Medical Genetics Commons^™

Safety And Tolerability Of Online Adaptive High-Field Magnetic Resonance-Guided Radiotherapy, Jasmijn M Westerhoff, Lois A Daamen, John P Christodouleas, Erwin L A Blezer, Ananya Choudhury, Rosalyne L Westley, Beth A Erickson, Clifton D Fuller, Shaista Hafeez, Uulke A Van Der Heide, Martijn P W Intven, Anna M Kirby, Susan Lalondrelle, Bruce D Minsky, Stella Mook, Marlies E Nowee, Corrie A M Marijnen, Kristina M Orrling, Arjun Sahgal, Christopher J Schultz, Corinne Faivre-Finn, Robbert J H A Tersteeg, Alison C Tree, Chia-Lin Tseng, Tine Schytte, Dustin M Silk, Dave Eggert, Marco Luzzara, Jochem R N Van Der Voort Van Zyp, Helena M Verkooijen, William A Hall

Faculty, Staff and Student Publications

Importance: In 2018, the first online adaptive magnetic resonance (MR)-guided radiotherapy (MRgRT) system using a 1.5-T MR-equipped linear accelerator (1.5-T MR-Linac) was clinically introduced. This system enables online adaptive radiotherapy, in which the radiation plan is adapted to size and shape changes of targets at each treatment session based on daily MR-visualized anatomy.

Objective: To evaluate safety, tolerability, and technical feasibility of treatment with a 1.5-T MR-Linac, specifically focusing on the subset of patients treated with an online adaptive strategy (ie, the adapt-to-shape [ATS] approach).

Design, setting, and participants: This cohort study included adults with solid tumors treated with a …

Culturally Competent Education And Human Papillomavirus Self-Sampling Achieves Healthy People 2030 Cervical Screening Target Among Low-Income Non-Hispanic Black And Hispanic Women, Surendra S Shastri, Lorna H Mcneill, Sanjay Shete

Faculty, Staff and Student Publications

Purpose: Disparities in cervical cancer screening, incidence, and mortality exist in the United States. Cervical cancer incidence and mortality rates in Texas are 20% and 32% higher, respectively, than national averages. Within Texas, these rates are significantly higher among non-Hispanic (NH) Black and Hispanic women. Cervical cancer screening uptake is lower among NH Black and Hispanic women (72.9% and 75.9%, respectively) compared with White women (85.5%) in Texas.

Methods: During March-August 2023, we conducted a pilot study that offered culturally competent education and human papillomavirus (HPV) self-sampling kits to women in two public housing projects in Houston, TX, that have …

Fungi In Cancer, Jessica Galloway-Peña, Iliyan D Iliev, Florencia Mcallister

Faculty, Staff and Student Publications

Both the gut and the tumour microbiome are now established as crucial regulators of cancer phenotypes and have been implicated in cancer initiation, progression and therapy response. Although the role of bacteria in these processes is beginning to be unravelled, the relevance of fungi is only just emerging. In this Viewpoint, we asked experts to discuss the current knowledge on the mycobiome–cancer connection and share their opinion on how to best solve open questions.

Impact Of Revised International Staging System 2 Risk Stratification On Outcomes Of Patients With Multiple Myeloma Receiving Autologous Haematopoietic Stem Cell Transplantation, Kamal Alzahrani, Oren Pasvolsky, Zhongya Wang, Denái R Milton, Mark R Tanner, Qaiser Bashir, Samer Srour, Neeraj Saini, Paul Lin, Jeremy Ramdial, Yago Nieto, Hans C Lee, Krina K Patel, Elisabet E Manasanch, Partow Kebriaei, Sheeba K Thomas, Donna M Weber, Robert Z Orlowski, Elizabeth J Shpall, Richard Champlin, Muzaffar H Qazilbash

Faculty, Staff and Student Publications

The second revision of the International Staging System (R2-ISS) is a simple tool to risk-stratify newly diagnosed multiple myeloma (NDMM) patients. Here, we completed a retrospective analysis to evaluate the utility of R2-ISS in NDMM patients who underwent up-front autologous haematopoietic stem cell transplantation (auto-HCT). A total of 1291 patients were included, with a median age of 62 years (range 29-83). The distribution of R2-ISS stages was: 123 (10%) stage I, 471 (36%) stage II, 566 (44%) stage III and 131 (10%) stage IV. With a median follow-up of 42.2 months (range 0.3-181.0), the median PFS was 73.0, 65.2, 44.0 …

Impact Of Pretransplant Minimal Residual Disease In Patients With Multiple Myeloma And A Very Good Partial Response Or Better Receiving Autologous Hematopoietic Stem Cell Transplantation, Oren Pasvolsky, Sarah Pasyar, Roland L Bassett, Hina N Khan, Mark R Tanner, Qaiser Bashir, Samer Srour, Neeraj Saini, Paul Lin, Jeremy Ramdial, Yago Nieto, Hans C Lee, Krina K Patel, Partow Kebriaei, Sheeba K Thomas, Donna M Weber, Robert Z Orlowski, Elizabeth J Shpall, Richard E Champlin, Muzaffar H Qazilbash

Faculty, Staff and Student Publications

Background: The prognostic significance of minimal residual disease (MRD) status before autologous hematopoietic stem cell transplantation (autoHCT) in patients with multiple myeloma (MM) has not been clearly elucidated.

