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1. Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Author

Johnson, Janel O., Chia, Ruth, Miller, Danny E., Li, Rachel, Kumaran, Ravindran, Abramzon, Yevgeniya, Alahmady, Nada, Renton, Alan E., Topp, Simon D., Gibbs, J. Raphael, Cookson, Mark R., Sabir, Marya S., Dalgard, Clifton L., Troakes, Claire, Jones, Ashley R., Shatunov, Aleksey, Iacoangeli, Alfredo, Al Khleifat, Ahmad, Ticozzi, Nicola, Silani, Vincenzo, Gellera, Cinzia, Blair, Ian P., Dobson-Stone, Carol, Kwok, John B., Bonkowski, Emily S., Palvadeau, Robin, Tienari, Pentti J., Morrison, Karen E., Shaw, Pamela J., Al-Chalabi, Ammar, Brown, Robert H., Calvo, Andrea, Mora, Gabriele, Al-Saif, Hind, Gotkine, Marc, Leigh, Fawn, Chang, Irene J., Perlman, Seth J., Glass, Ian, Scott, Anna I., Shaw, Christopher E., Basak, A. Nazli, Landers, John E., Chiò, Adriano, Crawford, Thomas O., Smith, Bradley N., Traynor, Bryan J., Smith, Bradley N., Ticozzi, Nicola, Fallini, Claudia, Gkazi, Athina Soragia, Topp, Simon D., Scotter, Emma L., Kenna, Kevin P., Keagle, Pamela, Tiloca, Cinzia, Vance, Caroline, Troakes, Claire, Colombrita, Claudia, King, Andrew, Pensato, Viviana, Castellotti, Barbara, Baas, Frank, ten Asbroek, Anneloor L. M. A., McKenna-Yasek, Diane, McLaughlin, Russell L., Polak, Meraida, Asress, Seneshaw, Esteban-Pérez, Jesús, Stevic, Zorica, D’Alfonso, Sandra, Mazzini, Letizia, Comi, Giacomo P., Del Bo, Roberto, Ceroni, Mauro, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, van Rheenen, Wouter, Rademakers, Rosa, van Blitterswijk, Marka, Lauria, Giuseppe, Duga, Stefano, Corti, Stefania, Cereda, Cristina, Corrado, Lucia, Sorarù, Gianni, Williams, Kelly L., Nicholson, Garth A., Blair, Ian P., Leblond-Manry, Claire, Rouleau, Guy A., Hardiman, Orla, Morrison, Karen E., Veldink, Jan H., van den Berg, Leonard H., Al-Chalabi, Ammar, Pall, Hardev, Shaw, Pamela J., Turner, Martin R., Talbot, Kevin, Taroni, Franco, García-Redondo, Alberto, Wu, Zheyang, Glass, Jonathan D., Gellera, Cinzia, Ratti, Antonia, Brown, Robert H., Silani, Vincenzo, Shaw, Christopher E., Landers, John E., Dalgard, Clifton L., Adeleye, Adelani, Soltis, Anthony R., Alba, Camille, Viollet, Coralie, Bacikova, Dagmar, Hupalo, Daniel N., Sukumar, Gauthaman, Pollard, Harvey B., Wilkerson, Matthew D., Martinez, Elisa McGrath, Abramzon, Yevgeniya, Ahmed, Sarah, Arepalli, Sampath, Baloh, Robert H., Bowser, Robert, Brady, Christopher B., Brice, Alexis, Broach, James, Campbell, Roy H., Camu, William, Chia, Ruth, Cooper-Knock, John, Ding, Jinhui, Drepper, Carsten, Drory, Vivian E., Dunckley, Travis L., Eicher, John D., England, Bryce K., Faghri, Faraz, Feldman, Eva, Floeter, Mary Kay, Fratta, Pietro, Geiger, Joshua T., Gerhard, Glenn, Gibbs, J. Raphael, Gibson, Summer