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1. Multi-omics in nasal epithelium reveals three axes of dysregulation for asthma risk in the African Diaspora populations

Author

Brooke Szczesny, Meher Preethi Boorgula, Sameer Chavan, Monica Campbell, Randi K. Johnson, Kai Kammers, Emma E. Thompson, Madison S. Cox, Gautam Shankar, Corey Cox, Andréanne Morin, Wendy Lorizio, Michelle Daya, Samir N. P. Kelada, Terri H. Beaty, Ayo P. Doumatey, Alvaro A. Cruz, Harold Watson, Edward T. Naureckas, B. Louise Giles, Ganiyu A. Arinola, Olumide Sogaolu, Adegoke G. Falade, Nadia N. Hansel, Ivana V. Yang, Christopher O. Olopade, Charles N. Rotimi, R. Clive Landis, Camila A. Figueiredo, Matthew C. Altman, Eimear Kenny, Ingo Ruczinski, Andrew H. Liu, Carole Ober, Margaret A. Taub, Kathleen C. Barnes, and Rasika A. Mathias

Subjects
Science
Abstract

Abstract Asthma has striking disparities across ancestral groups, but the molecular underpinning of these differences is poorly understood and minimally studied. A goal of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to understand multi-omic signatures of asthma focusing on populations of African ancestry. RNASeq and DNA methylation data are generated from nasal epithelium including cases (current asthma, N = 253) and controls (never-asthma, N = 283) from 7 different geographic sites to identify differentially expressed genes (DEGs) and gene networks. We identify 389 DEGs; the top DEG, FN1, was downregulated in cases (q = 3.26 × 10−9) and encodes fibronectin which plays a role in wound healing. The top three gene expression modules implicate networks related to immune response (CEACAM5; p = 9.62 × 10−16 and CPA3; p = 2.39 × 10−14) and wound healing (FN1; p = 7.63 × 10−9). Multi-omic analysis identifies FKBP5, a co-chaperone of glucocorticoid receptor signaling known to be involved in drug response in asthma, where the association between nasal epithelium gene expression is likely regulated by methylation and is associated with increased use of inhaled corticosteroids. This work reveals molecular dysregulation on three axes – increased Th2 inflammation, decreased capacity for wound healing, and impaired drug response – that may play a critical role in asthma within the African Diaspora.

Published
2024
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2. Predictive genetic panel for adult asthma using machine learning methods

Author

Luciano Gama da Silva Gomes, PhD, Álvaro Augusto Souza da Cruz, MD, PhD, Maria Borges Rabêlo de Santana, PhD, Gabriela Pimentel Pinheiro, PhD, Cinthia Vila Nova Santana, PhD, Carolina Barbosa Souza Santos, PhD, Meher Preethi Boorgula, MS, Monica Campbell, MS, Adelmir de Souza Machado, MD, PhD, Rafael Valente Veiga, PhD, Kathleen C. Barnes, PhD, Ryan dos Santos Costa, PhD, and Camila Alexandrina Figueiredo, PhD

Subjects
Asthma, genetics, machine learning, single-nucleotide variants, prediction, Immunologic diseases. Allergy, RC581-607
Abstract

Background: Asthma is a chronic inflammatory disease of the airways that is heterogeneous and multifactorial, making its accurate characterization a complex process. Therefore, identifying the genetic variations associated with asthma and discovering the molecular interactions between the omics that confer risk of developing this disease will help us to unravel the biological pathways involved in its pathogenesis. Objective: We sought to develop a predictive genetic panel for asthma using machine learning methods. Methods: We tested 3 variable selection methods: Boruta’s algorithm, the top 200 genome-wide association study markers according to their respective P values, and an elastic net regression. Ten different algorithms were chosen for the classification tests. A predictive panel was built on the basis of joint scores between the classification algorithms. Results: Two variable selection methods, Boruta and genome-wide association studies, were statistically similar in terms of the average accuracies generated, whereas elastic net had the worst overall performance. The predictive genetic panel was completed with 155 single-nucleotide variants, with 91.18% accuracy, 92.75% sensitivity, and 89.55% specificity using the support vector machine algorithm. The markers used range from known single-nucleotide variants to those not previously described in the literature. Our study shows potential in creating genetic prediction panels with tailored penalties per marker, aiding in the identification of optimal machine learning methods for intricate results. Conclusions: This method is able to classify asthma and nonasthma effectively, proving its potential utility in clinical prediction and diagnosis.

Published
2024
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3. 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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4. African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans

Author

Charles Washington, Matthew Dapas, Arjun Biddanda, Kevin M. Magnaye, Ivy Aneas, Britney A. Helling, Brooke Szczesny, Meher Preethi Boorgula, Margaret A. Taub, Eimear Kenny, Rasika A. Mathias, Kathleen C. Barnes, CAAPA, Gurjit K. Khurana Hershey, Carolyn M. Kercsmar, Jessica D. Gereige, Melanie Makhija, Rebecca S. Gruchalla, Michelle A. Gill, Andrew H. Liu, Deepa Rastogi, William Busse, Peter J. Gergen, Cynthia M. Visness, Diane R. Gold, Tina Hartert, Christine C. Johnson, Robert F. Lemanske, Fernando D. Martinez, Rachel L. Miller, Dennis Ownby, Christine M. Seroogy, Anne L. Wright, Edward M. Zoratti, Leonard B. Bacharier, Meyer Kattan, George T. O’Connor, Robert A. Wood, Marcelo A. Nobrega, Matthew C. Altman, Daniel J. Jackson, James E. Gern, Christopher G. McKennan, and Carole Ober

Subjects
Asthma, Fine mapping, Integrated omics, Whole-genome sequencing, Health disparities, Medicine, Genetics, QH426-470
Abstract

Abstract Background Asthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry. Methods We tested for association with haplotypes at the most replicated and significant childhood-onset asthma locus at 17q12-q21 and asthma in European American and African American children. Following this, we used whole-genome sequencing data from 1060 African American and 100 European American individuals to identify novel variants on a high-risk African American–specific haplotype. We characterized these variants in silico using gene expression and ATAC-seq data from airway epithelial cells, functional annotations from ENCODE, and promoter capture (pc)Hi-C maps in airway epithelial cells. Candidate causal variants were then assessed for correlation with asthma-associated phenotypes in African American children and adults. Results Our studies revealed nine novel African-specific common variants, enriched on a high-risk asthma haplotype, which regulated the expression of GSDMA in airway epithelial cells and were associated with features of severe asthma. Using ENCODE annotations, ATAC-seq, and pcHi-C, we narrowed the associations to two candidate causal variants that are associated with features of T2 low severe asthma. Conclusions Previously unknown genetic variation at the 17q12-21 childhood-onset asthma locus contributes to asthma severity in individuals with African ancestries. We suggest that many other population-specific variants that have not been discovered in GWAS contribute to the genetic risk for asthma and other common diseases.

Published
2022
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5. Whole-exome sequence analysis of anthropometric traits illustrates challenges in identifying effects of rare genetic variants

Author

Kristin L. Young, Virginia Fisher, Xuan Deng, Jennifer A. Brody, Misa Graff, Elise Lim, Bridget M. Lin, Hanfei Xu, Najaf Amin, Ping An, Stella Aslibekyan, Alison E. Fohner, Bertha Hidalgo, Petra Lenzini, Robert Kraaij, Carolina Medina-Gomez, Ivana Prokić, Fernando Rivadeneira, Colleen Sitlani, Ran Tao, Jeroen van Rooij, Di Zhang, Jai G. Broome, Erin J. Buth, Benjamin D. Heavner, Deepti Jain, Albert V. Smith, Kathleen Barnes, Meher Preethi Boorgula, Sameer Chavan, Dawood Darbar, Mariza De Andrade, Xiuqing Guo, Jeffrey Haessler, Marguerite R. Irvin, Rita R. Kalyani, Sharon L.R. Kardia, Charles Kooperberg, Wonji Kim, Rasika A. Mathias, Merry-Lynn McDonald, Braxton D. Mitchell, Patricia A. Peyser, Elizabeth A. Regan, Susan Redline, Alexander P. Reiner, Stephen S. Rich, Jerome I. Rotter, Jennifer A. Smith, Scott Weiss, Kerri L. Wiggins, Lisa R. Yanek, Donna Arnett, Nancy L. Heard-Costa, Suzanne Leal, Danyu Lin, Barbara McKnight, Michael Province, Cornelia M. van Duijn, Kari E. North, L. Adrienne Cupples, and Ching-Ti Liu

Subjects
body mass index, central obesity, height, exome sequencing, Genetics, QH426-470
Abstract

Summary: Anthropometric traits, measuring body size and shape, are highly heritable and significant clinical risk factors for cardiometabolic disorders. These traits have been extensively studied in genome-wide association studies (GWASs), with hundreds of genome-wide significant loci identified. We performed a whole-exome sequence analysis of the genetics of height, body mass index (BMI) and waist/hip ratio (WHR). We meta-analyzed single-variant and gene-based associations of whole-exome sequence variation with height, BMI, and WHR in up to 22,004 individuals, and we assessed replication of our findings in up to 16,418 individuals from 10 independent cohorts from Trans-Omics for Precision Medicine (TOPMed). We identified four trait associations with single-nucleotide variants (SNVs; two for height and two for BMI) and replicated the LECT2 gene association with height. Our expression quantitative trait locus (eQTL) analysis within previously reported GWAS loci implicated CEP63 and RFT1 as potential functional genes for known height loci. We further assessed enrichment of SNVs, which were monogenic or syndromic variants within loci associated with our three traits. This led to the significant enrichment results for height, whereas we observed no Bonferroni-corrected significance for all SNVs. With a sample size of ∼20,000 whole-exome sequences in our discovery dataset, our findings demonstrate the importance of genomic sequencing in genetic association studies, yet they also illustrate the challenges in identifying effects of rare genetic variants.

Published
2023
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6. Host methylation predicts SARS-CoV-2 infection and clinical outcome

Author

Iain R. Konigsberg, Bret Barnes, Monica Campbell, Elizabeth Davidson, Yingfei Zhen, Olivia Pallisard, Meher Preethi Boorgula, Corey Cox, Debmalya Nandy, Souvik Seal, Kristy Crooks, Evan Sticca, Genelle F. Harrison, Andrew Hopkinson, Alexis Vest, Cosby G. Arnold, Michael G. Kahn, David P. Kao, Brett R. Peterson, Stephen J. Wicks, Debashis Ghosh, Steve Horvath, Wanding Zhou, Rasika A. Mathias, Paul J. Norman, Rishi Porecha, Ivana V. Yang, Christopher R. Gignoux, Andrew A. Monte, Alem Taye, and Kathleen C. Barnes

Subjects
Medicine
Abstract

Konigsberg et al. profile DNA methylation in blood samples from SARS-CoV-2 cases and controls. The authors use machine learning to classify infected vs. non-infected individuals and predict clinical outcomes related to disease severity.