Methods: Retrospective single-center study of adult MM patients who achieved ≥very good partial response (VGPR) after induction therapy from 2015 to 2021 received upfront autoHCT and had available pretransplant MRD status by next-generation flow cytometry. The cohort was divided into pretransplant MRD-negative (MRDneg) and MRD-positive (MRDpos) groups.

Results: A total of 733 patients were included in our analysis; 425 were MRDneg and 308 MRDpos at autoHCT. In the MRDpos group, more patients …

Safety And Long-Term Survival Results Of The Addition Of Inotuzumab Ozogamicin To The Conditioning Regimen Of Allogeneic Stem Cell Transplantation: A Single-Center Phase 1,2 Trial, Issa F Khouri, Kamal Alzahrani, Hagop Kantarjian, Denái R Milton, Alison M Gulbis, Koji Sasaki, Nitin Jain, Nicholas J Short, Tapan Kadia, May Daher, Hind Rafei, Jin S Im, David Marin, Amanda L Olson, Uday Popat, Muzaffar Qazilbash, Jeremy Ramdial, Gabriela Rondon, Samer Srour, Partow Kebriaei, Elizabeth Shpall, Richard Champlin, Elias J Jabbour

Faculty, Staff and Student Publications

Here we report on the first prospective study evaluating the safety and long-term survival when an escalating dose of inotuzumab ozogamicin (INO) (0.6, 1.2, or 1.8 mg/m2 on day 13) was added to one alkylator-containing conditioning regimen in patients with relapsed CD22 (+) lymphoid malignancies who were candidates for hematopoietic stem cell transplantation (HSCT). Twenty-six patients were enrolled. Six (23%) of these patients entered the phase 1 study: four were treated at an INO dose of 0.6 mg/m2 and two at dose of 1.2 mg/m2. None of these patients experienced dose-limiting toxicities. The remaining 20 (77%) patients entered the phase …

Circulating Immune Signatures In Chronic Pancreatitis With And Without Preceding Acute Pancreatitis: A Pilot Study, Rasmus Hagn-Meincke, Dhiraj Yadav, Dana K Andersen, Santhi Swaroop Vege, Evan L Fogel, Jose Serrano, Melena D Bellin, Mark D Topazian, Darwin L Conwell, Liang Li, Stephen K Van Den Eeden, Asbjørn M Drewes, Stephen J Pandol, Chris E Forsmark, William E Fisher, Phil A Hart, Søren S Olesen, Walter G Park, Consortium For The Study Of Chronic Pancreatitis, Diabetes, And Pancreatic Cancer (Cpdpc)

Faculty, Staff and Student Publications

Objective: To investigate profiles of circulating immune signatures in healthy controls and chronic pancreatitis patients (CP) with and without a preceding history of acute pancreatitis (AP).

Methods: We performed a phase 1, cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies (PROCEED) study. All samples were collected during a clinically quiescent phase. CP subjects were categorized into two subgroups based on preceding episode(s) of AP. Healthy controls were included for comparison. Blinded samples were analyzed using an 80-plex Luminex assay of cytokines, chemokines, and adhesion molecules. Group and pairwise comparisons …

Genome-Wide Analysis In Over 1 Million Individuals Of European Ancestry Yields Improved Polygenic Risk Scores For Blood Pressure Traits, Jacob M Keaton, Zoha Kamali, Tian Xie, Ahmad Vaez, Ariel Williams, Slavina B Goleva, Alireza Ani, Evangelos Evangelou, Jacklyn N Hellwege, Loic Yengo, William J Young, Matthew Traylor, Ayush Giri, Zhili Zheng, Jian Zeng, Daniel I Chasman, Andrew P Morris, Mark J Caulfield, Shih-Jen Hwang, Jaspal S Kooner, David Conen, John R Attia, Alanna C Morrison, Ruth J F Loos, Kati Kristiansson, Reinhold Schmidt, Andrew A Hicks, Peter P Pramstaller, Christopher P Nelson, Nilesh J Samani, Lorenz Risch, Ulf Gyllensten, Olle Melander, Harriette Riese, James F Wilson, Harry Campbell, Stephen S Rich, Bruce M Psaty, Yingchang Lu, Jerome I Rotter, Xiuqing Guo, Kenneth M Rice, Peter Vollenweider, Johan Sundström, Claudia Langenberg, Martin D Tobin, Vilmantas Giedraitis, Jian'an Luan, Jaakko Tuomilehto, Zoltan Kutalik, Samuli Ripatti, Veikko Salomaa, Giorgia Girotto, Stella Trompet, J Wouter Jukema, Pim Van Der Harst, Paul M Ridker, Franco Giulianini, Veronique Vitart, Anuj Goel, Hugh Watkins, Sarah E Harris, Ian J Deary, Peter J Van Der Most, Albertine J Oldehinkel, Bernard D Keavney, Caroline Hayward, Archie Campbell, Michael Boehnke, Laura J Scott, Thibaud Boutin, Chrysovalanto Mamasoula, Marjo-Riitta Järvelin, Annette Peters, Christian Gieger, Edward G Lakatta, Francesco Cucca, Jennie Hui, Paul Knekt, Stefan Enroth, Martin H De Borst, Ozren Polašek, Maria Pina Concas, Eulalia Catamo, Massimiliano Cocca, Ruifang Li-Gao, Edith Hofer, Helena Schmidt, Beatrice Spedicati, Melanie Waldenberger, David P Strachan, Maris Laan, Alexander Teumer, Marcus Dörr, Vilmundur Gudnason, James P Cook, Daniela Ruggiero, Ivana Kolcic, Eric Boerwinkle, Michela Traglia, Terho Lehtimäki, Olli T Raitakari, Andrew D Johnson, Christopher Newton-Cheh, Morris J Brown, Anna F Dominiczak, Peter J Sever, Neil Poulter, John C Chambers, Roberto Elosua, David Siscovick, Tõnu Esko, Andres Metspalu, Rona J Strawbridge, Markku Laakso, Anders Hamsten, Jouke-Jan Hottenga, Eco De Geus, Andrew D Morris, Colin N A Palmer, Ilja M Nolte, Yuri Milaneschi, Jonathan Marten, Alan Wright, Eleftheria Zeggini, Joanna M M Howson, Christopher J O'Donnell, Tim Spector, Mike A Nalls, Eleanor M Simonsick, Yongmei Liu, Cornelia M Van Duijn, Adam S Butterworth, John N Danesh, Cristina Menni, Nicholas J Wareham, Kay-Tee Khaw, Yan V Sun, Peter W F Wilson, Kelly Cho, Peter M Visscher, Joshua C Denny, Million Veteran Program, Lifelines Cohort Study, Charge Consortium, Icbp Consortium, Daniel Levy, Todd L Edwards, Patricia B Munroe, Harold Snieder, Helen R Warren

