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1. A missense variant in human perilipin 2 (PLIN2 Ser251Pro) reduces hepatic steatosis in mice

Author

Eleonora Scorletti, Yedidya Saiman, Sookyoung Jeon, Carolin V. Schneider, Delfin G. Buyco, Chelsea Lin, Blanca E. Himes, Clementina A. Mesaros, Marijana Vujkovic, Kate Townsend Creasy, Emma E. Furth, Jeffrey T. Billheimer, Nicholas J. Hand, David E. Kaplan, Kyong-Mi Chang, Philip S. Tsao, Julie A. Lynch, Joseph L. Dempsey, Julia Harkin, Susovon Bayen, Donna Conlon, Marie Guerraty, Michael C. Phillips, Daniel J. Rader, and Rotonya M. Carr

Subjects
NAFLD, Lipid droplets, Perilipin, DGAT2, triglycerides, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is characterised by the accumulation of lipid droplets (LDs) within hepatocytes. Perilipin 2 (PLIN2) is the most abundant protein in hepatic LDs and its expression correlates with intracellular lipid accumulation. A recently discovered PLIN2 coding variant, Ser251Pro (rs35568725), was found to promote the accumulation of small LDs in embryonic kidney cells. In this study, we investigate the role of PLIN2-Ser251Pro (PLIN2-Pro251) on hepatic LD metabolism in vivo and research the metabolic phenotypes associated with this variant in humans. Methods: For our animal model, we used Plin2 knockout mice in which we expressed either human PLIN2-Pro251 (Pro251 mice) or wild-type human PLIN2-Ser251 (Ser251 mice) in a hepatocyte-specific manner. We fed both cohorts a lipogenic high-fat, high-cholesterol, high-fructose diet for 12 weeks. Results: Pro251 mice were associated with reduced liver triglycerides (TGs) and had lower mRNA expression of fatty acid synthase and diacylglycerol O-acyltransferase-2 compared with Ser251 mice. Moreover, Pro251 mice had a reduction of polyunsaturated fatty acids-TGs and reduced expression of epoxygenase genes. For our human study, we analysed the Penn Medicine BioBank, the Million Veteran Program, and UK Biobank. Across these databases, the minor allele frequency of PLIN2-Pro251 was approximately 5%. There was no association with the clinical diagnosis of NAFLD, however, there was a trend toward reduced liver fat in PLIN2-Pro251 carriers by MRI-spectroscopy in UK Biobank subjects. Conclusions: In mice lacking endogenous Plin2, expression of human PLIN2-Pro251 attenuated high-fat, high-fructose, high-cholesterol, diet-induced hepatic steatosis compared with human wild-type PLIN2-Ser251. Moreover, Pro251 mice had lower polyunsaturated fatty acids-TGs and epoxygenase genes expression, suggesting less liver oxidative stress. In humans, PLIN2-Pro251 is not associated with NAFLD. Impact and Implications: Lipid droplet accumulation in hepatocytes is the distinctive characteristic of non-alcoholic fatty liver disease. Perilipin 2 (PLIN2) is the most abundant protein in hepatic lipid droplets; however, little is known on the role of a specific polymorphism PLIN2-Pro251 on hepatic lipid droplet metabolism. PLIN2-Pro251 attenuates liver triglycerides accumulation after a high-fat-high-glucose-diet. PLIN2-Pro251 may be a novel lipid droplet protein target for the treatment of liver steatosis.

Published
2024
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2. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Author

Stavroula Kanoni, Sarah E. Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L. Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Greg J. M. Zajac, Kuan-Han H. Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T. Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F. Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A. Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J. Kullo, Akira Narita, Jun Takayama, Hilary C. Martin, Karen A. Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, Asif Rasheed, George Hindy, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R. Brown, Weihua Zhang, Ketian Yu, Ellen M. Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian’an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A. Yousri, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Anne A. Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R. Warren, Julia Ramirez, Jette Bork-Jensen, Line L. Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F. McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, Sanni E. Ruotsalainen, EWarwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Miguel Vazquez-Moreno, Mary F. Feitosa, Mary K. Wojczynski, Zhe Wang, Michael H. Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W. Benjamins, Jorgen Engmann, Noah L. Tsao, Anurag Verma, Roderick C. Slieker, Ken Sin Lo, Nuno R. Zilhao, Phuong Le, Marcus E. Kleber, Graciela E. Delgado, Shaofeng Huo, Daisuke D. Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L. Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J. Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S. Nongmaithem, Swati Bayyana, Heather M. Stringham, Marguerite R. Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R. H. J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N. Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C. Warner, Ya Xing Wang, Wen B. Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkänen, Brian E. Cade, Sander W. van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R. Bentley, Ayo P. Doumatey, Adebowale A. Adeyemo, Jong Young Lee, Eva R. B. Petersen, Aneta A. Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W. Rayner, Carol A. Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alexander P. Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C. Bis, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J. de Borst, Eung Kweon Kim, Hieab H. H. Adams, M. Arfan Ikram, Xiaofeng Zhu, Folkert W. Asselbergs, Adriaan O. Kraaijeveld, Joline W. J. Beulens, Xiao-Ou Shu, Loukianos S. Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W. Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M. Heid, Klaus J. Stark, Martina E. Zimmermann, Henry Völzke, Georg Homuth, Michele K. Evans, Alan B. Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E. Hoefer, Susan Redline, Katja Pahkala, Albertine J. Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L. R. Kardia, Patricia A. Peyser, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Carsten A. Böger, Bettina Jung, Peter K. Joshi, David A. Bennett, Philip L. De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J. Caulfield, Patricia B. Munroe, Xiuqing Guo, Marina Ciullo, Jost B. Jonas, Nilesh J. Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A. Aguilar-Salinas, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G. Wilson, Lars Lind, Chew-Kiat Heng, Amanda E. Nelson, Yvonne M. Golightly, James F. Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J. Scott, D. C. Rao, Donna K. Arnett, Steven C. Hunt, Mark Walker, Heikki A. Koistinen, Giriraj R. Chandak, Josep M. Mercader, Maria C. Costanzo, Dongkeun Jang, Noël P. Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, EShyong Tai, Rob M. van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I. McCarthy, Colin N. A. Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M. van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M.‘t Hart, Petra J. M. Elders, Scott M. Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D. Spector, Ruth J. F. Loos, Michael A. Province, Esteban J. Parra, Miguel Cruz, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Charles N. Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F. A. Grant, Lambertus A. L. M. Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W. Franks, Allan Linneberg, J. Wouter Jukema, Amit V. Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O. Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I. Rotter, Thomas M. Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K. E. Magnusson, Dorret I. Boomsma, Allegonda H. M. Willemsen, LAdrienne Cupples, Joyce B. J. van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J. Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C. Chambers, Jaspal S. Kooner, Paul S. de Vries, Alanna C. Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E. North, Martha Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin G. Walters, Michael V. Holmes, Corri Black, Blair H. Smith, Aris Baras, Anne E. Justice, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A. van Heel, Richard C. Trembath, Wei-Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, YEugene Chen, Yuk-Lam Ho, Julie A. Lynch, Daniel J. Rader, Philip S. Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J. O’Donnell, John M. Gaziano, Peter W. F. Wilson, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Karen L. Mohlke, Yan V. Sun, Andrew P. Morris, Michael Boehnke, Christopher D. Brown, Pradeep Natarajan, Panos Deloukas, Cristen J. Willer, Themistocles L. Assimes, and Gina M. Peloso

Subjects
Cholesterol, Lipids, Genetics, Genome-wide association study, GWAS, Biology (General), QH301-705.5, QH426-470
Abstract

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Published
2022
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3. Genomics and phenomics of body mass index reveals a complex disease network

Author

Jie Huang, Jennifer E. Huffman, Yunfeng Huang, Ítalo Do Valle, Themistocles L. Assimes, Sridharan Raghavan, Benjamin F. Voight, Chang Liu, Albert-László Barabási, Rose D. L. Huang, Qin Hui, Xuan-Mai T. Nguyen, Yuk-Lam Ho, Luc Djousse, Julie A. Lynch, Marijana Vujkovic, Catherine Tcheandjieu, Hua Tang, Scott M. Damrauer, Peter D. Reaven, Donald Miller, Lawrence S. Phillips, Maggie C. Y. Ng, Mariaelisa Graff, Christopher A. Haiman, Ruth J. F. Loos, Kari E. North, Loic Yengo, George Davey Smith, Danish Saleheen, J. Michael Gaziano, Daniel J. Rader, Philip S. Tsao, Kelly Cho, Kyong-Mi Chang, Peter W. F. Wilson, VA Million Veteran Program, Yan V. Sun, and Christopher J. O’Donnell

Subjects
Science
Abstract

Elevated body mass index is heritable and associated with many health conditions that impact morbidity and mortality. Here, the authors identify greater than 900 genetic loci for body mass index (BMI) and find over 300 diagnoses associated with increasing BMI.

Published
2022
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4. Large-scale identification of undiagnosed hepatic steatosis using natural language processingResearch in context

Author

Carolin V. Schneider, Tang Li, David Zhang, Anya I. Mezina, Puru Rattan, Helen Huang, Kate Townsend Creasy, Eleonora Scorletti, Inuk Zandvakili, Marijana Vujkovic, Leonida Hehl, Jacob Fiksel, Joseph Park, Kirk Wangensteen, Marjorie Risman, Kyong-Mi Chang, Marina Serper, Rotonya M. Carr, Kai Markus Schneider, Jinbo Chen, and Daniel J. Rader

Subjects
Liver disease, NAFLD, Biopsy, EHR, Natural language processing, Medicine (General), R5-920
Abstract

Summary: Background: Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity in people with and without diabetes, but it is underdiagnosed, posing challenges for research and clinical management. Here, we determine if natural language processing (NLP) of data in the electronic health record (EHR) could identify undiagnosed patients with hepatic steatosis based on pathology and radiology reports. Methods: A rule-based NLP algorithm was built using a Linguamatics literature text mining tool to search 2.15 million pathology report and 2.7 million imaging reports in the Penn Medicine EHR from November 2014, through December 2020, for evidence of hepatic steatosis. For quality control, two independent physicians manually reviewed randomly chosen biopsy and imaging reports (n = 353, PPV 99.7%). Findings: After exclusion of individuals with other causes of hepatic steatosis, 3007 patients with biopsy-proven NAFLD and 42,083 patients with imaging-proven NAFLD were identified. Interestingly, elevated ALT was not a sensitive predictor of the presence of steatosis, and only half of the biopsied patients with steatosis ever received an ICD diagnosis code for the presence of NAFLD/NASH. There was a robust association for PNPLA3 and TM6SF2 risk alleles and steatosis identified by NLP. We identified 234 disorders that were significantly over- or underrepresented in all subjects with steatosis and identified changes in serum markers (e.g., GGT) associated with presence of steatosis. Interpretation: This study demonstrates clear feasibility of NLP-based approaches to identify patients whose steatosis was indicated in imaging and pathology reports within a large healthcare system and uncovers undercoding of NAFLD in the general population. Identification of patients at risk could link them to improved care and outcomes. Funding: The study was funded by US and German funding sources that did provide financial support only and had no influence or control over the research process.

Published
2023
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5. Pharmacogenetic variants and risk of remdesivir‐associated liver enzyme elevations in Million Veteran Program participants hospitalized with COVID‐19

Author

Sony Tuteja, Zhihong Yu, Otis Wilson, Hua‐Chang Chen, Frank Wendt, Cecilia P. Chung, Shailja C. Shah, Christine M. Hunt, Ayako Suzuki, Catherine Chanfreau, Bryan R. Gorman, Jacob Joseph, Shiuh‐Wen Luoh, Valerio Napolioni, Cassianne Robinson‐Cohen, Ran Tao, Jin Zhou, Kyong‐Mi Chang, Adriana M. Hung, and the VA Million Veteran Program COVID‐19 Science Initiative

Subjects
Therapeutics. Pharmacology, RM1-950, Public aspects of medicine, RA1-1270
Abstract

Abstract Remdesivir is the first US Food and Drug Administration (FDA)‐approved drug for the treatment of coronavirus disease 2019 (COVID‐19). We conducted a retrospective pharmacogenetic study to examine remdesivir‐associated liver enzyme elevation among Million Veteran Program participants hospitalized with COVID‐19 between March 15, 2020, and June 30, 2021. Pharmacogene phenotypes were assigned using Stargazer. Linear regression was performed on peak log‐transformed enzyme values, stratified by population, adjusted for age, sex, baseline liver enzymes, comorbidities, and 10 population‐specific principal components. Patients on remdesivir had higher peak alanine aminotransferase (ALT) values following treatment initiation compared with patients not receiving remdesivir. Remdesivir administration was associated with a 33% and 24% higher peak ALT in non‐Hispanic White (NHW) and non‐Hispanic Black (NHB) participants (p

Published
2022
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6. Effects of metabolic traits, lifestyle factors, and pharmacological interventions on liver fat: mendelian randomisation study

Author

Dipender Gill, Jie Chen, Susanna C Larsson, Xue Li, Shuai Yuan, Kyong-Mi Chang, and Marijana Vujkovic

Subjects
Medicine
Abstract

Objective To investigate the effects of metabolic traits, lifestyle factors, and drug interventions on liver fat using the mendelian randomisation paradigm.Design Mendelian randomisation study.Setting Publicly available summary level data from genome-wide association studies.Participants Genome-wide association studies of 32 974 to 1 407 282 individuals who were predominantly of European descent.Exposures Genetic variants predicting nine metabolic traits, six lifestyle factors, four lipid lowering drug targets, three antihypertensive drug targets, and genetic association estimates formagnetic resonance imaging measured liver fat.Main outcome measures Mendelian randomisation analysis was used to investigate the effects of these exposures on liver fat, incorporating sensitivity analyses that relaxed the requisite modelling assumptions.Results Genetically predicted liability to obesity, type 2 diabetes, elevated blood pressure, elevated triglyceride levels, cigarette smoking, and sedentary time watching television were associated with higher levels of liver fat. Genetically predicted lipid lowering drug effects were not associated with liver fat; however, β blocker and calcium channel blocker antihypertensive drug effects were associated with lower levels of liver fat.Conclusion These analyses provide evidence of a causal effect of various metabolic traits, lifestyle factors, and drug targets on liver fat. The findings complement existing epidemiological associations, further provide mechanistic insight, and potentially supports a role for drug interventions in reducing the burden of hepatic steatosis and related disease. Further clinical study is now warranted to investigate the relevance of these genetic analyses for patient care.

Published
2022
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7. 72 Establishing a histologically defined NAFLD cohort in the Million Veteran Program for further genetic analyses

Author

Samiran Mukherjee, Marijana Vujkovic, and Kyong-Mi Chang

Subjects
Medicine
Abstract

OBJECTIVES/GOALS: Research in Non Alcoholic Fatty Liver Disease Genetics is ongoing. In this project, we aim to: 1.Identify and describe a histological NAFLD Cohort in the MVP Biobank by extracting liver biopsy proven NAFLD patients using natural language processing (NLP) 2.Confirm previously defined NALFD genetic loci (via look up-GWAS) in the histological NLP cohort METHODS/STUDY POPULATION: We will utilize the Million Veteran Program Biobank where a total of 10,959 subjects have been identified using liver biopsy reports in the EMR via CPT codes. Cases will be based on i) steatosis, steatohepatitis, inflammation or fibrosis in liver biopsy reports with ii) exclusion of other causes of liver disease. Controls will be comprised of the general VA population. In collaboration with the Applied NLP and Precision Medicine groups at the VA Informatics and Computing Infrastructure(VINCI); we will attempt to create and validate a histological cohort of NAFLD in the MVP database by: 1)Annotation of biopsy reports for the NLP algorithm 2)Automation/training of the NLP algorithm We will then perform a multi-ancestry genetic lookup of previously established genetic loci among the cases identified. RESULTS/ANTICIPATED RESULTS: Recently published data: the MVP NAFLD research led by Dr. Chang and Dr. Vujkovic had first validated a proxy NAFLD phenotype based on chronic alanine aminotransferase elevation (cALT). A GWAS was then performed using this phenotype which revealed 77 loci of genome-wide significance including 10 established NAFLD- and 52 ALT-associated SNPs were identified. Replication in external Liver Biopsy and Imaging Cohorts validated 17 SNPs of which 9 were novel. Preliminary data on Liver Biopsy reports: Using CPT codes for Liver Biopsy we estimated a total of 10,959 unique patients and 18,812 notes in the MVP biobank. We anticipate 2,000-3,000 NAFLD cases (based on the prevalence of NAFLD in the general population). Initial review reveals 90% concordance between analysts for the purposes of developing an NLP. DISCUSSION/SIGNIFICANCE: NAFLD is a major cause for morbidity and mortality in liver disease. Gold standard for diagnosis is based on biopsy. GWAS studies with biopsy proven phenotypes are limited. The study will aim to isolate a histologically defined NAFLD cohort in MVP to conduct further GWAS that can provide new clinically relevant knowledge for future research.

Published
2023
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8. Association of the transthyretin variant V122I with polyneuropathy among individuals of African ancestry

Author

Margaret M. Parker, Scott M. Damrauer, Catherine Tcheandjieu, David Erbe, Emre Aldinc, Philip N. Hawkins, Julian D. Gillmore, Leland E. Hull, Julie A. Lynch, Jacob Joseph, Simina Ticau, Alexander O. Flynn-Carroll, Aimee M. Deaton, Lucas D. Ward, Themistocles L. Assimes, Philip S. Tsao, Kyong-Mi Chang, Daniel J. Rader, Kevin Fitzgerald, Akshay K. Vaishnaw, Gregory Hinkle, and Paul Nioi

Subjects
Medicine, Science
Abstract

Abstract Hereditary transthyretin-mediated (hATTR) amyloidosis is an underdiagnosed, progressively debilitating disease caused by mutations in the transthyretin (TTR) gene. V122I, a common pathogenic TTR mutation, is found in 3–4% of individuals of African ancestry in the United States and has been associated with cardiomyopathy and heart failure. To better understand the phenotypic consequences of carrying V122I, we conducted a phenome-wide association study scanning 427 ICD diagnosis codes in UK Biobank participants of African ancestry (n = 6062). Significant associations were tested for replication in the Penn Medicine Biobank (n = 5737) and the Million Veteran Program (n = 82,382). V122I was significantly associated with polyneuropathy in the UK Biobank (odds ratio [OR] = 6.4, 95% confidence interval [CI] 2.6–15.6, p = 4.2 × 10−5), which was replicated in the Penn Medicine Biobank (OR = 1.6, 95% CI 1.2–2.4, p = 6.0 × 10–3) and Million Veteran Program (OR = 1.5, 95% CI 1.2–1.8, p = 1.8 × 10−4). Polyneuropathy prevalence among V122I carriers was 2.1%, 9.0%, and 4.8% in the UK Biobank, Penn Medicine Biobank, and Million Veteran Program, respectively. The cumulative incidence of common hATTR amyloidosis manifestations (carpal tunnel syndrome, polyneuropathy, cardiomyopathy, heart failure) was significantly enriched in V122I carriers compared with non-carriers (HR = 2.8, 95% CI 1.7–4.5, p = 2.6 × 10−5) in the UK Biobank, with 37.4% of V122I carriers having at least one of these manifestations by age 75. Our findings show that V122I carriers are at increased risk of polyneuropathy. These results also emphasize the underdiagnosis of disease in V122I carriers with a significant proportion of subjects showing phenotypic changes consistent with hATTR amyloidosis. Greater understanding of the manifestations associated with V122I is critical for earlier diagnosis and treatment.