Published
2021
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7. Association study in African-admixed populations across the Americas recapitulates asthma risk loci in non-African populations

Author

Michelle Daya, Nicholas Rafaels, Tonya M. Brunetti, Sameer Chavan, Albert M. Levin, Aniket Shetty, Christopher R. Gignoux, Meher Preethi Boorgula, Genevieve Wojcik, Monica Campbell, Candelaria Vergara, Dara G. Torgerson, Victor E. Ortega, Ayo Doumatey, Henry Richard Johnston, Nathalie Acevedo, Maria Ilma Araujo, Pedro C. Avila, Gillian Belbin, Eugene Bleecker, Carlos Bustamante, Luis Caraballo, Alvaro Cruz, Georgia M. Dunston, Celeste Eng, Mezbah U. Faruque, Trevor S. Ferguson, Camila Figueiredo, Jean G. Ford, Weiniu Gan, Pierre-Antoine Gourraud, Nadia N. Hansel, Ryan D. Hernandez, Edwin Francisco Herrera-Paz, Silvia Jiménez, Eimear E. Kenny, Jennifer Knight-Madden, Rajesh Kumar, Leslie A. Lange, Ethan M. Lange, Antoine Lizee, Pissamai Maul, Trevor Maul, Alvaro Mayorga, Deborah Meyers, Dan L. Nicolae, Timothy D. O’Connor, Ricardo Riccio Oliveira, Christopher O. Olopade, Olufunmilayo Olopade, Zhaohui S. Qin, Charles Rotimi, Nicolas Vince, Harold Watson, Rainford J. Wilks, James G. Wilson, Steven Salzberg, Carole Ober, Esteban G. Burchard, L. Keoki Williams, Terri H. Beaty, Margaret A. Taub, Ingo Ruczinski, Rasika A. Mathias, Kathleen C. Barnes, and CAAPA

Subjects
Science
Abstract

The burden of asthma varies between ancestries, but GWAS have so far focused on mainly European ancestry populations. Here, Daya et al. perform GWAS for asthma in 14,654 individuals of African ancestry and, besides confirming previously known loci, identify two potentially African ancestry-specific loci.

Published
2019
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8. A continuum of admixture in the Western Hemisphere revealed by the African Diaspora genome

Author

Rasika Ann Mathias, Margaret A. Taub, Christopher R. Gignoux, Wenqing Fu, Shaila Musharoff, Timothy D. O'Connor, Candelaria Vergara, Dara G. Torgerson, Maria Pino-Yanes, Suyash S. Shringarpure, Lili Huang, Nicholas Rafaels, Meher Preethi Boorgula, Henry Richard Johnston, Victor E. Ortega, Albert M. Levin, Wei Song, Raul Torres, Badri Padhukasahasram, Celeste Eng, Delmy-Aracely Mejia-Mejia, Trevor Ferguson, Zhaohui S. Qin, Alan F. Scott, Maria Yazdanbakhsh, James G. Wilson, Javier Marrugo, Leslie A. Lange, Rajesh Kumar, Pedro C. Avila, L. Keoki Williams, Harold Watson, Lorraine B. Ware, Christopher Olopade, Olufunmilayo Olopade, Ricardo Oliveira, Carole Ober, Dan L. Nicolae, Deborah Meyers, Alvaro Mayorga, Jennifer Knight-Madden, Tina Hartert, Nadia N. Hansel, Marilyn G. Foreman, Jean G. Ford, Mezbah U. Faruque, Georgia M. Dunston, Luis Caraballo, Esteban G. Burchard, Eugene Bleecker, Maria Ilma Araujo, Edwin Francisco Herrera-Paz, Kimberly Gietzen, Wendy E. Grus, Michael Bamshad, Carlos D. Bustamante, Eimear E. Kenny, Ryan D. Hernandez, Terri H. Beaty, Ingo Ruczinski, Joshua Akey, CAAPA, and Kathleen C. Barnes

Subjects
Science
Abstract

The Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) aims to better understand population genetics of the African diaspora. Here, it uses deeply sequenced whole-genomes to describe the impact of admixture and potential disease burden of deleterious variants.

Published
2016
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9. Author Correction: Association study in African-admixed populations across the Americas recapitulates asthma risk loci in non-African populations

Author

Michelle Daya, Nicholas Rafaels, Tonya M. Brunetti, Sameer Chavan, Albert M. Levin, Aniket Shetty, Christopher R. Gignoux, Meher Preethi Boorgula, Genevieve Wojcik, Monica Campbell, Candelaria Vergara, Dara G. Torgerson, Victor E. Ortega, Ayo Doumatey, Henry Richard Johnston, Nathalie Acevedo, Maria Ilma Araujo, Pedro C. Avila, Gillian Belbin, Eugene Bleecker, Carlos Bustamante, Luis Caraballo, Alvaro Cruz, Georgia M. Dunston, Celeste Eng, Mezbah U. Faruque, Trevor S. Ferguson, Camila Figueiredo, Jean G. Ford, Weiniu Gan, Pierre-Antoine Gourraud, Nadia N. Hansel, Ryan D. Hernandez, Edwin Francisco Herrera-Paz, Silvia Jiménez, Eimear E. Kenny, Jennifer Knight-Madden, Rajesh Kumar, Leslie A. Lange, Ethan M. Lange, Antoine Lizee, Pissamai Maul, Trevor Maul, Alvaro Mayorga, Deborah Meyers, Dan L. Nicolae, Timothy D. O’Connor, Ricardo Riccio Oliveira, Christopher O. Olopade, Olufunmilayo Olopade, Zhaohui S. Qin, Charles Rotimi, Nicolas Vince, Harold Watson, Rainford J. Wilks, James G. Wilson, Steven Salzberg, Carole Ober, Esteban G. Burchard, L. Keoki Williams, Terri H. Beaty, Margaret A. Taub, Ingo Ruczinski, Rasika A. Mathias, Kathleen C. Barnes, and CAAPA

Subjects
Science
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019
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10. Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing

Author

Fang Chen, Xingyan Wang, Seon-Kyeong Jang, Bryan C. Quach, J. Dylan Weissenkampen, Chachrit Khunsriraksakul, Lina Yang, Renan Sauteraud, Christine M. Albert, Nicholette D. D. Allred, Donna K. Arnett, Allison E. Ashley-Koch, Kathleen C. Barnes, R. Graham Barr, Diane M. Becker, Lawrence F. Bielak, Joshua C. Bis, John Blangero, Meher Preethi Boorgula, Daniel I. Chasman, Sameer Chavan, Yii-Der I. Chen, Lee-Ming Chuang, Adolfo Correa, Joanne E. Curran, Sean P. David, Lisa de las Fuentes, Ranjan Deka, Ravindranath Duggirala, Jessica D. Faul, Melanie E. Garrett, Sina A. Gharib, Xiuqing Guo, Michael E. Hall, Nicola L. Hawley, Jiang He, Brian D. Hobbs, John E. Hokanson, Chao A. Hsiung, Shih-Jen Hwang, Thomas M. Hyde, Marguerite R. Irvin, Andrew E. Jaffe, Eric O. Johnson, Robert Kaplan, Sharon L. R. Kardia, Joel D. Kaufman, Tanika N. Kelly, Joel E. Kleinman, Charles Kooperberg, I-Te Lee, Daniel Levy, Sharon M. Lutz, Ani W. Manichaikul, Lisa W. Martin, Olivia Marx, Stephen T. McGarvey, Ryan L. Minster, Matthew Moll, Karine A. Moussa, Take Naseri, Kari E. North, Elizabeth C. Oelsner, Juan M. Peralta, Patricia A. Peyser, Bruce M. Psaty, Nicholas Rafaels, Laura M. Raffield, Muagututi’a Sefuiva Reupena, Stephen S. Rich, Jerome I. Rotter, David A. Schwartz, Aladdin H. Shadyab, Wayne H-H. Sheu, Mario Sims, Jennifer A. Smith, Xiao Sun, Kent D. Taylor, Marilyn J. Telen, Harold Watson, Daniel E. Weeks, David R. Weir, Lisa R. Yanek, Kendra A. Young, Kristin L. Young, Wei Zhao, Dana B. Hancock, Bibo Jiang, Scott Vrieze, and Dajiang J. Liu

Subjects
Tobacco Smoke and Health, Human Genome, Drug Repositioning, Single Nucleotide, Biological Sciences, Medical and Health Sciences, Brain Disorders, Tobacco Use, Substance Misuse, Good Health and Well Being, Tobacco, Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, Transcriptome, Drug Abuse (NIDA only), Biology, Genome-Wide Association Study, Developmental Biology
Abstract

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

Published
2023

11. 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

12. 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

13. 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

14. Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program

Author

Nicholas L. Smith, James A. Perry, Cecelia A. Laurie, Nancy J. Cox, Gonçalo R. Abecasis, Jerome I. Rotter, Laura Almasy, Zhe Wang, Michelle Daya, Yun Li, Eric Jorgenson, Adolfo Correa, Jai G. Broome, Nancy Min, Lisa R. Yanek, Alanna C. Morrison, Lynette Ekunwe, Debby Ngo, Victor E. Ortega, Klaudia Walter, John Blangero, Laura M. Raffield, Corey Cox, Terri H. Beaty, Deborah A. Meyers, Hua Tang, Marsha M. Wheeler, Kari E. North, Xue Zhong, Yann Ilboudo, Andrew D. Johnson, Caitlin P. McHugh, Jeffrey R. O'Connell, Ming-Huei Chen, Russell P. Tracy, Ramachandran S. Vasan, Nathan Pankratz, Joshua P. Lewis, Dawn L. DeMeo, Linda M. Polfus, Leslie A. Lange, Nancy L. Heard-Costa, Robert C. Kaplan, Meher Preethi Boorgula, Robert E. Gerszten, Albert V. Smith, Paul L. Auer, Sameer Chavan, Jennifer A. Brody, Charles Kooperberg, Michael Preuss, David C. Glahn, Rasika A. Mathias, Paul S. de Vries, Jonathon Rosen, Anna V. Mikhaylova, Joe Zein, Eric Boerwinkle, Nathalie Chami, Kathleen C. Barnes, Joanne E. Curran, Edwin K. Silverman, Matthew P. Conomos, Stephen S. Rich, Nicole Soranzo, Heather M. Highland, Michael H. Cho, Donald M. Lloyd-Jones, Myriam Fornage, Guillaume Lettre, Tyne W Miller-Fleming, Kathleen A. Ryan, Thomas W. Blackwell, Bruce M. Psaty, Lewis C. Becker, Nauder Faraday, Hélène Choquet, Alexander P. Reiner, Adam S. Butterworth, Kousik Kundu, Deepti Jain, Timothy A. Thornton, Brian D. Hobbs, Braxton D. Mitchell, Jee-Young Moon, Lifang Hou, Ani Manichaikul, Praveen Surendran, Suraj S. Nongmaithem, Quan Sun, Bingshan Li, Deborah A. Nickerson, and Ruth J. F. Loos

Subjects
Proteome, Quantitative Trait Loci, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, Dermatitis, Atopic, Pulmonary Disease, Chronic Obstructive, Leukocytes, Genetics, medicine, Humans, Genetic Predisposition to Disease, Gene, Genetics (clinical), X chromosome, Genetic association, Whole genome sequencing, Autosome, Whole Genome Sequencing, Genome, Human, Monocyte, Prognosis, Asthma, United Kingdom, United States, Phenotype, medicine.anatomical_structure, National Heart, Lung, and Blood Institute (U.S.), Biomarkers, Imputation (genetics), Genome-Wide Association Study
Abstract

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.

