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1. Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthmaResearch in context

Author: Kathryn Recto, Priyadarshini Kachroo, Tianxiao Huan, David Van Den Berg, Gha Young Lee, Helena Bui, Dong Heon Lee, Jessica Gereige, Chen Yao, Shih-Jen Hwang, Roby Joehanes, Scott T. Weiss, George T. O’Connor, Daniel Levy, Dawn L. DeMeo, Namiko Abe, Gonçalo Abecasis, Francois Aguet, Christine Albert, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Kristin Ardlie, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, Najib Ayas, Adithya Balasubramanian, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Lucas Barwick, Terri Beaty, Gerald Beck, Diane Becker, Lewis Becker, Rebecca Beer, Amber Beitelshees, Emelia Benjamin, Takis Benos, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Nathan Blue, Eric Boerwinkle, Donald W. Bowden, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Deborah Brown, Karen Bunting, Esteban Burchard, Carlos Bustamante, Erin Buth, Brian Cade, Jonathan Cardwell, Vincent Carey, Julie Carrier, April P. Carson, Cara Carty, Richard Casaburi, Juan P. Casas Romero, James Casella, Peter Castaldi, Mark Chaffin, Christy Chang, Yi-Cheng Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Yii-Der Ida Chen, Michael Cho, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Ren-Hua Chung, Clary Clish, Suzy Comhair, Matthew Conomos, Elaine Cornell, Adolfo Correa, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sean David, Colleen Davis, Michelle Daya, Mariza de Andrade, Lisa de las Fuentes, Paul de Vries, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Huyen Dinh, Harsha Doddapaneni, Qing Duan, Shannon Dugan-Perez, Ravi Duggirala, Jon Peter Durda, Susan K. Dutcher, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Patrick Ellinor, Leslie Emery, Serpil Erzurum, Charles Farber, Jesse Farek, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Shanshan Gao, Yan Gao, Margery Gass, Heather Geiger, Bruce Gelb, Mark Geraci, Soren Germer, Robert Gerszten, Auyon Ghosh, Richard Gibbs, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, Sharon Graw, Kathryn J. Gray, Daniel Grine, Colin Gross, C. Charles Gu, Yue Guan, Xiuqing Guo, Namrata Gupta, Jeff Haessler, Michael Hall, Yi Han, Patrick Hanly, Daniel Harris, Nicola L. Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, Brian Hobbs, John Hokanson, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Jianhong Hu, Yi-Jen Hung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Ziad Khan, Wonji Kim, John Kimoff, Greg Kinney, Barbara Konkle, Charles Kooperberg, Holly Kramer, Christoph Lange, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Jiwon Lee, Sandra Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Joshua Lewis, Xiaohui Li, Yun Li, Henry Lin, Honghuang Lin, Xihong Lin, Simin Liu, Yongmei Liu, Yu Liu, Ruth J.F. Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Ulysses Magalang, Michael Mahaney, Barry Make, Ani Manichaikul, Alisa Manning, JoAnn Manson, Lisa Martin, Melissa Marton, Susan Mathai, Rasika Mathias, Susanne May, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Daniel McGoldrick, Caitlin McHugh, Becky McNeil, Hao Mei, James Meigs, Vipin Menon, Luisa Mestroni, Ginger Metcalf, Deborah A. Meyers, Emmanuel Mignot, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton D. Mitchell, Matt Moll, Zeineen Momin, May E. Montasser, Courtney Montgomery, Donna Muzny, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Take Naseri, Pradeep Natarajan, Sergei Nekhai, Sarah C. Nelson, Bonnie Neltner, Caitlin Nessner, Deborah Nickerson, Osuji Nkechinyere, Kari North, Jeff O'Connell, Tim O'Connor, Heather Ochs-Balcom, Geoffrey Okwuonu, Allan Pack, David T. Paik, Nicholette Palmer, James Pankow, George Papanicolaou, Cora Parker, Gina Peloso, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Jacob Pleiness, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Bruce Psaty, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Mahitha Rajendran, Vasan S. Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Catherine Reeves, Elizabeth Regan, Alex Reiner, Muagututi‘a Sefuiva Reupena, Ken Rice, Stephen Rich, Rebecca Robillard, Nicolas Robine, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Alexi Runnels, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Ester Cerdeira Sabino, Danish Saleheen, Shabnam Salimi, Sejal Salvi, Steven Salzberg, Kevin Sandow, Vijay G. Sankaran, Jireh Santibanez, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Frédéric Sériès, Vivien Sheehan, Stephanie L. Sherman, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Robert Skomro, Albert Vernon Smith, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Michael Snyder, Tamar Sofer, Nona Sotoodehnia, Adrienne M. Stilp, Garrett Storm, Elizabeth Streeten, Jessica Lasky Su, Yun Ju Sung, Jody Sylvia, Adam Szpiro, Daniel Taliun, Hua Tang, Margaret Taub, Kent Taylor, Matthew Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah Tishkoff, Hemant Tiwari, Catherine Tong, Russell Tracy, Michael Tsai, Dhananjay Vaidya, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Fei Fei Wang, Heming Wang, Jiongming Wang, Karol Watson, Jennifer Watt, Daniel E. Weeks, Joshua Weinstock, Bruce Weir, Lu-Chen Weng, Jennifer Wessel, Cristen Willer, Kayleen Williams, L. Keoki Williams, Scott Williams, Carla Wilson, James Wilson, Lara Winterkorn, Quenna Wong, Baojun Wu, Joseph Wu, Huichun Xu, Lisa Yanek, Ivana Yang, Ketian Yu, Seyedeh Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiaofeng Zhu, Elad Ziv, Michael Zody, and Sebastian Zoellner
Subjects: EWAS, DNA methylation, IgE, Asthma, RNA-Sequencing, Mendelian randomization, Medicine, Medicine (General), R5-920
Abstract: Summary: Background: Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of molecular mechanisms underlying asthma and IgE-mediated diseases. Methods: We performed an epigenome-wide association study using whole blood from Framingham Heart Study (FHS; n = 3,471, 46% females) participants and validated results using the Childhood Asthma Management Program (CAMP; n = 674, 39% females) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n = 787, 41% females). Using the closest gene to each IgE-associated CpG, we highlighted biologically plausible pathways underlying IgE regulation and analyzed the transcription patterns linked to IgE-associated CpGs (expression quantitative trait methylation loci; eQTMs). Using prior UK Biobank summary data from genome-wide association studies of asthma and allergy, we performed Mendelian randomization (MR) for causal inference testing using the IgE-associated CpGs from FHS with methylation quantitative trait loci (mQTLs) as instrumental variables. Findings: We identified 490 statistically significant differentially methylated CpGs associated with IgE in FHS, of which 193 (39.3%) replicated in CAMP and CRA (FDR < 0.05). Gene ontology analysis revealed enrichment in pathways related to transcription factor binding, asthma, and other immunological processes. eQTM analysis identified 124 cis-eQTMs for 106 expressed genes (FDR < 0.05). MR in combination with drug-target analysis revealed CTSB and USP20 as putatively causal regulators of IgE levels (Bonferroni adjusted P
Published: 2023
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2. A robust and adaptive framework for interaction testing in quantitative traits between multiple genetic loci and exposure variables.

Author: Julian Hecker, Dmitry Prokopenko, Matthew Moll, Sanghun Lee, Wonji Kim, Dandi Qiao, Kirsten Voorhies, Woori Kim, Stijn Vansteelandt, Brian D Hobbs, Michael H Cho, Edwin K Silverman, Sharon M Lutz, Dawn L DeMeo, Scott T Weiss, and Christoph Lange
Subjects: Genetics, QH426-470
Abstract: The identification and understanding of gene-environment interactions can provide insights into the pathways and mechanisms underlying complex diseases. However, testing for gene-environment interaction remains a challenge since a.) statistical power is often limited and b.) modeling of environmental effects is nontrivial and such model misspecifications can lead to false positive interaction findings. To address the lack of statistical power, recent methods aim to identify interactions on an aggregated level using, for example, polygenic risk scores. While this strategy can increase the power to detect interactions, identifying contributing genes and pathways is difficult based on these relatively global results. Here, we propose RITSS (Robust Interaction Testing using Sample Splitting), a gene-environment interaction testing framework for quantitative traits that is based on sample splitting and robust test statistics. RITSS can incorporate sets of genetic variants and/or multiple environmental factors. Based on the user's choice of statistical/machine learning approaches, a screening step selects and combines potential interactions into scores with improved interpretability. In the testing step, the application of robust statistics minimizes the susceptibility to main effect misspecifications. Using extensive simulation studies, we demonstrate that RITSS controls the type 1 error rate in a wide range of scenarios, and we show how the screening strategy influences statistical power. In an application to lung function phenotypes and human height in the UK Biobank, RITSS identified highly significant interactions based on subcomponents of genetic risk scores. While the contributing single variant interaction signals are weak, our results indicate interaction patterns that result in strong aggregated effects, providing potential insights into underlying gene-environment interaction mechanisms.
Published: 2022
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3. Heterozygosity of the Alpha 1‐Antitrypsin Pi*Z Allele and Risk of Liver Disease

Author: Aaron Hakim, Matthew Moll, Dandi Qiao, Jiangyuan Liu, Jessica A. Lasky‐Su, Edwin K. Silverman, Silvia Vilarinho, Z. Gordon Jiang, Brian D. Hobbs, and Michael H. Cho
Subjects: Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: The serpin family A member 1 (SERPINA1) Z allele is present in approximately one in 25 individuals of European ancestry. Z allele homozygosity (Pi*ZZ) is the most common cause of alpha 1‐antitrypsin deficiency and is a proven risk factor for cirrhosis. We examined whether heterozygous Z allele (Pi*Z) carriers in United Kingdom (UK) Biobank, a population‐based cohort, are at increased risk of liver disease. We replicated findings in Massachusetts General Brigham Biobank, a hospital‐based cohort. We also examined variants associated with liver disease and assessed for gene–gene and gene–environment interactions. In UK Biobank, we identified 1,493 cases of cirrhosis, 12,603 Z allele heterozygotes, and 129 Z allele homozygotes among 312,671 unrelated white British participants. Heterozygous carriage of the Z allele was associated with cirrhosis compared to noncarriage (odds ratio [OR], 1.53; P = 1.1×10−04); homozygosity of the Z allele also increased the risk of cirrhosis (OR, 11.8; P = 1.8 × 10−09). The OR for cirrhosis of the Z allele was comparable to that of well‐established genetic variants, including patatin‐like phospholipase domain containing 3 (PNPLA3) I148M (OR, 1.48; P = 1.1 × 10−22) and transmembrane 6 superfamily member 2 (TM6SF2) E167K (OR, 1.34; P = 2.6 × 10−06). In heterozygotes compared to noncarriers, the Z allele was associated with higher alanine aminotransferase (ALT; P = = 4.6 × 10−46), aspartate aminotransferase (AST; P = 2.2 × 10−27), alkaline phosphatase (P = 3.3 × 10−43), gamma‐glutamyltransferase (P = 1.2 × 10−05), and total bilirubin (P = 6.4 × 10−06); Z allele homozygotes had even greater elevations in liver biochemistries. Body mass index (BMI) amplified the association of the Z allele for ALT (P interaction = 0.021) and AST (P interaction = 0.0040), suggesting a gene–environment interaction. Finally, we demonstrated genetic interactions between variants in PNPLA3, TM6SF2, and hydroxysteroid 17‐beta dehydrogenase 13 (HSD17B13); there was no evidence of epistasis between the Z allele and these variants. Conclusion: SERPINA1 Z allele heterozygosity is an important risk factor for liver disease; this risk is amplified by increasing BMI.
Published: 2021
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4. Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants

Author: Xutong Zhao, Dandi Qiao, Chaojie Yang, Silva Kasela, Wonji Kim, Yanlin Ma, Nick Shrine, Chiara Batini, Tamar Sofer, Sarah A. Gagliano Taliun, Phuwanat Sakornsakolpat, Pallavi P. Balte, Dmitry Prokopenko, Bing Yu, Leslie A. Lange, Josée Dupuis, Brian E. Cade, Jiwon Lee, Sina A. Gharib, Michelle Daya, Cecelia A. Laurie, Ingo Ruczinski, L. Adrienne Cupples, Laura R. Loehr, Traci M. Bartz, Alanna C. Morrison, Bruce M. Psaty, Ramachandran S. Vasan, James G. Wilson, Kent D. Taylor, Peter Durda, W. Craig Johnson, Elaine Cornell, Xiuqing Guo, Yongmei Liu, Russell P. Tracy, Kristin G. Ardlie, François Aguet, David J. VanDenBerg, George J. Papanicolaou, Jerome I. Rotter, Kathleen C. Barnes, Deepti Jain, Deborah A. Nickerson, Donna M. Muzny, Ginger A. Metcalf, Harshavardhan Doddapaneni, Shannon Dugan-Perez, Namrata Gupta, Stacey Gabriel, Stephen S. Rich, George T. O’Connor, Susan Redline, Robert M. Reed, Cathy C. Laurie, Martha L. Daviglus, Liana K. Preudhomme, Kristin M. Burkart, Robert C. Kaplan, Louise V. Wain, Martin D. Tobin, Stephanie J. London, Tuuli Lappalainen, Elizabeth C. Oelsner, Goncalo R. Abecasis, Edwin K. Silverman, R. Graham Barr, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Lung Working Group, Michael H. Cho, and Ani Manichaikul
Subjects: Science
Abstract: Chronic obstructive pulmonary disease is a leading cause of morbidity and mortality. Here, the authors analyse whole genome sequence data and find new loci associated with lung function and COPD.
Published: 2020
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5. Tempo-spatial regulation of the Wnt pathway by FAM13A modulates the stemness of alveolar epithelial progenitors

Author: Xin Lin, Yujun Li, Lu Gong, Jeong H. Yun, Shuang Xu, Yohannes Tesfaigzi, Dandi Qiao, and Xiaobo Zhou
Subjects: FAM13A, β-catenin/Wnt pathway, Repair/regeneration, Epithelial organoids, Cigarette smoke, COPD/emphysema, Medicine, Medicine (General), R5-920
Abstract: Background: Family with Sequence Similarity 13, Member A (FAM13A) gene has been consistently associated with COPD by Genome-wide association studies (GWAS). Our previous study demonstrated that FAM13A was mainly expressed in the lung epithelial progenitors including Club cells and alveolar type II epithelial (ATII) cells. Fam13a−/− mice were resistant to cigarette smoke (CS)–induced emphysema through promoting β-catenin/Wnt activation. Given the important roles of β-catenin/Wnt activation in alveolar regeneration during injury, it is unclear when and where FAM13A regulates the Wnt pathway, the requisite pathway for alveolar epithelial repair, in vivo during CS exposure in lung epithelial progenitors. Methods: Fam13a+/+ or Fam13a−/− mice were crossed with TCF/Lef:H2B-GFP Wnt-signaling reporter mouse line to indicate β-catenin/Wnt-activated cells labeled with GFP followed by acute (1 month) or chronic (7 months) CS exposure. Fluorescence-activated flow cytometry analysis, immunofluorescence and organoid culture system were performed to identify the β-catenin/Wnt-activated cells in Fam13a+/+ or Fam13a−/− mice exposed to CS. Fam13a;SftpcCreERT2;Rosa26RmTmG mouse line, where GFP labels ATII cells, was generated for alveolar organoid culture followed by analyses of organoid number, immunofluorescence and gene expression. Single cell RNA-seq data from COPD ever smokers and nonsmoker control lungs were further analyzed. Findings: We found that FAM13A-deficiency significantly increased Wnt activation mainly in lung epithelial cells. Consistently, after long-term CS exposure in vivo, FAM13A deficiency bestows alveolar epithelial progenitor cells with enhanced proliferation and differentiation in the ex vivo organoid model. Importantly, expression of FAM13A is significantly increased in human COPD-derived ATII cells compared to healthy ATII cells as suggested by single cell RNA-sequencing data. Interpretation: Our findings suggest that FAM13A-deficiency promotes the Wnt pathway-mediated ATII cell repair/regeneration, and thereby possibly mitigating CS-induced alveolar destruction. Fund: This project is funded by the National Institutes of Health of United States of America (NIH) grants R01HL127200, R01HL137927, R01HL148667 and R01HL147148 (XZ).
Published: 2021
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6. Corrigendum to ‘A linear prognostic score based on the ratio of interleukin-6 to interleukin-10 predicts outcomes in COVID-19’

Author: Oliver J McElvaney, Brian D Hobbs, Dandi Qiao, Oisín F McElvaney, Matthew Moll, Natalie L McEvoy, Jennifer Clarke, Eoin O'Connor, Sean Walsh, Michael H Cho, Gerard F Curley, and Noel G McElvaney
Subjects: Medicine, Medicine (General), R5-920
Published: 2020
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7. A linear prognostic score based on the ratio of interleukin-6 to interleukin-10 predicts outcomes in COVID-19

Author: Oliver J McElvaney, Brian D Hobbs, Dandi Qiao, Oisín F McElvaney, Matthew Moll, Natalie L McEvoy, Jennifer Clarke, Eoin O'Connor, Seán Walsh, Michael H Cho, Gerard F Curley, and Noel G McElvaney
Subjects: COVID-19, Interleukin-6, Interleukin-10, Prognostic score, Clinical outcome, Inflammation, Medicine, Medicine (General), R5-920
Abstract: Background: Prognostic tools are required to guide clinical decision-making in COVID-19. Methods: We studied the relationship between the ratio of interleukin (IL)-6 to IL-10 and clinical outcome in 80 patients hospitalized for COVID-19, and created a simple 5-point linear score predictor of clinical outcome, the Dublin-Boston score. Clinical outcome was analysed as a three-level ordinal variable (“Improved”, “Unchanged”, or “Declined”). For both IL-6:IL-10 ratio and IL-6 alone, we associated clinical outcome with a) baseline biomarker levels, b) change in biomarker level from day 0 to day 2, c) change in biomarker from day 0 to day 4, and d) slope of biomarker change throughout the study. The associations between ordinal clinical outcome and each of the different predictors were performed with proportional odds logistic regression. Associations were run both “unadjusted” and adjusted for age and sex. Nested cross-validation was used to identify the model for incorporation into the Dublin-Boston score. Findings: The 4-day change in IL-6:IL-10 ratio was chosen to derive the Dublin-Boston score. Each 1 point increase in the score was associated with a 5.6 times increased odds for a more severe outcome (OR 5.62, 95% CI -3.22–9.81, P = 1.2 × 10−9). Both the Dublin-Boston score and the 4-day change in IL-6:IL-10 significantly outperformed IL-6 alone in predicting clinical outcome at day 7. Interpretation: The Dublin-Boston score is easily calculated and can be applied to a spectrum of hospitalized COVID-19 patients. More informed prognosis could help determine when to escalate care, institute or remove mechanical ventilation, or drive considerations for therapies. Funding: Funding was received from the Elaine Galwey Research Fellowship, American Thoracic Society, National Institutes of Health and the Parker B Francis Research Opportunity Award.
Published: 2020
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8. FAM13A Represses AMPK Activity and Regulates Hepatic Glucose and Lipid Metabolism