Published
2021
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9. A multi-population phenome-wide association study of genetically-predicted height in the Million Veteran Program

Author

Sridharan Raghavan, Jie Huang, Catherine Tcheandjieu, Jennifer E. Huffman, Elizabeth Litkowski, Chang Liu, Yuk-Lam A. Ho, Haley Hunter-Zinck, Hongyu Zhao, Eirini Marouli, Kari E. North, the VA Million Veteran Program, Ethan Lange, Leslie A. Lange, Benjamin F. Voight, J. Michael Gaziano, Saiju Pyarajan, Elizabeth R. Hauser, Philip S. Tsao, Peter W. F. Wilson, Kyong-Mi Chang, Kelly Cho, Christopher J. O’Donnell, Yan V. Sun, and Themistocles L. Assimes

Subjects
Genetics, QH426-470
Abstract

Background Height has been associated with many clinical traits but whether such associations are causal versus secondary to confounding remains unclear in many cases. To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and genetic data from a national healthcare system biobank. Methods and findings Analyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n = 222,300) and non-Hispanic Black (AA, n = 58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy in the presence and absence of diabetes. As a number of traits associated with genetically-predicted height frequently co-occur with CHD, we evaluated effect modification by CHD status of genetically-predicted height associations with risk factors for and complications of CHD. We found modification of effects of MR associations by CHD status for atrial fibrillation/flutter but not for hypertension, hyperlipidemia, or venous circulatory disorders. Conclusions We conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study. Author summary Adult height has been associated with several clinical traits, for example with increased risk of atrial fibrillation and with decreased risk of cardiovascular disease. Using data from the VA Million Veteran Program that includes genetic data linked to clinical records in >200,000 non-Hispanic White adults and >50,000 non-Hispanic Black adults, we examined associations of measured height and genetically-predicted height with clinical traits phenome-wide. By comparing associations of traits with measured and with genetically-predicted height, we aimed to discriminate between potentially causal associations (those associated with genetically-predicted height) from associations that may be confounded by environmental exposures over the life course (those associated with measured height but not with genetically-predicted height). Of approximately 350 traits associated with measured height, we found 127 associated with genetically-predicted height in non-Hispanic White individuals. While only 2 were also statistically significant in non-Hispanic Black individuals, we found evidence for consistent directions of effect for associations of traits with genetically-predicted height in non-Hispanic Black and White individuals. We conclude that height may be an unrecognized non-modifiable risk factor for several common conditions in adults.

Published
2022

10. Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes

Author

Raha Pazoki, Marijana Vujkovic, Joshua Elliott, Evangelos Evangelou, Dipender Gill, Mohsen Ghanbari, Peter J. van der Most, Rui Climaco Pinto, Matthias Wielscher, Matthias Farlik, Verena Zuber, Robert J. de Knegt, Harold Snieder, André G. Uitterlinden, Lifelines Cohort Study, Julie A. Lynch, Xiyun Jiang, Saredo Said, David E. Kaplan, Kyung Min Lee, Marina Serper, Rotonya M. Carr, Philip S. Tsao, Stephen R. Atkinson, Abbas Dehghan, Ioanna Tzoulaki, M. Arfan Ikram, Karl-Heinz Herzig, Marjo-Riitta Järvelin, Behrooz Z. Alizadeh, Christopher J. O’Donnell, Danish Saleheen, Benjamin F. Voight, Kyong-Mi Chang, Mark R. Thursz, Paul Elliott, and the VA Million Veteran Program

Subjects
Science
Abstract

Plasma levels of liver enzymes provide insights into hepatic function and related diseases. Here, the authors perform a genome-wide association study on three liver enzymes, identifying genetic variants associated with their plasma concentration as well as links to metabolic and cardiovascular diseases.

Published
2021
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11. Multi-trait association studies discover pleiotropic loci between Alzheimer’s disease and cardiometabolic traits

Author

William P. Bone, Katherine M. Siewert, Anupama Jha, Derek Klarin, Scott M. Damrauer, The VA Million Veteran Program, Kyong-Mi Chang, Philip S. Tsao, Themistocles L. Assimes, Marylyn D. Ritchie, and Benjamin F. Voight

Subjects
Pleiotropy, Cardiometabolic traits, Multi-trait GWAS, Colocalization, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Identification of genetic risk factors that are shared between Alzheimer’s disease (AD) and other traits, i.e., pleiotropy, can help improve our understanding of the etiology of AD and potentially detect new therapeutic targets. Previous epidemiological correlations observed between cardiometabolic traits and AD led us to assess the pleiotropy between these traits. Methods We performed a set of bivariate genome-wide association studies coupled with colocalization analysis to identify loci that are shared between AD and eleven cardiometabolic traits. For each of these loci, we performed colocalization with Genotype-Tissue Expression (GTEx) project expression quantitative trait loci (eQTL) to identify candidate causal genes. Results We identified three previously unreported pleiotropic trait associations at known AD loci as well as four novel pleiotropic loci. One associated locus was tagged by a low-frequency coding variant in the gene DOCK4 and is potentially implicated in its alternative splicing. Colocalization with GTEx eQTL data identified additional candidate genes for the loci we detected, including ACE, the target of the hypertensive drug class of ACE inhibitors. We found that the allele associated with decreased ACE expression in brain tissue was also associated with increased risk of AD, providing human genetic evidence of a potential increase in AD risk from use of an established anti-hypertensive therapeutic. Conclusion Our results support a complex genetic relationship between AD and these cardiometabolic traits, and the candidate causal genes identified suggest that blood pressure and immune response play a role in the pleiotropy between these traits.

Published
2021
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12. A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program.

Author

Anurag Verma, Noah L Tsao, Lauren O Thomann, Yuk-Lam Ho, Sudha K Iyengar, Shiuh-Wen Luoh, Rotonya Carr, Dana C Crawford, Jimmy T Efird, Jennifer E Huffman, Adriana Hung, Kerry L Ivey, Michael G Levin, Julie Lynch, Pradeep Natarajan, Saiju Pyarajan, Alexander G Bick, Lauren Costa, Giulio Genovese, Richard Hauger, Ravi Madduri, Gita A Pathak, Renato Polimanti, Benjamin Voight, Marijana Vujkovic, Seyedeh Maryam Zekavat, Hongyu Zhao, Marylyn D Ritchie, VA Million Veteran Program COVID-19 Science Initiative, Kyong-Mi Chang, Kelly Cho, Juan P Casas, Philip S Tsao, J Michael Gaziano, Christopher O'Donnell, Scott M Damrauer, and Katherine P Liao

Subjects
Genetics, QH426-470
Abstract

The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n = 35) or hospitalization (n = 42) due to severe COVID-19 using genome-wide association summary data from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (nrs495828 = 53 and nrs505922 = 59); strongest association with venous embolism, odds ratio (ORrs495828 1.33 (p = 1.32 x 10-199), and thrombosis ORrs505922 1.33, p = 2.2 x10-265. Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p = 4.12 × 10-191; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p = 2.26× 10-12. The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p = 6.48 x10-23, lupus OR 0.84, p = 3.97 x 10-06. PheWAS stratified by ancestry demonstrated differences in genotype-phenotype associations. LMNA (rs581342) associated with neutropenia OR 1.29 p = 4.1 x 10-13 among Veterans of African and Hispanic ancestry but not European. Overall, we observed a shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets.

Published
2022
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13. Multi-Trait Genome-Wide Association Study of Atherosclerosis Detects Novel Pleiotropic Loci

Author

Tiffany R. Bellomo, William P. Bone, Brian Y. Chen, Katerina A. B. Gawronski, David Zhang, Joseph Park, Michael Levin, Noah Tsao, Derek Klarin, Julie Lynch, Themistocles L. Assimes, J. Michael Gaziano, Peter W. Wilson, Kelly Cho, Marijana Vujkovic, the VA Million Veteran Program, Christopher J. O’Donnell, Kyong-Mi Chang, Philip S. Tsao, Daniel J. Rader, Marylyn D. Ritchie, Scott M. Damrauer, and Benjamin F. Voight

Subjects
peripheral artery disease, atherosclerosis, multi-trait analyses, GWAS—genome-wide association study, pleiotropy, Genetics, QH426-470
Abstract

Although affecting different arterial territories, the related atherosclerotic vascular diseases coronary artery disease (CAD) and peripheral artery disease (PAD) share similar risk factors and have shared pathobiology. To identify novel pleiotropic loci associated with atherosclerosis, we performed a joint analysis of their shared genetic architecture, along with that of common risk factors. Using summary statistics from genome-wide association studies of nine known atherosclerotic (CAD, PAD) and atherosclerosis risk factors (body mass index, smoking initiation, type 2 diabetes, low density lipoprotein, high density lipoprotein, total cholesterol, and triglycerides), we perform 15 separate multi-trait genetic association scans which resulted in 25 novel pleiotropic loci not yet reported as genome-wide significant for their respective traits. Colocalization with single-tissue eQTLs identified candidate causal genes at 14 of the detected signals. Notably, the signal between PAD and LDL-C at the PCSK6 locus affects PCSK6 splicing in human liver tissue and induced pluripotent derived hepatocyte-like cells. These results show that joint analysis of related atherosclerotic disease traits and their risk factors allowed identification of unified biology that may offer the opportunity for therapeutic manipulation. The signal at PCSK6 represent possible shared causal biology where existing inhibitors may be able to be leveraged for novel therapies.

Published
2022
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14. Genome-wide and phenome-wide analysis of ideal cardiovascular health in the VA Million Veteran Program

Author

Rose D. L. Huang, Xuan-Mai T. Nguyen, Gina M. Peloso, Mark Trinder, Daniel C. Posner, Krishna G. Aragam, Yuk-Lam Ho, Julie A. Lynch, Scott M. Damrauer, Kyong-Mi Chang, Philip S. Tsao, Pradeep Natarajan, Themistocles Assimes, J. Michael Gaziano, Luc Djousse, Kelly Cho, Peter W. F. Wilson, Jennifer E. Huffman, Christopher J. O’Donnell, and on behalf of the Veterans Affairs’ Million Veteran Program

Subjects
Medicine, Science
Abstract

Background Genetic studies may help identify causal pathways; therefore, we sought to identify genetic determinants of ideal CVH and their association with CVD outcomes in the multi-population Veteran Administration Million Veteran Program. Methods An ideal health score (IHS) was calculated from 3 clinical factors (blood pressure, total cholesterol, and blood glucose levels) and 3 behavioral factors (smoking status, physical activity, and BMI), ascertained at baseline. Multi-population genome-wide association study (GWAS) was performed on IHS and binary ideal health using linear and logistic regression, respectively. Using the genome-wide significant SNPs from the IHS GWAS, we created a weighted IHS polygenic risk score (PRSIHS) which was used (i) to conduct a phenome-wide association study (PheWAS) of associations between PRSIHS and ICD-9 phenotypes and (ii) to further test for associations with mortality and selected CVD outcomes using logistic and Cox regression and, as an instrumental variable, in Mendelian Randomization. Results The discovery and replication cohorts consisted of 142,404 (119,129 European American (EUR); 16,495 African American (AFR)), and 45,766 (37,646 EUR; 5,366 AFR) participants, respectively. The mean age was 65.8 years (SD = 11.2) and 92.7% were male. Overall, 4.2% exhibited ideal CVH based on the clinical and behavioral factors. In the multi-population meta-analysis, variants at 17 loci were associated with IHS and each had known GWAS associations with multiple components of the IHS. PheWAS analysis in 456,026 participants showed that increased PRSIHS was associated with a lower odds ratio for many CVD outcomes and risk factors. Both IHS and PRSIHS measures of ideal CVH were associated with significantly less CVD outcomes and CVD mortality. Conclusion A set of high interest genetic variants contribute to the presence of ideal CVH in a multi-ethnic cohort of US Veterans. Genetically influenced ideal CVH is associated with lower odds of CVD outcomes and mortality.

Published
2022

15. Genetic Evidence for Repurposing of GLP1R (Glucagon‐Like Peptide‐1 Receptor) Agonists to Prevent Heart Failure

Author

Iyas Daghlas, Ville Karhunen, Devleena Ray, Verena Zuber, Stephen Burgess, Philip S. Tsao, Julie A. Lynch, Kyung Min Lee, Benjamin F. Voight, Kyong‐Mi Chang, Emma H. Baker, Scott M. Damrauer, Joanna M. M. Howson, Marijana Vujkovic, and Dipender Gill

Subjects
diabetes mellitus, ejection fraction, GLP1R, heart failure, Mendelian randomization, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background This study was designed to investigate the genetic evidence for repurposing of GLP1R (glucagon‐like peptide‐1 receptor) agonists to prevent heart failure (HF) and whether the potential benefit exceeds the benefit conferred by more general glycemic control. Methods and Results We applied 2‐sample Mendelian randomization of genetically proxied GLP1R agonism on HF as the main outcome and left ventricular ejection fraction as the secondary outcome. The associations were compared with those of general glycemic control on the same outcomes. Genetic associations were obtained from genome‐wide association study summary statistics of type 2 diabetes mellitus (228 499 cases and 1 178 783 controls), glycated hemoglobin (n=344 182), HF (47,309 cases and 930 014 controls), and left ventricular ejection fraction (n=16 923). Genetic proxies for GLP1R agonism associated with reduced risk of HF (odds ratio per 1 mmol/mol decrease in glycated hemoglobin 0.75; 95% CI, 0.64–0.87; P=1.69×10−4), and higher left ventricular ejection fraction (SD change in left ventricular ejection fraction per 1 mmol/mol decrease in glycated hemoglobin 0.22%; 95% CI, 0.03–0.42; P=0.03). The magnitude of these benefits exceeded those expected from improved glycemic control more generally. The results were similar in sensitivity analyses, and we did not find evidence to suggest that these associations were mediated by reduced coronary artery disease risk. Conclusions This genetic evidence supports the repurposing of GLP1R agonists for preventing HF.

Published
2021
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16. Highly multiplexed 2-dimensional imaging mass cytometry analysis of HBV-infected liver

Author

Daniel Traum, Yue J. Wang, Kathleen B. Schwarz, Jonathan Schug, David K.H. Wong, Harry L.A. Janssen, Norah A. Terrault, Mandana Khalili, Abdus S. Wahed, Karen F. Murray, Phillip Rosenthal, Simon C. Ling, Norberto Rodriguez-Baez, Richard K. Sterling, Daryl T.Y. Lau, Timothy M. Block, Michael D. Feldman, Elizabeth E. Furth, William M. Lee, David E. Kleiner, Anna S. Lok, Klaus H. Kaestner, and Kyong-Mi Chang

Subjects
Hepatology, Infectious disease, Medicine
Abstract

Studies of human hepatitis B virus (HBV) immune pathogenesis are hampered by limited access to liver tissues and technologies for detailed analyses. Here, utilizing imaging mass cytometry (IMC) to simultaneously detect 30 immune, viral, and structural markers in liver biopsies from patients with hepatitis B e antigen+ (HBeAg+) chronic hepatitis B, we provide potentially novel comprehensive visualization, quantitation, and phenotypic characterizations of hepatic adaptive and innate immune subsets that correlated with hepatocellular injury, histological fibrosis, and age. We further show marked correlations between adaptive and innate immune cell frequencies and phenotype, highlighting complex immune interactions within the hepatic microenvironment with relevance to HBV pathogenesis.

Published
2021
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17. Correction: A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease.

Author

Connor A Emdin, Mary E Haas, Amit V Khera, Krishna Aragam, Mark Chaffin, Derek Klarin, George Hindy, Lan Jiang, Wei-Qi Wei, Qiping Feng, Juha Karjalainen, Aki Havulinna, Tuomo Kiiskinen, Alexander Bick, Diego Ardissino, James G Wilson, Heribert Schunkert, Ruth McPherson, Hugh Watkins, Roberto Elosua, Matthew J Bown, Nilesh J Samani, Usman Baber, Jeanette Erdmann, Namrata Gupta, John Danesh, Danish Saleheen, Kyong-Mi Chang, Marijana Vujkovic, Ben Voight, Scott Damrauer, Julie Lynch, David Kaplan, Marina Serper, Philip Tsao, Million Veteran Program, Josep Mercader, Craig Hanis, Mark Daly, Joshua Denny, Stacey Gabriel, and Sekar Kathiresan

Subjects
Genetics, QH426-470
Abstract

[This corrects the article DOI: 10.1371/journal.pgen.1008629.].

Published
2021
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18. Phenome-wide association of 1809 phenotypes and COVID-19 disease progression in the Veterans Health Administration Million Veteran Program.

Author

Rebecca J Song, Yuk-Lam Ho, Petra Schubert, Yojin Park, Daniel Posner, Emily M Lord, Lauren Costa, Hanna Gerlovin, Katherine E Kurgansky, Tori Anglin-Foote, Scott DuVall, Jennifer E Huffman, Saiju Pyarajan, Jean C Beckham, Kyong-Mi Chang, Katherine P Liao, Luc Djousse, David R Gagnon, Stacey B Whitbourne, Rachel Ramoni, Sumitra Muralidhar, Philip S Tsao, Christopher J O'Donnell, John Michael Gaziano, Juan P Casas, Kelly Cho, and VA Million Veteran Program COVID-19 Science Initiative

Subjects
Medicine, Science
Abstract

BackgroundThe risk factors associated with the stages of Coronavirus Disease-2019 (COVID-19) disease progression are not well known. We aim to identify risk factors specific to each state of COVID-19 progression from SARS-CoV-2 infection through death.Methods and resultsWe included 648,202 participants from the Veteran Affairs Million Veteran Program (2011-). We identified characteristics and 1,809 ICD code-based phenotypes from the electronic health record. We used logistic regression to examine the association of age, sex, body mass index (BMI), race, and prevalent phenotypes to the stages of COVID-19 disease progression: infection, hospitalization, intensive care unit (ICU) admission, and 30-day mortality (separate models for each). Models were adjusted for age, sex, race, ethnicity, number of visit months and ICD codes, state infection rate and controlled for multiple testing using false discovery rate (≤0.1). As of August 10, 2020, 5,929 individuals were SARS-CoV-2 positive and among those, 1,463 (25%) were hospitalized, 579 (10%) were in ICU, and 398 (7%) died. We observed a lower risk in women vs. men for ICU and mortality (Odds Ratio (95% CI): 0.48 (0.30-0.76) and 0.59 (0.31-1.15), respectively) and a higher risk in Black vs. Other race patients for hospitalization and ICU (OR (95%CI): 1.53 (1.32-1.77) and 1.63 (1.32-2.02), respectively). We observed an increased risk of all COVID-19 disease states with older age and BMI ≥35 vs. 20-24 kg/m2. Renal failure, respiratory failure, morbid obesity, acid-base balance disorder, white blood cell diseases, hydronephrosis and bacterial infections were associated with an increased risk of ICU admissions; sepsis, chronic skin ulcers, acid-base balance disorder and acidosis were associated with mortality.ConclusionsOlder age, higher BMI, males and patients with a history of respiratory, kidney, bacterial or metabolic comorbidities experienced greater COVID-19 severity. Future studies to investigate the underlying mechanisms associated with these phenotype clusters and COVID-19 are warranted.