Published
2021

15. 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

16. Lipid mediators are detectable in the nasal epithelium and differ by asthma status in female subjects

Author

Randi K. Johnson, Jonathan Manke, Monica Campbell, Michael Armstrong, Meher Preethi Boorgula, Gabriela Pinheiro, Cinthia Vila Nova Santana, Rasika A. Mathias, Kathleen C. Barnes, Alvaro Cruz, Nichole Reisdorph, and Camila A. Figueiredo

Subjects
Nasal Mucosa, Immunology, Immunology and Allergy, Eicosanoids, Humans, Female, Pilot Projects, Asthma, Dinoprostone
Abstract

Lipid mediators, bioactive products of polyunsaturated fatty acid metabolism, contribute to inflammation initiation and resolution in allergic diseases; however, their presence in lung-related biosamples has not been fully described.We aimed to quantify lipid mediators in the nasal airway epithelium and characterize preliminary associations with asthma.Using liquid chromatography-mass spectrometry, we conducted a pilot study to quantify 56 lipid mediators from nasal epithelial samples collected from 11 female participants of an outpatient asthma clinic and community controls (aged 30-55 years). We examined the presence of each compound using descriptive statistics to test whether lipid mediators could distinguish subjects with asthma (n = 8) from control subjects (n = 3) using linear regression and partial least squares discriminant analysis.Fifteen lipid mediators were detectable in all samples, including resolvin (Rv) D5 (RvD5), with the highest median concentrations (in pg/μg protein) of 13-HODE (126.481), 15-HETE (32.869), and 13-OxoODE (13.251). From linear regression adjusted for age, prostaglandin ELipid mediators are detectable in the nasal epithelium, and their levels distinguish asthma cases from controls.

Published
2021

17. Host methylation predicts SARS-CoV-2 infection and clinical outcome

Author

Bret Barnes, David P. Kao, Alem Taye, Andrew Hopkinson, Evan Sticca, Brett R. Peterson, Wanding Zhou, Elizabeth J. Davidson, Genelle F. Harrison, Rishi Porecha, Michael G. Kahn, Debmalya Nandy, Corey Cox, Kristy Crooks, Alexis Vest, Cosby G. Arnold, Steve Horvath, Ivana V. Yang, Andrew A. Monte, Yingfei Zhen, Kathleen C. Barnes, Paul Norman, Debashis Ghosh, Rasika A. Mathias, Monica Campbell, Christopher R. Gignoux, Souvik Seal, Iain R. Konigsberg, Olivia Pallisard, Stephen J. Wicks, and Meher Preethi Boorgula

Subjects
Immune system, business.industry, DNA methylation, medicine, Disease, Methylation, Epigenome, Epigenetics, medicine.disease_cause, Bioinformatics, business, Coronavirus, Genetic association
Abstract

Since the onset of the SARS-CoV-2 pandemic, most clinical testing has focused on RT-PCR1. Host epigenome manipulation post coronavirus infection2–4 suggests that DNA methylation signatures may differentiate patients with SARS-CoV-2 infection from uninfected individuals, and help predict COVID-19 disease severity, even at initial presentation. We customized Illumina’s Infinium MethylationEPIC array to enhance immune response detection and profiled peripheral blood samples from 164 COVID-19 patients with longitudinal measurements of disease severity and 296 patient controls. Epigenome-wide association analysis revealed 13,033 genome-wide significant methylation sites for case-vs-control status. Genes and pathways involved in interferon signaling and viral response were significantly enriched among differentially methylated sites. We observe highly significant associations at genes previously reported in genetic association studies (e.g. IRF7, OAS1). Using machine learning techniques, models built using sparse regression yielded highly predictive findings: cross-validated best fit AUC was 93.6% for case-vs-control status, and 79.1%, 80.8%, and 84.4% for hospitalization, ICU admission, and progression to death, respectively. In summary, the strong COVID-19-specific epigenetic signature in peripheral blood driven by key immune-related pathways related to infection status, disease severity, and clinical deterioration provides insights useful for diagnosis and prognosis of patients with viral infections. Viral infections affect the body in many ways, including via changes to the epigenome, the sum of chemical modifications to an individual’s collection of genes that affect gene activity. Here, we analyzed the epigenome in blood samples from people with and without COVID-19 to determine whether we could find changes consistent with SARS-CoV-2 infection. Using a combination of statistical and machine learning techniques, we identify markers of SARS-CoV-2 infection as well as of severity and progression of COVID-19 disease. These signals of disease progression were present from the initial blood draw when first walking into the hospital. Together, these approaches demonstrate the potential of measuring the epigenome for monitoring SARS-CoV-2 status and severity. Konigsberg et al. profile DNA methylation in blood samples from SARS-CoV-2 cases and controls. The authors use machine learning to classify infected vs. non-infected individuals and predict clinical outcomes related to disease severity.

Published
2021

18. 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

19. Polygenic prediction of atopic dermatitis improves with atopic training and filaggrin factors

Author

Lynda C. Schneider, Richard L. Gallo, Kathleen C. Barnes, Jon M. Hanifin, Sameer Chavan, Christopher H. Arehart, Emma Guttman-Yassky, Mark K. Slifka, Rasika A. Mathias, Jonathan M. Spergel, Donald Y.M. Leung, Michelle Daya, Gloria David, Amy S. Paller, Monica Campbell, Christopher R. Gignoux, Lisa A. Beck, Meher Preethi Boorgula, Peck Y. Ong, Tissa Hata, and Nicholas M. Rafaels

Subjects
filaggrin, Male, Linkage disequilibrium, Allergy, Immunology, Dermatitis, Genome-wide association study, Filaggrin Proteins, Eczema Area and Severity Index, Atopic, Linkage Disequilibrium, Article, Dermatitis, Atopic, Atopy, Clinical Research, Loss of Function Mutation, Genetics, Genetic predisposition, medicine, 2.1 Biological and endogenous factors, Immunology and Allergy, Humans, Genetic Predisposition to Disease, Aetiology, Atopic dermatitis, Genetic association, atopic march, business.industry, Prevention, Human Genome, Infant, Odds ratio, medicine.disease, genetic architecture, allergic disease, Phenotype, polygenic risk score, Female, business, genetic predisposition, disease prediction, Genome-Wide Association Study
Abstract

BACKGROUND: While numerous genetic loci associated with atopic dermatitis (AD) have been discovered, to date, work leveraging the combined burden of AD risk variants across the genome to predict disease risk has been limited. OBJECTIVES: This study aims to determine whether polygenic risk scores (PRSs) relying on genetic determinants for AD provide useful predictions for disease occurrence and severity. It also explicitly tests the value of including genome-wide association studies of related allergic phenotypes and known FLG loss-of-function (LOF) variants. METHODS: AD PRSs were constructed for 1619 European American individuals from the Atopic Dermatitis Research Network using an AD training dataset and an atopic training dataset including AD, childhood onset asthma, and general allergy. Additionally, whole genome sequencing data were used to explore genetic scoring specific to FLG LOF mutations. RESULTS: Genetic scores derived from the AD-only genome-wide association studies were predictive of AD cases (PRS(AD): odds ratio [OR], 1.70; 95% CI, 1.49–1.93). Accuracy was first improved when PRSs were built off the larger atopy genome-wide association studies (PRS(AD+): OR, 2.16; 95% CI, 1.89–2.47) and further improved when including FLG LOF mutations (PRS(AD++): OR, 3.23; 95% CI, 2.57–4.07). Importantly, while all 3 PRSs correlated with AD severity, the best prediction was from PRS(AD++), which distinguished individuals with severe AD from control subjects with OR of 3.86 (95% CI, 2.77–5.36). CONCLUSIONS: This study demonstrates how PRSs for AD that include genetic determinants across atopic phenotypes and FLG LOF variants may be a promising tool for identifying individuals at high risk for developing disease and specifically severe disease.

