Browsing by Author "Keavney, Bernard"

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    Genetic resiliency associated with dominant lethal TPM1 mutation causing atrial septal defect with high heritability
    (Elsevier, 2022-02-15) Teekakirikul, Polakit; Zhu, Wenjuan; Xu, Xinxiu; Young, Cullen B.; Tan, Tuantuan; Smith, Amanda M.; Wang, Chengdong; Peterson, Kevin A.; Gabriel, George C.; Ho, Sebastian; Sheng, Yi; de Bellaing, Anne Moreau; Sonnenberg, Daniel A.; Lin, Jiuann-huey; Fotiou, Elisavet; Tenin, Gennadiy; Wang, Michael X.; Wu, Yijen L.; Feinstein, Timothy; Devine, William; Gou, Honglan; Bais, Abha S.; Glennon, Benjamin J.; Zahid, Maliha; Wong, Timothy C.; Ahmad, Ferhaan; Rynkiewicz, Michael J.; Lehman, William J.; Keavney, Bernard; Alastalo, Tero-Pekka; Freckmann, Mary-Louise; Orwig, Kyle; Murray, Steve; Ware, Stephanie M.; Zhao, Hui; Feingold, Brian; Lo, Cecilia W.; Pediatrics, School of Medicine
    Analysis of large-scale human genomic data has yielded unexplained mutations known to cause severe disease in healthy individuals. Here, we report the unexpected recovery of a rare dominant lethal mutation in TPM1, a sarcomeric actin-binding protein, in eight individuals with large atrial septal defect (ASD) in a five-generation pedigree. Mice with Tpm1 mutation exhibit early embryonic lethality with disrupted myofibril assembly and no heartbeat. However, patient-induced pluripotent-stem-cell-derived cardiomyocytes show normal beating with mild myofilament defect, indicating disease suppression. A variant in TLN2, another myofilament actin-binding protein, is identified as a candidate suppressor. Mouse CRISPR knock-in (KI) of both the TLN2 and TPM1 variants rescues heart beating, with near-term fetuses exhibiting large ASD. Thus, the role of TPM1 in ASD pathogenesis unfolds with suppression of its embryonic lethality by protective TLN2 variant. These findings provide evidence that genetic resiliency can arise with genetic suppression of a deleterious mutation.
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    Genome-wide analysis identifies 12 loci influencing human reproductive behavior
    (Nature, 2016-10) Barban, Nicola; Jansen, Rick; de Vlaming, Ronald; Vaez, Ahmad; Mandemakers, Jornt J.; Tropf, Felix C.; Shen, Xia; Wilson, James F.; Chasman, Daniel I.; Nolte, Ilja M.; Tragante, Vinicius; van der Laan, Sander W.; Perry, John R. B.; Kong, Augustine; Ahluwalia, Tarunveer; Albrecht, Eva; Yerges-Armstrong, Laura; Atzmon, Gil; Auro, Kirsi; Ayers, Kristin; Bakshi, Andrew; Ben-Avraham, Danny; Berger, Klaus; Bergman, Aviv; Bertram, Lars; Bielak, Lawrence F.; Bjornsdottir, Gyda; Bonder, Marc Jan; Broer, Linda; Bui, Minh; Barbieri, Caterina; Cavadino, Alana; Chavarro, Jorge E; Turman, Constance; Concas, Maria Pina; Cordell, Heather J.; Davies, Gail; Eibich, Peter; Eriksson, Nicholas; Esko, Tõnu; Eriksson, Joel; Falahi, Fahimeh; Felix, Janine F.; Fontana, Mark Alan; Franke, Lude; Gandin, Ilaria; Gaskins, Audrey J.; Gieger, Christian; Gunderson, Erica P.; Guo, Xiuqing; Hayward, Caroline; He, Chunyan; Hofer, Edith; Huang, Hongyan; Joshi, Peter K.; Kanoni, Stavroula; Karlsson, Robert; Kiechl, Stefan; Kifley, Annette; Kluttig, Alexander; Kraft, Peter; Lagou, Vasiliki; Lecoeur, Cecile; Lahti, Jari; Li-Gao, Ruifang; Lind, Penelope A.; Liu, Tian; Makalic, Enes; Mamasoula, Crysovalanto; Matteson, Lindsay; Mbarek, Hamdi; McArdle, Patrick F.; McMahon, George; Meddens, S. Fleur