Faculty, Staff and Student Publications

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

A West African Ancestry-Associated Snp On 8q24 Predicts A Positive Biopsy In African American Men With Suspected Prostate Cancer Following Psa Screening, Jian Gu, Lisly Chery, Graciela M Nogueras González, Chad Huff, Sara Strom, Jeffrey A Jones, Donald P Griffith, Steven E Canfield, Xuemei Wang, Xuelin Huang, Pamela Roberson, Qing H Meng, Patricia Troncoso, Michael Ittmann, Michael Covinsky, Michael Scheurer, Margarita Irizarry Ramirez, Curtis A Pettaway

Faculty, Staff and Student Publications

BACKGROUND: African American (AA) men have the highest incidence and mortality rates of prostate cancer (PCa) among all racial groups in the United States. While race is a social construct, for AA men, this overlaps with west African ancestry. Many of the PCa susceptibility variants exhibit distinct allele frequencies and risk estimates across different races and contribute substantially to the large disparities of PCa incidence among races. We previously reported that a single-nucleotide polymorphism (SNP) in 8q24, rs7824364, was strongly associated with west African ancestry and increased risks of PCa in both AA and Puerto Rican men. In this study, …

Fatigue Impacts Quality Of Life In People With Spinocerebellar Ataxias, Ruo-Yah Lai, Christian Rummey, Christian J Amlang, Chi-Ying R Lin, Tiffany X Chen, Susan Perlman, George Wilmot, Christopher M Gomez, Jeremy D Schmahmann, Henry Paulson, Sarah H Ying, Chiadi U Onyike, Theresa A Zesiewicz, Khalaf O Bushara, Michael D Geschwind, Karla P Figueroa, Stefan M Pulst, Sub H Subramony, Matthew R Burns, Puneet Opal, Antoine Duquette, Tetsuo Ashizawa, Ali G Hamedani, Marie Y Davis, Sharan R Srinivasan, Lauren R Moore, Vikram G Shakkottai, Liana S Rosenthal, Sheng-Han Kuo

Faculty, Staff and Students Publications

Background: Fatigue is a prevalent and debilitating symptom in neurological disorders, including spinocerebellar ataxias (SCAs). However, the risk factors of fatigue in the SCAs as well as its impact have not been well investigated.

Objectives: To study the prevalence of fatigue in SCAs, the factors contributing to fatigue, and the influence of fatigue on quality of life.

Methods: Fatigue was assessed in 418 participants with SCA1, SCA2, SCA3, and SCA6 from the Clinical Research Consortium for the Study of Cerebellar Ataxia using the Fatigue Severity Scale. We conducted multi-variable linear regression models to examine the factors contributing to fatigue as …

Proton Therapy Mediates Dose Reductions To Brain Structures Associated With Cognition In Children With Medulloblastoma, Julianna Sienna, Lisa S Kahalley, Donald Mabbott, David Grosshans, Anna Theresa Santiago, Arnold Dela Cruz Paulino, Thomas E Merchant, Gohar S Manzar, Hitesh Dama, David C Hodgson, Murali Chintagumpala, Mehmet Fatih Okcu, William E Whitehead, Normand Laperriere, Vijay Ramaswamy, Ute Bartels, Uri Tabori, Julie M Bennett, Anirban Das, Tim Craig, Derek S Tsang

Faculty, Staff and Student Publications

Purpose: Emerging evidence suggests proton radiation therapy may offer cognitive sparing advantages over photon radiation therapy, yet dosimetry has not been compared previously. The purpose of this study was to examine dosimetric correlates of cognitive outcomes in children with medulloblastoma treated with proton versus photon radiation therapy.

Methods and materials: In this retrospective, bi-institutional study, dosimetric and cognitive data from 75 patients (39 photon and 36 proton) were analyzed. Doses to brain structures were compared between treatment modalities. Linear mixed-effects models were used to create models of global IQ and cognitive domain scores.

