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3,554 results on '"Hakonarson, Hakon"'

1. Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Author

Kentistou, Katherine, Kaisinger, Lena, Stankovic, Stasa, Vaudel, Marc, Mendes de Oliveira, Edson, Messina, Andrea, Walters, Robin, Liu, Xiaoxi, Busch, Alexander, Helgason, Hannes, Thompson, Deborah, Santoni, Federico, Petricek, Konstantin, Zouaghi, Yassine, Huang-Doran, Isabel, Gudbjartsson, Daniel, Bratland, Eirik, Lin, Kuang, Gardner, Eugene, Zhao, Yajie, Jia, Raina, Terao, Chikashi, Riggan, Marjorie, Bolla, Manjeet, Yazdanpanah, Mojgan, Yazdanpanah, Nahid, Bradfield, Jonathan, Broer, Linda, Campbell, Archie, Chasman, Daniel, Cousminer, Diana, Franceschini, Nora, Franke, Lude, Girotto, Giorgia, He, Chunyan, Järvelin, Marjo-Riitta, Joshi, Peter, Kamatani, Yoichiro, Karlsson, Robert, Luan, Jianan, Lunetta, Kathryn, Mägi, Reedik, Mangino, Massimo, Medland, Sarah, Meisinger, Christa, Noordam, Raymond, Nutile, Teresa, Concas, Maria, Polašek, Ozren, Porcu, Eleonora, Ring, Susan, Sala, Cinzia, Smith, Albert, Tanaka, Toshiko, van der Most, Peter, Vitart, Veronique, Wang, Carol, Willemsen, Gonneke, Zygmunt, Marek, Ahearn, Thomas, Andrulis, Irene, Anton-Culver, Hoda, Antoniou, Antonis, Auer, Paul, Barnes, Catriona, Beckmann, Matthias, Berrington de Gonzalez, Amy, Bogdanova, Natalia, Bojesen, Stig, Brenner, Hermann, Buring, Julie, Canzian, Federico, Chang-Claude, Jenny, Couch, Fergus, Cox, Angela, Crisponi, Laura, Czene, Kamila, Daly, Mary, Demerath, Ellen, Dennis, Joe, Devilee, Peter, De Vivo, Immaculata, Dörk, Thilo, Dunning, Alison, Dwek, Miriam, Eriksson, Johan, Fasching, Peter, Fernandez-Rhodes, Lindsay, Ferreli, Liana, Fletcher, Olivia, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José, González-Neira, Anna, Grallert, Harald, Guénel, Pascal, Haiman, Christopher, Hall, Per, Hamann, Ute, and Hakonarson, Hakon

Subjects
Humans, Female, Menarche, Puberty, Gene Frequency, Animals, Multifactorial Inheritance, Mice, Genome-Wide Association Study, Adolescent, Puberty, Precocious, Polymorphism, Single Nucleotide, Receptors, G-Protein-Coupled, Puberty, Delayed, Child
Abstract

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Published
2024

3. The Infection Rate of COVID-19 in Wuhan, China: Combined Analysis of Population Samples

Author

Qu, Hui-Qi, Cheng, Zhangkai Jason, Duan, Zhifeng, Tian, Lifeng, and Hakonarson, Hakon

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Public aspects of medicine, RA1-1270
Abstract

BackgroundThe coronavirus disease (COVID-19) pandemic began in Wuhan, China, in December 2019. Wuhan had a much higher mortality rate than the rest of China. However, a large number of asymptomatic infections in Wuhan may have never been diagnosed, contributing to an overestimated mortality rate. ObjectiveThis study aims to obtain an accurate estimate of infections in Wuhan using internet data. MethodsIn this study, we performed a combined analysis of the infection rate among evacuated foreign citizens to estimate the infection rate in Wuhan in late January and early February. ResultsBased on our analysis, the combined infection rate of the foreign evacuees was 0.013 (95% CI 0.008-0.022). Therefore, we estimate the number of infected people in Wuhan to be 143,000 (range 88,000-242,000), which is significantly higher than previous estimates. Our study indicates that a large number of infections in Wuhan were not diagnosed, which has resulted in an overestimated case fatality rate. ConclusionsIncreased awareness of the original infection rate of Wuhan is critical for proper public health measures at all levels, as well as to eliminate panic caused by overestimated mortality rates that may bias health policy actions by the authorities.

Published
2020
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5. Biliary atresia is associated with polygenic susceptibility in ciliogenesis and planar polarity effector genes

Author

Glessner, Joseph T, Ningappa, Mylarappa B, Ngo, Kim A, Zahid, Maliha, So, Juhoon, Higgs, Brandon W, Sleiman, Patrick MA, Narayanan, Tejaswini, Ranganathan, Sarangarajan, March, Michael, Prasadan, Krishna, Vaccaro, Courtney, Reyes-Mugica, Miguel, Velazquez, Jeremy, Salgado, Claudia M, Ebrahimkhani, Mo R, Schmitt, Lori, Rajasundaram, Dhivyaa, Paul, Morgan, Pellegrino, Renata, Gittes, George K, Li, Dong, Wang, Xiang, Billings, Jonathan, Squires, Robert, Ashokkumar, Chethan, Sharif, Khalid, Kelly, Deirdre, Dhawan, Anil, Horslen, Simon, Lo, Cecilia W, Shin, Donghun, Subramaniam, Shankar, Hakonarson, Hakon, and Sindhi, Rakesh

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Genetics, Digestive Diseases, Human Genome, Congenital Structural Anomalies, Prevention, Liver Disease, Infant Mortality, Pediatric, Rare Diseases, Perinatal Period - Conditions Originating in Perinatal Period, Chronic Liver Disease and Cirrhosis, Aetiology, 2.1 Biological and endogenous factors, Child, Animals, Mice, Humans, Biliary Atresia, Genome-Wide Association Study, Genetic Predisposition to Disease, Zebrafish, Canada, Ciliogenesis, Polygenic Susceptibility, Portal Vein, Tube Morphogenesis, Vascular Development, Public Health and Health Services, Gastroenterology & Hepatology, Clinical sciences
Abstract

Background & aimsBiliary atresia (BA) is poorly understood and leads to liver transplantation (LT), with the requirement for and associated risks of lifelong immunosuppression, in most children. We performed a genome-wide association study (GWAS) to determine the genetic basis of BA.MethodsWe performed a GWAS in 811 European BA cases treated with LT in US, Canadian and UK centers, and 4,654 genetically matched controls. Whole-genome sequencing of 100 cases evaluated synthetic association with rare variants. Functional studies included whole liver transcriptome analysis of 64 BA cases and perturbations in experimental models.ResultsA GWAS of common single nucleotide polymorphisms (SNPs), i.e. allele frequencies >1%, identified intronic SNPs rs6446628 in AFAP1 with genome-wide significance (p = 3.93E-8) and rs34599046 in TUSC3 at sub-threshold genome-wide significance (p = 1.34E-7), both supported by credible peaks of neighboring SNPs. Like other previously reported BA-associated genes, AFAP1 and TUSC3 are ciliogenesis and planar polarity effectors (CPLANE). In gene-set-based GWAS, BA was associated with 6,005 SNPs in 102 CPLANE genes (p = 5.84E-15). Compared with non-CPLANE genes, more CPLANE genes harbored rare variants (allele frequency

Published
2023

6. GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.

Author

Docherty, Anna, Mullins, Niamh, Ashley-Koch, Allison, Qin, Xuejun, Coleman, Jonathan, Shabalin, Andrey, Kang, JooEun, Murnyak, Balasz, Wendt, Frank, Adams, Mark, Campos, Adrian, DiBlasi, Emily, Fullerton, Janice, Kranzler, Henry, Bakian, Amanda, Monson, Eric, Rentería, Miguel, Walss-Bass, Consuelo, Andreassen, Ole, Behera, Chittaranjan, Bulik, Cynthia, Edenberg, Howard, Kessler, Ronald, Mann, J, Nurnberger, John, Pistis, Giorgio, Streit, Fabian, Ursano, Robert, Polimanti, Renato, Dennis, Michelle, Garrett, Melanie, Hair, Lauren, Harvey, Philip, Hauser, Elizabeth, Hauser, Michael, Huffman, Jennifer, Jacobson, Daniel, Madduri, Ravi, McMahon, Benjamin, Oslin, David, Trafton, Jodie, Awasthi, Swapnil, Berrettini, Wade, Bohus, Martin, Chang, Xiao, Chen, Hsi-Chung, Chen, Wei, Christensen, Erik, Crow, Scott, Duriez, Philibert, Edwards, Alexis, Fernández-Aranda, Fernando, Galfalvy, Hanga, Gandal, Michael, Gorwood, Philip, Guo, Yiran, Hafferty, Jonathan, Hakonarson, Hakon, Halmi, Katherine, Hishimoto, Akitoyo, Jain, Sonia, Jamain, Stéphane, Jiménez-Murcia, Susana, Johnson, Craig, Kaplan, Allan, Kaye, Walter, Keel, Pamela, Kennedy, James, Kim, Minsoo, Klump, Kelly, Levey, Daniel, Li, Dong, Liao, Shih-Cheng, Lieb, Klaus, Lilenfeld, Lisa, Marshall, Christian, Mitchell, James, Okazaki, Satoshi, Otsuka, Ikuo, Pinto, Dalila, Powers, Abigail, Ramoz, Nicolas, Ripke, Stephan, Roepke, Stefan, Rozanov, Vsevolod, Scherer, Stephen, Schmahl, Christian, Sokolowski, Marcus, Starnawska, Anna, Strober, Michael, Su, Mei-Hsin, Thornton, Laura, Treasure, Janet, Ware, Erin, Watson, Hunna, Witt, Stephanie, Woodside, D, Yilmaz, Zeynep, Zillich, Lea, and Adolfsson, Rolf