W.; Mihailov, Evelin; Miller, Mike; Missmer, Stacey A.; Monnereau, Claire; van der Most, Peter J.; Myhre, Ronny; Nalls, Mike A.; Nutile, Teresa; Panagiota, Kalafati Ioanna; Porcu, Eleonora; Prokopenko, Inga; Rajan, Kumar B.; Rich-Edwards, Janet; Rietveld, Cornelius A.; Robino, Antonietta; Rose, Lynda M.; Rueedi, Rico; Ryan, Kathy; Saba, Yasaman; Schmidt, Daniel; Smith, Jennifer A.; Stolk, Lisette; Streeten, Elizabeth; Tonjes, Anke; Thorleifsson, Gudmar; Ulivi, Sheila; Wedenoja, Juho; Wellman, Juergen; Willeit, Peter; Yao, Jie; Yengo, Loic; Zhao, Jing Hua; Zhao, Wei; Zhernakova, Daria V.; Amin, Najaf; Andrews, Howard; Balkau, Beverly; Barzilai, Nir; Bergmann, Sven; Biino, Ginevra; Bisgaard, Hans; Bønnelykke, Klaus; Boomsma, Dorret I.; Buring, Julie E.; Campbell, Harry; Cappellani, Stefania; Ciullo, Marina; Cox, Simon R.; Cucca, Francesco; Daniela, Toniolo; Davey-Smith, George; Deary, Ian J.; Dedoussis, George; Deloukas, Panos; van Duijn, Cornelia M.; de Geus, Eco J. C.; Eriksson, Johan G.; Evans, Denis A.; Faul, Jessica D.; Felicita, Sala Cinzia; Froguel, Philippe; Gasparini, Paolo; Girotto, Giorgia; Grabe, Hans-Jörgen; Greiser, Karin Halina; Groenen, Patrick J. F.; de Haan, Hugoline G.; Haerting, Johannes; Harris, Tamara B.; Heath, Andrew C.; Heikkilä, Kauko; Hofman, Albert; Homuth, Georg; Holliday, Elizabeth G.; Hopper, John; Hypponen, Elina; Jacobsson, Bo; Jaddoe, Vincent W.; Johannesson, Magnus; Jugessur, Astanand; Kähönen, Mika; Kajantie, Eero; Kardia, Sharon L. R.; Keavney, Bernard; Kolcic, Ivana; Koponen, Päivikki; Kovacs, Peter; Kronenberg, Florian; Kutalik, Zoltan; La Bianca, Martina; Lachance, Genevieve; Iacono, William; Lai, Sandra; Lehtimäki, Terho; Liewald, David C.; Lindgren, Cecilia; Liu, Yongmei; Luben, Robert; Lucht, Michael; Luoto, Riitta; Magnus, Per; Magnusson, Patrik K. E.; Martin, Nicholas G.; McGue, Matt; McQuillan, Ruth; Medland, Sarah E.; Meisinger, Christa; Mellström, Dan; Metspalu, Andres; Michela, Traglia; Milani, Lili; Mitchell, Paul; Montgomery, Grant W.; Mook-Kanamori, Dennis; de Mutsert, Renée; Nohr, Ellen A.; Ohlsson, Claes; Olsen, Jørn; Ong, Ken K.; Paternoster, Lavinia; Pattie, Alison; Penninx, Brenda W. J. H.; Perola, Markus; Peyser, Patricia A.; Pirastu, Mario; Polasek, Ozren; Power, Chris; Kaprio, Jaakko; Raffel, Leslie J.; Räikkönen, Katri; Raitakari, Olli; Ridker, Paul M.; Ring, Susan M.; Roll, Kathryn; Rudan, Igor; Ruggiero, Daniela; Rujescu, Dan; Salomaa, Veikko; Schlessinger, David; Schmidt, Helena; Schmidt, Reinhold; Schupf, Nicole; Smit, Johannes; Sorice, Rossella; Spector, Tim D.; Starr, John M.; Stöckl, Doris; Strauch, Konstantin; Stumvoll, Michael; Swertz, Morris A.; Thorsteinsdottir, Unnur; Thurik, A. Roy; Timpson, Nicholas J.; Tönjes, Anke; Tung, Joyce Y.; Uitterlinden, André G.; Vaccargiu, Simona; Viikari, Jorma; Vitart, Veronique; Völzke, Henry; Vollenweider, Peter; Vuckovic, Dragana; Waage, Johannes; Wagner, Gert G.; Wang, Jie Jin; Wareham, Nicholas J.; Weir, David R.; Willemsen, Gonneke; Willeit, Johann; Wright, Alan F.; Zondervan, Krina T.; Stefannson, Kari; Krueger, Robert F.; Lee, James J.; Benjamin, Daniel J.; Cesarini, David; Koellinger, Philipp D.; den Hoed, Marcel; Snieder, Harold; Mills, Melinda C.; Department of Epidemiology, Richard M. Fairbanks School of Public Health
    The genetic architecture of human reproductive behavior—age at first birth (AFB) and number of children ever born (NEB)—has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.
