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1. Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes

Author

Keener, Rebecca, Chhetri, Surya B, Connelly, Carla J, Taub, Margaret A, Conomos, Matthew P, Weinstock, Joshua, Ni, Bohan, Strober, Benjamin, Aslibekyan, Stella, Auer, Paul L, Barwick, Lucas, Becker, Lewis C, Blangero, John, Bleecker, Eugene R, Brody, Jennifer A, Cade, Brian E, Celedon, Juan C, Chang, Yi-Cheng, Cupples, L Adrienne, Custer, Brian, Freedman, Barry I, Gladwin, Mark T, Heckbert, Susan R, Hou, Lifang, Irvin, Marguerite R, Isasi, Carmen R, Johnsen, Jill M, Kenny, Eimear E, Kooperberg, Charles, Minster, Ryan L, Naseri, Take, Viali, Satupa’itea, Nekhai, Sergei, Pankratz, Nathan, Peyser, Patricia A, Taylor, Kent D, Telen, Marilyn J, Wu, Baojun, Yanek, Lisa R, Yang, Ivana V, Albert, Christine, Arnett, Donna K, Ashley-Koch, Allison E, Barnes, Kathleen C, Bis, Joshua C, Blackwell, Thomas W, Boerwinkle, Eric, Burchard, Esteban G, Carson, April P, Chen, Zhanghua, Chen, Yii-Der Ida, Darbar, Dawood, de Andrade, Mariza, Ellinor, Patrick T, Fornage, Myriam, Gelb, Bruce D, Gilliland, Frank D, He, Jiang, Islam, Talat, Kaab, Stefan, Kardia, Sharon LR, Kelly, Shannon, Konkle, Barbara A, Kumar, Rajesh, Loos, Ruth JF, Martinez, Fernando D, McGarvey, Stephen T, Meyers, Deborah A, Mitchell, Braxton D, Montgomery, Courtney G, North, Kari E, Palmer, Nicholette D, Peralta, Juan M, Raby, Benjamin A, Redline, Susan, Rich, Stephen S, Roden, Dan, Rotter, Jerome I, Ruczinski, Ingo, Schwartz, David, Sciurba, Frank, Shoemaker, M Benjamin, Silverman, Edwin K, Sinner, Moritz F, Smith, Nicholas L, Smith, Albert V, Tiwari, Hemant K, Vasan, Ramachandran S, Weiss, Scott T, Williams, L Keoki, Zhang, Yingze, Ziv, Elad, Raffield, Laura M, Reiner, Alexander P, Arvanitis, Marios, Greider, Carol W, Mathias, Rasika A, and Battle, Alexis

Subjects
Biological Sciences, Genetics, Human Genome, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Generic health relevance, Humans, Genome-Wide Association Study, Telomere, K562 Cells, Telomere Homeostasis, Polymorphism, Single Nucleotide, Gene Expression Regulation, CRISPR-Cas Systems, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology and Hemostasis Working Group, TOPMed Structural Variation Working Group
Abstract

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.

Published
2024

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

Author

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

Published
2024
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5. Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program

Author

Hu, Xiaowei, Qiao, Dandi, Kim, Wonji, Moll, Matthew, Balte, Pallavi P, Lange, Leslie A, Bartz, Traci M, Kumar, Rajesh, Li, Xingnan, Yu, Bing, Cade, Brian E, Laurie, Cecelia A, Sofer, Tamar, Ruczinski, Ingo, Nickerson, Deborah A, Muzny, Donna M, Metcalf, Ginger A, Doddapaneni, Harshavardhan, Gabriel, Stacy, Gupta, Namrata, Dugan-Perez, Shannon, Cupples, L Adrienne, Loehr, Laura R, Jain, Deepti, Rotter, Jerome I, Wilson, James G, Psaty, Bruce M, Fornage, Myriam, Morrison, Alanna C, Vasan, Ramachandran S, Washko, George, Rich, Stephen S, O’Connor, George T, Bleecker, Eugene, Kaplan, Robert C, Kalhan, Ravi, Redline, Susan, Gharib, Sina A, Meyers, Deborah, Ortega, Victor, Dupuis, Josée, London, Stephanie J, Lappalainen, Tuuli, Oelsner, Elizabeth C, Silverman, Edwin K, Barr, R Graham, Thornton, Timothy A, Wheeler, Heather E, Group, TOPMed Lung Working, Cho, Michael H, Im, Hae Kyung, and Manichaikul, Ani

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Clinical Research, Lung, Prevention, Tobacco, Chronic Obstructive Pulmonary Disease, Tobacco Smoke and Health, Respiratory, Good Health and Well Being, Humans, National Heart, Lung, and Blood Institute (U.S.), Pulmonary Disease, Chronic Obstructive, Risk Factors, Transcriptome, United States, TOPMed Lung Working Group, cross-ethnic portability, gene expression, integrative analysis, polygenic transcriptome risk score, pulmonary disease, risk prediction, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

While polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1 s [FEV1] and its ratio to forced vital capacity [FEV1/FVC]) in the UK Biobank. We examined prediction performance and cross-ethnic portability of PTRS through smoking-stratified analyses both on 29,381 multi-ethnic participants from TOPMed population/family-based cohorts and on 11,771 multi-ethnic participants from TOPMed COPD-enriched studies. Analyses were carried out for two dichotomous COPD traits (moderate-to-severe and severe COPD) and two quantitative lung function traits (FEV1 and FEV1/FVC). While the proposed PTRS showed weaker associations with disease than PRS for European ancestry, the PTRS showed stronger association with COPD than PRS for African Americans (e.g., odds ratio [OR] = 1.24 [95% confidence interval [CI]: 1.08-1.43] for PTRS versus 1.10 [0.96-1.26] for PRS among heavy smokers with ≥ 40 pack-years of smoking) for moderate-to-severe COPD. Cross-ethnic portability of the PTRS was significantly higher than the PRS (paired t test p