Results: The mean dose and dose to …

Targeted Accurate Rna Consensus Sequencing (Tarc-Seq) Reveals Mechanisms Of Replication Error Affecting Sars-Cov-2 Divergence, Catherine C Bradley, Chen Wang, Alasdair J E Gordon, Alice X Wen, Pamela N Luna, Matthew B Cooke, Brendan F Kohrn, Scott R Kennedy, Vasanthi Avadhanula, Pedro A Piedra, Olivier Lichtarge, Chad A Shaw, Shannon E Ronca, Christophe Herman

Duncan NRI Faculty and Staff Publications

RNA viruses, like SARS-CoV-2, depend on their RNA-dependent RNA polymerases (RdRp) for replication, which is error-prone. Monitoring replication errors is crucial for understanding the virus’s evolution. Current methods lack the precision to detect rare de novo RNA mutations, particularly in low-input samples such as those from patients. Here, we introduce a new targeted Accurate RNA Consensus sequencing method (tARC-seq) to accurately determine the mutation frequency and types in SARS-CoV-2, both in cell culture and clinical samples. Our findings show an average of 2.68×10−5 new errors per cycle with a C>T bias that cannot be solely attributed to APOBEC …

Patient Interest In And Clinician Reservations On Polygenic Embryo Screening: A Qualitative Study Of Stakeholder Perspectives, D Barlevy, I Cenolli, T Campbell, R Furrer, M Mukherjee, K Kostick-Quenet, S Carmi, T Lencz, G Lázaro-Muñoz, S Pereira

Center for Medical Ethics and Health Policy Staff Publications

Purpose: We explored and compared perspectives of reproductive endocrinology and infertility specialists (REIs) and in vitro fertilization (IVF) patients regarding polygenic embryo screening (PES), a new type of preimplantation screening that estimates the genetic chances of developing polygenic conditions and traits in the future.

Methods: Qualitative thematic analysis of semi-structured interviews with US-based REIs and IVF patients.

Results: Clinicians and patients often held favorable views of screening embryos for physical or psychiatric conditions, though clinicians tended to temper their positive attitudes with specific caveats. Clinicians also expressed negative views about screening embryos for traits more frequently than patients, who generally …

Ethical Concerns For Remote Computer Perception In Cardiology: New Stages For Digital Health Technologies, Artificial Intelligence, And Machine Learning, Kristin Kostick-Quenet, Jerry Estep, Jennifer S Blumenthal-Barby

Center for Medical Ethics and Health Policy Staff Publications

No abstract provided.

Public Attitudes, Interests, And Concerns Regarding Polygenic Embryo Screening, Rémy A Furrer, Dorit Barlevy, Stacey Pereira, Shai Carmi, Todd Lencz, Gabriel Lázaro-Muñoz

Center for Medical Ethics and Health Policy Staff Publications

Importance: Polygenic embryo screening (PES) is a novel technology that estimates the likelihood of developing future conditions (eg, diabetes or depression) and traits (eg, height or cognitive ability) in human embryos, with the goal of selecting which embryos to use. Given its commercial availability and concerns raised by researchers, clinicians, bioethicists, and professional organizations, it is essential to inform key stakeholders and relevant policymakers about the public's perspectives on this technology.

Objective: To survey US adults to examine general attitudes, interests, and concerns regarding PES use.

Design, setting, and participants: For this survey study, data were collected from 1 stratified …

Development Of A Weight-Band Dosing Approach For Vosoritide In Children With Achondroplasia Using A Population Pharmacokinetic Model, Yulan Qi, Ming Liang Chan, Diane R Mould, Kevin Larimore, Elena Fisheleva, Anu Cherukuri, Jonathan Day, Ravi Savarirayan, Melita Irving, Carlos A Bacino, Julie Hoover-Fong, Keiichi Ozono, Klaus Mohnike, William R Wilcox, Michael B Bober, Joshua Henshaw

Faculty, Staff and Students Publications

BACKGROUND AND OBJECTIVE: Vosoritide is a recently approved therapy for achondroplasia, the most common form of disproportionate short stature, that has been shown to be well tolerated and effective in increasing linear growth. This study aimed to develop a population pharmacokinetic (PPK) model to characterize pharmacokinetics (PK) of vosoritide and establish a weight-band dosing regimen.

METHODS: A PPK model was developed using data from five clinical trials in children with achondroplasia (aged 0.95-15 years) who received daily per-kg doses of vosoritide. The model was used to simulate expected exposures in children with a refined weight-band dosing regimen. Simulated exposure was …

