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1. Maternal educational attainment in pregnancy and epigenome-wide DNA methylation changes in the offspring from birth until adolescence

Author

Choudhary, Priyanka, Monasso, Giulietta S, Karhunen, Ville, Ronkainen, Justiina, Mancano, Giulia, Howe, Caitlin G, Niu, Zhongzheng, Zeng, Xuehuo, Guan, Weihua, Dou, John, Feinberg, Jason I, Mordaunt, Charles, Pesce, Giancarlo, Baïz, Nour, Alfano, Rossella, Martens, Dries S, Wang, Congrong, Isaevska, Elena, Keikkala, Elina, Mustaniemi, Sanna, Thio, Chris HL, Fraszczyk, Eliza, Tobi, Elmar W, Starling, Anne P, Cosin-Tomas, Marta, Urquiza, Jose, Röder, Stefan, Hoang, Thanh T, Page, Christian, Jima, Dereje D, House, John S, Maguire, Rachel L, Ott, Raffael, Pawlow, Xenia, Sirignano, Lea, Zillich, Lea, Malmberg, Anni, Rauschert, Sebastian, Melton, Phillip, Gong, Tong, Karlsson, Robert, Fore, Ruby, Perng, Wei, Laubach, Zachary M, Czamara, Darina, Sharp, Gemma, Breton, Carrie V, Schisterman, Enrique, Yeung, Edwina, Mumford, Sunni L, Fallin, M Daniele, LaSalle, Janine M, Schmidt, Rebecca J, Bakulski, Kelly M, Annesi-Maesano, Isabella, Heude, Barbara, Nawrot, Tim S, Plusquin, Michelle, Ghantous, Akram, Herceg, Zdenko, Nisticò, Lorenza, Vafeiadi, Marina, Kogevinas, Manolis, Vääräsmäki, Marja, Kajantie, Eero, Snieder, Harold, Corpeleijn, Eva, Steegers-Theunissen, Regine PM, Yang, Ivana V, Dabelea, Dana, Fossati, Serena, Zenclussen, Ana C, Herberth, Gunda, Magnus, Maria, Håberg, Siri E, London, Stephanie J, Munthe-Kaas, Monica Cheng, Murphy, Susan K, Hoyo, Cathrine, Ziegler, Anette-G, Hummel, Sandra, Witt, Stephanie H, Streit, Fabian, Frank, Josef, Räikkönen, Katri, Lahti, Jari, Huang, Rae-chi, Almqvist, Catarina, Hivert, Marie-France, Jaddoe, Vincent WV, Järvelin, Marjo-Riitta, Kantomaa, Marko, Felix, Janine F, and Sebert, Sylvain

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Pediatric, Genetics, Human Genome, Social Determinants of Health, Maternal Health, Prevention, Pregnancy, Nutrition, Women's Health, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, 1.1 Normal biological development and functioning, Generic health relevance, Reproductive health and childbirth, Good Health and Well Being, Humans, DNA Methylation, Female, Adolescent, Epigenome, Child, Educational Status, Male, Genome-Wide Association Study, Epigenesis, Genetic, Prenatal Exposure Delayed Effects, Child, Preschool, Infant, Mothers, Infant, Newborn, Adult, Academic Success, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract

Maternal educational attainment (MEA) shapes offspring health through multiple potential pathways. Differential DNA methylation may provide a mechanistic understanding of these long-term associations. We aimed to quantify the associations of MEA with offspring DNA methylation levels at birth, in childhood and in adolescence. Using 37 studies from high-income countries, we performed meta-analysis of epigenome-wide association studies (EWAS) to quantify the associations of completed years of MEA at the time of pregnancy with offspring DNA methylation levels at birth (n = 9 881), in childhood (n = 2 017), and adolescence (n = 2 740), adjusting for relevant covariates. MEA was found to be associated with DNA methylation at 473 cytosine-phosphate-guanine sites at birth, one in childhood, and four in adolescence. We observed enrichment for findings from previous EWAS on maternal folate, vitamin-B12 concentrations, maternal smoking, and pre-pregnancy BMI. The associations were directionally consistent with MEA being inversely associated with behaviours including smoking and BMI. Our findings form a bridge between socio-economic factors and biology and highlight potential pathways underlying effects of maternal education. The results broaden our understanding of bio-social associations linked to differential DNA methylation in multiple early stages of life. The data generated also offers an important resource to help a more precise understanding of the social determinants of health.

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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4. 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 L. R., Kelly, Shannon, Konkle, Barbara A., Kumar, Rajesh, Loos, Ruth J. F., 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

Published
2024
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5. Progressive lung fibrosis: reprogramming a genetically vulnerable bronchoalveolar epithelium

Author

Bridges, James P., Vladar, Eszter K., Kurche, Jonathan S., Krivoi, Andrei, Stancil, Ian T., Dobrinskikh, Evgenia, Hu, Yan, Sasse, Sarah K., Lee, Joyce S., Blumhagen, Rachel Z., Yang, Ivana V., Gerber, Anthony N., Peljto, Anna L., Evans, Christopher M., Redente, Elizabeth F., Riches, David W.H., and Schwartz, David A.

Subjects
Pulmonary fibrosis -- Risk factors -- Genetic aspects -- Development and progression, Epithelial cells -- Health aspects -- Genetic aspects, Health care industry
Abstract

Idiopathic pulmonary fibrosis (IPF) is etiologically complex, with well- documented genetic and nongenetic origins. In this Review, we speculate that the development of IPF requires two hits: the first establishes a vulnerable bronchoalveolar epithelium, and the second triggers mechanisms that reprogram distal epithelia to initiate and perpetuate a profibrotic phenotype. While vulnerability of the bronchoalveolar epithelia is most often driven by common or rare genetic variants, subsequent injury of the bronchoalveolar epithelia results in persistent changes in cell biology that disrupt tissue homeostasis and activate fibroblasts. The dynamic biology of IPF can best be contextualized etiologically and temporally, including stages of vulnerability, early disease, and persistent and progressive lung fibrosis. These dimensions of IPF highlight critical mechanisms that adversely disrupt epithelial function, activate fibroblasts, and lead to lung remodeling. Together with better recognition of early disease, this conceptual approach should lead to the development of novel therapeutics directed at the etiologic and temporal drivers of lung fibrosis that will ultimately transform the care of patients with IPF from palliative to curative., Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease, characterized by heterogeneous subpleural patches of fibrotic remodeled lung, that follows a bronchocentric distribution (1-3). The median survival is 3-5 years [...]

Published
2025
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7. Rare genetic variants explain missing heritability in smoking.