B., Glass, Jonathan D., Hardy, John, Harms, Matthew B., Heiman-Patterson, Terry D., Hernandez, Dena G., Jansson, Lilja, Kirby, Janine, Kowall, Neil W., Laaksovirta, Hannu, Landeck, Natalie, Landi, Francesco, Le Ber, Isabelle, Lumbroso, Serge, MacGowan, Daniel J. L., Maragakis, Nicholas J., Mora, Gabriele, Mouzat, Kevin, Murphy, Natalie A., Myllykangas, Liisa, Nalls, Mike A., Orrell, Richard W., Ostrow, Lyle W., Pamphlett, Roger, Pickering-Brown, Stuart, Pioro, Erik P., Pletnikova, Olga, Pliner, Hannah A., Pulst, Stefan M., Ravits, John M., Renton, Alan E., Rivera, Alberto, Robberecht, Wim, Rogaeva, Ekaterina, Rollinson, Sara, Rothstein, Jeffrey D., Scholz, Sonja W., Sendtner, Michael, Shaw, Pamela J., Sidle, Katie C., Simmons, Zachary, Singleton, Andrew B., Smith, Nathan, Stone, David J., Tienari, Pentti J., Troncoso, Juan C., Valori, Miko, Van Damme, Philip, Van Deerlin, Vivianna M., Van Den Bosch, Ludo, Zinman, Lorne, Landers, John E., Chiò, Adriano, Traynor, Bryan J., Angelocola, Stefania M., Ausiello, Francesco P., Barberis, Marco, Bartolomei, Ilaria, Battistini, Stefania, Bersano, Enrica, Bisogni, Giulia, Borghero, Giuseppe, Brunetti, Maura, Cabona, Corrado, Calvo, Andrea, Canale, Fabrizio, Canosa, Antonio, Cantisani, Teresa A., Capasso, Margherita, Caponnetto, Claudia, Cardinali, Patrizio, Carrera, Paola, Casale, Federico, Chiò, Adriano, Colletti, Tiziana, Conforti, Francesca L., Conte, Amelia, Conti, Elisa, Corbo, Massimo, Cuccu, Stefania, Dalla Bella, Eleonora, D’Errico, Eustachio, DeMarco, Giovanni, Dubbioso, Raffaele, Ferrarese, Carlo, Ferraro, Pilar M., Filippi, Massimo, Fini, Nicola, Floris, Gianluca, Fuda, Giuseppe, Gallone, Salvatore, Gianferrari, Giulia, Giannini, Fabio, Grassano, Maurizio, Greco, Lucia, Iazzolino, Barbara, Introna, Alessandro, La Bella, Vincenzo, Lattante, Serena, Lauria, Giuseppe, Liguori, Rocco, Logroscino, Giancarlo, Logullo, Francesco O., Lunetta, Christian, Mandich, Paola, Mandrioli, Jessica, Manera, Umberto, Manganelli, Fiore, Marangi, Giuseppe, Marinou, Kalliopi, Marrosu, Maria Giovanna, Martinelli, Ilaria, Messina, Sonia, Moglia, Cristina, Mora, Gabriele, Mosca, Lorena, Murru, Maria R., Origone, Paola, Passaniti, Carla, Petrelli, Cristina, Petrucci, Antonio, Pozzi, Susanna, Pugliatti, Maura, Quattrini, Angelo, Ricci, Claudia, Riolo, Giulia, Riva, Nilo, Russo, Massimo, Sabatelli, Mario, Salamone, Paolina, Salivetto, Marco, Salvi, Fabrizio, Santarelli, Marialuisa, Sbaiz, Luca, Sideri, Riccardo, Simone, Isabella, Simonini, Cecilia, Spataro, Rossella, Tanel, Raffaella, Tedeschi, Gioacchino, Ticca, Anna, Torriello, Antonella, Tranquilli, Stefania, Tremolizzo, Lucio, Trojsi, Francesca, Vasta, Rosario, Vacchiano, Veria, Vita, Giuseppe, Volanti, Paolo, Zollino, Marcella, and Zucchi, Elisabetta