Published
2020

20. Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries

Author

Cashell E. Jaquish, Craig P. Hersh, Emily Barron-Casella, Larry Phillips, James S. Pankow, JoAnn E. Manson, Mariza de Andrade, Vivien A. Sheehan, Norann A. Zaghloul, Yongmei Liu, Sergei Nekhai, Russell P. Tracy, Bruce S. Weir, Pankaj Qasba, Adrienne M. Stilp, Tasha E. Fingerlin, Heather M. Ochs-Balcom, L. Adrienne Cupples, Rongze Yang, David A. Schwartz, Shannon Kelly, Scott E. Devine, Tanja Smith, G.L. Kinney, Beverly Snively, Kent D. Taylor, Manolis Kellis, Ruth J. F. Loos, Seth A. Ament, Kathleen C. Barnes, Robert C. Kaplan, Ulrich Broeckel, Hemant K. Tiwari, Karin F. Hoth, Peter Durda, Julie L. Mikulla, Charles B. Eaton, Cotton Seed, Merry Lynn McDonald, Eric Boerwinkle, Josh Smith, Honghuang Lin, Ingrid B. Borecki, Jeffrey L. Curtis, Emelia J. Benjamin, Kenneth Rice, Sharon L.R. Kardia, Nicholas L. Smith, Coleen M. Damcott, Jeffrey Haessler, Kimberly L. Jones, Elaine Cornell, Nona Sotoodehnia, Adolfo Correa, Rich Johnston, C. Charles Gu, Chii Min Hwu, Peter C. Anderson, Lesley F. Tinker, Colleen Davis, R. Graham Barr, Scott T. Weiss, Leanna Farnam, Chao Hsiung, Brian Silver, Patrick F. McArdle, Lisa W. Martin, Yii-Der Ida Chen, John Barnard, Holly Kramer, Sekar Kathiresan, Gonçalo R. Abecasis, Barry Make, Michael C. Mahaney, Marco V Perez, Donna K. Arnett, Mark Chaffin, Xiuqing Guo, Joshua C. Bis, Pamela Russell, Paul L. Auer, James G. Wilson, Marilyn J. Telen, David K. Levine, Jennifer A. Smith, Christopher Scheller, Meher Preethi Boorgula, Aakrosh Ratan, Kari E. North, Dan E. Arking, Elizabeth A. Regan, Margaret G. Parker, Andres Metspalu, Jai G. Broome, Daniel Taliun, Lynette Ekunwe, Alyna T. Khan, Hao Mei, Dhananjay Vaidya, Ellen M. Schmidt, Stanford Mwasongwe, Joshua P. Lewis, Stacey Gabriel, Christine E. Seidman, Margery Gass, Deborah A. Nickerson, Nicola L. Hawley, Rebecca L. Beer, Afshin Parsa, Steven L. Salzberg, Terri H. Beaty, Stella Aslibekyan, Girish N. Nadkarni, Wei Zhao, David L. Tirschwell, Karen Bunting, Dawn L. DeMeo, Laura J. Rasmussen-Torvik, Julia Powers Becker, Dmitry Prokopenko, Karen Schwander, Bruce D. Gelb, Stephanie Krauter, Laura M. Raffield, Michael E. Hall, Frank C. Sciurba, Lauren Margolin, Nora Franceschini, Daniel N. Harris, Seyedeh M. Zekavat, Dawood Darbar, Keng-Han Lin, Haley Huston, Steven A. Lubitz, Andrea Ganna, Carole Sztalryd, Cathy C. Laurie, Christy Chang, James E. Hixson, Steven A. McCarroll, Barbara A. Konkle, Michael D. Kessler, Scott I. Vrieze, Yingze Zhang, Sarah Ruuska, George J. Papanicolaou, Weiniu Gan, Maris Alver, Elizabeth A. Streeten, Fei Fei Wang, Lu-Chen Weng, Braxton D. Mitchell, Lee-Ming Chuang, Sean P. David, Wei-Min Chen, Susan R. Heckbert, Ryan D. Hernandez, Andrew D. Johnson, Cristen J. Willer, Ani Manichaikul, Jonathan M. Bloom, Timothy D. O’Connor, Sylvia Smoller, Marguerite R. Irvin, Seung Hoan Choi, Ida Surakka, Veikko Salomaa, Diane M. Becker, Ron Do, W. Craig Johnson, Cecelia A. Laurie, Meryl S. LeBoff, Aniket Shetty, Tõnu Esko, Michael C. Zody, Xiaoqi Geng, Da Wei Gong, Snow Xueyan Zhao, Esteban G. Burchard, Xiuwen Zheng, Cara L. Carty, Alexander P. Reiner, Tim Assimes, Deborah A. Meyers, Mina K. Chung, Harald H H Göring, Benjamin M. Neale, Pradeep Natarajan, Yan Gao, Stephen S. Rich, Yun Ju Sung, Susan K. Dutcher, Ferdouse Begum, Stephanie M. Gogarten, John Blangero, Jonathan Cardwell, Kayleen Williams, Rakhi P. Naik, Amol C. Shetty, Sayantan Das, Myriam Fornage, May E. Montasser, Michelle Daya, Edwin K. Silverman, Daniel E. Weeks, Laura J. Kaufman, Dimitrios Avramopoulos, Michael Y. Tsai, Christine M. Albert, Vijay G. Sankaran, Jeffrey R. O'Connell, Thomas W. Blackwell, Stephen T. McGarvey, Robert M. Reed, Leslie A. Lange, Qing Duan, Bruce M. Psaty, Leslie S. Emery, Bertha Hidalgo, Jennifer A. Brody, L. Keoki Williams, Soren Germer, Zhaohui S. Qin, Deepti Jain, Deborah Applebaum-Bowden, Carla Wilson, Degui Zhi, Christoph Lange, Elliott Hong, L.F. Bielak, Wen Jane Lee, Yue Guan, Tarik Walker, Rebecca D. Jackson, Charles R. Farber, Mark J. Daly, Stephanie M. Fullerton, John E. Hokanson, Karol E. Watson, James Luo, Richard Casaburi, Seunggeun Lee, Jill M. Johnsen, Margaret A. Taub, Ryan L. Minster, Ravi Duggirala, Susan K. Mathai, Yun Li, Quenna Wong, Matthew Flickinger, Huichun Xu, Susan Redline, Ulrike Peters, Ivana V. Yang, Jesse M. Engreitz, Sanni Ruotsalainen, Sean K. McFarland, Avram D Walts, Patricia A. Peyser, Allison E. Ashley-Koch, Lewis C. Becker, Nicholette Palmer Allred, James A. Perry, Jody S. Sylvia, Tamar Sofer, Vasan S. Ramachandran, Laura Almasy, Matthew J. Budoff, Ranjan Deka, David M. Herrington, Simeon I. Taylor, Daniel Levy, Chaojie Yang, Sameer Chavan, Kathleen A. Ryan, Josyf C. Mychaleckyj, Ingo Ruczinski, Sebastian Zoellner, Michael Preuss, Tim Poterba, Wendy S. Post, Amber L. Beitelshees, Ben Heavner, Carolina Roselli, Namiko Abe, Jonathon LeFaive, Mark T. Gladwin, Brian Custer, Robert B. Wallace, Simin Liu, Michael H. Cho, Robert E. Handsaker, Dabeeru C. Rao, Bo Juen Chen, Wayne Hui Heng Sheu, Xiang Zhou, Marcos Bezerra, Solomon K. Musani, Eimear E. Kenny, James F. Casella, Kathryn L. Lunetta, Nancy Min, Nicholas Rafaels, Lisa R. Yanek, Min A. Jhun, David C. Glahn, Rasika A. Mathias, Mollie A. Minear, Russell P. Bowler, Jason Ernst, Carolyn J. Crandall, Sara Penchev, Alvaro Alonso, Timothy A. Thornton, Toni I. Pollin, Charles Kooperberg, Ethan M. Lange, Juan M. Peralta, Pramod Anugu, Lucinda Fulton, Adam A. Szpiro, Michael R. DeBaun, M. Benjamin Shoemaker, Sam Phillips, Dan M. Roden, Mao Fu, Daniel I. Chasman, James D. Crapo, Hua Tang, Gina M. Peloso, Hyun Min Kang, Samuli Ripatti, Phuwanat Sakornsakolpat, Christopher R. Gignoux, Peter VandeHaar, Jerome I. Rotter, Dandi Qiao, Emily S. Wan, Shabnam Salimi, Kevin Sandow, Jiang He, Patrick T. Ellinor, Joanne E. Curran, Institute for Molecular Medicine Finland, Samuli Olli Ripatti / Principal Investigator, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Clinicum, Doctoral Programme in Population Health, Department of Public Health, and Complex Disease Genetics

Subjects
0301 basic medicine, Apolipoprotein B, General Physics and Astronomy, Gene Expression, Genome-wide association study, 030204 cardiovascular system & hematology, Cardiovascular, Lipoprotein particle, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, GENETIC-VARIANTS, 2.1 Biological and endogenous factors, WIDE ASSOCIATION, Aetiology, lcsh:Science, African Continental Ancestry Group, Genetics, Multidisciplinary, Genome, biology, CHOLESTEROL, Adaptor Proteins, Lipoprotein(a), Single Nucleotide, NHLBI TOPMed Lipids Working Group, 3142 Public health care science, environmental and occupational health, 3. Good health, Cholesterol, Heart Disease, Cardiovascular Diseases, CARDIOVASCULAR-DISEASE, RARE VARIANTS, lipids (amino acids, peptides, and proteins), LOW-FREQUENCY, Human, DNA Copy Number Variations, Science, Quantitative Trait Loci, European Continental Ancestry Group, Black People, POPULATION-SCALE, Quantitative trait locus, Article, White People, General Biochemistry, Genetics and Molecular Biology, LDL, Structural variation, 03 medical and health sciences, COMPONENTS-ANALYSIS, RISK-FACTOR, Humans, CORONARY-HEART-DISEASE, Polymorphism, Whole Genome Sequencing, Prevention, Human Genome, General Chemistry, Atherosclerosis, Vesicular Transport, Good Health and Well Being, 030104 developmental biology, chemistry, biology.protein, lcsh:Q, 3111 Biomedicine, Lipoprotein, Genome-Wide Association Study
Abstract

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans., Circulating lipoprotein(a) is an important risk factor for cardiovascular disease and shows variability between different ethnic groups. Here, Zekavat et al. perform whole-genome sequencing in individuals of European and African ancestries and find ancestry-specific genetic determinants for lipoprotein(a) levels.