Published
2021
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19. 259 Proton pump inhibitor use is not significantly associated with severe COVID-19 related outcomes after extensive covariate adjustment

Author

Shailja C. Shah, Alese E. Halvorson, Brandon McBay, Chad Dorn, Otis Wilson, Jason Denton, Sony Tuteja, Kyong-Mi Chang, Kelly Cho, Richard L. Hauger, Ayako Suzuki, Christine M. Hunt, Edward Siew, Michael E. Matheny, Adriana Hung, Robert A. Greevy, and Christianne L. Roumie

Subjects
Medicine
Abstract

OBJECTIVES/GOALS: Using the covariate-rich Veteran Health Administration data, estimate the association between Proton Pump Inhibitor (PPI) use and severe COVID-19, rigorously adjusting for confounding using propensity score (PS)-weighting. METHODS/STUDY POPULATION: We assembled a national retrospective cohort of United States veterans who tested positive for SARS-CoV-2, with information on 33 covariates including comorbidity diagnoses, lab values, and medications. Current outpatient PPI use was compared to non-use (two or more fills and pills on hand at admission vs no PPI prescription fill in prior year). The primary composite outcome was mechanical ventilation use or death within 60 days; the secondary composite outcome included ICU admission. PS-weighting mimicked a 1:1 matching cohort, allowing inclusion of all patients while achieving good covariate balance. The weighted cohort was analyzed using logistic regression. RESULTS/ANTICIPATED RESULTS: Our analytic cohort included 97,674 veterans with SARS-CoV-2 testing, of whom 14,958 (15.3%) tested positive (6,262 [41.9%] current PPI-users, 8,696 [58.1%] non-users). After weighting, all covariates were well-balanced with standardized mean differences less than a threshold of 0.1. Prior to PS-weighting (no covariate adjustment), we observed higher odds of the primary (9.3% vs 7.5%; OR 1.27, 95% CI 1.13-1.43) and secondary (25.8% vs 21.4%; OR 1.27, 95% CI 1.18-1.37) outcomes among PPI users vs non-users. After PS-weighting, PPI use vs non-use was not associated with the primary (8.2% vs 8.0%; OR 1.03, 95% CI 0.91-1.16) or secondary (23.4% vs 22.9%;OR 1.03, 95% CI 0.95-1.12) outcomes. DISCUSSION/SIGNIFICANCE: The associations between PPI use and severe COVID-19 outcomes that have been previously reported may be due to limitations in the covariates available for adjustment. With respect to COVID-19, our robust PS-weighted analysis provides patients and providers with further evidence for PPI safety.

Published
2022
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20. The relationship between circulating lipids and breast cancer risk: A Mendelian randomization study.

Author

Kelsey E Johnson, Katherine M Siewert, Derek Klarin, Scott M Damrauer, VA Million Veteran Program, Kyong-Mi Chang, Philip S Tsao, Themistocles L Assimes, Kara N Maxwell, and Benjamin F Voight

Subjects
Medicine
Abstract

BackgroundA number of epidemiological and genetic studies have attempted to determine whether levels of circulating lipids are associated with risks of various cancers, including breast cancer (BC). However, it remains unclear whether a causal relationship exists between lipids and BC. If alteration of lipid levels also reduced risk of BC, this could present a target for disease prevention. This study aimed to assess a potential causal relationship between genetic variants associated with plasma lipid traits (high-density lipoprotein, HDL; low-density lipoprotein, LDL; triglycerides, TGs) with risk for BC using Mendelian randomization (MR).Methods and findingsData from genome-wide association studies in up to 215,551 participants from the Million Veteran Program (MVP) were used to construct genetic instruments for plasma lipid traits. The effect of these instruments on BC risk was evaluated using genetic data from the BCAC (Breast Cancer Association Consortium) based on 122,977 BC cases and 105,974 controls. Using MR, we observed that a 1-standard-deviation genetically determined increase in HDL levels is associated with an increased risk for all BCs (HDL: OR [odds ratio] = 1.08, 95% confidence interval [CI] = 1.04-1.13, P < 0.001). Multivariable MR analysis, which adjusted for the effects of LDL, TGs, body mass index (BMI), and age at menarche, corroborated this observation for HDL (OR = 1.06, 95% CI = 1.03-1.10, P = 4.9 × 10-4) and also found a relationship between LDL and BC risk (OR = 1.03, 95% CI = 1.01-1.07, P = 0.02). We did not observe a difference in these relationships when stratified by breast tumor estrogen receptor (ER) status. We repeated this analysis using genetic variants independent of the leading association at core HDL pathway genes and found that these variants were also associated with risk for BCs (OR = 1.11, 95% CI = 1.06-1.16, P = 1.5 × 10-6), including locus-specific associations at ABCA1 (ATP Binding Cassette Subfamily A Member 1), APOE-APOC1-APOC4-APOC2 (Apolipoproteins E, C1, C4, and C2), and CETP (Cholesteryl Ester Transfer Protein). In addition, we found evidence that genetic variation at the ABO locus is associated with both lipid levels and BC. Through multiple statistical approaches, we minimized and tested for the confounding effects of pleiotropy and population stratification on our analysis; however, the possible existence of residual pleiotropy and stratification remains a limitation of this study.ConclusionsWe observed that genetically elevated plasma HDL and LDL levels appear to be associated with increased BC risk. Future studies are required to understand the mechanism underlying this putative causal relationship, with the goal of developing potential therapeutic strategies aimed at altering the cholesterol-mediated effect on BC risk.

Published
2020
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21. A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease.

Author

Connor A Emdin, Mary E Haas, Amit V Khera, Krishna Aragam, Mark Chaffin, Derek Klarin, George Hindy, Lan Jiang, Wei-Qi Wei, Qiping Feng, Juha Karjalainen, Aki Havulinna, Tuomo Kiiskinen, Alexander Bick, Diego Ardissino, James G Wilson, Heribert Schunkert, Ruth McPherson, Hugh Watkins, Roberto Elosua, Matthew J Bown, Nilesh J Samani, Usman Baber, Jeanette Erdmann, Namrata Gupta, John Danesh, Danish Saleheen, Kyong-Mi Chang, Marijana Vujkovic, Ben Voight, Scott Damrauer, Julie Lynch, David Kaplan, Marina Serper, Philip Tsao, Million Veteran Program, Josep Mercader, Craig Hanis, Mark Daly, Joshua Denny, Stacey Gabriel, and Sekar Kathiresan

Subjects
Genetics, QH426-470
Abstract

Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10-11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10-43), alkaline phosphatase (-0.025 SD, 1.2*10-37), total cholesterol (-0.030 SD, p = 1.9*10-36) and LDL cholesterol (-0.027 SD, p = 5.1*10-30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.

Published
2020
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22. Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study.

Author

Yao Hu, Mariaelisa Graff, Jeffrey Haessler, Steven Buyske, Stephanie A Bien, Ran Tao, Heather M Highland, Katherine K Nishimura, Niha Zubair, Yingchang Lu, Marie Verbanck, Austin T Hilliard, Derek Klarin, Scott M Damrauer, Yuk-Lam Ho, VA Million Veteran Program, Peter W F Wilson, Kyong-Mi Chang, Philip S Tsao, Kelly Cho, Christopher J O'Donnell, Themistocles L Assimes, Lauren E Petty, Jennifer E Below, Ozan Dikilitas, Daniel J Schaid, Matthew L Kosel, Iftikhar J Kullo, Laura J Rasmussen-Torvik, Gail P Jarvik, Qiping Feng, Wei-Qi Wei, Eric B Larson, Frank D Mentch, Berta Almoguera, Patrick M Sleiman, Laura M Raffield, Adolfo Correa, Lisa W Martin, Martha Daviglus, Tara C Matise, Jose Luis Ambite, Christopher S Carlson, Ron Do, Ruth J F Loos, Lynne R Wilkens, Loic Le Marchand, Chris Haiman, Daniel O Stram, Lucia A Hindorff, Kari E North, Charles Kooperberg, Iona Cheng, and Ulrike Peters

Subjects
Genetics, QH426-470
Abstract

Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine.

Published
2020
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23. PCSK9 loss of function is protective against extra-coronary atherosclerotic cardiovascular disease in a large multi-ethnic cohort.

Author

Aeron M Small, Jennifer E Huffman, Derek Klarin, Julie A Lynch, Themistocles Assimes, Scott DuVall, Yan V Sun, Labiba Shere, Pradeep Natarajan, Michael Gaziano, Daniel J Rader, Peter W F Wilson, Philip S Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J O'Donnell, Juan P Casas, Scott M Damrauer, and VA Million Veteran Program

Subjects
Medicine, Science
Abstract

BackgroundTherapeutic inhibition of PCSK9 protects against coronary artery disease (CAD) and ischemic stroke (IS). The impact on other diseases remains less well characterized.MethodsWe created a genetic risk score (GRS) for PCSK9 using four single nucleotide polymorphisms (SNPs) at or near the PCSK9 locus known to impact lower LDL-Cholesterol (LDL-C): rs11583680, rs11591147, rs2479409, and rs11206510. We then used our GRS to calculate weighted odds ratios reflecting the impact of a genetically determined 10 mg/dL decrease in LDL-C on several pre-specified phenotypes including CAD, IS, peripheral artery disease (PAD), abdominal aortic aneurysm (AAA), type 2 diabetes, dementia, chronic obstructive pulmonary disease, and cancer. Finally, we used our weighted GRS to perform a phenome-wide association study.ResultsGenetic and electronic health record data that passed quality control was available in 312,097 individuals, (227,490 White participants, 58,907 Black participants, and 25,700 Hispanic participants). PCSK9 mediated reduction in LDL-C was associated with a reduced risk of CAD and AAA in trans-ethnic meta-analysis (CAD OR 0.83 [95% CI 0.80-0.87], p = 6.0 x 10-21; AAA OR 0.76 [95% CI 0.68-0.86], p = 2.9 x 10-06). Significant protective effects were noted for PAD in White individuals (OR 0.83 [95% CI 0.71-0.97], p = 2.3 x 10-04) but not in other genetic ancestries. Genetically reduced PCSK9 function associated with a reduced risk of dementia in trans-ethnic meta-analysis (OR 0.86 [95% CI 0.78-0.93], p = 5.0 x 10-04).ConclusionsGenetically reduced PCSK9 function results in a reduction in risk of several important extra-coronary atherosclerotic phenotypes in addition to known effects on CAD and IS, including PAD and AAA. We also highlight a novel reduction in risk of dementia, supporting a well-recognized vascular component to cognitive impairment and an opportunity for therapeutic repositioning.

Published
2020
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24. Validating a non-invasive, ALT-based non-alcoholic fatty liver phenotype in the million veteran program.

Author

Marina Serper, Marijana Vujkovic, David E Kaplan, Rotonya M Carr, Kyung Min Lee, Qing Shao, Donald R Miller, Peter D Reaven, Lawrence S Phillips, Christopher J O'Donnell, James B Meigs, Peter W F Wilson, Rachel Vickers-Smith, Henry R Kranzler, Amy C Justice, John M Gaziano, Sumitra Muralidhar, Saiju Pyarajan, Scott L DuVall, Themistocles L Assimes, Jennifer S Lee, Philip S Tsao, Daniel J Rader, Scott M Damrauer, Julie A Lynch, Danish Saleheen, Benjamin F Voight, Kyong-Mi Chang, and VA Million Veteran Program

Subjects
Medicine, Science
Abstract

Background & aimsGiven ongoing challenges in non-invasive non-alcoholic liver disease (NAFLD) diagnosis, we sought to validate an ALT-based NAFLD phenotype using measures readily available in electronic health records (EHRs) and population-based studies by leveraging the clinical and genetic data in the Million Veteran Program (MVP), a multi-ethnic mega-biobank of US Veterans.MethodsMVP participants with alanine aminotransferases (ALT) >40 units/L for men and >30 units/L for women without other causes of liver disease were compared to controls with normal ALT. Genetic variants spanning eight NAFLD risk or ALT-associated loci (LYPLAL1, GCKR, HSD17B13, TRIB1, PPP1R3B, ERLIN1, TM6SF2, PNPLA3) were tested for NAFLD associations with sensitivity analyses adjusting for metabolic risk factors and alcohol consumption. A manual EHR review assessed performance characteristics of the NAFLD phenotype with imaging and biopsy data as gold standards. Genetic associations with advanced fibrosis were explored using FIB4, NAFLD Fibrosis Score and platelet counts.ResultsAmong 322,259 MVP participants, 19% met non-invasive criteria for NAFLD. Trans-ethnic meta-analysis replicated associations with previously reported genetic variants in all but LYPLAL1 and GCKR loci (PConclusionsWe validate a simple, non-invasive ALT-based NAFLD phenotype using EHR data by leveraging previously established NAFLD risk-associated genetic polymorphisms.

Published
2020
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25. Glaucoma Genetic Risk Scores in the Million Veteran Program

Author

Andrea R. Waksmunski, Tyler G. Kinzy, Lauren A. Cruz, Cari L. Nealon, Christopher W. Halladay, Piana Simpson, Rachael L. Canania, Scott A. Anthony, David P. Roncone, Lea Sawicki Rogers, Jenna N. Leber, Jacquelyn M. Dougherty, Paul B. Greenberg, Jack M. Sullivan, Wen-Chih Wu, Sudha K. Iyengar, Dana C. Crawford, Neal S. Peachey, Jessica N. Cooke Bailey, J. Michael Gaziano, Rachel Ramoni, Jim Breeling, Kyong-Mi Chang, Grant Huang, Sumitra Muralidhar, Christopher J. O’Donnell, Philip S. Tsao, Jennifer Moser, Stacey B. Whitbourne, Jessica V. Brewer, John Concato, Stuart Warren, Dean P. Argyres, Brady Stephens, Mary T. Brophy, Donald E. Humphries, Nhan Do, Shahpoor Shayan, Xuan-Mai T. Nguyen, Saiju Pyarajan, Kelly Cho, Elizabeth Hauser, Yan Sun, Hongyu Zhao, Peter Wilson, Rachel McArdle, Louis Dellitalia, John Harley, Jeffrey Whittle, Jean Beckham, John Wells, Salvador Gutierrez, Gretchen Gibson, Laurence Kaminsky, Gerardo Villareal, Scott Kinlay, Junzhe Xu, Mark Hamner, Kathlyn Sue Haddock, Sujata Bhushan, Pran Iruvanti, Michael Godschalk, Zuhair Ballas, Malcolm Buford, Stephen Mastorides, Jon Klein, Nora Ratcliffe, Hermes Florez, Alan Swann, Maureen Murdoch, Peruvemba Sriram, Shing Shing Yeh, Ronald Washburn, Darshana Jhala, Samuel Aguayo, David Cohen, Satish Sharma, John Callaghan, Kris Ann Oursler, Mary Whooley, Sunil Ahuja, Amparo Gutierrez, Ronald Schifman, Jennifer Greco, Michael Rauchman, Richard Servatius, Mary Oehlert, Agnes Wallbom, Ronald Fernando, Timothy Morgan, Todd Stapley, Scott Sherman, Gwenevere Anderson, Philip Tsao, Elif Sonel, Edward Boyko, Laurence Meyer, Samir Gupta, Joseph Fayad, Adriana Hung, Jack Lichy, Robin Hurley, Brooks Robey, and Robert Striker

Subjects
Ophthalmology, Cross-Sectional Studies, Risk Factors, Case-Control Studies, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Glaucoma, Open-Angle, Genome-Wide Association Study, Veterans
Abstract

Primary open-angle glaucoma (POAG) is a degenerative eye disease for which early treatment is critical to mitigate visual impairment and irreversible blindness. POAG-associated loci individually confer incremental risk. Genetic risk score(s) (GRS) could enable POAG risk stratification. Despite significantly higher POAG burden among individuals of African ancestry (AFR), GRS are limited in this population. A recent large-scale, multi-ancestry meta-analysis identified 127 POAG-associated loci and calculated cross-ancestry and ancestry-specific effect estimates, including in European ancestry (EUR) and AFR individuals. We assessed the utility of the 127-variant GRS for POAG risk stratification in EUR and AFR Veterans in the Million Veteran Program (MVP). We also explored the association between GRS and documented invasive glaucoma surgery (IGS).Cross-sectional study.MVP Veterans with imputed genetic data, including 5830 POAG cases (445 with IGS documented in the electronic health record) and 64 476 controls.We tested unweighted and weighted GRS of 127 published risk variants in EUR (3382 cases and 58 811 controls) and AFR (2448 cases and 5665 controls) Veterans in the MVP. Weighted GRS were calculated using effect estimates from the most recently published report of cross-ancestry and ancestry-specific meta-analyses. We also evaluated GRS in POAG cases with documented IGS.Performance of 127-variant GRS in EUR and AFR Veterans for POAG risk stratification and association with documented IGS.GRS were significantly associated with POAG (Plt; 5 × 10sup-5/sup) in both groups; a higher proportion of EUR compared with AFR were consistently categorized in the top GRS decile (21.9%-23.6% and 12.9%-14.5%, respectively). Only GRS weighted by ancestry-specific effect estimates were associated with IGS documentation in AFR cases; all GRS types were associated with IGS in EUR cases.Varied performance of the GRS for POAG risk stratification and documented IGS association in EUR and AFR Veterans highlights (1) the complex risk architecture of POAG, (2) the importance of diverse representation in genomics studies that inform GRS construction and evaluation, and (3) the necessity of expanding diverse POAG-related genomic data so that GRS can equitably aid in screening individuals at high risk of POAG and who may require more aggressive treatment.

Published
2022
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26. 296. SARS-CoV-2 Illness Severity and Early Hospitalization Outcomes in a Multicenter Prospective Cohort Study Among Veterans

Author

Jennifer M Ross, Jonathan D Sugimoto, Andrew Timmons, Kathryn Moore, Jonathan Adams, Deanna Wilson, Cindy H Liu, Katrina V Deardoff, Anna Korpak, Kyong-Mi Chang, Kelly Cho, Kristina Crothers, Michael Gaziano, Mark Holodniy, Christine M Hunt, Stuart N Isaacs, Barbara E Jones, Elizabeth Le, Javeed Shah, Nicholas L Smith, and Jennifer S Lee

Subjects
Infectious Diseases, Oncology
Abstract

Background Over 600,000 SARS-CoV-2 infections and 20,000 deaths have occurred among users of the Veterans Health Administration, the US’s largest integrated health care system. We explored early outcomes of SARS-COV-2 infection in Veterans. Methods An ongoing, prospective longitudinal cohort study of Veterans ages ≥ 18 enrolled 1,826 participants (29.0% inpatient; 49.1% vaccinated; 68.3% SARS-CoV-2-positive; 85.0% male, mean age = 57.1 years) seeking inpatient or outpatient care after SARS-CoV-2 testing at 15 Department of Veterans Affairs medical centers in July 2020 to February 13, 2022. Using multivariable regression, we estimated relationships of baseline demographic characteristics, COVID-19 vaccination, and clinical history to illness severity and cumulative length of hospital stay within 60 days of study entry. Illness severity was defined by a Veterans Affairs adaptation of the WHO COVID-19 severity scale and included 4 levels (mild, moderate, severe, or death). We derived the Charlson co-morbidity index (CCI) and other baseline characteristics from electronic health data and study questionnaires, and reported qualitative SARS-CoV-2 IgG responses using inpatients’ study-collected blood specimens. Results High CCI scores (≥ 5) occurred in 47 (42.7%) vaccinated SARS-CoV-2-positive inpatients and 47 (21.2%) unvaccinated. Severe illness occurred in 17 (15.5%) vaccinated inpatients, 37 (16.7%) unvaccinated inpatients, 4 (0.9%) vaccinated outpatients, and 3 (0.7%) unvaccinated outpatients. Eleven (10%) of 110 vaccinated SARS-CoV-2-positive inpatients died, as did 15 (6.8%) of the 222 unvaccinated. In SARS-CoV-2-positive inpatients, a one-step higher CCI was associated with more severe illness (aOR 1.10, 95% CI 1.01-1.20) and more hospitalization days (aIRR 1.06, 95% CI 1.03-1.10), adjusting for vaccination status. Respectively, 93% of vaccinated and 63% of unvaccinated SARS-CoV-2 positive inpatients with baseline antibody results had an anti-spike IgG response. Conclusion In an ongoing longitudinal cohort study of COVID-19 in US Veterans, comorbidity burden was higher among vaccinated than unvaccinated inpatients and was associated with more severe illness and hospitalization days, independent of vaccination status. Disclosures Christine M. Hunt, MD, MPH, Adaptive Phage Therapeutics: Advisor/Consultant|Akebia: Advisor/Consultant|Galmed: Advisor/Consultant|Otsuka: Advisor/Consultant|Palladio: Advisor/Consultant.