Author: Xin Lin, Yae-Huei Liou, Yujun Li, Lu Gong, Yan Li, Yuan Hao, Betty Pham, Shuang Xu, Zhiqiang Jiang, Lijia Li, Yifan Peng, Dandi Qiao, Honghuang Lin, Pengda Liu, Wenyi Wei, Guo Zhang, Chih-Hao Lee, and Xiaobo Zhou
Subjects: Science
Abstract: Summary: Obesity commonly co-exists with fatty liver disease with increasing health burden worldwide. Family with Sequence Similarity 13, Member A (FAM13A) has been associated with lipid levels and fat mass by genome-wide association studies (GWAS). However, the function of FAM13A in maintaining metabolic homeostasis in vivo remains unclear. Here, we demonstrated that rs2276936 in this locus has allelic-enhancer activity in massively parallel reporter assays (MPRA) and reporter assay. The DNA region containing rs2276936 regulates expression of endogenous FAM13A in HepG2 cells. In vivo, Fam13a−/− mice are protected from high-fat diet (HFD)-induced fatty liver accompanied by increased insulin sensitivity and reduced glucose production in liver. Mechanistically, loss of Fam13a led to the activation of AMP-activated protein kinase (AMPK) and increased mitochondrial respiration in primary hepatocytes. These findings demonstrate that FAM13A mediates obesity-related dysregulation of lipid and glucose homeostasis. Targeting FAM13A might be a promising treatment of obesity and fatty liver disease. : Biological Sciences; Cell Biology; Functional Aspects of Cell Biology Subject Areas: Biological Sciences, Cell Biology, Functional Aspects of Cell Biology
Published: 2020
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9. WISARD: workbench for integrated superfast association studies for related datasets

Author: Sungyoung Lee, Sungkyoung Choi, Dandi Qiao, Michael Cho, Edwin K. Silverman, Taesung Park, and Sungho Won
Subjects: Family-based design, Genome-wide association analyses, Next generation sequencing, Multi-threaded analyses, Related samples, Internal medicine, RC31-1245, Genetics, QH426-470
Abstract: Abstract Background A Mendelian transmission produces phenotypic and genetic relatedness between family members, giving family-based analytical methods an important role in genetic epidemiological studies—from heritability estimations to genetic association analyses. With the advance in genotyping technologies, whole-genome sequence data can be utilized for genetic epidemiological studies, and family-based samples may become more useful for detecting de novo mutations. However, genetic analyses employing family-based samples usually suffer from the complexity of the computational/statistical algorithms, and certain types of family designs, such as incorporating data from extended families, have rarely been used. Results We present a Workbench for Integrated Superfast Association studies for Related Data (WISARD) programmed in C/C++. WISARD enables the fast and a comprehensive analysis of SNP-chip and next-generation sequencing data on extended families, with applications from designing genetic studies to summarizing analysis results. In addition, WISARD can automatically be run in a fully multithreaded manner, and the integration of R software for visualization makes it more accessible to non-experts. Conclusions Comparison with existing toolsets showed that WISARD is computationally suitable for integrated analysis of related subjects, and demonstrated that WISARD outperforms existing toolsets. WISARD has also been successfully utilized to analyze the large-scale massive sequencing dataset of chronic obstructive pulmonary disease data (COPD), and we identified multiple genes associated with COPD, which demonstrates its practical value.
Published: 2018
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10. metaFARVAT: An Efficient Tool for Meta-Analysis of Family-Based, Case-Control, and Population-Based Rare Variant Association Studies

Author: Longfei Wang, Sungyoung Lee, Dandi Qiao, Michael H. Cho, Edwin K. Silverman, Christoph Lange, and Sungho Won
Subjects: meta-analysis, family-based design, rare variant association analysis, metaFARVAT, chronic obstructive pulmonary disease, Genetics, QH426-470
Abstract: Family-based designs have been shown to be powerful in detecting the significant rare variants associated with human diseases. However, very few significant results have been found owing to relatively small sample sizes and the fact that statistical analyses often suffer from high false-negative error rates. These limitations can be avoided by combining results from multiple studies via meta-analysis. However, statistical methods for meta-analysis with rare variants are limited for family-based samples. In this report, we propose a tool for the meta-analysis of family-based rare variant associations, metaFARVAT. metaFARVAT is based on a quasi-likelihood score for each variant. These scores are combined to generate burden test, variable-threshold test, sequence kernel association test (SKAT), and optimal SKAT statistics. The proposed method tests homogeneous and heterogeneous effects of variants among different studies and can be applied to both quantitative and dichotomous phenotypes. Simulation results demonstrated the robustness and efficiency of the proposed method in different scenarios. By applying metaFARVAT to data from a family-based study and a case-control study, we identified a few promising candidate genes, including DLEC1, which is associated with chronic obstructive pulmonary disease.
Published: 2019
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11. A Genome-Wide Linkage Study for Chronic Obstructive Pulmonary Disease in a Dutch Genetic Isolate Identifies Novel Rare Candidate Variants

Author: Ivana Nedeljkovic, Natalie Terzikhan, Judith M. Vonk, Diana A. van der Plaat, Lies Lahousse, Cleo C. van Diemen, Brian D. Hobbs, Dandi Qiao, Michael H. Cho, Guy G. Brusselle, Dirkje S. Postma, H. M. Boezen, Cornelia M. van Duijn, and Najaf Amin
Subjects: COPD, genetic linkage analysis, genetic isolate, rare variants, chromosome 11, Genetics, QH426-470
Abstract: Chronic obstructive pulmonary disease (COPD) is a complex and heritable disease, associated with multiple genetic variants. Specific familial types of COPD may be explained by rare variants, which have not been widely studied. We aimed to discover rare genetic variants underlying COPD through a genome-wide linkage scan. Affected-only analysis was performed using the 6K Illumina Linkage IV Panel in 142 cases clustered in 27 families from a genetic isolate, the Erasmus Rucphen Family (ERF) study. Potential causal variants were identified by searching for shared rare variants in the exome-sequence data of the affected members of the families contributing most to the linkage peak. The identified rare variants were then tested for association with COPD in a large meta-analysis of several cohorts. Significant evidence for linkage was observed on chromosomes 15q14–15q25 [logarithm of the odds (LOD) score = 5.52], 11p15.4–11q14.1 (LOD = 3.71) and 5q14.3–5q33.2 (LOD = 3.49). In the chromosome 15 peak, that harbors the known COPD locus for nicotinic receptors, and in the chromosome 5 peak we could not identify shared variants. In the chromosome 11 locus, we identified four rare (minor allele frequency (MAF)
Published: 2018
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12. Clinical Markers Associated With Risk of Suicide or Drug Overdose Among Individuals With Smoking Exposure

Author: Brigid A. Adviento, Elizabeth A. Regan, Barry J. Make, MeiLan K. Han, Marilyn G. Foreman, Anand S. Iyer, Surya P. Bhatt, Victor Kim, Jessica Bon, Xavier Soler, Gregory L. Kinney, Nicola A. Hanania, Katherine E. Lowe, Kristen E. Holm, Abebaw M. Yohannes, Gen Shinozaki, Karin F. Hoth, Jess G. Fiedorowicz, James D. Crapo, Edwin K. Silverman, Terri H. Beaty, Peter J. Castaldi, Michael H. Cho, Dawn L. DeMeo, Adel El Boueiz, Auyon Ghosh, Lystra P. Hayden, Craig P. Hersh, Jacqueline Hetmanski, Brian D. Hobbs, John E. Hokanson, Wonji Kim, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Dmitry Prokopenko, Matthew Moll, Jarrett Morrow, Dandi Qiao, Aabida Saferali, Phuwanat Sakornsakolpat, Emily S. Wan, Jeong Yun, Juan Pablo Centeno, Jean-Paul Charbonnier, Harvey O. Coxson, Craig J. Galban, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, Pietro Nardelli, John D. Newell, Aleena Notary, Andrea Oh, James C. Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, Gonzalo Vegas Sanchez-Ferrero, Lucas Veitel, George R. Washko, Carla G. Wilson, Robert Jensen, Matthew Strand, Jim Crooks, Katherine Pratte, Aastha Khatiwada, Erin Austin, Gregory Kinney, Kendra A. Young, Alejandro A. Diaz, Barry Make, Susan Murray, Elizabeth Regan, Russell P. Bowler, Katerina Kechris, Farnoush Banaei-Kashani, Jeffrey L. Curtis, Perry G. Pernicano, Nicola Hanania, Mustafa Atik, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Amit Parulekar, Craig Hersh, George Washko, R. Graham Barr, John Austin, Belinda D’Souza, Byron Thomashow, Neil MacIntyre, H. Page McAdams, Lacey Washington, Charlene McEvoy, Joseph Tashjian, Robert Wise, Robert Brown, Nadia N. Hansel, Karen Horton, Allison Lambert, Nirupama Putcha, Richard Casaburi, Alessandra Adami, Matthew Budoff, Hans Fischer, Janos Porszasz, Harry Rossiter, William Stringer, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, Ken M. Kunisaki, Eric L. Flenaugh, Hirut Gebrekristos, Mario Ponce, Silanath Terpenning, Gloria Westney, Russell Bowler, Richard Rosiello, David Pace, Gerard Criner, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D’Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, A. James Mamary, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, Anand Iyer, Hrudaya Nath, J. Michael Wells, Douglas Conrad, Andrew Yen, Alejandro P. Comellas, John Newell, Brad Thompson, Ella Kazerooni, Wassim Labaki, Craig Galban, Dharshan Vummidi, Joanne Billings, Abbie Begnaud, Tadashi Allen, Frank Sciurba, Divay Chandra, Joel Weissfeld, Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, Mario E. Ruiz, and Harjinder Singh
Subjects: Pulmonary and Respiratory Medicine, Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine
Published: 2023
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13. Assessing the contribution of rare genetic variants to phenotypes of chronic obstructive pulmonary disease using whole-genome sequence data

Author: Wonji, Kim, Julian, Hecker, R Graham, Barr, Eric, Boerwinkle, Brian, Cade, Adolfo, Correa, Josée, Dupuis, Sina A, Gharib, Leslie, Lange, Stephanie J, London, Alanna C, Morrison, George T, O'Connor, Elizabeth C, Oelsner, Bruce M, Psaty, Ramachandran S, Vasan, Susan, Redline, Stephen S, Rich, Jerome I, Rotter, Bing, Yu, Christoph, Lange, Ani, Manichaikul, Jin J, Zhou, Tamar, Sofer, Edwin K, Silverman, Dandi, Qiao, and Michael H, Cho
Subjects: Pulmonary Disease, Chronic Obstructive, Phenotype, Genetics, Humans, Genetic Predisposition to Disease, Original Article, General Medicine, Polymorphism, Single Nucleotide, Molecular Biology, Genetics (clinical), Genome-Wide Association Study
Abstract: Rationale: Genetic variation has a substantial contribution to chronic obstructive pulmonary disease (COPD) and lung function measurements. Heritability estimates using genome-wide genotyping data can be biased if analyses do not appropriately account for the nonuniform distribution of genetic effects across the allele frequency and linkage disequilibrium (LD) spectrum. In addition, the contribution of rare variants has been unclear. Objectives: We sought to assess the heritability of COPD and lung function using whole-genome sequence data from the Trans-Omics for Precision Medicine program. Methods: Using the genome-based restricted maximum likelihood method, we partitioned the genome into bins based on minor allele frequency and LD scores and estimated heritability of COPD, FEV1% predicted and FEV1/FVC ratio in 11 051 European ancestry and 5853 African-American participants. Measurements and Main Results: In European ancestry participants, the estimated heritability of COPD, FEV1% predicted and FEV1/FVC ratio were 35.5%, 55.6% and 32.5%, of which 18.8%, 19.7%, 17.8% were from common variants, and 16.6%, 35.8%, and 14.6% were from rare variants. These estimates had wide confidence intervals, with common variants and some sets of rare variants showing a statistically significant contribution (P-value
Published: 2022
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14. Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program

Author: Xiaowei Hu, Dandi Qiao, Wonji Kim, Matthew Moll, Pallavi P. Balte, Leslie A. Lange, Traci M. Bartz, Rajesh Kumar, Xingnan Li, Bing Yu, Brian E. Cade, Cecelia A. Laurie, Tamar Sofer, Ingo Ruczinski, Deborah A. Nickerson, Donna M. Muzny, Ginger A. Metcalf, Harshavardhan Doddapaneni, Stacy Gabriel, Namrata Gupta, Shannon Dugan-Perez, L. Adrienne Cupples, Laura R. Loehr, Deepti Jain, Jerome I. Rotter, James G. Wilson, Bruce M. Psaty, Myriam Fornage, Alanna C. Morrison, Ramachandran S. Vasan, George Washko, Stephen S. Rich, George T. O’Connor, Eugene Bleecker, Robert C. Kaplan, Ravi Kalhan, Susan Redline, Sina A. Gharib, Deborah Meyers, Victor Ortega, Josée Dupuis, Stephanie J. London, Tuuli Lappalainen, Elizabeth C. Oelsner, Edwin K. Silverman, R. Graham Barr, Timothy A. Thornton, Heather E. Wheeler, Michael H. Cho, Hae Kyung Im, and Ani Manichaikul
Subjects: Pulmonary Disease, Chronic Obstructive, Risk Factors, Genetics, Humans, National Heart, Lung, and Blood Institute (U.S.), Transcriptome, Lung, Article, United States, Genetics (clinical)
Abstract: While polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1 s [FEV(1)] and its ratio to forced vital capacity [FEV(1)/FVC]) in the UK Biobank. We examined prediction performance and cross-ethnic portability of PTRS through smoking-stratified analyses both on 29,381 multi-ethnic participants from TOPMed population/family-based cohorts and on 11,771 multi-ethnic participants from TOPMed COPD-enriched studies. Analyses were carried out for two dichotomous COPD traits (moderate-to-severe and severe COPD) and two quantitative lung function traits (FEV(1) and FEV(1)/FVC). While the proposed PTRS showed weaker associations with disease than PRS for European ancestry, the PTRS showed stronger association with COPD than PRS for African Americans (e.g., odds ratio [OR] = 1.24 [95% confidence interval [CI]: 1.08–1.43] for PTRS versus 1.10 [0.96–1.26] for PRS among heavy smokers with ≥ 40 pack-years of smoking) for moderate-to-severe COPD. Cross-ethnic portability of the PTRS was significantly higher than the PRS (paired t test p
Published: 2022
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15. Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease

Author: Daniel H. Katz, Usman A. Tahir, Alexander G. Bick, Akhil Pampana, Debby Ngo, Mark D. Benson, Zhi Yu, Jeremy M. Robbins, Zsu-Zsu Chen, Daniel E. Cruz, Shuliang Deng, Laurie Farrell, Sumita Sinha, Alec A. Schmaier, Dongxiao Shen, Yan Gao, Michael E. Hall, Adolfo Correa, Russell P. Tracy, Peter Durda, Kent D. Taylor, Yongmei Liu, W. Craig Johnson, Xiuqing Guo, Jie Yao, Yii-Der Ida Chen, Ani W. Manichaikul, Deepti Jain, Claude Bouchard, Mark A. Sarzynski, Stephen S. Rich, Jerome I. Rotter, Thomas J. Wang, James G. Wilson, Pradeep Natarajan, Robert E. Gerszten, Namiko Abe, Gonçalo Abecasis, Francois Aguet, Christine Albert, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Kristin Ardlie, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, Najib Ayas, Adithya Balasubramanian, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Lucas Barwick, Terri Beaty, Gerald Beck, Diane Becker, Lewis Becker, Rebecca Beer, Amber Beitelshees, Emelia Benjamin, Takis Benos, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Eric Boerwinkle, Donald W. Bowden, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Deborah Brown, Karen Bunting, Esteban Burchard, Carlos Bustamante, Erin Buth, Brian Cade, Jonathan Cardwell, Vincent Carey, Julie Carrier, April Carson, Cara Carty, Richard Casaburi, Juan P. Casas Romero, James Casella, Peter Castaldi, Mark Chaffin, Christy Chang, Yi-Cheng Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Michael Cho, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Ren-Hua Chung, Clary Clish, Suzy Comhair, Matthew Conomos, Elaine Cornell, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sean David, Colleen Davis, Michelle Daya, Mariza de Andrade, Lisa de las Fuentes, Paul de Vries, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Huyen Dinh, Harsha Doddapaneni, Qing Duan, Shannon Dugan-Perez, Ravi Duggirala, Jon Peter Durda, Susan K. Dutcher, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Patrick Ellinor, Leslie Emery, Serpil Erzurum, Charles Farber, Jesse Farek, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Shanshan Gao, Margery Gass, Heather Geiger, Bruce Gelb, Mark Geraci, Soren Germer, Robert Gerszten, Auyon Ghosh, Richard Gibbs, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, Sharon Graw, Kathryn J. Gray, Daniel Grine, Colin Gross, C. Charles Gu, Yue Guan, Namrata Gupta, David M. Haas, Jeff Haessler, Michael Hall, Yi Han, Patrick Hanly, Daniel Harris, Nicola L. Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, Brian Hobbs, John Hokanson, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Jianhong Hu, Yi-Jen Hung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Cashell Jaquish, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Ziad Khan, Wonji Kim, John Kimoff, Greg Kinney, Barbara Konkle, Charles Kooperberg, Holly Kramer, Christoph Lange, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Jiwon Lee, Sandra Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Dan Levy, Joshua Lewis, Xiaohui Li, Yun Li, Henry Lin, Honghuang Lin, Xihong Lin, Simin Liu, Yu Liu, Ruth J.F. Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Ulysses Magalang, Michael Mahaney, Barry Make, Ani Manichaikul, Alisa Manning, JoAnn Manson, Lisa Martin, Melissa Marton, Susan Mathai, Rasika Mathias, Susanne May, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Daniel McGoldrick, Caitlin McHugh, Becky McNeil, Hao Mei, James Meigs, Vipin Menon, Luisa Mestroni, Ginger Metcalf, Deborah A. Meyers, Emmanuel Mignot, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton D. Mitchell, Matt Moll, Zeineen Momin, May E. Montasser, Courtney Montgomery, Donna Muzny, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Take Naseri, Sergei Nekhai, Sarah C. Nelson, Bonnie Neltner, Caitlin Nessner, Deborah Nickerson, Osuji Nkechinyere, Kari North, Jeff O’Connell, Tim O’Connor, Heather Ochs-Balcom, Geoffrey Okwuonu, Allan Pack, David T. Paik, Nicholette Palmer, James Pankow, George Papanicolaou, Cora Parker, Gina Peloso, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Jacob Pleiness, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Bruce Psaty, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Mahitha Rajendran, Vasan S. Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Catherine Reeves, Elizabeth Regan, Alex Reiner, Muagututi’a Sefuiva Reupena, Ken Rice, Stephen Rich, Rebecca Robillard, Nicolas Robine, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Alexi Runnels, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Ester Cerdeira Sabino, Danish Saleheen, Shabnam Salimi, Sejal Salvi, Steven Salzberg, Kevin Sandow, Vijay G. Sankaran, Jireh Santibanez, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Frédéric Sériès, Vivien Sheehan, Stephanie L. Sherman, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Robert Skomro, Albert Vernon Smith, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Michael Snyder, Tamar Sofer, Nona Sotoodehnia, Adrienne M. Stilp, Garrett Storm, Elizabeth Streeten, Jessica Lasky Su, Yun Ju Sung, Jody Sylvia, Adam Szpiro, Daniel Taliun, Hua Tang, Margaret Taub, Matthew Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah Tishkoff, Hemant Tiwari, Catherine Tong, Russell Tracy, Michael Tsai, Dhananjay Vaidya, David Van Den Berg, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Fei Fei Wang, Heming Wang, Jiongming Wang, Karol Watson, Jennifer Watt, Daniel E. Weeks, Joshua Weinstock, Bruce Weir, Scott T. Weiss, Lu-Chen Weng, Jennifer Wessel, Cristen Willer, Kayleen Williams, L. Keoki Williams, Carla Wilson, James Wilson, Lara Winterkorn, Quenna Wong, Joseph Wu, Huichun Xu, Lisa Yanek, Ivana Yang, Ketian Yu, Seyedeh Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiaofeng Zhu, Michael Zody, and Sebastian Zoellner
Subjects: Adult, Male, Proteomics, Aging, Whole genome sequence analysis, Proteome, Clinical Sciences, Black People, Disease, Computational biology, race and ethnicity, Cardiorespiratory Medicine and Haematology, Cardiovascular, Article, proteomics, cardiovascular disease, Physiology (medical), Genetics, 2.1 Biological and endogenous factors, Humans, Medicine, Aetiology, Lung, Heart Disease - Coronary Heart Disease, and Blood Institute TOPMed (Trans-Omics for Precision Medicine) Consortium†, business.industry, Prevention, Human Genome, National Heart, Genomics, Blood proteins, Genetic architecture, Heart Disease, Good Health and Well Being, Cardiovascular System & Hematology, Cardiovascular Diseases, Public Health and Health Services, Female, Cardiology and Cardiovascular Medicine, business, Biotechnology, Genome-Wide Association Study
Abstract: Background: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Methods: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10 -11 . These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-0.60±0.05, P =1.67×10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P =1.34×10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. Conclusions: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.
Published: 2022
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16. Development of a Blood-based Transcriptional Risk Score for Chronic Obstructive Pulmonary Disease