Genome-Wide Association Analyses Identify 95 Risk Loci And Provide Insights Into The Neurobiology Of Post-Traumatic Stress Disorder, Caroline M Nievergelt, Adam X Maihofer, Elizabeth G Atkinson, Chia-Yen Chen, Karmel W Choi, Jonathan R I Coleman, Nikolaos P Daskalakis, Laramie E Duncan, Renato Polimanti, Cindy Aaronson, Ananda B Amstadter, Soren B Andersen, Ole A Andreassen, Paul A Arbisi, Allison E Ashley-Koch, S Bryn Austin, Esmina Avdibegoviç, Dragan Babić, Silviu-Alin Bacanu, Dewleen G Baker, Anthony Batzler, Jean C Beckham, Sintia Belangero, Corina Benjet, Carisa Bergner, Linda M Bierer, Joanna M Biernacka, Laura J Bierut, Jonathan I Bisson, Marco P Boks, Elizabeth A Bolger, Amber Brandolino, Gerome Breen, Rodrigo Affonseca Bressan, Richard A Bryant, Angela C Bustamante, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Anders D Børglum, Sigrid Børte, Leah Cahn, Joseph R Calabrese, Jose Miguel Caldas-De-Almeida, Chris Chatzinakos, Sheraz Cheema, Sean A P Clouston, Lucía Colodro-Conde, Brandon J Coombes, Carlos S Cruz-Fuentes, Anders M Dale, Shareefa Dalvie, Lea K Davis, Jürgen Deckert, Douglas L Delahanty, Michelle F Dennis, Frank Desarnaud, Christopher P Dipietro, Seth G Disner, Anna R Docherty, Katharina Domschke, Grete Dyb, Alma Džubur Kulenović, Howard J Edenberg, Alexandra Evans, Chiara Fabbri, Negar Fani, Lindsay A Farrer, Adriana Feder, Norah C Feeny, Janine D Flory, David Forbes, Carol E Franz, Sandro Galea, Melanie E Garrett, Bizu Gelaye, Joel Gelernter, Elbert Geuze, Charles F Gillespie, Slavina B Goleva, Scott D Gordon, Aferdita Goçi, Lana Ruvolo Grasser, Camila Guindalini, Magali Haas, Saskia Hagenaars, Michael A Hauser, Andrew C Heath, Sian M J Hemmings, Victor Hesselbrock, Ian B Hickie, Kelleigh Hogan, David Michael Hougaard, Hailiang Huang, Laura M Huckins, Kristian Hveem, Miro Jakovljević, Arash Javanbakht, Gregory D Jenkins, Jessica Johnson, Ian Jones, Tanja Jovanovic, Karen-Inge Karstoft, Milissa L Kaufman, James L Kennedy, Ronald C Kessler, Alaptagin Khan, Nathan A Kimbrel, Anthony P King, Nastassja Koen, Roman Kotov, Henry R Kranzler, Kristi Krebs, William S Kremen, Pei-Fen Kuan, Bruce R Lawford, Lauren A M Lebois, Kelli Lehto, Daniel F Levey, Catrin Lewis, Israel Liberzon, Sarah D Linnstaedt, Mark W Logue, Adriana Lori, Yi Lu, Benjamin J Luft, Michelle K Lupton, Jurjen J Luykx, Iouri Makotkine, Jessica L Maples-Keller, Shelby Marchese, Charles Marmar, Nicholas G Martin, Gabriela A Martínez-Levy, Kerrie Mcaloney, Alexander Mcfarlane, Katie A Mclaughlin, Samuel A Mclean, Sarah E Medland, Divya Mehta, Jacquelyn Meyers, Vasiliki Michopoulos, Elizabeth A Mikita, Lili Milani, William Milberg, Mark W Miller, Rajendra A Morey, Charles Phillip Morris, Ole Mors, Preben Bo Mortensen, Mary S Mufford, Elliot C Nelson, Merete Nordentoft, Sonya B Norman, Nicole R Nugent, Meaghan O'Donnell, Holly K Orcutt, Pedro M Pan, Matthew S Panizzon, Gita A Pathak, Edward S Peters, Alan L Peterson, Matthew Peverill, Robert H Pietrzak, Melissa A Polusny, Bernice Porjesz, Abigail Powers, Xue-Jun Qin, Andrew Ratanatharathorn, Victoria B Risbrough, Andrea L Roberts, Alex O Rothbaum, Barbara O Rothbaum, Peter Roy-Byrne, Kenneth J Ruggiero, Ariane Rung, Heiko Runz, Bart P F Rutten, Stacey Saenz De Viteri, Giovanni Abrahão Salum, Laura Sampson, Sixto E Sanchez, Marcos Santoro, Carina Seah, Soraya Seedat, Julia S Seng, Andrey Shabalin, Christina M Sheerin, Derrick Silove, Alicia K Smith, Jordan W Smoller, Scott R Sponheim, Dan J Stein, Synne Stensland, Jennifer S Stevens, Jennifer A Sumner, Martin H Teicher, Wesley K Thompson, Arun K Tiwari, Edward Trapido, Monica Uddin, Robert J Ursano, Unnur Valdimarsdóttir, Miranda Van Hooff, Eric Vermetten, Christiaan H Vinkers, Joanne Voisey, Yunpeng Wang, Zhewu Wang, Monika Waszczuk, Heike Weber, Frank R Wendt, Thomas Werge, Michelle A Williams, Douglas E Williamson, Bendik S Winsvold, Sherry Winternitz, Christiane Wolf, Erika J Wolf, Yan Xia, Ying Xiong, Rachel Yehuda, Keith A Young, Ross Mcd Young, Clement C Zai, Gwyneth C Zai, Mark Zervas, Hongyu Zhao, Lori A Zoellner, John-Anker Zwart, Terri Deroon-Cassini, Sanne J H Van Rooij, Leigh L Van Den Heuvel, Murray B Stein, Kerry J Ressler, Karestan C Koenen

Faculty, Staff and Students Publications

Post-traumatic 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 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), …

A Phenome-Wide Association And Mendelian Randomisation Study Of Alcohol Use Variants In A Diverse Cohort Comprising Over 3 Million Individuals, Mariela V Jennings, José Jaime Martínez-Magaña, Natasia S Courchesne-Krak, Renata B Cupertino, Laura Vilar-Ribó, Sevim B Bianchi, Alexander S Hatoum, Elizabeth G Atkinson, Paola Giusti-Rodriguez, Janitza L Montalvo-Ortiz, Joel Gelernter, María Soler Artigas, Sarah L Elson, Howard J Edenberg, Pierre Fontanillas, Abraham A Palmer, Sandra Sanchez-Roige

Faculty, Staff and Students Publications

BACKGROUND: Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes.