Subjects
Biological Markers, Depressive Disorders, Genetics, Schizophrenia Spectrum and Other Psychotic Disorders, Self-Harm, Suicide, Humans, Genome-Wide Association Study, Suicide, Attempted, Depressive Disorder, Major, Risk Factors, Suicidal Ideation, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Genetic Loci
Abstract

OBJECTIVE: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. METHODS: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. RESULTS: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values

Published
2023

7. Publisher Correction: Understanding the genetic complexity of puberty timing across the allele frequency spectrum

Author

Kentistou, Katherine A., Kaisinger, Lena R., Stankovic, Stasa, Vaudel, Marc, Mendes de Oliveira, Edson, Messina, Andrea, Walters, Robin G., Liu, Xiaoxi, Busch, Alexander S., Helgason, Hannes, Thompson, Deborah J., Santoni, Federico, Petricek, Konstantin M., Zouaghi, Yassine, Huang-Doran, Isabel, Gudbjartsson, Daniel F., Bratland, Eirik, Lin, Kuang, Gardner, Eugene J., Zhao, Yajie, Jia, Raina Y., Terao, Chikashi, Riggan, Marjorie J., Bolla, Manjeet K., Yazdanpanah, Mojgan, Yazdanpanah, Nahid, Bradfield, Jonathan P., Broer, Linda, Campbell, Archie, Chasman, Daniel I., Cousminer, Diana L., Franceschini, Nora, Franke, Lude H., Girotto, Giorgia, He, Chunyan, Järvelin, Marjo-Riitta, Joshi, Peter K., Kamatani, Yoichiro, Karlsson, Robert, Luan, Jian’an, Lunetta, Kathryn L., Mägi, Reedik, Mangino, Massimo, Medland, Sarah E., Meisinger, Christa, Noordam, Raymond, Nutile, Teresa, Concas, Maria Pina, Polašek, Ozren, Porcu, Eleonora, Ring, Susan M., Sala, Cinzia, Smith, Albert V., Tanaka, Toshiko, van der Most, Peter J., Vitart, Veronique, Wang, Carol A., Willemsen, Gonneke, Zygmunt, Marek, Ahearn, Thomas U., Andrulis, Irene L., Anton-Culver, Hoda, Antoniou, Antonis C., Auer, Paul L., Barnes, Catriona L. K., Beckmann, Matthias W., Berrington de Gonzalez, Amy, Bogdanova, Natalia V., Bojesen, Stig E., Brenner, Hermann, Buring, Julie E., Canzian, Federico, Chang-Claude, Jenny, Couch, Fergus J., Cox, Angela, Crisponi, Laura, Czene, Kamila, Daly, Mary B., Demerath, Ellen W., Dennis, Joe, Devilee, Peter, De Vivo, Immaculata, Dörk, Thilo, Dunning, Alison M., Dwek, Miriam, Eriksson, Johan G., Fasching, Peter A., Fernandez-Rhodes, Lindsay, Ferreli, Liana, Fletcher, Olivia, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A., González-Neira, Anna, Grallert, Harald, Guénel, Pascal, Haiman, Christopher A., Hall, Per, Hamann, Ute, Hakonarson, Hakon, Hart, Roger J., Hickey, Martha, Hooning, Maartje J., Hoppe, Reiner, Hopper, John L., Hottenga, Jouke-Jan, Hu, Frank B., Huebner, Hanna, Hunter, David J., Jernström, Helena, John, Esther M., Karasik, David, Khusnutdinova, Elza K., Kristensen, Vessela N., Lacey, James V., Lambrechts, Diether, Launer, Lenore J., Lind, Penelope A., Lindblom, Annika, Magnusson, Patrik K. E., Mannermaa, Arto, McCarthy, Mark I., Meitinger, Thomas, Menni, Cristina, Michailidou, Kyriaki, Millwood, Iona Y., Milne, Roger L., Montgomery, Grant W., Nevanlinna, Heli, Nolte, Ilja M., Nyholt, Dale R., Obi, Nadia, O’Brien, Katie M., Offit, Kenneth, Oldehinkel, Albertine J., Ostrowski, Sisse R., Palotie, Aarno, Pedersen, Ole B., Peters, Annette, Pianigiani, Giulia, Plaseska-Karanfilska, Dijana, Pouta, Anneli, Pozarickij, Alfred, Radice, Paolo, Rennert, Gad, Rosendaal, Frits R., Ruggiero, Daniela, Saloustros, Emmanouil, Sandler, Dale P., Schipf, Sabine, Schmidt, Carsten O., Schmidt, Marjanka K., Small, Kerrin, Spedicati, Beatrice, Stampfer, Meir, Stone, Jennifer, Tamimi, Rulla M., Teras, Lauren R., Tikkanen, Emmi, Turman, Constance, Vachon, Celine M., Wang, Qin, Winqvist, Robert, Wolk, Alicja, Zemel, Babette S., Zheng, Wei, van Dijk, Ko W., Alizadeh, Behrooz Z., Bandinelli, Stefania, Boerwinkle, Eric, Boomsma, Dorret I., Ciullo, Marina, Chenevix-Trench, Georgia, Cucca, Francesco, Esko, Tõnu, Gieger, Christian, Grant, Struan F. A., Gudnason, Vilmundur, Hayward, Caroline, Kolčić, Ivana, Kraft, Peter, Lawlor, Deborah A., Martin, Nicholas G., Nøhr, Ellen A., Pedersen, Nancy L., Pennell, Craig E., Ridker, Paul M., Robino, Antonietta, Snieder, Harold, Sovio, Ulla, Spector, Tim D., Stöckl, Doris, Sudlow, Cathie, Timpson, Nic J., Toniolo, Daniela, Uitterlinden, André, Ulivi, Sheila, Völzke, Henry, Wareham, Nicholas J., Widen, Elisabeth, Wilson, James F., Pharoah, Paul D. P., Li, Liming, Easton, Douglas F., Njølstad, Pål R., Sulem, Patrick, Murabito, Joanne M., Murray, Anna, Manousaki, Despoina, Juul, Anders, Erikstrup, Christian, Stefansson, Kari, Horikoshi, Momoko, Chen, Zhengming, Farooqi, I. Sadaf, Pitteloud, Nelly, Johansson, Stefan, Day, Felix R., Perry, John R. B., and Ong, Ken K.

Published
2024
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8. Genome-wide analyses of neonatal jaundice reveal a marked departure from adult bilirubin metabolism

Author

Solé-Navais, Pol, Juodakis, Julius, Ytterberg, Karin, Wu, Xiaoping, Bradfield, Jonathan P., Vaudel, Marc, LaBella, Abigail L., Helgeland, Øyvind, Flatley, Christopher, Geller, Frank, Finel, Moshe, Zhao, Mengqi, Lazarus, Philip, Hakonarson, Hakon, Magnus, Per, Andreassen, Ole A., Njølstad, Pål R., Grant, Struan F. A., Feenstra, Bjarke, Muglia, Louis J., Johansson, Stefan, Zhang, Ge, and Jacobsson, Bo

Published
2024
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10. Author Correction: Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes

Author

Bradfeld, Jonathan P., Kember, Rachel L., Ulrich, Anna, Balkhiyarova, Zhanna, Alyass, Akram, Aris, Izzuddin M., Bell, Joshua A., Broadaway, K. Alaine, Chen, Zhanghua, Chai, Jin-Fang, Davies, Neil M., Fernandez-Orth, Dietmar, Bustamante, Mariona, Fore, Ruby, Ganguli, Amitavo, Heiskala, Anni, Hottenga, Jouke-Jan, Íñiguez, Carmen, Kobes, Sayuko, Leinonen, Jaakko, Lowry, Estelle, Lyytikainen, Leo-Pekka, Mahajan, Anubha, Pitkänen, Niina, Schnurr, Theresia M., Have, Christian Theil, Strachan, David P., Thiering, Elisabeth, Vogelezang, Suzanne, Wade, Kaitlin H., Wang, Carol A., Wong, Andrew, Holm, Louise Aas, Chesi, Alessandra, Choong, Catherine, Cruz, Miguel, Elliott, Paul, Franks, Steve, Frithiof-Bøjsøe, Christine, Gauderman, W. James, Glessner, Joseph T., Gilsanz, Vicente, Griesman, Kendra, Hanson, Robert L., Kaakinen, Marika, Kalkwarf, Heidi, Kelly, Andrea, Kindler, Joseph, Kähönen, Mika, Lanca, Carla, Lappe, Joan, Lee, Nanette R., McCormack, Shana, Mentch, Frank D., Mitchell, Jonathan A., Mononen, Nina, Niinikoski, Harri, Oken, Emily, Pahkala, Katja, Sim, Xueling, Teo, Yik-Ying, Baier, Leslie J., van Beijsterveldt, Toos, Adair, Linda S., Boomsma, Dorret I., de Geus, Eco, Guxens, Mònica, Eriksson, Johan G., Felix, Janine F., Gilliland, Frank D., Hansen, Torben, Hardy, Rebecca, Hivert, Marie-France, Holm, Jens-Christian, Jaddoe, Vincent W. V., Järvelin, Marjo-Riitta, Lehtimäki, Terho, Mackey, David A., Meyre, David, Mohlke, Karen L., Mykkänen, Juha, Oberfeld, Sharon, Pennell, Craig E., Perry, John R. B., Raitakari, Olli, Rivadeneira, Fernando, Saw, Seang-Mei, Sebert, Sylvain, Shepherd, John A., Standl, Marie, Sørensen, Thorkild I. A., Timpson, Nicholas J., Torrent, Maties, Willemsen, Gonneke, Hypponen, Elina, Power, Chris, McCarthy, Mark I., Freathy, Rachel M., Widén, Elisabeth, Hakonarson, Hakon, Prokopenko, Inga, Voight, Benjamin F., Zemel, Babette S., Grant, Struan F. A., and Cousminer, Diana L.

Published
2024
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11. Clinical associations with a polygenic predisposition to benign lower white blood cell counts

Author

Mosley, Jonathan D., Shelley, John P., Dickson, Alyson L., Zanussi, Jacy, Daniel, Laura L., Zheng, Neil S., Bastarache, Lisa, Wei, Wei-Qi, Shi, Mingjian, Jarvik, Gail P., Rosenthal, Elisabeth A., Khan, Atlas, Sherafati, Alborz, Kullo, Iftikhar J., Walunas, Theresa L., Glessner, Joseph, Hakonarson, Hakon, Cox, Nancy J., Roden, Dan M., Frangakis, Stephan G., Vanderwerff, Brett, Stein, C. Michael, Van Driest, Sara L., Borinstein, Scott C., Shu, Xiao-Ou, Zawistowski, Matthew, Chung, Cecilia P., and Kawai, Vivian K.

Published
2024
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12. The Tehran longitudinal family-based cardiometabolic cohort study sheds new light on dyslipidemia transmission patterns

Author

Akbarzadeh, Mahdi, Riahi, Parisa, Saeidian, Amir Hossein, Zarkesh, Maryam, Masjoudi, Sajedeh, Asgarian, Sara, Guity, Kamran, Moheimani, Hamed, Masoudi, Homayoon, Roudbar, Mahmoud Amiri, Khalili, Davood, Hosseinpanah, Farhad, Barzin, Maryam, Hogan, Carolyn T., Hakonarson, Hakon, Hedayati, Mehdi, Daneshpour, Maryam S., and Azizi, Fereidoun

Published
2024
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13. Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes

Author

Bradfield, Jonathan P., Kember, Rachel L., Ulrich, Anna, Balkhiyarova, Zhanna, Alyass, Akram, Aris, Izzuddin M., Bell, Joshua A., Broadaway, K. Alaine, Chen, Zhanghua, Chai, Jin-Fang, Davies, Neil M., Fernandez-Orth, Dietmar, Bustamante, Mariona, Fore, Ruby, Ganguli, Amitavo, Heiskala, Anni, Hottenga, Jouke-Jan, Íñiguez, Carmen, Kobes, Sayuko, Leinonen, Jaakko, Lowry, Estelle, Lyytikainen, Leo-Pekka, Mahajan, Anubha, Pitkänen, Niina, Schnurr, Theresia M., Have, Christian Theil, Strachan, David P., Thiering, Elisabeth, Vogelezang, Suzanne, Wade, Kaitlin H., Wang, Carol A., Wong, Andrew, Holm, Louise Aas, Chesi, Alessandra, Choong, Catherine, Cruz, Miguel, Elliott, Paul, Franks, Steve, Frithioff-Bøjsøe, Christine, Gauderman, W. James, Glessner, Joseph T., Gilsanz, Vicente, Griesman, Kendra, Hanson, Robert L., Kaakinen, Marika, Kalkwarf, Heidi, Kelly, Andrea, Kindler, Joseph, Kähönen, Mika, Lanca, Carla, Lappe, Joan, Lee, Nanette R., McCormack, Shana, Mentch, Frank D., Mitchell, Jonathan A., Mononen, Nina, Niinikoski, Harri, Oken, Emily, Pahkala, Katja, Sim, Xueling, Teo, Yik-Ying, Baier, Leslie J., van Beijsterveldt, Toos, Adair, Linda S., Boomsma, Dorret I., de Geus, Eco, Guxens, Mònica, Eriksson, Johan G., Felix, Janine F., Gilliland, Frank D., Biobank, Penn Medicine, Hansen, Torben, Hardy, Rebecca, Hivert, Marie-France, Holm, Jens-Christian, Jaddoe, Vincent W. V., Järvelin, Marjo-Riitta, Lehtimäki, Terho, Mackey, David A., Meyre, David, Mohlke, Karen L., Mykkänen, Juha, Oberfield, Sharon, Pennell, Craig E., Perry, John R. B., Raitakari, Olli, Rivadeneira, Fernando, Saw, Seang-Mei, Sebert, Sylvain, Shepherd, John A., Standl, Marie, Sørensen, Thorkild I. A., Timpson, Nicholas J., Torrent, Maties, Willemsen, Gonneke, Hypponen, Elina, Power, Chris, McCarthy, Mark I., Freathy, Rachel M., Widén, Elisabeth, Hakonarson, Hakon, Prokopenko, Inga, Voight, Benjamin F., Zemel, Babette S., Grant, Struan F. A., and Cousminer, Diana L.

Published
2024
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14. Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populations

Author

Lennon, Niall J., Kottyan, Leah C., Kachulis, Christopher, Abul-Husn, Noura S., Arias, Josh, Belbin, Gillian, Below, Jennifer E., Berndt, Sonja I., Chung, Wendy K., Cimino, James J., Clayton, Ellen Wright, Connolly, John J., Crosslin, David R., Dikilitas, Ozan, Velez Edwards, Digna R., Feng, QiPing, Fisher, Marissa, Freimuth, Robert R., Ge, Tian, Glessner, Joseph T., Gordon, Adam S., Patterson, Candace, Hakonarson, Hakon, Harden, Maegan, Harr, Margaret, Hirschhorn, Joel N., Hoggart, Clive, Hsu, Li, Irvin, Marguerite R., Jarvik, Gail P., Karlson, Elizabeth W., Khan, Atlas, Khera, Amit, Kiryluk, Krzysztof, Kullo, Iftikhar, Larkin, Katie, Limdi, Nita, Linder, Jodell E., Loos, Ruth J. F., Luo, Yuan, Malolepsza, Edyta, Manolio, Teri A., Martin, Lisa J., McCarthy, Li, McNally, Elizabeth M., Meigs, James B., Mersha, Tesfaye B., Mosley, Jonathan D., Musick, Anjene, Namjou, Bahram, Pai, Nihal, Pesce, Lorenzo L., Peters, Ulrike, Peterson, Josh F., Prows, Cynthia A., Puckelwartz, Megan J., Rehm, Heidi L., Roden, Dan M., Rosenthal, Elisabeth A., Rowley, Robb, Sawicki, Konrad Teodor, Schaid, Daniel J., Smit, Roelof A. J., Smith, Johanna L., Smoller, Jordan W., Thomas, Minta, Tiwari, Hemant, Toledo, Diana M., Vaitinadin, Nataraja Sarma, Veenstra, David, Walunas, Theresa L., Wang, Zhe, Wei, Wei-Qi, Weng, Chunhua, Wiesner, Georgia L., Yin, Xianyong, and Kenny, Eimear E.