Published
2022
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27. Race and Ethnicity Stratification for Polygenic Risk Score Analyses May Mask Disparities in Hispanics

Author

Shoa L. Clarke, Rose D.L. Huang, Austin T. Hilliard, Catherine Tcheandjieu, Julie Lynch, Scott M. Damrauer, Kyong-Mi Chang, Philip S. Tsao, and Themistocles L. Assimes

Subjects
Risk Factors, Physiology (medical), Ethnicity, Humans, Human Genetics, Hispanic or Latino, Healthcare Disparities, Precision Medicine, Cardiology and Cardiovascular Medicine, White People, Article
Published
2022
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28. Predicting short-term interruptions of antiretroviral therapy from summary adherence data: Development and test of a probability model.

Author

Rebecca Arden Harris, Jessica E Haberer, Nicholas Musinguzi, Kyong-Mi Chang, Clyde B Schechter, Chyke A Doubeni, and Robert Gross

Subjects
Medicine, Science
Abstract

Antiretroviral therapy (ART) for HIV is vulnerable to unplanned treatment interruptions-consecutively missed doses over a series of days-which can result in virologic rebound. Yet clinicians lack a simple, valid method for estimating the risk of interruptions. If the likelihood of ART interruption could be derived from a convenient-to-gather summary measure of medication adherence, it might be a valuable tool for both clinical decision-making and research. We constructed an a priori probability model of ART interruption based on average adherence and tested its predictions using data collected on 185 HIV-infected, treatment-naïve individuals over the first 90 days of ART in a prospective cohort study in Mbarara, Uganda. The outcome of interest was the presence or absence of a treatment gap, defined as >72 hours without a dose. Using the pre-determined value of 0.50 probability as the cut point for predicting an interruption, the classification accuracy of the model was 73% (95% CI = 66%- 79%), the specificity was 87% (95% CI = 79%- 93%), and the sensitivity was 59% (95% CI = 48%- 69%). Overall model performance was satisfactory, with an area under the receiver operator characteristic curve (AUROC) of 0.85 (95% CI = 0.80-0.91) and Brier score of 0.20. The study serves as proof-of-concept that the probability model can accurately differentiate patients on the continuum of risk for short-term ART interruptions using a summary measure of adherence. The model may also aid in the design of targeted interventions.

Published
2018
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29. Proton-pump inhibitor use is not associated with severe COVID-19-related outcomes: a propensity score-weighted analysis of a national veteran cohort

Author

Ayako Suzuki, Brandon McBay, Adriana M. Hung, Kelly Cho, Sony Tuteja, Richard L. Hauger, Christine M. Hunt, Christianne L. Roumie, Otis D. Wilson, Shailja C. Shah, Robert A. Greevy, Edward D. Siew, Kyong-Mi Chang, Michael E. Matheny, Chad Dorn, and Alese E. Halvorson

Subjects
Male, medicine.medical_specialty, medicine.medical_treatment, Stomach Diseases, Comorbidity, Logistic regression, Severity of Illness Index, Article, law.invention, COVID-19 Testing, law, Cause of Death, Oxygen therapy, Internal medicine, Republic of Korea, Epidemiology, Humans, Medicine, Propensity Score, Veterans, Mechanical ventilation, SARS-CoV-2, business.industry, Gastroenterology, COVID-19, Proton Pump Inhibitors, Retrospective cohort study, Middle Aged, Respiration, Artificial, Intensive care unit, Hospitalization, Intensive Care Units, Outcome and Process Assessment, Health Care, Cohort, Propensity score matching, Female, business
Abstract

The adverse effects of proton pump inhibitors (PPIs) have been documented for pneumonia; however, there is no consensus regarding whether the use of PPIs might be harmful regarding the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this regard, we aimed to measure the potential associations of the current use of PPIs with the infection rates of COVID-19 among patients who underwent SARS-CoV-2 testing.Data were derived from a Korean nationwide cohort study with propensity score matching. We included 132 316 patients older than 18 years who tested for SARS-CoV-2 between 1 January and 15 May 2020. Endpoints were SARS-CoV-2 positivity (primary) and severe clinical outcomes of COVID-19 (secondary: admission to intensive care unit, administration of invasive ventilation or death).In the entire cohort, there were 111 911 non-users, 14 163 current PPI users and 6242 past PPI users. After propensity score matching, the SARS-CoV-2 test positivity rate was not associated with the current or past use of PPIs. Among patients with confirmed COVID-19, the current use of PPIs conferred a 79% greater risk of severe clinical outcomes of COVID-19, while the relationship with the past use of PPIs remained insignificant. Current PPI use starting within the previous 30 days was associated with a 90% increased risk of severe clinical outcomes of COVID-19.Patients taking PPIs are at increased risk for severe clinical outcomes of COVID-19 but not susceptible to SARS-CoV-2 infection. This suggests that physicians need to assess benefit-risk assessments in the management of acid-related diseases amid the COVID-19 pandemic.

Published
2021
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30. The effects of metabolic traits, lifestyle factors and pharmacological interventions on liver fat: a mendelian randomisation study

Author

Shuai Yuan, Jie Chen, Marijana Vujkovic, Kyong-Mi Chang, Xue Li, Susanna C Larsson, and Dipender Gill

Abstract

ObjectiveTo investigate the effects of metabolic traits, lifestyle factors, and drug interventions on liver fat using the mendelian randomisation paradigm.DesignMendelian randomisation study.SettingPublicly available summary level data from genome-wide association studies.ParticipantsGenome-wide association studies of 32 974 to 1 407 282 individuals who were predominantly of European descent.ExposuresGenetic variants predicting nine metabolic traits, six lifestyle factors, four lipid lowering drug targets, three antihypertensive drug targets, and genetic association estimates formagnetic resonance imaging measured liver fat.Main outcome measuresMendelian randomisation analysis was used to investigate the effects of these exposures on liver fat, incorporating sensitivity analyses that relaxed the requisite modelling assumptions.ResultsGenetically predicted liability to obesity, type 2 diabetes, elevated blood pressure, elevated triglyceride levels, cigarette smoking, and sedentary time watching television were associated with higher levels of liver fat. Genetically predicted lipid lowering drug effects were not associated with liver fat; however, β blocker and calcium channel blocker antihypertensive drug effects were associated with lower levels of liver fat.ConclusionThese analyses provide evidence of a causal effect of various metabolic traits, lifestyle factors, and drug targets on liver fat. The findings complement existing epidemiological associations, further provide mechanistic insight, and potentially supports a role for drug interventions in reducing the burden of hepatic steatosis and related disease. Further clinical study is now warranted to investigate the relevance of these genetic analyses for patient care.

Published
2022

31. Characteristics of Older Patients With Immunotolerant Chronic Hepatitis B Virus Infection

Author

Jordan J. Feld, Wendy C. King, Marc G. Ghany, Kyong-Mi Chang, Norah Terrault, Robert P. Perrillo, Mandana Khalili, Amanda S. Hinerman, Harry LA. Janssen, and Anna S. Lok

Subjects
Hepatology, Gastroenterology
Abstract

Most patients in the immunotolerant (IT) phase of chronic hepatitis B (CHB) transition to the immune active (IA-hepatitis B surface antigen [HBeAg]+) phase by early adulthood. We examined characteristics of adults in the IT vs IA-HBeAg+ phase and rate of transition from IT to other phases of CHB, with a focus on those ≥40 years.Demographic, clinical, and virologic characteristics of participants in the Hepatitis B Research Network adult cohort study with IT CHB (alanine aminotransferase ≤1.5 × upper limit of normal, hepatitis B virus DNA10Of 107 adult IT participants, 52 (48%) were30, 33 (31%) were 30 to 39, and 22 (21%) were ≥40 years old (maximum, 71 years). Among IT groups, the proportion born in Asia and duration of CHB were greater in older IT groups, but virologic and liver disease characteristics were similar. Compared with IA-HBeAg+ participants (n = 192), IT participants were younger, fewer were men, more were Asian, and platelets, qHBsAg, and qHBeAg levels were higher. Similar differences were observed when comparisons were made with the ≥40 years IT group. Among IT participants, 60 (56%) transitioned during 206 person-years of follow-up. The phase transition rate per 100 person-years was highest in the30 years group (33.0 [95% confidence interval [CI], 23.4-46.7]) vs the 30 to 39 years group (24.8 [95% CI, 15.6-39.4]) and ≥40 group (27.4 [95% CI, 14.8-50.9]), but 95% CIs overlapped.In a large North American population, over 50% of adults in the IT phase of CHB were ≥30 years and 20% were ≥40 years old, but older IT patients had similar characteristics and rates of transition as younger IT patients.

Published
2023
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32. A

Author

Anurag, Verma, Jessica, Minnier, Emily S, Wan, Jennifer E, Huffman, Lina, Gao, Jacob, Joseph, Yuk-Lam, Ho, Wen-Chih, Wu, Kelly, Cho, Bryan R, Gorman, Nallakkandi, Rajeevan, Saiju, Pyarajan, Helene, Garcon, James B, Meigs, Yan V, Sun, Peter D, Reaven, John E, McGeary, Ayako, Suzuki, Joel, Gelernter, Julie A, Lynch, Jeffrey M, Petersen, Seyedeh Maryam, Zekavat, Pradeep, Natarajan, Sharvari, Dalal, Darshana N, Jhala, Mehrdad, Arjomandi, Elise, Gatsby, Kristine E, Lynch, Robert A, Bonomo, Matthew, Freiberg, Gita A, Pathak, Jin J, Zhou, Curtis J, Donskey, Ravi K, Madduri, Quinn S, Wells, Rose D L, Huang, Renato, Polimanti, Kyong-Mi, Chang, Katherine P, Liao, Philip S, Tsao, Peter W F, Wilson, Adriana M, Hung, Christopher J, O'Donnell, John M, Gaziano, Richard L, Hauger, Sudha K, Iyengar, and Shiuh-Wen, Luoh

Subjects
Hospitalization, Polymorphism, Genetic, Genotype, Humans, COVID-19, Genetic Predisposition to Disease, Mucin-5B, Idiopathic Pulmonary Fibrosis
Published
2022

33. Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes

Author

Stephen R. Atkinson, Philip S. Tsao, Evangelos Evangelou, VA Million Veteran Program, Karl-Heinz Herzig, David E. Kaplan, Marina Serper, Behrooz Z. Alizadeh, Benjamin F. Voight, Xiyun Jiang, Julie A. Lynch, Dipender Gill, Danish Saleheen, Marjo-Riitta Järvelin, André G. Uitterlinden, Rui Pinto, Raha Pazoki, Peter J. van der Most, Paul Elliott, Verena Zuber, Matthias Farlik, Ioanna Tzoulaki, Mark Thursz, Harold Snieder, Marijana Vujkovic, Christopher J. O'Donnell, Mohsen Ghanbari, Kyung Min Lee, Saredo Said, Matthias Wielscher, Kyong-Mi Chang, M. Arfan Ikram, Joshua Elliott, Rotonya M. Carr, Robert J. de Knegt, Abbas Dehghan, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Medical Research Council (MRC), Epidemiology, Gastroenterology & Hepatology, and Internal Medicine

Subjects
Enzymologic, Male, 0301 basic medicine, LD SCORE REGRESSION, General Physics and Astronomy, Physiology, Genome-wide association study, Cardiovascular, Oral and gastrointestinal, DISEASE, Cohort Studies, Rotterdam Study, 0302 clinical medicine, Risk Factors, Databases, Genetic, 2.1 Biological and endogenous factors, Aetiology, POPULATION, RISK, education.field_of_study, Multidisciplinary, biology, medicine.diagnostic_test, HERITABILITY, Liver Disease, Alanine Transaminase, gamma-Glutamyltransferase, Single Nucleotide, Middle Aged, Heart Disease, Liver, Cardiovascular Diseases, VA Million Veteran Program, MENDELIAN RANDOMIZATION, Female, 030211 gastroenterology & hepatology, HEALTH, Science, Population, Single-nucleotide polymorphism, BIOBANK, Polymorphism, Single Nucleotide, Gene Expression Regulation, Enzymologic, White People, General Biochemistry, Genetics and Molecular Biology, Databases, 03 medical and health sciences, Insulin resistance, Metabolic Diseases, Genetic, Lifelines Cohort Study, SDG 3 - Good Health and Well-being, Mendelian randomization, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Polymorphism, GENOME-WIDE ASSOCIATION, education, Metabolic and endocrine, METAANALYSIS, Aged, Genetic testing, business.industry, General Chemistry, Mendelian Randomization Analysis, Alkaline Phosphatase, Lipid Metabolism, medicine.disease, Good Health and Well Being, 030104 developmental biology, Gene Expression Regulation, Alanine transaminase, biology.protein, Insulin Resistance, Digestive Diseases, business, Genome-Wide Association Study
Abstract

Plasma levels of liver enzymes provide insights into hepatic function and related diseases. Here, the authors perform a genome-wide association study on three liver enzymes, identifying genetic variants associated with their plasma concentration as well as links to metabolic and cardiovascular diseases.Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.

Published
2021

34. Hepatitis C virus: virology and life cycle

Author

Chang Wook Kim and Kyong-Mi Chang

Subjects
Hepatitis C virus, Virology, Life cycle, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Hepatitis C virus (HCV) is a positive sense, single-stranded RNA virus in the Flaviviridae family. It causes acute hepatitis with a high propensity for chronic infection. Chronic HCV infection can progress to severe liver disease including cirrhosis and hepatocellular carcinoma. In the last decade, our basic understanding of HCV virology and life cycle has advanced greatly with the development of HCV cell culture and replication systems. Our ability to treat HCV infection has also been improved with the combined use of interferon, ribavirin and small molecule inhibitors of the virally encoded NS3/4A protease, although better therapeutic options are needed with greater antiviral efficacy and less toxicity. In this article, we review various aspects of HCV life cycle including viral attachment, entry, fusion, viral RNA translation, posttranslational processing, HCV replication, viral assembly and release. Each of these steps provides potential targets for novel antiviral therapeutics to cure HCV infection and prevent the adverse consequences of progressive liver disease.

Published
2013
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35. Multiple Roles for Hepatitis B and C Viruses and the Host in the Development of Hepatocellular Carcinoma

Author

Kirk J. Wangensteen and Kyong-Mi Chang

Subjects
0301 basic medicine, Carcinoma, Hepatocellular, Cirrhosis, Sustained Virologic Response, medicine.medical_treatment, Inflammation, medicine.disease_cause, Article, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, neoplasms, Hepatology, Host (biology), business.industry, Liver Neoplasms, Immunotherapy, Hepatitis B, Endoplasmic Reticulum Stress, medicine.disease, Hepatitis C, digestive system diseases, 030104 developmental biology, Hepatocellular carcinoma, Immunology, 030211 gastroenterology & hepatology, medicine.symptom, Carcinogenesis, business
Abstract

Chronic hepatitis B and C viral infections are major risk factors for hepatocellular carcinoma (HCC) in the United States and worldwide. Direct and indirect mechanisms of viral infection lead to the development of HCC. Chronic viral infection leads to inflammation and liver damage, culminating in cirrhosis, the penultimate step in the progression toward HCC. Host, viral, and environmental factors likely interact to promote oncogenesis. Clinical considerations include recommendations for screening for HCC in persons at risk, treatment with antivirals, and an emerging role for immunotherapy in HCC. We pose unanswered questions regarding HCC susceptibility and pathogenesis in the setting of chronic hepatitis B and C.

Published
2020
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36. Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program

Author

Derek Klarin, Shefali Setia Verma, Renae Judy, Ozan Dikilitas, Brooke N. Wolford, Ishan Paranjpe, Michael G. Levin, Cuiping Pan, Catherine Tcheandjieu, Joshua M. Spin, Julie Lynch, Themistocles L. Assimes, Linn Åldstedt Nyrønning, Erney Mattsson, Todd L. Edwards, Josh Denny, Eric Larson, Ming Ta Michael Lee, David Carrell, Yanfei Zhang, Gail P. Jarvik, Ali G. Gharavi, John Harley, Frank Mentch, Jennifer A. Pacheco, Hakon Hakonarson, Anne Heidi Skogholt, Laurent Thomas, Maiken Elvestad Gabrielsen, Kristian Hveem, Jonas Bille Nielsen, Wei Zhou, Lars Fritsche, Jie Huang, Pradeep Natarajan, Yan V. Sun, Scott L. DuVall, Daniel J. Rader, Kelly Cho, Kyong-Mi Chang, Peter W.F. Wilson, Christopher J. O’Donnell, Sekar Kathiresan, Salvatore T. Scali, Scott A. Berceli, Cristen Willer, Gregory T. Jones, Matthew J. Bown, Girish Nadkarni, Iftikhar J. Kullo, Marylyn Ritchie, Scott M. Damrauer, Philip S. Tsao, J. Michael Gaziano, Rachel Ramoni, Jean Beckham, Jim Breeling, Grant Huang, Sumitra Muralidhar, J.P. Casas Romero, Jennifer Moser, Stacey B. Whitbourne, Jessica V. Brewer, John Concato, Stuart Warren, Dean P. Argyres, Brady Stephens, Mary T. Brophy, Donald E. Humphries, Nhan Do, Shahpoor Shayan, Xuan-Mai T. Nguyen, Saiju Pyarajan, Elizabeth Hauser, Yan Sun, Hongyu Zhao, Peter Wilson, Rachel McArdle, Louis Dellitalia, Clement J. Zablocki, Jeffrey Whittle, John Wells, Salvador Gutierrez, Gretchen Gibson, Laurence Kaminsky, Gerardo Villareal, Scott Kinlay, Junzhe Xu, Mark Hamner, Kathlyn Sue Haddock, Sujata Bhushan, Pran Iruvanti, Michael Godschalk, Zuhair Ballas, Malcolm Buford, Stephen Mastorides, Jon Klein, Nora Ratcliffe, Hermes Florez, Alan Swann, Maureen Murdoch, Peruvemba Sriram, Shing Shing Yeh, Ronald Washburn, Darshana Jhala, Samuel Aguayo, David Cohen, Satish Sharma, John Callaghan, Kris Ann Oursler, Mary Whooley, Sunil Ahuja, Amparo Gutierrez, Ronald Schifman, Jennifer Greco, Michael Rauchman, Richard Servatius, Mary Oehlert, Agnes Wallbom, Ronald Fernando, Timothy Morgan, Todd Stapley, Scott Sherman, Gwenevere Anderson, Philip Tsao, Elif Sonel, Edward Boyko, Laurence Meyer, Samir Gupta, Joseph Fayad, Adriana Hung, Jack Lichy, Robin Hurley, Brooks Robey, and Robert Striker

Subjects
medicine.medical_specialty, Genome-wide association study, 030204 cardiovascular system & hematology, Aortic disease, aortic diseases, 03 medical and health sciences, 0302 clinical medicine, Aneurysm, Original Research Articles, Physiology (medical), Internal medicine, medicine, Humans, Veterans, 030304 developmental biology, Cardiovascular mortality, 0303 health sciences, genome-wide association study, business.industry, medicine.disease, Abdominal aortic aneurysm, Genetic architecture, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, aneurysm, Cardiology, Cardiology and Cardiovascular Medicine, business, Aortic Aneurysm, Abdominal
Abstract

Supplemental Digital Content is available in the text., Background: Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability. Methods: We performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease. Results: Through a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24–1.66]; P=1.6×10−6), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97–1.15]; P=0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratioPRS, 1.26 [95% CI, 1.18–1.36]; PPRS=2.7×10−11 per SD increase in PRS), independent of family history and smoking risk factors (odds ratioPRS+family history+smoking, 1.24 [95% CI, 1.14–1.35]; PPRS=1.27×10−6). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines. Conclusions: We identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.