METHODS: We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e.g., substance-use, mental health, sleep, immune, cardiovascular, metabolic) from a diverse 23andMe cohort, including European (N ≤ 2,619,939), Latin American (N ≤ 446,646) and African …

Consensus Guidelines For The Diagnosis And Management Of Succinic Semialdehyde Dehydrogenase Deficiency, Itay Tokatly Latzer, Mariarita Bertoldi, Nenad Blau, Melissa L Dibacco, Sarah H Elsea, Àngels García-Cazorla, K Michael Gibson, Andrea L Gropman, Ellen Hanson, Carolyn Hoffman, Kathrin Jeltsch, Natalia Juliá-Palacios, Ina Knerr, Henry H C Lee, Patrizia Malaspina, Alice Mcconnell, Thomas Opladen, Mari Oppebøen, Alexander Rotenberg, Mark Walterfang, Lee Wang-Tso, Ron A Wevers, Jean-Baptiste Roullet, Phillip L Pearl

Faculty, Staff and Students Publications

Succinic semialdehyde dehydrogenase deficiency (SSADHD) (OMIM #271980) is a rare autosomal recessive metabolic disorder caused by pathogenic variants of ALDH5A1. Deficiency of SSADH results in accumulation of γ-aminobutyric acid (GABA) and other GABA-related metabolites. The clinical phenotype of SSADHD includes a broad spectrum of non-pathognomonic symptoms such as cognitive disabilities, communication and language deficits, movement disorders, epilepsy, sleep disturbances, attention problems, anxiety, and obsessive-compulsive traits. Current treatment options for SSADHD remain supportive, but there are ongoing attempts to develop targeted genetic therapies. This study aimed to create consensus guidelines for the diagnosis and management of SSADHD. Thirty relevant statements were …

Financial Hardship And Neighborhood Socioeconomic Disadvantage In Long-Term Childhood Cancer Survivors, Alex J Fauer, Weiyu Qiu, I-Chan Huang, Patricia A Ganz, Jacqueline N Casillas, K Robin Yabroff, Gregory T Armstrong, Wendy Leisenring, Rebecca Howell, Carrie R Howell, Anne C Kirchhoff, Yutaka Yasui, Paul C Nathan

Faculty, Staff and Student Publications

Background: Long-term survivors of childhood cancer face elevated risk for financial hardship. We evaluate whether childhood cancer survivors live in areas of greater deprivation and the association with self-reported financial hardships.

Methods: We performed a cross-sectional analysis of data from the Childhood Cancer Survivor Study between 1970 and 1999 and self-reported financial information from 2017 to 2019. We measured neighborhood deprivation with the Area Deprivation Index (ADI) based on current zip code. Financial hardship was measured with validated surveys that captured behavioral, material and financial sacrifice, and psychological hardship. Bivariate analyses described neighborhood differences between survivors and siblings. Generalized linear …

Core Planar Cell Polarity Genes Vangl1 And Vangl2 In Predisposition To Congenital Vertebral Malformations, Xin Feng, Yongyu Ye, Jianan Zhang, Yuanqiang Zhang, Sen Zhao, Judith C W Mak, Nao Otomo, Zhengye Zhao, Yuchen Niu, Yoshiro Yonezawa, Guozhuang Li, Mao Lin, Xiaoxin Li, Prudence Wing Hang Cheung, Kexin Xu, Kazuki Takeda, Shengru Wang, Junjie Xie, Toshiaki Kotani, Vanessa N T Choi, You-Qiang Song, Yang Yang, Keith Dip Kei Luk, Kin Shing Lee, Ziquan Li, Pik Shan Li, Connie Y H Leung, Xiaochen Lin, Xiaolu Wang, Guixing Qiu, Disco (Deciphering Disorders Involving Scoliosis And Comorbidities) Study Group, Kota Watanabe, Japanese Early Onset Scoliosis Research Group, Zhihong Wu, Jennifer E Posey, Shiro Ikegawa, James R Lupski, Jason Pui Yin Cheung, Terry Jianguo Zhang, Bo Gao, Nan Wu

Faculty, Staff and Students Publications

Congenital scoliosis (CS) is the most common congenital spinal disorder caused by congenital vertebral malformations (CVMs), influenced by genetic and environmental factors and exhibiting diverse clinical presentations. Here, we identified the critical roles of Vangl1 and Vangl2, two core components in the Wnt/planar cell polarity (Wnt/PCP) signaling pathway, in vertebral development and in predisposition to CVMs in CS patients. We found that in Vangl mutant mouse models, the CVMs present in a Vangl gene dose- and gestational hypoxia-dependent manner. Our studies reveal a complex etiology of CS and its association with Wnt/PCP signaling.