Published
2018

21. Do COPD subtypes really exist? COPD heterogeneity and clustering in 10 independent cohorts

Author

Marta Benet, Russell P. Bowler, Massimo Pistolesi, James D. Crapo, Kathleen C. Barnes, Gianna Camiciottoli, Alvar Agusti, Judith Garcia-Aymerich, Yohannes Tesfaigzi, Stephen I. Rennard, Diether Lambrechts, Josep M. Antó, Els Wauters, Nadia N. Hansel, Jennifer G. Dy, James H. Finigan, Milo A. Puhan, Peter J. Castaldi, Wim Janssens, Hans Petersen, Craig P. Hersh, Edwin K. Silverman, Matteo Paoletti, Nicholas Rafaels, Francesca Bigazzi, Judith M. Vonk, Meher Preethi Boorgula, H. Marike Boezen, Michael H. Cho, University of Zurich, Castaldi, Peter J, Groningen Research Institute for Asthma and COPD (GRIAC), and Life Course Epidemiology (LCE)

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Concordance, PHENOTYPES, 610 Medicine & health, Disease cluster, OBSTRUCTIVE PULMONARY-DISEASE, Article, Body Mass Index, Correlation, Pulmonary Disease, Chronic Obstructive, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, Forced Expiratory Volume, Internal medicine, Statistics, medicine, Cluster Analysis, Humans, 030212 general & internal medicine, Cluster analysis, Asthma, RISK, COPD, business.industry, Reproducibility of Results, 10060 Epidemiology, Biostatistics and Prevention Institute (EBPI), medicine.disease, United States, COPD, Phenotyping, Cluster analysis, respiratory tract diseases, Hierarchical clustering, Europe, Phenotype, 030228 respiratory system, 2740 Pulmonary and Respiratory Medicine, business
Abstract

Background COPD is a heterogeneous disease, but there is little consensus on specific definitions for COPD subtypes. Unsupervised clustering offers the promise of 'unbiased' data-driven assessment of COPD heterogeneity. Multiple groups have identified COPD subtypes using cluster analysis, but there has been no systematic assessment of the reproducibility of these subtypes.Objective We performed clustering analyses across 10 cohorts in North America and Europe in order to assess the reproducibility of (1) correlation patterns of key COPD-related clinical characteristics and (2) clustering results.Methods We studied 17 146 individuals with COPD using identical methods and common COPD-related characteristics across cohorts (FEV1, FEV1/FVC, FVC, body mass index, Modified Medical Research Council score, asthma and cardiovascular comorbid disease). Correlation patterns between these clinical characteristics were assessed by principal components analysis (PCA). Cluster analysis was performed using k-medoids and hierarchical clustering, and concordance of clustering solutions was quantified with normalised mutual information (NMI), a metric that ranges from 0 to 1 with higher values indicating greater concordance.Results The reproducibility of COPD clustering subtypes across studies was modest (median NMI range 0.17-0.43). For methods that excluded individuals that did not clearly belong to any cluster, agreement was better but still suboptimal (median NMI range 0.32-0.60). Continuous representations of COPD clinical characteristics derived from PCA were much more consistent across studies.Conclusions Identical clustering analyses across multiple COPD cohorts showed modest reproducibility. COPD heterogeneity is better characterised by continuous disease traits coexisting in varying degrees within the same individual, rather than by mutually exclusive COPD subtypes.

Published
2017

22. Author Correction: Association study in African-admixed populations across the Americas recapitulates asthma risk loci in non-African populations

Author

Eugene R. Bleecker, Alvaro A. Cruz, Meher Preethi Boorgula, Rasika A. Mathias, Camila Alexandrina Figueiredo, Monica Campbell, Dara G. Torgerson, Trevor Maul, Carlos Bustamante, Trevor S. Ferguson, Genevieve L. Wojcik, Nicolas Vince, Olufunmilayo I. Olopade, Charles N. Rotimi, Henry Richard Johnston, Zhaohui S. Qin, Rajesh Kumar, Silvia Jiménez, Antoine Lizee, Ingo Ruczinski, Maria Ilma Araujo, Ryan D. Hernandez, Rainford J. Wilks, Ethan M. Lange, Terri H. Beaty, Caapa, Ricardo Riccio Oliveira, Edwin Francisco Herrera-Paz, Eimear E. Kenny, Leslie A. Lange, Alvaro Mayorga, Pedro C. Avila, Christopher R. Gignoux, Harold Watson, Nicholas Rafaels, Pissamai Maul, Margaret A. Taub, Carole Ober, Mezbah U. Faruque, Luis Caraballo, Aniket Shetty, Michelle Daya, Sameer Chavan, Timothy D. O’Connor, Weiniu Gan, Steven L. Salzberg, Nadia N. Hansel, Deborah A. Meyers, Albert M. Levin, Gillian M. Belbin, Pierre-Antoine Gourraud, Victor E. Ortega, Georgia M. Dunston, Jean G. Ford, Celeste Eng, Nathalie Acevedo, Dan L. Nicolae, L. Keoki Williams, Christopher O. Olopade, Candelaria Vergara, Esteban G. Burchard, Jennifer Knight-Madden, Ayo P. Doumatey, Tonya M. Brunetti, Kathleen C. Barnes, and James G. Wilson

Subjects
0301 basic medicine, Science, media_common.quotation_subject, General Physics and Astronomy, 02 engineering and technology, Genome-wide association studies, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, CAAPA, Immunogenetics, Humans, Genetic Predisposition to Disease, Genetic variation, lcsh:Science, Author Correction, media_common, Chromosomes, Human, Pair 12, Multidisciplinary, Hispanic or Latino, General Chemistry, Art, 021001 nanoscience & nanotechnology, Asthma, United States, Black or African American, 030104 developmental biology, Genetic Loci, lcsh:Q, 0210 nano-technology, Humanities, Chromosomes, Human, Pair 17, Chromosomes, Human, Pair 8, Genome-Wide Association Study
Abstract

Author(s): Daya, Michelle; Rafaels, Nicholas; Brunetti, Tonya M; Chavan, Sameer; Levin, Albert M; Shetty, Aniket; Gignoux, Christopher R; Boorgula, Meher Preethi; Wojcik, Genevieve; Campbell, Monica; Vergara, Candelaria; Torgerson, Dara G; Ortega, Victor E; Doumatey, Ayo; Johnston, Henry Richard; Acevedo, Nathalie; Araujo, Maria Ilma; Avila, Pedro C; Belbin, Gillian; Bleecker, Eugene; Bustamante, Carlos; Caraballo, Luis; Cruz, Alvaro; Dunston, Georgia M; Eng, Celeste; Faruque, Mezbah U; Ferguson, Trevor S; Figueiredo, Camila; Ford, Jean G; Gan, Weiniu; Gourraud, Pierre-Antoine; Hansel, Nadia N; Hernandez, Ryan D; Herrera-Paz, Edwin Francisco; Jimenez, Silvia; Kenny, Eimear E; Knight-Madden, Jennifer; Kumar, Rajesh; Lange, Leslie A; Lange, Ethan M; Lizee, Antoine; Maul, Pissamai; Maul, Trevor; Mayorga, Alvaro; Meyers, Deborah; Nicolae, Dan L; O'Connor, Timothy D; Oliveira, Ricardo Riccio; Olopade, Christopher O; Olopade, Olufunmilayo; Qin, Zhaohui S; Rotimi, Charles; Vince, Nicolas; Watson, Harold; Wilks, Rainford J; Wilson, James G; Salzberg, Steven; Ober, Carole; Burchard, Esteban G; Williams, L Keoki; Beaty, Terri H; Taub, Margaret A; Ruczinski, Ingo; Mathias, Rasika A; Barnes, Kathleen C; CAAPA | Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019

23. Replicated methylation changes associated with eczema herpeticum and allergic response

Author

Monica Campbell, Margaret A. Taub, Donald Y.M. Leung, Richard L. Gallo, Sameer Chavan, Chris Cheadle, Jinshui Fan, Ingo Ruczinski, Michelle Daya, Nicholas Rafaels, Lynda C. Schneider, Terri H. Beaty, Amy S. Paller, Aniket Shetty, Rasika A. Mathias, Sangjucta Barkataki, Kathleen C. Barnes, Gloria David, Meher Preethi Boorgula, Lisa A. Beck, and Jon M. Hanifin

Subjects
0301 basic medicine, Male, Dermatitis, medicine.disease_cause, Severity of Illness Index, Epigenesis, Genetic, 0302 clinical medicine, Eczema herpeticum, 2.1 Biological and endogenous factors, Aetiology, Infinium Methylation 450K array, Genetics (clinical), DNA methylation, Eczema / Atopic Dermatitis, Atopic dermatitis, Methylation, 3. Good health, Human epigenetics, medicine.anatomical_structure, CpG site, 030220 oncology & carcinogenesis, Allergic response, Female, Clinical Sciences, Kaposi Varicelliform Eruption, Biology, Atopic, Dermatitis, Atopic, Paediatrics and Reproductive Medicine, 03 medical and health sciences, Th2 Cells, Methylation EPIC array, Genetic, Clinical Research, medicine, Genetics, Humans, Epigenetics, Molecular Biology, Research, Prevention, Human Genome, Eosinophil, Immunoglobulin E, medicine.disease, Eosinophils, 030104 developmental biology, Case-Control Studies, Immunology, CpG Islands, Interleukin-4, Developmental Biology, Epigenesis, Genome-Wide Association Study
Abstract

Background Although epigenetic mechanisms are important risk factors for allergic disease, few studies have evaluated DNA methylation differences associated with atopic dermatitis (AD), and none has focused on AD with eczema herpeticum (ADEH+). We will determine how methylation varies in AD individuals with/without EH and associated traits. We modeled differences in genome-wide DNA methylation in whole blood cells from 90 ADEH+, 83 ADEH−, and 84 non-atopic, healthy control subjects, replicating in 36 ADEH+, 53 ADEH−, and 55 non-atopic healthy control subjects. We adjusted for cell-type composition in our models and used genome-wide and candidate-gene approaches. Results We replicated one CpG which was significantly differentially methylated by severity, with suggestive replication at four others showing differential methylation by phenotype or severity. Not adjusting for eosinophil content, we identified 490 significantly differentially methylated CpGs (ADEH+ vs healthy controls, genome-wide). Many of these associated with severity measures, especially eosinophil count (431/490 sites). Conclusions We identified a CpG in IL4 associated with serum tIgE levels, supporting a role for Th2 immune mediating mechanisms in AD. Changes in eosinophil level, a measure of disease severity, are associated with methylation changes, providing a potential mechanism for phenotypic changes in immune response-related traits. Electronic supplementary material The online version of this article (10.1186/s13148-019-0714-1) contains supplementary material, which is available to authorized users.