Published
2020
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37. Genetic determinants of increased body mass index mediate the effect of smoking on increased risk for type 2 diabetes but not coronary artery disease

Author

Peter W.F. Wilson, Scott M. Damrauer, Philip S. Tsao, Yan V. Sun, Kelly Cho, Zhuoran Ding, Christopher J. O'Donnell, Marijana Vujkovic, Kyung Min Lee, VA Million Veteran Program, Julie A. Lynch, Themistocles L. Assimes, Kyong-Mi Chang, Benjamin F. Voight, Christopher S. Thom, and Michael G. Levin

Subjects
AcademicSubjects/SCI01140, medicine.medical_specialty, Diabetes risk, Coronary Artery Disease, Type 2 diabetes, Biology, Polymorphism, Single Nucleotide, Body Mass Index, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Mendelian randomization, Genetics, medicine, Humans, Genetic Predisposition to Disease, Obesity, 030212 general & internal medicine, Risk factor, Association Studies Article, Molecular Biology, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Smoking, Mendelian Randomization Analysis, General Medicine, medicine.disease, Diabetes Mellitus, Type 2, Body mass index, Genome-Wide Association Study
Abstract

Clinical observations have linked tobacco smoking with increased type 2 diabetes risk. Mendelian randomization analysis has recently suggested smoking may be a causal risk factor for type 2 diabetes. However, this association could be mediated by additional risk factors correlated with smoking behavior, which have not been investigated. We hypothesized that body mass index (BMI) could help to explain the association between smoking and diabetes risk. First, we confirmed that genetic determinants of smoking initiation increased risk for type 2 diabetes (OR 1.21, 95% CI: 1.15–1.27, P = 1 × 10−12) and coronary artery disease (CAD; OR 1.21, 95% CI: 1.16–1.26, P = 2 × 10−20). Additionally, 2-fold increased smoking risk was positively associated with increased BMI (~0.8 kg/m2, 95% CI: 0.54–0.98 kg/m2, P = 1.8 × 10−11). Multivariable Mendelian randomization analyses showed that BMI accounted for nearly all the risk smoking exerted on type 2 diabetes (OR 1.06, 95% CI: 1.01–1.11, P = 0.03). In contrast, the independent effect of smoking on increased CAD risk persisted (OR 1.12, 95% CI: 1.08–1.17, P = 3 × 10−8). Causal mediation analyses agreed with these estimates. Furthermore, analysis using individual-level data from the Million Veteran Program independently replicated the association of smoking behavior with CAD (OR 1.24, 95% CI: 1.12–1.37, P = 2 × 10−5), but not type 2 diabetes (OR 0.98, 95% CI: 0.89–1.08, P = 0.69), after controlling for BMI. Our findings support a model whereby genetic determinants of smoking increase type 2 diabetes risk indirectly through their relationship with obesity. Smokers should be advised to stop smoking to limit type 2 diabetes and CAD risk. Therapeutic efforts should consider pathophysiology relating smoking and obesity.

Published
2020
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38. Serum alanine aminotransferase flares in chronic hepatitis B infection: the good and the bad

Author

Jordan J. Feld, Marc G. Ghany, Anna S.F. Lok, Henry Lik-Yuen Chan, Kumar Visvanathan, Kyong-Mi Chang, and Harry L.A. Janssen

Subjects
Male, Hepatitis B virus, medicine.medical_specialty, Kupffer Cells, T-Lymphocytes, Symptom Flare Up, Context (language use), Disease, medicine.disease_cause, Antiviral Agents, Article, 03 medical and health sciences, Hepatitis B, Chronic, 0302 clinical medicine, Humans, Medicine, Clinical significance, Hepatitis B e Antigens, skin and connective tissue diseases, Intensive care medicine, Hepatitis, B-Lymphocytes, Hepatitis B Surface Antigens, Hepatology, business.industry, Myeloid-Derived Suppressor Cells, Gastroenterology, Alanine Transaminase, Nucleosides, Hepatitis B, medicine.disease, Killer Cells, Natural, Chronic infection, 030220 oncology & carcinogenesis, DNA, Viral, Cytokines, Female, 030211 gastroenterology & hepatology, Chemokines, business
Abstract

Chronic hepatitis B virus (HBV) infection follows a dynamic and variable course. At different stages in the disease, hepatitis flares may occur, which can be challenging to predict and manage. Flares are believed to be primarily immune-mediated and may mark transitions to inactive disease or even clearance of infection, but in certain scenarios they may also lead to hepatic decompensation or even death. As such, understanding the significance of flares in different patient populations and different clinical scenarios, is critical for optimal management. In this review, what is known about flares in different stages of chronic HBV infection is summarized. Descriptions of flares in the natural history of chronic infection along with definitions of flares, is followed by a summary of the immunological mechanisms underlying flares. Flares are then described in different clinical scenarios including on-treatment flares, treatment withdrawal flares, reactivation flares with immunosuppressive therapy and pregnancy-related flares. Each section reviews existing knowledge and highlights key unanswered questions that need to be addressed to improve our understanding of flares, hopefully providing insights into their pathogenesis which can be used to improve current clinical management and ideally to further development of new curative therapeutic approaches for HBV.

Published
2020
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39. Coronary Artery Disease Risk of Familial Hypercholesterolemia Genetic Variants Independent of Clinically Observed Longitudinal Cholesterol Exposure

Author

Shoa L, Clarke, Catherine, Tcheandjieu, Austin T, Hilliard, Kyung Min, Lee, Julie, Lynch, Kyong-Mi, Chang, Donald, Miller, Joshua W, Knowles, Christopher, O'Donnell, Philip S, Tsao, Daniel J, Rader, Peter W, Wilson, Yan V, Sun, J Michael, Gaziano, and Themistocles L, Assimes

Subjects
Hyperlipoproteinemia Type II, Receptors, LDL, Case-Control Studies, Humans, General Medicine, Cholesterol, LDL, Coronary Artery Disease, Proprotein Convertase 9
Abstract

Background: Familial hypercholesterolemia (FH) genetic variants confer risk for coronary artery disease independent of LDL-C (low-density lipoprotein cholesterol) when considering a single measurement. In real clinical settings, longitudinal LDL-C data are often available through the electronic health record. It is unknown whether genetic testing for FH variants provides additional risk-stratifying information once longitudinal LDL-C is considered. Methods: We used the extensive electronic health record data available through the Million Veteran Program to conduct a nested case-control study. The primary outcome was coronary artery disease, derived from electronic health record codes for acute myocardial infarction and coronary revascularization. Incidence density sampling was used to match case/control exposure windows, defined by the date of the first LDL-C measurement to the date of the first coronary artery disease code of the index case. Adjustments for the first, maximum, or mean LDL-C were analyzed. FH variants in LDLR , APOB , and PCSK9 (Proprotein convertase subtilisin/kexin type 9) were assessed by custom genotype array. Results: In a cohort of 23 091 predominantly prevalent cases at enrollment and 230 910 matched controls, FH variant carriers had an increased risk for coronary artery disease (odds ratio [OR], 1.53 [95% CI, 1.24–1.89]). Adjusting for mean LDL-C led to the greatest attenuation of the risk estimate, but significant risk remained (odds ratio, 1.33 [95% CI, 1.08–1.64]). The degree of attenuation was not affected by the number and the spread of LDL-C measures available. Conclusions: The risk associated with carrying an FH variant cannot be fully captured by the LDL-C data available in the electronic health record, even when considering multiple LDL-C measurements spanning more than a decade.