Author

Jang, Seon-Kyeong, Evans, Luke, Fialkowski, Allison, Arnett, Donna K, Ashley-Koch, Allison E, Barnes, Kathleen C, Becker, Diane M, Bis, Joshua C, Blangero, John, Bleecker, Eugene R, Boorgula, Meher Preethi, Bowden, Donald W, Brody, Jennifer A, Cade, Brian E, Jenkins, Brenda W Campbell, Carson, April P, Chavan, Sameer, Cupples, L Adrienne, Custer, Brian, Damrauer, Scott M, David, Sean P, de Andrade, Mariza, Dinardo, Carla L, Fingerlin, Tasha E, Fornage, Myriam, Freedman, Barry I, Garrett, Melanie E, Gharib, Sina A, Glahn, David C, Haessler, Jeffrey, Heckbert, Susan R, Hokanson, John E, Hou, Lifang, Hwang, Shih-Jen, Hyman, Matthew C, Judy, Renae, Justice, Anne E, Kaplan, Robert C, Kardia, Sharon LR, Kelly, Shannon, Kim, Wonji, Kooperberg, Charles, Levy, Daniel, Lloyd-Jones, Donald M, Loos, Ruth JF, Manichaikul, Ani W, Gladwin, Mark T, Martin, Lisa Warsinger, Nouraie, Mehdi, Melander, Olle, Meyers, Deborah A, Montgomery, Courtney G, North, Kari E, Oelsner, Elizabeth C, Palmer, Nicholette D, Payton, Marinelle, Peljto, Anna L, Peyser, Patricia A, Preuss, Michael, Psaty, Bruce M, Qiao, Dandi, Rader, Daniel J, Rafaels, Nicholas, Redline, Susan, Reed, Robert M, Reiner, Alexander P, Rich, Stephen S, Rotter, Jerome I, Schwartz, David A, Shadyab, Aladdin H, Silverman, Edwin K, Smith, Nicholas L, Smith, J Gustav, Smith, Albert V, Smith, Jennifer A, Tang, Weihong, Taylor, Kent D, Telen, Marilyn J, Vasan, Ramachandran S, Gordeuk, Victor R, Wang, Zhe, Wiggins, Kerri L, Yanek, Lisa R, Yang, Ivana V, Young, Kendra A, Young, Kristin L, Zhang, Yingze, Liu, Dajiang J, Keller, Matthew C, and Vrieze, Scott

Subjects
Smoking, Gene Frequency, Phenotype, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Tobacco, Genetics, Tobacco Smoke and Health, Human Genome, Cancer
Abstract

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.

Published
2022

8. Genetically increased circulating FUT3 level leads to reduced risk of idiopathic pulmonary fibrosis: a Mendelian randomisation study

Author

Nakanishi, Tomoko, Cerani, Agustin, Forgetta, Vincenzo, Zhou, Sirui, Allen, Richard J, Leavy, Olivia C, Koido, Masaru, Assayag, Deborah, Jenkins, R Gisli, Wain, Louise V, Yang, Ivana V, Lathrop, G Mark, Wolters, Paul J, Schwartz, David A, and Richards, J Brent

Subjects
Rare Diseases, Lung, Clinical Research, Genetics, Autoimmune Disease, Prevention, Aetiology, 2.1 Biological and endogenous factors, Fucosyltransferases, Genome-Wide Association Study, Humans, Idiopathic Pulmonary Fibrosis, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Medical and Health Sciences, Respiratory System
Abstract

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive, fatal fibrotic interstitial lung disease. Few circulating biomarkers have been identified to have causal effects on IPF.MethodsTo identify candidate IPF-influencing circulating proteins, we undertook an efficient screen of circulating proteins by applying a two-sample Mendelian randomisation (MR) approach with existing publicly available data. For instruments, we used genetic determinants of circulating proteins which reside cis to the encoded gene (cis-single nucleotide polymorphisms (SNPs)), identified by two genome-wide association studies (GWASs) in European individuals (3301 and 3200 subjects). We then applied MR methods to test if the levels of these circulating proteins influenced IPF susceptibility in the largest IPF GWAS (2668 cases and 8591 controls). We validated the MR results using colocalisation analyses to ensure that both the circulating proteins and IPF shared a common genetic signal.ResultsMR analyses of 834 proteins found that a 1 sd increase in circulating galactoside 3(4)-l-fucosyltransferase (FUT3) and α-(1,3)-fucosyltransferase 5 (FUT5) was associated with a reduced risk of IPF (OR 0.81, 95% CI 0.74-0.88; p=6.3×10-7 and OR 0.76, 95% CI 0.68-0.86; p=1.1×10-5, respectively). Sensitivity analyses including multiple cis-SNPs provided similar estimates both for FUT3 (inverse variance weighted (IVW) OR 0.84, 95% CI 0.78-0.91; p=9.8×10-6 and MR-Egger OR 0.69, 95% CI 0.50-0.97; p=0.03) and FUT5 (IVW OR 0.84, 95% CI 0.77-0.92; p=1.4×10-4 and MR-Egger OR 0.59, 95% CI 0.38-0.90; p=0.01). FUT3 and FUT5 signals colocalised with IPF signals, with posterior probabilities of a shared genetic signal of 99.9% and 97.7%, respectively. Further transcriptomic investigations supported the protective effects of FUT3 for IPF.ConclusionsAn efficient MR scan of 834 circulating proteins provided evidence that genetically increased circulating FUT3 level is associated with reduced risk of IPF.

Published
2022

9. Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Author

Taub, Margaret A, Conomos, Matthew P, Keener, Rebecca, Iyer, Kruthika R, Weinstock, Joshua S, Yanek, Lisa R, Lane, John, Miller-Fleming, Tyne W, Brody, Jennifer A, Raffield, Laura M, McHugh, Caitlin P, Jain, Deepti, Gogarten, Stephanie M, Laurie, Cecelia A, Keramati, Ali, Arvanitis, Marios, Smith, Albert V, Heavner, Benjamin, Barwick, Lucas, Becker, Lewis C, Bis, Joshua C, Blangero, John, Bleecker, Eugene R, Burchard, Esteban G, Celedón, Juan C, Chang, Yen Pei C, Custer, Brian, Darbar, Dawood, de las Fuentes, Lisa, DeMeo, Dawn L, Freedman, Barry I, Garrett, Melanie E, Gladwin, Mark T, Heckbert, Susan R, Hidalgo, Bertha A, Irvin, Marguerite R, Islam, Talat, Johnson, W Craig, Kaab, Stefan, Launer, Lenore, Lee, Jiwon, Liu, Simin, Moscati, Arden, North, Kari E, Peyser, Patricia A, Rafaels, Nicholas, Seidman, Christine, Weeks, Daniel E, Wen, Fayun, Wheeler, Marsha M, Williams, L Keoki, Yang, Ivana V, Zhao, Wei, Aslibekyan, Stella, Auer, Paul L, Bowden, Donald W, Cade, Brian E, Chen, Zhanghua, Cho, Michael H, Cupples, L Adrienne, Curran, Joanne E, Daya, Michelle, Deka, Ranjan, Eng, Celeste, Fingerlin, Tasha E, Guo, Xiuqing, Hou, Lifang, Hwang, Shih-Jen, Johnsen, Jill M, Kenny, Eimear E, Levin, Albert M, Liu, Chunyu, Minster, Ryan L, Naseri, Take, Nouraie, Mehdi, Reupena, Muagututi A Sefuiva, Sabino, Ester C, Smith, Jennifer A, Smith, Nicholas L, Lasky-Su, Jessica, Taylor, James G, Telen, Marilyn J, Tiwari, Hemant K, Tracy, Russell P, White, Marquitta J, Zhang, Yingze, Wiggins, Kerri L, Weiss, Scott T, Vasan, Ramachandran S, Taylor, Kent D, Sinner, Moritz F, Silverman, Edwin K, Shoemaker, M Benjamin, Sheu, Wayne H-H, Sciurba, Frank, Schwartz, David A, Rotter, Jerome I, Roden, Daniel, Redline, Susan, and Raby, Benjamin A

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Generic health relevance, Good Health and Well Being, NHLBI CARE Network, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology and Hemostasis Working Group, TOPMed Structural Variation Working Group
Abstract