Published
2024
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15. Lymphatic disorders caused by mosaic, activating KRAS variants respond to MEK inhibition

Author

Sheppard, Sarah E, March, Michael E, Seiler, Christoph, Matsuoka, Leticia S, Kim, Sophia E, Kao, Charlly, Rubin, Adam I, Battig, Mark R, Khalek, Nahla, Schindewolf, Erica, O’Connor, Nora, Pinto, Erin, Priestley, Jessica RC, Sanders, Victoria R, Niazi, Rojeen, Ganguly, Arupa, Hou, Cuiping, Slater, Diana, Frieden, Ilona J, Huynh, Thy, Shieh, Joseph T, Krantz, Ian D, Guerrero, Jessenia C, Surrey, Lea F, Biko, David M, Laje, Pablo, Castelo-Soccio, Leslie, Nakano, Taizo A, Snyder, Kristen, Smith, Christopher L, Li, Dong, Dori, Yoav, and Hakonarson, Hakon

Subjects
Rare Diseases, Pediatric, Animals, Humans, Zebrafish, Proto-Oncogene Proteins p21(ras), Endothelial Cells, Phosphorylation, Mitogen-Activated Protein Kinase Kinases, Zebrafish Proteins, Cardiology, Cardiovascular disease, Genetics, Molecular biology, Molecular genetics
Abstract

Central conducting lymphatic anomaly (CCLA) due to congenital maldevelopment of the lymphatics can result in debilitating and life-threatening disease with limited treatment options. We identified 4 individuals with CCLA, lymphedema, and microcystic lymphatic malformation due to pathogenic, mosaic variants in KRAS. To determine the functional impact of these variants and identify a targeted therapy for these individuals, we used primary human dermal lymphatic endothelial cells (HDLECs) and zebrafish larvae to model the lymphatic dysplasia. Expression of the p.Gly12Asp and p.Gly13Asp variants in HDLECs in a 2‑dimensional (2D) model and 3D organoid model led to increased ERK phosphorylation, demonstrating these variants activate the RAS/MAPK pathway. Expression of activating KRAS variants in the venous and lymphatic endothelium in zebrafish resulted in lymphatic dysplasia and edema similar to the individuals in the study. Treatment with MEK inhibition significantly reduced the phenotypes in both the organoid and the zebrafish model systems. In conclusion, we present the molecular characterization of the observed lymphatic anomalies due to pathogenic, somatic, activating KRAS variants in humans. Our preclinical studies suggest that MEK inhibition should be studied in future clinical trials for CCLA due to activating KRAS pathogenic variants.

Published
2023

16. Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits—The Hispanic/Latino Anthropometry Consortium

Author

Fernández-Rhodes, Lindsay, Graff, Mariaelisa, Buchanan, Victoria L, Justice, Anne E, Highland, Heather M, Guo, Xiuqing, Zhu, Wanying, Chen, Hung-Hsin, Young, Kristin L, Adhikari, Kaustubh, Palmer, Nicholette D, Below, Jennifer E, Bradfield, Jonathan, Pereira, Alexandre C, Glover, LáShauntá, Kim, Daeeun, Lilly, Adam G, Shrestha, Poojan, Thomas, Alvin G, Zhang, Xinruo, Chen, Minhui, Chiang, Charleston WK, Pulit, Sara, Horimoto, Andrea, Krieger, Jose E, Guindo-Martínez, Marta, Preuss, Michael, Schumann, Claudia, Smit, Roelof AJ, Torres-Mejía, Gabriela, Acuña-Alonzo, Victor, Bedoya, Gabriel, Bortolini, Maria-Cátira, Canizales-Quinteros, Samuel, Gallo, Carla, González-José, Rolando, Poletti, Giovanni, Rothhammer, Francisco, Hakonarson, Hakon, Igo, Robert, Adler, Sharon G, Iyengar, Sudha K, Nicholas, Susanne B, Gogarten, Stephanie M, Isasi, Carmen R, Papnicolaou, George, Stilp, Adrienne M, Qi, Qibin, Kho, Minjung, Smith, Jennifer A, Langefeld, Carl D, Wagenknecht, Lynne, Mckean-Cowdin, Roberta, Gao, Xiaoyi Raymond, Nousome, Darryl, Conti, David V, Feng, Ye, Allison, Matthew A, Arzumanyan, Zorayr, Buchanan, Thomas A, Chen, Yii-Der Ida, Genter, Pauline M, Goodarzi, Mark O, Hai, Yang, Hsueh, Willa, Ipp, Eli, Kandeel, Fouad R, Lam, Kelvin, Li, Xiaohui, Nadler, Jerry L, Raffel, Leslie J, Roll, Kathryn, Sandow, Kevin, Tan, Jingyi, Taylor, Kent D, Xiang, Anny H, Yao, Jie, Audirac-Chalifour, Astride, Peralta Romero, Jose de Jesus, Hartwig, Fernando, Horta, Bernando, Blangero, John, Curran, Joanne E, Duggirala, Ravindranath, Lehman, Donna E, Puppala, Sobha, Fejerman, Laura, John, Esther M, Aguilar-Salinas, Carlos, Burtt, Noël P, Florez, Jose C, García-Ortíz, Humberto, González-Villalpando, Clicerio, Mercader, Josep, Orozco, Lorena, Tusié-Luna, Teresa, Blanco, Estela, Gahagan, Sheila, Cox, Nancy J, and Hanis, Craig

Abstract

[This corrects the article DOI: 10.1016/j.xhgg.2022.100099.].

Published
2023

19. Common Genetic Variation and Age of Onset of Anorexia Nervosa.

Author

Watson, Hunna J, Thornton, Laura M, Yilmaz, Zeynep, Baker, Jessica H, Coleman, Jonathan RI, Adan, Roger AH, Alfredsson, Lars, Andreassen, Ole A, Ask, Helga, Berrettini, Wade H, Boehnke, Michael, Boehm, Ilka, Boni, Claudette, Buehren, Katharina, Bulant, Josef, Burghardt, Roland, Chang, Xiao, Cichon, Sven, Cone, Roger D, Courtet, Philippe, Crow, Scott, Crowley, James J, Danner, Unna N, de Zwaan, Martina, Dedoussis, George, DeSocio, Janiece E, Dick, Danielle M, Dikeos, Dimitris, Dina, Christian, Djurovic, Srdjan, Dmitrzak-Weglarz, Monika, Docampo-Martinez, Elisa, Duriez, Philibert, Egberts, Karin, Ehrlich, Stefan, Eriksson, Johan G, Escaramís, Geòrgia, Esko, Tõnu, Estivill, Xavier, Farmer, Anne, Fernández-Aranda, Fernando, Fichter, Manfred M, Föcker, Manuel, Foretova, Lenka, Forstner, Andreas J, Frei, Oleksandr, Gallinger, Steven, Giegling, Ina, Giuranna, Johanna, Gonidakis, Fragiskos, Gorwood, Philip, Gratacòs, Mònica, Guillaume, Sébastien, Guo, Yiran, Hakonarson, Hakon, Hauser, Joanna, Havdahl, Alexandra, Hebebrand, Johannes, Helder, Sietske G, Herms, Stefan, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Hinney, Anke, Hübel, Christopher, Hudson, James I, Imgart, Hartmut, Jamain, Stephanie, Janout, Vladimir, Jiménez-Murcia, Susana, Jones, Ian R, Julià, Antonio, Kalsi, Gursharan, Kaminská, Deborah, Kaprio, Jaakko, Karhunen, Leila, Kas, Martien JH, Keel, Pamela K, Kennedy, James L, Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Klareskog, Lars, Klump, Kelly L, Knudsen, Gun Peggy S, La Via, Maria C, Le Hellard, Stephanie, Leboyer, Marion, Li, Dong, Lilenfeld, Lisa, Lin, Bochao, Lissowska, Jolanta, Luykx, Jurjen, Magistretti, Pierre, Maj, Mario, Marsal, Sara, Marshall, Christian R, Mattingsdal, Morten, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, Karen S, and Monteleone, Alessio Maria

Subjects
Age of onset, Anorexia nervosa, Early-onset, GWAS, Genetic risk score, Genetics, Menarche, Mendelian randomization, Puberty, Mental Health, Human Genome, Eating Disorders, Anorexia, Brain Disorders, Pediatric, Prevention, Aetiology, 2.1 Biological and endogenous factors
Abstract

BackgroundGenetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche.MethodsA secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (

Published
2022

20. Oncogene-induced matrix reorganization controls [CD8.sup.+] T cell function in the soft-tissue sarcoma microenvironment

Author

Fuller, Ashley M., Pruit, Hawley C., Ying, Liu, Irizarry-Negron, Valerie M., Pan, Hehai, Song, Hoogeun, DeVine, Ann, Katti, Rohan S., Devalaraja, Samir, Ciotti, Gabrielle E., Gonzalez, Michael V., Williams, Erik F., Murazzi, Ileana, Ntekoumes, Dimitris, Skuli, Nicolas, Hakonarson, Hakon, Zabransky, Daniel J., Trevino, Jose G., Weeraratna, Ashani, Weber, Kristy, Haldar, Malay, Fraietta, Joseph A., Gerech, Sharon, and Eisinger-Mathason, T.S. Karin