Critical Assessment Of Variant Prioritization Methods For Rare Disease Diagnosis Within The Rare Genomes Project, Sarah L Stenton, Melanie C O'Leary, Gabrielle Lemire, Grace E Vannoy, Stephanie Ditroia, Vijay S Ganesh, Emily Groopman, Emily O'Heir, Brian Mangilog, Ikeoluwa Osei-Owusu, Lynn S Pais, Jillian Serrano, Moriel Singer-Berk, Ben Weisburd, Michael W Wilson, Christina Austin-Tse, Marwa Abdelhakim, Azza Althagafi, Giulia Babbi, Riccardo Bellazzi, Samuele Bovo, Maria Giulia Carta, Rita Casadio, Pieter-Jan Coenen, Federica De Paoli, Matteo Floris, Manavalan Gajapathy, Robert Hoehndorf, Julius O B Jacobsen, Thomas Joseph, Akash Kamandula, Panagiotis Katsonis, Cyrielle Kint, Olivier Lichtarge, Ivan Limongelli, Yulan Lu, Paolo Magni, Tarun Karthik Kumar Mamidi, Pier Luigi Martelli, Marta Mulargia, Giovanna Nicora, Keith Nykamp, Vikas Pejaver, Yisu Peng, Thi Hong Cam Pham, Maurizio S Podda, Aditya Rao, Ettore Rizzo, Vangala G Saipradeep, Castrense Savojardo, Peter Schols, Yang Shen, Naveen Sivadasan, Damian Smedley, Dorian Soru, Rajgopal Srinivasan, Yuanfei Sun, Uma Sunderam, Wuwei Tan, Naina Tiwari, Xiao Wang, Yaqiong Wang, Amanda Williams, Elizabeth A Worthey, Rujie Yin, Yuning You, Daniel Zeiberg, Susanna Zucca, Constantina Bakolitsa, Steven E Brenner, Stephanie M Fullerton, Predrag Radivojac, Heidi L Rehm, Anne O'Donnell-Luria

Faculty, Staff and Students Publications

BACKGROUND: A major obstacle faced by families with rare diseases is obtaining a genetic diagnosis. The average "diagnostic odyssey" lasts over five years and causal variants are identified in under 50%, even when capturing variants genome-wide. To aid in the interpretation and prioritization of the vast number of variants detected, computational methods are proliferating. Knowing which tools are most effective remains unclear. To evaluate the performance of computational methods, and to encourage innovation in method development, we designed a Critical Assessment of Genome Interpretation (CAGI) community challenge to place variant prioritization models head-to-head in a real-life clinical diagnostic setting.

METHODS: …

Angiotensin-Converting-Enzyme Inhibitors And Angiotensin Receptor Blockers For Preventing The Progression Of Diabetic Kidney Disease, Patrizia Natale, Suetonia C Palmer, Sankar D Navaneethan, Jonathan C Craig, Giovanni Fm Strippoli

Faculty, Staff and Students Publications

Background: Guidelines suggest that adults with diabetes and kidney disease receive treatment with angiotensin-converting-enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). This is an update of a Cochrane review published in 2006.

Objectives: We compared the efficacy and safety of ACEi and ARB therapy (either as monotherapy or in combination) on cardiovascular and kidney outcomes in adults with diabetes and kidney disease.

Search methods: We searched the Cochrane Kidney and Transplants Register of Studies to 17 March 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of …

Evolution Of Chromosome-Arm Aberrations In Breast Cancer Through Genetic Network Rewiring, Elena Kuzmin, Toby M Baker, Tom Lesluyes, Jean Monlong, Kento T Abe, Paula P Coelho, Michael Schwartz, Joseph Del Corpo, Dongmei Zou, Genevieve Morin, Alain Pacis, Yang Yang, Constanza Martinez, Jarrett Barber, Hellen Kuasne, Rui Li, Mathieu Bourgey, Anne-Marie Fortier, Peter G Davison, Atilla Omeroglu, Marie-Christine Guiot, Quaid Morris, Claudia L Kleinman, Sidong Huang, Anne-Claude Gingras, Jiannis Ragoussis, Guillaume Bourque, Peter Van Loo, Morag Park

Faculty, Staff and Student Publications

The basal breast cancer subtype is enriched for triple-negative breast cancer (TNBC) and displays consistent large chromosomal deletions. Here, we characterize evolution and maintenance of chromosome 4p (chr4p) loss in basal breast cancer. Analysis of The Cancer Genome Atlas data shows recurrent deletion of chr4p in basal breast cancer. Phylogenetic analysis of a panel of 23 primary tumor/patient-derived xenograft basal breast cancers reveals early evolution of chr4p deletion. Mechanistically we show that chr4p loss is associated with enhanced proliferation. Gene function studies identify an unknown gene, C4orf19, within chr4p, which suppresses proliferation when overexpressed-a member of the PDCD10-GCKIII kinase module …

Six-Year Follow-Up And Subgroup Analyses Of A Phase 2 Trial Of Venetoclax For Del(17p) Chronic Lymphocytic Leukemia, Stephan Stilgenbauer, Eugen Tausch, Andrew W Roberts, Matthew S Davids, Barbara Eichhorst, Michael Hallek, Peter Hillmen, Christof Schneider, Johannes Schetelig, Sebastian Böttcher, Arnon P Kater, Yanwen Jiang, Michelle Boyer, Relja Popovic, Majd T Ghanim, Michael Moran, Wendy J Sinai, Xifeng Wang, Nabanita Mukherjee, Brenda Chyla, William G Wierda, John F Seymour

Faculty, Staff and Student Publications

Chromosome 17p deletion (del[17p]) is associated with poor prognosis in patients with chronic lymphocytic leukemia (CLL). Venetoclax is approved for treatment of previously untreated and relapsed/refractory (R/R) CLL, including patients with del(17p), based on the open-label, multicenter, phase 2 M13-982 trial (NCT01889186). Here, we detail the 6-year follow-up analysis for M13-982. A total of 158 patients with previously untreated (n = 5) or R/R (n = 153) del(17p) CLL received 400 mg venetoclax daily after initial ramp-up until progressive disease. After a median follow-up of 70 months, the best objective response rate (ORR) was 77% (21% complete remission …

Human Dna Polymerase Θ Does Not Harbor Intrinsic Nuclease Activity, Denisse Carvajal-Maldonado, Karl Zahn, Ryan Jensen, Richard D Wood, Sylvie Doublié

Faculty, Staff and Student Publications

No abstract provided.