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value

Published
2022

11. Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude

Author

Kadalayil, Latha, Alam, Md. Zahangir, White, Cory Haley, Ghantous, Akram, Walton, Esther, Gruzieva, Olena, Merid, Simon Kebede, Kumar, Ashish, Roy, Ritu P., Solomon, Olivia, Huen, Karen, Eskenazi, Brenda, Rzehak, Peter, Grote, Veit, Langhendries, Jean-Paul, Verduci, Elvira, Ferre, Natalia, Gruszfeld, Darek, Gao, Lu, Guan, Weihua, Zeng, Xuehuo, Schisterman, Enrique F., Dou, John F., Bakulski, Kelly M., Feinberg, Jason I., Soomro, Munawar Hussain, Pesce, Giancarlo, Baiz, Nour, Isaevska, Elena, Plusquin, Michelle, Vafeiadi, Marina, Roumeliotaki, Theano, Langie, Sabine A. S., Standaert, Arnout, Allard, Catherine, Perron, Patrice, Bouchard, Luigi, van Meel, Evelien R., Felix, Janine F., Jaddoe, Vincent W. V., Yousefi, Paul D., Ramlau-Hansen, Cecilia H., Relton, Caroline L., Tobi, Elmar W., Starling, Anne P., Yang, Ivana V., Llambrich, Maria, Santorelli, Gillian, Lepeule, Johanna, Salas, Lucas A., Bustamante, Mariona, Ewart, Susan L., Zhang, Hongmei, Karmaus, Wilfried, Röder, Stefan, Zenclussen, Ana Claudia, Jin, Jianping, Nystad, Wenche, Page, Christian M., Magnus, Maria, Jima, Dereje D., Hoyo, Cathrine, Maguire, Rachel L., Kvist, Tuomas, Czamara, Darina, Räikkönen, Katri, Gong, Tong, Ullemar, Vilhelmina, Rifas-Shiman, Sheryl L., Oken, Emily, Almqvist, Catarina, Karlsson, Robert, Lahti, Jari, Murphy, Susan K., Håberg, Siri E., London, Stephanie, Herberth, Gunda, Arshad, Hasan, Sunyer, Jordi, Grazuleviciene, Regina, Dabelea, Dana, Steegers-Theunissen, Régine P. M., Nohr, Ellen A., Sørensen, Thorkild I. A., Duijts, Liesbeth, Hivert, Marie-France, Nelen, Vera, Popovic, Maja, Kogevinas, Manolis, Nawrot, Tim S., Herceg, Zdenko, Annesi-Maesano, Isabella, Fallin, M. Daniele, Yeung, Edwina, Breton, Carrie V., Koletzko, Berthold, Holland, Nina, Wiemels, Joseph L., Melén, Erik, Sharp, Gemma C., Silver, Matt J., Rezwan, Faisal I., and Holloway, John W.

Published
2023
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13. Genetically increased circulating FUT3 level leads to reduced risk of Idiopathic Pulmonary Fibrosis: a Mendelian Randomisation Study.

Author

Nakanishi, Tomoko, Cerani, Agustin, Forgetta, Vincenzo, Zhou, Sirui, Allen, Richard J, Leavy, Olivia C, Koido, Masaru, Assayag, Deborah, Jenkins, R Gisli, Wain, Louise V, Yang, Ivana V, Lathrop, G Mark, Wolters, Paul J, Schwartz, David A, and Richards, J Brent

Subjects
Respiratory System, Medical and Health Sciences
Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal fibrotic interstitial lung disease. Few circulating biomarkers have been identified to have causal effects on IPF.To identify candidate IPF-influencing circulating proteins, we undertook an efficient screen of circulating proteins by applying a two-sample Mendelian randomisation (MR) approach with existing publicly available data. For instruments we used genetic determinants of circulating proteins which reside cis to the encoded gene (cis-SNPs), identified by two genome-wide association studies (GWASs) in European individuals (3301 and 3200 subjects). We then applied MR methods to test if the levels of these circulating proteins influenced IPF susceptibility in the largest IPF GWAS (2668 cases and 8591 controls). We validated the MR results using colocalization analyses to ensure that both the circulating proteins and IPF shared a common genetic signal.MR analyses of 834 proteins found that a one sd increase in circulating FUT3 and FUT5 was associated with a reduced risk of IPF (OR: 0.81, 95%CI: 0.74-0.88, p=6.3×10-7, and OR: 0.76, 95%CI: 0.68-0.86, p=1.1×10-5). Sensitivity analyses including multiple-cis SNPs provided similar estimates both for FUT3 (inverse variance weighted [IVW] OR: 0.84, 95%CI: 0.78-0.91, p=9.8×10-6, MR-Egger OR: 0.69, 95%CI: 0.50-0.97, p=0.03) and FUT5 (IVW OR: 0.84, 95%CI: 0.77-0.92, p=1.4×10-4, MR-Egger OR: 0.59, 95%CI: 0.38-0.90, p=0.01) FUT3 and FUT5 signals colocalized with IPF signals, with posterior probabilities of a shared genetic signal of 99.9% and 97.7%. Further transcriptomic investigations supported the protective effects of FUT3 for IPF.An efficient MR scan of 834 circulating proteins provided evidence that genetically increased circulating FUT3 level is associated with reduced risk of IPF.

Published
2021

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

Author

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

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Human Genome, Emerging Infectious Diseases, Prevention, Lung, Vaccine Related, Biodefense, Clinical Research, Infectious Diseases, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Infection, Good Health and Well Being, Pneumonia & Influenza, Predictive markers, Viral infection
Abstract

BackgroundSince the onset of the SARS-CoV-2 pandemic, most clinical testing has focused on RT-PCR1. Host epigenome manipulation post coronavirus infection2-4 suggests that DNA methylation signatures may differentiate patients with SARS-CoV-2 infection from uninfected individuals, and help predict COVID-19 disease severity, even at initial presentation.MethodsWe customized Illumina's Infinium MethylationEPIC array to enhance immune response detection and profiled peripheral blood samples from 164 COVID-19 patients with longitudinal measurements of disease severity and 296 patient controls.ResultsEpigenome-wide association analysis revealed 13,033 genome-wide significant methylation sites for case-vs-control status. Genes and pathways involved in interferon signaling and viral response were significantly enriched among differentially methylated sites. We observe highly significant associations at genes previously reported in genetic association studies (e.g. IRF7, OAS1). Using machine learning techniques, models built using sparse regression yielded highly predictive findings: cross-validated best fit AUC was 93.6% for case-vs-control status, and 79.1%, 80.8%, and 84.4% for hospitalization, ICU admission, and progression to death, respectively.ConclusionsIn summary, the strong COVID-19-specific epigenetic signature in peripheral blood driven by key immune-related pathways related to infection status, disease severity, and clinical deterioration provides insights useful for diagnosis and prognosis of patients with viral infections.