Published
2022

6. A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels

Author

Abe, Namiko, Abecasis, Gonçalo, Aguet, Francois, Albert, Christine, Almasy, Laura, Alonso, Alvaro, Ament, Seth, Anderson, Peter, Anugu, Pramod, Applebaum-Bowden, Deborah, Ardlie, Kristin, Arking, Dan, Arnett, Donna K, Ashley-Koch, Allison, Aslibekyan, Stella, Assimes, Tim, Auer, Paul, Avramopoulos, Dimitrios, Ayas, Najib, Balasubramanian, Adithya, Barnard, John, Barnes, Kathleen, Barr, R. Graham, Barron-Casella, Emily, Barwick, Lucas, Beaty, Terri, Beck, Gerald, Becker, Diane, Becker, Lewis, Beer, Rebecca, Beitelshees, Amber, Benjamin, Emelia, Benos, Takis, Bezerra, Marcos, Bielak, Larry, Bis, Joshua, Blackwell, Thomas, Blangero, John, Blue, Nathan, Boerwinkle, Eric, Bowden, Donald W., Bowler, Russell, Brody, Jennifer, Broeckel, Ulrich, Broome, Jai, Brown, Deborah, Bunting, Karen, Burchard, Esteban, Bustamante, Carlos, Buth, Erin, Cade, Brian, Cardwell, Jonathan, Carey, Vincent, Carrier, Julie, Carson, April P., Carty, Cara, Casaburi, Richard, Casas Romero, Juan P, Casella, James, Castaldi, Peter, Chaffin, Mark, Chang, Christy, Chang, Yi-Cheng, Chasman, Daniel, Chavan, Sameer, Chen, Bo-Juen, Chen, Wei-Min, Ida Chen, Yii-Der, Cho, Michael, Choi, Seung Hoan, Chuang, Lee-Ming, Chung, Mina, Chung, Ren-Hua, Clish, Clary, Comhair, Suzy, Conomos, Matthew, Cornell, Elaine, Correa, Adolfo, Crandall, Carolyn, Crapo, James, Cupples, L. Adrienne, Curran, Joanne, Curtis, Jeffrey, Custer, Brian, Damcott, Coleen, Darbar, Dawood, David, Sean, Davis, Colleen, Daya, Michelle, de Andrade, Mariza, de las Fuentes, Lisa, de Vries, Paul, DeBaun, Michael, Deka, Ranjan, DeMeo, Dawn, Devine, Scott, Dinh, Huyen, Doddapaneni, Harsha, Duan, Qing, Dugan-Perez, Shannon, Duggirala, Ravi, Durda, Jon Peter, Dutcher, Susan K., Eaton, Charles, Ekunwe, Lynette, El Boueiz, Adel, Ellinor, Patrick, Emery, Leslie, Erzurum, Serpil, Farber, Charles, Farek, Jesse, Fingerlin, Tasha, Flickinger, Matthew, Fornage, Myriam, Franceschini, Nora, Frazar, Chris, Fu, Mao, Fullerton, Stephanie M., Fulton, Lucinda, Gabriel, Stacey, Gan, Weiniu, Gao, Shanshan, Gao, Yan, Gass, Margery, Geiger, Heather, Gelb, Bruce, Geraci, Mark, Germer, Soren, Gerszten, Robert, Ghosh, Auyon, Gibbs, Richard, Gignoux, Chris, Gladwin, Mark, Glahn, David, Gogarten, Stephanie, Gong, Da-Wei, Goring, Harald, Graw, Sharon, Gray, Kathryn J., Grine, Daniel, Gross, Colin, Gu, C. Charles, Guan, Yue, Guo, Xiuqing, Gupta, Namrata, Haessler, Jeff, Hall, Michael, Han, Yi, Hanly, Patrick, Harris, Daniel, Hawley, Nicola L., He, Jiang, Heavner, Ben, Heckbert, Susan, Hernandez, Ryan, Herrington, David, Hersh, Craig, Hidalgo, Bertha, Hixson, James, Hobbs, Brian, Hokanson, John, Hong, Elliott, Hoth, Karin, Hsiung, Chao (Agnes), Hu, Jianhong, Hung, Yi-Jen, Huston, Haley, Hwu, Chii Min, Irvin, Marguerite Ryan, Jackson, Rebecca, Jain, Deepti, Jaquish, Cashell, Johnsen, Jill, Johnson, Andrew, Johnson, Craig, Johnston, Rich, Jones, Kimberly, Kang, Hyun Min, Kaplan, Robert, Kardia, Sharon, Kelly, Shannon, Kenny, Eimear, Kessler, Michael, Khan, Alyna, Khan, Ziad, Kim, Wonji, Kimoff, John, Kinney, Greg, Konkle, Barbara, Kooperberg, Charles, Kramer, Holly, Lange, Christoph, Lange, Ethan, Lange, Leslie, Laurie, Cathy, Laurie, Cecelia, LeBoff, Meryl, Lee, Jiwon, Lee, Sandra, Lee, Wen-Jane, LeFaive, Jonathon, Levine, David, Levy, Dan, Lewis, Joshua, Li, Xiaohui, Li, Yun, Lin, Henry, Lin, Honghuang, Lin, Xihong, Liu, Simin, Liu, Yongmei, Liu, Yu, Loos, Ruth J. F., Lubitz, Steven, Lunetta, Kathryn, Luo, James, Magalang, Ulysses, Mahaney, Michael, Make, Barry, Manichaikul, Ani, Manning, Alisa, Manson, JoAnn, Martin, Lisa, Marton, Melissa, Mathai, Susan, Mathias, Rasika, May, Susanne, McArdle, Patrick, McDonald, Merry-Lynn, McFarland, Sean, McGarvey, Stephen, McGoldrick, Daniel, McHugh, Caitlin, McNeil, Becky, Mei, Hao, Meigs, James, Menon, Vipin, Mestroni, Luisa, Metcalf, Ginger, Meyers, Deborah A, Mignot, Emmanuel, Mikulla, Julie, Min, Nancy, Minear, Mollie, Minster, Ryan L, Mitchell, Braxton D., Moll, Matt, Momin, Zeineen, Montasser, May E., Montgomery, Courtney, Muzny, Donna, Mychaleckyj, Josyf C, Nadkarni, Girish, Naik, Rakhi, Naseri, Take, Natarajan, Pradeep, Nekhai, Sergei, Nelson, Sarah C., Neltner, Bonnie, Nessner, Caitlin, Nickerson, Deborah, Nkechinyere, Osuji, North, Kari, O'Connell, Jeff, O'Connor, Tim, Ochs-Balcom, Heather, Okwuonu, Geoffrey, Pack, Allan, Paik, David T., Palmer, Nicholette, Pankow, James, Papanicolaou, George, Parker, Cora, Peloso, Gina, Peralta, Juan Manuel, Perez, Marco, Perry, James, Peters, Ulrike, Peyser, Patricia, Phillips, Lawrence S, Pleiness, Jacob, Pollin, Toni, Post, Wendy, Becker, Julia Powers, Boorgula, Meher Preethi, Preuss, Michael, Psaty, Bruce, Qasba, Pankaj, Qiao, Dandi, Qin, Zhaohui, Rafaels, Nicholas, Raffield, Laura, Rajendran, Mahitha, Ramachandran, Vasan S., Rao, D. C., Rasmussen-Torvik, Laura, Ratan, Aakrosh, Redline, Susan, Reed, Robert, Reeves, Catherine, Regan, Elizabeth, Reiner, Alex, Reupena, Muagututi‘a Sefuiva, Rice, Ken, Rich, Stephen, Robillard, Rebecca, Robine, Nicolas, Roden, Dan, Roselli, Carolina, Rotter, Jerome, Ruczinski, Ingo, Runnels, Alexi, Russell, Pamela, Ruuska, Sarah, Ryan, Kathleen, Sabino, Ester Cerdeira, Saleheen, Danish, Salimi, Shabnam, Salvi, Sejal, Salzberg, Steven, Sandow, Kevin, Sankaran, Vijay G., Santibanez, Jireh, Schwander, Karen, Schwartz, David, Sciurba, Frank, Seidman, Christine, Seidman, Jonathan, Sériès, Frédéric, Sheehan, Vivien, Sherman, Stephanie L., Shetty, Amol, Shetty, Aniket, Hui-Heng Sheu, Wayne, Shoemaker, M. Benjamin, Silver, Brian, Silverman, Edwin, Skomro, Robert, Smith, Albert Vernon, Smith, Jennifer, Smith, Josh, Smith, Nicholas, Smith, Tanja, Smoller, Sylvia, Snively, Beverly, Snyder, Michael, Sofer, Tamar, Sotoodehnia, Nona, Stilp, Adrienne M., Storm, Garrett, Streeten, Elizabeth, Su, Jessica Lasky, Sung, Yun Ju, Sylvia, Jody, Szpiro, Adam, Taliun, Daniel, Tang, Hua, Taub, Margaret, Taylor, Kent D., Taylor, Matthew, Taylor, Simeon, Telen, Marilyn, Thornton, Timothy A., Threlkeld, Machiko, Tinker, Lesley, Tirschwell, David, Tishkoff, Sarah, Tiwari, Hemant, Tong, Catherine, Tracy, Russell, Tsai, Michael, Vaidya, Dhananjay, Van Den Berg, David, VandeHaar, Peter, Vrieze, Scott, Walker, Tarik, Wallace, Robert, Walts, Avram, Wang, Fei Fei, Wang, Heming, Wang, Jiongming, Watson, Karol, Watt, Jennifer, Weeks, Daniel E., Weinstock, Joshua, Weir, Bruce, Weiss, Scott T, Weng, Lu-Chen, Wessel, Jennifer, Willer, Cristen, Williams, Kayleen, Williams, L. Keoki, Wilson, Carla, Wilson, James, Winterkorn, Lara, Wong, Quenna, Wu, Joseph, Xu, Huichun, Yanek, Lisa, Yang, Ivana, Yu, Ketian, Zekavat, Seyedeh Maryam, Zhang, Yingze, Zhao, Snow Xueyan, Zhao, Wei, Zhu, Xiaofeng, Ziv, Elad, Zody, Michael, Zoellner, Sebastian, Lindstrom, Sara, Wang, Lu, Smith, Erin N., Gordon, William, van Hylckama Vlieg, Astrid, Brody, Jennifer A., Pattee, Jack W., Haessler, Jeffrey, Brumpton, Ben M., Chasman, Daniel I., Suchon, Pierre, Chen, Ming-Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri L., MacDonald, James, Braekkan, Sigrid K., Armasu, Sebastian M., Pankratz, Nathan, Jackson, Rabecca D., Nielsen, Jonas B., Giulianini, Franco, Puurunen, Marja K., Ibrahim, Manal, Heckbert, Susan R., Bammler, Theo K., Frazer, Kelly A., McCauley, Bryan M., Taylor, Kent, Pankow, James S., Reiner, Alexander P., Gabrielsen, Maiken E., Deleuze, Jean-François, O'Donnell, Chris J., Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John-Bjarne, Rosendaal, Frits R., Heit, John A., Psaty, Bruce M., Tang, Weihong, Hveem, Kristian, Ridker, Paul M., Morange, Pierre-Emmanuel, Johnson, Andrew D., Kabrhel, Christopher, AlexandreTrégouët, David, Smith, Nicholas L., de Vries, Paul S., Reventun, Paula, Brown, Michael R., Heath, Adam S., Huffman, Jennifer E., Le, Ngoc-Quynh, Bebo, Allison, Temprano-Sagrera, Gerard, Raffield, Laura M., Ozel, Ayse Bilge, Thibord, Florian, Lewis, Joshua P., Rodriguez, Benjamin A. T., Polasek, Ozren, Yanek, Lisa R., Carrasquilla, German D., Marioni, Riccardo E., Kleber, Marcus E., Trégouët, David-Alexandre, Yao, Jie, Li-Gao, Ruifang, Joshi, Peter K., Trompet, Stella, Martinez-Perez, Angel, Ghanbari, Mohsen, Howard, Tom E., Reiner, Alex P., Arvanitis, Marios, Ryan, Kathleen A., Bartz, Traci M., Rudan, Igor, Faraday, Nauder, Linneberg, Allan, Davies, Gail, Delgado, Graciela E., Klaric, Lucija, Noordam, Raymond, van Rooij, Frank, Curran, Joanne E., Wheeler, Marsha M., Osburn, William O., O'Connell, Jeffrey R., Beswick, Andrew, Kolcic, Ivana, Souto, Juan Carlos, Becker, Lewis C., Hansen, Torben, Doyle, Margaret F., Harris, Sarah E., Moissl, Angela P., Rich, Stephen S., Campbell, Harry, Stott, David J., Soria, Jose Manuel, de Maat, Moniek P. M., Brody, Lawrence C., Auer, Paul L., Ben-Shlomo, Yoav, Hayward, Caroline, Mathias, Rasika A., Kilpeläinen, Tuomas O., Lange, Leslie A., Cox, Simon R., März, Winfried, Rotter, Jerome I., Mook-Kanamori, Dennis O., Wilson, James F., van der Harst, Pim, Jukema, J. Wouter, Ikram, M. Arfan, Desch, Karl C., Sabater-Lleal, Maria, Lowenstein, Charles J., and Morrison, Alanna C.

Published
2024
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7. HLA-associated outcomes in peanut oral immunotherapy trials identify mechanistic and clinical determinants of therapeutic success.

Author

Kanchan, Kanika, Shankar, Gautam, Huffaker, Michelle F, Bahnson, Henry T, Chinthrajah, R Sharon, Sanda, Srinath, Manohar, Monali, Ling, Hua, Paschall, Justin E, Toit, George Du, Ruczinski, Ingo, Togias, Alkis, Lack, Gideon, Nadeau, Kari C, Jones, Stacie M, Nepom, Gerald T, and Mathias, Rasika A

Subjects
Humans, Peanut Hypersensitivity, Immunoglobulin G, Immunologic Factors, Immunotherapy, Adolescent, Adult, Middle Aged, Child, Clinical Trials as Topic, Young Adult, Arachis, HLA, desensitization, oral immunotherapy, peanut allergy, remission, tolerance, Clinical Research, Genetics, Prevention, Human Genome, Good Health and Well Being, Immunology, Medical Microbiology
Abstract

RationalePrevious studies identified an interaction between HLA and oral peanut exposure. HLA-DQA1*01:02 had a protective role with the induction of Ara h 2 epitope-specific IgG4 associated with peanut consumption during the LEAP clinical trial for prevention of peanut allergy, while it was a risk allele for peanut allergy in the peanut avoidance group. We have now evaluated this gene-environment interaction in two subsequent peanut oral immunotherapy (OIT) trials - IMPACT and POISED - to better understand the potential for the HLA-DQA1*01:02 allele as an indicator of higher likelihood of desensitization, sustained unresponsiveness, and peanut allergy remission.MethodsWe determined HLA-DQA1*01:02 carrier status using genome sequencing from POISED (N=118, age: 7-55yr) and IMPACT (N=126, age: 12-