Subjects
Sarcoma -- Risk factors -- Development and progression -- Models, T cells -- Physiological aspects -- Health aspects -- Control, Oncogenes -- Physiological aspects -- Influence -- Health aspects, Health care industry
Abstract

[CD8.sup.+] T cell dysfunction impedes antitumor immunity in solid cancers, but the underlying mechanisms are diverse and poorly understood. Extracellular matrix (ECM) composition has been linked to impaired T cell migration and enhanced tumor progression; however, impacts of individual ECM molecules on T cell function in the tumor microenvironment (TME) are only beginning to be elucidated. Upstream regulators of aberrant ECM deposition and organization in solid tumors are equally ill-defined. Therefore, we investigated how ECM composition modulates [CD8.sup.+] T cell function in undifferentiated pleomorphic sarcoma (UPS), an immunologically active desmoplastic tumor. Using an autochthonous murine model of UPS and data from multiple human patient cohorts, we discovered a multifaceted mechanism wherein the transcriptional coactivator YAP1 promotes collagen VI (COLVI) deposition in the UPS TME. In turn, COLVI induces [CD8.sup.+] T cell dysfunction and immune evasion by remodeling fibrillar collagen and inhibiting T cell autophagic flux. Unexpectedly, collagen I (COLI) opposed COLVI in this setting, promoting [CD8.sup.+] T cell function and acting as a tumor suppressor. Thus, [CD8.sup.+] T cell responses in sarcoma depend on oncogene-mediated ECM composition and remodeling., Introduction Immunosuppression in the solid tumor microenvironment (TME) impedes T cell-mediated antitumor immunity. Tumors evade host adaptive immune responses by inducing [CD8.sup.+] T cell dysfunction, a hypofunctional state characterized by [...]

Published
2024
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21. The common variable immunodeficiency IgM repertoire narrowly recognizes erythrocyte and platelet glycans

Author

Le Coz, Carole, Trofa, Melissa, Butler, Dorothy L., Yoon, Samuel, Tian, Tian, Reid, Whitney, Cruz Cabrera, Emylette, Knox, Ainsley V.C., Khanna, Caroline, Sullivan, Kathleen E., Heimall, Jennifer, Takach, Patricia, Fadugba, Olajumoke O., Lawrence, Monica, Jyonouchi, Soma, Hakonarson, Hakon, Wells, Andrew D., Handler, Steven, Zur, Karen B., Pillai, Vinodh, Gildersleeve, Jeffrey C., and Romberg, Neil

Published
2024
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24. Novel insights into the phenotypic spectrum and pathogenesis of Hardikar syndrome

Author

Strong, Alanna, March, Michael E., Cardinale, Christopher J., Liu, Yichuan, Battig, Mark R., Finoti, Livia Sertori, Matsuoka, Leticia S., Watson, Deborah, Sridhar, Sindura, Jarrett, James F., Cannon, India, Li, Dong, Bhoj, Elizabeth, Zackai, Elaine H., Rand, Elizabeth B., Wenger, Tara, Lerman, Bruce B., Shikany, Amy, Weaver, K. Nicole, and Hakonarson, Hakon

Published
2024
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25. Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits—The Hispanic/Latino Anthropometry Consortium

Author

Fernández-Rhodes, Lindsay, Graff, Mariaelisa, Buchanan, Victoria L, Justice, Anne E, Highland, Heather M, Guo, Xiuqing, Zhu, Wanying, Chen, Hung-Hsin, Young, Kristin L, Adhikari, Kaustubh, Palmer, Nicholette D, Below, Jennifer E, Bradfield, Jonathan, Pereira, Alexandre C, Glover, LáShauntá, Kim, Daeeun, Lilly, Adam G, Shrestha, Poojan, Thomas, Alvin G, Zhang, Xinruo, Chen, Minhui, Chiang, Charleston WK, Pulit, Sara, Horimoto, Andrea, Krieger, Jose E, Guindo-Martínez, Marta, Preuss, Michael, Schumann, Claudia, Smit, Roelof AJ, Torres-Mejía, Gabriela, Acuña-Alonzo, Victor, Bedoya, Gabriel, Bortolini, Maria-Cátira, Canizales-Quinteros, Samuel, Gallo, Carla, González-José, Rolando, Poletti, Giovanni, Rothhammer, Francisco, Hakonarson, Hakon, Igo, Robert, Adler, Sharon G, Iyengar, Sudha K, Nicholas, Susanne B, Gogarten, Stephanie M, Isasi, Carmen R, Papnicolaou, George, Stilp, Adrienne M, Qi, Qibin, Kho, Minjung, Smith, Jennifer A, Langefeld, Carl D, Wagenknecht, Lynne, Mckean-Cowdin, Roberta, Gao, Xiaoyi Raymond, Nousome, Darryl, Conti, David V, Feng, Ye, Allison, Matthew A, Arzumanyan, Zorayr, Buchanan, Thomas A, Chen, Yii-Der Ida, Genter, Pauline M, Goodarzi, Mark O, Hai, Yang, Hsueh, Willa, Ipp, Eli, Kandeel, Fouad R, Lam, Kelvin, Li, Xiaohui, Nadler, Jerry L, Raffel, Leslie J, Roll, Kathryn, Sandow, Kevin, Tan, Jingyi, Taylor, Kent D, Xiang, Anny H, Yao, Jie, Audirac-Chalifour, Astride, de Jesus Peralta Romero, Jose, Hartwig, Fernando, Horta, Bernando, Blangero, John, Curran, Joanne E, Duggirala, Ravindranath, Lehman, Donna E, Puppala, Sobha, Fejerman, Laura, John, Esther M, Aguilar-Salinas, Carlos, Burtt, Noël P, Florez, Jose C, García-Ortíz, Humberto, González-Villalpando, Clicerio, Mercader, Josep, Orozco, Lorena, Tusié-Luna, Teresa, Blanco, Estela, Gahagan, Sheila, Cox, Nancy J, and Hanis, Craig

Subjects
Biological Sciences, Genetics, Obesity, Human Genome, Hispanic/Latino, anthropometrics, diversity, fine-mapping, obesity, population stratification, trans-ancestral or trans-ethnic
Abstract

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (stage 1, n = 59,771) and generalized our findings in 9 additional studies (stage 2, n = 10,538). We conducted a trans-ancestral GWAS with summary statistics from HISLA stage 1 and existing consortia of European and African ancestries. In our HISLA stage 1 + 2 analyses, we discovered one BMI locus, as well as two BMI signals and another height signal each within established anthropometric loci. In our trans-ancestral meta-analysis, we discovered three BMI loci, one height locus, and one WHRadjBMI locus. We also identified 3 secondary signals for BMI, 28 for height, and 2 for WHRadjBMI in established loci. We show that 336 known BMI, 1,177 known height, and 143 known WHRadjBMI (combined) SNPs demonstrated suggestive transferability (nominal significance and effect estimate directional consistency) in Hispanic/Latino adults. Of these, 36 BMI, 124 height, and 11 WHRadjBMI SNPs were significant after trait-specific Bonferroni correction. Trans-ancestral meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our findings demonstrate that future studies may also benefit from leveraging diverse ancestries and differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification.

Published
2022

26. Managing differential performance of polygenic risk scores across groups: Real-world experience of the eMERGE Network

Author

Lewis, Anna C.F., Chisholm, Rex L., Connolly, John J., Esplin, Edward D., Glessner, Joe, Gordon, Adam, Green, Robert C., Hakonarson, Hakon, Harr, Margaret, Holm, Ingrid A., Jarvik, Gail P., Karlson, Elizabeth, Kenny, Eimear E., Kottyan, Leah, Lennon, Niall, Linder, Jodell E., Luo, Yuan, Martin, Lisa J., Perez, Emma, Puckelwartz, Megan J., Rasmussen-Torvik, Laura J., Sabatello, Maya, Sharp, Richard R., Smoller, Jordan W., Sterling, Rene, Terek, Shannon, Wei, Wei-Qi, and Fullerton, Stephanie M.