Published
2022

40. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author

Niamh Mullins, JooEun Kang, Adrian I. Campos, Jonathan R.I. Coleman, Alexis C. Edwards, Hanga Galfalvy, Daniel F. Levey, Adriana Lori, Andrey Shabalin, Anna Starnawska, Mei-Hsin Su, Hunna J. Watson, Mark Adams, Swapnil Awasthi, Michael Gandal, Jonathan D. Hafferty, Akitoyo Hishimoto, Minsoo Kim, Satoshi Okazaki, Ikuo Otsuka, Stephan Ripke, Erin B. Ware, Andrew W. Bergen, Wade H. Berrettini, Martin Bohus, Harry Brandt, Xiao Chang, Wei J. Chen, Hsi-Chung Chen, Steven Crawford, Scott Crow, Emily DiBlasi, Philibert Duriez, Fernando Fernández-Aranda, Manfred M. Fichter, Steven Gallinger, Stephen J. Glatt, Philip Gorwood, Yiran Guo, Hakon Hakonarson, Katherine A. Halmi, Hai-Gwo Hwu, Sonia Jain, Stéphane Jamain, Susana Jiménez-Murcia, Craig Johnson, Allan S. Kaplan, Walter H. Kaye, Pamela K. Keel, James L. Kennedy, Kelly L. Klump, Dong Li, Shih-Cheng Liao, Klaus Lieb, Lisa Lilenfeld, Chih-Min Liu, Pierre J. Magistretti, Christian R. Marshall, James E. Mitchell, Eric T. Monson, Richard M. Myers, Dalila Pinto, Abigail Powers, Nicolas Ramoz, Stefan Roepke, Vsevolod Rozanov, Stephen W. Scherer, Christian Schmahl, Marcus Sokolowski, Michael Strober, Laura M. Thornton, Janet Treasure, Ming T. Tsuang, Stephanie H. Witt, D. Blake Woodside, Zeynep Yilmaz, Lea Zillich, Rolf Adolfsson, Ingrid Agartz, Tracy M. Air, Martin Alda, Lars Alfredsson, Ole A. Andreassen, Adebayo Anjorin, Vivek Appadurai, María Soler Artigas, Sandra Van der Auwera, M. Helena Azevedo, Nicholas Bass, Claiton H.D. Bau, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Joanna M. Biernacka, Tim B. Bigdeli, Elisabeth B. Binder, Michael Boehnke, Marco P. Boks, Rosa Bosch, David L. Braff, Richard Bryant, Monika Budde, Enda M. Byrne, Wiepke Cahn, Miguel Casas, Enrique Castelao, Jorge A. Cervilla, Boris Chaumette, Sven Cichon, Aiden Corvin, Nicholas Craddock, David Craig, Franziska Degenhardt, Srdjan Djurovic, Howard J. Edenberg, Ayman H. Fanous, Jerome C. Foo, Andreas J. Forstner, Mark Frye, Janice M. Fullerton, Justine M. Gatt, Pablo V. Gejman, Ina Giegling, Hans J. Grabe, Melissa J. Green, Eugenio H. Grevet, Maria Grigoroiu-Serbanescu, Blanca Gutierrez, Jose Guzman-Parra, Steven P. Hamilton, Marian L. Hamshere, Annette Hartmann, Joanna Hauser, Stefanie Heilmann-Heimbach, Per Hoffmann, Marcus Ising, Ian Jones, Lisa A. Jones, Lina Jonsson, René S. Kahn, John R. Kelsoe, Kenneth S. Kendler, Stefan Kloiber, Karestan C. Koenen, Manolis Kogevinas, Bettina Konte, Marie-Odile Krebs, Mikael Landén, Jacob Lawrence, Marion Leboyer, Phil H. Lee, Douglas F. Levinson, Calwing Liao, Jolanta Lissowska, Susanne Lucae, Fermin Mayoral, Susan L. McElroy, Patrick McGrath, Peter McGuffin, Andrew McQuillin, Sarah E. Medland, Divya Mehta, Ingrid Melle, Yuri Milaneschi, Philip B. Mitchell, Esther Molina, Gunnar Morken, Preben Bo Mortensen, Bertram Müller-Myhsok, Caroline Nievergelt, Vishwajit Nimgaonkar, Markus M. Nöthen, Michael C. O’Donovan, Roel A. Ophoff, Michael J. Owen, Carlos Pato, Michele T. Pato, Brenda W.J.H. Penninx, Jonathan Pimm, Giorgio Pistis, James B. Potash, Robert A. Power, Martin Preisig, Digby Quested, Josep Antoni Ramos-Quiroga, Andreas Reif, Marta Ribasés, Vanesa Richarte, Marcella Rietschel, Margarita Rivera, Andrea Roberts, Gloria Roberts, Guy A. Rouleau, Diego L. Rovaris, Dan Rujescu, Cristina Sánchez-Mora, Alan R. Sanders, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Alessandro Serretti, Jianxin Shi, Stanley I. Shyn, Lea Sirignano, Pamela Sklar, Olav B. Smeland, Jordan W. Smoller, Edmund J.S. Sonuga-Barke, Gianfranco Spalletta, John S. Strauss, Beata Świątkowska, Maciej Trzaskowski, Gustavo Turecki, Laura Vilar-Ribó, John B. Vincent, Henry Völzke, James T.R. Walters, Cynthia Shannon Weickert, Thomas W. Weickert, Myrna M. Weissman, Leanne M. Williams, Naomi R. Wray, Clement C. Zai, Allison E. Ashley-Koch, Jean C. Beckham, Elizabeth R. Hauser, Michael A. Hauser, Nathan A. Kimbrel, Jennifer H. Lindquist, Benjamin McMahon, David W. Oslin, Xuejun Qin, Esben Agerbo, Anders D. Børglum, Gerome Breen, Annette Erlangsen, Tõnu Esko, Joel Gelernter, David M. Hougaard, Ronald C. Kessler, Henry R. Kranzler, Qingqin S. Li, Nicholas G. Martin, Andrew M. McIntosh, Ole Mors, Merete Nordentoft, Catherine M. Olsen, David Porteous, Robert J. Ursano, Danuta Wasserman, Thomas Werge, David C. Whiteman, Cynthia M. Bulik, Hilary Coon, Ditte Demontis, Anna R. Docherty, Po-Hsiu Kuo, Cathryn M. Lewis, J. John Mann, Miguel E. Rentería, Daniel J. Smith, Eli A. Stahl, Murray B. Stein, Fabian Streit, Virginia Willour, Douglas M. Ruderfer, Manuel Mattheisen, Abdel Abdellaoui, Mark J. Adams, Till F.M. Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T.F. Beekman, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Jane Hvarregaard Christensen, Toni-Kim Clarke, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Josef Frank, Héléna A. Gaspar, Michael Gill, Fernando S. Goes, Scott D. Gordon, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Dorret I. Boomsma, Udo Dannlowski, E.J.C. de Geus, J. Raymond Depaulo, Enrico Domenici, Katharina Domschke, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas F. Hansen, Stefan Herms, Ian B. Hickie, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M. Howard, Rick Jansen, Eric Jorgenson, James A. Knowles, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert M. Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Christel M. Middeldorp, Evelin Mihailov, Lili Milani, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O’Reilly, Hogni Oskarsson, Caroline Hayward, Andrew C. Heath, Glyn Lewis, Pamela A.F. Madden, Patrik K. Magnusson, Andres Metspalu, Sara A. Paciga, Nancy L. Pedersen, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Wouter J. Peyrot, Danielle Posthuma, Jorge A. Quiroz, Per Qvist, John P. Rice, Brien P. Riley, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Engilbert Sigurdsson, Grant C.B. Sinnamon, Johannes H. Smit, Hreinn Stefansson, Stacy Steinberg, Jana Strohmaier, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Alexander Viktorin, Peter M. Visscher, Yunpeng Wang, Bradley T. Webb, Roy H. Perlis, David J. Porteous, Catherine Schaefer, Kari Stefansson, Henning Tiemeier, Rudolf Uher, Patrick F. Sullivan, Kevin S. O’Connell, Brandon Coombes, Zhen Qiao, Thomas D. Als, Sigrid Børte, Alexander W. Charney, Ole Kristian Drange, Michael J. Gandal, Saskia P. Hagenaars, Masashi Ikeda, Nolan Kamitaki, Kristi Krebs, Georgia Panagiotaropoulou, Brian M. Schilder, Laura G. Sloofman, Bendik S. Winsvold, Hong-Hee Won, Liliya Abramova, Kristina Adorjan, Mariam Al Eissa, Diego Albani, Ney Alliey-Rodriguez, Verneri Antilla, Anastasia Antoniou, Ji Hyun Baek, Michael Bauer, Eva C. Beins, Sarah E. Bergen, Armin Birner, Erlend Bøen, Murielle Brum, Ben M. Brumpton, Nathalie Brunkhorst-Kanaan, William Byerley, Murray Cairns, Miquel Casas, Pablo Cervantes, Cristiana Cruceanu, Alfredo Cuellar-Barboza, Julie Cunningham, David Curtis, Piotr M. Czerski, Anders M. Dale, Nina Dalkner, Friederike S. David, Amanda L. Dobbyn, Athanassios Douzenis, Torbjørn Elvsåshagen, I. Nicol Ferrier, Alessia Fiorentino, Tatiana M. Foroud, Liz Forty, Oleksandr Frei, Nelson B. Freimer, Louise Frisén, Katrin Gade, Julie Garnham, Ian R. Gizer, Katherine Gordon-Smith, Tiffany A. Greenwood, José Guzman-Parra, Kyooseob Ha, Magnus Haraldsson, Martin Hautzinger, Urs Heilbronner, Dennis Hellgren, Peter A. Holmans, Laura Huckins, Jessica S. Johnson, Janos L. Kalman, Yoichiro Kamatani, Sarah Kittel-Schneider, Maria Koromina, Thorsten M. Kranz, Michiaki Kubo, Ralph Kupka, Steven A. Kushner, Catharina Lavebratt, Markus Leber, Heon-Jeong Lee, Shawn E. Levy, Catrin Lewis, Martin Lundberg, Sigurdur H. Magnusson, Adam Maihofer, Dolores Malaspina, Eirini Maratou, Lina Martinsson, Nathaniel W. McGregor, James D. McKay, Helena Medeiros, Vincent Millischer, Jennifer L. Moran, Derek W. Morris, Thomas W. Mühleisen, Niamh O’Brien, Claire O’Donovan, Loes M. Olde Loohuis, Lilijana Oruc, Sergi Papiol, Antonio F. Pardiñas, Amy Perry, Andrea Pfennig, Evgenia Porichi, Towfique Raj, Mark H. Rapaport, J. Raymond DePaulo, Eline J. Regeer, Fabio Rivas, Julian Roth, Panos Roussos, Fanny Senner, Sally Sharp, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Maria Soler Artigas, Anne T. Spijker, Dan J. Stein, Chikashi Terao, Claudio Toma, Paul Tooney, Evangelia-Eirini Tsermpini, Marquis P. Vawter, Helmut Vedder, Simon Xi, Wei Xu, Jessica Mei Kay Yang, Allan H. Young, Hannah Young, Peter P. Zandi, Hang Zhou, null HUNT All-In Psychiatry, Gulja Babadjanova, Lena Backlund, Susanne Bengesser, Douglas H.R. Blackwood, Vaughan J. Carr, Stanley Catts, Dimitris Dikeos, Bruno Etain, Panagiotis Ferentinos, Micha Gawlik, Elliot S. Gershon, Frans Henskens, Jan Hillert, Kyung Sue Hong, Christina M. Hultman, Kristian Hveem, Nakao Iwata, Assen V. Jablensky, George Kirov, Christine Lochner, Carmel Loughland, Carol A. Mathews, Francis J. McMahon, Patricia Michie, Bryan Mowry, Benjamin M. Neale, Caroline M. Nievergelt, Ketil J. Oedegaard, Tomas Olsson, Chris Pantelis, George P. Patrinos, Eva Z. Reininghaus, Takeo Saito, Ulrich Schall, Martin Schalling, Rodney J. Scott, Eystein Stordal, Arne E. Vaaler, Eduard Vieta, Irwin D. Waldman, John-Anker Zwart, John I. Nurnberger, Arianna Di Florio, Roger A.H. Adan, Tetsuya Ando, Harald Aschauer, Jessica H. Baker, Vladimir Bencko, Andreas Birgegård, Joseph M. Boden, Ilka Boehm, Claudette Boni, Vesna Boraska Perica, Katharina Buehren, Roland Burghardt, Laura Carlberg, Matteo Cassina, Maurizio Clementi, Roger D. Cone, Philippe Courtet, James J. Crowley, Unna N. Danner, Oliver S.P. Davis, Martina de Zwaan, George Dedoussis, Daniela Degortes, Janiece E. DeSocio, Danielle M. Dick, Christian Dina, Monika Dmitrzak-Weglarz, Elisa Docampo Martinez, Laramie E. Duncan, Karin Egberts, Morten Mattingsdal, Sara McDevitt, Ingrid Meulenbelt, Nadia Micali, James Mitchell, Karen Mitchell, Palmiero Monteleone, Alessio Maria Monteleone, Melissa A. Munn-Chernoff, Benedetta Nacmias, Marie Navratilova, Ioanna Ntalla, Julie K. O’Toole, Leonid Padyukov, Aarno Palotie, Jacques Pantel, Hana Papezova, Richard Parker, John F. Pearson, Stefan Ehrlich, Geòrgia Escaramís, Thomas Espeseth, Xavier Estivill, Anne Farmer, Angela Favaro, Krista Fischer, James A.B. Floyd, Manuel Föcker, Lenka Foretova, Monica Forzan, Christopher S. Franklin, Giovanni Gambaro, Johanna Giuranna, Paola Giusti-Rodríquez, Fragiskos Gonidakis, Scott Gordon, Monica Gratacos Mayora, Sébastien Guillaume, Ken B. Hanscombe, Konstantinos Hatzikotoulas, Johannes Hebebrand, Sietske G. Helder, Anjali K. Henders, Beate Herpertz-Dahlmann, Wolfgang Herzog, Anke Hinney, L. John Horwood, Christopher Hübel, Liselotte V. Petersen, Kirstin L. Purves, Anu Raevuori, Ted Reichborn-Kjennerud, Valdo Ricca, Samuli Ripatti, Franziska Ritschel, Marion Roberts, Filip Rybakowski, Paolo Santonastaso, André Scherag, Ulrike Schmidt, Nicholas J. Schork, Alexandra Schosser, Jochen Seitz, Lenka Slachtova, P. Eline Slagboom, Margarita C.T. Slof-Op ‘t Landt, Agnieszka Slopien, Nicole Soranzo, Sandro Sorbi, Lorraine Southam, Vidar W. Steen, Laura M. Huckins, James I. Hudson, Hartmut Imgart, Hidetoshi Inoko, Vladimir Janout, Jennifer Jordan, Antonio Julià, Gursharan Kalsi, Deborah Kaminská, Jaakko Kaprio, Leila Karhunen, Andreas Karwautz, Martien J.H. Kas, Martin A. Kennedy, Anna Keski-Rahkonen, Kirsty Kiezebrink, Youl-Ri Kim, Katherine M. Kirk, Lars Klareskog, Gun Peggy S. Knudsen, Janne T. Larsen, Stephanie Le Hellard, Virpi M. Leppä, Paul Lichtenstein, Bochao Danae Lin, Astri Lundervold, Jurjen Luykx, Mario Maj, Katrin Mannik, Sara Marsal, Garret D. Stuber, Jin P. Szatkiewicz, Ioanna Tachmazidou, Elena Tenconi, Alfonso Tortorella, Federica Tozzi, Artemis Tsitsika, Marta Tyszkiewicz-Nwafor, Konstantinos Tziouvas, Annemarie A. van Elburg, Eric F. van Furth, Tracey D. Wade, Gudrun Wagner, Esther Walton, H. Erich Wichmann, Elisabeth Widen, Shuyang Yao, Eleftheria Zeggini, Stephanie Zerwas, Stephan Zipfel, Martin Jungkunz, Lydie Dietl, Cornelia E. Schwarze, Norbert Dahmen, Björn H. Schott, Arian Mobascher, Silvia Crivelli, Michelle F. Dennis, Phillip D. Harvey, Bruce W. Carter, Jennifer E. Huffman, Daniel Jacobson, Ravi Madduri, Maren K. Olsen, John Pestian, J. Michael Gaziano, Sumitra Muralidhar, Rachel Ramoni, Jean Beckham, Kyong-Mi Chang, Christopher J. O’Donnell, Philip S. Tsao, James Breeling, Grant Huang, J.P. Casas Romero, Jennifer Moser, Stacey B. Whitbourne, Jessica V. Brewer, Mihaela Aslan, Todd Connor, Dean P. Argyres, Brady Stephens, Mary T. Brophy, Donald E. Humphries, Luis E. Selva, Nhan Do, Shahpoor Shayan, Kelly Cho, Saiju Pyarajan, Elizabeth Hauser, Yan Sun, Hongyu Zhao, Peter Wilson, Rachel McArdle, Louis Dellitalia, Kristin Mattocks, John Harley, Clement J. Zablocki, Jeffrey Whittle, Frank Jacono, Salvador Gutierrez, Gretchen Gibson, Kimberly Hammer, Laurence Kaminsky, Gerardo Villareal, Scott Kinlay, Junzhe Xu, Mark Hamner, Roy Mathew, Sujata Bhushan, Pran Iruvanti, Michael Godschalk, Zuhair Ballas, Douglas Ivins, Stephen Mastorides, Jonathan Moorman, Saib Gappy, Jon Klein, Nora Ratcliffe, Hermes Florez, Olaoluwa Okusaga, Maureen Murdoch, Peruvemba Sriram, Shing Shing Yeh, Neeraj Tandon, Darshana Jhala, Samuel Aguayo, David Cohen, Satish Sharma, Suthat Liangpunsakul, Kris Ann Oursler, Mary Whooley, Sunil Ahuja, Joseph Constans, Paul Meyer, Jennifer Greco, Michael Rauchman, Richard Servatius, Melinda Gaddy, Agnes Wallbom, Timothy Morgan, Todd Stapley, Scott Sherman, George Ross, Philip Tsao, Patrick Strollo, Edward Boyko, Laurence Meyer, Samir Gupta, Mostaqul Huq, Joseph Fayad, Adriana Hung, Jack Lichy, Robin Hurley, Brooks Robey, Robert Striker, Dietl, Lydie, Schwarze, Cornelia E., Dahmen, Norbert, Schott, Björn H., Nöthen, Markus M., Ripke, Stephan, Mobascher, Arian, Rujescu, Dan, Lieb, Klaus, Roepke, Stefan, Schmahl, Christian, Bohus, Martin, Rietschel, Marcella, Crivelli, Silvia, Dennis, Michelle F., Harvey, Phillip D., Carter, Bruce W., Huffman, Jennifer E., Jacobson, Daniel, Madduri, Ravi, Olsen, Maren K., Pestian, John, Gaziano, J. Michael, Muralidhar, Sumitra, Ramoni, Rachel, Beckham, Jean, Chang, Kyong-Mi, O'Donnell, Christopher J., Tsao, Philip S., Breeling, James, Huang, Grant, Romero, J. P. Casas, Moser, Jennifer, Whitbourne, Stacey B., Brewer, Jessica V., Aslan, Mihaela, Connor, Todd, Argyres, Dean P., Stephens, Brady, Brophy, Mary T., Humphries, Donald E., Selva, Luis E., Do, Nhan, Shayan, Shahpoor, Cho, Kelly, Pyarajan, Saiju, Hauser, Elizabeth, Sun, Yan, Zhao, Hongyu, Wilson, Peter, McArdle, Rachel, Dellitalia, Louis, Mattocks, Kristin, Harley, John, Zablocki, Clement J., Whittle, Jeffrey, Jacono, Frank, Gutierrez, Salvador, Gibson, Gretchen, Hammer, Kimberly, Kaminsky, Laurence, Villareal, Gerardo, Kinlay, Scott, Xu, Junzhe, Hamner, Mark, Mathew, Roy, Bhushan, Sujata, Iruvanti, Pran, Godschalk, Michael, Ballas, Zuhair, Ivins, Douglas, Mastorides, Stephen, Moorman, Jonathan, Gappy, Saib, Klein, Jon, Ratcliffe, Nora, Florez, Hermes, Okusaga, Olaoluwa, Murdoch, Maureen, Sriram, Peruvemba, Yeh, Shing Shing, Tandon, Neeraj, Jhala, Darshana, Aguayo, Samuel, Cohen, David, Sharma, Satish, Liangpunsakul, Suthat, Oursler, Kris Ann, Whooley, Mary, Ahuja, Sunil, Constans, Joseph, Meyer, Paul, Greco, Jennifer, Rauchman, Michael, Servatius, Richard, Gaddy, Melinda, Wallbom, Agnes, Morgan, Timothy, Stapley, Todd, Sherman, Scott, Ross, George, Tsao, Philip, Strollo, Patrick, Boyko, Edward, Meyer, Laurence, Gupta, Samir, Huq, Mostaqul, Fayad, Joseph, Hung, Adriana, Lichy, Jack, Hurley, Robin, Robey, Brooks, Striker, Robert, Wray, Naomi R., Mattheisen, Manuel, Trzaskowski, Maciej, Byrne, Enda M., Abdellaoui, Abdel, Adams, Mark J., Agerbo, Esben, Air, Tracy M., Andlauer, Till F. M., Bacanu, Silviu-Alin, Bækvad-Hansen, Marie, Beekman, Aartjan T. F., Bigdeli, Tim B., Binder, Elisabeth B., Bryois, Julien, Buttenschøn, Henriette N., Bybjerg-Grauholm, Jonas, Cai, Na, Castelao, Enrique, Christensen, Jane Hvarregaard, Clarke, Toni-Kim, Coleman, Jonathan R. I., Colodro-Conde, Lucía, Couvy-Duchesne, Baptiste, Craddock, Nick, Crawford, Gregory E., Davies, Gail, Degenhardt, Franziska, Derks, Eske M., Direk, Nese, Dolan, Conor V., Dunn, Erin C., Eley, Thalia C., Escott-Price, Valentina, Hassan Kiadeh, Farnush Farhadi, Finucane, Hilary K., Foo, Jerome C., Forstner, Andreas J., Frank, Josef, Gaspar, Héléna A., Gill, Michael, Goes, Fernando S., Gordon, Scott D., Weinsheimer, Shantel Marie, Wellmann, Jürgen, Willemsen, Gonneke, Witt, Stephanie H., Wu, Yang, Xi, Hualin S., Yang, Jian, Zhang, Futao, Arolt, Volker, Baune, Bernhard T., Berger, Klaus, Boomsma, Dorret I., Cichon, Sven, Dannlowski, Udo, de Geus, E. J. C., DePaulo, J. Raymond, Domenici, Enrico, Domschke, Katharina, Esko, Tõnu, Grabe, Hans J., Hamilton, Steven P., Grove, Jakob, Hall, Lynsey S., Hansen, Christine Søholm, Hansen, Thomas F., Herms, Stefan, Hickie, Ian B., Hoffmann, Per, Homuth, Georg, Horn, Carsten, Hottenga, Jouke-Jan, Hougaard, David M., Howard, David M., Ising, Marcus, Jansen, Rick, Jones, Ian, Jones, Lisa A., Jorgenson, Eric, Knowles, James A., Kohane, Isaac S., Kraft, Julia, Kretzschmar, Warren W., Kutalik, Zoltán, Li, Yihan, Lind, Penelope A., MacIntyre, Donald J., MacKinnon, Dean F., Maier, Robert M., Maier, Wolfgang, Marchini, Jonathan, Mbarek, Hamdi, McGrath, Patrick, McGuffin, Peter, Medland, Sarah E., Mehta, Divya, Middeldorp, Christel M., Mihailov, Evelin, Milaneschi, Yuri, Milani, Lili, Mondimore, Francis M., Montgomery, Grant W., Mostafavi, Sara, Mullins, Niamh, Nauck, Matthias, Ng, Bernard, Nivard, Michel G., Nyholt, Dale R., O'Reilly, Paul F., Oskarsson, Hogni, Hayward, Caroline, Heath, Andrew C., Kendler, Kenneth S., Kloiber, Stefan, Lewis, Glyn, Li, Qingqin S., Lucae, Susanne, Madden, Pamela A. F., Magnusson, Patrik K., Martin, Nicholas G., McIntosh, Andrew M., Metspalu, Andres, Mors, Ole, Mortensen, Preben Bo, Müller-Myhsok, Bertram, Nordentoft, Merete, O'Donovan, Michael C., Paciga, Sara A., Pedersen, Nancy L., Owen, Michael J., Painter, Jodie N., Pedersen, Carsten Bøcker, Pedersen, Marianne Giørtz, Peterson, Roseann E., Peyrot, Wouter J., Pistis, Giorgio, Posthuma, Danielle, Quiroz, Jorge A., Qvist, Per, Rice, John P., Riley, Brien P., Rivera, Margarita, Mirza, Saira Saeed, Schoevers, Robert, Schulte, Eva C., Shen, Ling, Shi, Jianxin, Shyn, Stanley I., Sigurdsson, Engilbert, Sinnamon, Grant C. B., Smit, Johannes H., Smith, Daniel J., Stefansson, Hreinn, Steinberg, Stacy, Streit, Fabian, Strohmaier, Jana, Tansey, Katherine E., Teismann, Henning, Teumer, Alexander, Thompson, Wesley, Thomson, Pippa A., Thorgeirsson, Thorgeir E., Traylor, Matthew, Treutlein, Jens, Trubetskoy, Vassily, Uitterlinden, André G., Umbricht, Daniel, Van der Auwera, Sandra, van Hemert, Albert M., Viktorin, Alexander, Visscher, Peter M., Wang, Yunpeng, Webb, Bradley T., Penninx, Brenda W. J. H., Perlis, Roy H., Porteous, David J., Potash, James B., Preisig, Martin, Schaefer, Catherine, Schulze, Thomas G., Smoller, Jordan W., Stefansson, Kari, Tiemeier, Henning, Uher, Rudolf, Völzke, Henry, Weissman, Myrna M., Werge, Thomas, Lewis, Cathryn M., Levinson, Douglas F., Breen, Gerome, Børglum, Anders D., Sullivan, Patrick F., O'Connell, Kevin S., Coombes, Brandon, Qiao, Zhen, Als, Thomas D., Børte, Sigrid, Charney, Alexander W., Drange, Ole Kristian, Gandal, Michael J., Hagenaars, Saskia P., Ikeda, Masashi, Kamitaki, Nolan, Kim, Minsoo, Krebs, Kristi, Panagiotaropoulou, Georgia, Schilder, Brian M., Sloofman, Laura G., Winsvold, Bendik S., Won, Hong-Hee, Abramova, Liliya, Adorjan, Kristina, Al Eissa, Mariam, Albani, Diego, Alliey-Rodriguez, Ney, Anjorin, Adebayo, Antilla, Verneri, Antoniou, Anastasia, Awasthi, Swapnil, Baek, Ji Hyun, Bass, Nicholas, Bauer, Michael, Beins, Eva C., Bergen, Sarah E., Birner, Armin, Bøen, Erlend, Boks, Marco P., Bosch, Rosa, Brum, Murielle, Brumpton, Ben M., Brunkhorst-Kanaan, Nathalie, Budde, Monika, Byerley, William, Cairns, Murray, Casas, Miquel, Cervantes, Pablo, Cruceanu, Cristiana, Cuellar-Barboza, Alfredo, Cunningham, Julie, Curtis, David, Czerski, Piotr M., Dale, Anders M., Dalkner, Nina, David, Friederike S., Djurovic, Srdjan, Dobbyn, Amanda L., Douzenis, Athanassios, Elvsåshagen, Torbjørn, Ferrier, I. Nicol, Fiorentino, Alessia, Foroud, Tatiana M., Forty, Liz, Frei, Oleksandr, Freimer, Nelson B., Frisén, Louise, Gade, Katrin, Garnham, Julie, Gelernter, Joel, Gizer, Ian R., Gordon-Smith, Katherine, Greenwood, Tiffany A., Guzman-Parra, José, Ha, Kyooseob, Haraldsson, Magnus, Hautzinger, Martin, Heilbronner, Urs, Hellgren, Dennis, Holmans, Peter A., Huckins, Laura, Jamain, Stéphane, Johnson, Jessica S., Kalman, Janos L., Kamatani, Yoichiro, Kennedy, James L., Kittel-Schneider, Sarah, Kogevinas, Manolis, Koromina, Maria, Kranz, Thorsten M., Kranzler, Henry R., Kubo, Michiaki, Kupka, Ralph, Kushner, Steven A., Lavebratt, Catharina, Lawrence, Jacob, Leber, Markus, Lee, Heon-Jeong, Lee, Phil H., Levy, Shawn E., Lewis, Catrin, Liao, Calwing, Lundberg, Martin, Magnusson, Sigurdur H., Maihofer, Adam, Malaspina, Dolores, Maratou, Eirini, Martinsson, Lina, McGregor, Nathaniel W., McKay, James D., Medeiros, Helena, Millischer, Vincent, Moran, Jennifer L., Morris, Derek W., Mühleisen, Thomas W., O'Brien, Niamh, O'Donovan, Claire, Olde Loohuis, Loes M., Oruc, Lilijana, Papiol, Sergi, Pardiñas, Antonio F., Perry, Amy, Pfennig, Andrea, Porichi, Evgenia, Quested, Digby, Raj, Towfique, Rapaport, Mark H., Regeer, Eline J., Rivas, Fabio, Roth, Julian, Roussos, Panos, Ruderfer, Douglas M., Sánchez-Mora, Cristina, Senner, Fanny, Sharp, Sally, Shilling, Paul D., Sirignano, Lea, Slaney, Claire, Smeland, Olav B., Sobell, Janet L., Artigas, Maria Soler, Spijker, Anne T., Stein, Dan J., Strauss, John S., Świątkowska, Beata, Terao, Chikashi, Toma, Claudio, Tooney, Paul, Tsermpini, Evangelia-Eirini, Vawter, Marquis P., Vedder, Helmut, Walters, James T. R., Xi, Simon, Xu, Wei, Kay Yang, Jessica Mei, Young, Allan H., Young, Hannah, Zandi, Peter P., Zhou, Hang, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Alda, Martin, Alfredsson, Lars, Babadjanova, Gulja, Backlund, Lena, Bellivier, Frank, Bengesser, Susanne, Berrettini, Wade H., Blackwood, Douglas H. R., Boehnke, Michael, Carr, Vaughan J., Catts, Stanley, Corvin, Aiden, Craddock, Nicholas, Dikeos, Dimitris, Etain, Bruno, Ferentinos, Panagiotis, Frye, Mark, Fullerton, Janice M., Gawlik, Micha, Gershon, Elliot S., Green, Melissa J., Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Henskens, Frans, Hillert, Jan, Hong, Kyung Sue, Hultman, Christina M., Hveem, Kristian, Iwata, Nakao, Jablensky, Assen V., Kahn, René S., Kelsoe, John R., Kirov, George, Landén, Mikael, Leboyer, Marion, Lissowska, Jolanta, Lochner, Christine, Loughland, Carmel, Mathews, Carol A., Mayoral, Fermin, McElroy, Susan L., McMahon, Francis J., Melle, Ingrid, Michie, Patricia, Mitchell, Philip B., Morken, Gunnar, Mowry, Bryan, Myers, Richard M., Neale, Benjamin M., Nievergelt, Caroline M., Oedegaard, Ketil J., Olsson, Tomas, Pantelis, Chris, Pato, Carlos, Pato, Michele T., Patrinos, George P., Ramos-Quiroga, Josep Antoni, Reif, Andreas, Reininghaus, Eva Z., Ribasés, Marta, Rouleau, Guy A., Saito, Takeo, Schall, Ulrich, Schalling, Martin, Schofield, Peter R., Scott, Laura J., Scott, Rodney J., Serretti, Alessandro, Weickert, Cynthia Shannon, Stordal, Eystein, Turecki, Gustavo, Vaaler, Arne E., Vieta, Eduard, Vincent, John B., Waldman, Irwin D., Weickert, Thomas W., Zwart, John-Anker, Biernacka, Joanna M., Nurnberger, John I., Edenberg, Howard J., Stahl, Eli A., McQuillin, Andrew, Di Florio, Arianna, Ophoff, Roel A., Andreassen, Ole A., Adan, Roger A. H., Ando, Tetsuya, Aschauer, Harald, Baker, Jessica H., Bencko, Vladimir, Bergen, Andrew W., Birgegård, Andreas, Boden, Joseph M., Boehm, Ilka, Boni, Claudette, Perica, Vesna Boraska, Brandt, Harry, Buehren, Katharina, Bulik, Cynthia M., Burghardt, Roland, Carlberg, Laura, Cassina, Matteo, Clementi, Maurizio, Cone, Roger D., Courtet, Philippe, Crawford, Steven, Crow, Scott, Crowley, James J., Danner, Unna N., Davis, Oliver S. P., de Zwaan, Martina, Dedoussis, George, Degortes, Daniela, DeSocio, Janiece E., Dick, Danielle M., Dina, Christian, Dmitrzak-Weglarz, Monika, Martinez, Elisa Docampo, Duncan, Laramie E., Egberts, Karin, Marshall, Christian R., Mattingsdal, Morten, McDevitt, Sara, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, James, Mitchell, Karen, Monteleone, Palmiero, Monteleone, Alessio Maria, Munn-Chernoff, Melissa A., Nacmias, Benedetta, Navratilova, Marie, Ntalla, Ioanna, Olsen, Catherine M., O'Toole, Julie K., Padyukov, Leonid, Palotie, Aarno, Pantel, Jacques, Papezova, Hana, Parker, Richard, Pearson, John F., Ehrlich, Stefan, Escaramís, Geòrgia, Espeseth, Thomas, Estivill, Xavier, Farmer, Anne, Favaro, Angela, Fernández-Aranda, Fernando, Fichter, Manfred M., Fischer, Krista, Floyd, James A. B., Föcker, Manuel, Foretova, Lenka, Forzan, Monica, Franklin, Christopher S., Gallinger, Steven, Gambaro, Giovanni, Giegling, Ina, Giuranna, Johanna, Giusti-Rodríquez, Paola, Gonidakis, Fragiskos, Gordon, Scott, Gorwood, Philip, Mayora, Monica Gratacos, Guillaume, Sébastien, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine A., Hanscombe, Ken B., Hatzikotoulas, Konstantinos, Hebebrand, Johannes, Helder, Sietske G., Henders, Anjali K., Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Hinney, Anke, Horwood, L. John, Hübel, Christopher, Petersen, Liselotte V., Pinto, Dalila, Purves, Kirstin L., Raevuori, Anu, Ramoz, Nicolas, Reichborn-Kjennerud, Ted, Ricca, Valdo, Ripatti, Samuli, Ritschel, Franziska, Roberts, Marion, Rybakowski, Filip, Santonastaso, Paolo, Scherag, André, Scherer, Stephen W., Schmidt, Ulrike, Schork, Nicholas J., Schosser, Alexandra, Seitz, Jochen, Slachtova, Lenka, Slagboom, P. Eline, Slof-Op 't Landt, Margarita C. T., Slopien, Agnieszka, Soranzo, Nicole, Sorbi, Sandro, Southam, Lorraine, Steen, Vidar W., Strober, Michael, Huckins, Laura M., Hudson, James I., Imgart, Hartmut, Inoko, Hidetoshi, Janout, Vladimir, Jiménez-Murcia, Susana, Johnson, Craig, Jordan, Jennifer, Julià, Antonio, Kalsi, Gursharan, Kaminská, Deborah, Kaplan, Allan S., Kaprio, Jaakko, Karhunen, Leila, Karwautz, Andreas, Kas, Martien J. H., Kaye, Walter H., Kennedy, Martin A., Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Kim, Youl-Ri, Kirk, Katherine M., Klareskog, Lars, Klump, Kelly L., Knudsen, Gun Peggy S., Larsen, Janne T., Le Hellard, Stephanie, Leppä, Virpi M., Li, Dong, Lichtenstein, Paul, Lilenfeld, Lisa, Lin, Bochao Danae, Lundervold, Astri, Luykx, Jurjen, Magistretti, Pierre J., Maj, Mario, Mannik, Katrin, Marsal, Sara, Stuber, Garret D., Szatkiewicz, Jin P., Tachmazidou, Ioanna, Tenconi, Elena, Thornton, Laura M., Tortorella, Alfonso, Tozzi, Federica, Treasure, Janet, Tsitsika, Artemis, Tyszkiewicz-Nwafor, Marta, Tziouvas, Konstantinos, van Elburg, Annemarie A., van Furth, Eric F., Wade, Tracey D., Wagner, Gudrun, Walton, Esther, Watson, Hunna J., Whiteman, David C., Wichmann, H. Erich, Widen, Elisabeth, Woodside, D. Blake, Yao, Shuyang, Yilmaz, Zeynep, Zeggini, Eleftheria, Zerwas, Stephanie, Zipfel, Stephan, Jungkunz, Martin, Mullins, N., Kang, J., Campos, A. I., Coleman, J. R. I., Edwards, A. C., Galfalvy, H., Levey, D. F., Lori, A., Shabalin, A., Starnawska, A., Su, M. -H., Watson, H. J., Adams, M., Awasthi, S., Gandal, M., Hafferty, J. D., Hishimoto, A., Kim, M., Okazaki, S., Otsuka, I., Ripke, S., Ware, E. B., Bergen, A. W., Berrettini, W. H., Bohus, M., Brandt, H., Chang, X., Chen, W. J., Chen, H. -C., Crawford, S., Crow, S., Diblasi, E., Duriez, P., Fernandez-Aranda, F., Fichter, M. M., Gallinger, S., Glatt, S. J., Gorwood, P., Guo, Y., Hakonarson, H., Halmi, K. A., Hwu, H. -G., Jain, S., Jamain, S., Jimenez-Murcia, S., Johnson, C., Kaplan, A. S., Kaye, W. H., Keel, P. K., Kennedy, J. L., Klump, K. L., Li, D., Liao, S. -C., Lieb, K., Lilenfeld, L., Liu, C. -M., Magistretti, P. J., Marshall, C. R., Mitchell, J. E., Monson, E. T., Myers, R. M., Pinto, D., Powers, A., Ramoz, N., Roepke, S., Rozanov, V., Scherer, S. W., Schmahl, C., Sokolowski, M., Strober, M., Thornton, L. M., Treasure, J., Tsuang, M. T., Witt, S. H., Woodside, D. B., Yilmaz, Z., Zillich, L., Adolfsson, R., Agartz, I., Air, T. M., Alda, M., Alfredsson, L., Andreassen, O. A., Anjorin, A., Appadurai, V., Soler Artigas, M., Van der Auwera, S., Azevedo, M. H., Bass, N., Bau, C. H. D., Baune, B. T., Bellivier, F., Berger, K., Biernacka, J. M., Bigdeli, T. B., Binder, E. B., Boehnke, M., Boks, M. P., Bosch, R., Braff, D. L., Bryant, R., Budde, M., Byrne, E. M., Cahn, W., Casas, M., Castelao, E., Cervilla, J. A., Chaumette, B., Cichon, S., Corvin, A., Craddock, N., Craig, D., Degenhardt, F., Djurovic, S., Edenberg, H. J., Fanous, A. H., Foo, J. C., Forstner, A. J., Frye, M., Fullerton, J. M., Gatt, J. M., Gejman, P. V., Giegling, I., Grabe, H. J., Green, M. J., Grevet, E. H., Grigoroiu-Serbanescu, M., Gutierrez, B., Guzman-Parra, J., Hamilton, S. P., Hamshere, M. L., Hartmann, A., Hauser, J., Heilmann-Heimbach, S., Hoffmann, P., Ising, M., Jones, I., Jones, L. A., Jonsson, L., Kahn, R. S., Kelsoe, J. R., Kendler, K. S., Kloiber, S., Koenen, K. C., Kogevinas, M., Konte, B., Krebs, M. -O., Landen, M., Lawrence, J., Leboyer, M., Lee, P. H., Levinson, D. F., Liao, C., Lissowska, J., Lucae, S., Mayoral, F., Mcelroy, S. L., Mcgrath, P., Mcguffin, P., Mcquillin, A., Medland, S. E., Mehta, D., Melle, I., Milaneschi, Y., Mitchell, P. B., Molina, E., Morken, G., Mortensen, P. B., Muller-Myhsok, B., Nievergelt, C., Nimgaonkar, V., Nothen, M. M., O'Donovan, M. C., Ophoff, R. A., Owen, M. J., Pato, C., Pato, M. T., Penninx, B. W. J. H., Pimm, J., Pistis, G., Potash, J. B., Power, R. A., Preisig, M., Quested, D., Ramos-Quiroga, J. A., Reif, A., Ribases, M., Richarte, V., Rietschel, M., Rivera, M., Roberts, A., Roberts, G., Rouleau, G. A., Rovaris, D. L., Rujescu, D., Sanchez-Mora, C., Sanders, A. R., Schofield, P. R., Schulze, T. G., Scott, L. J., Serretti, A., Shi, J., Shyn, S. I., Sirignano, L., Sklar, P., Smeland, O. B., Smoller, J. W., Sonuga-Barke, E. J. S., Spalletta, G., Strauss, J. S., Swiatkowska, B., Trzaskowski, M., Turecki, G., Vilar-Ribo, L., Vincent, J. B., Volzke, H., Walters, J. T. R., Shannon Weickert, C., Weickert, T. W., Weissman, M. M., Williams, L. M., Wray, N. R., Zai, C. C., Ashley-Koch, A. E., Beckham, J. C., Hauser, E. R., Hauser, M. A., Kimbrel, N. A., Lindquist, J. H., Mcmahon, B., Oslin, D. W., Qin, X., Mattheisen, M., Abdellaoui, A., Adams, M. J., Agerbo, E., Andlauer, T. F. M., Bacanu, S. -A., Baekvad-Hansen, M., Beekman, A. T. F., Bryois, J., Buttenschon, H. N., Bybjerg-Grauholm, J., Cai, N., Christensen, J. H., Clarke, T. -K., Colodro-Conde, L., Couvy-Duchesne, B., Crawford, G. E., Davies, G., Derks, E. M., Direk, N., Dolan, C. V., Dunn, E. C., Eley, T. C., Escott-Price, V., Hassan Kiadeh, F. F., Finucane, H. K., Frank, J., Gaspar, H. A., Gill, M., Goes, F. S., Gordon, S. D., Weinsheimer, S. M., Wellmann, J., Willemsen, G., Wu, Y., Xi, H. S., Yang, J., Zhang, F., Arolt, V., Boomsma, D. I., Dannlowski, U., Depaulo, J. 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C., Shen, L., Sigurdsson, E., Sinnamon, G. C. B., Smit, J. H., Smith, D. J., Stefansson, H., Steinberg, S., Streit, F., Strohmaier, J., Tansey, K. E., Teismann, H., Teumer, A., Thompson, W., Thomson, P. A., Thorgeirsson, T. E., Traylor, M., Treutlein, J., Trubetskoy, V., Uitterlinden, A. G., Umbricht, D., der Auwera, S. V., van Hemert, A. M., Viktorin, A., Visscher, P. M., Wang, Y., Webb, B. T., Perlis, R. H., Porteous, D. J., Schaefer, C., Stefansson, K., Tiemeier, H., Uher, R., Werge, T., Lewis, C. M., Breen, G., Borglum, A. D., Sullivan, P. F., O'Connell, K. S., Coombes, B., Qiao, Z., Als, T. D., Borte, S., Charney, A. W., Drange, O. K., Gandal, M. J., Hagenaars, S. P., Ikeda, M., Kamitaki, N., Krebs, K., Panagiotaropoulou, G., Schilder, B. M., Sloofman, L. G., Winsvold, B. S., Won, H. -H., Abramova, L., Adorjan, K., Al Eissa, M., Albani, D., Alliey-Rodriguez, N., Antilla, V., Antoniou, A., Baek, J. H., Bauer, M., Beins, E. C., Bergen, S. 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J., Wasserman, D., Coon, H., Demontis, D., Docherty, A. R., Kuo, P. -H., Mann, J. J., Renteria, M. E., Stein, M. 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E.Z., Saito T., Schall U., Schalling M., Scott R.J., Weickert C.S., Stordal E., Vaaler A.E., Vieta E., Waldman I.D., Zwart J.-A., Nurnberger J.I., Stahl E.A., Di Florio A., Adan R.A.H., Ando T., Aschauer H., Baker J.H., Bencko V., Birgegard A., Boden J.M., Boehm I., Boni C., Perica V.B., Buehren K., Bulik C.M., Burghardt R., Carlberg L., Cassina M., Clementi M., Cone R.D., Courtet P., Crowley J.J., Danner U.N., Davis O.S.P., de Zwaan M., Dedoussis G., Degortes D., DeSocio J.E., Dick D.M., Dina C., Dmitrzak-Weglarz M., Martinez E.D., Duncan L.E., Egberts K., Mattingsdal M., McDevitt S., Meulenbelt I., Micali N., Mitchell J., Mitchell K., Monteleone P., Monteleone A.M., Munn-Chernoff M.A., Nacmias B., Navratilova M., Ntalla I., Olsen C.M., O'Toole J.K., Padyukov L., Palotie A., Pantel J., Papezova H., Parker R., Pearson J.F., Ehrlich S., Escaramis G., Espeseth T., Estivill X., Farmer A., Favaro A., Fischer K., Floyd J.A.B., Focker M., Foretova L., Forzan M., Franklin C.S., Gambaro G., Giuranna J., Giusti-Rodriquez P., Gonidakis F., Gordon S., Mayora M.G., Guillaume S., Hanscombe K.B., Hatzikotoulas K., Hebebrand J., Helder S.G., Henders A.K., Herpertz-Dahlmann B., Herzog W., Hinney A., Horwood L.J., Hubel C., Petersen L.V., Purves K.L., Raevuori A., Reichborn-Kjennerud T., Ricca V., Ripatti S., Ritschel F., Roberts M., Rybakowski F., Santonastaso P., Scherag A., Schmidt U., Schork N.J., Schosser A., Seitz J., Slachtova L., Slagboom P.E., Slof-Op 't Landt M.C.T., Slopien A., Soranzo N., Sorbi S., Southam L., Steen V.W., Huckins L.M., Hudson J.I., Imgart H., Inoko H., Janout V., Jordan J., Julia A., Kalsi G., Kaminska D., Kaprio J., Karhunen L., Karwautz A., Kas M.J.H., Kennedy M.A., Keski-Rahkonen A., Kiezebrink K., Kim Y.-R., Kirk K.M., Klareskog L., Knudsen G.P.S., Larsen J.T., Le Hellard S., Leppa V.M., Lichtenstein P., Lin B.D., Lundervold A., Luykx J., Maj M., Mannik K., Marsal S., Stuber G.D., Szatkiewicz J.P., Tachmazidou I., Tenconi E., Tortorella A., Tozzi F., Tsitsika A., Tyszkiewicz-Nwafor M., Tziouvas K., van Elburg A.A., van Furth E.F., Wade T.D., Wagner G., Walton E., Whiteman D.C., Wichmann H.E., Widen E., Yao S., Zeggini E., Zerwas S., Zipfel S., Jungkunz M., Dietl L., Schwarze C.E., Dahmen N., Schott B.H., Mobascher A., Crivelli S., Dennis M.F., Harvey P.D., Carter B.W., Huffman J.E., Jacobson D., Madduri R., Olsen M.K., Pestian J., Gaziano J.M., Muralidhar S., Ramoni R., Beckham J., Chang K.-M., O'Donnell C.J., Tsao P.S., Breeling J., Huang G., Romero J.P.C., Moser J., Whitbourne S.B., Brewer J.V., Aslan M., Connor T., Argyres D.P., Stephens B., Brophy M.T., Humphries D.E., Selva L.E., Do N., Shayan S., Cho K., Pyarajan S., Hauser E., Sun Y., Zhao H., Wilson P., McArdle R., Dellitalia L., Mattocks K., Harley J., Zablocki C.J., Whittle J., Jacono F., Gutierrez S., Gibson G., Hammer K., Kaminsky L., Villareal G., Kinlay S., Xu J., Hamner M., Mathew R., Bhushan S., Iruvanti P., Godschalk M., Ballas Z., Ivins D., Mastorides S., Moorman J., Gappy S., Klein J., Ratcliffe N., Florez H., Okusaga O., Murdoch M., Sriram P., Yeh S.S., Tandon N., Jhala D., Aguayo S., Cohen D., Sharma S., Liangpunsakul S., Oursler K.A., Whooley M., Ahuja S., Constans J., Meyer P., Greco J., Rauchman M., Servatius R., Gaddy M., Wallbom A., Morgan T., Stapley T., Sherman S., Ross G., Tsao P., Strollo P., Boyko E., Meyer L., Gupta S., Huq M., Fayad J., Hung A., Lichy J., Hurley R., Robey B., Striker R., Erlangsen A., Kessler R.C., Porteous D., Ursano R.J., Wasserman D., Coon H., Demontis D., Docherty A.R., Kuo P.-H., Mann J.J., Renteria M.E., Stein M.B., and Willour V.