Fourteen-Day Vonoprazan-Based Bismuth Quadruple Therapy For H Pylori Eradication In An Area With High Clarithromycin And Levofloxacin Resistance: A Prospective Randomized Study (Vq-Hp Trial), Nuttapat Tungtrongchitr, Phubordee Bongkotvirawan, Sarita Ratana-Amornpin, Sith Siramolpiwat, Thanee Eiamsitrakoon, Pornpen Gamnarai, Arti Wongcha-Um, Yoshio Yamaoka, Kammal Kumar Pawa, Ratha-Korn Vilaichone

Faculty, Staff and Students Publications

Potassium-competitive acid blockers (P-CABs) provide potent acid inhibition, yet studies on P-CAB-based quadruple therapy for H. pylori eradication are limited. We theorized that integrating bismuth subsalicylate into a quadruple therapy regimen could enhance eradication rates. However, data on the efficacy of vonoprazan bismuth quadruple therapy are notably scarce. Therefore, the aim of this study was to evaluate the efficacy of vonoprazan-based bismuth quadruple therapy in areas with high clarithromycin and levofloxacin resistance. This was a prospective, single-center, randomized trial conducted to compare the efficacy of 7-day and 14-day vonoprazan-based bismuth quadruple therapy for H. pylori eradication between June 1, 2021, …

Cdk8/Cdk19 Promotes Mitochondrial Fission Through Drp1 Phosphorylation And Can Phenotypically Suppress Pink1 Deficiency In Drosophila, Jenny Zhe Liao, Hyung-Lok Chung, Claire Shih, Kenneth Kin Lam Wong, Debdeep Dutta, Zelha Nil, Catherine Grace Burns, Oguz Kanca, Ye-Jin Park, Zhongyuan Zuo, Paul C Marcogliese, Katherine Sew, Hugo J Bellen, Esther M Verheyen

Faculty, Staff and Students Publications

Cdk8 in Drosophila is the orthologue of vertebrate CDK8 and CDK19. These proteins have been shown to modulate transcriptional control by RNA polymerase II. We found that neuronal loss of Cdk8 severely reduces fly lifespan and causes bang sensitivity. Remarkably, these defects can be rescued by expression of human CDK19, found in the cytoplasm of neurons, suggesting a non-nuclear function of CDK19/Cdk8. Here we show that Cdk8 plays a critical role in the cytoplasm, with its loss causing elongated mitochondria in both muscles and neurons. We find that endogenous GFP-tagged Cdk8 can be found in both the cytoplasm and nucleus. …

Somatic Mutations Of Esophageal Adenocarcinoma: A Comparison Between Black And White Patients, Hyeyeun Lim, Marie-Claude Gingras, Jing Zhao, Jinyoung Byun, Patricia D Castro, Spiridon Tsavachidis, Jianhong Hu, Harshavardhan Doddapaneni, Yi Han, Donna M Muzny, Richard A Gibbs, Christopher I Amos, Aaron P Thrift

Faculty, Staff and Students Publications

Esophageal adenocarcinoma is the most common histological subtype of esophageal cancer in Western countries and shows poor prognosis with rapid growth. EAC is characterized by a strong male predominance and racial disparity. EAC is up to fivefold more common among Whites than Blacks, yet Black patients with EAC have poorer survival rates. The racial disparity remains largely unknown, and there is limited knowledge of mutations in EAC regarding racial disparities. We used whole-exome sequencing to show somatic mutation profiles derived from tumor samples from 18 EAC male patients. We identified three molecular subgroups based on the pre-defined esophageal cancer-specific mutational …

Revolutionizing Diabetic Foot Ulcer Care: The Senotherapeutic Approach, Guiqin Zhang, Priyadarshani Nadeeshika Samarawickrama, Li Gui, Yuan Ma, Mei Cao, Hong Zhu, Wei Li, Honglin Yang, Kecheng Li, Yang Yang, Enfang Zhu, Wen Li, Yonghan He

Faculty, Staff and Student Publications

Diabetic foot ulcers (DFUs) are a prevalent and profoundly debilitating complication that afflicts individuals with diabetes mellitus (DM). These ulcers are associated with substantial morbidity, recurrence rates, disability, and mortality, imposing substantial economic, psychological, and medical burdens. Timely detection and intervention can mitigate the morbidity and disparities linked to DFU. Nevertheless, current therapeutic approaches for DFU continue to grapple with multifaceted limitations. A growing body of evidence emphasizes the crucial role of cellular senescence in the pathogenesis of chronic wounds. Interventions that try to delay cellular senescence, eliminate senescent cells (SnCs), or suppress the senescence-associated secretory phenotype (SASP) have shown …