Published
2024
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28. Causal effect of serum 25 hydroxyvitamin D concentration on cardioembolic stroke: Evidence from two-sample Mendelian randomization

Author

Habibi, Danial, Teymoori, Farshad, Ebrahimi, Navid, Fateh, Sahand Tehrani, Najd-Hassan-Bonab, Leila, Saeidian, Amir Hossein, Soleymani Taloubaghi, Alireza, Asgarian, Sara, Hosseinpanah, Farhad, Hakonarson, Hakon, Azizi, Fereidoun, Hedayati, Mehdi, Daneshpour, Maryam Sadat, Akbarzadeh, Mahdi, and Mansourian, Marjan

Published
2024
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30. CRISPR/Cas9 screenings unearth protein arginine methyltransferase 7 as a novel essential gene in prostate cancer metastasis

Author

Rodrigo-Faus, Maria, Vincelle-Nieto, Africa, Vidal, Natalia, Puente, Javier, Saiz-Pardo, Melchor, Lopez-Garcia, Alejandra, Mendiburu-Eliçabe, Marina, Palao, Nerea, Baquero, Cristina, Linzoain-Agos, Paula, Cuesta, Angel M., Qu, Hui-Qi, Hakonarson, Hakon, Musteanu, Monica, Reyes-Palomares, Armando, Porras, Almudena, Bragado, Paloma, and Gutierrez-Uzquiza, Alvaro

Published
2024
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32. Germline Exome Sequencing for Men with Testicular Germ Cell Tumor Reveals Coding Defects in Chromosomal Segregation and Protein-targeting Genes

Author

Pyle, Louise C., Kim, Jung, Bradfield, Jonathan, Damrauer, Scott M., D'Andrea, Kurt, Einhorn, Lawrence H., Godse, Rama, Hakonarson, Hakon, Kanetsky, Peter A., Kember, Rachel L., Jacobs, Linda A., Maxwell, Kara N., Rader, Daniel J., Vaughn, David J., Weathers, Benita, Wubbenhorst, Bradley, Regeneron Genetics Center Research Team, Cancer Genomics Research Laboratory, Greene, Mark H., Nathanson, Katherine L., and Stewart, Douglas R.

Published
2024
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33. Author Correction: Genetic variation in the human leukocyte antigen region confers susceptibility to Clostridioides difficile infection

Author

Ferar, Kathleen, Hall, Taryn O., Crawford, Dana C., Rowley, Robb, Satterfield, Benjamin A., Li, Rongling, Gragert, Loren, Karlson, Elizabeth W., de Andrade, Mariza, Kullo, Iftikhar J., McCarty, Catherine A., Kho, Abel, Hayes, M. Geoffrey, Ritchie, Marylyn D., Crane, Paul K., Mirel, Daniel B., Carlson, Christopher, Connolly, John J., Hakonarson, Hakon, Crenshaw, Andrew T., Carrell, David, Luo, Yuan, Dikilitas, Ozan, Denny, Joshua C., Jarvik, Gail P., and Crosslin, David R.

Published
2023
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34. Genetic variation in the human leukocyte antigen region confers susceptibility to Clostridioides difficile infection

Author

Ferar, Kathleen, Hall, Taryn O., Crawford, Dana C., Rowley, Robb, Satterfield, Benjamin A., Li, Rongling, Gragert, Loren, Karlson, Elizabeth W., de Andrade, Mariza, Kullo, Iftikhar J., McCarty, Catherine A., Kho, Abel, Hayes, M. Geoffrey, Ritchie, Marylyn D., Crane, Paul K., Mirel, Daniel B., Carlson, Christopher, Connolly, John J., Hakonarson, Hakon, Crenshaw, Andrew T., Carrell, David, Luo, Yuan, Dikilitas, Ozan, Denny, Joshua C., Jarvik, Gail P., and Crosslin, David R.

Published
2023
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35. European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation

Author

Budu-Aggrey, Ashley, Kilanowski, Anna, Sobczyk, Maria K., Shringarpure, Suyash S., Mitchell, Ruth, Reis, Kadri, Reigo, Anu, Mägi, Reedik, Nelis, Mari, Tanaka, Nao, Brumpton, Ben M., Thomas, Laurent F., Sole-Navais, Pol, Flatley, Christopher, Espuela-Ortiz, Antonio, Herrera-Luis, Esther, Lominchar, Jesus V. T., Bork-Jensen, Jette, Marenholz, Ingo, Arnau-Soler, Aleix, Jeong, Ayoung, Fawcett, Katherine A., Baurecht, Hansjorg, Rodriguez, Elke, Alves, Alexessander Couto, Kumar, Ashish, Sleiman, Patrick M., Chang, Xiao, Medina-Gomez, Carolina, Hu, Chen, Xu, Cheng-jian, Qi, Cancan, El-Heis, Sarah, Titcombe, Philip, Antoun, Elie, Fadista, João, Wang, Carol A., Thiering, Elisabeth, Wu, Baojun, Kress, Sara, Kothalawala, Dilini M., Kadalayil, Latha, Duan, Jiasong, Zhang, Hongmei, Hadebe, Sabelo, Hoffmann, Thomas, Jorgenson, Eric, Choquet, Hélène, Risch, Neil, Njølstad, Pål, Andreassen, Ole A., Johansson, Stefan, Almqvist, Catarina, Gong, Tong, Ullemar, Vilhelmina, Karlsson, Robert, Magnusson, Patrik K. E., Szwajda, Agnieszka, Burchard, Esteban G., Thyssen, Jacob P., Hansen, Torben, Kårhus, Line L., Dantoft, Thomas M., Jeanrenaud, Alexander C.S.N., Ghauri, Ahla, Arnold, Andreas, Homuth, Georg, Lau, Susanne, Nöthen, Markus M., Hübner, Norbert, Imboden, Medea, Visconti, Alessia, Falchi, Mario, Bataille, Veronique, Hysi, Pirro, Ballardini, Natalia, Boomsma, Dorret I., Hottenga, Jouke J., Müller-Nurasyid, Martina, Ahluwalia, Tarunveer S., Stokholm, Jakob, Chawes, Bo, Schoos, Ann-Marie M., Esplugues, Ana, Bustamante, Mariona, Raby, Benjamin, Arshad, Syed, German, Chris, Esko, Tõnu, Milani, Lili A., Metspalu, Andres, Terao, Chikashi, Abuabara, Katrina, Løset, Mari, Hveem, Kristian, Jacobsson, Bo, Pino-Yanes, Maria, Strachan, David P., Grarup, Niels, Linneberg, Allan, Lee, Young-Ae, Probst-Hensch, Nicole, Weidinger, Stephan, Jarvelin, Marjo-Riitta, Melén, Erik, Hakonarson, Hakon, Irvine, Alan D., Jarvis, Deborah, Nijsten, Tamar, Duijts, Liesbeth, Vonk, Judith M., Koppelmann, Gerard H., Godfrey, Keith M., Barton, Sheila J., Feenstra, Bjarke, Pennell, Craig E., Sly, Peter D., Holt, Patrick G., Williams, L. Keoki, Bisgaard, Hans, Bønnelykke, Klaus, Curtin, John, Simpson, Angela, Murray, Clare, Schikowski, Tamara, Bunyavanich, Supinda, Weiss, Scott T., Holloway, John W., Min, Josine L., Brown, Sara J., Standl, Marie, and Paternoster, Lavinia

Published
2023
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37. Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders

Author

Gracia-Diaz, Carolina, Zhou, Yijing, Yang, Qian, Maroofian, Reza, Espana-Bonilla, Paula, Lee, Chul-Hwan, Zhang, Shuo, Padilla, Natàlia, Fueyo, Raquel, Waxman, Elisa A., Lei, Sunyimeng, Otrimski, Garrett, Li, Dong, Sheppard, Sarah E., Mark, Paul, Harr, Margaret H., Hakonarson, Hakon, Rodan, Lance, Jackson, Adam, Vasudevan, Pradeep, Powel, Corrina, Mohammed, Shehla, Maddirevula, Sateesh, Alzaidan, Hamad, Faqeih, Eissa A., Efthymiou, Stephanie, Turchetti, Valentina, Rahman, Fatima, Maqbool, Shazia, Salpietro, Vincenzo, Ibrahim, Shahnaz H., di Rosa, Gabriella, Houlden, Henry, Alharbi, Maha Nasser, Al-Sannaa, Nouriya Abbas, Bauer, Peter, Zifarelli, Giovanni, Estaras, Conchi, Hurst, Anna C. E., Thompson, Michelle L., Chassevent, Anna, Smith-Hicks, Constance L., de la Cruz, Xavier, Holtz, Alexander M., Elloumi, Houda Zghal, Hajianpour, M J, Rieubland, Claudine, Braun, Dominique, Banka, Siddharth, French, Deborah L., Heller, Elizabeth A., Saade, Murielle, Song, Hongjun, Ming, Guo-li, Alkuraya, Fowzan S., Agrawal, Pankaj B., Reinberg, Danny, Bhoj, Elizabeth J., Martínez-Balbás, Marian A., and Akizu, Naiara

Published
2023
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40. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors.