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    Response to correspondence on “Reproducibility of CRISPR-Cas9 methods for generation of conditional mouse alleles: a multi-center evaluation”
    (BMC, 2021-04-07) Gurumurthy, Channabasavaiah B.; O’Brien, Aidan R.; Quadros, Rolen M.; Adams, John, Jr.; Alcaide, Pilar; Ayabe, Shinya; Ballard, Johnathan; Batra, Surinder K.; Beauchamp, Marie-Claude; Becker, Kathleen A.; Bernas, Guillaume; Brough, David; Carrillo-Salinas, Francisco; Chan, Wesley; Chen, Hanying; Dawson, Ruby; DeMambro, Victoria; D’Hont, Jinke; Dibb, Katharine; Eudy, James D.; Gan, Lin; Gao, Jing; Gonzales, Amy; Guntur, Anyonya; Guo, Huiping; Harms, Donald W.; Harrington, Anne; Hentges, Kathryn E.; Humphreys, Neil; Imai, Shiho; Ishii, Hideshi; Iwama, Mizuho; Jonasch, Eric; Karolak, Michelle; Keavney, Bernard; Khin, Nay-Chi; Konno, Masamitsu; Kotani, Yuko; Kunihiro, Yayoi; Lakshmanan, Imayavaramban; Larochelle, Catherine; Lawrence, Catherine B.; Li, Lin; Lindner, Volkhard; Liu, Xian-De; Lopez-Castejon, Gloria; Loudon, Andrew; Lowe, Jenna; Jerome-Majeweska, Loydie; Matsusaka, Taiji; Miura, Hiromi; Miyasaka, Yoshiki; Morpurgo, Benjamin; Moty, Katherine; Nabeshima, Yo-ichi; Nakade, Koji; Nakashiba, Toshiaki; Nakashima, Kenichi; Obata, Yuichi; Ogiwara, Sanae; Ouellet, Mariette; Oxburgh, Leif; Piltz, Sandra; Pinz, Ilka; Ponnusamy, Moorthy P.; Ray, David; Redder, Ronald J.; Rosen, Clifford J.; Ross, Nikki; Ruhe, Mark T.; Ryzhova, Larisa; Salvador, Ane M.; Shameen Alam, Sabrina; Sedlacek, Radislav; Sharma, Karan; Smith, Chad; Staes, Katrien; Starrs, Lora; Sugiyama, Fumihiro; Takahashi, Satoru; Tanaka, Tomohiro; Trafford, Andrew; Uno, Yoshihiro; Vanhoutte, Leen; Vanrockeghem, Frederique; Willis, Brandon J.; Wright, Christian S.; Yamauchi, Yuko; Yi, Xin; Yoshimi, Kazuto; Zhang, Xuesong; Zhang, Yu; Ohtsuka, Masato; Das, Satyabrata; Garry, Daniel J.; Hochepied, Tino; Thomas, Paul; Parker-Thornburg, Jan; Adamson, Antony D.; Yoshiki, Atsushi; Schmouth, Jean-Francois; Golovko, Andrei; Thompson, William R.; Lloyd, K.C. Kent; Wood, Joshua A.; Cowan, Mitra; Mashimo, Tomoji; Mizuno, Seiya; Zhu, Hao; Kasparek, Petr; Liaw, Lucy; Miano, Joseph M.; Burgio, Gaetan; Medicine, School of Medicine