Published
2019

24. Association of HLA-DRB1∗09:01 with tIgE levels among African-ancestry individuals with asthma

Author

Victor E. Ortega, Nadia N. Hansel, Dara G. Torgerson, Dan L. Nicolae, Candelaria Vergara, Emiko Noguchi, Monica Campbell, Meher Preethi Boorgula, Terri H. Beaty, James G. Wilson, Wataru Morii, Deborah A. Meyers, Carole Ober, Jean G. Ford, Sophie Limou, Leslie A. Lange, Alexandre Walencik, Margaret A. Taub, Estelle Geffard, Mezbah U. Faruque, Kathleen C. Barnes, Ingo Ruczinski, Sameer Chavan, Rasika A. Mathias, Michelle Daya, Eugene R. Bleecker, Nicolas Vince, Harold Watson, Nicholas Rafaels, Venceslas Douillard, Pierre-Antoine Gourraud, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Department of Medicine [Aurora, CO, USA], University of Colorado [Denver], Université de Tsukuba = University of Tsukuba, Johns Hopkins University (JHU), Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center, University of Mississippi Medical Center (UMMC), The University of the West Indies, Titu Maiorescu University Bucharest, Titu Maiorescu University = Universitatea Titu Maiorescu [Buchares] (UTM), Center for Human Genomics, Wake Forest University, Einstein Medical Center [Philadelphia, PA, USA], Howard University College of Medicine [Washington, DC, USA], University of Arizona, University of Illinois [Chicago] (UIC), University of Illinois System, University of California [San Francisco] (UCSF), University of California, European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No.846520., University of California [San Francisco] (UC San Francisco), University of California (UC), and CCSD, Accord Elsevier

Subjects
0301 basic medicine, Male, [SDV]Life Sciences [q-bio], Immunology, Single-nucleotide polymorphism, Genome-wide association study, Human leukocyte antigen, Admixture, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, medicine, CAAPA, Immunology and Allergy, Humans, Allele, HLA-DRB1, Alleles, Genetic association, Asthma, Imputation, business.industry, Atopy, Haplotype, tIgE levels, Immunoglobulin E, medicine.disease, 3. Good health, respiratory tract diseases, [SDV] Life Sciences [q-bio], HLA, Black or African American, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, business, HLA-DRB1 Chains
Abstract

Background Asthma is a complex chronic inflammatory disease of the airways. Association studies between HLA and asthma were first reported in the 1970s, and yet, the precise role of HLA alleles in asthma is not fully understood. Numerous genome-wide association studies were recently conducted on asthma, but were always limited to simple genetic markers (single nucleotide polymorphisms) and not complex HLA gene polymorphisms (alleles/haplotypes), therefore not capturing the biological relevance of this complex locus for asthma pathogenesis. Objective To run the first HLA-centric association study with asthma and specific asthma-related phenotypes in a large cohort of African-ancestry individuals. Methods We collected high-density genomics data for the Consortium on Asthma among African-ancestry Populations in the Americas (N = 4993) participants. Using computer-intensive machine-learning attribute bagging methods to infer HLA alleles, and Easy-HLA to infer HLA 5-gene haplotypes, we conducted a high-throughput HLA-centric association study of asthma susceptibility and total serum IgE (tIgE) levels in subjects with and without asthma. Results Among the 1607 individuals with asthma, 972 had available tIgE levels, with a mean tIgE level of 198.7 IU/mL. We could not identify any association with asthma susceptibility. However, we showed that HLA-DRB1∗09:01 was associated with increased tIgE levels (P = 8.5 × 10−4; weighted effect size, 0.51 [0.15-0.87]). Conclusions We identified for the first time an HLA allele associated with tIgE levels in African-ancestry individuals with asthma. Our report emphasizes that by leveraging powerful computational machine-learning methods, specific/extreme phenotypes, and population diversity, we can explore HLA gene polymorphisms in depth and reveal the full extent of complex disease associations.

Published
2019

25. The MALT1 locus and Peanut Avoidance in the Risk for Peanut Allergy

Author

Marshall Plaut, Henry T. Bahnson, Sameer Chavan, Gerald T. Nepom, Rasika A. Mathias, Gideon Lack, Karen Cerosaletti, Meher Preethi Boorgula, Claire Malley, Ali R. Keramati, Kathleen C. Barnes, Peter H. Sayre, David E. Larson, Ingo Ruczinski, George Du Toit, and Alexandra H. Winters

Subjects
0301 basic medicine, Extramural, business.industry, Immunology, Peanut allergy, food and beverages, Locus (genetics), medicine.disease, Article, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine, Immunology and Allergy, business, 030215 immunology
Abstract

We identified a strong association between peanut allergy and the MALT1 locus in LEAP participants in the peanut avoidance group with 58.6% of carriers developing peanut allergy at 60 months as compared to 12.7% of non-carriers.

Published
2019

27. Whole Genome Sequencing Analyses Identify SIDT2 Loss-of-function Mutations In Patients with Eczema Herpeticum

Author

Lianghua Bin, Donald Y.M. Leung, Sameer Chavan, Rasika A. Mathias, Brittany N. Richers, Claire Malley, Ingo Ruczinski, Nicholas Rafaels, Kathleen C. Barnes, Patricia Taylor, Meher Preethi Boorgula, and Malaika Mathias

Subjects
Genetics, Whole genome sequencing, business.industry, Immunology, Eczema herpeticum, medicine, Immunology and Allergy, In patient, medicine.disease, business, Loss function
Published
2020

29. Assembly of a pan-genome from deep sequencing of 910 humans of African descent

Author

Steven L. Salzberg, Nadia N. Hansel, Albert M. Levin, Candelaria Vergara, Monica Campbell, Kathleen C. Barnes, Valentin Antonescu, Alvaro Mayorga, Victor E. Ortega, Esteban G. Burchard, Edwin Francisco Herrera-Paz, Cassandra Foster, Javier Marrugo, Michelle Daya, Margaret A. Taub, Christopher O. Olopade, Georgia M. Dunston, Marilyn G. Foreman, Mezbah U. Faruque, Carole Ober, Eugene R. Bleecker, Jennifer Knight-Madden, Rasika A. Mathias, Sameer Chavan, Deborah A. Meyers, Dan L. Nicolae, Lorraine B. Ware, Maria Yazdanbakhsh, Ingo Ruczinski, Celeste Eng, Daniela Puiu, Terri H. Beaty, L. Keoki Williams, Harold Watson, Nicholas Rafaels, James G. Wilson, Leslie A. Lange, Tina V. Hartert, Olufunmilayo I. Olopade, Maria Ilma Araujo, Luis Caraballo, Juliet Forman, Rachel M. Sherman, Ricardo Riccio Oliveira, Meher Preethi Boorgula, and Jean G. Ford

Subjects
0303 health sciences, Contig, Genome, Human, food and beverages, Black People, High-Throughput Nucleotide Sequencing, Genomics, Computational biology, Sequence Analysis, DNA, Biology, Genome, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, Intergenic region, Gene mapping, Genetics, Humans, Human genome, 030217 neurology & neurosurgery, 030304 developmental biology, Reference genome
Abstract

We used a deeply sequenced dataset of 910 individuals, all of African descent, to construct a set of DNA sequences that is present in these individuals but missing from the reference human genome. We aligned 1.19 trillion reads from the 910 individuals to the reference genome (GRCh38), collected all reads that failed to align, and assembled these reads into contiguous sequences (contigs). We then compared all contigs to one another to identify a set of unique sequences representing regions of the African pan-genome missing from the reference genome. Our analysis revealed 296,485,284 bp in 125,715 distinct contigs present in the populations of African descent, demonstrating that the African pan-genome contains ~10% more DNA than the current human reference genome. Although the functional significance of nearly all of this sequence is unknown, 387 of the novel contigs fall within 315 distinct protein-coding genes, and the rest appear to be intergenic. Assembly of a pan-genome from 910 humans of African descent identifies 296.5 Mb of novel DNA mapping to 125,715 distinct contigs. This African pan-genome contains ~10% more DNA than the current human reference genome.

Published
2017

30. Mobilization of epithelial mesenchymal transition genes distinguishes active from inactive lesional tissue in patients with ulcerative colitis

Author

Aimin Li, Chris Cheadle, Meher Preethi Boorgula, Sangjucta Barkataki, Yuqing Chen, Chen Li, Xinmei Zhao, Jinshui Fan, Alan E. Berger, Fachao Zhi, Kathleen C. Barnes, and Jean-Paul Courneya

Subjects
Adult, Male, Epithelial-Mesenchymal Transition, MMP1, Colorectal cancer, Biology, Metastasis, Gene expression, Genetics, medicine, Humans, Epithelial–mesenchymal transition, Molecular Biology, Genetics (clinical), Regulation of gene expression, Extracellular Matrix Proteins, Cancer, General Medicine, Middle Aged, medicine.disease, Ulcerative colitis, Gene Expression Regulation, Immunology, Colitis, Ulcerative, Female, Matrix Metalloproteinase 1
Abstract

Ulcerative colitis (UC) is a chronic, relapsing and debilitating idiopathic inflammation, with variable and complex pathophysiologies. Our objective was to elucidate patterns of gene expression underlying the progression of UC disease. Single endoscopic pinch FFPE biopsies (n = 41) were sampled at both active and inactive stages at the same site in individual UC patients and compared with each other and with non-inflammatory bowel disease healthy controls. Gene expression results were validated by quantitative reverse transcriptase-PCR (QRT-PCR), and results at the protein level were validated by immunohistochemistry and western blot. Analysis of microarray results demonstrated that UC patients in remission display an intermediate gene expression phenotype between active UC patients and controls. It is clear that UC active site recovery does not revert fully back to a healthy control phenotype. Both UC active and inactive tissue displayed evidence, at both the gene expression and protein level, of a positive precancerous state as indicated by increases in the expression of Chitinase 3-Like-1, and the colorectal cancer metastasis marker MMP1. A key distinguishing feature between active and inactive UC, however, was the mobilization of marker genes and proteins for the Epithelial Mesenchymal Transition (EMT) pathway only in active UC. Analysis of the gene expression signatures associated with UC remission identified multiple pathways which appear to be permanently dysregulated in UC patients at formerly active sites in spite of clear histological recovery. Among these pathways, the EMT pathway was specifically up-regulated only in active UC emphasizing the potential for cancer progression in these patients.