Author: Matthew Moll, Adel Boueiz, Auyon J. Ghosh, Aabida Saferali, Sool Lee, Zhonghui Xu, Jeong H. Yun, Brian D. Hobbs, Craig P. Hersh, Don D. Sin, Ruth Tal-Singer, Edwin K. Silverman, Michael H. Cho, Peter J. Castaldi, James D. Crapo, Barry J. Make, Elizabeth A. Regan, Terri Beaty, Ferdouse Begum, Michael Cho, Dawn L. DeMeo, Adel R. Boueiz, Marilyn G. Foreman, Eitan Halper-Stromberg, Lystra P. Hayden, Jacqueline Hetmanski, John E. Hokanson, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Margaret M. Parker, Dmitry Prokopenko, Dandi Qiao, Phuwanat Sakornsakolpat, Emily S. Wan, Juan Pablo Centeno, Jean-Paul Charbonnier, Harvey O. Coxson, Craig J. Galban, MeiLan K. Han, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, Pietro Nardelli, John D. Newell, Aleena Notary, Andrea Oh, James C. Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, Gonzalo Vegas Sanchez-Ferrero, Lucas Veitel, George R. Washko, Carla G. Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Katherine Pratte, Matt Strand, Gregory Kinney, Kendra A. Young, Surya P. Bhatt, Jessica Bon, Alejandro A. Diaz, Susan Murray, Xavier Soler, Russell P. Bowler, Katerina Kechris, and Farnoush Banaei-Kashani
Subjects: Pulmonary and Respiratory Medicine, COPD, Framingham Risk Score, business.industry, Pulmonary disease, Critical Care and Intensive Care Medicine, medicine.disease, Bioinformatics, Peripheral blood, respiratory tract diseases, Transcriptome, Gene expression, medicine, Polygenic risk score, business
Abstract: Rationale: The ability of peripheral blood biomarkers to assess COPD risk and progression is unknown. Genetics and gene expression may capture important aspects of COPD-related biology that predict...
Published: 2022
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17. Clinically Significant and Comorbid Anxiety and Depression Symptoms Predict Severe Respiratory Exacerbations in Smokers: A Post Hoc Analysis of the COPDGene and SPIROMICS Cohorts

Author: Anand S. Iyer, Trisha M. Parekh, Jacqueline O’Toole, Surya P. Bhatt, Michelle N. Eakin, Jerry A. Krishnan, Abebaw M. Yohannes, Prescott G. Woodruff, Christopher B. Cooper, Richard E. Kanner, Nicola A. Hanania, Mark T. Dransfield, Elizabeth A. Regan, Karin F. Hoth, Victor Kim, James D. Crapo, Edwin K. Silverman, Barry J. Make, Terri Beaty, Ferdouse Begum, Peter J. Castaldi, Michael Cho, Dawn L. DeMeo, Adel R. Boueiz, Marilyn G. Foreman, Eitan Halper-Stromberg, Lystra P. Hayden, Craig P. Hersh, Jacqueline Hetmanski, Brian D. Hobbs, John E. Hokanson, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Margaret M. Parker, Dmitry Prokopenko, Dandi Qiao, Phuwanat Sakornsakolpat, Emily S. Wan, Sungho Won, Juan Pablo Centeno, Jean-Paul Charbonnier, Harvey O. Coxson, Craig J. Galban, MeiLan K. Han, Eric A. Hoffman, Stephen Huries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, Pietro Nardelli, John D. Newell, Aleena Notary, Andrea Oh, James C. Ross, Raul San José Estépar, Joyce Schroeder, Jered Sieren, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, Gonzalo Vegas Sanchez-Ferrero, Lucas Veitel, George R. Washko, Carla G. Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Katherine Pratte, Matt Strand, Gregory Kinney, Kendra A. Young, Jessica Bon, Alejandro A. Diaz, Barry Make, Susan Murray, Elizabeth Regan, Xavier Soler, Russell P. Bowler, Katerina Kechris, Farnoush Banaei-Kashani, Jeffrey L. Curtis, Perry G. Pernicano, Nicola Hanania, Mustafa Atik, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Amit Parulekar, Craig Hersh, George Washko, R. Graham Barr, John Austin, Belinda D’Souza, Byron Thomashow, Neil MacIntyre, H. Page McAdams, Robert Wise, Robert Brown, Nadia N. Hansel, Karen Horton, Allison Lambert, Los Angeles, Richard Casaburi, Alessandra Adami, Matthew Budoff, Hans Fischer, Janos Porszasz, Harry Rossiter, William Stringer, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, Ken M. Kunisaki, Russell Bowler, Richard Rosiello, David Pace, Gerard Criner, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D’Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, A. James Mamary, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, Anand Iyer, Hrudaya Nath, J. Michael Wells, Douglas Conrad, Andrew Yen, Alejandro P. Comellas, John Newell, Brad Thompson, Ella Kazerooni, Wassim Labaki, Craig Galban, Dharshan Vummidi, Joanne Billings, Abbie Begnaud, Tadashi Allen, Frank Sciurba, Divay Chandra, Carl Fuhrman, Joel Weissfeld, Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, Mario E. Ruiz, and Harjinder Singh
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Comorbid anxiety, business.industry, Internal medicine, Post-hoc analysis, Medicine, Respiratory system, business, Depressive symptoms
Published: 2022
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18. Multiethnic genome-wide and HLA association study of total serum IgE level

Author: Lynda C. Schneider, Craig P. Hersh, Caitlin P. McHugh, Amy S. Paller, Tissa Hata, Dandi Qiao, Ingo Ruczinski, Harold Watson, Nicholas Rafaels, Camila Alexandrina Figueiredo, Edwin K. Silverman, Scott T. Weiss, Luis Caraballo, Victor E. Ortega, Donald Y.M. Leung, Monica Campbell, Nirupama Putcha, Karine A. Viaud-Martinez, George T. O'Connor, Michelle Daya, Priyadarshini Kachroo, Nadia N. Hansel, Emma Guttman-Yassky, Corey Cox, Terri H. Beaty, Gloria David, Nathalie Acevedo, Sameer Chavan, Rasika A. Mathias, Jon M. Hanifin, Jessica Lasky-Su, Adrienne Cupples, Mark K. Slifka, Michael H. Cho, Richard L. Gallo, Eugene R. Bleecker, Deborah A. Meyers, Xingnan Li, Carole Ober, Meher Preethi Boorgula, Peck Y. Ong, Robert M. Reed, Ramachandran S. Vasan, Jonathan M. Spergel, Kathleen C. Barnes, Jennifer Knight-Madden, and Lisa A. Beck
Subjects: Adult, Male, Linkage disequilibrium, Adolescent, Genotype, Immunology, Genome-wide association study, Disease, Human leukocyte antigen, Biology, Genome, Article, Dermatitis, Atopic, Young Adult, Gene Frequency, HLA-A2 Antigen, Ethnicity, HLA-DQ beta-Chains, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Allele, Child, Aged, Genetic association, Genetics, Whole Genome Sequencing, Immunoglobulin E, Middle Aged, Asthma, United States, Child, Preschool, Female, National Heart, Lung, and Blood Institute (U.S.), Genome-Wide Association Study
Abstract: BACKGROUND: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE. OBJECTIVE: By leveraging data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) and the Atopic Dermatitis Research Network (ADRN), we aim to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum (N=21,901). METHODS: We performed genome-wide association within strata of study, disease, and ancestry groups, and combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data. For details, please see the Methods section in this article’s Online Repository at www.jacionline.org. RESULTS: We identified six loci at genome-wide significance (P
Published: 2021
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19. The Association Between Lung Hyperinflation and Coronary Artery Disease in Smokers

Author: Divay Chandra, Aman Gupta, Gregory L. Kinney, Carl R. Fuhrman, Joseph K. Leader, Alejandro A. Diaz, Jessica Bon, R. Graham Barr, George Washko, Matthew Budoff, John Hokanson, Frank C. Sciurba, James D. Crapo, Edwin K. Silverman, Barry J. Make, Elizabeth A. Regan, Terri Beaty, Ferdouse Begum, Adel R. Boueiz, Peter J. Castaldi, Michael Cho, Dawn L. DeMeo, Marilyn G. Foreman, Eitan Halper-Stromberg, Lystra P. Hayden, Craig P. Hersh, Jacqueline Hetmanski, Brian D. Hobbs, John E. Hokanson, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Margaret M. Parker, Dmitry Prokopenko, Dandi Qiao, Phuwanat Sakornsakolpat, Emily S. Wan, Sungho Won, Mustafa Al Qaisi, Harvey O. Coxson, Teresa Gray, MeiLan K. Han, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, John D. Newell, James C. Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Douglas Stinson, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, Carla G. Wilson, Robert Jensen, Jim Crooks, Douglas Everett, Camille Moore, null Strand, John Hughes, Gregory Kinney, Katherine Pratte, Kendra A. Young, Surya Bhatt, Carlos Martinez, Susan Murray, Xavier Soler, Farnoush Banaei-Kashani, Russell P. Bowler, Katerina Kechris, Jeffrey L. Curtis, Perry G. Pernicano, Nicola Hanania, Mustafa Atik, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Amit Parulekar, Craig Hersh, John Austin, Belinda D’Souza, Byron Thomashow, Neil MacIntyre, H. Page McAdams, Lacey Washington, Charlene McEvoy, Joseph Tashjian, Robert Wise, Robert Brown, Nadia N. Hansel, Karen Horton, Allison Lambert, Nirupama Putcha, Richard Casaburi, Alessandra Adami, Hans Fischer, Janos Porszasz, Harry Rossiter, William Stringer, Michael E. DeBakey, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, Ken M. Kunisaki, Eugene Berkowitz, Gloria Westney, Russell Bowler, Richard Rosiello, David Pace, Gerard Criner, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D’Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, Victor Kim, A. James Mamary, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, Surya P. Bhatt, Anand Iyer, Hrudaya Nath, J. Michael Wells, Joe Ramsdell, Paul Friedman, Andrew Yen, Alejandro P. Comellas, Karin F. Hoth, John Newell, Brad Thompson, Ella Kazerooni, Carlos H. Martinez, Joanne Billings, Abbie Begnaud, Tadashi Allen, Frank Sciurba, Carl Fuhrman, Joel Weissfeld, Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, and Mario E. Ruiz
Subjects: Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Coronary Artery Disease, Critical Care and Intensive Care Medicine, COPD: Original Research, Coronary artery disease, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, Functional residual capacity, Risk Factors, Internal medicine, medicine, Humans, Lung volumes, 030212 general & internal medicine, Myocardial infarction, Lung, Subclinical infection, COPD, business.industry, Smoking, Organ Size, Middle Aged, respiratory system, medicine.disease, Coronary Vessels, United States, Respiratory Function Tests, respiratory tract diseases, Airway Obstruction, Plethysmography, Biological Variation, Population, Pulmonary Emphysema, 030228 respiratory system, Asymptomatic Diseases, Cohort, Cardiology, Airway Remodeling, Female, Tomography, X-Ray Computed, Cardiology and Cardiovascular Medicine, business
Abstract: BACKGROUND: Smokers manifest varied phenotypes of pulmonary impairment. RESEARCH QUESTION: Which pulmonary phenotypes are associated with coronary artery disease (CAD) in smokers? STUDY DESIGN AND METHODS: We analyzed data from the University of Pittsburgh COPD Specialized Center for Clinically Oriented Research (SCCOR) cohort (n = 481) and the Genetic Epidemiology of COPD (COPDGene) cohort (n = 2,580). Participants were current and former smokers with > 10 pack-years of tobacco exposure. Data from the two cohorts were analyzed separately because of methodologic differences. Lung hyperinflation was assessed by plethysmography in the SCCOR cohort and by inspiratory and expiratory CT scan lung volumes in the COPDGene cohort. Subclinical CAD was assessed as the coronary artery calcium score, whereas clinical CAD was defined as a self-reported history of CAD or myocardial infarction (MI). Analyses were performed in all smokers and then repeated in those with airflow obstruction (FEV(1) to FVC ratio, < 0.70). RESULTS: Pulmonary phenotypes, including airflow limitation, emphysema, lung hyperinflation, diffusion capacity, and radiographic measures of airway remodeling, showed weak to moderate correlations (r < 0.7) with each other. In multivariate models adjusted for pulmonary phenotypes and CAD risk factors, lung hyperinflation was the only phenotype associated with calcium score, history of clinical CAD, or history of MI (per 0.2 higher expiratory and inspiratory CT scan lung volume; coronary calcium: OR, 1.2; 95% CI, 1.1-1.5; P = .02; clinical CAD: OR, 1.6; 95% CI, 1.1-2.3; P = .01; and MI in COPDGene: OR, 1.7; 95% CI, 1.0-2.8; P = .05). FEV(1) and emphysema were associated with increased risk of CAD (P < .05) in models adjusted for CAD risk factors; however, these associations were attenuated on adjusting for lung hyperinflation. Results were the same in those with airflow obstruction and were present in both cohorts. INTERPRETATION: Lung hyperinflation is associated strongly with clinical and subclinical CAD in smokers, including those with airflow obstruction. After lung hyperinflation was accounted for, FEV(1) and emphysema no longer were associated with CAD. Subsequent studies should consider measuring lung hyperinflation and examining its mechanistic role in CAD in current and former smokers.
Published: 2021
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20. Rare genetic variants explain missing heritability in smoking

Author: Seon-Kyeong Jang, Luke Evans, Allison Fialkowski, Donna K. Arnett, Allison E. Ashley-Koch, Kathleen C. Barnes, Diane M. Becker, Joshua C. Bis, John Blangero, Eugene R. Bleecker, Meher Preethi Boorgula, Donald W. Bowden, Jennifer A. Brody, Brian E. Cade, Brenda W. Campbell Jenkins, April P. Carson, Sameer Chavan, L. Adrienne Cupples, Brian Custer, Scott M. Damrauer, Sean P. David, Mariza de Andrade, Carla L. Dinardo, Tasha E. Fingerlin, Myriam Fornage, Barry I. Freedman, Melanie E. Garrett, Sina A. Gharib, David C. Glahn, Jeffrey Haessler, Susan R. Heckbert, John E. Hokanson, Lifang Hou, Shih-Jen Hwang, Matthew C. Hyman, Renae Judy, Anne E. Justice, Robert C. Kaplan, Sharon L. R. Kardia, Shannon Kelly, Wonji Kim, Charles Kooperberg, Daniel Levy, Donald M. Lloyd-Jones, Ruth J. F. Loos, Ani W. Manichaikul, Mark T. Gladwin, Lisa Warsinger Martin, Mehdi Nouraie, Olle Melander, Deborah A. Meyers, Courtney G. Montgomery, Kari E. North, Elizabeth C. Oelsner, Nicholette D. Palmer, Marinelle Payton, Anna L. Peljto, Patricia A. Peyser, Michael Preuss, Bruce M. Psaty, Dandi Qiao, Daniel J. Rader, Nicholas Rafaels, Susan Redline, Robert M. Reed, Alexander P. Reiner, Stephen S. Rich, Jerome I. Rotter, David A. Schwartz, Aladdin H. Shadyab, Edwin K. Silverman, Nicholas L. Smith, J. Gustav Smith, Albert V. Smith, Jennifer A. Smith, Weihong Tang, Kent D. Taylor, Marilyn J. Telen, Ramachandran S. Vasan, Victor R. Gordeuk, Zhe Wang, Kerri L. Wiggins, Lisa R. Yanek, Ivana V. Yang, Kendra A. Young, Kristin L. Young, Yingze Zhang, Dajiang J. Liu, Matthew C. Keller, and Scott Vrieze
Subjects: Social Psychology, Tobacco Smoke and Health, Smoking, Human Genome, Experimental and Cognitive Psychology, Single Nucleotide, Polymorphism, Single Nucleotide, Article, Behavioral Neuroscience, Phenotype, Gene Frequency, Tobacco, Genetics, Polymorphism, Genome-Wide Association Study, Cancer
Abstract: Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.
Published: 2022

21. Heterozygosity of the Alpha 1‐Antitrypsin Pi*Z Allele and Risk of Liver Disease

Author: Jiangyuan Liu, Dandi Qiao, Brian D. Hobbs, Aaron Hakim, Jessica Lasky-Su, Michael H. Cho, Z. Gordon Jiang, Silvia Vilarinho, Matthew Moll, and Edwin K. Silverman
Subjects: medicine.medical_specialty, education.field_of_study, Cirrhosis, Hepatology, business.industry, Population, Original Articles, Odds ratio, RC799-869, Diseases of the digestive system. Gastroenterology, medicine.disease, Loss of heterozygosity, Liver disease, Endocrinology, Internal medicine, Medicine, Original Article, Allele, Risk factor, business, education, TM6SF2
Abstract: The serpin family A member 1 (SERPINA1) Z allele is present in approximately one in 25 individuals of European ancestry. Z allele homozygosity (Pi*ZZ) is the most common cause of alpha 1‐antitrypsin deficiency and is a proven risk factor for cirrhosis. We examined whether heterozygous Z allele (Pi*Z) carriers in United Kingdom (UK) Biobank, a population‐based cohort, are at increased risk of liver disease. We replicated findings in Massachusetts General Brigham Biobank, a hospital‐based cohort. We also examined variants associated with liver disease and assessed for gene–gene and gene–environment interactions. In UK Biobank, we identified 1,493 cases of cirrhosis, 12,603 Z allele heterozygotes, and 129 Z allele homozygotes among 312,671 unrelated white British participants. Heterozygous carriage of the Z allele was associated with cirrhosis compared to noncarriage (odds ratio [OR], 1.53; P = 1.1×10−04); homozygosity of the Z allele also increased the risk of cirrhosis (OR, 11.8; P = 1.8 × 10−09). The OR for cirrhosis of the Z allele was comparable to that of well‐established genetic variants, including patatin‐like phospholipase domain containing 3 (PNPLA3) I148M (OR, 1.48; P = 1.1 × 10−22) and transmembrane 6 superfamily member 2 (TM6SF2) E167K (OR, 1.34; P = 2.6 × 10−06). In heterozygotes compared to noncarriers, the Z allele was associated with higher alanine aminotransferase (ALT; P = = 4.6 × 10−46), aspartate aminotransferase (AST; P = 2.2 × 10−27), alkaline phosphatase (P = 3.3 × 10−43), gamma‐glutamyltransferase (P = 1.2 × 10−05), and total bilirubin (P = 6.4 × 10−06); Z allele homozygotes had even greater elevations in liver biochemistries. Body mass index (BMI) amplified the association of the Z allele for ALT (P interaction = 0.021) and AST (P interaction = 0.0040), suggesting a gene–environment interaction. Finally, we demonstrated genetic interactions between variants in PNPLA3, TM6SF2, and hydroxysteroid 17‐beta dehydrogenase 13 (HSD17B13); there was no evidence of epistasis between the Z allele and these variants. Conclusion: SERPINA1 Z allele heterozygosity is an important risk factor for liver disease; this risk is amplified by increasing BMI.
Published: 2021

