan, Michelle, additional, Shi, Mingjian, additional, Perera, Minoli, additional, Thomas, Minta, additional, Elkind, Mitch, additional, Abbass, Mohammad, additional, Saadatagah, Mohammad, additional, Hess, Molly, additional, Maradik, Molly, additional, Vaitinadin, Nataraja “RJ”, additional, Vaitinadin, Nataraja, additional, Netherly, Neil, additional, Lennon, Niall, additional, Shang, Ning, additional, Limdi, Nita, additional, Forrest, Noah, additional, Romero, Noheli, additional, Robinson, Nora, additional, Abul-Husn, Noura, additional, Elsekaily, Omar, additional, Kovatch, Patricia, additional, Appelbaum, Paul, additional, Francaviglia, Paul, additional, O’Reilly, Paul, additional, Chandler, Paulette, additional, Caraballo, Pedro, additional, Tarczy-Hornoch, Peter, additional, Shum, Pierre, additional, Marathe, Priya, additional, Feng, Qiping, additional, Wells, Quinn, additional, Atchley, Rachel, additional, Narla, Radhika, additional, Barton, Rene, additional, Chisholm, Rex, additional, Sharp, Richard, additional, Peters, Riki, additional, Kukafka, Rita, additional, Freimuth, Robert, additional, Green, Robert, additional, Winter, Robert, additional, Mueller, Roger, additional, Loos, Ruth, additional, Irvin, Ryan, additional, Suckiel, Sabrina, additional, Hussain, Sajjad, additional, Sharba, Samer, additional, Aronson, Sandy, additional, Jones, Sarah, additional, Knerr, Sarah, additional, Nigbur, Scott, additional, Weiss, Scott, additional, Mooney, Sean, additional, Aufox, Sharon, additional, Nirenberg, Sharon, additional, Murphy, Shawn, additional, O’Byrne, Sheila, additional, Wang (Sam) Choi, Shing, additional, Aguilar, Sienna, additional, Bland, S.T., additional, Rodrigues, Stefanie, additional, Ledbetter, Stephanie, additional, Rutledge, Stephanie, additional, Booth, Stuart James, additional, Xian, Su, additional, Trinidad, Susan Brown, additional, Bakken, Suzanne, additional, Manolio, Teri, additional, Mersha, Tesfaye, additional, Chandereng, Thevaa, additional, Ge, Tian, additional, Edwards, Todd, additional, Kaszemacher, Tom, additional, Willis, Valerie, additional, Desai, Vemi, additional, Desai, Vimi, additional, Lorenzi, Virginia, additional, Gainer, Vivian, additional, Chung, Wendy, additional, Su, Wu-Chen, additional, Chang, Xiao, additional, Zhao, Yiqing, additional, Luo, Yuan, additional, and Shen, Yufeng, additional

Published
2023
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39. Exploring Risk Factors in Suicidal Ideation and Attempt Concept Cooccurrence Networks

Author

Krause, KJ, Shelley, John, Becker, Alex, and Walsh, Colin

Subjects
Articles
Abstract

Suicide is a significant and rising threat to public health. In the United States, 47,500 people died from suicide in 2019, a 10-year increase of 30%. Many researchers are interested in studying the risk factors associated with suicidal ideation and suicide attempt to help inform clinical screening, intervention, and prevention efforts. Many suicide risk factor analyses draw from clinical subdomains and quantify risk factors independently. While traditional modeling approaches might assume independence between risk factors, current suicide research suggests that the development of suicidal intent is a complex, multifactorial process. Thus, it may be beneficial to how suicide risk-factors interact with one another. In this study, we used network analysis to generate visual suicidality risk relationship diagrams. We extract medical concepts from free-text clinical notes and generate cooccurrence-based risk networks for suicidal ideation and suicide attempt. In addition, we generate a network of risk factors for suicidal ideation which evolves into a suicide attempt. Our networks were able to replicate existing risk factor findings and provide additional insight into the degree to which risk factors behave as independent morbidities or as interacting comorbidities with other risk factors. These results highlight potential avenues for risk factor analyses of complex outcomes using network analysis.

Published
2023

40. Shearing friction behaviour of synthetic polymers compared to a functionalized polysaccharide on biomimetic surfaces: models for the prediction of performance of eco-designed formulations

Author

Coscia, Benjamin J., primary, Shelley, John C., additional, Browning, Andrea R., additional, Sanders, Jeffrey M., additional, Chaudret, Robin, additional, Rozot, Roger, additional, Léonforte, Fabien, additional, Halls, Mathew D., additional, and Luengo, Gustavo S., additional

Published
2023
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45. Shearing Friction Behaviour of Synthetic Polymers Compared to a Functionalized Polysaccharide on Biomimetic Surfaces: Models for the Prediction of Performance of Eco-designed Formulations

Author

Coscia, Benjamin J., primary, Shelley, John C., additional, Browning, Andrea R., additional, Sanders, Jeffrey M., additional, Chaudret, Robin, additional, Rozot, Roger, additional, Léonforte, Fabien, additional, Halls, Mathew D., additional, and Luengo, Gustavo S., additional

Published
2022
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47. Abstract 1441: Genetic determinants of PSA levels improve prostate cancer screening

Author

Kachuri, Linda, primary, Graff, Rebecca E., additional, Berndt, Sonja I., additional, Machiela, Mitchell, additional, Freedman, Neal D., additional, Chanock, Stephen J., additional, Shelley, John P., additional, Schaffer, Kerry, additional, Mosley, Jonathan D., additional, Goodman, Phyllis J., additional, Till, Cathee, additional, Thompson, Ian, additional, Klein, Robert J., additional, Van Den Eeden, Stephen K., additional, Hoffmann, Thomas J., additional, and Witte, John S., additional

Published
2022
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50. Leveraging Genetic Determinants of Prostate-Specific Antigen Levels Towards Improving Prostate Cancer Screening

Author

Kachuri, Linda, primary, Hoffmann, Thomas J., additional, Jiang, Yu, additional, Berndt, Sonja I., additional, Shelley, John P., additional, Schaffer, Kerry, additional, Machiela, Mitchell J., additional, Freedman, Neal D., additional, Huang, Wen-Yi, additional, Li, Shengchao A., additional, Easterlin, Ryder, additional, Goodman, Phyllis J., additional, Till, Cathee, additional, Thompson, Ian, additional, Lilja, Hans, additional, Van Den Eeden, Stephen K., additional, Chanock, Stephen, additional, Haiman, Christopher A., additional, Conti, David V., additional, Klein, Robert J., additional, Mosley, Jonathan D., additional, Graff, Rebecca E., additional, and Witte, John S., additional

Published
2022
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