Published
2022

8. Multiethnic genome-wide and HLA association study of total serum IgE level

Author

Daya, Michelle, Cox, Corey, Acevedo, Nathalie, Boorgula, Meher P, Campbell, Monica, Chavan, Sameer, Cho, Michael H, David, Gloria L, Kachroo, Priyadarshini, Lasky-Su, Jessica, Li, Xingnan, McHugh, Caitlin P, Qiao, Dandi, Rafaels, Nicholas, Beck, Lisa A, Bleecker, Eugene R, Caraballo, Luis, Cupples, Adrienne L, Figueiredo, Camila A, Gallo, Richard L, Hanifin, Jon, Hansel, Nadia N, Hata, Tissa R, Hersh, Craig P, Knight-Madden, Jennifer, Leung, Donald YM, Guttman-Yassky, Emma, Meyers, Deborah A, O’Connor, George, Ober, Carole, Ong, Peck Y, Ortega, Victor E, Paller, Amy S, Putcha, Nirupama, Reed, Robert M, Schneider, Lynda C, Silverman, Edwin K, Slifka, Mark K, Spergel, Jonathan M, Vasan, Ramachandran S, Viaud-Martinez, Karine A, Watson, Harold, Weiss, Scott T, Consortium, NHLBI Trans-Omics for Precision Medicine, Ruczinski, Ingo, Beaty, Terri H, Mathias, Rasika A, and Barnes, Kathleen C

Subjects
Clinical Research, Genetics, Lung, Asthma, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Good Health and Well Being, Adolescent, Adult, Aged, Child, Child, Preschool, Dermatitis, Atopic, Ethnicity, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, HLA-A2 Antigen, HLA-DQ beta-Chains, Humans, Immunoglobulin E, Male, Middle Aged, National Heart, Lung, and Blood Institute (U.S.), United States, Whole Genome Sequencing, Young Adult, Total serum IgE, human leukocyte antigen, genome-wide association study, atopic dermatitis, asthma, multiethnic, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Immunology, Allergy
Abstract

BackgroundTotal serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE.ObjectiveWe aimed to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum by leveraging data from the National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine program; the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA); and the Atopic Dermatitis Research Network (N = 21,901).MethodsWe performed genome-wide association within strata of study, disease, and ancestry groups, and we 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.ResultsWe identified 6 loci at genome-wide significance (P < 5 × 10-9), including 4 loci previously reported as genome-wide significant for tIgE, as well as new regions in chr11q13.5 and chr15q22.2, which were also identified in prior genome-wide association studies of atopic dermatitis and asthma. In the HLA allele association study, HLA-A∗02:01 was associated with decreased tIgE level (Pdiscovery = 2 × 10-4; Preplication = 5 × 10-4; Pdiscovery+replication = 4 × 10-7), and HLA-DQB1∗03:02 was strongly associated with decreased tIgE level in Hispanic/Latino ancestry populations (PHispanic/Latino discovery+replication = 8 × 10-8).ConclusionWe performed the largest genome-wide association study and HLA association study of tIgE focused on ancestrally diverse populations and found several known tIgE and allergic disease loci that are relevant in non-European ancestry populations.

Published
2021

9. Whole genome sequencing identifies novel genetic mutations in patients with eczema herpeticum

Author

Bin, Lianghua, Malley, Claire, Taylor, Patricia, Boorgula, Meher Preethi, Chavan, Sameer, Daya, Michelle, Mathias, Malaika, Shankar, Gautam, Rafaels, Nicholas, Vergara, Candelaria, Potee, Joseph, Campbell, Monica, Hanifin, Jon M, Simpson, Eric, Schneider, Lynda C, Gallo, Richard L, Hata, Tissa, Paller, Amy S, De Benedetto, Anna, Beck, Lisa A, Ong, Peck Y, Guttman‐Yassky, Emma, Richers, Brittany, Baraghoshi, David, Ruczinski, Ingo, Barnes, Kathleen C, Leung, Donald YM, and Mathias, Rasika A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Genetics, Biotechnology, Sexually Transmitted Infections, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Skin, Dermatitis, Atopic, Glutathione Transferase, Herpesvirus 1, Human, Humans, Kaposi Varicelliform Eruption, Mutation, Nucleotide Transport Proteins, Whole Genome Sequencing, atopic dermatitis, eczema herpeticum, genetics, herpes simplex virus, SIDT2, whole genome sequencing, SIDT2, Immunology, Allergy
Abstract

BackgroundEczema herpeticum (EH) is a rare complication of atopic dermatitis (AD) caused by disseminated herpes simplex virus (HSV) infection. The role of rare and/or deleterious genetic variants in disease etiology is largely unknown. This study aimed to identify genes that harbor damaging genetic variants associated with HSV infection in AD with a history of recurrent eczema herpeticum (ADEH+).MethodsWhole genome sequencing (WGS) was performed on 49 recurrent ADEH+ (≥3 EH episodes), 491 AD without a history of eczema herpeticum (ADEH-) and 237 non-atopic control (NA) subjects. Variants were annotated, and a gene-based approach (SKAT-O) was used to identify genes harboring damaging genetic variants associated with ADEH+. Genes identified through WGS were studied for effects on HSV responses and keratinocyte differentiation.ResultsEight genes were identified in the comparison of recurrent ADEH+to ADEH-and NA subjects: SIDT2, CLEC7A, GSTZ1, TPSG1, SP110, RBBP8NL, TRIM15, and FRMD3. Silencing SIDT2 and RBBP8NL in normal human primary keratinocytes (NHPKs) led to significantly increased HSV-1 replication. SIDT2-silenced NHPKs had decreased gene expression of IFNk and IL1b in response to HSV-1 infection. RBBP8NL-silenced NHPKs had decreased gene expression of IFNk, but increased IL1b. Additionally, silencing SIDT2 and RBBP8NL also inhibited gene expression of keratinocyte differentiation markers keratin 10 (KRT10) and loricrin (LOR).ConclusionSIDT2 and RBBP8NL participate in keratinocyte's response to HSV-1 infection. SIDT2 and RBBP8NL also regulate expression of keratinocyte differentiation genes of KRT10 and LOR.

Published
2021

10. Genome sequencing unveils a regulatory landscape of platelet reactivity.

Author

Keramati, Ali R, Chen, Ming-Huei, Rodriguez, Benjamin AT, Yanek, Lisa R, Bhan, Arunoday, Gaynor, Brady J, Ryan, Kathleen, Brody, Jennifer A, Zhong, Xue, Wei, Qiang, NHLBI Trans-Omics for Precision (TOPMed) Consortium, Kammers, Kai, Kanchan, Kanika, Iyer, Kruthika, Kowalski, Madeline H, Pitsillides, Achilleas N, Cupples, L Adrienne, Li, Bingshan, Schlaeger, Thorsten M, Shuldiner, Alan R, O'Connell, Jeffrey R, Ruczinski, Ingo, Mitchell, Braxton D, Faraday, Nauder, Taub, Margaret A, Becker, Lewis C, Lewis, Joshua P, Mathias, Rasika A, and Johnson, Andrew D

Subjects
NHLBI Trans-Omics for Precision (TOPMed) Consortium, Blood Platelets, K562 Cells, Humans, Thrombosis, GTP-Binding Proteins, RGS Proteins, Receptors, Cell Surface, Platelet Function Tests, Chromosome Mapping, Base Sequence, Platelet Aggregation, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study, HEK293 Cells, Whole Genome Sequencing
Abstract

Platelet aggregation at the site of atherosclerotic vascular injury is the underlying pathophysiology of myocardial infarction and stroke. To build upon prior GWAS, here we report on 16 loci identified through a whole genome sequencing (WGS) approach in 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) participants deeply phenotyped for platelet aggregation. We identify the RGS18 locus, which encodes a myeloerythroid lineage-specific regulator of G-protein signaling that co-localizes with expression quantitative trait loci (eQTL) signatures for RGS18 expression in platelets. Gene-based approaches implicate the SVEP1 gene, a known contributor of coronary artery disease risk. Sentinel variants at RGS18 and PEAR1 are associated with thrombosis risk and increased gastrointestinal bleeding risk, respectively. Our WGS findings add to previously identified GWAS loci, provide insights regarding the mechanism(s) by which genetics may influence cardiovascular disease risk, and underscore the importance of rare variant and regulatory approaches to identifying loci contributing to complex phenotypes.

Published
2021

11. Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma

Author

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

Published
2023
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12. Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants.

Author

Zhao, Xutong, Qiao, Dandi, Yang, Chaojie, Kasela, Silva, Kim, Wonji, Ma, Yanlin, Shrine, Nick, Batini, Chiara, Sofer, Tamar, Taliun, Sarah A Gagliano, Sakornsakolpat, Phuwanat, Balte, Pallavi P, Prokopenko, Dmitry, Yu, Bing, Lange, Leslie A, Dupuis, Josée, Cade, Brian E, Lee, Jiwon, Gharib, Sina A, Daya, Michelle, Laurie, Cecelia A, Ruczinski, Ingo, Cupples, L Adrienne, Loehr, Laura R, Bartz, Traci M, Morrison, Alanna C, Psaty, Bruce M, Vasan, Ramachandran S, Wilson, James G, Taylor, Kent D, Durda, Peter, Johnson, W Craig, Cornell, Elaine, Guo, Xiuqing, Liu, Yongmei, Tracy, Russell P, Ardlie, Kristin G, Aguet, François, VanDenBerg, David J, Papanicolaou, George J, Rotter, Jerome I, Barnes, Kathleen C, Jain, Deepti, Nickerson, Deborah A, Muzny, Donna M, Metcalf, Ginger A, Doddapaneni, Harshavardhan, Dugan-Perez, Shannon, Gupta, Namrata, Gabriel, Stacey, Rich, Stephen S, O'Connor, George T, Redline, Susan, Reed, Robert M, Laurie, Cathy C, Daviglus, Martha L, Preudhomme, Liana K, Burkart, Kristin M, Kaplan, Robert C, Wain, Louise V, Tobin, Martin D, London, Stephanie J, Lappalainen, Tuuli, Oelsner, Elizabeth C, Abecasis, Goncalo R, Silverman, Edwin K, Barr, R Graham, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Lung Working Group, Cho, Michael H, and Manichaikul, Ani

Subjects
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Lung Working Group, Lung, Humans, Pulmonary Disease, Chronic Obstructive, Genetic Predisposition to Disease, Intracellular Signaling Peptides and Proteins, Calcium-Binding Proteins, Small Ubiquitin-Related Modifier Proteins, Follow-Up Studies, Feasibility Studies, Polymorphism, Single Nucleotide, Adult, Aged, Aged, 80 and over, Middle Aged, African Americans, Female, Male, Protein Inhibitors of Activated STAT, Respiratory Physiological Phenomena, Genome-Wide Association Study, Genetic Loci, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Whole Genome Sequencing, and over, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive
Abstract

Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.