Subjects
LD SCORE REGRESSION, Genome-wide association study, Suicide, Attempted, 3124 Neurology and psychiatry, 0302 clinical medicine, Risk Factors, Insomnia, Suicide attempt, GWAS, Suïcidi, Depression (differential diagnoses), Cause of death, Psychiatry, 0303 health sciences, Factors de risc en les malalties, Mental Disorders, Genetic Correlation, Genome-wide Association Study, Pleiotropy, Polygenicity, Suicide, Suicide Attempt, DEPRESSION, 3. Good health, Genetic correlation, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Depressive Disorder, Major, Mental illness, Cohort, SEX, medicine.symptom, Human, medicine.medical_specialty, Risk factors in diseases, BF, Locus (genetics), BEHAVIORS, Psykiatri, EVENTS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, ddc:610, GENOME-WIDE ASSOCIATION, IDEATION, Socioeconomic status, METAANALYSIS, Biological Psychiatry, 030304 developmental biology, business.industry, Risk Factor, Genetic architecture, THOUGHTS, RC0321, business, Malalties mentals, 030217 neurology & neurosurgery
Abstract

Statistical analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu), which is supported by the Office of Research Infrastructure of the National Institutes of Health (Grant Nos. S10OD018522 and S10OD026880). This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. This work was funded by the National Institutes of Health (Grant Nos. R01MH116269 and R01MH121455 [to DMR]), NIGMS of the National Institutes of Health (Grant No. T32GM007347 [to JK]), and the Brain & Behavior Research Foundation (NARSAD Young Investigator Award No. 29551 [to NM])., BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., Office of Research Infrastructure of the National Institutes of Health S10OD018522 S10OD026880, United States Department of Health & Human Services, National Institutes of Health (NIH) - USA R01MH116269 R01MH121455, NIH National Institute of General Medical Sciences (NIGMS) T32GM007347 NARSAD 29551

Published
2022
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41. Current Best Practice in Hepatitis B Management and Understanding Long-term Prospects for Cure

Author

David Yardeni, Kyong-Mi Chang, and Marc G. Ghany

Subjects
Hepatitis B virus, Hepatitis B Surface Antigens, Hepatitis B, Chronic, Hepatology, Liver Neoplasms, DNA, Viral, Gastroenterology, Humans, DNA, Circular, Hepatitis B, Virus Replication, Antiviral Agents
Abstract

The hepatitis B virus (HBV) is a major cause of cirrhosis and hepatocellular carcinoma worldwide. Despite an effective vaccine, the prevalence of chronic infection remains high. Current therapy is effective at achieving on-treatment, but not off-treatment, viral suppression. Loss of hepatitis B surface antigen, the best surrogate marker of off-treatment viral suppression, is associated with improved clinical outcomes. Unfortunately, this end point is rarely achieved with current therapy because of their lack of effect on covalently closed circular DNA, the template of viral transcription and genome replication. Major advancements in our understanding of HBV virology along with better understanding of immunopathogenesis have led to the development of a multitude of novel therapeutic approaches with the prospect of achieving functional cure (hepatitis B surface antigen loss) and perhaps complete cure (clearance of covalently closed circular DNA and integrated HBV DNA). This review will cover current best practice for managing chronic HBV infection and emerging novel therapies for HBV infection and their prospect for cure.