Published
2021

16. DNA methylation and body mass index from birth to adolescence: meta-analyses of epigenome-wide association studies

Author

Vehmeijer, Florianne OL, Küpers, Leanne K, Sharp, Gemma C, Salas, Lucas A, Lent, Samantha, Jima, Dereje D, Tindula, Gwen, Reese, Sarah, Qi, Cancan, Gruzieva, Olena, Page, Christian, Rezwan, Faisal I, Melton, Philip E, Nohr, Ellen, Escaramís, Geòrgia, Rzehak, Peter, Heiskala, Anni, Gong, Tong, Tuominen, Samuli T, Gao, Lu, Ross, Jason P, Starling, Anne P, Holloway, John W, Yousefi, Paul, Aasvang, Gunn Marit, Beilin, Lawrence J, Bergström, Anna, Binder, Elisabeth, Chatzi, Leda, Corpeleijn, Eva, Czamara, Darina, Eskenazi, Brenda, Ewart, Susan, Ferre, Natalia, Grote, Veit, Gruszfeld, Dariusz, Håberg, Siri E, Hoyo, Cathrine, Huen, Karen, Karlsson, Robert, Kull, Inger, Langhendries, Jean-Paul, Lepeule, Johanna, Magnus, Maria C, Maguire, Rachel L, Molloy, Peter L, Monnereau, Claire, Mori, Trevor A, Oken, Emily, Räikkönen, Katri, Rifas-Shiman, Sheryl, Ruiz-Arenas, Carlos, Sebert, Sylvain, Ullemar, Vilhelmina, Verduci, Elvira, Vonk, Judith M, Xu, Cheng-jian, Yang, Ivana V, Zhang, Hongmei, Zhang, Weiming, Karmaus, Wilfried, Dabelea, Dana, Muhlhausler, Beverly S, Breton, Carrie V, Lahti, Jari, Almqvist, Catarina, Jarvelin, Marjo-Riitta, Koletzko, Berthold, Vrijheid, Martine, Sørensen, Thorkild IA, Huang, Rae-Chi, Arshad, Syed Hasan, Nystad, Wenche, Melén, Erik, Koppelman, Gerard H, London, Stephanie J, Holland, Nina, Bustamante, Mariona, Murphy, Susan K, Hivert, Marie-France, Baccarelli, Andrea, Relton, Caroline L, Snieder, Harold, Jaddoe, Vincent WV, and Felix, Janine F

Subjects
Biological Sciences, Genetics, Prevention, Clinical Research, Human Genome, Nutrition, Childhood Obesity, Obesity, Pediatric, 2.1 Biological and endogenous factors, Metabolic and endocrine, Cardiovascular, Cancer, Stroke, Oral and gastrointestinal, Adolescent, Body Mass Index, Child, Child, Preschool, CpG Islands, Cross-Sectional Studies, DNA Methylation, Epigenesis, Genetic, Epigenome, Female, Fetal Blood, Humans, Male, Parturition, Pediatric Obesity, Pregnancy, Body mass index, Childhood obesity, DNA methylation, Epigenetics, Clinical Sciences
Abstract

BackgroundDNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits.MethodsWe examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment.ResultsDNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P

Published
2020

17. Chronic Hypersensitivity Pneumonitis, an Interstitial Lung Disease with Distinct Molecular Signatures.

Author

Furusawa, Haruhiko, Cardwell, Jonathan H, Okamoto, Tsukasa, Walts, Avram D, Konigsberg, Iain R, Kurche, Jonathan S, Bang, Tami J, Schwarz, Marvin I, Brown, Kevin K, Kropski, Jonathan A, Rojas, Mauricio, Cool, Carlyne D, Lee, Joyce S, Wolters, Paul J, Yang, Ivana V, and Schwartz, David A

Subjects
Genetics, Infectious Diseases, Lung, Autoimmune Disease, Rare Diseases, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Respiratory, Adult, Aged, Aged, 80 and over, Alveolitis, Extrinsic Allergic, Female, Gene Expression, Gene Expression Profiling, Humans, Idiopathic Pulmonary Fibrosis, Lung Diseases, Interstitial, Male, Middle Aged, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, gene expression profiling, transcriptome, Chronic Hypersensitivity Pneumonitis, Idiopathic Pulmonary Fibrosis, gene transcriptome analysis, Medical and Health Sciences, Respiratory System
Abstract

Rationale: Chronic hypersensitivity pneumonitis (CHP) is caused by an immune response to antigen inhalation and is characterized by variable histopathological and clinical features. A subset of subjects with CHP have usual interstitial pneumonia and appear to be clinically similar to subjects with idiopathic pulmonary fibrosis (IPF).Objectives: To determine the common and unique molecular features of CHP and IPF.Methods: Transcriptome analysis of lung samples from CHP (n = 82), IPF (n = 103), and unaffected controls (n = 103) was conducted. Differential gene expression was determined adjusting for sex, race, age, and smoking history and using false discovery rate to control for multiple comparisons.Measurements and Main Results: When compared with controls, we identified 413 upregulated and 317 downregulated genes in CHP and 861 upregulated and 322 downregulated genes in IPF. Concordantly upregulated or downregulated genes in CHP and IPF were related to collagen catabolic processes and epithelial development, whereas genes specific to CHP (differentially expressed in CHP when compared with control and not differentially expressed in IPF) were related to chemokine-mediated signaling and immune responsiveness. Using weighted gene coexpression network analysis, we found that among subjects with CHP, genes involved in adaptive immunity or epithelial cell development were associated with improved or reduced lung function, respectively, and that MUC5B expression was associated with epithelial cell development. MUC5B expression was also associated with lung fibrosis and honeycombing.Conclusions: Gene expression analysis of CHP and IPF identified signatures common to CHP and IPF, as well as genes uniquely expressed in CHP. Select modules of gene expression are characterized by distinct clinical and pathological features of CHP.

Published
2020

18. Inherited causes of clonal haematopoiesis in 97,691 whole genomes

Author

Bick, Alexander G, Weinstock, Joshua S, Nandakumar, Satish K, Fulco, Charles P, Bao, Erik L, Zekavat, Seyedeh M, Szeto, Mindy D, Liao, Xiaotian, Leventhal, Matthew J, Nasser, Joseph, Chang, Kyle, Laurie, Cecelia, Burugula, Bala Bharathi, Gibson, Christopher J, Niroula, Abhishek, Lin, Amy E, Taub, Margaret A, Aguet, Francois, Ardlie, Kristin, Mitchell, Braxton D, Barnes, Kathleen C, Moscati, Arden, Fornage, Myriam, Redline, Susan, Psaty, Bruce M, Silverman, Edwin K, Weiss, Scott T, Palmer, Nicholette D, Vasan, Ramachandran S, Burchard, Esteban G, Kardia, Sharon LR, He, Jiang, Kaplan, Robert C, Smith, Nicholas L, Arnett, Donna K, Schwartz, David A, Correa, Adolfo, de Andrade, Mariza, Guo, Xiuqing, Konkle, Barbara A, Custer, Brian, Peralta, Juan M, Gui, Hongsheng, Meyers, Deborah A, McGarvey, Stephen T, Chen, Ida Yii-Der, Shoemaker, M Benjamin, Peyser, Patricia A, Broome, Jai G, Gogarten, Stephanie M, Wang, Fei Fei, Wong, Quenna, Montasser, May E, Daya, Michelle, Kenny, Eimear E, North, Kari E, Launer, Lenore J, Cade, Brian E, Bis, Joshua C, Cho, Michael H, Lasky-Su, Jessica, Bowden, Donald W, Cupples, L Adrienne, Mak, Angel CY, Becker, Lewis C, Smith, Jennifer A, Kelly, Tanika N, Aslibekyan, Stella, Heckbert, Susan R, Tiwari, Hemant K, Yang, Ivana V, Heit, John A, Lubitz, Steven A, Johnsen, Jill M, Curran, Joanne E, Wenzel, Sally E, Weeks, Daniel E, Rao, Dabeeru C, Darbar, Dawood, Moon, Jee-Young, Tracy, Russell P, Buth, Erin J, Rafaels, Nicholas, Loos, Ruth JF, Durda, Peter, Liu, Yongmei, Hou, Lifang, Lee, Jiwon, Kachroo, Priyadarshini, Freedman, Barry I, Levy, Daniel, Bielak, Lawrence F, Hixson, James E, Floyd, James S, Whitsel, Eric A, Ellinor, Patrick T, Irvin, Marguerite R, Fingerlin, Tasha E, Raffield, Laura M, and Armasu, Sebastian M