Published
2020

13. A Risk Prediction Model for Mortality Among Smokers in the COPDGene® Study.

Author

Strand, Matthew, Austin, Erin, Moll, Matthew, Pratte, Katherine A, Regan, Elizabeth A, Hayden, Lystra P, Bhatt, Surya P, Boriek, Aladin M, Casaburi, Richard, Silverman, Edwin K, Fortis, Spyridon, Ruczinski, Ingo, Koegler, Harald, Rossiter, Harry B, Occhipinti, Mariaelena, Hanania, Nicola A, Gebrekristos, Hirut T, Lynch, David A, Kunisaki, Ken M, Young, Kendra A, Sieren, Jessica C, Ragland, Margaret, Hokanson, John E, Lutz, Sharon M, Make, Barry J, Kinney, Gregory L, Cho, Michael H, Pistolesi, Massimo, DeMeo, Dawn L, Sciurba, Frank C, Comellas, Alejandro P, Diaz, Alejandro A, Barjaktarevic, Igor, Bowler, Russell P, Kanner, Richard E, Peters, Stephen P, Ortega, Victor E, Dransfield, Mark T, and Crapo, James D

Subjects
Biomedical and Clinical Sciences, Epidemiology, Public Health, Health Sciences, Clinical Sciences, Prevention, Tobacco Smoke and Health, Lung, Tobacco, Chronic Obstructive Pulmonary Disease, Clinical Research, Respiratory, Good Health and Well Being, COPD, COPD Genetic Epidemiology study, COPDGene, spirometry, preserved ratio-impaired spiromety, PRISm, risk score, copd, preserved ratio-impaired spirometry
Abstract

BackgroundRisk factor identification is a proven strategy in advancing treatments and preventive therapy for many chronic conditions. Quantifying the impact of those risk factors on health outcomes can consolidate and focus efforts on individuals with specific high-risk profiles. Using multiple risk factors and longitudinal outcomes in 2 independent cohorts, we developed and validated a risk score model to predict mortality in current and former cigarette smokers.MethodsWe obtained extensive data on current and former smokers from the COPD Genetic Epidemiology (COPDGene®) study at enrollment. Based on physician input and model goodness-of-fit measures, a subset of variables was selected to fit final Weibull survival models separately for men and women. Coefficients and predictors were translated into a point system, allowing for easy computation of mortality risk scores and probabilities. We then used the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) cohort for external validation of our model.ResultsOf 9867 COPDGene participants with standard baseline data, 17.6% died over 10 years of follow-up, and 9074 of these participants had the full set of baseline predictors (standard plus 6-minute walk distance and computed tomography variables) available for full model fits. The average age of participants in the cohort was 60 for both men and women, and the average predicted 10-year mortality risk was 18% for women and 25% for men. Model time-integrated area under the receiver operating characteristic curve statistics demonstrated good predictive model accuracy (0.797 average), validated in the external cohort (0.756 average). Risk of mortality was impacted most by 6-minute walk distance, forced expiratory volume in 1 second and age, for both men and women.ConclusionsCurrent and former smokers exhibited a wide range of mortality risk over a 10- year period. Our models can identify higher risk individuals who can be targeted for interventions to reduce risk of mortality, for participants with or without chronic obstructive pulmonary disease (COPD) using current Global initiative for obstructive Lung Disease (GOLD) criteria.

Published
2020

14. Genomic integrity of human induced pluripotent stem cells across nine studies in the NHLBI NextGen program

Author

Kanchan, Kanika, Iyer, Kruthika, Yanek, Lisa R, Carcamo-Orive, Ivan, Taub, Margaret A, Malley, Claire, Baldwin, Kristin, Becker, Lewis C, Broeckel, Ulrich, Cheng, Linzhao, Cowan, Chad, D'Antonio, Matteo, Frazer, Kelly A, Quertermous, Thomas, Mostoslavsky, Gustavo, Murphy, George, Rabinovitch, Marlene, Rader, Daniel J, Steinberg, Martin H, Topol, Eric, Yang, Wenli, Knowles, Joshua W, Jaquish, Cashell E, Ruczinski, Ingo, and Mathias, Rasika A

Subjects
Biological Sciences, Genetics, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Stem Cell Research - Induced Pluripotent Stem Cell, Biotechnology, Human Genome, Cancer, Stem Cell Research, 2.1 Biological and endogenous factors, Aetiology, Cell Differentiation, DNA Copy Number Variations, DNA-Binding Proteins, Genomic Instability, Genomics, Humans, Induced Pluripotent Stem Cells, National Heart, Lung, and Blood Institute (U.S.), United States, hiPSCs, Structural integrity, GWAS, VanillaICE, Oncogenes, Tumor suppressor genes, Medical and Health Sciences, Developmental Biology, Medical biotechnology, Oncology and carcinogenesis
Abstract

Human induced pluripotent stem cell (hiPSC) lines have previously been generated through the NHLBI sponsored NextGen program at nine individual study sites. Here, we examined the structural integrity of 506 hiPSC lines as determined by copy number variations (CNVs). We observed that 149 hiPSC lines acquired 258 CNVs relative to donor DNA. We identified six recurrent regions of CNVs on chromosomes 1, 2, 3, 16 and 20 that overlapped with cancer associated genes. Furthermore, the genes mapping to regions of acquired CNVs show an enrichment in cancer related biological processes (IL6 production) and signaling cascades (JNK cascade & NFκB cascade). The genomic region of instability on chr20 (chr20q11.2) includes transcriptomic signatures for cancer associated genes such as ID1, BCL2L1, TPX2, PDRG1 and HCK. Of these HCK shows statistically significant differential expression between carrier and non-carrier hiPSC lines. Overall, while a low level of genomic instability was observed in the NextGen generated hiPSC lines, the observation of structural instability in regions with known cancer associated genes substantiates the importance of systematic evaluation of genetic variations in hiPSCs before using them as disease/research models.

Published
2020

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

Author

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

Subjects
Biological Sciences, Genetics, Eczema / Atopic Dermatitis, Clinical Research, Human Genome, Prevention, Aetiology, 2.1 Biological and endogenous factors, Case-Control Studies, CpG Islands, DNA Methylation, Dermatitis, Atopic, Eosinophils, Epigenesis, Genetic, Female, Genome-Wide Association Study, Humans, Immunoglobulin E, Interleukin-4, Kaposi Varicelliform Eruption, Male, Severity of Illness Index, Th2 Cells, Atopic dermatitis, Eczema herpeticum, Human epigenetics, DNA methylation, Infinium Methylation 450K array, Methylation EPIC array, Infinium Methylation 450K array, Clinical Sciences, Paediatrics and Reproductive Medicine
Abstract

BackgroundAlthough 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.ResultsWe 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).ConclusionsWe 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.

Published
2019

16. COPDGene® 2019: Redefining the Diagnosis of Chronic Obstructive Pulmonary Disease.

Author

Lowe, Katherine E, Regan, Elizabeth A, Anzueto, Antonio, Austin, Erin, Austin, John HM, Beaty, Terri H, Benos, Panayiotis V, Benway, Christopher J, Bhatt, Surya P, Bleecker, Eugene R, Bodduluri, Sandeep, Bon, Jessica, Boriek, Aladin M, Boueiz, Adel Re, Bowler, Russell P, Budoff, Matthew, Casaburi, Richard, Castaldi, Peter J, Charbonnier, Jean-Paul, Cho, Michael H, Comellas, Alejandro, Conrad, Douglas, Costa Davis, Corinne, Criner, Gerard J, Curran-Everett, Douglas, Curtis, Jeffrey L, DeMeo, Dawn L, Diaz, Alejandro A, Dransfield, Mark T, Dy, Jennifer G, Fawzy, Ashraf, Fleming, Margaret, Flenaugh, Eric L, Foreman, Marilyn G, Fortis, Spyridon, Gebrekristos, Hirut, Grant, Sarah, Grenier, Philippe A, Gu, Tian, Gupta, Abhya, Han, MeiLan K, Hanania, Nicola A, Hansel, Nadia N, Hayden, Lystra P, Hersh, Craig P, Hobbs, Brian D, Hoffman, Eric A, Hogg, James C, Hokanson, John E, Hoth, Karin F, Hsiao, Albert, Humphries, Stephen, Jacobs, Kathleen, Jacobson, Francine L, Kazerooni, Ella A, Kim, Victor, Kim, Woo Jin, Kinney, Gregory L, Koegler, Harald, Lutz, Sharon M, Lynch, David A, MacIntye, Neil R, Make, Barry J, Marchetti, Nathaniel, Martinez, Fernando J, Maselli, Diego J, Mathews, Anne M, McCormack, Meredith C, McDonald, Merry-Lynn N, McEvoy, Charlene E, Moll, Matthew, Molye, Sarah S, Murray, Susan, Nath, Hrudaya, Newell, John D, Occhipinti, Mariaelena, Paoletti, Matteo, Parekh, Trisha, Pistolesi, Massimo, Pratte, Katherine A, Putcha, Nirupama, Ragland, Margaret, Reinhardt, Joseph M, Rennard, Stephen I, Rosiello, Richard A, Ross, James C, Rossiter, Harry B, Ruczinski, Ingo, San Jose Estepar, Raul, Sciurba, Frank C, Sieren, Jessica C, Singh, Harjinder, Soler, Xavier, Steiner, Robert M, Strand, Matthew J, Stringer, William W, Tal-Singer, Ruth, Thomashow, Byron, Vegas Sánchez-Ferrero, Gonzalo, and Walsh, John W

Subjects
COPD Genetic Epidemiology study, preserved ratio-impaired spirometry, COPD diagnosis, COPD diagnosis, COPDGene, GOLD, Global initiative for chronic Obstructive Lung Dis, PRISm, chronic obstructive pulmonary disease, copd, preserved ratio-impaired spirometry, spirometry, Prevention, Tobacco Smoke and Health, Tobacco, Lung, Chronic Obstructive Pulmonary Disease, Biomedical Imaging, Clinical Research, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Respiratory, Good Health and Well Being, COPD, COPD Genetic Epidemiology study, Global initiative for chronic Obstructive Lung Disease
Abstract

BackgroundChronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene®), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality.MethodsFour key disease characteristics - environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry - were evaluated in a group of 8784 current and former smokers who were participants in COPDGene® Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV1 > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined.ResultsUsing smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene® 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15-6.48) in those with all 4 disease characteristics.ConclusionsA substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop.