22. Genome‐wide association analysis of COVID‐19 mortality risk in SARS‐CoV‐2 genomes identifies mutation in the SARS‐CoV‐2 spike protein that colocalizes with P.1 of the Brazilian strain

Author: Behzad Etemad, Dandi Qiao, Sharon M. Lutz, Rudolph E. Tanzi, Nan M. Laird, Chloe M. Wu, Sanghun Lee, Edwin K. Silverman, Jonathan Z. Li, Surender Khurana, Julian Hecker, Dawn L. DeMeo, Sebastien Haneuse, Abbas Mohammadi, Michael H. Cho, Katharina Ribbeck, Christoph Lange, Adrienne G. Randolph, Manish Chandra Choudhary, Scott T. Weiss, Lindsey R. Baden, Georg Hahn, and Elmira Esmaeilzadeh
Subjects: Epidemiology, GISAID database, Locus (genetics), Genome-wide association study, Biology, spike protein, Genome, SARS‐CoV‐2, 03 medical and health sciences, Viral entry, Humans, Mutation frequency, Phylogeny, Research Articles, Genetics (clinical), 030304 developmental biology, Genetic association, Whole genome sequencing, Genetics, 0303 health sciences, SARS-CoV-2, logistic regression, 030305 genetics & heredity, COVID-19, mortality, Mutation, Spike Glycoprotein, Coronavirus, Mutation (genetic algorithm), whole‐genome sequencing, Brazil, Genome-Wide Association Study, Research Article
Abstract: SARS‐CoV‐2 mortality has been extensively studied in relation to host susceptibility. How sequence variations in the SARS‐CoV‐2 genome affect pathogenicity is poorly understood. Starting in October 2020, using the methodology of genome‐wide association studies (GWAS), we looked at the association between whole‐genome sequencing (WGS) data of the virus and COVID‐19 mortality as a potential method of early identification of highly pathogenic strains to target for containment. Although continuously updating our analysis, in December 2020, we analyzed 7548 single‐stranded SARS‐CoV‐2 genomes of COVID‐19 patients in the GISAID database and associated variants with mortality using a logistic regression. In total, evaluating 29,891 sequenced loci of the viral genome for association with patient/host mortality, two loci, at 12,053 and 25,088 bp, achieved genome‐wide significance (p values of 4.09e−09 and 4.41e−23, respectively), though only 25,088 bp remained significant in follow‐up analyses. Our association findings were exclusively driven by the samples that were submitted from Brazil (p value of 4.90e−13 for 25,088 bp). The mutation frequency of 25,088 bp in the Brazilian samples on GISAID has rapidly increased from about 0.4 in October/December 2020 to 0.77 in March 2021. Although GWAS methodology is suitable for samples in which mutation frequencies varies between geographical regions, it cannot account for mutation frequencies that change rapidly overtime, rendering a GWAS follow‐up analysis of the GISAID samples that have been submitted after December 2020 as invalid. The locus at 25,088 bp is located in the P.1 strain, which later (April 2021) became one of the distinguishing loci (precisely, substitution V1176F) of the Brazilian strain as defined by the Centers for Disease Control. Specifically, the mutations at 25,088 bp occur in the S2 subunit of the SARS‐CoV‐2 spike protein, which plays a key role in viral entry of target host cells. Since the mutations alter amino acid coding sequences, they potentially imposing structural changes that could enhance viral infectivity and symptom severity. Our analysis suggests that GWAS methodology can provide suitable analysis tools for the real‐time detection of new more transmissible and pathogenic viral strains in databases such as GISAID, though new approaches are needed to accommodate rapidly changing mutation frequencies over time, in the presence of simultaneously changing case/control ratios. Improvements of the associated metadata/patient information in terms of quality and availability will also be important to fully utilize the potential of GWAS methodology in this field.
Published: 2021
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23. Interstitial lung abnormalities are associated with decreased mean telomere length

Author: Rachel K. Putman, Gisli Thor Axelsson, Samuel Y. Ash, Jason L. Sanders, Aravind A. Menon, Tetsuro Araki, Mizuki Nishino, Masahiro Yanagawa, Elías F. Gudmundsson, Dandi Qiao, Raúl San José Estépar, Josée Dupuis, George T. O'Connor, Ivan O. Rosas, George R. Washko, Souheil El-Chemaly, Benjamin A. Raby, Vilmundur Gudnason, Dawn L. DeMeo, Edwin K. Silverman, Hiroto Hatabu, Immaculata DeVivo, Michael H. Cho, Gunnar Gudmundsson, and Gary M. Hunninghake
Subjects: Pulmonary and Respiratory Medicine, Pulmonary Disease, Chronic Obstructive, Humans, Telomere, Lung Diseases, Interstitial, Tomography, X-Ray Computed, Lung, Article
Abstract: BackgroundInterstitial lung abnormalities (ILA) share many features with idiopathic pulmonary fibrosis; however, it is not known if ILA are associated with decreased mean telomere length (MTL).MethodsTelomere length was measured with quantitative PCR in the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) and Age Gene/Environment Susceptibility Reykjavik (AGES-Reykjavik) cohorts and Southern blot analysis was used in the Framingham Heart Study (FHS). Logistic and linear regression were used to assess the association between ILA and MTL; Cox proportional hazards models were used to assess the association between MTL and mortality.ResultsIn all three cohorts, ILA were associated with decreased MTL. In the COPDGene and AGES-Reykjavik cohorts, after adjustment there was greater than twofold increase in the odds of ILA when comparing the shortest quartile of telomere length to the longest quartile (OR 2.2, 95% CI 1.5–3.4, p=0.0001, and OR 2.6, 95% CI 1.4–4.9, p=0.003, respectively). In the FHS, those with ILA had shorter telomeres than those without ILA (−767 bp, 95% CI 76–1584 bp, p=0.03). Although decreased MTL was associated with chronic obstructive pulmonary disease (OR 1.3, 95% CI 1.1–1.6, p=0.01) in COPDGene, the effect estimate was less than that noted with ILA. There was no consistent association between MTL and risk of death when comparing the shortest quartile of telomere length in COPDGene and AGES-Reykjavik (HR 0.82, 95% CI 0.4–1.7, p=0.6, and HR 1.2, 95% CI 0.6–2.2, p=0.5, respectively).ConclusionILA are associated with decreased MTL.
Published: 2022

24. Machine Learning Prediction of Progression in Forced Expiratory Volume in 1 Second in the COPDGene® Study

Author: Adel Boueiz, Zhonghui Xu, Yale Chang, Aria Masoomi, Andrew Gregory, Sharon M. Lutz, Dandi Qiao, James D. Crapo, Jennifer G. Dy, Edwin K. Silverman, and Peter J. Castaldi
Subjects: Pulmonary and Respiratory Medicine, Origianl Research
Abstract: Background: The heterogeneous nature of chronic obstructive pulmonary disease (COPD) complicates the identification of the predictors of disease progression. We aimed to improve the prediction of disease progression in COPD by using machine learning and incorporating a rich dataset of phenotypic features. Methods: We included 4496 smokers with available data from their enrollment and 5-year follow-up visits in the COPD Genetic Epidemiology (COPDGene(®)) study. We constructed linear regression (LR) and supervised random forest models to predict 5-year progression in forced expiratory in 1 second (FEV(1)) from 46 baseline features. Using cross-validation, we randomly partitioned participants into training and testing samples. We also validated the results in the COPDGene 10-year follow-up visit. Results: Predicting the change in FEV(1) over time is more challenging than simply predicting the future absolute FEV(1) level. For random forest, R-squared was 0.15 and the area under the receiver operator characteristic (ROC) curves for the prediction of participants in the top quartile of observed progression was 0.71 (testing) and respectively, 0.10 and 0.70 (validation). Random forest provided slightly better performance than LR. The accuracy was best for Global initiative for chronic Obstructive Lung Disease (GOLD) grades 1–2 participants, and it was harder to achieve accurate prediction in advanced stages of the disease. Predictive variables differed in their relative importance as well as for the predictions by GOLD. Conclusion: Random forest, along with deep phenotyping, predicts FEV(1) progression with reasonable accuracy. There is significant room for improvement in future models. This prediction model facilitates the identification of smokers at increased risk for rapid disease progression. Such findings may be useful in the selection of patient populations for targeted clinical trials.
Published: 2022

25. Prevalence of abnormal spirometry in individuals with a smoking history and no known obstructive lung disease

Author: Thuonghien V. Tran, Gregory L. Kinney, Alejandro Comellas, Karin F. Hoth, Arianne K. Baldomero, A. James Mamary, Jeffrey L. Curtis, Nicola Hanania, Richard Casaburi, Kendra A. Young, Victor Kim, Barry Make, Emily S. Wan, Alejandro A. Diaz, John Hokanson, James D. Crapo, Edwin K. Silverman, Surya P. Bhatt, Elizabeth Regan, Spyridon Fortis, Barry J. Make, Elizabeth A. Regan, Terri H. Beaty, Peter J. Castaldi, Michael H. Cho, Dawn L. DeMeo, Adel El Boueiz, Marilyn G. Foreman, Auyon Ghosh, Lystra P. Hayden, Craig P. Hersh, Jacqueline Hetmanski, Brian D. Hobbs, John E. Hokanson, Wonji Kim, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Dmitry Prokopenko, Matthew Moll, Jarrett Morrow, Dandi Qiao, Aabida Saferali, Phuwanat Sakornsakolpat, Jeong Yun, Juan Pablo Centeno, Jean-Paul Charbonnier, Harvey O. Coxson, Craig J. Galban, MeiLan K. Han, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, Pietro Nardelli, John D. Newell, Aleena Notary, Andrea Oh, James C. Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, Gonzalo Vegas Sanchez Ferrero, Lucas Veitel, George R. Washko, Carla G. Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Katherine Pratte, Matt Strand, Erin Austin, Gregory Kinney, Jessica Bon, Susan Murray, Xavier Soler, Russell P. Bowler, Katerina Kechris, Farnoush BanaeiKashani, Perry G. Pernicano, Mustafa Atik, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Amit Parulekar, Craig Hersh, George Washko, R. Graham Barr, John Austin, Belinda D'Souza, Byron Thomashow, Neil MacIntyre, H. Page McAdams, Lacey Washington, Charlene McEvoy, Joseph Tashjian, Robert Wise, Robert Brown, Nadia N. Hansel, Karen Horton, Allison Lambert, Nirupama Putcha, Alessandra Adami, Matthew Budoff, Hans Fischer, Janos Porszasz, Harry Rossiter, William Stringer, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, Ken M. Kunisaki, Eric L. Flenaugh, Hirut Gebrekristos, Mario Ponce, Silanath Terpenning, Gloria Westney, Russell Bowler, Richard Rosiello, David Pace, Gerard Criner, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D'Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, Anand Iyer, Hrudaya Nath, J. Michael Wells, Douglas Conrad, Andrew Yen, Alejandro P. Comellas, John Newell, Brad Thompson, Ella Kazerooni, Wassim Labaki, Craig Galban, Dharshan Vummidi, Joanne Billings, Abbie Begnaud, Tadashi Allen, Frank Sciurba, Divay Chandra, Joel Weissfeld, Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, Mario E. Ruiz, and Harjinder Singh
Subjects: Pulmonary and Respiratory Medicine
Published: 2023
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26. Clinical outcomes of digital health in adults with cystic fibrosis

Author: Vincenzo Carnovale, Paola Iacotucci, Dandi Qiao, Lorenza Ferrillo, Jolanda Somma, Serena Buonaurio, null Marcella d’Ippolito, Assunta Celardo, and Daniela Savi
Subjects: Pulmonary and Respiratory Medicine, Adult, Male, Young Adult, Cystic Fibrosis, Surveys and Questionnaires, Quality of Life, Cystic Fibrosis Transmembrane Conductance Regulator, Humans, Female, Respiratory Function Tests
Abstract: The aim of this study was to assess the long-term clinical impact of the application of e-health as part of a virtual model of care in patients with Cystic Fibrosis (CF).Digital care group (DCG) were deemed suitable for using the NuvoAir Home platform to monitor their disease at home as part of a virtual model of care project. The usual care group (UCG) remained on usual care. NuvoAir Home platform consists of a smartphone application, Bluetooth spirometer and a clinician portal. Data on pulmonary function, Cystic Fibrosis Questionnaire-Revised (CFQR) and pulmonary exacerbations were collected at baseline and after twelve months. A survey for the digital care group was emailed to evaluate their experience using the technology.Between February 2020 and May 2020 a cohort of 43 CF patients were recruited for the DCG (26 females; mean age 31.6 ± 6.8; 16 homozygous for delta F508; FEVThe application of digital technologies in the management of adults with CF showed an improvement in patients' quality of life. Using a virtual model of care was well accepted by CF patients and improved their understanding of their medical condition.
Published: 2022

27. Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential

Author: Tetsushi, Nakao, Alexander G, Bick, Margaret A, Taub, Seyedeh M, Zekavat, Md M, Uddin, Abhishek, Niroula, Cara L, Carty, John, Lane, Michael C, Honigberg, Joshua S, Weinstock, Akhil, Pampana, Christopher J, Gibson, Gabriel K, Griffin, Shoa L, Clarke, Romit, Bhattacharya, Themistocles L, Assimes, Leslie S, Emery, Adrienne M, Stilp, Quenna, Wong, Jai, Broome, Cecelia A, Laurie, Alyna T, Khan, Albert V, Smith, Thomas W, Blackwell, Veryan, Codd, Christopher P, Nelson, Zachary T, Yoneda, Juan M, Peralta, Donald W, Bowden, Marguerite R, Irvin, Meher, Boorgula, Wei, Zhao, Lisa R, Yanek, Kerri L, Wiggins, James E, Hixson, C Charles, Gu, Gina M, Peloso, Dan M, Roden, Muagututi'a S, Reupena, Chii-Min, Hwu, Dawn L, DeMeo, Kari E, North, Shannon, Kelly, Solomon K, Musani, Joshua C, Bis, Donald M, Lloyd-Jones, Jill M, Johnsen, Michael, Preuss, Russell P, Tracy, Patricia A, Peyser, Dandi, Qiao, Pinkal, Desai, Joanne E, Curran, Barry I, Freedman, Hemant K, Tiwari, Sameer, Chavan, Jennifer A, Smith, Nicholas L, Smith, Tanika N, Kelly, Bertha, Hidalgo, L Adrienne, Cupples, Daniel E, Weeks, Nicola L, Hawley, Ryan L, Minster, Ranjan, Deka, Take T, Naseri, Lisa, de Las Fuentes, Laura M, Raffield, Alanna C, Morrison, Paul S, Vries, Christie M, Ballantyne, Eimear E, Kenny, Stephen S, Rich, Eric A, Whitsel, Michael H, Cho, M Benjamin, Shoemaker, Betty S, Pace, John, Blangero, Nicholette D, Palmer, Braxton D, Mitchell, Alan R, Shuldiner, Kathleen C, Barnes, Susan, Redline, Sharon L R, Kardia, Gonçalo R, Abecasis, Lewis C, Becker, Susan R, Heckbert, Jiang, He, Wendy, Post, Donna K, Arnett, Ramachandran S, Vasan, Dawood, Darbar, Scott T, Weiss, Stephen T, McGarvey, Mariza, de Andrade, Yii-Der Ida, Chen, Robert C, Kaplan, Deborah A, Meyers, Brian S, Custer, Adolfo, Correa, Bruce M, Psaty, Myriam, Fornage, JoAnn E, Manson, Eric, Boerwinkle, Barbara A, Konkle, Ruth J F, Loos, Jerome I, Rotter, Edwin K, Silverman, Charles, Kooperberg, John, Danesh, Nilesh J, Samani, Siddhartha, Jaiswal, Peter, Libby, Patrick T, Ellinor, Nathan, Pankratz, Benjamin L, Ebert, Alexander P, Reiner, Rasika A, Mathias, Ron, Do, and Pradeep, Natarajan
Subjects: Multidisciplinary
Abstract: Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program ( n = 63,302) and UK Biobank ( n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.
Published: 2022
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28. Statistical considerations for the analysis of massively parallel reporter assays data

Author: Edwin K. Silverman, Peter J. Castaldi, Michael H. Cho, Nan H. Laird, Corwin M. Zigler, Dandi Qiao, and Xiaobo Zhou
Subjects: RNA, Untranslated, Epidemiology, Computer science, Gene Expression, Computational biology, Regulatory Sequences, Nucleic Acid, Article, 03 medical and health sciences, Humans, Massively parallel, Alleles, Genetics (clinical), 030304 developmental biology, 0303 health sciences, 030305 genetics & heredity, Genetic variants, Nonparametric statistics, Genetic Variation, High-Throughput Nucleotide Sequencing, DNA, Noncoding DNA, Fully developed, R package, Research Design, Allelic Imbalance, Software, Type I and type II errors
Abstract: Noncoding DNA contains gene regulatory elements that alter gene expression, and the function of these elements can be modified by genetic variation. Massively parallel reporter assays (MPRA) enable high-throughput identification and characterization of functional genetic variants, but the statistical methods to identify allelic effects in MPRA data have not been fully developed. In this study, we demonstrate how the baseline allelic imbalance in MPRA libraries can produce biased results, and we propose a novel, nonparametric, adaptive testing method that is robust to this bias. We compare the performance of this method with other commonly used methods, and we demonstrate that our novel adaptive method controls Type I error in a wide range of scenarios while maintaining excellent power. We have implemented these tests along with routines for simulating MPRA data in the Analysis Toolset for MPRA (@MPRA), an R package for the design and analyses of MPRA experiments. It is publicly available at http://github.com/redaq/atMPRA.
Published: 2020
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29. Machine Learning Characterization of COPD Subtypes