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Regenerative Medicine, Hematology, Stem Cell Research - Nonembryonic - Non-Human, Stem Cell Research, Precision Medicine, Human Genome, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Inflammatory and immune system, Cardiovascular, Good Health and Well Being, Adult, Africa, Aged, Aged, 80 and over, Black People, Cell Self Renewal, Clonal Hematopoiesis, DNA-Binding Proteins, Dioxygenases, Female, Genetic Predisposition to Disease, Genome, Human, Germ-Line Mutation, Hematopoietic Stem Cells, Humans, Intracellular Signaling Peptides and Proteins, Male, Middle Aged, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Proto-Oncogene Proteins, Tripartite Motif Proteins, United States, Whole Genome Sequencing, alpha Karyopherins, Black or African American, NHLBI Trans-Omics for Precision Medicine Consortium, General Science & Technology
Abstract

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2-4 and coronary heart disease5-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

Published
2020

19. Erratum: 'Prenatal Exposure to per- and Polyfluoroalkyl Substances, Umbilical Cord Blood DNA Methylation, and Cardio-Metabolic Indicators in Newborns: The Healthy Start Study'

Author

Starling, Anne P., Liu, Cuining, Shen, Guannan, Yang, Ivana V., Kechris, Katerina, Borengasser, Sarah J., Boyle, Kristen E., Zhang, Weiming, Smith, Harry A., Calafat, Antonia M., Hamman, Richard F., Adgate, John L., and Dabelea, Dana

Subjects
DNA -- Research, Genetic research, Methylation -- Research, Pregnant women -- Research, Infants (Newborn) -- Research, Environmental issues, Health
Abstract

The published article contained errors in the descriptive reporting of the number of per- and polyfluoroalkyl substances (PFAS) concentrations that were below the method limit of detection (LOD; 0.1 ng/mL) [...]

Published
2023
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20. Resequencing Study Confirms That Host Defense and Cell Senescence Gene Variants Contribute to the Risk of Idiopathic Pulmonary Fibrosis

Author

Moore, Camille, Blumhagen, Rachel Z, Yang, Ivana V, Walts, Avram, Powers, Julie, Walker, Tarik, Bishop, Makenna, Russell, Pamela, Vestal, Brian, Cardwell, Jonathan, Markin, Cheryl R, Mathai, Susan K, Schwarz, Marvin I, Steele, Mark P, Lee, Joyce, Brown, Kevin K, Loyd, James E, Crapo, James D, Silverman, Edwin K, Cho, Michael H, James, Judith A, Guthridge, Joel M, Cogan, Joy D, Kropski, Jonathan A, Swigris, Jeffrey J, Bair, Carol, Kim, Dong Soon, Ji, Wonjun, Kim, Hocheol, Song, Jin Woo, Maier, Lisa A, Pacheco, Karin A, Hirani, Nikhil, Poon, Azin S, Li, Feng, Jenkins, R Gisli, Braybrooke, Rebecca, Saini, Gauri, Maher, Toby M, Molyneaux, Philip L, Saunders, Peter, Zhang, Yingze, Gibson, Kevin F, Kass, Daniel J, Rojas, Mauricio, Sembrat, John, Wolters, Paul J, Collard, Harold R, Sundy, John S, O’Riordan, Thomas, Strek, Mary E, Noth, Imre, Ma, Shwu-Fan, Porteous, Mary K, Kreider, Maryl E, Patel, Namrata B, Inoue, Yoshikazu, Hirose, Masaki, Arai, Toru, Akagawa, Shinobu, Eickelberg, Oliver, Fernandez, Isis Enlil, Behr, Jürgen, Mogulkoc, Nesrin, Corte, Tamera J, Glaspole, Ian, Tomassetti, Sara, Ravaglia, Claudia, Poletti, Venerino, Crestani, Bruno, Borie, Raphael, Kannengiesser, Caroline, Parfrey, Helen, Fiddler, Christine, Rassl, Doris, Molina-Molina, Maria, Machahua, Carlos, Worboys, Ana Montes, Gudmundsson, Gunnar, Isaksson, Helgi J, Lederer, David J, Podolanczuk, Anna J, Montesi, Sydney B, Bendstrup, Elisabeth, Danchel, Vivi, Selman, Moises, Pardo, Annie, Henry, Michael T, Keane, Michael P, Doran, Peter, Vašáková, Martina, Sterclova, Martina, Ryerson, Christopher J, Wilcox, Pearce G, Okamoto, Tsukasa, Furusawa, Haruhiko, Miyazaki, Yasunari, Laurent, Geoffrey, Baltic, Svetlana, and Prele, Cecilia

Subjects
Human Genome, Autoimmune Disease, Clinical Research, Lung, Genetics, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, ATP-Binding Cassette Transporters, Case-Control Studies, Cellular Senescence, DNA Helicases, Exoribonucleases, Female, GTPase-Activating Proteins, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, Host-Pathogen Interactions, Humans, Idiopathic Pulmonary Fibrosis, Logistic Models, Male, Mucin-5B, Promoter Regions, Genetic, Pulmonary Surfactant-Associated Protein A, Pulmonary Surfactant-Associated Protein C, RNA, Sequence Analysis, DNA, Telomerase, Telomere-Binding Proteins, targeted resequencing, idiopathic pulmonary fibrosis, genetic variants, rare variants, disease risk alleles, Medical and Health Sciences, Respiratory System
Abstract

Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 × 10-295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.

Published
2019

21. Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight.

Author

Küpers, Leanne K, Monnereau, Claire, Sharp, Gemma C, Yousefi, Paul, Salas, Lucas A, Ghantous, Akram, Page, Christian M, Reese, Sarah E, Wilcox, Allen J, Czamara, Darina, Starling, Anne P, Novoloaca, Alexei, Lent, Samantha, Roy, Ritu, Hoyo, Cathrine, Breton, Carrie V, Allard, Catherine, Just, Allan C, Bakulski, Kelly M, Holloway, John W, Everson, Todd M, Xu, Cheng-Jian, Huang, Rae-Chi, van der Plaat, Diana A, Wielscher, Matthias, Merid, Simon Kebede, Ullemar, Vilhelmina, Rezwan, Faisal I, Lahti, Jari, van Dongen, Jenny, Langie, Sabine AS, Richardson, Tom G, Magnus, Maria C, Nohr, Ellen A, Xu, Zongli, Duijts, Liesbeth, Zhao, Shanshan, Zhang, Weiming, Plusquin, Michelle, DeMeo, Dawn L, Solomon, Olivia, Heimovaara, Joosje H, Jima, Dereje D, Gao, Lu, Bustamante, Mariona, Perron, Patrice, Wright, Robert O, Hertz-Picciotto, Irva, Zhang, Hongmei, Karagas, Margaret R, Gehring, Ulrike, Marsit, Carmen J, Beilin, Lawrence J, Vonk, Judith M, Jarvelin, Marjo-Riitta, Bergström, Anna, Örtqvist, Anne K, Ewart, Susan, Villa, Pia M, Moore, Sophie E, Willemsen, Gonneke, Standaert, Arnout RL, Håberg, Siri E, Sørensen, Thorkild IA, Taylor, Jack A, Räikkönen, Katri, Yang, Ivana V, Kechris, Katerina, Nawrot, Tim S, Silver, Matt J, Gong, Yun Yun, Richiardi, Lorenzo, Kogevinas, Manolis, Litonjua, Augusto A, Eskenazi, Brenda, Huen, Karen, Mbarek, Hamdi, Maguire, Rachel L, Dwyer, Terence, Vrijheid, Martine, Bouchard, Luigi, Baccarelli, Andrea A, Croen, Lisa A, Karmaus, Wilfried, Anderson, Denise, de Vries, Maaike, Sebert, Sylvain, Kere, Juha, Karlsson, Robert, Arshad, Syed Hasan, Hämäläinen, Esa, Routledge, Michael N, Boomsma, Dorret I, Feinberg, Andrew P, Newschaffer, Craig J, Govarts, Eva, Moisse, Matthieu, Fallin, M Daniele, Melén, Erik, and Prentice, Andrew M