Published
2015

31. Genome-wide association study of asthma in individuals of African ancestry reveals novel asthma susceptibility loci

Author

Michelle Daya, Nicholas Rafaels, Sameer Chavan, Henry Richard Johnston, Aniket Shetty, Christopher R. Gignoux, Meher Preethi Boorgula, Monica Campbell, Pissamai Maul, Trevor Maul, Candelaria Vergara, Albert M. Levin, Genevieve Wojcik, Dara G. Torgerson, Victor E. Ortega, Ayo Doumatey, Maria Ilma Araujo, Pedro C. Avila, Eugene Bleecker, Carlos Bustamante, Luis Caraballo, Georgia M. Dunston, Mezbah U. Faruque, Trevor S. Ferguson, Camila Figueiredo, Jean G. Ford, Pierre-Antoine Gourraud, Nadia N. Hansel, Ryan D. Hernandez, Edwin Francisco Herrera-Paz, Eimear E. Kenny, Jennifer Knight-Madden, Rajesh Kumar, Lesli A. Lange, Ethan M. Lange, Antoine Lizee, Alvaro Mayorga, Deborah Meyers, Dan L. Nicolae, Timothy D. O’Connor, Ricardo Riccio Oliveira, Christopher O. Olopade, Olufunmilayo Olopade, Zhaohui S. Qin, Charles Rotimi, Harold Watson, Rainford J. Wilks, L. Keoki Williams, James G. Wilson, Carole Ober, Esteban G. Burchard, Terri H. Beaty, Margaret A. Taub, Ingo Ruczinski, Rasika Ann Mathias, Kathleen C. Barnes, Ayola Akim Adegnika, Ganiyu Arinola, Ulysse Ateba-Ngoa, Gerardo Ayestas, Adolfo Correa, Francisco M. De La Vega, Celeste Eng, Said Omar Leiva Erazo, Marilyn G. Foreman, Cassandra Foster, Li Gao, Jingjing Gao, Kimberly Gietzen, Leslie Grammer, Linda Gutierrez, Mark Hansen, Tina Hartert, Yijuan Hu, Kwang-Youn A. Kim, Pamela Landaverde-Torres, Javier Marrugo, Beatriz Martinez, Rosella Martinez, Luis F. Mayorga, Delmy-Aracely Mejia-Mejia, Catherine Meza, Solomon Musani, Shaila Musharoff, Oluwafemi Oluwole, Maria Pino-Yanes, Hector Ramos, Allan Saenz, Steven Salzberg, Maureen Samms-Vaughan, Robert Schleimer, Alan F. Scott, Suyash S. Shringarpure, Wei Song, Zachary A. Szpiech, Raul Torres, Gloria Varela, Olga Marina Vasquez, Lorraine B. Ware, and Maria Yazdanbakhsh

Subjects
Genetics, Genotype, medicine, Chromosome, SNP, Genetic admixture, Single-nucleotide polymorphism, Genome-wide association study, Allele, Biology, medicine.disease, Asthma
Abstract

BACKGROUNDAsthma is a complex disease with striking disparities across racial and ethnic groups, which may be partly attributable to genetic factors. One of the main goals of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to discover genes conferring risk to asthma in populations of African descent.METHODSWe performed a genome-wide meta-analysis of asthma across 11 CAAPA datasets (4,827 asthma cases and 5,397 controls), genotyped on the African Diaspora Power Chip (ADPC) and including existing GWAS array data. The genotype data were imputed up to a whole genome sequence reference panel from n=880 African ancestry individuals for a total of 61,904,576 SNPs. Statistical models appropriate to each study design were used to test for association, and results were combined using the weighted Z-score method. We also used admixture mapping as a complementary approach to identify loci involved in asthma pathogenesis in subjects of African ancestry.RESULTSSNPs rs787160 and rs17834780 on chromosome 2q22.3 were significantly associated with asthma (p=6.57 × 10−9 and 2.97 × 10−8, respectively). These SNPs lie in the intergenic region between the Rho GTPase Activating Protein 15 (ARHGAP15) and Glycosyltransferase Like Domain Containing 1 (GTDC1) genes. Four low frequency variants on chromosome 1q21.3, which may be involved in the “atopic march” and which are not polymorphic in Europeans, also showed evidence for association with asthma (1.18 ×10−6 ≤ p ≤ 3.06 ×10−6). SNP rs11264909 on chromosome 1q23.1, close to a region previously identified by the EVE asthma meta-analysis as having a putative African ancestry specific effect, only showed differences in counts in subjects homozygous for alleles of African ancestry. Admixture mapping also identified a significantly associated region on chromosome 6q23.2, which includes the Transcription Factor 21 (TCF21) gene, previously shown to be differentially expressed in bronchial tissues of asthmatics and non-asthmatics.CONCLUSIONSWe have identified a number of novel asthma association signals warranting further investigation.

Published
2017
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33. Author Correction: Assembly of a pan-genome from deep sequencing of 910 humans of African descent

Author

Monica Campbell, Alvaro Mayorga, Carole Ober, Candelaria Vergara, Jennifer Knight-Madden, James G. Wilson, Dan L. Nicolae, Margaret A. Taub, Ricardo Riccio Oliveira, Valentin Antonescu, Michelle Daya, Rachel M. Sherman, Mezbah U. Faruque, Georgia M. Dunston, Daniela Puiu, Ingo Ruczinski, Sameer Chavan, Kathleen C. Barnes, Esteban G. Burchard, Deborah A. Meyers, Terri H. Beaty, Maria Yazdanbakhsh, Christopher O. Olopade, Eugene R. Bleecker, Marilyn G. Foreman, Harold Watson, Nicholas Rafaels, Steven L. Salzberg, Nadia N. Hansel, Meher Preethi Boorgula, Victor E. Ortega, Lorraine B. Ware, Albert M. Levin, Cassandra Foster, Edwin Francisco Herrera-Paz, Javier Marrugo, Celeste Eng, L. Keoki Williams, Rasika A. Mathias, Luis Caraballo, Jean G. Ford, Leslie A. Lange, Juliet Forman, Tina V. Hartert, Olufunmilayo I. Olopade, and Maria Ilma Araujo

Subjects
0303 health sciences, Statement (logic), Published Erratum, African descent, Pan-genome, Biology, Genealogy, Deep sequencing, 03 medical and health sciences, 0302 clinical medicine, Genetics, Plant species, ComputingMethodologies_GENERAL, Animal species, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

In the version of this article initially published, the statement "there are no pan-genomes for any other animal or plant species" was incorrect. The statement has been corrected to "there are no reported pan-genomes for any other animal species, to our knowledge." We thank David Edwards for bringing this error to our attention. The error has been corrected in the HTML and PDF versions of the article.

Published
2019

34. Longitudinal Transcriptome Analysis Reveals a Sustained Differential Gene Expression Signature in Patients Treated for Acute Lyme Disease

Author

Mark J. Soloski, Andrea Swei, Alison W. Rebman, Scot Federman, John N. Aucott, Jerome Bouquet, Chris Cheadle, Beniwende Kabre, Richard Halpert, Jean Noel Billaud, Charles Y. Chiu, and Meher Preethi Boorgula

Subjects
0301 basic medicine, Adult, Male, medicine.drug_class, 030106 microbiology, Antibiotics, Window period, Biology, Microbiology, Transcriptome, 03 medical and health sciences, Lyme disease, Virology, medicine, Animals, Humans, Borrelia burgdorferi, Gene, Lyme Disease, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Middle Aged, medicine.disease, biology.organism_classification, bacterial infections and mycoses, QR1-502, United States, 3. Good health, Gene expression profiling, 030104 developmental biology, Immunology, Lyme disease microbiology, Female, Biomarkers, Metabolic Networks and Pathways, Research Article
Abstract

Lyme disease is a tick-borne illness caused by the bacterium Borrelia burgdorferi, and approximately 10 to 20% of patients report persistent symptoms lasting months to years despite appropriate treatment with antibiotics. To gain insights into the molecular basis of acute Lyme disease and the ensuing development of post-treatment symptoms, we conducted a longitudinal transcriptome study of 29 Lyme disease patients (and 13 matched controls) enrolled at the time of diagnosis and followed for up to 6 months. The differential gene expression signature of Lyme disease following the acute phase of infection persisted for at least 3 weeks and had fewer than 44% differentially expressed genes (DEGs) in common with other infectious or noninfectious syndromes. Early Lyme disease prior to antibiotic therapy was characterized by marked upregulation of Toll-like receptor signaling but lack of activation of the inflammatory T-cell apoptotic and B-cell developmental pathways seen in other acute infectious syndromes. Six months after completion of therapy, Lyme disease patients were found to have 31 to 60% of their pathways in common with three different immune-mediated chronic diseases. No differential gene expression signature was observed between Lyme disease patients with resolved illness to those with persistent symptoms at 6 months post-treatment. The identification of a sustained differential gene expression signature in Lyme disease suggests that a panel of selected human host-based biomarkers may address the need for sensitive clinical diagnostics during the “window period” of infection prior to the appearance of a detectable antibody response and may also inform the development of new therapeutic targets., IMPORTANCE Lyme disease is the most common tick-borne infection in the United States, and some patients report lingering symptoms lasting months to years despite antibiotic treatment. To better understand the role of the human host response in acute Lyme disease and the development of post-treatment symptoms, we conducted the first longitudinal gene expression (transcriptome) study of patients enrolled at the time of diagnosis and followed up for up to 6 months after treatment. Importantly, we found that the gene expression signature of early Lyme disease is distinct from that of other acute infectious diseases and persists for at least 3 weeks following infection. This study also uncovered multiple previously undescribed pathways and genes that may be useful in the future as human host biomarkers for diagnosis and that constitute potential targets for the development of new therapies.

Published
2016

35. Whole Genome Sequencing Identifies Four Novel Variants in the Epidermal Differentiation Complex That Increase Risk and Severity for Atopic Dermatitis

Author

Meher Preethi Boorgula, Emma Guttman-Yassky, Peck Y. Ong, Rasika A. Mathias, Jon M. Hanifin, Sameer Chavan, Kathleen C. Barnes, Richard L. Gallo, William O.C.M. Cookson, Amy S. Paller, Lisa A. Beck, Saffron A.G. Willis-Owen, Donald Y.M. Leung, Miriam F Moffat, Ingo Ruczinski, Nicholas Rafaels, Terri H. Beaty, Li Gao, and Lynda C. Schneider

Subjects
Genetics, Whole genome sequencing, Immunology, medicine, Immunology and Allergy, Epidermal differentiation complex, Atopic dermatitis, Biology, medicine.disease
Published
2017

36. A genome-wide survey of CD4+ lymphocyte regulatory genetic variants identifies novel asthma genes

Author

Dan L. Nicolae, Albino Barraza-Villareal, Chris Cheadle, Jinshui Fan, Mario Castro, N. Franklin Adkinson, Derek Thibault, Jerry A. Krishnan, Sunita Sharma, Julian Solway, Manuel E. Soto-Quiros, Lydiana Avila, Blanca E. Himes, Carole Ober, Benjamin A. Raby, Robert F. Lemanske, Meher Preethi Boorgula, Fernando J. Martinez, Vincent J. Carey, Alan E. Berger, Stanley J. Szefler, Scott T. Weiss, Stephanie J. London, Kathleen C. Barnes, Gregory B. Diette, Juan C. Celedón, Nadia N. Hansel, Frank D. Gilliland, Robert C. Strunk, Steven James White, Becky M. Vonakis, Andrew H. Liu, and Xiaobo Zhou