Author: Peter J. Castaldi, Adel Boueiz, Jeong Yun, Raul San Jose Estepar, James C. Ross, George Washko, Michael H. Cho, Craig P. Hersh, Gregory L. Kinney, Kendra A. Young, Elizabeth A. Regan, David A. Lynch, Gerald J. Criner, Jennifer G. Dy, Stephen I. Rennard, Richard Casaburi, Barry J. Make, James Crapo, Edwin K. Silverman, John E. Hokanson, James D. Crapo, Terri Beaty, Ferdouse Begum, Michael Cho, Dawn L. DeMeo, Adel R. Boueiz, Marilyn G. Foreman, Eitan Halper-Stromberg, Lystra P. Hayden, Jacqueline Hetmanski, Brian D. Hobbs, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Margaret M. Parker, Dmitry Prokopenko, Dandi Qiao, Phuwanat Sakornsakolpat, Emily S. Wan, Sungho Won, Juan Pablo Centeno, Jean-Paul Charbonnier, Harvey O. Coxson, Craig J. Galban, MeiLan K. Han, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, Pietro Nardelli, John D. Newell, Aleena Notary, Andrea Oh, Joyce Schroeder, Jered Sieren, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, Gonzalo Vegas Sanchez-Ferrero, Lucas Veitel, George R. Washko, Carla G. Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Katherine Pratte, Matt Strand, Gregory Kinney, Surya P. Bhatt, Jessica Bon, Alejandro A. Diaz, Barry Make, Susan Murray, Elizabeth Regan, Xavier Soler, Russell P. Bowler, Katerina Kechris, and Farnoush Banaei-Kashani
Subjects: Pulmonary and Respiratory Medicine, Spirometry, COPD, medicine.diagnostic_test, business.industry, Context (language use), Disease, Critical Care and Intensive Care Medicine, medicine.disease, Machine learning, computer.software_genre, Subtyping, respiratory tract diseases, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Genetic epidemiology, medicine, Clinical significance, 030212 general & internal medicine, Artificial intelligence, Genetic risk, Cardiology and Cardiovascular Medicine, business, computer
Abstract: COPD is a heterogeneous syndrome. Many COPD subtypes have been proposed, but there is not yet consensus on how many COPD subtypes there are and how they should be defined. The COPD Genetic Epidemiology Study (COPDGene), which has generated 10-year longitudinal chest imaging, spirometry, and molecular data, is a rich resource for relating COPD phenotypes to underlying genetic and molecular mechanisms. In this article, we place COPDGene clustering studies in context with other highly cited COPD clustering studies, and summarize the main COPD subtype findings from COPDGene. First, most manifestations of COPD occur along a continuum, which explains why continuous aspects of COPD or disease axes may be more accurate and reproducible than subtypes identified through clustering methods. Second, continuous COPD-related measures can be used to create subgroups through the use of predictive models to define cut-points, and we review COPDGene research on blood eosinophil count thresholds as a specific example. Third, COPD phenotypes identified or prioritized through machine learning methods have led to novel biological discoveries, including novel emphysema genetic risk variants and systemic inflammatory subtypes of COPD. Fourth, trajectory-based COPD subtyping captures differences in the longitudinal evolution of COPD, addressing a major limitation of clustering analyses that are confounded by disease severity. Ongoing longitudinal characterization of subjects in COPDGene will provide useful insights about the relationship between lung imaging parameters, molecular markers, and COPD progression that will enable the identification of subtypes based on underlying disease processes and distinct patterns of disease progression, with the potential to improve the clinical relevance and reproducibility of COPD subtypes.
Published: 2020
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30. A statistical physics approach for disease module detection

Author: Xu-Wen Wang, Dandi Qiao, Michael H. Cho, Dawn L. DeMeo, Edwin K. Silverman, and Yang-Yu Liu
Subjects: Physics, Genetics, Humans, Protein Interaction Maps, Genetics (clinical), Algorithms, Genome-Wide Association Study
Abstract: Extensive evidence indicates that the pathobiological processes of a complex disease are associated with perturbation within specific disease neighborhoods of the human protein-protein interaction (PPI) network (a.k.a. the interactome), often referred to as the disease module. Many computational methods have been developed to integrate the interactome and omics profiles to extract context-dependent disease modules. Yet, existing methods all have fundamental limitations in terms of rigor and/or efficiency. Here, we developed a statistical physics approach based on the random-field Ising model (RFIM) for disease module detection, which is both mathematically rigorous and computationally efficient. We applied our RFIM approach with genome-wide association studies (GWAS) of six complex diseases to examine its performance for disease module detection. We found that our RFIM approach outperforms existing methods in terms of computational efficiency, connectivity of disease modules, and robustness to the interactome incompleteness.
Published: 2022

31. Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children With Asthma

Author: Priyadarshini Kachroo, Julian Hecker, Bo L. Chawes, Tarunveer S. Ahluwalia, Michael H. Cho, Dandi Qiao, Rachel S. Kelly, Su H. Chu, Yamini V. Virkud, Mengna Huang, Kathleen C. Barnes, Esteban G. Burchard, Celeste Eng, Donglei Hu, Juan C. Celedón, Michelle Daya, Albert M. Levin, Hongsheng Gui, L. Keoki Williams, Erick Forno, Angel C.Y. Mak, Lydiana Avila, Manuel E. Soto-Quiros, Michelle M. Cloutier, Edna Acosta-Pérez, Glorisa Canino, Klaus Bønnelykke, Hans Bisgaard, Benjamin A. Raby, Christoph Lange, Scott T. Weiss, Jessica A. Lasky-Su, Namiko Abe, Goncalo Abecasis, Christine Albert, Nicholette (Nichole) Palmer Allred, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Terri Beaty, Diane Becker, Lewis Becker, Rebecca Beer, Ferdouse Begum, Amber Beitelshees, Emelia Benjamin, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Eric Boerwinkle, Ingrid Borecki, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Karen Bunting, Esteban Burchard, Jonathan Cardwell, Cara Carty, Richard Casaburi, James Casella, Mark Chaffin, Christy Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Yii-Der Ida Chen, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Elaine Cornell, Adolfo Correa, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sayantan Das, Sean David, Colleen Davis, Mariza de Andrade, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Ron Do, Qing Duan, Ravi Duggirala, Peter Durda, Susan Dutcher, Charles Eaton, Lynette Ekunwe, Patrick Ellinor, Leslie Emery, Charles Farber, Leanna Farnam, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Yan Gao, Margery Gass, Bruce Gelb, Xiaoqi (Priscilla) Geng, Soren Germer, Chris Gignoux, Mark Gladwin, David Glahn, Stephanie Gogarten, Da-Wei Gong, Harald Goring, C. Charles Gu, Yue Guan, Xiuqing Guo, Jeff Haessler, Michael Hall, Daniel Harris, Nicola Hawley, Jiang He, Ben Heavner, Susan Heckbert, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, James Hixson, John Hokanson, Kramer Holly, Elliott Hong, Karin Hoth, Chao (Agnes) Hsiung, Haley Huston, Chii Min Hwu, Marguerite Ryan Irvin, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Min A. Jhun, Jill Johnsen, Andrew Johnson, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Robert Kaplan, Sharon Kardia, Sekar Kathiresan, Laura Kaufman, Shannon Kelly, Eimear Kenny, Michael Kessler, Alyna Khan, Greg Kinney, Barbara Konkle, Charles Kooperberg, Stephanie Krauter, Ethan Lange, Leslie Lange, Cathy Laurie, Cecelia Laurie, Meryl LeBoff, Seunggeun Shawn Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Dan Levy, Joshua Lewis, Yun Li, Honghuang Lin, Keng Han Lin, Simin Liu, Yongmei Liu, Ruth Loos, Steven Lubitz, Kathryn Lunetta, James Luo, Michael Mahaney, Barry Make, Ani Manichaikul, JoAnn Manson, Lauren Margolin, Lisa Martin, Susan Mathai, Rasika Mathias, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Stephen McGarvey, Hao Mei, Deborah A. Meyers, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L. Minster, Braxton Mitchell, May E. Montasser, Solomon Musani, Stanford Mwasongwe, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Pradeep Natarajan, Sergei Nekhai, Deborah Nickerson, Kari North, Jeff O'Connell, Tim O'Connor, Heather Ochs-Balcom, James Pankow, George Papanicolaou, Margaret Parker, Afshin Parsa, Sara Penchev, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S. Phillips, Sam Phillips, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Dmitry Prokopenko, Bruce Psaty, Pankaj Qasba, Zhaohui Qin, Nicholas Rafaels, Laura Raffield, Vasan Ramachandran, D.C. Rao, Laura Rasmussen-Torvik, Aakrosh Ratan, Susan Redline, Robert Reed, Elizabeth Regan, Alex Reiner, Ken Rice, Stephen Rich, Dan Roden, Carolina Roselli, Jerome Rotter, Ingo Ruczinski, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Phuwanat Sakornsakolpat, Shabnam Salimi, Steven Salzberg, Kevin Sandow, Vijay Sankaran, Christopher Scheller, Ellen Schmidt, Karen Schwander, David Schwartz, Frank Sciurba, Christine Seidman, Jonathan Seidman, Vivien Sheehan, Amol Shetty, Aniket Shetty, Wayne Hui-Heng Sheu, M. Benjamin Shoemaker, Brian Silver, Edwin Silverman, Jennifer Smith, Josh Smith, Nicholas Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Tamar Sofer, Nona Sotoodehnia, Adrienne Stilp, Elizabeth Streeten, Yun Ju Sung, Jessica Su-Lasky, Jody Sylvia, Adam Szpiro, Carole Sztalryd, Daniel Taliun, Hua Tang, Margaret Taub, Kent Taylor, Simeon Taylor, Marilyn Telen, Timothy A. Thornton, Lesley Tinker, David Tirschwell, Hemant Tiwari, Russell Tracy, Michael Tsai, Dhananjay Vaidya, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Emily Wan, Fei Fei Wang, Karol Watson, Daniel E. Weeks, Bruce Weir, Scott Weiss, Lu-Chen Weng, Cristen Willer, Kayleen Williams, Carla Wilson, James Wilson, Quenna Wong, Huichun Xu, Lisa Yanek, Ivana Yang, Rongze Yang, Norann Zaghloul, Maryam Zekavat, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Xiuwen Zheng, Degui Zhi, Xiang Zhou, Michael Zody, and Sebastian Zoellner
Subjects: Adult, Costa Rica, Male, Pulmonary and Respiratory Medicine, Adolescent, Vital Capacity, Single-nucleotide polymorphism, Pedigree chart, Critical Care and Intensive Care Medicine, Young Adult, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, Polymorphism (computer science), Forced Expiratory Volume, Humans, Medicine, SNP, 030212 general & internal medicine, Child, Asthma, Whole Genome Sequencing, business.industry, Middle Aged, respiratory system, medicine.disease, respiratory tract diseases, Minor allele frequency, 030228 respiratory system, Genetic epidemiology, Child, Preschool, Interferon Regulatory Factors, Immunology, Respiratory Physiological Phenomena, Female, Cardiology and Cardiovascular Medicine, business, Cell Adhesion Molecules
Abstract: BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician’s diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. RESULTS: A genome-wide significant association was identified between baseline FEV(1)/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10(−8) in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10(−6)). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV(1) (P = 3.3 × 10(−3)), postbronchodilator (PB) FEV(1) (7.3 × 10(−3)), and PB FEV(1)/FVC ratio (P = 2.7 × 10(−3)). The identified baseline FEV(1)/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR. CONCLUSIONS: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.
Published: 2019
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32. Clonal hematopoiesis is driven by aberrant activation of TCL1A

Author: Joshua S. Weinstock, Jayakrishnan Gopakumar, Bala Bharathi Burugula, Md Mesbah Uddin, Nikolaus Jahn, Julia A. Belk, Bence Daniel, Nghi Ly, Taralyn M. Mack, Cecelia A. Laurie, Jai G. Broome, Kent D. Taylor, Xiuqing Guo, Moritz F. Sinner, Aenne S. von Falkenhausen, Stefan Kääb, Alan R. Shuldiner, Jeffrey R. O’Connell, Joshua P. Lewis, Eric Boerwinkle, Kathleen C. Barnes, Nathalie Chami, Eimear E. Kenny, Ruth J. Loos, Myriam Fornage, Lifang Hou, Donald M. Lloyd-Jones, Susan Redline, Brian E. Cade, Bruce M. Psaty, Joshua C. Bis, Jennifer A. Brody, Edwin K. Silverman, Jeong H. Yun, Dandi Qiao, Nicholette D. Palmer, Barry I. Freedman, Donald W. Bowden, Michael H. Cho, Dawn L. DeMeo, Ramachandran S. Vasan, Lisa R. Yanek, Lewis C. Becker, Sharon Kardia, Patricia A. Peyser, Jiang He, Michiel Rienstra, Pim Van der Harst, Robert Kaplan, Susan R. Heckbert, Nicholas L. Smith, Kerri L. Wiggins, Donna K. Arnett, Marguerite R. Irvin, Hemant Tiwari, Michael J. Cutler, Stacey Knight, J Brent. Muhlestein, Adolfo Correa, Laura M. Raffield, Yan Gao, Mariza de Andrade, Jerome I. Rotter, Stephen S. Rich, Russell P. Tracy, Barbara A. Konkle, Jill M. Johnsen, Marsha M. Wheeler, J. Gustav Smith, Olle Melander, Peter M. Nilsson, Brian S. Custer, Ravindranath Duggirala, Joanne E. Curran, John Blangero, Stephen McGarvey, L. Keoki Williams, Shujie Xiao, Mao Yang, C. Charles. Gu, Yii-Der Ida. Chen, Wen-Jane Lee, Gregory M. Marcus, John P. Kane, Clive R. Pullinger, M. Benjamin Shoemaker, Dawood Darbar, Dan Roden, Christine Albert, Charles Kooperberg, Ying Zhou, JoAnn E. Manson, Pinkal Desai, Andrew Johnson, Rasika Mathias, Thomas W. Blackwell, Goncalo R. Abecasis, Albert V. Smith, Hyun M. Kang, Ansuman T. Satpathy, Pradeep Natarajan, Jacob Kitzman, Eric Whitsel, Alexander P. Reiner, Alexander G. Bick, and Sidd Jaiswal
Abstract: A diverse set of driver genes, such as regulators of DNA methylation, RNA splicing, and chromatin remodeling, have been associated with pre-malignant clonal expansion of hematopoietic stem cells (HSCs). The factors mediating expansion of these mutant clones remain largely unknown, partially due to a paucity of large cohorts with longitudinal blood sampling. To circumvent this limitation, we developed and validated a method to infer clonal expansion rate from single timepoint data called PACER (passenger-approximated clonal expansion rate). Applying PACER to 5,071 persons with clonal hematopoiesis accurately recapitulated the known fitness effects due to different driver mutations. A genome-wide association study of PACER revealed that a common inherited polymorphism in the TCL1A promoter was associated with slower clonal expansion. Those carrying two copies of this protective allele had up to 80% reduced odds of having driver mutations in TET2, ASXL1, SF3B1, SRSF2, and JAK2, but not DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 by CRISPR editing led to aberrant expression of TCL1A and expansion of HSCs in vitro. These effects were abrogated in HSCs from donors carrying the protective TCL1A allele. Our results indicate that the fitness advantage of multiple common driver genes in clonal hematopoiesis is mediated through TCL1A activation. PACER is an approach that can be widely applied to uncover genetic and environmental determinants of pre-malignant clonal expansion in blood and other tissues.
Published: 2021
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33. A robust and adaptive framework for interaction testing in quantitative traits between multiple genetic loci and exposure variables

Author: Julian Hecker, Dmitry Prokopenko, Matthew Moll, Sanghun Lee, Wonji Kim, Dandi Qiao, Kirsten Voorhies, Woori Kim, Stijn Vansteelandt, Brian D. Hobbs, Michael H. Cho, Edwin K. Silverman, Sharon M. Lutz, Dawn L. DeMeo, Scott T. Weiss, and Christoph Lange
Subjects: Cancer Research, Phenotype, Models, Genetic, Genetic Loci, Genetics, Humans, Gene-Environment Interaction, Computer Simulation, Molecular Biology, Polymorphism, Single Nucleotide, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Genome-Wide Association Study
Abstract: The identification and understanding of gene-environment interactions can provide insights into the pathways and mechanisms underlying complex diseases. However, testing for gene-environment interaction remains a challenge since statistical power is often limited, the specification of environmental effects is nontrivial, and such misspecifications can lead to false positive findings. To address the lack of statistical power, recent methods aim to identify interactions on an aggregated level using, for example, polygenic risk scores. While this strategy increases power to detect interactions, identifying contributing key genes and pathways is difficult based on these global results.Here, we propose RITSS (Robust Interaction Testing using Sample Splitting), a gene-environment interaction testing framework for quantitative traits that is based on sample splitting and robust test statistics. RITSS can incorporate multiple genetic variants and/or multiple environmental factors. Using sample splitting, a screening step enables the selection and combination of potential interactions into scores with improved interpretability, based on the user’s unrestricted choices for statistical/machine learning approaches. In the testing step, the application of robust test statistics minimizes the susceptibility of the results to main effect misspecifications.Using extensive simulation studies, we demonstrate that RITSS controls the type 1 error rate in a wide range of scenarios. In an application to lung function phenotypes and human height in the UK Biobank, RITSS identified genome-wide significant interactions with subcomponents of genetic risk scores. While the contributing single variant interactions are moderate, our analysis results indicate interesting interaction patterns that result in strong aggregated signals that provide further insights into gene-environment interaction mechanisms.
Published: 2021
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34. Alpha-1 Antitrypsin MZ Heterozygosity Is an Endotype of Chronic Obstructive Pulmonary Disease