Subjects
Fetus, Humans, Prenatal Exposure Delayed Effects, Birth Weight, Folic Acid, DNA, Body Mass Index, Smoking, DNA Methylation, Epigenesis, Genetic, CpG Islands, Fetal Development, Pregnancy, Genome, Human, Adolescent, Adult, Child, Infant, Newborn, Female, Male, Genome-Wide Association Study, Epigenesis, Genetic, Genome, Human, Infant, Newborn
Abstract

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni

Published
2019

24. Longitudinal changes in DNA methylation during the onset of islet autoimmunity differentiate between reversion versus progression of islet autoimmunity

Author

Carry, Patrick M., primary, Vanderlinden, Lauren A., additional, Johnson, Randi K., additional, Buckner, Teresa, additional, Steck, Andrea K., additional, Kechris, Katerina, additional, Yang, Ivana V., additional, Fingerlin, Tasha E., additional, Fiehn, Oliver, additional, Rewers, Marian, additional, and Norris, Jill M., additional

Published
2024
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27. Small-Magnitude Effect Sizes in Epigenetic End Points are Important in Children’s Environmental Health Studies: The Children’s Environmental Health and Disease Prevention Research Center’s Epigenetics Working Group

Author

Breton, Carrie V, Marsit, Carmen J, Faustman, Elaine, Nadeau, Kari, Goodrich, Jaclyn M, Dolinoy, Dana C, Herbstman, Julie, Holland, Nina, LaSalle, Janine M, Schmidt, Rebecca, Yousefi, Paul, Perera, Frederica, Joubert, Bonnie R, Wiemels, Joseph, Taylor, Michele, Yang, Ivana V, Chen, Rui, Hew, Kinjal M, Freeland, Deborah M Hussey, Miller, Rachel, and Murphy, Susan K

Subjects
Public Health, Health Sciences, Genetics, Prevention, Human Genome, Pediatric, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, Good Health and Well Being, Child, Child Health, Child Welfare, DNA Methylation, Environmental Exposure, Environmental Health, Epigenesis, Genetic, Epigenomics, Female, Group Processes, Humans, Longitudinal Studies, Pregnancy, Research, Environmental Sciences, Medical and Health Sciences, Toxicology, Biomedical and clinical sciences, Environmental sciences, Health sciences
Abstract

BackgroundCharacterization of the epigenome is a primary interest for children's environmental health researchers studying the environmental influences on human populations, particularly those studying the role of pregnancy and early-life exposures on later-in-life health outcomes.ObjectivesOur objective was to consider the state of the science in environmental epigenetics research and to focus on DNA methylation and the collective observations of many studies being conducted within the Children's Environmental Health and Disease Prevention Research Centers, as they relate to the Developmental Origins of Health and Disease (DOHaD) hypothesis.MethodsWe address the current laboratory and statistical tools available for epigenetic analyses, discuss methods for validation and interpretation of findings, particularly when magnitudes of effect are small, question the functional relevance of findings, and discuss the future for environmental epigenetics research.DiscussionA common finding in environmental epigenetic studies is the small-magnitude epigenetic effect sizes that result from such exposures. Although it is reasonable and necessary that we question the relevance of such small effects, we present examples in which small effects persist and have been replicated across populations and across time. We encourage a critical discourse on the interpretation of such small changes and further research on their functional relevance for children's health.ConclusionThe dynamic nature of the epigenome will require an emphasis on future longitudinal studies in which the epigenome is profiled over time, over changing environmental exposures, and over generations to better understand the multiple ways in which the epigenome may respond to environmental stimuli.

Published
2017

31. MUC5B Idiopathic Pulmonary Fibrosis Risk Variant Promotes a Mucosecretory Phenotype and Loss of Small Airway Secretory Cells.

Author

Kurche, Jonathan S., Cool, Carlyne D., Blumhagen, Rachel Z., Dobrinskikh, Evgenia, Heinz, David, Herrera, Jeremy A., Yang, Ivana V., and Schwartz, David A.

Subjects
PHENOTYPES, METHACHOLINE chloride, PULMONARY fibrosis, CELL differentiation, AIRWAY (Anatomy), IDIOPATHIC pulmonary fibrosis
Abstract

The article discusses a study on how the MUC5B variant influences idiopathic pulmonary fibrosis (IPF) using a spatial gene expression approach. Topics include the dominant risk factor for the development of IPF, analysis of specimens, and implication of the loss of small airway secretory cells (SASC) markers in small airways of MUC5B variant carriers.

Published
2024
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32. Nasal DNA methylation profiling of asthma and rhinitis

Author

Qi, Cancan, Jiang, Yale, Yang, Ivana V., Forno, Erick, Wang, Ting, Vonk, Judith M., Gehring, Ulrike, Smit, Henriëtte A., Milanzi, Edith B., Carpaij, Orestes A., Berg, Marijn, Hesse, Laura, Brouwer, Sharon, Cardwell, Jonathan, Vermeulen, Cornelis J., Acosta-Pérez, Edna, Canino, Glorisa, Boutaoui, Nadia, van den Berge, Maarten, Teichmann, Sarah A., Nawijn, Martijn C., Chen, Wei, Celedón, Juan C., Xu, Cheng-Jian, and Koppelman, Gerard H.

Published
2020
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33. Epigenetic timing effects on child developmental outcomes: A longitudinal meta-regression of findings from the Pregnancy And Childhood Epigenetics Consortium