Author

Mullins, Niamh, Kang, JooEun, Campos, Adrian I, Coleman, Jonathan RI, Edwards, Alexis C, Galfalvy, Hanga, Levey, Daniel F, Lori, Adriana, Shabalin, Andrey, Starnawska, Anna, Su, Mei-Hsin, Watson, Hunna J, Adams, Mark, Awasthi, Swapnil, Gandal, Michael, Hafferty, Jonathan D, Hishimoto, Akitoyo, Kim, Minsoo, Okazaki, Satoshi, Otsuka, Ikuo, Ripke, Stephan, Ware, Erin B, Bergen, Andrew W, Berrettini, Wade H, Bohus, Martin, Brandt, Harry, Chang, Xiao, Chen, Wei J, Chen, Hsi-Chung, Crawford, Steven, Crow, Scott, DiBlasi, Emily, Duriez, Philibert, Fernández-Aranda, Fernando, Fichter, Manfred M, Gallinger, Steven, Glatt, Stephen J, Gorwood, Philip, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine A, Hwu, Hai-Gwo, Jain, Sonia, Jamain, Stéphane, Jiménez-Murcia, Susana, Johnson, Craig, Kaplan, Allan S, Kaye, Walter H, Keel, Pamela K, Kennedy, James L, Klump, Kelly L, Li, Dong, Liao, Shih-Cheng, Lieb, Klaus, Lilenfeld, Lisa, Liu, Chih-Min, Magistretti, Pierre J, Marshall, Christian R, Mitchell, James E, Monson, Eric T, Myers, Richard M, Pinto, Dalila, Powers, Abigail, Ramoz, Nicolas, Roepke, Stefan, Rozanov, Vsevolod, Scherer, Stephen W, Schmahl, Christian, Sokolowski, Marcus, Strober, Michael, Thornton, Laura M, Treasure, Janet, Tsuang, Ming T, Witt, Stephanie H, Woodside, D Blake, Yilmaz, Zeynep, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Air, Tracy M, Alda, Martin, Alfredsson, Lars, Andreassen, Ole A, Anjorin, Adebayo, Appadurai, Vivek, Soler Artigas, María, Van der Auwera, Sandra, Azevedo, M Helena, Bass, Nicholas, Bau, Claiton HD, Baune, Bernhard T, Bellivier, Frank, Berger, Klaus, Biernacka, Joanna M, Bigdeli, Tim B, Binder, Elisabeth B, Boehnke, Michael, Boks, Marco P, Bosch, Rosa, and Braff, David L

Subjects
Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Eating Disorders Working Group of the Psychiatric Genomics Consortium, German Borderline Genomics Consortium, MVP Suicide Exemplar Workgroup, VA Million Veteran Program, Humans, Risk Factors, Suicide, Attempted, Mental Disorders, Depressive Disorder, Major, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic correlation, Genome-wide association study, Pleiotropy, Polygenicity, Suicide, Suicide attempt, Human Genome, Behavioral and Social Science, Mental Health, Prevention, Genetics, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Mental health, Good Health and Well Being, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

BackgroundSuicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.MethodsWe conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.ResultsTwo loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.ConclusionsOur results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

Published
2022

41. Genome-wide association study in minority children with asthma implicates DNAH5 in bronchodilator responsiveness

Author

Joo, Jaehyun, Mak, Angel CY, Xiao, Shujie, Sleiman, Patrick M, Hu, Donglei, Huntsman, Scott, Eng, Celeste, Kan, Mengyuan, Diwakar, Avantika R, Lasky-Su, Jessica A, Weiss, Scott T, Sordillo, Joanne E, Wu, Ann C, Cloutier, Michelle, Canino, Glorisa, Forno, Erick, Celedón, Juan C, Seibold, Max A, Hakonarson, Hakon, Williams, L Keoki, Burchard, Esteban G, and Himes, Blanca E

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Pharmacology and Pharmaceutical Sciences, Minority Health, Health Disparities, Precision Medicine, Pediatric, Prevention, Asthma, Human Genome, Lung, Clinical Research, Biotechnology, 2.1 Biological and endogenous factors, Respiratory, Good Health and Well Being, Axonemal Dyneins, Bronchodilator Agents, Child, Ethnicity, Genome-Wide Association Study, Hispanic or Latino, Humans, Mexican Americans, Minority Groups, Polymorphism, Single Nucleotide
Abstract

Variability in response to short-acting β2-agonists (e.g., albuterol) among patients with asthma from diverse racial/ethnic groups may contribute to asthma disparities. We sought to identify genetic variants associated with bronchodilator response (BDR) to identify potential mechanisms of drug response and risk factors for worse asthma outcomes. Genome-wide association studies of bronchodilator response (BDR) were performed using TOPMed Whole Genome Sequencing data of the Asthma Translational Genomic Collaboration (ATGC), which corresponded to 1136 Puerto Rican, 656 Mexican and 4337 African American patients with asthma. With the population-specific GWAS results, a trans-ethnic meta-analysis was performed to identify BDR-associated variants shared across the three populations. Replication analysis was carried out in three pediatric asthma cohorts, including CAMP (Childhood Asthma Management Program; n = 560), GACRS (Genetics of Asthma in Costa Rica Study; n = 967) and HPR (Hartford-Puerto Rico; n = 417). A genome-wide significant locus (rs35661809; P = 3.61 × 10-8) in LINC02220, a non-coding RNA gene, was identified in Puerto Ricans. While this region was devoid of protein-coding genes, capture Hi-C data showed a distal interaction with the promoter of the DNAH5 gene in lung tissue. In replication analysis, the GACRS cohort yielded a nominal association (1-tailed P

Published
2022

42. Genetics of Inflammatory Bowel Diseases

Author

Cardinale, Christopher J., Hakonarson, Hakon, Mamula, Petar, editor, Kelsen, Judith R., editor, Grossman, Andrew B., editor, Baldassano, Robert N., editor, and Markowitz, Jonathan E., editor

Published
2023
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43. Genomic profiling informs diagnoses and treatment in vascular anomalies

Author

Li, Dong, Sheppard, Sarah E., March, Michael E., Battig, Mark R., Surrey, Lea F., Srinivasan, Abhay S., Matsuoka, Leticia S., Tian, Lifeng, Wang, Fengxiang, Seiler, Christoph, Dayneka, Jill, Borst, Alexandra J., Matos, Mary C., Paulissen, Scott M., Krishnamurthy, Ganesh, Nriagu, Bede, Sikder, Tamjeed, Casey, Melissa, Williams, Lydia, Rangu, Sneha, O’Connor, Nora, Thomas, Alexandria, Pinto, Erin, Hou, Cuiping, Nguyen, Kenny, Pellegrino da Silva, Renata, Chehimi, Samar N., Kao, Charlly, Biroc, Lauren, Britt, Allison D., Queenan, Maria, Reid, Janet R., Napoli, Joseph A., Low, David M., Vatsky, Seth, Treat, James, Smith, Christopher L., Cahill, Anne Marie, Snyder, Kristen M., Adams, Denise M., Dori, Yoav, and Hakonarson, Hakon

Published
2023
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44. Genetic effects on the timing of parturition and links to fetal birth weight

Author

Solé-Navais, Pol, Flatley, Christopher, Steinthorsdottir, Valgerdur, Vaudel, Marc, Juodakis, Julius, Chen, Jing, Laisk, Triin, LaBella, Abigail L., Westergaard, David, Bacelis, Jonas, Brumpton, Ben, Skotte, Line, Borges, Maria C., Helgeland, Øyvind, Mahajan, Anubha, Wielscher, Matthias, Lin, Frederick, Briggs, Catherine, Wang, Carol A., Moen, Gunn-Helen, Beaumont, Robin N., Bradfield, Jonathan P., Abraham, Abin, Thorleifsson, Gudmar, Gabrielsen, Maiken E., Ostrowski, Sisse R., Modzelewska, Dominika, Nohr, Ellen A., Hypponen, Elina, Srivastava, Amit, Talbot, Octavious, Allard, Catherine, Williams, Scott M., Menon, Ramkumar, Shields, Beverley M., Sveinbjornsson, Gardar, Xu, Huan, Melbye, Mads, Lowe, Jr, William, Bouchard, Luigi, Oken, Emily, Pedersen, Ole B., Gudbjartsson, Daniel F., Erikstrup, Christian, Sørensen, Erik, Lie, Rolv T., Teramo, Kari, Hallman, Mikko, Juliusdottir, Thorhildur, Hakonarson, Hakon, Ullum, Henrik, Hattersley, Andrew T., Sletner, Line, Merialdi, Mario, Rifas-Shiman, Sheryl L., Steingrimsdottir, Thora, Scholtens, Denise, Power, Christine, West, Jane, Nyegaard, Mette, Capra, John A., Skogholt, Anne H., Magnus, Per, Andreassen, Ole A., Thorsteinsdottir, Unnur, Grant, Struan F. A., Qvigstad, Elisabeth, Pennell, Craig E., Hivert, Marie-France, Hayes, Geoffrey M., Jarvelin, Marjo-Riitta, McCarthy, Mark I., Lawlor, Deborah A., Nielsen, Henriette S., Mägi, Reedik, Rokas, Antonis, Hveem, Kristian, Stefansson, Kari, Feenstra, Bjarke, Njolstad, Pål, Muglia, Louis J., Freathy, Rachel M., Johansson, Stefan, Zhang, Ge, and Jacobsson, Bo

Published
2023
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46. De novo variants in RNF213 are associated with a clinical spectrum ranging from Leigh syndrome to early-onset stroke