Author: Auyon J. Ghosh, Brian D. Hobbs, Matthew Moll, Aabida Saferali, Adel Boueiz, Jeong H. Yun, Frank Sciurba, Lucas Barwick, Andrew H. Limper, Kevin Flaherty, Gerard Criner, Kevin K. Brown, Robert Wise, Fernando J. Martinez, David Lomas, Peter J. Castaldi, Vincent J. Carey, Dawn L. DeMeo, Michael H. Cho, Edwin K. Silverman, Craig P. Hersh, James D. Crapo, Barry J. Make, Elizabeth A. Regan, Terri H. Beaty, Adel El-Boueiz, Marilyn G. Foreman, Lystra P. Hayden, Jacqueline Hetmanski, John E. Hokanson, Wonji Kim, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Dmitry Prokopenko, Jarrett Morrow, Dandi Qiao, Phuwanat Sakornsakolpat, Emily S. Wan, Juan Pablo Centeno, Jean-Paul Charbonnier, Harvey O. Coxson, Craig J. Galban, MeiLan K. Han, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, Pietro Nardelli, John D. Newell, Aleena Notary, Andrea Oh, James C. Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, Gonzalo Vegas Sanchez-Ferrero, Lucas Veitel, George R. Washko, Carla G. Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Katherine Pratte, Matt Strand, Erin Austin, Gregory Kinney, Kendra A. Young, Surya P. Bhatt, Jessica Bon, Alejandro A. Diaz, Barry Make, Susan Murray, Elizabeth Regan, Xavier Soler, Russell P. Bowler, Katerina Kechris, Farnoush Banaei-Kashani, Jeffrey L. Curtis, Perry G. Pernicano, Nicola Hanania, Mustafa Atik, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Amit Parulekar, Craig Hersh, George Washko, R. Graham Barr, John Austin, Belinda D’Souza, Byron Thomashow, Neil MacIntyre, H. Page McAdams, Lacey Washington, Charlene McEvoy, Joseph Tashjian, Robert Brown, Nadia N. Hansel, Karen Horton, Allison Lambert, Nirupama Putcha, Richard Casaburi, Alessandra Adami, Matthew Budoff, Hans Fischer, Janos Porszasz, Harry Rossiter, William Stringer, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, Ken M. Kunisaki, Eric L. Flenaugh, Hirut Gebrekristos, Mario Ponce, Silanath Terpenning, Gloria Westney, Richard Rosiello, David Pace, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D’Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, Victor Kim, A. James Mamary, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, Anand Iyer, Hrudaya Nath, J. Michael Wells, Douglas Conrad, Andrew Yen, Alejandro P. Comellas, Karin F. Hoth, John Newell, Brad Thompson, Ella Kazerooni, Wassim Labaki, Craig Galban, Dharshan Vummidi, Joanne Billings, Abbie Begnaud, Tadashi Allen, Divay Chandra, Joel Weissfeld, Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, Mario E. Ruiz, and Harjinder Singh
Subjects: Male, Endotype, Respiratory System, Critical Care and Intensive Care Medicine, Medical and Health Sciences, Gastroenterology, Loss of heterozygosity, Pulmonary Disease, Chronic Obstructive, Genotype, 80 and over, 2.1 Biological and endogenous factors, Medicine, Longitudinal Studies, Aetiology, Lung, Aged, 80 and over, COPD, RNA sequencing, Middle Aged, Respiratory Function Tests, medicine.anatomical_structure, Phenotype, Meta-analysis, Respiratory, Female, alpha-1 antitrypsin, Genetic Markers, Adult, Pulmonary and Respiratory Medicine, Chronic Obstructive, Heterozygote, medicine.medical_specialty, Chronic Obstructive Pulmonary Disease, Pulmonary disease, Pulmonary Disease, Clinical Research, Internal medicine, alpha 1-Antitrypsin Deficiency, Humans, Allele, Aged, Emphysema, COPDGene Investigators, Whole Genome Sequencing, business.industry, Original Articles, medicine.disease, Survival Analysis, respiratory tract diseases, meta-analysis, alpha 1-Antitrypsin, Case-Control Studies, business
Abstract: RATIONALE: Multiple studies have demonstrated an increased risk of chronic obstructive pulmonary disease (COPD) in heterozygous carriers of the AAT (alpha-1 antitrypsin) Z allele. However, it is not known if MZ subjects with COPD are phenotypically different from noncarriers (MM genotype) with COPD. OBJECTIVES: To assess if MZ subjects with COPD have different clinical features compared with MM subjects with COPD. METHODS: Genotypes of SERPINA1 were ascertained by using whole-genome sequencing data in three independent studies. We compared outcomes between MM subjects with COPD and MZ subjects with COPD in each study and combined the results in a meta-analysis. We performed longitudinal and survival analyses to compare outcomes in MM and MZ subjects with COPD over time. MEASUREMENTS AND MAIN RESULTS: We included 290 MZ subjects with COPD and 6,184 MM subjects with COPD across the three studies. MZ subjects had a lower FEV(1)% predicted and greater quantitative emphysema on chest computed tomography scans compared with MM subjects. In a meta-analysis, the FEV(1) was 3.9% lower (95% confidence interval [CI], −6.55% to −1.26%) and emphysema (the percentage of lung attenuation areas
Published: 2021

35. Longitudinal Association Between Muscle Loss and Mortality in Ever Smokers

Author: Stefanie E. Mason, Rafael Moreta-Martinez, Wassim W. Labaki, Matthew J. Strand, Elizabeth A. Regan, Jessica Bon, Ruben San Jose Estepar, Richard Casaburi, Merry-Lynn McDonald, Harry B. Rossiter, Barry Make, Mark T. Dransfield, MeiLan K. Han, Kendra Young, Jeffrey L. Curtis, Kathleen Stringer, Greg Kinney, John E. Hokanson, Raul San Jose Estepar, George R. Washko, James D. Crapo, Edwin K. Silverman, Sara Cummings, Kelley Madden, Barry J. Make, Juliet Nabbosa, Emily Port, Serine Rashdi, Lori Stepp, Shandi Watts, Michael Weaver, Terri Beaty, Russell P. Bowler, David A. Lynch, Gary Anderson, Eugene R. Bleecker, Harvey O. Coxson, Ronald G. Crystal, James C. Hogg, Michael A. Province, Stephen I. Rennard, Thomas Croxton, Weiniu Gan, Lisa A. Postow, Lisa M. Viviano, Corinne Costa-Davis, Elisha Malanga, Delia Prieto, Ruth Tal-Singer, Homayoon Farzadegan, Akila Hadji, Leena Sathe, David Baraghoshi, Grace Chen, James Crooks, Ruthie Knowles, Katherine Pratte, Carla Wilson, Pearlanne T. Zelarney, Katerina J. Kechris, Sonia Leach, Erin E. Austin, Annika Czizik, Gregory Kinney, Yisha Li, Sharon M. Lutz, Margaret F. Ragland, Nicole Richmond, Kendra A. Young, Michael Cho, Peter J. Castaldi, Kimberly Glass, Craig Hersh, Wonji Kim, Yang-Yu Liu, Craig P. Hersh, Jacqueline Bidinger, Michael H. Cho, Douglas Conrad, Dawn L. DeMeo, Adel R. El-Boueiz, Marilyn G. Foreman, Auyon Ghosh, Georg Hahn, Nadia N. Hansel, Lystra P. Hayden, Brian Hobbs, Woori Kim, Christoph Lange, Merry- Lynn McDonald, Michael McGeachie, Matthew Moll, Melody Morris, Nikolaos A. Patsopoulos, Dandi Qiao, Ingo Ruczinski, Emily S. Wan, Jennifer G. Dy, Sean B. Fain, Shoshana Ginsburg, Eric A. Hoffman, Stephen Humphries, Philip F. Judy, Alex Kluiber Stefanie Mason, Andrea Oh, Clare Poynton, Joseph M. Reinhardt, James Ross, Joyce D. Schroeder, Arkadiusz Sitek, Robert M. Steiner, Edwin van Beek, Bram van Ginneken, Eva van Rikxoort, Robert Jensen, Co-Chair: John E. Hokanson, Surya P. Bhatt, Victor Kim, Nirupama Putcha, MeiLan Han, Alejandro A. Diaz, Elizabeth Regan, Antonio Anzueto, William C. Bailey, Gerard J. Criner, Kim Sprenger, Takis Benos, Nicola A. Hanania, Karin F. Hoth, Allison Lambert, Katherine Lowe, Gabriela Oates, Trisha Parekh, Gloria Westney, Aparna Balasubramanian, Aladin Boriek, Ashraf Fawzy, Francine Jacobson, David C. LaFon, Neil MacIntyre, Diego Maselli-Caceres, Meredith C. McCormack, Frank Sciurba, Xavier Soler, Vickram Tejwani, Edwin JR. van Beek, Raymond C. Wade, Mike Wells, Chris H. Wendt, Jeong H. Yun, Jingzhou Zhang, Lucas Gillenwater, Katherine E. Lowe, Katherine A. Pratte, Margaret Ragland, Amy Attaway, Stefanie Mason, Punam Kumar Saha, Ava Wilson, Hannatu Amaza, Adrienne Baldomero, A. James Mamary, James O’Brien, Robert A. Wise, Michelle Eakin, Jess G. Fiedorowicz, Ben Henkle, Kristen Holm, Anand Iyer, Ken M. Kunisaki, Charlene McEvoy, Takudzwa Mkorombindo, Gen Shinozaki, Abebaw Yohannes, Brian D. Hobbs, Bruce E. Miller, Tara Retson, Lisa McCloskey, Perry G. Pernicano, Mustafa Atik, Laura Bertrand, Thomas Monaco, Dharani Narendra, Veronica V. Lenge de Rosen, Kwame Badu-Danso, Francine L. Jacobson, Laura Kaufman, Cherie Maguire, Sophie Struble, Seth Wilson, R. Graham Barr, Casandra Almonte, John H.M. Austin, Maria Lorena Gomez Blum, Belinda M. D’Souza, Emilay Florez, Rodney Martinez, Wendy Curry, H. Page McAdams, Charlotte V. Reikofski, Lacey Washington, Robert Brown, Cheryl Clare, Marie Daniel, Karen Horton, Cheng Ting 'Tony' Lin, Tahira Mirza, Meagan Scott, Becky Shade, Matt Budoff, Robert Calmelat, Deborah Cavanaugh, Chris Dailing, Leticia Diaz, Hans Fischer, Renee Love Indelicato, Janos Porszasz, April Soriano, William Stringer, Miriam Urrutia, Arianne Baldomero, Brian Bell, Miranda Deconcini, Linda Loes, Jonathan Phelan, Camille Robichaux, Cheryl Sasse, Joseph H. Tashjian, Eric L. Flenaugh, Kema Abson, Hirut Gebrekristos, Priscilla Johnson, Jessica Jordan, Mario Ponce, Silanath Terpenning, Derrick Wilson, Grace Broadhurst, Debra Dyer, Elena Engel, Jay Finigan, Andrew Hill, Alex Jones, Ryan Jones, Jordan Owen, Richard Rosiello, Nicole Andries, Mary Charpentier, Diane Kirk, David Pace, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D’Alonzo, Valena Davis, Parag Desai, Dee Fehrle, Carla Grabianowski, Michael Jacobs, Laurie Jameson, Gayle M. Jones, Steven Kelsen, Nathaniel Marchetti, Francine McGonagle, Aditi Satti, Kartik Shenoy, Regina Sheridan, Maria Vega-Sanchez, Samantha Wallace, Samuel Akinseye-kolapo, Matthew Baker, Arnissa Goggins, Anny McClain, Hrudaya Nath, Satinder P. Singh, Sushil K. Sonavane, Elizabeth Westfall, Marissa Gil, Tarek El Hajjaoui, Albert Hsiao, Amber Martineau, Jenna Mielke, Karl Perez, Gabriel Querido, Tara Reston, Andrew Yen, Alejandro Comellas, Spyridon Fortis, Mauricio Galizia, Eric Garcia, Janet Keating, Archana Laroia, Changhyun Lee, Amber Meyer, Brian Mullan, Prashant Nagpal, Oloigbe Ofori, and Sierra Suiter
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Chronic Obstructive, Clinical Sciences, Respiratory System, Critical Care and Intensive Care Medicine, COPD: Original Research, Body Mass Index, Pectoralis Muscles, Pulmonary Disease, sarcopenia, Pulmonary Disease, Chronic Obstructive, Interquartile range, Clinical Research, Internal medicine, medicine, Tobacco Smoking, COPD, 2.1 Biological and endogenous factors, Humans, Longitudinal Studies, Aetiology, Pectoralis Muscle, Lung, Nutrition, Smokers, COPDGene Investigators, Proportional hazards model, business.industry, Prevention, Smoking, muscle wasting, medicine.disease, mortality, Confidence interval, Good Health and Well Being, Sarcopenia, Cardiology, Body Composition, Cardiology and Cardiovascular Medicine, business, Body mass index, Bioelectrical impedance analysis, Biomarkers
Abstract: BackgroundBody composition measures, specifically low weight or reduced muscle mass, are associated with mortality in COPD, but the effect of longitudinal body composition changes is undefined.Research questionIs the longitudinal loss of fat-free mass (FFM) associated with increased mortality, including in those with initially normal or elevated body composition metrics?Study design and methodsParticipants with complete data for at least one visit in the COPDGene study (n= 9,268) and the ECLIPSE study (n= 1,760) were included and monitored for 12 and 8 years, respectively. Pectoralis muscle area (PMA) was derived from thoracic CT scans and used as a proxy for FFM. A longitudinal mixed submodel for PMA and a Cox proportional hazards submodel for survival were fitted on a joint distribution, using a shared random intercept parameter and Markov chain Monte Carlo parameter estimation.ResultsBoth cohorts demonstrated a left-shifted distribution of baseline FFM, not reflected in BMI, and an increase in all-cause mortality risk associated with longitudinal loss of PMA. For each 1-cm2 PMA loss, mortality increased 3.1%(95%CI, 2.4%-3.7%; P< .001) in COPDGene, and 2.4%(95%CI, 0.9%-4.0%; P< .001) in ECLIPSE. Increased mortality risk was independent of enrollment values for BMI and disease severity [BODE (body mass, airflow obstruction, dyspnea, and exercise capacity) index quartiles] and was significant even in participants with initially greater than average PMA.InterpretationLongitudinal loss of PMA is associated with increased all-cause mortality, regardless of BMI or initial muscle mass. Consideration of novel screening tests and further research into mechanisms contributing to muscle decline may improve risk stratification and identify novel therapeutic targets in ever smokers.
Published: 2021

36. Integrative Genomics Analysis Identifies ACVR1B as a Candidate Causal Gene of Emphysema Distribution

Author: Adel Boueiz, Betty Pham, Robert Chase, Andrew Lamb, Sool Lee, Zun Zar Chi Naing, Michael H. Cho, Margaret M. Parker, Phuwanat Sakornsakolpat, Craig P. Hersh, James D. Crapo, Andrew B. Stergachis, Ruth Tal-Singer, Dawn L. DeMeo, Edwin K. Silverman, Xiaobo Zhou, Peter J. Castaldi, Barry J. Make, Elizabeth A. Regan, Terri Beaty, Ferdouse Begum, Michael Cho, Marilyn G. Foreman, Eitan Halper-Stromberg, Lystra P. Hayden, Jacqueline Hetmanski, Brian D. Hobbs, John E. Hokanson, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Dandi Qiao, Emily S. Wan, Sungho Won, Dmitry Prokopenko, Mustafa Al Qaisi, Harvey O. Coxson, Teresa Gray, MeiLan K. Han, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, John D. Newell, James C. Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Douglas Stinson, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, George Washko, Carla G. Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Camille Moore, Matt Strand, John Hughes, Gregory Kinney, Katherine Pratte, Kendra A. Young, Surya Bhatt, Jessica Bon, Barry Make, Carlos Martinez, Susan Murray, Elizabeth Regan, Xavier Soler, Russell P. Bowler, Katerina Kechris, Farnoush Banaei-Kashani, Y. Ivanov, K. Kostov, J. Bourbeau, M. Fitzgerald, P. Hernandez, K. Killian, R. Levy, F. Maltais, D. O’Donnell, J. Krepelka, J. Vestbo, E. Wouters, D. Quinn, P. Bakke, M. Kosnik, A. Agusti, J. Sauleda, Y. Feschenko, V. Gavrisyuk, L. Yashina, N. Monogarova, P. Calverley, D. Lomas, W. MacNee, D. Singh, J. Wedzicha, A. Anzueto, S. Braman, R. Casaburi, B. Celli, G. Giessel, M. Gotfried, G. Greenwald, Rancho Mirage, N. Hanania, D. Mahler, B. Make, S. Rennard, C. Rochester, P. Scanlon, D. Schuller, F. Sciurba, A. Sharafkhaneh, T. Siler, E. Silverman, A. Wanner, R. Wise, R. ZuWallack, H. Coxson, C. Crim, L. Edwards, R. Tal-Singer, J. Yates, B. Miller, Per Bakke, Amund Gulsvik, RS: NUTRIM - R3 - Respiratory & Age-related Health, Pulmonologie, and MUMC+: MA Longziekten (3)
Subjects: EXPRESSION, 0301 basic medicine, Pulmonary and Respiratory Medicine, Quantitative Trait Loci, Clinical Biochemistry, Genome-wide association study, Computational biology, Biology, Polymorphism, Single Nucleotide, Proof of Concept Study, OBSTRUCTIVE PULMONARY-DISEASE, chronic obstructive pulmonary disease, Transforming Growth Factor beta1, Jurkat Cells, Pulmonary Disease, Chronic Obstructive, integrative genomics, 03 medical and health sciences, 0302 clinical medicine, T-Lymphocyte Subsets, Cell Line, Tumor, Humans, WIDE ASSOCIATION, GWAS, Distribution (pharmacology), Genetic Predisposition to Disease, LUNG-VOLUME-REDUCTION, Lung, Molecular Biology, Gene, ACVR1B, Original Research, ACVR1B gene, Genetic association, Emphysema, emphysema distribution, LANDSCAPE, transforming growth factor-beta signaling, Editorials, DNA, Genomics, Cell Biology, Integrative genomics, Causal gene, ACVR1B Gene, 030104 developmental biology, Pulmonary Emphysema, 030228 respiratory system, Activin Receptors, Type I, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) have identified multiple associations with emphysema apicobasal distribution (EABD), but the biological functions of these variants are unknown. To characterize the functions of EABD-associated variants, we integrated GWAS results with 1) expression quantitative trait loci (eQTL) from the Genotype Tissue Expression (GTEx) project and subjects in the COPDGene (Genetic Epidemiology of COPD) study and 2) cell type epigenomic marks from the Roadmap Epigenomics project. On the basis of these analyses, we selected a variant near ACVR1B (activin A receptor type 1B) for functional validation. SNPs from 168 loci with P values less than 5 × 10(−5) in the largest GWAS meta-analysis of EABD were analyzed. Eighty-four loci overlapped eQTL, with 12 of these loci showing greater than 80% likelihood of harboring a single, shared GWAS and eQTL causal variant. Seventeen cell types were enriched for overlap between EABD loci and Roadmap Epigenomics marks (permutation P
Published: 2019
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37. New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries

Author: Phuwanat Sakornsakolpat, James F. Wilson, María Soler Artigas, Beate Stubbe, Nicholas J. Wareham, James D. Crapo, Victoria E. Jackson, Eleftheria Zeggini, Olga G. Troyanskaya, Medea Imboden, A. Mesut Erzurumluoglu, Adam S. Butterworth, Carl A. Melbourne, Ian Sayers, Lars Lind, Stefan Weiss, Margaret M. Parker, Timmers Prhj, Edwin K. Silverman, John C. Whittaker, Ian P. Hall, Ozren Polasek, Mika Kähönen, Katherine A. Fawcett, Anna Hansell, Liming Li, David J. Porteous, Louise V. Wain, Robert A. Scott, Richard Packer, Richard J. Allen, Robin G Walters, Anna L. Guyatt, Terho Lehtimäki, Nicole Probst-Hensch, Shona M. Kerr, Christian Gieger, Matthias Wielscher, Rajesh Rawal, Jing Hua Zhao, John E. Hokanson, Holger Schulz, Nicola F. Reeve, Claudia Langenberg, Ke Hao, Corry-Anke Brandsma, Megan L. Paynton, Vitart, Dmitry Prokopenko, Jennie Hui, Eugene R. Bleecker, Ma'en Obeidat, John Danesh, Ralf Ewert, Benjamin B. Sun, Frank Dudbridge, Jian Zhou, Brian D. Hobbs, Blair H. Smith, Don D. Sin, Dawn L. DeMeo, Joseph C. Maranville, Ida Surakka, Alison Catherine Murray, Nicholas Locantore, Katherine A. Kentistou, Terri H. Beaty, Igor Rudan, Kuang Lin, Amund Gulsvik, Ian J. Deary, Ruth Tal-Singer, Kijoung Song, David C. Nickle, Michael H. Cho, Jian'an Luan, Joshua D. Hoffman, Georg Homuth, Zhengming Chen, Dandi Qiao, Heiko Runz, Per Bakke, Chiara Batini, Caroline Hayward, Stefan Karrasch, Alan James, Andrew P. Morris, Prescott G. Woodruff, Laura M Yerges Armstrong, David Sparrow, Ulf Gyllensten, James P. Cook, Jonathan Marten, Olli T. Raitakari, Nick Shrine, Deborah A. Meyers, Tobin, Ruth Boxall, Marjo-Riitta Järvelin, David P. Strachan, Sarah E. Harris, Philippe Joubert, Stefan Enroth, Xingnan Li, van den Berge M, Anubha Mahajan, Yohan Bossé, Peter K. Joshi, Shrine, Nick [0000-0003-3641-4371], Guyatt, Anna L [0000-0003-1860-6337], Hobbs, Brian D [0000-0001-9564-0745], Sakornsakolpat, Phuwanat [0000-0002-4308-0974], Obeidat, Ma'en [0000-0002-5443-2752], Weiss, Stefan [0000-0002-3553-4315], Kentistou, Katherine A [0000-0002-5816-664X], Sun, Benjamin B [0000-0001-6347-2281], Enroth, Stefan [0000-0002-5056-9137], Vitart, Veronique [0000-0002-4991-3797], Allen, Richard J [0000-0002-8450-3056], Beaty, Terri H [0000-0002-7644-1705], Bossé, Yohan [0000-0002-3067-3711], Joshi, Peter K [0000-0002-6361-5059], Mahajan, Anubha [0000-0001-5585-3420], Murray, Alison [0000-0003-4915-4847], Porteous, David J [0000-0003-1249-6106], Sayers, Ian [0000-0001-5601-5410], Smith, Blair H [0000-0002-5362-9430], Tal-Singer, Ruth [0000-0002-5275-8062], Timmers, Paul RHJ [0000-0002-5197-1267], Troyanskaya, Olga G [0000-0002-5676-5737], Rudan, Igor [0000-0001-6993-6884], Wilson, James F [0000-0001-5751-9178], Zeggini, Eleftheria [0000-0003-4238-659X], Hayward, Caroline [0000-0002-9405-9550], Morris, Andrew P [0000-0002-6805-6014], Butterworth, Adam S [0000-0002-6915-9015], Walters, Robin G [0000-0002-9179-0321], Cho, Michael H [0000-0002-4907-1657], Strachan, David P [0000-0001-7854-1366], Tobin, Martin D [0000-0002-3596-7874], Wain, Louise V [0000-0003-4951-1867], Apollo - University of Cambridge Repository, Institute for Molecular Medicine Finland, Groningen Research Institute for Asthma and COPD (GRIAC), UNIVERSITY OF OULU, and Commission of the European Communities
Subjects: Male, Smoking/genetics, LOCI, Genome-wide association study, VARIANTS, Bioinformatics, Genome-wide association studies, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Polymorphism (computer science), Risk Factors, GWAS, GENOME-WIDE ASSOCIATION, HERITABILITY, COPD, Lung, 11 Medical and Health Sciences, Genetics & Heredity, Aged, 80 and over, 0303 health sciences, Genetic Predisposition to Disease/genetics, Smoking, 1184 Genetics, developmental biology, physiology, Middle Aged, Polymorphism, Single Nucleotide/genetics, 3. Good health, medicine.anatomical_structure, Meta-analysis, Genome-Wide Association Study/methods, Medical genetics, Female, Life Sciences & Biomedicine, medicine.medical_specialty, Understanding Society Scientific Group, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Genetics, medicine, Humans, Genetic Predisposition to Disease, 030304 developmental biology, Genetic association, Aged, Respiratory tract diseases, Science & Technology, Case-control study, Lung/physiopathology, 06 Biological Sciences, medicine.disease, Pulmonary Disease, Chronic Obstructive/genetics, respiratory tract diseases, Case-Control Studies, 3111 Biomedicine, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract: Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent patient populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD., Editorial summary: A genome-wide association study in over 400,000 individuals identifies 139 new signals for lung function. These variants can predict chronic obstructive pulmonary disease in independent, trans-ethnic cohorts.
Published: 2019
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38. Identification of Functional Variants in the FAM13A Chronic Obstructive Pulmonary Disease Genome-Wide Association Study Locus by Massively Parallel Reporter Assays

Author: Michael H. Cho, Fei Du, Xiaobo Zhou, Dandi Qiao, Tarjei S. Mikkelsen, Betty Pham, Yan Li, Feng Guo, Edwin K. Silverman, Zun Zar Chi Naing, and Peter J. Castaldi
Subjects: Pulmonary and Respiratory Medicine, Quantitative Trait Loci, Genome-wide association study, Locus (genetics), Computational biology, Disease, Critical Care and Intensive Care Medicine, Polymorphism, Single Nucleotide, Chromosome conformation capture, Pulmonary Disease, Chronic Obstructive, 03 medical and health sciences, 0302 clinical medicine, CRISPR-Associated Protein 9, Humans, Medicine, Genetic Predisposition to Disease, 030212 general & internal medicine, Massively parallel, Genetic association, Reporter gene, business.industry, GTPase-Activating Proteins, High-Throughput Nucleotide Sequencing, Original Articles, 030228 respiratory system, CRISPR-Cas Systems, business, Functional genomics, Genome-Wide Association Study
Abstract: Rationale: The identification of causal variants responsible for disease associations from genome-wide association studies (GWASs) facilitates functional understanding of the biological mechanisms by which those genetic variants influence disease susceptibility. Objective: We aim to identify causal variants in or near the FAM13A (family with sequence similarity member 13A) GWAS locus associated with chronic obstructive pulmonary disease (COPD). Methods: We used an integrated approach featuring conditional genetic analysis, massively parallel reporter assays (MPRAs), traditional reporter assays, chromatin conformation capture assays, and clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing to characterize COPD-associated regulatory variants in the FAM13A region in human bronchial epithelial cell lines. Measurements and Main Results: Conditional genetic association suggests the presence of two independent COPD association signals in FAM13A. MPRAs identified 45 regulatory variants within FAM13A, among which six variants were prioritized for further investigation. Three COPD-associated variants demonstrated significant allele-specific activity in reporter assays. One of three variants, rs2013701, was tested in the endogenous genomic context by CRISPR-based genome editing that confirmed its allele-specific effects on FAM13A expression and on cell proliferation, providing functional characterization for this COPD-associated variant. Conclusions: The human GWAS association near FAM13A may contain independent association signals. MPRAs identified multiple functional variants in this region, including rs2013701, a putative COPD-causing variant with allele-specific regulatory activity.
Published: 2019
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39. Longitudinal Phenotypes and Mortality in Preserved Ratio Impaired Spirometry in the COPDGene Study

Author: Emily S. Wan, Spyridon Fortis, Elizabeth A. Regan, John Hokanson, MeiLan K. Han, Richard Casaburi, Barry J. Make, James D. Crapo, Dawn L. DeMeo, Edwin K. Silverman, Terri Beaty, Ferdouse Begum, Peter J. Castaldi, Michael Cho, Adel R. Boueiz, Marilyn G. Foreman, Eitan Halper-Stromberg, Lystra P. Hayden, Craig P. Hersh, Jacqueline Hetmanski, Brian D. Hobbs, John E. Hokanson, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Margaret M. Parker, Dandi Qiao, Sungho Won, Phuwanat Sakornsakolpat, Dmitry Prokopenko, Mustafa Al Qaisi, Harvey O. Coxson, Teresa Gray, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, John D. Newell, James C. Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Douglas Stinson, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, George Washko, Carla G. Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Camille Moore, Matt Strand, John Hughes, Gregory Kinney, Katherine Pratte, Kendra A. Young, Surya Bhatt, Jessica Bon, Barry Make, Carlos Martinez, Susan Murray, Elizabeth Regan, Xavier Soler, Russell P. Bowler, Katerina Kechris, Farnoush Banaei-Kashani, Jeffrey L. Curtis, Carlos H. Martinez, Perry G. Pernicano, Nicola Hanania, Philip Alapat, Mustafa Atik, Venkata Bandi, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Arun Nachiappan, Amit Parulekar, Craig Hersh, R. Graham Barr, John Austin, Belinda D’Souza, Gregory D. N. Pearson, Anna Rozenshtein, Byron Thomashow, Neil MacIntyre, H. Page McAdams, Lacey Washington, Charlene McEvoy, Joseph Tashjian, Robert Wise, Robert Brown, Nadia N. Hansel, Karen Horton, Allison Lambert, Nirupama Putcha, Alessandra Adami, Matthew Budoff, Hans Fischer, Janos Porszasz, Harry Rossiter, William Stringer, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, Eugene Berkowitz, Gloria Westney, Russell Bowler, Richard Rosiello, David Pace, Gerard Criner, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D’Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, Victor Kim, A. James Mamary, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, Anand Iyer, Hrudaya Nath, J. Michael Wells, Joe Ramsdell, Paul Friedman, Andrew Yen, Alejandro P. Comellas, Karin F. Hoth, John Newell, Brad Thompson, Ella Kazerooni, Joanne Billings, Abbie Begnaud, Tadashi Allen, Frank Sciurba, Divay Chandra, Carl Fuhrman, Joel Weissfeld, Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, and Mario E. Ruiz
Subjects: Pulmonary and Respiratory Medicine, Spirometry, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Follow up studies, Critical Care and Intensive Care Medicine, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Internal medicine, Cardiology, medicine, 030212 general & internal medicine, Prism, business
Abstract: Rationale: Increasing awareness of the prevalence and significance of Preserved Ratio Impaired Spirometry (PRISm), alternatively known as restrictive or Global Initiative for Chronic Obstructive Lu...
Published: 2018
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40. Genetic architecture of smoking: Evaluating rare variant contribution from deep whole-genome sequencing of up to 26,000 individuals

Author: Anne E. Justice, Ruth J. F. Loos, Robert C. Kaplan, Seon-Kyeong Jang, Matthew C. Keller, Daniel J. Rader, Nicholas L. Smith, Scott M. Damrauer, Joshua C. Bis, Dajiang J. Liu, Charles Kooperberg, Yingze Zhang, Elizabeth C. Oelsner, Kari E. North, Kerri L. Wiggins, David A. Schwartz, Renae Judy, Jeffrey Haessler, Olle Melander, Scott I. Vrieze, Kent D. Taylor, Daniel Levy, Victor Gordeuk, Kendra A. Young, Weihong Tang, Deborah A. Meyers, Mariza de Andrade, John E. Hokanson, Donna K. Arnett, Luke M. Evans, Jerome I. Rotter, Anna L. Peljto, Kristin L. Young, Dandi Qiao, Sean P. David, Allison Fialkowski, Susan R. Heckbert, Shih-Jen Hwang, Zhe Wang, Lisa W. Martin, Lisa R. Yanek, Wonji Kim, Matthew Hyman, Ramachandran S. Vasan, Mark T. Gladwin, Stephen S. Rich, Albert V. Smith, Mehdi Nouraie, Edwin K. Silverman, John Blangero, Eugene R. Bleecker, Tasha E. Fingerlin, Jennifer A. Brody, L. Adrienne Cupples, Ani Manichaikul, Diane M. Becker, Ivana V. Yang, Bruce M. Psaty, Aladdin Shadyab, David C. Glahn, Sina A. Gharib, Michael Preuss, Gustav Smith, Alexander P. Reiner, and Robert M. Reed
Subjects: Whole genome sequencing, Computational biology, Biology, Genetic architecture
Abstract: Background Across complex traits, common variants explain only a modest amount of variance, with SNP-heritability consistently below heritability estimates from close relatives. Here, we examined the contribution of rare variant to tobacco use risk in up to 26,000 individuals of European ancestry in the Trans-Omics for Precision Medicine (TOPMed) program with whole genome sequence (WGS;~30X coverage).Method We grouped about 35 million genetic variants by their minor allele frequencies (MAF) and linkage disequilibrium (LD) and estimated SNP-heritability for age of smoking initiation (N = 14,747), cigarettes smoked per day (N = 15,425), smoking cessation (N = 17,871) and initiation (N = 26,340) using linear mixed model. Rare variant population structure is detected and adjusted for by permutation procedure. We estimated an upper bound for narrow-sense heritability for tobacco use using available pedigrees consisting of close relatives in TOPMed.Results Rare variants with MAF 0.1–0.01%, mostly from non-protein altering region, accounted for 26% of variation in age of initiation and 15% for cessation. Follow-up analysis indicated that about one-third of these rare variants contribtion is potentially confounded with rare variants structure even after adjusting for principal components. After further conservative adjustment of population structure, we estimated SNP-based heritability to be 0.21 (SE = 0.08) for age of initiation, 0.15 (0.06) for cigarettes per day, 0.21 (0.09) for cessation, and 0.24 (0.07) for initiation, 1.8–4.5 times higher than previous SNP-based estimates. Our pedigree-based upper-bound for SNP-based heritability ranged from 0.18–0.35.Conclusion The substantial contribution of rare variants for several smoking phenotypes sheds light on the missing heritability and genetic etiology of tobacco use. It also informs fine-mapping strategies since the majority of the rare variant contribution was located in non-coding regulatory regions.
Published: 2021
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41. Connecting COPD GWAS Genes: FAM13A Controls TGFβ2 Secretion by Modulating AP-3 Transport

Author: Victor W. Hsu, Dandi Qiao, Kimberly Glass, Samuel Bates, Jian Li, Xiaobo Zhou, Wenyi Wei, Lu Gong, and Edwin K. Silverman
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, Network medicine, Clinical Biochemistry, Complex disease, Pulmonary disease, Genome-wide association study, Bioinformatics, Genome, 03 medical and health sciences, Pulmonary Disease, Chronic Obstructive, Transforming Growth Factor beta2, 0302 clinical medicine, medicine, Humans, Secretion, Genetic Predisposition to Disease, Molecular Biology, Gene, Original Research, COPD, business.industry, Cell Biology, medicine.disease, respiratory tract diseases, 030104 developmental biology, 030228 respiratory system, business, Genome-Wide Association Study
Abstract: Chronic obstructive pulmonary disease (COPD) is a common, complex disease and a major cause of morbidity and mortality. Although multiple genetic determinants of COPD have been implicated by genome-wide association studies (GWASs), the pathophysiological significance of these associations remains largely unknown. From a COPD protein–protein interaction network module, we selected a network path between two COPD GWAS genes for validation studies: FAM13A (family with sequence similarity 13 member A)–AP3D1–CTGF– TGFβ2. We find that TGFβ2, FAM13A, and AP3D1 (but not CTGF) form a cellular protein complex. Functional characterization suggests that this complex mediates the secretion of TGFβ2 through an AP-3 (adaptor protein 3)–dependent pathway, with FAM13A acting as a negative regulator by targeting a late stage of this transport that involves the dissociation of coat–cargo interaction. Moreover, we find that TGFβ2 is a transmembrane protein that engages the AP-3 complex for delivery to the late endosomal compartments for subsequent secretion through exosomes. These results identify a pathophysiological context that unifies the biological network role of two COPD GWAS proteins and reveal novel mechanisms of cargo transport through an intracellular pathway.
Published: 2021

42. Robust, flexible, and scalable tests for Hardy–Weinberg equilibrium across diverse ancestries

Author: Nicholas L. Smith, Alan M. Kwong, Gonçalo R. Abecasis, Jennifer A. Smith, Celeste Eng, Charles Kooperberg, John Barnard, L. Adrienne Cupples, Ani Manichaikul, Wonji Kim, Dan M. Roden, Nicholette D. Palmer, M. Benjamin Shoemaker, Eric Boerwinkle, Michael Boehnke, John Blangero, Marguerite R. Irvin, Hemant K. Tiwari, Albert V. Smith, Alexander P. Reiner, Daniel E. Weeks, Tanika N. Kelly, Mariza de Andrade, Steven A. Lubitz, Laura J. Scott, Kathleen C. Barnes, Esteban G. Burchard, Han Chen, Scott T. Weiss, May E. Montasser, Yan Gao, Angel C.Y. Mak, Brian E. Cade, Thomas W. Blackwell, Courtney G. Montgomery, Solomon K. Musani, Xiuqing Guo, Daniel I. Chasman, Gina M. Peloso, Jessica Su, Hyun Min Kang, Dandi Qiao, Matthew P. Conomos, Patrick T. Ellinor, Jonathon LeFaive, and Rasika A. Mathias
Subjects: Genotype, Population structure, Biology, Linkage Disequilibrium, Statistical power, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Statistics, Genetics, False positive paradox, Humans, Alleles, 030304 developmental biology, Investigation, 0303 health sciences, Models, Statistical, Models, Genetic, Hardy–Weinberg principle, Exact test, Genetics, Population, Phenotype, Data quality, Metric (mathematics), Scalability, Software, 030217 neurology & neurosurgery
Abstract: Traditional Hardy–Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.
Published: 2021
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43. Bidirectional Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of intermediate potential

Author: Dan M. Roden, John Blangero, Myriam Fornage, Kerri L. Wiggins, Benjamin L. Ebert, Gina M. Peloso, Tetsushi Nakao, John Lane, Russell P. Tracy, Lisa de las Fuentes, Ryan L. Minster, Donna K. Arnett, Seyedeh M. Zekavat, Laura M. Raffield, Akhil Pampana, Stephen S. Rich, Kathleen C. Barnes, R. Mathias, Alyna T. Khan, Lewis C. Becker, James E. Hixson, Gabriel K. Griffin, Nicholas L. Smith, JoAnn E. Manson, Robert C. Kaplan, Gonçalo R. Abecasis, Nathan Pankratz, Alexander P. Reiner, Donald M. Lloyd-Jones, Sharon L.R. Kardia, C. Charles Gu, Wendy Post, Lisa R. Yanek, Tanika N. Kelly, Hemant K. Tiwari, Jennifer A. Smith, Shoa L. Clarke, Ramachandran S. Vasan, Themistocles L. Assimes, Betty S. Pace, Jill M. Johnsen, Cara L. Carty, Pinkal Desai, Barry I. Freedman, Pradeep Natarajan, Margaret A. Taub, S Redline, Adrienne M. Stilp, Ranjan Deka, Alexander G. Bick, Donald W. Bowden, Mariza de Andrade, Abhishek Niroula, Joanne E. Curran, Quenna Wong, Siddhartha Jaiswal, Chii-Min Hwu, Michael Preuss, Christie M. Ballantyne, Shannon Kelly, Patrick T. Ellinor, Sameer Chavan, Dandi Qiao, Nicola L. Hawley, Charles Kooperberg, Juan M. Peralta, Braxton D. Mitchell, Solomon K. Musani, Jerome I. Rotter, Ruth J.F. Loos, Zachary T. Yoneda, Bruce M. Psaty, Christopher J. Gibson, Ron Do, Barbara A. Konkle, Marguerite R. Irvin, Jai G. Broome, Take Naseri, Alanna C. Morrison, L. Adrienne Cupples, Bertha A. Hildalgo, Jiang He, Mesbah Uddin, Dawood Darbar, Cecelia A. Laurie, Eric A. Whitsel, Patricia A. Peyser, Brian Custer, Michael H. Cho, Scott T. Weiss, Peter Libby, Susan R. Heckbert, Albert V. Smith, Joshua S. Weinstock, Meher Preethi Boorgula, M. Benjamin Shoemaker, Muagututi’a S. Reupena, Michael C. Honigberg, Nicholette D. Palmer, Wei Zhao, Paul S. Vries, Edwin K. Silverman, Daniel E. Weeks, Romit Bhattacharya, Joshua C. Bis, Kari E. North, Thomas W. Blackwell, Dawn L. DeMeo, Stephen T. McGarvey, Leslie S. Emery, A. R. Shuldiner, Yii-Der Ida Chen, Eric Boerwinkle, Adolfo Correa, Deborah A. Meyers, and Eimear E. Kenny
Subjects: Mendelian randomization, Locus (genetics), Telomerase reverse transcriptase, CAD, Computational biology, Biology, Causality, Germline, Telomere, Genetic association
Abstract: Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in Trans-Omics for Precision Medicine (TOPMed) program (N=63,302) and UK Biobank (N=48,658). Bidirectional Mendelian randomization studies were consistent with LTL lengthening increasing propensity to develop CHIP, but CHIP then in turn hastening LTL shortening. We also demonstrated evidence of modest mediation between CHIP and CAD by LTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.
Published: 2021
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44. Tempo-Spatial Regulation of the Wnt Pathway by FAM13A Modulates the Stemness of Alveolar Epithelial Progenitors