Author

Neumann, Alexander, primary, Sammallahti, Sara, additional, Cosin-Tomas, Marta, additional, Reese, Sarah E, additional, Suderman, Matthew, additional, Alemany, Silvia, additional, Almqvist, Catarina, additional, Andrusaityte, Sandra, additional, Arshad, Syed H, additional, Bakermans-Kranenburg, Marian J, additional, Beilin, Lawrence, additional, Breton, Carrie, additional, Bustamante, Mariona, additional, Czamara, Darina, additional, Dabelea, Dana, additional, Eng, Celeste, additional, Eskenazi, Brenda, additional, Fuemmeler, Bernard F, additional, Gilliland, Frank D, additional, Grazuleviciene, Regina, additional, Håberg, Siri E, additional, Herberth, Gunda, additional, Holland, Nina, additional, Hough, Amy, additional, Hu, Donglei, additional, Huen, Karen, additional, Hüls, Anke, additional, Jin, Jianping, additional, Julvez, Jordi, additional, Koletzko, Berthold V, additional, Koppelman, Gerard H, additional, Kull, Inger, additional, Lu, Xueling, additional, Maitre, Léa, additional, Mason, Dan, additional, Mélen, Erik, additional, Merid, Simon K, additional, Molloy, Peter L, additional, Mori, Trevor A, additional, Mulder, Rosa H, additional, Page, Christian M, additional, Richmond, Rebecca C, additional, Roder, Stefan, additional, Ross, Jason P, additional, Schellhas, Laura, additional, Sebert, Sylvain, additional, Sheppard, Dean, additional, Snieder, Harold, additional, Starling, Anne P, additional, Stein, Dan J, additional, Tindula, Gwen, additional, van IJzendoorn, Marinus H, additional, Vonk, Judith, additional, Walton, Esther, additional, Witonsky, Jonathan, additional, Xu, Cheng-Jian, additional, Yang, Ivana V, additional, Yousefi, Paul D, additional, Zar, Heather J, additional, Zenclussen, Ana C, additional, Zhang, Hongmei, additional, Tiemeier, Henning, additional, London, Stephanie J, additional, Felix, Janine F, additional, and Cecil, Charlotte, additional

Published
2024
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34. Fast and accurate alignment of long bisulfite-seq reads

Author

Pedersen, Brent S., Eyring, Kenneth, De, Subhajyoti, Yang, Ivana V., and Schwartz, David A.

Subjects
Quantitative Biology - Genomics
Abstract

Summary: Longer sequencing reads, with at least 200 bases per template are now common. While traditional aligners have adopted new strategies to improve the mapping of longer reads, aligners specific to bisulfite-sequencing were optimized when much shorter reads were the norm. We sought to perform the first comparison using longer reads to determine which aligners were most accurate and efficient and to evaluate a novel software tool, bwa-meth, built on a traditional mapper that supports insertions, deletions and clipped alignments. We gauge accuracy by comparing the number of on and off-target reads from a targeted sequencing project and by simulations. Availability and Implementation: The benchmarking scripts and the bwa-meth software are available at https://github/com/brentp/bwa-meth/ under the MIT License.

Published
2014

36. CruzDB: software for annotation of genomic intervals with UCSC genome-browser data

Author

Pedersen, Brent S, Yang, Ivana V, and De, Subhajyoti

Subjects
Quantitative Biology - Genomics
Abstract

The biological significance of genomic features is often context-dependent. We present CruzDB, a fast and intuitive programmatic interface to the UCSC genome browser that facilitates integrative analyses of diverse local and remotely hosted datasets. We showcase the syntax of CruzDB using miRNA-binding sites as examples, and further demonstrate its utility with 3 novel biological discoveries. First, we find that while exons replicate early, introns tend to replicate late, suggesting a complex replication pattern in gene regions. Second, variants associated with cognitive functions map to lincRNA transcripts of relevant function. Third, lamina-associated domains are highly enriched in olfaction-related genes. CruzDB is available at https://github.com/brentp/cruzdb, Comment: 4 pages, 1 figure

Published
2013

38. Epigenome-wide meta-analysis of DNA methylation and childhood asthma

Author

Reese, Sarah E., Xu, Cheng-Jian, den Dekker, Herman T., Lee, Mi Kyeong, Sikdar, Sinjini, Ruiz-Arenas, Carlos, Merid, Simon K., Rezwan, Faisal I., Page, Christian M., Ullemar, Vilhelmina, Melton, Phillip E., Oh, Sam S., Yang, Ivana V., Burrows, Kimberley, Söderhäll, Cilla, Jima, Dereje D., Gao, Lu, Arathimos, Ryan, Küpers, Leanne K., Wielscher, Matthias, Rzehak, Peter, Lahti, Jari, Laprise, Catherine, Madore, Anne-Marie, Ward, James, Bennett, Brian D., Wang, Tianyuan, Bell, Douglas A., Vonk, Judith M., Håberg, Siri E., Zhao, Shanshan, Karlsson, Robert, Hollams, Elysia, Hu, Donglei, Richards, Adam J., Bergström, Anna, Sharp, Gemma C., Felix, Janine F., Bustamante, Mariona, Gruzieva, Olena, Maguire, Rachel L., Gilliland, Frank, Baïz, Nour, Nohr, Ellen A., Corpeleijn, Eva, Sebert, Sylvain, Karmaus, Wilfried, Grote, Veit, Kajantie, Eero, Magnus, Maria C., Örtqvist, Anne K., Eng, Celeste, Liu, Andrew H., Kull, Inger, Jaddoe, Vincent W.V., Sunyer, Jordi, Kere, Juha, Hoyo, Cathrine, Annesi-Maesano, Isabella, Arshad, Syed Hasan, Koletzko, Berthold, Brunekreef, Bert, Binder, Elisabeth B., Räikkönen, Katri, Reischl, Eva, Holloway, John W., Jarvelin, Marjo-Riitta, Snieder, Harold, Kazmi, Nabila, Breton, Carrie V., Murphy, Susan K., Pershagen, Göran, Anto, Josep Maria, Relton, Caroline L., Schwartz, David A., Burchard, Esteban G., Huang, Rae-Chi, Nystad, Wenche, Almqvist, Catarina, Henderson, A. John, Melén, Erik, Duijts, Liesbeth, Koppelman, Gerard H., and London, Stephanie J.

Published
2019
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39. Maternal educational attainment in pregnancy and epigenome-wide DNA methylation changes in the offspring from birth until adolescence

Author

Choudhary, Priyanka, primary, Monasso, Giulietta S., additional, Karhunen, Ville, additional, Ronkainen, Justiina, additional, Mancano, Giulia, additional, Howe, Caitlin G., additional, Niu, Zhongzheng, additional, Zeng, Xuehuo, additional, Guan, Weihua, additional, Dou, John, additional, Feinberg, Jason I., additional, Mordaunt, Charles, additional, Pesce, Giancarlo, additional, Baïz, Nour, additional, Alfano, Rossella, additional, Martens, Dries S., additional, Wang, Congrong, additional, Isaevska, Elena, additional, Keikkala, Elina, additional, Mustaniemi, Sanna, additional, Thio, Chris H. L., additional, Fraszczyk, Eliza, additional, Tobi, Elmar W., additional, Starling, Anne P., additional, Cosin-Tomas, Marta, additional, Urquiza, Jose, additional, Röder, Stefan, additional, Hoang, Thanh T., additional, Page, Christian, additional, Jima, Dereje D., additional, House, John S., additional, Maguire, Rachel L., additional, Ott, Raffael, additional, Pawlow, Xenia, additional, Sirignano, Lea, additional, Zillich, Lea, additional, Malmberg, Anni, additional, Rauschert, Sebastian, additional, Melton, Phillip, additional, Gong, Tong, additional, Karlsson, Robert, additional, Fore, Ruby, additional, Perng, Wei, additional, Laubach, Zachary M., additional, Czamara, Darina, additional, Sharp, Gemma, additional, Breton, Carrie V., additional, Schisterman, Enrique, additional, Yeung, Edwina, additional, Mumford, Sunni L., additional, Fallin, M. Daniele, additional, LaSalle, Janine M., additional, Schmidt, Rebecca J., additional, Bakulski, Kelly M., additional, Annesi-Maesano, Isabella, additional, Heude, Barbara, additional, Nawrot, Tim S., additional, Plusquin, Michelle, additional, Ghantous, Akram, additional, Herceg, Zdenko, additional, Nisticò, Lorenza, additional, Vafeiadi, Marina, additional, Kogevinas, Manolis, additional, Vääräsmäki, Marja, additional, Kajantie, Eero, additional, Snieder, Harold, additional, Corpeleijn, Eva, additional, Steegers-Theunissen, Regine P. M., additional, Yang, Ivana V., additional, Dabelea, Dana, additional, Fossati, Serena, additional, Zenclussen, Ana C., additional, Herberth, Gunda, additional, Magnus, Maria, additional, Håberg, Siri E., additional, London, Stephanie J., additional, Munthe-Kaas, Monica Cheng, additional, Murphy, Susan K., additional, Hoyo, Cathrine, additional, Ziegler, Anette-G, additional, Hummel, Sandra, additional, Witt, Stephanie H., additional, Streit, Fabian, additional, Frank, Josef, additional, Räikkönen, Katri, additional, Lahti, Jari, additional, Huang, Rae-chi, additional, Almqvist, Catarina, additional, Hivert, Marie-France, additional, Jaddoe, Vincent W. V., additional, Järvelin, Marjo-Riitta, additional, Kantomaa, Marko, additional, Felix, Janine F., additional, and Sebert, Sylvain, additional