Subjects
CD4-Positive T-Lymphocytes, Costa Rica, Fatty Acid Desaturases, Male, Linkage disequilibrium, Immunology, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, alpha-N-Acetylgalactosaminidase, Double-Blind Method, Immunology and Allergy, SNP, Humans, Child, Genetic association, Genetics, Haplotype, Asthma, Child, Preschool, Expression quantitative trait loci, Female, Chromatin immunoprecipitation, Genome-Wide Association Study
Abstract

Background Genome-wide association studies have yet to identify the majority of genetic variants involved in asthma. We hypothesized that expression quantitative trait locus (eQTL) mapping can identify novel asthma genes by enabling prioritization of putative functional variants for association testing. Objective We evaluated 6706 cis-acting expression-associated variants (eSNPs) identified through a genome-wide eQTL survey of CD4 + lymphocytes for association with asthma. Methods eSNPs were tested for association with asthma in 359 asthmatic patients and 846 control subjects from the Childhood Asthma Management Program, with verification by using family-based testing. Significant associations were tested for replication in 579 parent-child trios with asthma from Costa Rica. Further functional validation was performed by using formaldehyde-assisted isolation of regulatory elements (FAIRE) quantitative PCR and chromatin immunoprecipitation PCR in lung-derived epithelial cell lines (Beas-2B and A549) and Jurkat cells, a leukemia cell line derived from T lymphocytes. Results Cis-acting eSNPs demonstrated associations with asthma in both cohorts. We confirmed the previously reported association of ORMDL3 / GSDMB variants with asthma (combined P = 2.9 × 10 −8 ). Reproducible associations were also observed for eSNPs in 3 additional genes: fatty acid desaturase 2 ( FADS2 ; P = .002), N-acetyl-α-D-galactosaminidase ( NAGA ; P = .0002), and Factor XIII, A1 ( F13A1 ; P = .0001). Subsequently, we demonstrated that FADS2 mRNA is increased in CD4 + lymphocytes in asthmatic patients and that the associated eSNPs reside within DNA segments with histone modifications that denote open chromatin status and confer enhancer activity. Conclusions Our results demonstrate the utility of eQTL mapping in the identification of novel asthma genes and provide evidence for the importance of FADS2 , NAGA , and F13A1 in the pathogenesis of asthma.

Published
2014

37. Filaggrin Associated Risk for Atopic Dermatitis Is Offset By Protective Missense Variants in Rptn and LCE1B Genes in the Epidermal Differentiation Complex

Author

Donald Y.M. Leung, Ingo Ruczinski, Rasika A. Mathias, Kruthika R. Iyer, Terri H. Beaty, Nicholas Rafaels, Lisa A. Beck, Joseph Potee, Lynda C. Schneider, Richard L. Gallo, Amy S. Paller, Meher Preethi Boorgula, Peck Y. Ong, Sameer Chavan, Li Gao, Kathleen C. Barnes, E. Guttman-Yassky, and Jon M. Hanifin

Subjects
medicine.medical_specialty, Immunology, medicine, Immunology and Allergy, Missense mutation, Epidermal differentiation complex, Atopic dermatitis, Biology, medicine.disease, Gene, Dermatology, Filaggrin
Published
2016

38. Gene Expression Signatures As Clinical Indices Of Disease Severity

Author

Fernando J. Martinez, Chris Cheadle, Frank D. Gilliland, Jinshui Fan, Robert F. Lemanske, Carole Ober, Alan E. Berger, Sangjucta Barkataki, Meher Preethi Boorgula, Kathleen C. Barnes, Benjamin A. Raby, Yumiko Sugawara, Stephanie J. London, Scott T. Weiss, Andrew H. Liu, and Robert C. Strunk

Subjects
Disease severity, business.industry, Gene expression, Immunology, Medicine, business
Published
2012

39. Erythroid-Specific Transcriptional Changes in PBMCs from Pulmonary Hypertension Patients

Author

Chris Cheadle, Kathleen C. Barnes, Sangjucta Barkataki, Roger A. Johns, Paul M. Hassoun, Yumiko Sugawara, Tonya Watkins, Ari L. Zaiman, Jinshui Fan, F. M. Wigley, Stephen C. Mathai, Reda E. Girgis, Michael A. McDevitt, Dmitry N. Grigoryev, Laura K. Hummers, Meher Preethi Boorgula, and Alan E. Berger

Subjects
Male, Hemodynamics, lcsh:Medicine, Gene Expression, 030204 cardiovascular system & hematology, Cardiovascular, Scleroderma, Transcriptome, 0302 clinical medicine, Gene expression, Molecular Cell Biology, lcsh:Science, Immune Response, Lung, Regulation of gene expression, 0303 health sciences, Multidisciplinary, Genomics, Middle Aged, Functional Genomics, medicine.anatomical_structure, Hypertension, Medicine, Female, Research Article, Adult, Hypertension, Pulmonary, Immunology, Biology, Peripheral blood mononuclear cell, 03 medical and health sciences, Genomic Medicine, Rheumatology, Erythroid Cells, medicine, Humans, 030304 developmental biology, Aged, lcsh:R, Immunity, Immune Defense, medicine.disease, Pulmonary hypertension, Gene expression profiling, Gene Expression Regulation, Leukocytes, Mononuclear, lcsh:Q, Genome Expression Analysis
Abstract

Background Gene expression profiling of peripheral blood mononuclear cells (PBMCs) is a powerful tool for the identification of surrogate markers involved in disease processes. The hypothesis tested in this study was that chronic exposure of PBMCs to a hypertensive environment in remodeled pulmonary vessels would be reflected by specific transcriptional changes in these cells. Methodology/Principal Findings The transcript profiles of PBMCs from 30 idiopathic pulmonary arterial hypertension patients (IPAH), 19 patients with systemic sclerosis without pulmonary hypertension (SSc), 42 scleroderma-associated pulmonary arterial hypertensio patients (SSc-PAH), and 8 patients with SSc complicated by interstitial lung disease and pulmonary hypertension (SSc-PH-ILD) were compared to the gene expression profiles of PBMCs from 41 healthy individuals. Multiple gene expression signatures were identified which could distinguish various disease groups from controls. One of these signatures, specific for erythrocyte maturation, is enriched specifically in patients with PH. This association was validated in multiple published datasets. The erythropoiesis signature was strongly correlated with hemodynamic measures of increasing disease severity in IPAH patients. No significant correlation of the same type was noted for SSc-PAH patients, this despite a clear signature enrichment within this group overall. These findings suggest an association of the erythropoiesis signature in PBMCs from patients with PH with a variable presentation among different subtypes of disease. Conclusions/Significance In PH, the expansion of immature red blood cell precursors may constitute a response to the increasingly hypoxic conditions prevalent in this syndrome. A correlation of this erythrocyte signature with more severe hypertension cases may provide an important biomarker of disease progression.

Published
2012

40. Identifying Genetic Determinants of Atopic Dermatitis and Bacterial Colonization Using Whole Genome Sequencing

Author

Donald Y.M. Leung, Richard L. Gallo, Li Gao, Joseph Potee, Kathleen C. Barnes, Ingo Ruczinski, Nicholas Rafaels, Lynda C. Schneider, Terri H. Beaty, Jon M. Hanifin, Lisa A. Beck, Sameer Chavan, Amy S. Paller, Emma Guttman-Yassky, Rasika A. Mathias, Kruthika R. Iyer, Meher Preethi Boorgula, and Peck Y. Ong

Subjects
Whole genome sequencing, Genetics, medicine.medical_specialty, Public health, Immunology, Atopic dermatitis, Biology, medicine.disease, Genome, Bacterial colonization, medicine, Immunology and Allergy, Colonization, Epidermal differentiation complex, Late cornified envelope 1B
Abstract

L30 Identifying Genetic Determinants of Atopic Dermatitis and Bacterial Colonization Using Whole Genome Sequencing Rasika A. Mathias, ScD, Sameer Chavan, MS, Kruthika R. Iyer, Nicholas M. Rafaels, Meher Boorgula, Joseph Potee, Jon M. Hanifin, MD FAAAAI, Amy Paller, MD, Lynda C. Schneider, MD FAAAAI, Richard L. Gallo, MD PhD, Emma Guttman-Yassky, MD PhD, Peck Y. Ong, MD FAAAAI, Ingo Ruczinski, PhD, Terri H. Beaty, PhD, Li Gao, MD PhD, Lisa A. Beck, MD FAAAAI, Donald Y. M. Leung, MD PhD FAAAAI, Kathleen C. Barnes, PhD FAAAAI; Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, MD, Oregon Health & Science University, Portland, OR, Northwestern University Feinberg School of Medicine, Chicago, IL, Boston Children’s Hospital, Boston, MA, Division of Dermatology, University of California, San Diego, San Diego, CA, Mount Sinai School of Medicine, New York, NY, Children’s Hospital Los Angeles, Los Angeles, CA, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, University of Rochester Medical Center, Rochester, NY, National Jewish Health, Denver, CO. RATIONALE: The genetic basis of S. aureus colonization in atopic dermatitis (AD) is unknown. To extend prior studies in this field, we have implemented the first whole genome sequencing (WGS) study to identify genetic determinants associated with risk of AD and bacterial colonization. METHODS: DeepWGS (;30x) was performed on 248 AD subjects with S. aureus colonization, 245 AD subjects without S. aureus and 237 nonatopic controls. Herewe present an initial analysis focused on single nucleotide variants (SNVs) in the Epidermal Differentiation Complex (EDC; chr1:151972910-153642037), a region rich in genes important for epidermal maturation. RESULTS: We identified 17,231 SNVs, of which 47% have never been observed in public catalogs of human variation. Fourteen SNVs had a p

Published
2015

41. Tu1690 Genome-Wide Gene Expression Differences in Active and Quiescent Stages of Ulcerative Colitis From Endoscopic Pinch Biopsies: Insights Into Distinctive Pathogenesis

Author

Fachao Zhi, Aimin Li, Meher Preethi Boorgula, Chris Cheadle, Jinshui Fan, Xinmei Zhao, Alan E. Berger, Sangjucta Barkataki, and Kathleen C. Barnes

Subjects
Pathogenesis, Pathology, medicine.medical_specialty, Hepatology, Gene expression, Immunology, Gastroenterology, medicine, Biology, medicine.disease, Ulcerative colitis, Genome
Published
2013

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