Author: Jeong H. Yun, Lu Gong, Xiaobo Zhou, Dandi Qiao, Yujun Li, Xin Lin, Shuang Xu, and Yohannes Tesfaigzi
Subjects: medicine.anatomical_structure, Lung, In vivo, Regeneration (biology), Cell, Wnt signaling pathway, medicine, Organoid, Cancer research, respiratory system, Progenitor cell, Biology, Ex vivo
Abstract: Family with Sequence Similarity 13, Member A (FAM13A), consistently associated with COPD by Genome-wide association studies (GWAS), is mainly expressed in the lung epithelial progenitors including Club cells and alveolar type II epithelial (ATII) cells. Fam13a-/- mice are resistant to cigarette smoke (CS)–induced emphysema. Herein, we ask when and where FAM13A regulates the Wnt pathway, the requisite pathway for alveolar epithelial repair, in vivo during CS exposure in lung epithelial progenitors. Indeed, FAM13A-deficiency significantly increased Wnt activation mainly in lung epithelial cells. Consistently, after long-term CS exposure in vivo, FAM13A deficiency bestows alveolar epithelial progenitor cells with enhanced proliferation and differentiation in the ex vivo organoid model. Importantly, expression of FAM13A is significantly increased in human COPD-derived ATII cells compared to healthy ATII cells as suggested by single cell RNA-sequencing data. These results suggest that FAM13A-deficiency promotes the Wnt pathway-mediated ATII cell repair/regeneration, and thereby possibly mitigating CS-induced alveolar destruction. Funding Statement: This work was supported by U.S. National Institutes of Health (NIH) grants R01HL127200, R01HL137927, R01HL148667 and R01HL147148 to X.Z. Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: Mouse experiments were performed under IACUC guidelines and approved protocols at Brigham and Women’s Hospital.
Published: 2021
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45. Emphysema Progression and Lung Function Decline Among Angiotensin Converting Enzyme Inhibitors and Angiotensin-Receptor Blockade Users in the COPDGene Cohort

Author: Vickram Tejwani, Ashraf Fawzy, Nirupama Putcha, Peter J. Castaldi, Michael H. Cho, Katherine A. Pratte, Surya P. Bhatt, David A. Lynch, Stephen M. Humphries, Gregory L. Kinney, Franco R. D’Alessio, Nadia N. Hansel, James D. Crapo, Edwin K. Silverman, Barry J. Make, Elizabeth A. Regan, Terri Beaty, Ferdouse Begum, Michael Cho, Dawn L. DeMeo, Adel R. Boueiz, Marilyn G. Foreman, Eitan Halper-Stromberg, Lystra P. Hayden, Craig P. Hersh, Jacqueline Hetmanski, Brian D. Hobbs, John E. Hokanson, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Margaret M. Parker, Dmitry Prokopenko, Dandi Qiao, Phuwanat Sakornsakolpat, Emily S. Wan, Sungho Won, Juan Pablo Centeno, Jean-Paul Charbonnier, Harvey O. Coxson, Craig J. Galban, MeiLan K. Han, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, Pietro Nardelli, John D. Newell, Aleena Notary, Andrea Oh, James C. Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bramvan Ginneken, Eva van Rikxoort, Gonzalo Vegas Sanchez-Ferrero, Lucas Veitel, George R. Washko, Carla G. Wilson, Robert Jensen, Douglas Everett, Jim Crooks, Katherine Pratte, Matt Strand, Gregory Kinney, Kendra A. Young, Jessica Bon, Alejandro A. Diaz, Barry Make, Susan Murray, Elizabeth Regan, Xavier Soler, Russell P. Bowler, Katerina Kechris, Farnoush Banaei-Kashani, Jeffrey L. Curtis, Perry G. Pernicano, Nicola Hanania, Mustafa Atik, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Amit Parulekar, Craig Hersh, George Washko, R. Graham Barr, John Austin, Belinda D’Souza, Byron Thomashow, Neil MacIntyre, H. Page McAdams, Lacey Washington, Eric Flenaugh, Silanth Terpenning, Charlene McEvoy, Joseph Tashjian, Robert Wise, Robert Brown, Karen Horton, Allison Lambert, Richard Casaburi, Alessandra Adami, Matthew Budoff, Hans Fischer, Janos Porszasz, Harry Rossiter, William Stringer, Amir Sharafkhaneh, Charlie Lan, Christine Wendt, Brian Bell, KenM. Kunisaki, Russell Bowler, Richard Rosiello, David Pace, Gerard Criner, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D’Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, Victor Kim, A. James Mamary, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez, Mark Dransfield, William Bailey, Anand Iyer, Hrudaya Nath, J. Michael Wells, Douglas Conrad, Andrew Yen, Alejandro P. Comellas, Karin F. Hoth, John Newell, Brad Thompson, Ella Kazerooni, Wassim Labaki, Craig Galban, Dharshan Vummidi, Joanne Billings, Abbie Begnaud, Tadashi Allen, Frank Sciurba, Divay Chandra, Carl Fuhrman, and Joel Weissfeld
Subjects: Pulmonary and Respiratory Medicine, Male, Angiotensin receptor, medicine.medical_specialty, Population, Vital Capacity, Angiotensin-Converting Enzyme Inhibitors, Walk Test, Critical Care and Intensive Care Medicine, Cohort Studies, 03 medical and health sciences, Angiotensin Receptor Antagonists, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Internal medicine, Forced Expiratory Volume, Medicine, Humans, cardiovascular diseases, 030212 general & internal medicine, Prospective Studies, education, Aged, COPD, education.field_of_study, Lung, biology, business.industry, Angiotensin-converting enzyme, respiratory system, Middle Aged, Protective Factors, medicine.disease, Angiotensin II, respiratory tract diseases, medicine.anatomical_structure, 030228 respiratory system, Genetic epidemiology, Pulmonary Emphysema, Spirometry, Cohort, biology.protein, Cardiology, Disease Progression, Female, Cardiology and Cardiovascular Medicine, business, Lung Volume Measurements, Tomography, X-Ray Computed
Abstract: Background Attenuation of transforming growth factor β by blocking angiotensin II has been shown to reduce emphysema in a murine model. General population studies have demonstrated that the use of angiotensin converting enzyme inhibitors (ACEis) and angiotensin-receptor blockers (ARBs) is associated with reduction of emphysema progression in former smokers and that the use of ACEis is associated with reduction of FEV1 progression in current smokers. Research Question Is use of ACEi and ARB associated with less progression of emphysema and FEV1 decline among individuals with COPD or baseline emphysema? Methods Former and current smokers from the Genetic Epidemiology of COPD Study who attended baseline and 5-year follow-up visits, did not change smoking status, and underwent chest CT imaging were included. Adjusted linear mixed models were used to evaluate progression of adjusted lung density (ALD), percent emphysema (%total lung volume Results Over 5 years of follow-up, compared with nonusers, ACEi and ARB users with COPD showed slower ALD progression (adjusted mean difference [aMD], 1.6; 95% CI, 0.34-2.9). Slowed lung function decline was not observed based on phase 1 medication (aMD of FEV1 % predicted, 0.83; 95% CI, –0.62 to 2.3), but was when analysis was limited to consistent ACEi and ARB users (aMD of FEV1 % predicted, 1.9; 95% CI, 0.14-3.6). No effect modification by smoking status was found for radiographic outcomes, and the lung function effect was more pronounced in former smokers. Results were similar among participants with baseline emphysema. Interpretation Among participants with spirometry-confirmed COPD or baseline emphysema, ACEi and ARB use was associated with slower progression of emphysema and lung function decline. Trial Registry ClinicalTrials.gov ; No.: NCT00608764; URL: www.clinicaltrials.gov
Published: 2020

46. Two mutations in the SARS-CoV-2 spike protein and RNA polymerase complex are associated with COVID-19 mortality risk

Author: Katharina Ribbeck, Dandi Qiao, Jonathan Z. Li, Edwin K. Silverman, Nan M. Laird, Dawn L. DeMeo, Adrienne G. Randolph, Julian Hecker, Rudolph E. Tanzi, Georg Hahn, Elmira Esmaeilzadeh, Behzad Etemad, Sebastien Haneuse, Christoph Lange, Sanghun Lee, Sharon M. Lutz, Abbas Mohammadi, Michael M. Cho, Manish Chandra Choudhary, Chloe M. Wu, and Scott T. Weiss
Subjects: Genetics, Infectivity, Viral replication, Viral entry, Transcription (biology), Protein subunit, RNA polymerase complex, Biology, Gene, Genome
Abstract: BackgroundSARS-CoV-2 mortality has been extensively studied in relation to host susceptibility. How sequence variations in the SARS-CoV-2 genome affect pathogenicity is poorly understood. Whole-genome sequencing (WGS) of the virus with death in SARS-CoV-2 patients is one potential method of early identification of highly pathogenic strains to target for containment.MethodsWe analyzed 7,548 single stranded RNA-genomes of SARS-CoV-2 patients in the GISAID database (Elbe and Buckland-Merrett, 2017; Shu and McCauley, 2017) and associated variants with reported patient’s health status from COVID-19, i.e. deceased versus non-deceased. We probed each locus of the single stranded RNA of the SARS-CoV-2 virus for direct association with host/patient mortality using a logistic regression.ResultsIn total, evaluating 29,891 loci of the viral genome for association with patient/host mortality, two loci, at 12,053bp and 25,088bp, achieved genome-wide significance (p-values of 4.09e-09 and 4.41e-23, respectively).ConclusionsMutations at 25,088bp occur in the S2 subunit of the SARS-CoV-2 spike protein, which plays a key role in viral entry of target host cells. Additionally, mutations at 12,053bp are within the ORF1ab gene, in a region encoding for the protein nsp7, which is necessary to form the RNA polymerase complex responsible for viral replication and transcription. Both mutations altered amino acid coding sequences, potentially imposing structural changes that could enhance viral infectivity and symptom severity, and may be important to consider as targets for therapeutic development. Identification of these highly significant associations, unlikely to occur by chance, may assist with COVID-19 early containment of strains that are potentially highly pathogenic.
Published: 2020
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47. Mutations in SARS-CoV-2 spike protein and RNA polymerase complex are associated with COVID-19 mortality risk

Author: Christoph Lange, Georg Hahn, Chloe Wu, Sanghun Lee, Julian Hecker, Sharon Lutz, Sebastien Haneuse, Dandi Qiao, Michael Cho, Adrienne Randolph, Nan Laird, Scott Weiss, Edwin Silverman, and Katharina Ribbeck
Abstract: SARS-CoV-2 mortality has been extensively studied in relationship to a patient's predisposition to the disease. However, how sequence variations in the SARS-CoV-2 genome affect mortality is not understood. To address this issue, we used a whole-genome sequencing (WGS) association study to directly link death of SARS-CoV-2 patients with sequence variation in the viral genome. Specifically, we analyzed 3,626 single stranded RNA-genomes of SARS-CoV-2 patients in the GISAID database (Elbe and Buckland-Merrett, 2017; Shu and McCauley, 2017) with reported patient’s health status from COVID-19, i.e. deceased versus non-deceased. In total, evaluating 28,492 loci of the viral genome for association with patient/host mortality, two loci, 12,053bp and 25,088bp, achieved genome-wide significance (p-values of 1.24e-12, and 1.24e-26, respectively). Mutations at 25,088bp occur in the S2 subunit of the SARS-CoV-2 spike protein, which plays a key role in viral entry of target host cells. Additionally, mutations at 12,053bp are within the ORF1ab gene, in a region encoding for the protein nsp7, which is necessary to form the RNA polymerase complex responsible for viral replication and transcription. Both mutations altered amino acid coding sequences, potentially imposing structural changes that could enhance viral infectivity and symptom severity, and may be important to consider as targets for therapeutic development.
Published: 2020
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48. A linear prognostic score based on the ratio of interleukin-6 to interleukin-10 predicts outcomes in COVID-19

Author: Oisín F. McElvaney, Eoin O'Connor, Noel G. McElvaney, Matthew Moll, Brian D. Hobbs, Dandi Qiao, Seán Walsh, Michael H. Cho, Oliver J. McElvaney, Jennifer Clarke, Gerard F. Curley, and Natalie L McEvoy
Subjects: Male, 0301 basic medicine, Ordinal data, Time Factors, medicine.medical_treatment, lcsh:Medicine, Logistic regression, 0302 clinical medicine, Medicine, lcsh:R5-920, biology, Clinical outcome, Interleukin, General Medicine, Middle Aged, Prognosis, Interleukin-10, Interleukin 10, Treatment Outcome, 030220 oncology & carcinogenesis, Prognostic score, Biomarker (medicine), Cytokines, Female, Coronavirus Infections, Corrigendum, lcsh:Medicine (General), Research Paper, Adult, medicine.medical_specialty, Pneumonia, Viral, General Biochemistry, Genetics and Molecular Biology, Odds, Betacoronavirus, 03 medical and health sciences, Internal medicine, Humans, Interleukin 6, Pandemics, Aged, Quality of Health Care, Mechanical ventilation, Inflammation, business.industry, Interleukin-6, SARS-CoV-2, lcsh:R, COVID-19, Logistic Models, 030104 developmental biology, biology.protein, business
Abstract: Background Prognostic tools are required to guide clinical decision-making in COVID-19. Methods We studied the relationship between the ratio of interleukin (IL)-6 to IL-10 and clinical outcome in 80 patients hospitalized for COVID-19, and created a simple 5-point linear score predictor of clinical outcome, the Dublin-Boston score. Clinical outcome was analysed as a three-level ordinal variable (“Improved”, “Unchanged”, or “Declined”). For both IL-6:IL-10 ratio and IL-6 alone, we associated clinical outcome with a) baseline biomarker levels, b) change in biomarker level from day 0 to day 2, c) change in biomarker from day 0 to day 4, and d) slope of biomarker change throughout the study. The associations between ordinal clinical outcome and each of the different predictors were performed with proportional odds logistic regression. Associations were run both “unadjusted” and adjusted for age and sex. Nested cross-validation was used to identify the model for incorporation into the Dublin-Boston score. Findings The 4-day change in IL-6:IL-10 ratio was chosen to derive the Dublin-Boston score. Each 1 point increase in the score was associated with a 5.6 times increased odds for a more severe outcome (OR 5.62, 95% CI -3.22–9.81, P = 1.2 × 10−9). Both the Dublin-Boston score and the 4-day change in IL-6:IL-10 significantly outperformed IL-6 alone in predicting clinical outcome at day 7. Interpretation The Dublin-Boston score is easily calculated and can be applied to a spectrum of hospitalized COVID-19 patients. More informed prognosis could help determine when to escalate care, institute or remove mechanical ventilation, or drive considerations for therapies. Funding Funding was received from the Elaine Galwey Research Fellowship, American Thoracic Society, National Institutes of Health and the Parker B Francis Research Opportunity Award.
Published: 2020
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49. Machine Learning and Prediction of All-Cause Mortality in COPD

Author: Gary M. Hunninghake, Brian D. Hobbs, Barry J. Make, Michael H. Cho, James D. Crapo, Peter J. Castaldi, James M. Wells, George R. Washko, Dandi Qiao, Raúl San José Estépar, Jørgen Vestbo, Peter M.A. Calverley, Matthew Strand, MeiLan K. Han, David C. LaFon, Bartolome R. Celli, Ruth Tal-Singer, Matthew Moll, Elizabeth A. Regan, Michael J. McGeachie, Edwin K. Silverman, and Russell P. Bowler
Subjects: Pulmonary and Respiratory Medicine, COPD, business.industry, Proportional hazards model, Surrogate endpoint, Walk distance, Exercise capacity, Airflow obstruction, Machine learning, computer.software_genre, medicine.disease, Critical Care and Intensive Care Medicine, respiratory tract diseases, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Genetic epidemiology, medicine, 030212 general & internal medicine, Artificial intelligence, business, Cardiology and Cardiovascular Medicine, computer, All cause mortality
Abstract: Background COPD is a leading cause of mortality. Research Question We hypothesized that applying machine learning to clinical and quantitative CT imaging features would improve mortality prediction in COPD. Study Design and Methods We selected 30 clinical, spirometric, and imaging features as inputs for a random survival forest. We used top features in a Cox regression to create a machine learning mortality prediction (MLMP) in COPD model and also assessed the performance of other statistical and machine learning models. We trained the models in subjects with moderate to severe COPD from a subset of subjects in Genetic Epidemiology of COPD (COPDGene) and tested prediction performance in the remainder of individuals with moderate to severe COPD in COPDGene and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). We compared our model with the BMI, airflow obstruction, dyspnea, exercise capacity (BODE) index; BODE modifications; and the age, dyspnea, and airflow obstruction index. Results We included 2,632 participants from COPDGene and 1,268 participants from ECLIPSE. The top predictors of mortality were 6-min walk distance, FEV1 % predicted, and age. The top imaging predictor was pulmonary artery-to-aorta ratio. The MLMP-COPD model resulted in a C index ≥ 0.7 in both COPDGene and ECLIPSE (6.4- and 7.2-year median follow-ups, respectively), significantly better than all tested mortality indexes (P Interpretation An MLMP-COPD model outperformed four existing models for predicting all-cause mortality across two COPD cohorts. Performance of machine learning was similar to that of traditional statistical methods. The model is available online at: https://cdnm.shinyapps.io/cgmortalityapp/.
Published: 2020
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50. Robust, flexible, and scalable tests for Hardy-Weinberg Equilibrium across diverse ancestries

Author: Daniel E. Weeks, Matthew P. Conomos, Tanika N. Kelly, John Barnard, Celeste Eng, Daniel I. Chasman, Gina M. Peloso, L. Adrienne Cupples, Hyun Min Kang, Dan M. Roden, Angel C.Y. Mak, Yan Gao, Xiuqing Guo, Nicholette D. Palmer, Dandi Qiao, Eric Boerwinkle, Nicholas L. Smith, Marguerite R. Irvin, May E. Montasser, Patrick T. Ellinor, Alan Kwong, Gonçalo R. Abecasis, Kathleen C. Barnes, Courtney G. Montgomery, Jennifer A. Smith, Solomon K. Musani, Brian E. Cade, Michael Boehnke, John Blangero, Jessica Lasky-Su, Thomas W. Blackwell, Laura J. Scott, Wonji Kim, Esteban G. Burchard, Jonathon LeFaive, Hemant K. Tiwari, Rasika A. Mathias, Alexander P. Reiner, Charles Kooperberg, M. Benjamin Shoemaker, Albert V. Smith, Ani Manichaikul, Steven A. Lubitz, Mariza de Andrade, Han Chen, and Scott T. Weiss
Subjects: Exact test, Computer science, Metric (mathematics), Scalability, Statistics, False positive paradox, Hardy–Weinberg principle, Genotyping, Statistical power
Abstract: Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in datasets comprised of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence datasets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently amongst the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.
Published: 2020
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