Published
2023
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40. FUT2 Variants Confer Susceptibility to Familial Otitis Media

Author

Santos-Cortez, Regie Lyn P., Chiong, Charlotte M., Frank, Daniel N., Ryan, Allen F., Giese, Arnaud P.J., Bootpetch Roberts, Tori, Daly, Kathleen A., Steritz, Matthew J., Szeremeta, Wasyl, Pedro, Melquiadesa, Pine, Harold, Yarza, Talitha Karisse L., Scholes, Melissa A., Llanes, Erasmo Gonzalo d.V., Yousaf, Saira, Friedman, Norman, Tantoco, Ma. Leah C., Wine, Todd M., Labra, Patrick John, Benoit, Jeanne, Ruiz, Amanda G., de la Cruz, Rhodieleen Anne R., Greenlee, Christopher, Yousaf, Ayesha, Cardwell, Jonathan, Nonato, Rachelle Marie A., Ray, Dylan, Ong, Kimberly Mae C., So, Edward, Robertson, Charles E., Dinwiddie, Jordyn, Lagrana-Villagracia, Sheryl Mae, Gubbels, Samuel P., Shaikh, Rehan S., Cass, Stephen P., Einarsdottir, Elisabet, Lee, Nanette R., Schwartz, David A., Gloria-Cruz, Teresa Luisa I., Bamshad, Michael J., Yang, Ivana V., Kere, Juha, Abes, Generoso T., Prager, Jeremy D., Riazuddin, Saima, Chan, Abner L., Yoon, Patricia J., Nickerson, Deborah A., Cutiongco-de la Paz, Eva Maria, Streubel, Sven-Olrik, Reyes-Quintos, Maria Rina T., Jenkins, Herman A., Mattila, Petri, Chan, Kenny H., Mohlke, Karen L., Leal, Suzanne M., Hafrén, Lena, Chonmaitree, Tasnee, Sale, Michele M., and Ahmed, Zubair M.

Published
2018
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42. Muc5b is required for airway defence

Author

Roy, Michelle G, Livraghi-Butrico, Alessandra, Fletcher, Ashley A, McElwee, Melissa M, Evans, Scott E, Boerner, Ryan M, Alexander, Samantha N, Bellinghausen, Lindsey K, Song, Alfred S, Petrova, Youlia M, Tuvim, Michael J, Adachi, Roberto, Romo, Irlanda, Bordt, Andrea S, Bowden, M Gabriela, Sisson, Joseph H, Woodruff, Prescott G, Thornton, David J, Rousseau, Karine, De la Garza, Maria M, Moghaddam, Seyed J, Karmouty-Quintana, Harry, Blackburn, Michael R, Drouin, Scott M, Davis, C William, Terrell, Kristy A, Grubb, Barbara R, O’Neal, Wanda K, Flores, Sonia C, Cota-Gomez, Adela, Lozupone, Catherine A, Donnelly, Jody M, Watson, Alan M, Hennessy, Corinne E, Keith, Rebecca C, Yang, Ivana V, Barthel, Lea, Henson, Peter M, Janssen, William J, Schwartz, David A, Boucher, Richard C, Dickey, Burton F, and Evans, Christopher M

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Lung, Rare Diseases, Infectious Diseases, Cystic Fibrosis, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Respiratory, Animals, Asthma, Bacterial Infections, Cilia, Ear, Middle, Female, Inflammation, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Mucin 5AC, Mucin-5B, Phagocytosis, Pulmonary Disease, Chronic Obstructive, Respiratory Mucosa, Staphylococcus aureus, Survival Analysis, General Science & Technology
Abstract

Respiratory surfaces are exposed to billions of particulates and pathogens daily. A protective mucus barrier traps and eliminates them through mucociliary clearance (MCC). However, excessive mucus contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases. MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus. Genetic variants are linked to diverse lung diseases, but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that mouse Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc5ac is dispensable. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus, and to inflammation that failed to resolve normally. Apoptotic macrophages accumulated, phagocytosis was impaired, and interleukin-23 (IL-23) production was reduced in Muc5b(-/-) mice. By contrast, in mice that transgenically overexpress Muc5b, macrophage functions improved. Existing dogma defines mucous phenotypes in asthma and chronic obstructive pulmonary disease (COPD) as driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%. By distinguishing a specific role for Muc5b in MCC, and by determining its impact on bacterial infections and inflammation in mice, our results provide a refined framework for designing targeted therapies to control mucin secretion and restore MCC.

Published
2014

45. Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study

Author

Allen, Richard J, Porte, Joanne, Braybrooke, Rebecca, Flores, Carlos, Fingerlin, Tasha E, Oldham, Justin M, Guillen-Guio, Beatriz, Ma, Shwu-Fan, Okamoto, Tsukasa, John, Alison E, Obeidat, Ma'en, Yang, Ivana V, Henry, Amanda, Hubbard, Richard B, Navaratnam, Vidya, Saini, Gauri, Thompson, Norma, Booth, Helen L, Hart, Simon P, Hill, Mike R, Hirani, Nik, Maher, Toby M, McAnulty, Robin J, Millar, Ann B, Molyneaux, Philip L, Parfrey, Helen, Rassl, Doris M, Whyte, Moira K B, Fahy, William A, Marshall, Richard P, Oballa, Eunice, Bossé, Yohan, Nickle, David C, Sin, Don D, Timens, Wim, Shrine, Nick, Sayers, Ian, Hall, Ian P, Noth, Imre, Schwartz, David A, Tobin, Martin D, Wain, Louise V, and Jenkins, R Gisli

Published
2017
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48. The nasal methylome and childhood atopic asthma

Author

Yang, Ivana V., Pedersen, Brent S., Liu, Andrew H., O'Connor, George T., Pillai, Dinesh, Kattan, Meyer, Misiak, Rana Tawil, Gruchalla, Rebecca, Szefler, Stanley J., Khurana Hershey, Gurjit K., Kercsmar, Carolyn, Richards, Adam, Stevens, Allen D., Kolakowski, Christena A., Makhija, Melanie, Sorkness, Christine A., Krouse, Rebecca Z., Visness, Cynthia, Davidson, Elizabeth J., Hennessy, Corinne E., Martin, Richard J., Togias, Alkis, Busse, William W., and Schwartz, David A.

Published
2017
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