Published
2023
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42. Linear slope of serial FIB-4 measurements predicts liver-related complications and correlates with cirrhosis-associated genetic variants among patients with ALT-based NAFLD phenotype

Author

Craig Teerlink, David E. Kaplan, Marijana Vujkovic, Benjamin Voight, Kyong-Mi Chang, Julie Lynch, Scott Duvall, Tori Anglin, Timothy Morgan, Linus Schwantes-An Tae-Hwi, Trina Norden-Krichmar, Daniel Dochterman, Poornima Devineni, Philip Tsao, and Carolin Victoria Schneider

Subjects
Hepatology
Published
2022
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43. A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program

Author

Sudha K Iyengar, Shiuh-Wen Luoh, Julie Lynch, Jimmy T. Efird, Kelly Cho, Anurag Verma, Ravi Madduri, Noah L. Tsao, Lauren O Thomann, Juan P Casas, Saiju Pyarajan, Richard L. Hauger, Benjamin F. Voight, Marijana Vujkovic, Kerry L. Ivey, Christopher O Donnell, J. Michael Gaziano, Michael G. Levin, Rotonya M. Carr, Dana C. Crawford, Giulio Genovese, Scott M. Damrauer, Gita A. Pathak, Yuk-Lam Ho, Katherine P. Liao, Alexander G. Bick, Pradeep Natarajan, Kyong-Mi Chang, Renato Polimanti, Lauren Costa, Hongyu Zhao, Marylyn D. Ritchie, Philip S. Tsao, Maryam Zekavat, and Adriana Hung

Subjects
Genetics, Cancer Research, Systemic lupus erythematosus, business.industry, Genetic genealogy, COVID-19, Locus (genetics), Odds ratio, Phenome, medicine.disease, Polymorphism, Single Nucleotide, Article, Genetic architecture, ABO blood group system, medicine, Humans, business, Molecular Biology, Veterans Affairs, Genetic Association Studies, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Genome-Wide Association Study, Veterans
Abstract

The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n=35) or hospitalization (n=42) due to severe COVID-19 using genome-wide association summary from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (nrs495828= 53 and nrs505922=59); strongest association with venous embolism, odds ratio (ORrs495828 1.33 (p=1.32 × 10−199), and thrombosis ORrs505922 1.33, p=2.2 ×10−265. Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p=4.12 × 10−191; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p=2.26× 10−12. The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p=6.48 ×10−23, lupus OR 0.84, p=3.97 × 10−06. PheWAS stratified by genetic ancestry demonstrated differences in genotype-phenotype associations across ancestry. LMNA (rs581342) associated with neutropenia OR 1.29 p=4.1 × 10−13 among Veterans of African ancestry but not European. Overall, we observed a shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets.

Published
2021

44. Multi-Trait Genome-Wide Association Study of Atherosclerosis Detects Novel Pleiotropic Loci

Author

Tiffany R. Bellomo, William P. Bone, Brian Y. Chen, Katerina A. B. Gawronski, David Zhang, Joseph Park, Michael Levin, Noah Tsao, Derek Klarin, Julie Lynch, Themistocles L. Assimes, J. Michael Gaziano, Peter W. Wilson, Kelly Cho, Marijana Vujkovic, the VA Million Veteran Program, Christopher J. O’Donnell, Kyong-Mi Chang, Philip S. Tsao, Daniel J. Rader, Marylyn D. Ritchie, Scott M. Damrauer, and Benjamin F. Voight

Subjects
pleiotropy, Genetics, Molecular Medicine, multi-trait analyses, GWAS—genome-wide association study, atherosclerosis, QH426-470, peripheral artery disease, Genetics (clinical)
Abstract

Although affecting different arterial territories, the related atherosclerotic vascular diseases coronary artery disease (CAD) and peripheral artery disease (PAD) share similar risk factors and have shared pathobiology. To identify novel pleiotropic loci associated with atherosclerosis, we performed a joint analysis of their shared genetic architecture, along with that of common risk factors. Using summary statistics from genome-wide association studies of nine known atherosclerotic (CAD, PAD) and atherosclerosis risk factors (body mass index, smoking initiation, type 2 diabetes, low density lipoprotein, high density lipoprotein, total cholesterol, and triglycerides), we perform 15 separate multi-trait genetic association scans which resulted in 25 novel pleiotropic loci not yet reported as genome-wide significant for their respective traits. Colocalization with single-tissue eQTLs identified candidate causal genes at 14 of the detected signals. Notably, the signal between PAD and LDL-C at the PCSK6 locus affects PCSK6 splicing in human liver tissue and induced pluripotent derived hepatocyte-like cells. These results show that joint analysis of related atherosclerotic disease traits and their risk factors allowed identification of unified biology that may offer the opportunity for therapeutic manipulation. The signal at PCSK6 represent possible shared causal biology where existing inhibitors may be able to be leveraged for novel therapies.

Published
2021

45. Prospects for the Global Elimination of Hepatitis B

Author

Ju-Tao Guo, Timothy M. Block, and Kyong-Mi Chang

Subjects
Hepatitis B virus, Cirrhosis, medicine.medical_treatment, Immunotherapy, Biology, Hepatitis B, medicine.disease, medicine.disease_cause, DIRECT ACTING ANTIVIRALS, Virus Replication, Virology, Antiviral Agents, Virus, Hepatitis B, Chronic, Chronic hepatitis, Hepatocellular carcinoma, medicine, Humans
Abstract

Chronic hepatitis B virus (HBV) infection is the leading cause of liver cirrhosis and hepatocellular carcinoma, estimated to be globally responsible for ∼800,000 deaths annually. Although effective vaccines are available to prevent new HBV infection, treatment of existing chronic hepatitis B (CHB) is limited, as the current standard-of-care antiviral drugs can only suppress viral replication without achieving cure. In 2016, the World Health Organization called for the elimination of viral hepatitis as a global public health threat by 2030. The United States and other nations are working to meet this ambitious goal by developing strategies to cure CHB, as well as prevent HBV transmission. This review considers recent research progress in understanding HBV pathobiology and development of therapeutics for the cure of CHB, which is necessary for elimination of hepatitis B by 2030.

Published
2021

46. A MUC5Bgene polymorphism, rs35705950-T, confers protective effects in COVID-19 infection

Author

Jennifer E. Huffman, Saiju Pyarajan, Lina Gao, Helene Garcon, Pradeep Natarajan, Seyedeh M. Zekavat, Mehrdad Arjomandi, John Michael Gaziano, Bryan R Gorman, Nallakkandi Rajeevan, Julie Lynch, Wen-Chih Wu, Anurag Verma, Darshana Jhala, Kyong-Mi Chang, Katherine P. Liao, Kelly Cho, Jacob Joseph, Peter W.F. Wilson, Curtis J. Donskey, Philip S. Tsao, Yan V. Sun, Richard L. Hauger, Kristine E. Lynch, Joel Gelernter, Elise Gatsby, James B. Meigs, Yuk-Lam Ho, Jin J Zhou, Ayako Suzuki, Christopher J. O'Donnell, Robert A. Bonomo, Sharvari Dalal, Ravi Madduri, Cecelia J Madison, Mat Freiberg, Renato Polimanti, Shiuh-Wen Luoh, John E. McGeary, Gita A. Pathak, Peter D. Reaven, Rose Dl Huang, Sudha K Iyengar, Quinn S. Wells, Jeffrey Petersen, Emily S. Wan, and Jessica Minnier

Subjects
medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, Incidence (epidemiology), medicine.disease, MUC5B gene, Pathophysiology, Idiopathic pulmonary fibrosis, Pneumonia, Polymorphism (computer science), Internal medicine, medicine, Allele, business
Abstract

RationaleA commonMUC5Bgene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis, but its role in the SARS-CoV-2 infection and disease severity is unclear.ObjectivesTo assess whether rs35705950-T confers differential risk for clinical outcomes associated with COVID-19 infection among participants in the Million Veteran Program (MVP) and COVID-19 Host Genetics Initiative (HGI).MethodsMVP participants were examined for an association between the incidence or severity of COVID-19 and the presence of aMUC5Brs35705950-T allele. Comorbidities and clinical events were extracted from the electronic health records (EHR). The analysis was performed within each ancestry group in the MVP, adjusting for sex, age, age2,and first twenty principal components followed by a trans-ethnic meta-analysis. We then pursued replication and performed a meta-analysis with the trans-ethnic summary statistics from the HGI. A phenome-wide association study (PheWAS) of the rs35705950-T was conducted to explore associated pathophysiologic conditions.Measurements and Main ResultsA COVID-19 severity scale was modified from the World Health Organization criteria, and phenotypes derived from the International Classification of Disease-9/10 were extracted from EHR. Presence of rs35705950-T was associated with fewer hospitalizations (Ncases=25353, Ncontrols=631,024; OR=0.86 [0.80-0.93], p=7.4 × 10−5) in trans-ethnic meta-analysis within MVP and joint meta-analyses with the HGI (N=1641311; OR=0.89 [0.85-0.93], p =1.9 × 10−6). Moreover, individuals of European Ancestry with at least one copy of rs35705950-T had fewer post-COVID-19 pneumonia events (OR=0.85 [0.76-0.96], p =0.008). PheWAS exclusively revealed pulmonary involvement.ConclusionsTheMUC5Bvariant rs35705950-T is protective in COVID-19 infection.

Published
2021
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47. A Missense Variant in the IL-6 Receptor and Protection From Peripheral Artery Disease

Author

Benjamin F. Voight, Kyong-Mi Chang, Christopher J. O'Donnell, Julie Lynch, Scott M. Damrauer, Marios K. Georgakis, Michael G. Levin, Themistocles L. Assimes, Derek Klarin, Philip S. Tsao, and Katherine P. Liao

Subjects
biology, Physiology, business.industry, Arterial disease, Mutation, Missense, Inflammation, Disease, medicine.disease, Polymorphism, Single Nucleotide, Receptors, Interleukin-6, Article, Coronary artery disease, Peripheral Arterial Disease, Immunology, Interleukin-6 receptor, Mutation (genetic algorithm), biology.protein, medicine, Missense mutation, Humans, medicine.symptom, Cardiology and Cardiovascular Medicine, Interleukin 6, business
Published
2021

48. A multi-population phenome-wide association study of genetically-predicted height in the Million Veteran Program

Author

Sridharan, Raghavan, Jie, Huang, Catherine, Tcheandjieu, Jennifer E, Huffman, Elizabeth, Litkowski, Chang, Liu, Yuk-Lam A, Ho, Haley, Hunter-Zinck, Hongyu, Zhao, Eirini, Marouli, Kari E, North, Ethan, Lange, Leslie A, Lange, Benjamin F, Voight, J Michael, Gaziano, Saiju, Pyarajan, Elizabeth R, Hauser, Philip S, Tsao, Peter W F, Wilson, Kyong-Mi, Chang, Kelly, Cho, Christopher J, O'Donnell, Yan V, Sun, and Themistocles L, Assimes

Subjects
Adult, Cancer Research, Atrial Fibrillation, Hypertension, Genetics, Humans, Genetic Predisposition to Disease, Molecular Biology, Polymorphism, Single Nucleotide, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Genome-Wide Association Study, Veterans
Abstract

Background Height has been associated with many clinical traits but whether such associations are causal versus secondary to confounding remains unclear in many cases. To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and genetic data from a national healthcare system biobank. Methods and findings Analyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n = 222,300) and non-Hispanic Black (AA, n = 58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy in the presence and absence of diabetes. As a number of traits associated with genetically-predicted height frequently co-occur with CHD, we evaluated effect modification by CHD status of genetically-predicted height associations with risk factors for and complications of CHD. We found modification of effects of MR associations by CHD status for atrial fibrillation/flutter but not for hypertension, hyperlipidemia, or venous circulatory disorders. Conclusions We conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study.

Published
2021

49. American Association for the Study of Liver Diseases Expert Panel Consensus Statement: Vaccines to Prevent Coronavirus Disease 2019 Infection in Patients With Liver Disease

Author

David C. Mulligan, Elizabeth C. Verna, Hugo R. Rosen, Ryan M. Kwok, Brendan M. McGuire, Jaime Chu, Oren K Fix, Raymond T. Chung, Emily A. Blumberg, Nancy Reau, Kyong-Mi Chang, Bilal Hameed, Jennifer C. Price, Elizabeth Goacher, Andrew Reynolds, Michael L. Schilsky, Robert J. Fontana, Mark W. Russo, Laura Kulik, K. Rajender Reddy, Daniel R. Kaul, and John W. Ward

Subjects
0301 basic medicine, medicine.medical_specialty, Cirrhosis, Hepatology, business.industry, medicine.medical_treatment, Immunosuppression, Liver transplantation, medicine.disease, Vaccine efficacy, Chronic liver disease, Clinical trial, Transplantation, 03 medical and health sciences, Liver disease, 030104 developmental biology, 0302 clinical medicine, Internal medicine, medicine, 030211 gastroenterology & hepatology, business
Abstract

The aim of this document is to provide a concise scientific review of the currently available COVID-19 vaccines and those in development, including mRNA, adenoviral vectors, and recombinant protein approaches. The anticipated use of COVID-19 vaccines in patients with chronic liver disease (CLD) and liver transplant (LT) recipients is reviewed and practical guidance is provided for health care providers involved in the care of patients with liver disease and LT about vaccine prioritization and administration. The Pfizer and Moderna mRNA COVID-19 vaccines are associated with a 94%-95% vaccine efficacy compared to placebo against COVID-19. Local site reactions of pain and tenderness were reported in 70%-90% of clinical trial participants, and systemic reactions of fever and fatigue were reported in 40%-70% of participants, but these reactions were generally mild and self-limited and occurred more frequently in younger persons. Severe hypersensitivity reactions related to the mRNA COVID-19 vaccines are rare and more commonly observed in women and persons with a history of previous drug reactions for unclear reasons. Because patients with advanced liver disease and immunosuppressed patients were excluded from the vaccine licensing trials, additional data regarding the safety and efficacy of COVID-19 vaccines are eagerly awaited in these and other subgroups. Remarkably safe and highly effective mRNA COVID-19 vaccines are now available for widespread use and should be given to all adult patients with CLD and LT recipients. The online companion document located at https://www.aasld.org/about-aasld/covid-19-resources will be updated as additional data become available regarding the safety and efficacy of other COVID-19 vaccines in development.

Published
2021
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50. Proton pump inhibitor use is not associated with severe COVID-19 related outcomes: A propensity score weighted analysis of a national veteran cohort

Author

Christianne L. Roumie, Jason Denton, Sony Tuteja, Alese E. Halvorson, Michael E. Matheny, Brandon McBay, Adriana M. Hung, Chad Dorn, Richard L. Hauger, Christine M. Hunt, Shailja C. Shah, Robert A. Greevy, Ayako Suzuki, Kyong-Mi Chang, Edward D. Siew, Kelly Cho, and Otis D. Wilson

Subjects
Mechanical ventilation, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, medicine.drug_class, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), medicine.medical_treatment, Proton-pump inhibitor, Logistic regression, Internal medicine, Cohort, Propensity score matching, medicine, Medical prescription, business
Abstract

Background and AimsLow pH deactivates most pathogens, including coronaviruses. Proton pump inhibitors (PPIs) are potent gastric acid suppressing medications. Whether PPI use vs non-use is associated with severe Coronavirus disease-2019 (COVID-19) outcomes remains uncertain. We aimed to compare severe COVID-19 outcomes between current outpatient PPI users and non-users.MethodsWe conducted a retrospective propensity score-weighted analysis of a national cohort of US veterans with established care who tested positive for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) through January 9, 2021, and who had 60 days of follow-up. The positive test date was the index date. Current outpatient PPI use up to and including the index date (primary exposure) was compared to non-use, defined as no PPI prescription fill in the 365 days prior to the index date. The primary outcome was a composite of use of mechanical ventilation or death within 60 days. Weighted logistic regression models evaluated severe COVID-19 outcomes between current PPI users vs non-users.ResultsOf 97,674 Veterans with SARS-CoV-2 testing, 14,958 tested positive (6262 [41.9%] current PPI users, 8696 [58.1%] non-users) and comprised the analytic cohort. After weighting, all covariates were well-balanced. In the weighted cohort, there was no difference in the primary composite outcome (8.2% vs 8.0%; OR 1.03, 95% CI 0.91-1.16), secondary composite outcome, nor individual component outcomes between current PPI users and non-users. There was no significant interaction between age and PPI use on outcomes.ConclusionAmong patients with SARS-CoV-2 infection, current PPI use vs non-use is not associated with severe COVID-19 outcomes.

Published
2021
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