Published
2019

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

Author

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, Jiménez, 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, and CAAPA

Subjects
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

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

Author

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, Jiménez, 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, and CAAPA

Subjects
CAAPA, Chromosomes, Human, Pair 8, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 17, Humans, Asthma, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, African Americans, Hispanic Americans, United States, Genome-Wide Association Study, Genetic Loci, Chromosomes, Human, Pair 12, Pair 17, Pair 8, Polymorphism, Single Nucleotide
Abstract

Asthma is a complex disease with striking disparities across racial and ethnic groups. Despite its relatively high burden, representation of individuals of African ancestry in asthma genome-wide association studies (GWAS) has been inadequate, and true associations in these underrepresented minority groups have been inconclusive. We report the results of a genome-wide meta-analysis from the Consortium on Asthma among African Ancestry Populations (CAAPA; 7009 asthma cases, 7645 controls). We find strong evidence for association at four previously reported asthma loci whose discovery was driven largely by non-African populations, including the chromosome 17q12-q21 locus and the chr12q13 region, a novel (and not previously replicated) asthma locus recently identified by the Trans-National Asthma Genetic Consortium (TAGC). An additional seven loci reported by TAGC show marginal evidence for association in CAAPA. We also identify two novel loci (8p23 and 8q24) that may be specific to asthma risk in African ancestry populations.

Published
2019

19. Evaluation of multi-assay algorithms for cross-sectional HIV incidence estimation in settings with universal antiretroviral treatment

Author

Grant-McAuley, Wendy, Laeyendecker, Oliver, Monaco, Daniel, Chen, Athena, Hudelson, Sarah E., Klock, Ethan, Brookmeyer, Ron, Morrison, Douglas, Piwowar-Manning, Estelle, Morrison, Charles S., Hayes, Richard, Ayles, Helen, Bock, Peter, Kosloff, Barry, Shanaube, Kwame, Mandla, Nomtha, van Deventer, Anneen, Ruczinski, Ingo, Kammers, Kai, Larman, H. Benjamin, and Eshleman, Susan H.

Published
2022
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21. Longitudinal Association Between Muscle Loss and Mortality in Ever Smokers

Author

Crapo, James D., Silverman, Edwin K., Cummings, Sara, Madden, Kelley, Make, Barry J., Nabbosa, Juliet, Port, Emily, Rashdi, Serine, Regan, Elizabeth A., Stepp, Lori, Watts, Shandi, Weaver, Michael, Beaty, Terri, Bowler, Russell P., Curtis, Jeffrey L., Han, MeiLan K., Hokanson, John E., Lynch, David A., Strand, Matthew J., Anderson, Gary, Bleecker, Eugene R., Coxson, Harvey O., Crystal, Ronald G., Hogg, James C., Province, Michael A., Rennard, Stephen I., Croxton, Thomas, Gan, Weiniu, Postow, Lisa A., Viviano, Lisa M., Costa-Davis, Corinne, Malanga, Elisha, Prieto, Delia, Tal-Singer, Ruth, Farzadegan, Homayoon, Hadji, Akila, Sathe, Leena, Baraghoshi, David, Chen, Grace, Crooks, James, Knowles, Ruthie, Pratte, Katherine, Wilson, Carla, Zelarney, Pearlanne T., Kechris, Katerina J., Leach, Sonia, Austin, Erin E., Czizik, Annika, Kinney, Gregory, Li, Yisha, Lutz, Sharon M., Ragland, Margaret F., Richmond, Nicole, Young, Kendra A., Cho, Michael, Castaldi, Peter J., Glass, Kimberly, Hersh, Craig, Kim, Wonji, Liu, Yang-Yu, Hersh, Craig P., Bidinger, Jacqueline, Cho, Michael H., Conrad, Douglas, DeMeo, Dawn L., El-Boueiz, Adel R., Foreman, Marilyn G., Ghosh, Auyon, Hahn, Georg, Hansel, Nadia N., Hayden, Lystra P., Hobbs, Brian, Kim, Woori, Lange, Christoph, McDonald, Merry- Lynn, McGeachie, Michael, Moll, Matthew, Morris, Melody, Patsopoulos, Nikolaos A., Qiao, Dandi, Ruczinski, Ingo, Wan, Emily S., Dy, Jennifer G., Fain, Sean B., Ginsburg, Shoshana, Hoffman, Eric A., Humphries, Stephen, Judy, Philip F., Stefanie Mason, Alex Kluiber, Oh, Andrea, Poynton, Clare, Reinhardt, Joseph M., Ross, James, San Jose Estepar, Raul, Schroeder, Joyce D., Sitek, Arkadiusz, Steiner, Robert M., van Beek, Edwin, Ginneken, Bram van, van Rikxoort, Eva, Washko, George R., Jensen, Robert, John E. Hokanson, Co-Chair, Bhatt, Surya P., Casaburi, Richard, Kim, Victor, Putcha, Nirupama, Han, MeiLan, Bon, Jessica, Diaz, Alejandro A., Regan, Elizabeth, Anzueto, Antonio, Bailey, William C., Criner, Gerard J., Dransfield, Mark T., Kinney, Greg, Sprenger, Kim, Benos, Takis, Hanania, Nicola A., Hoth, Karin F., Lambert, Allison, Lowe, Katherine, Oates, Gabriela, Parekh, Trisha, Westney, Gloria, Young, Kendra, Balasubramanian, Aparna, Boriek, Aladin, Fawzy, Ashraf, Jacobson, Francine, LaFon, David C., MacIntyre, Neil, Maselli-Caceres, Diego, McCormack, Meredith C., McDonald, Merry-Lynn, Sciurba, Frank, Soler, Xavier, Tejwani, Vickram, van Beek, Edwin JR., Wade, Raymond C., Wells, Mike, Wendt, Chris H., Yun, Jeong H., Zhang, Jingzhou, Gillenwater, Lucas, Lowe, Katherine E., Pratte, Katherine A., Ragland, Margaret, Attaway, Amy, Mason, Stefanie, Rossiter, Harry B., Saha, Punam Kumar, Wilson, Ava, Amaza, Hannatu, Baldomero, Adrienne, Mamary, A. James, O’Brien, James, Wise, Robert A., Eakin, Michelle, Fiedorowicz, Jess G., Henkle, Ben, Holm, Kristen, Iyer, Anand, Kunisaki, Ken M., McEvoy, Charlene, Mkorombindo, Takudzwa, Shinozaki, Gen, Yohannes, Abebaw, Hobbs, Brian D., Miller, Bruce E., Retson, Tara, McCloskey, Lisa, Pernicano, Perry G., Atik, Mustafa, Bertrand, Laura, Monaco, Thomas, Narendra, Dharani, Lenge de Rosen, Veronica V., Badu-Danso, Kwame, Jacobson, Francine L., Kaufman, Laura, Maguire, Cherie, Struble, Sophie, Wilson, Seth, Barr, R. Graham, Almonte, Casandra, Austin, John H.M., Gomez Blum, Maria Lorena, D’Souza, Belinda M., Florez, Emilay, Martinez, Rodney, MacIntyre, Neil, Jr., Curry, Wendy, McAdams, H. Page, Reikofski, Charlotte V., Washington, Lacey, Brown, Robert, Clare, Cheryl, Daniel, Marie, Horton, Karen, Ting “Tony” Lin, Cheng, Mirza, Tahira, Scott, Meagan, Shade, Becky, Budoff, Matt, Calmelat, Robert, Cavanaugh, Deborah, Dailing, Chris, Diaz, Leticia, Fischer, Hans, Indelicato, Renee Love, Porszasz, Janos, Soriano, April, Stringer, William, Urrutia, Miriam, Baldomero, Arianne, Bell, Brian, Deconcini, Miranda, Loes, Linda, Phelan, Jonathan, Robichaux, Camille, Sasse, Cheryl, Tashjian, Joseph H., Flenaugh, Eric L., Abson, Kema, Gebrekristos, Hirut, Johnson, Priscilla, Jordan, Jessica, Ponce, Mario, Terpenning, Silanath, Wilson, Derrick, Broadhurst, Grace, Dyer, Debra, Engel, Elena, Finigan, Jay, Hill, Andrew, Jones, Alex, Jones, Ryan, Owen, Jordan, Rosiello, Richard, Andries, Nicole, Charpentier, Mary, Kirk, Diane, Pace, David, Ciccolella, David, Cordova, Francis, Dass, Chandra, D’Alonzo, Gilbert, Davis, Valena, Desai, Parag, Fehrle, Dee, Grabianowski, Carla, Jacobs, Michael, Jameson, Laurie, Jones, Gayle M., Kelsen, Steven, Marchetti, Nathaniel, McGonagle, Francine, Satti, Aditi, Shenoy, Kartik, Sheridan, Regina, Vega-Sanchez, Maria, Wallace, Samantha, Akinseye-kolapo, Samuel, Baker, Matthew, Goggins, Arnissa, McClain, Anny, Nath, Hrudaya, Singh, Satinder P., Sonavane, Sushil K., Westfall, Elizabeth, Gil, Marissa, El Hajjaoui, Tarek, Hsiao, Albert, Martineau, Amber, Mielke, Jenna, Perez, Karl, Querido, Gabriel, Reston, Tara, Yen, Andrew, Comellas, Alejandro, Fortis, Spyridon, Galizia, Mauricio, Garcia, Eric, Keating, Janet, Laroia, Archana, Lee, Changhyun, Meyer, Amber, Mullan, Brian, Nagpal, Prashant, Ofori, Oloigbe, Suiter, Sierra, Mason, Stefanie E., Moreta-Martinez, Rafael, Labaki, Wassim W., San Jose Estepar, Ruben, Make, Barry, and Stringer, Kathleen

Published
2022
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22. Identification of antibody targets associated with lower HIV viral load and viremic control.