Author

Brunet, Theresa, Zott, Benedikt, Lieftüchter, Victoria, Lenz, Dominic, Schmidt, Axel, Peters, Philipp, Kopajtich, Robert, Zaddach, Malin, Zimmermann, Hanna, Hüning, Irina, Ballhausen, Diana, Staufner, Christian, Bianzano, Alyssa, Hughes, Joanne, Taylor, Robert W., McFarland, Robert, Devlin, Anita, Mihaljević, Mihaela, Barišić, Nina, Rohlfs, Meino, Wilfling, Sibylle, Sondheimer, Neal, Hewson, Stacy, Marinakis, Nikolaos M., Kosma, Konstantina, Traeger-Synodinos, Joanne, Elbracht, Miriam, Begemann, Matthias, Trepels-Kottek, Sonja, Hasan, Dimah, Scala, Marcello, Capra, Valeria, Zara, Federico, van der Ven, Amelie T., Driemeyer, Joenna, Apitz, Christian, Krämer, Johannes, Strong, Alanna, Hakonarson, Hakon, Watson, Deborah, Mayr, Johannes A., Prokisch, Holger, Meitinger, Thomas, Borggraefe, Ingo, Spiegler, Juliane, Baric, Ivo, Paolini, Marco, Gerstl, Lucia, and Wagner, Matias

Published
2024
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47. Secondary ACMG and non-ACMG genetic findings in a multiethnic cohort of 16,713 pediatric participants

Author

Aliazami, Farnoush, Ribeiro Carneiro, Thaise Nayane, Akbarzadeh, Mahdi, Kazemioula, Golnesa, Saeidian, Amir Hesam, Palizban, Fahimeh, Biglari, Sajjad, Coleman, David, Snyder, James, Wang, Fengxiang, Billings, Jonathan, Terek, Shannon, Mentch, Frank, Regan-Fendt, Kelly, Tsoi, Lam C., Dorrani, Naghmeh, Saeidian, Amir Hossein, March, Michael E., Youssefian, Leila, Watson, Deborah J., Bhandari, Esha, Wang, Xiang, Zhao, Xiaonan, Owen, Nichole Marie, Strong, Alanna, Harr, Margaret H., Bhoj, Elizabeth, Zackai, Elaine, Vahidnezhad, Hassan, Gudjonsson, Johann, Cederbaum, Stephen D., Deignan, Joshua L., Glessner, Joseph, Grody, Wayne W., and Hakonarson, Hakon

Published
2024
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48. Mapping the human genetic architecture of COVID-19

Author

Niemi, Mari EK, Karjalainen, Juha, Liao, Rachel G, Neale, Benjamin M, Daly, Mark, Ganna, Andrea, Davis, Lea, Lee, Sulggi, Priest, James, Renieri, Alessandra, Sankaran, Vijay G, van Heel, David, Deelen, Patrick, Richards, J Brent, Nakanishi, Tomoko, Biesecker, Les, Kerchberger, V Eric, Baillie, J Kenneth, Mari, Francesca, Bernasconi, Anna, Baillie, Stefano Ceri, Canakoglu, Arif, Chang, Xiao, Glessner, Joseph R, and Hakonarson, Hakon

Subjects
Genetics, Prevention, Human Genome, Biodefense, Vaccine Related, Clinical Research, Lung, Emerging Infectious Diseases, Pneumonia, Infectious Diseases, Aetiology, 2.1 Biological and endogenous factors, Infection, Good Health and Well Being, Autoimmunity, Body Mass Index, COVID-19, Critical Illness, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Geographic Mapping, Hospitalization, Host-Pathogen Interactions, Humans, Inflammation, Information Dissemination, Male, Multifactorial Inheritance, Racial Groups, SARS-CoV-2, Smoking, COVID-19 Host Genetics Initiative, General Science & Technology
Abstract

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3-7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

Published
2021

49. SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Author

D’Antonio, Matteo, Nguyen, Jennifer P, Arthur, Timothy D, Matsui, Hiroko, Neale, Benjamin M, Daly, Mark, Ganna, Andrea, Stevens, Christine, Pathak, Gita A, Andrews, Shea J, Kanai, Masahiro, Cordioli, Mattia, Karjalainen, Juha, Polimanti, Renato, Pirinen, Matti, Harerimana, Nadia, Veerapen, Kumar, Wolford, Brooke, Nguyen, Huy, Solomonson, Matthew, Liao, Rachel G, Chwialkowska, Karolina, Trankiem, Amy, Balaconis, Mary K, Hayward, Caroline, Richmond, Anne, Campbell, Archie, Morris, Marcela, Fawns-Ritchie, Chloe, Glessner, Joseph T, Shaw, Douglas M, Chang, Xiao, Polikowski, Hannah, Lauren, E, Chen, Hung-Hsin, Wanying, Zhu, Hakonarson, Hakon, Porteous, David J, Below, Jennifer, North, Kari, McCormick, Joseph B, Timmers, Paul RHJ, Wilson, James F, Tenesa, Albert, D’Mellow, Kenton, Kerr, Shona M, Niemi, Mari EK, Nkambul, Lindokuhle, von Hohenstaufen, Kathrin Aprile, Sobh, Ali, Eltoukhy, Madonna M, Yassen, Amr M, Hegazy, Mohamed AF, Okasha, Kamal, Eid, Mohammed A, Moahmed, Hanteera S, Shahin, Doaa, El-Sherbiny, Yasser M, Elhadidy, Tamer A, Elghafar, Mohamed S Abd, El-Jawhari, Jehan J, Mohamed, Attia AS, Elnagdy, Marwa H, Samir, Amr, Abdel-Aziz, Mahmoud, Khafaga, Walid T, El-Lawaty, Walaa M, Torky, Mohamed S, El-shanshory, Mohamed R, Batini, Chiara, Lee, Paul H, Shrine, Nick, Williams, Alexander T, Tobin, Martin D, Guyatt, Anna L, John, Catherine, Packer, Richard J, Ali, Altaf, Free, Robert C, Wang, Xueyang, Wain, Louise V, Hollox, Edward J, Venn, Laura D, Bee, Catherine E, Adams, Emma L, Niavarani, Ahmadreza, Sharififard, Bahareh, Aliannejad, Rasoul, Amirsavadkouhi, Ali, and Naderpour, Zeinab

Subjects
Biological Sciences, Genetics, Human Genome, Lung, Coronaviruses, Infectious Diseases, Coronaviruses Disparities and At-Risk Populations, Biotechnology, Emerging Infectious Diseases, 2.1 Biological and endogenous factors, Good Health and Well Being, COVID-19, Chromosome Mapping, Computational Biology, Databases, Genetic, Ethnicity, Gene Expression, Gene Expression Profiling, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Organ Specificity, Polymorphism, Single Nucleotide, Quantitative Trait Loci, SARS-CoV-2, Severity of Illness Index, Transcriptome, COVID-19 Host Genetics Initiative, GWAS, colocalization, eQTL, Biochemistry and Cell Biology, Medical Physiology, Biological sciences
Abstract

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types.

Published
2021

50. Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients

Author

Le Coz, Carole, Nguyen, David N, Su, Chun, Nolan, Brian E, Albrecht, Amanda V, Xhani, Suela, Sun, Di, Demaree, Benjamin, Pillarisetti, Piyush, Khanna, Caroline, Wright, Francis, Chen, Peixin Amy, Yoon, Samuel, Stiegler, Amy L, Maurer, Kelly, Garifallou, James P, Rymaszewski, Amy, Kroft, Steven H, Olson, Timothy S, Seif, Alix E, Wertheim, Gerald, Grant, Struan FA, Vo, Linda T, Puck, Jennifer M, Sullivan, Kathleen E, Routes, John M, Zakharova, Viktoria, Shcherbina, Anna, Mukhina, Anna, Rudy, Natasha L, Hurst, Anna CE, Atkinson, T Prescott, Boggon, Titus J, Hakonarson, Hakon, Abate, Adam R, Hajjar, Joud, Nicholas, Sarah K, Lupski, James R, Verbsky, James, Chinn, Ivan K, Gonzalez, Michael V, Wells, Andrew D, Marson, Alex, Poon, Gregory MK, and Romberg, Neil

Subjects
Human Genome, Clinical Research, Stem Cell Research - Nonembryonic - Human, Biotechnology, Regenerative Medicine, Genetics, Stem Cell Research, Stem Cell Research - Nonembryonic - Non-Human, Hematology, Adolescent, Adult, Agammaglobulinemia, B-Lymphocytes, Cell Differentiation, Cell Line, Child, Child, Preschool, Chromatin, Dendritic Cells, Female, Gene Expression Regulation, Developmental, HEK293 Cells, Hematopoiesis, Hematopoietic Stem Cells, Humans, Infant, Lymphopoiesis, Male, Mutation, Precursor Cells, B-Lymphoid, Proto-Oncogene Proteins, Stem Cells, Trans-Activators, Young Adult, Medical and Health Sciences, Immunology
Abstract

The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1's critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.

Published
2021

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