Author

Grant-McAuley, Wendy, Morgenlander, William R., Ruczinski, Ingo, Kammers, Kai, Laeyendecker, Oliver, Hudelson, Sarah E., Thakar, Manjusha, Piwowar-Manning, Estelle, Clarke, William, Breaud, Autumn, Ayles, Helen, Bock, Peter, Moore, Ayana, Kosloff, Barry, Shanaube, Kwame, Meehan, Sue-Ann, van Deventer, Anneen, Fidler, Sarah, Hayes, Richard, and Larman, H. Benjamin

Subjects
HIV antibodies, HIV infections, VIRAL load, HIV prevention, HUMORAL immunity
Abstract

Background: High HIV viral loads (VL) are associated with increased morbidity, mortality, and on-going transmission. HIV controllers maintain low VLs in the absence of antiretroviral therapy (ART). We previously used a massively multiplexed antibody profiling assay (VirScan) to compare antibody profiles in HIV controllers and persons living with HIV (PWH) who were virally suppressed on ART. In this report, we used VirScan to evaluate whether antibody reactivity to specific HIV targets and broad reactivity across the HIV genome was associated with VL and controller status 1–2 years after infection. Methods: Samples were obtained from participants who acquired HIV infection in a community-randomized trial in Africa that evaluated an integrated strategy for HIV prevention (HPTN 071 PopART). Controller status was determined using VL and antiretroviral (ARV) drug data obtained at the seroconversion visit and 1 year later. Viremic controllers had VLs <2,000 copies/mL at both visits; non-controllers had VLs >2,000 copies/mL at both visits. Both groups had no ARV drugs detected at either visit. VirScan testing was performed at the second HIV-positive visit (1–2 years after HIV infection). Results: The study cohort included 13 viremic controllers and 64 non-controllers. We identified ten clusters of homologous peptides that had high levels of antibody reactivity (three in gag, three in env, two in integrase, one in protease, and one in vpu). Reactivity to 43 peptides (eight unique epitopes) in six of these clusters was associated with lower VL; reactivity to six of the eight epitopes was associated with HIV controller status. Higher aggregate antibody reactivity across the eight epitopes (more epitopes targeted, higher mean reactivity across all epitopes) and across the HIV genome was also associated with lower VL and controller status. Conclusions: We identified HIV antibody targets associated with lower VL and HIV controller status 1–2 years after infection. Robust aggregate responses to these targets and broad antibody reactivity across the HIV genome were also associated with lower VL and controller status. These findings provide novel insights into the relationship between humoral immunity and viral containment that could help inform the design of antibody-based approaches for reducing HIV VL. [ABSTRACT FROM AUTHOR]

Published
2024
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24. Association of HLA-DRB1∗09:01 with tIgE levels among African-ancestry individuals with asthma

Author

Vince, Nicolas, Limou, Sophie, Daya, Michelle, Morii, Wataru, Rafaels, Nicholas, Geffard, Estelle, Douillard, Venceslas, Walencik, Alexandre, Boorgula, Meher Preethi, Chavan, Sameer, Vergara, Candelaria, Ortega, Victor E., Wilson, James G., Lange, Leslie A., Watson, Harold, Nicolae, Dan L., Meyers, Deborah A., Hansel, Nadia N., Ford, Jean G., Faruque, Mezbah U., Bleecker, Eugene R., Campbell, Monica, Beaty, Terri H., Ruczinski, Ingo, Mathias, Rasika A., Taub, Margaret A., Ober, Carole, Noguchi, Emiko, Barnes, Kathleen C., Torgerson, Dara, and Gourraud, Pierre-Antoine

Published
2020
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25. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

Author

Taliun, Daniel, Harris, Daniel N., Kessler, Michael D., Carlson, Jedidiah, Szpiech, Zachary A., Torres, Raul, Taliun, Sarah A. Gagliano, Corvelo, André, Gogarten, Stephanie M., Kang, Hyun Min, Pitsillides, Achilleas N., LeFaive, Jonathon, Lee, Seung-been, Tian, Xiaowen, Browning, Brian L., Das, Sayantan, Emde, Anne-Katrin, Clarke, Wayne E., Loesch, Douglas P., Shetty, Amol C., Blackwell, Thomas W., Smith, Albert V., Wong, Quenna, Liu, Xiaoming, Conomos, Matthew P., Bobo, Dean M., Aguet, François, Albert, Christine, Alonso, Alvaro, Ardlie, Kristin G., Arking, Dan E., Aslibekyan, Stella, Auer, Paul L., Barnard, John, Barr, R. Graham, Barwick, Lucas, Becker, Lewis C., Beer, Rebecca L., Benjamin, Emelia J., Bielak, Lawrence F., Blangero, John, Boehnke, Michael, Bowden, Donald W., Brody, Jennifer A., Burchard, Esteban G., Cade, Brian E., Casella, James F., Chalazan, Brandon, Chasman, Daniel I., Chen, Yii-Der Ida, Cho, Michael H., Choi, Seung Hoan, Chung, Mina K., Clish, Clary B., Correa, Adolfo, Curran, Joanne E., Custer, Brian, Darbar, Dawood, Daya, Michelle, de Andrade, Mariza, DeMeo, Dawn L., Dutcher, Susan K., Ellinor, Patrick T., Emery, Leslie S., Eng, Celeste, Fatkin, Diane, Fingerlin, Tasha, Forer, Lukas, Fornage, Myriam, Franceschini, Nora, Fuchsberger, Christian, Fullerton, Stephanie M., Germer, Soren, Gladwin, Mark T., Gottlieb, Daniel J., Guo, Xiuqing, Hall, Michael E., He, Jiang, Heard-Costa, Nancy L., Heckbert, Susan R., Irvin, Marguerite R., Johnsen, Jill M., Johnson, Andrew D., Kaplan, Robert, Kardia, Sharon L. R., Kelly, Tanika, Kelly, Shannon, Kenny, Eimear E., Kiel, Douglas P., Klemmer, Robert, Konkle, Barbara A., Kooperberg, Charles, Köttgen, Anna, Lange, Leslie A., Lasky-Su, Jessica, Levy, Daniel, Lin, Xihong, Lin, Keng-Han, Liu, Chunyu, Loos, Ruth J. F., Garman, Lori, Gerszten, Robert, Lubitz, Steven A., Lunetta, Kathryn L., Mak, Angel C. Y., Manichaikul, Ani, Manning, Alisa K., Mathias, Rasika A., McManus, David D., McGarvey, Stephen T., Meigs, James B., Meyers, Deborah A., Mikulla, Julie L., Minear, Mollie A., Mitchell, Braxton D., Mohanty, Sanghamitra, Montasser, May E., Montgomery, Courtney, Morrison, Alanna C., Murabito, Joanne M., Natale, Andrea, Natarajan, Pradeep, Nelson, Sarah C., North, Kari E., O’Connell, Jeffrey R., Palmer, Nicholette D., Pankratz, Nathan, Peloso, Gina M., Peyser, Patricia A., Pleiness, Jacob, Post, Wendy S., Psaty, Bruce M., Rao, D. C., Redline, Susan, Reiner, Alexander P., Roden, Dan, Rotter, Jerome I., Ruczinski, Ingo, Sarnowski, Chloé, Schoenherr, Sebastian, Schwartz, David A., Seo, Jeong-Sun, Seshadri, Sudha, Sheehan, Vivien A., Sheu, Wayne H., Shoemaker, M. Benjamin, Smith, Nicholas L., Smith, Jennifer A., Sotoodehnia, Nona, Stilp, Adrienne M., Tang, Weihong, Taylor, Kent D., Telen, Marilyn, Thornton, Timothy A., Tracy, Russell P., Van Den Berg, David J., Vasan, Ramachandran S., Viaud-Martinez, Karine A., Vrieze, Scott, Weeks, Daniel E., Weir, Bruce S., Weiss, Scott T., Weng, Lu-Chen, Willer, Cristen J., Zhang, Yingze, Zhao, Xutong, Arnett, Donna K., Ashley-Koch, Allison E., Barnes, Kathleen C., Boerwinkle, Eric, Gabriel, Stacey, Gibbs, Richard, Rice, Kenneth M., Rich, Stephen S., Silverman, Edwin K., Qasba, Pankaj, Gan, Weiniu, Papanicolaou, George J., Nickerson, Deborah A., Browning, Sharon R., Zody, Michael C., Zöllner, Sebastian, Wilson, James G., Cupples, L. Adrienne, Laurie, Cathy C., Jaquish, Cashell E., Hernandez, Ryan D., O’Connor, Timothy D., and Abecasis, Gonçalo R.

Published
2021
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26. Targeted deep sequencing identifies rare loss-of-function variants in IFNGR1 for risk of atopic dermatitis complicated by eczema herpeticum

Author

Gao, Li, Bin, Lianghua, Rafaels, Nicholas M, Huang, Lili, Potee, Joseph, Ruczinski, Ingo, Beaty, Terri H, Paller, Amy S, Schneider, Lynda C, Gallo, Rich, Hanifin, Jon M, Beck, Lisa A, Geha, Raif S, Mathias, Rasika A, Barnes, Kathleen C, and Leung, Donald YM

Subjects
Human Genome, Genetic Testing, Prevention, Genetics, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Adolescent, Adult, Aged, Aged, 80 and over, Cell Line, Child, Child, Preschool, Dermatitis, Atopic, Female, Genes, Reporter, Genetic Predisposition to Disease, Genotype, High-Throughput Nucleotide Sequencing, Humans, Infant, Interferon-gamma, Kaposi Varicelliform Eruption, Male, Middle Aged, Polymorphism, Single Nucleotide, Receptors, Interferon, Risk, STAT1 Transcription Factor, Young Adult, IFNGR1, genetic variants, atopic dermatitis, eczema herpeticum, Immunology, Allergy
Abstract

BackgroundA subset of atopic dermatitis is associated with increased susceptibility to eczema herpeticum (ADEH+). We previously reported that common single nucleotide polymorphisms (SNPs) in the IFN-γ (IFNG) and IFN-γ receptor 1 (IFNGR1) genes were associated with the ADEH+ phenotype.ObjectiveWe sought to interrogate the role of rare variants in interferon pathway genes for the risk of ADEH+.MethodsWe performed targeted sequencing of interferon pathway genes (IFNG, IFNGR1, IFNAR1, and IL12RB1) in 228 European American patients with AD selected according to their eczema herpeticum status, and severity was measured by using the Eczema Area and Severity Index. Replication genotyping was performed in independent samples of 219 European American and 333 African American subjects. Functional investigation of loss-of-function variants was conducted by using site-directed mutagenesis.ResultsWe identified 494 single nucleotide variants encompassing 105 kb of sequence, including 145 common, 349 (70.6%) rare (minor allele frequency

Published
2015

27. Impact of Amerind ancestry and FADS genetic variation on omega-3 deficiency and cardiometabolic traits in Hispanic populations

Author

Yang, Chaojie, Hallmark, Brian, Chai, Jin Choul, O’Connor, Timothy D., Reynolds, Lindsay M., Wood, Alexis C., Seeds, Michael, Chen, Yii-Der Ida, Steffen, Lyn M., Tsai, Michael Y., Kaplan, Robert C., Daviglus, Martha L., Mandarino, Lawrence J., Fretts, Amanda M., Lemaitre, Rozenn N., Coletta, Dawn K., Blomquist, Sarah A., Johnstone, Laurel M., Tontsch, Chandra, Qi, Qibin, Ruczinski, Ingo, Rich, Stephen S., Mathias, Rasika A., Chilton, Floyd H., and Manichaikul, Ani

Published
2021
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28. Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children With Asthma

Author

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

Published
2019
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29. Genome-wide association study in two populations to determine genetic variants associated with Toxoplasma gondii infection and relationship to schizophrenia risk

Author

Wang, Alex W., Avramopoulos, Dimitrios, Lori, Adriana, Mulle, Jennifer, Conneely, Karen, Powers, Abigail, Duncan, Erica, Almli, Lynn, Massa, Nicholas, McGrath, John, Schwartz, Ann C., Goes, Fernando S., Weng, Lei, Wang, Ruihua, Yolken, Robert, Ruczinski, Ingo, Gillespie, Charles F., Jovanovic, Tanja, Ressler, Kerry, Pulver, Ann E., and Pearce, Brad D.

Published
2019
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30. Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function

Author

Tang, Wenbo, Kowgier, Matthew, Loth, Daan W, Soler Artigas, María, Joubert, Bonnie R, Hodge, Emily, Gharib, Sina A, Smith, Albert V, Ruczinski, Ingo, Gudnason, Vilmundur, Mathias, Rasika A, Harris, Tamara B, Hansel, Nadia N, Launer, Lenore J, Barnes, Kathleen C, Hansen, Joyanna G, Albrecht, Eva, Aldrich, Melinda C, Allerhand, Michael, Barr, R Graham, Brusselle, Guy G, Couper, David J, Curjuric, Ivan, Davies, Gail, Deary, Ian J, Dupuis, Josée, Fall, Tove, Foy, Millennia, Franceschini, Nora, Gao, Wei, Gläser, Sven, Gu, Xiangjun, Hancock, Dana B, Heinrich, Joachim, Hofman, Albert, Imboden, Medea, Ingelsson, Erik, James, Alan, Karrasch, Stefan, Koch, Beate, Kritchevsky, Stephen B, Kumar, Ashish, Lahousse, Lies, Li, Guo, Lind, Lars, Lindgren, Cecilia, Liu, Yongmei, Lohman, Kurt, Lumley, Thomas, McArdle, Wendy L, Meibohm, Bernd, Morris, Andrew P, Morrison, Alanna C, Musk, Bill, North, Kari E, Palmer, Lyle J, Probst-Hensch, Nicole M, Psaty, Bruce M, Rivadeneira, Fernando, Rotter, Jerome I, Schulz, Holger, Smith, Lewis J, Sood, Akshay, Starr, John M, Strachan, David P, Teumer, Alexander, Uitterlinden, André G, Völzke, Henry, Voorman, Arend, Wain, Louise V, Wells, Martin T, Wilk, Jemma B, Williams, O Dale, Heckbert, Susan R, Stricker, Bruno H, London, Stephanie J, Fornage, Myriam, Tobin, Martin D, O'Connor, George T, Hall, Ian P, and Cassano, Patricia A

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Chronic Obstructive Pulmonary Disease, Human Genome, Lung, Clinical Research, Prevention, Respiratory, Adult, Chromosomes, Human, Pair 11, Female, Gene Expression Regulation, Genetic Loci, Genome-Wide Association Study, Humans, Longitudinal Studies, Male, Respiration, General Science & Technology
Abstract

BackgroundGenome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.MethodsWe performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.ResultsThe overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.ConclusionsIn this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.

Published
2014

31. Comprehensive profiling of pre-infection antibodies identifies HIV targets associated with viremic control and viral load

Author

Grant-McAuley, Wendy, primary, Morgenlander, William, additional, Hudelson, Sarah E., additional, Thakar, Manjusha, additional, Piwowar-Manning, Estelle, additional, Clarke, William, additional, Breaud, Autumn, additional, Blankson, Joel, additional, Wilson, Ethan, additional, Ayles, Helen, additional, Bock, Peter, additional, Moore, Ayana, additional, Kosloff, Barry, additional, Shanaube, Kwame, additional, Meehan, Sue-Ann, additional, van Deventer, Anneen, additional, Fidler, Sarah, additional, Hayes, Richard, additional, Ruczinski, Ingo, additional, Kammers, Kai, additional, Laeyendecker, Oliver, additional, Larman, H. Benjamin, additional, and Eshleman, Susan H., additional

Published
2023
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32. Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma

Author

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

Published
2023
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33. Hidden Markov models for the assessment of chromosomal alterations using high-throughput SNP arrays

Author

Scharpf, Robert B., Parmigiani, Giovanni, Pevsner, Jonathan, and Ruczinski, Ingo

Subjects
Statistics - Applications
Abstract

Chromosomal DNA is characterized by variation between individuals at the level of entire chromosomes (e.g., aneuploidy in which the chromosome copy number is altered), segmental changes (including insertions, deletions, inversions, and translocations), and changes to small genomic regions (including single nucleotide polymorphisms). A variety of alterations that occur in chromosomal DNA, many of which can be detected using high density single nucleotide polymorphism (SNP) microarrays, are linked to normal variation as well as disease and are therefore of particular interest. These include changes in copy number (deletions and duplications) and genotype (e.g., the occurrence of regions of homozygosity). Hidden Markov models (HMM) are particularly useful for detecting such alterations, modeling the spatial dependence between neighboring SNPs. Here, we improve previous approaches that utilize HMM frameworks for inference in high throughput SNP arrays by integrating copy number, genotype calls, and the corresponding measures of uncertainty when available. Using simulated and experimental data, we, in particular, demonstrate how confidence scores control smoothing in a probabilistic framework. Software for fitting HMMs to SNP array data is available in the R package VanillaICE., Comment: Published in at http://dx.doi.org/10.1214/07-AOAS155 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org)

Published
2008
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36. Assembly of a pan-genome from deep sequencing of 910 humans of African descent

Author

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

Published
2019
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37. HLA alleles and sustained peanut consumption promote IgG4 responses in subjects protected from peanut allergy

Author

Kanchan, Kanika, Grinek, Stepan, Bahnson, Henry T., Ruczinski, Ingo, Shankar, Gautam, Larson, David, Toit, George Du, Barnes, Kathleen C., Sampson, Hugh A., Suarez-Farinas, Mayte, Lack, Gideon, Nepom, Gerald T., Cerosaletti, Karen, and Mathias, Rasika A.

Subjects
HLA histocompatibility antigens -- Health aspects, Immune response -- Genetic aspects, Immunoglobulin G -- Health aspects, Allelomorphism -- Health aspects, Histocompatibility antigens -- Health aspects, Peanut allergy -- Genetic aspects -- Prevention, Health care industry
Abstract

We investigated the interplay between genetics and oral peanut protein exposure in the determination of the immunological response to peanut using the targeted intervention in the LEAP clinical trial. We identified an association between peanut-specific IgG4 and HLA-DQA1*01:02 that was only observed in the presence of sustained oral peanut protein exposure. The association between IgG4 and HLA-DQA1*01:02 was driven by IgG4 specific for the Ara h 2 component. Once peanut consumption ceased, the association between IgG4-specific Ara h 2 and HLA-DQA1*01:02 was attenuated. The association was validated by observing expanded IgG4-specific epitopes in people who carried HLA-DQA1*01:02. Notably, we confirmed the previously reported associations with HLA-DQA1*01:02 and peanut allergy risk in the absence of oral peanut protein exposure. Interaction between HLA and presence or absence of exposure to peanut in an allergen- and epitope-specific manner implicates a mechanism of antigen recognition that is fundamental to driving immune responses related to allergy risk or protection., Introduction The interplay between an individual's genetics and exposure to particular environmental or therapeutic modulators influences mechanisms of disease, prognosis, and treatment. Clinical trials of food allergy tolerance, in which [...]

Published
2022
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38. Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations.

Author

Torgerson, Dara G, Ampleford, Elizabeth J, Chiu, Grace Y, Gauderman, W James, Gignoux, Christopher R, Graves, Penelope E, Himes, Blanca E, Levin, Albert M, Mathias, Rasika A, Hancock, Dana B, Baurley, James W, Eng, Celeste, Stern, Debra A, Celedón, Juan C, Rafaels, Nicholas, Capurso, Daniel, Conti, David V, Roth, Lindsey A, Soto-Quiros, Manuel, Togias, Alkis, Li, Xingnan, Myers, Rachel A, Romieu, Isabelle, Van Den Berg, David J, Hu, Donglei, Hansel, Nadia N, Hernandez, Ryan D, Israel, Elliott, Salam, Muhammad T, Galanter, Joshua, Avila, Pedro C, Avila, Lydiana, Rodriquez-Santana, Jose R, Chapela, Rocio, Rodriguez-Cintron, William, Diette, Gregory B, Adkinson, N Franklin, Abel, Rebekah A, Ross, Kevin D, Shi, Min, Faruque, Mezbah U, Dunston, Georgia M, Watson, Harold R, Mantese, Vito J, Ezurum, Serpil C, Liang, Liming, Ruczinski, Ingo, Ford, Jean G, Huntsman, Scott, Chung, Kian Fan, Vora, Hita, Li, Xia, Calhoun, William J, Castro, Mario, Sienra-Monge, Juan J, del Rio-Navarro, Blanca, Deichmann, Klaus A, Heinzmann, Andrea, Wenzel, Sally E, Busse, William W, Gern, James E, Lemanske, Robert F, Beaty, Terri H, Bleecker, Eugene R, Raby, Benjamin A, Meyers, Deborah A, London, Stephanie J, Mexico City Childhood Asthma Study (MCAAS), Gilliland, Frank D, Children's Health Study (CHS) and HARBORS study, Burchard, Esteban G, Genetics of Asthma in Latino Americans (GALA) Study, Study of Genes-Environment and Admixture in Latino Americans (GALA2) and Study of African Americans, Asthma, Genes & Environments (SAGE), Martinez, Fernando D, Childhood Asthma Research and Education (CARE) Network, Weiss, Scott T, Childhood Asthma Management Program (CAMP), Williams, L Keoki, Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE), Barnes, Kathleen C, Genetic Research on Asthma in African Diaspora (GRAAD) Study, Ober, Carole, and Nicolae, Dan L

Subjects
Mexico City Childhood Asthma Study, Children's Health Study (CHS) and HARBORS study, Genetics of Asthma in Latino Americans (GALA) Study, Study of Genes-Environment and Admixture in Latino Americans (GALA2) and Study of African Americans, Asthma, Genes & Environments, Childhood Asthma Research and Education (CARE) Network, Childhood Asthma Management Program, Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity, Genetic Research on Asthma in African Diaspora (GRAAD) Study, Humans, Asthma, Genetic Predisposition to Disease, Risk, African Americans, European Continental Ancestry Group, Hispanic Americans, Caribbean Region, North America, Genome-Wide Association Study, Genetic Loci, Genetics of Asthma in Latino Americans (GALA) Study, Study of Genes-Environment and Admixture in Latino Americans (GALA2) and Study of African Americans, Genes & Environments, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.

Published
2011

39. Enhanced statistical tests for GWAS in admixed populations: assessment using African Americans from CARe and a Breast Cancer Consortium.

Author

Pasaniuc, Bogdan, Zaitlen, Noah, Lettre, Guillaume, Chen, Gary K, Tandon, Arti, Kao, WH Linda, Ruczinski, Ingo, Fornage, Myriam, Siscovick, David S, Zhu, Xiaofeng, Larkin, Emma, Lange, Leslie A, Cupples, L Adrienne, Yang, Qiong, Akylbekova, Ermeg L, Musani, Solomon K, Divers, Jasmin, Mychaleckyj, Joe, Li, Mingyao, Papanicolaou, George J, Millikan, Robert C, Ambrosone, Christine B, John, Esther M, Bernstein, Leslie, Zheng, Wei, Hu, Jennifer J, Ziegler, Regina G, Nyante, Sarah J, Bandera, Elisa V, Ingles, Sue A, Press, Michael F, Chanock, Stephen J, Deming, Sandra L, Rodriguez-Gil, Jorge L, Palmer, Cameron D, Buxbaum, Sarah, Ekunwe, Lynette, Hirschhorn, Joel N, Henderson, Brian E, Myers, Simon, Haiman, Christopher A, Reich, David, Patterson, Nick, Wilson, James G, and Price, Alkes L

Subjects
Humans, Breast Neoplasms, Coronary Disease, Diabetes Mellitus, Type 2, Odds Ratio, Chromosome Mapping, Genetics, Population, Gene Frequency, Genotype, Linkage Disequilibrium, Phenotype, Polymorphism, Single Nucleotide, Genome, Human, Algorithms, Principal Component Analysis, Software, African Americans, Female, Male, Receptor, Fibroblast Growth Factor, Type 2, Genetic Variation, Genome-Wide Association Study, Diabetes Mellitus, Type 2, Genetics, Population, Polymorphism, Single Nucleotide, Genome, Human, Receptor, Fibroblast Growth Factor, Developmental Biology
Abstract

While genome-wide association studies (GWAS) have primarily examined populations of European ancestry, more recent studies often involve additional populations, including admixed populations such as African Americans and Latinos. In admixed populations, linkage disequilibrium (LD) exists both at a fine scale in ancestral populations and at a coarse scale (admixture-LD) due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered SNP association (LD mapping) or admixture association (mapping by admixture-LD), but not both. Here, we introduce a new statistical framework for combining SNP and admixture association in case-control studies, as well as methods for local ancestry-aware imputation. We illustrate the gain in statistical power achieved by these methods by analyzing data of 6,209 unrelated African Americans from the CARe project genotyped on the Affymetrix 6.0 chip, in conjunction with both simulated and real phenotypes, as well as by analyzing the FGFR2 locus using breast cancer GWAS data from 5,761 African-American women. We show that, at typed SNPs, our method yields an 8% increase in statistical power for finding disease risk loci compared to the power achieved by standard methods in case-control studies. At imputed SNPs, we observe an 11% increase in statistical power for mapping disease loci when our local ancestry-aware imputation framework and the new scoring statistic are jointly employed. Finally, we show that our method increases statistical power in regions harboring the causal SNP in the case when the causal SNP is untyped and cannot be imputed. Our methods and our publicly available software are broadly applicable to GWAS in admixed populations.

Published
2011

40. Random-Coil Behavior and the Dimensions of Chemically Unfolded Proteins

Author

Kohn, Jonathan E., Millett, Ian S., Jacob, Jaby, Zagrovic, Bojan, Dillon, Thomas M., Cingel, Nikolina, Dothager, Robin S., Seifert, Soenke, Thiyagarajan, P., Sosnick, Tobin R., Hasan, M. Zahid, Pande, Vijay S., Ruczinski, Ingo, Doniach, Sebastian, Plaxco, Kevin W., and Baldwin, Robert L.

Published
2004

42. Efficient encoding of large antigenic spaces by epitope prioritization with Dolphyn

Author

Liebhoff, Anna-Maria, primary, Venkataraman, Thiagarajan, additional, Morgenlander, William R, additional, Na, Miso, additional, Kula, Tomasz, additional, Waugh, Kathleen, additional, Morrison, Charles, additional, Rewers, Marian, additional, Longman, Randy, additional, Round, June, additional, Elledge, Stephen, additional, Ruczinski, Ingo, additional, Langmead, Ben, additional, and Larman, H Benjamin, additional

Published
2023
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43. Logic Regression

Author

Ruczinski, Ingo, Kooperberg, Charles, and LeBlanc, Michael

Published
2003

45. Bayesian copy number detection and association in large-scale studies

Author

Cristiano, Stephen, McKean, David, Carey, Jacob, Bracci, Paige, Brennan, Paul, Chou, Michael, Du, Mengmeng, Gallinger, Steven, Goggins, Michael G., Hassan, Manal M., Hung, Rayjean J., Kurtz, Robert C., Li, Donghui, Lu, Lingeng, Neale, Rachel, Olson, Sara, Petersen, Gloria, Rabe, Kari G., Fu, Jack, Risch, Harvey, Rosner, Gary L., Ruczinski, Ingo, Klein, Alison P., and Scharpf, Robert B.

Published
2020
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48. Antibody responses to endemic coronaviruses modulate COVID-19 convalescent plasma functionality

Author

Morgenlander, William R., Henson, Stephanie N., Monaco, Daniel R., Chen, Athena, Littlefield, Kirsten, Bloch, Evan M., Fujimura, Eric, Ruczinski, Ingo, Crowley, Andrew R., Natarajan, Harini, Butler, Savannah E., Weiner, Joshua A., Li, Mamie Z., Bonny, Tania S., Benner, Sarah E., Balagopal, Ashwin, Sullivan, David, Shoham, Shmuel, Quinn, Thomas C., Eshleman, Susan H., Casadevall, Arturo, Redd, Andrew D., Laeyendecker, Oliver, Ackerman, Margaret E., Pekosz, Andrew, Elledge, Stephen J., Robinson, Matthew, Tobian, Aaron A.R., and Larman, H. Benjamin

Subjects
Antigen-antibody reactions -- Research, Immunological research, Health care industry
Abstract

SARS-CoV-2 (CoV2) antibody therapies, including COVID-19 convalescent plasma (CCP), monoclonal antibodies, and hyperimmune globulin, are among the leading treatments for individuals with early COVID-19 infection. The functionality of convalescent plasma varies greatly, but the association of antibody epitope specificities with plasma functionality remains uncharacterized. We assessed antibody functionality and reactivities to peptides across the CoV2 and the 4 endemic human coronavirus (HCoV) genomes in 126 CCP donations. We found strong correlation between plasma functionality and polyclonal antibody targeting of CoV2 spike protein peptides. Antibody reactivity to many HCoV spike peptides also displayed strong correlation with plasma functionality, including pan-coronavirus cross-reactive epitopes located in a conserved region of the fusion peptide. After accounting for antibody cross- reactivity, we identified an association between greater alphacoronavirus NL63 antibody responses and development of highly neutralizing antibodies against CoV2. We also found that plasma preferentially reactive to the CoV2 spike receptor binding domain (RBD), versus the betacoronavirus HKU1 RBD, had higher neutralizing titer. Finally, we developed a 2-peptide serosignature that identifies plasma donations with high anti-spike titer, but that suffer from low neutralizing activity. These results suggest that analysis of coronavirus antibody fine specificities may be useful for selecting desired therapeutics and understanding the complex immune responses elicited by CoV2 infection., Introduction Coronaviruses cause human respiratory diseases that range from asymptomatic to fatal. Endemic human coronaviruses (HCoVs) that cause the common cold include 2 alphacoronaviruses (229E and NL63) and 2 betacoronaviruses [...]

Published
2021
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49. Structural variation across 138,134 samples in the TOPMed consortium

Author

Jun, Goo, primary, English, Adam, additional, Metcalf, Ginger, additional, Yang, Jianzhi, additional, Chaisson, Mark, additional, Pankratz, Nathan, additional, Menon, Vipin, additional, Salerno, William, additional, Krasheninina, Olga, additional, Smith, Albert, additional, Lane, John, additional, Blackwell, Thomas, additional, Kang, Hyun Min, additional, Salvi, Sejal, additional, Meng, Qingchang, additional, Shen, Hua, additional, Pasham, Divya, additional, Bhamidipati, Sravya, additional, Kottapalli, Kavya, additional, Arnett, Donna, additional, Ashley-Koch, Allison, additional, Auer, Paul, additional, Beutel, KAthleen, additional, Bis, Joshua, additional, Blangero, John, additional, Bowden, Donald, additional, Brody, Jennifer, additional, Cade, Brian, additional, Chen, Yii-Der Ida, additional, Cho, Michael, additional, Curran, Joanne, additional, Fornage, Myriam, additional, Frredman, Barry, additional, Fingerlin, Tasha, additional, Gelb, Bruce, additional, Hou, Lifang, additional, Hung, Yi-Jen, additional, Kane, John P, additional, Kaplan, Robert, additional, Kim, Wonji, additional, Loos, Ruth, additional, Marcus, Gregory, additional, Mathias, Rasika, additional, McGarvey, Stephen, additional, Montgomery, Courtney, additional, Naseri, Take, additional, Nouraie, Seyed, additional, Preuss, Michael, additional, Palmer, Nicholette, additional, Peyser, Patricia, additional, Raffield, Laura, additional, Ratan, Aakrosh, additional, Redline, Susan, additional, Reupena, Muagututia, additional, Rotter, Jerome, additional, Rich, Stephen, additional, Rienstra, Michiel, additional, Ruczinski, Ingo, additional, Sankaran, Vijay, additional, Schwartz, David, additional, Seidman, Christine, additional, Seidman, Jonathan, additional, Silverman, Edwin, additional, Smith, Jennifer, additional, Stilp, Adrienne, additional, Taylor, Kent, additional, Telen, Marilyn, additional, Weiss, Scott, additional, Williams, L. Keoki, additional, Wu, Baojun, additional, Yanek, Lisa, additional, Zhang, Yingze, additional, Lasky-Su, Jessica, additional, Gingras, Marie-Claude, additional, Dutcher, Susan, additional, Eichler, Evan, additional, Gabriel, Stacey, additional, Germer, Soren, additional, Kim, Ryan, additional, Martinez, Karine, additional, Nickerson, Deborah, additional, Luo, James, additional, Reiner, Alexander, additional, Gibbs, Richard, additional, Boerwinkle, Eric, additional, Abecasis, Goncaol, additional, and Sedlazeck, Fritz, additional

Published
2023
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