Abstract

IMPORTANCE: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. OBJECTIVE: To identify the genetic variants associated with juvenile ALS. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. MAIN OUTCOMES AND MEASURES: De novo variants present only in the index case and not in unaffected family members. RESULTS: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. CONCLUSIONS AND RELEVANCE: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.

Published
2021
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2. Genetic architecture of subcortical brain structures in 38,851 individuals

Author

Satizabal, Claudia L., Adams, Hieab H. H., Hibar, Derrek P., White, Charles C., Knol, Maria J., Stein, Jason L., Scholz, Markus, Sargurupremraj, Muralidharan, Jahanshad, Neda, Roshchupkin, Gennady V., Smith, Albert V., Bis, Joshua C., Jian, Xueqiu, Luciano, Michelle, Hofer, Edith, Teumer, Alexander, van der Lee, Sven J., Yang, Jingyun, Yanek, Lisa R., Lee, Tom V., Li, Shuo, Hu, Yanhui, Koh, Jia Yu, Eicher, John D., Desrivières, Sylvane, Arias-Vasquez, Alejandro, Chauhan, Ganesh, Athanasiu, Lavinia, Rentería, Miguel E., Kim, Sungeun, Hoehn, David, Armstrong, Nicola J., Chen, Qiang, Holmes, Avram J., den Braber, Anouk, Kloszewska, Iwona, Andersson, Micael, Espeseth, Thomas, Grimm, Oliver, Abramovic, Lucija, Alhusaini, Saud, Milaneschi, Yuri, Papmeyer, Martina, Axelsson, Tomas, Ehrlich, Stefan, Roiz-Santiañez, Roberto, Kraemer, Bernd, Håberg, Asta K., Jones, Hannah J., Pike, G. Bruce, Stein, Dan J., Stevens, Allison, Bralten, Janita, Vernooij, Meike W., Harris, Tamara B., Filippi, Irina, Witte, A. Veronica, Guadalupe, Tulio, Wittfeld, Katharina, Mosley, Thomas H., Becker, James T., Doan, Nhat Trung, Hagenaars, Saskia P., Saba, Yasaman, Cuellar-Partida, Gabriel, Amin, Najaf, Hilal, Saima, Nho, Kwangsik, Mirza-Schreiber, Nazanin, Arfanakis, Konstantinos, Becker, Diane M., Ames, David, Goldman, Aaron L., Lee, Phil H., Boomsma, Dorret I., Lovestone, Simon, Giddaluru, Sudheer, Le Hellard, Stephanie, Mattheisen, Manuel, Bohlken, Marc M., Kasperaviciute, Dalia, Schmaal, Lianne, Lawrie, Stephen M., Agartz, Ingrid, Walton, Esther, Tordesillas-Gutierrez, Diana, Davies, Gareth E., Shin, Jean, Ipser, Jonathan C., Vinke, Louis N., Hoogman, Martine, Jia, Tianye, Burkhardt, Ralph, Klein, Marieke, Crivello, Fabrice, Janowitz, Deborah, Carmichael, Owen, Haukvik, Unn K., Aribisala, Benjamin S., Schmidt, Helena, Strike, Lachlan T., Cheng, Ching-Yu, Risacher, Shannon L., Pütz, Benno, Fleischman, Debra A., Assareh, Amelia A., Mattay, Venkata S., Buckner, Randy L., Mecocci, Patrizia, Dale, Anders M., Cichon, Sven, Boks, Marco P., Matarin, Mar, Penninx, Brenda W. J. H., Calhoun, Vince D., Chakravarty, M. Mallar, Marquand, Andre F., Macare, Christine, Kharabian Masouleh, Shahrzad, Oosterlaan, Jaap, Amouyel, Philippe, Hegenscheid, Katrin, Rotter, Jerome I., Schork, Andrew J., Liewald, David C. M., de Zubicaray, Greig I., Wong, Tien Yin, Shen, Li, Sämann, Philipp G., Brodaty, Henry, Roffman, Joshua L., de Geus, Eco J. C., Tsolaki, Magda, Erk, Susanne, van Eijk, Kristel R., Cavalleri, Gianpiero L., van der Wee, Nic J. A., McIntosh, Andrew M., Gollub, Randy L., Bulayeva, Kazima B., Bernard, Manon, Richards, Jennifer S., Himali, Jayandra J., Loeffler, Markus, Rommelse, Nanda, Hoffmann, Wolfgang, Westlye, Lars T., Valdés Hernández, Maria C., Hansell, Narelle K., van Erp, Theo G. M., Wolf, Christiane, Kwok, John B. J., Vellas, Bruno, Heinz, Andreas, Olde Loohuis, Loes M., Delanty, Norman, Ho, Beng-Choon, Ching, Christopher R. K., Shumskaya, Elena, Singh, Baljeet, Hofman, Albert, van der Meer, Dennis, Homuth, Georg, Psaty, Bruce M., Bastin, Mark E., Montgomery, Grant W., Foroud, Tatiana M., Reppermund, Simone, Hottenga, Jouke-Jan, Simmons, Andrew, Meyer-Lindenberg, Andreas, Cahn, Wiepke, Whelan, Christopher D., van Donkelaar, Marjolein M. J., Yang, Qiong, Hosten, Norbert, Green, Robert C, Thalamuthu, Anbupalam, Mohnke, Sebastian, Hulshoff Pol, Hilleke E., Lin, Honghuang, Jack, Clifford R., Schofield, Peter R., Mühleisen, Thomas W., Maillard, Pauline, Potkin, Steven G., Wen, Wei, Fletcher, Evan, Toga, Arthur W., Gruber, Oliver, Huentelman, Matthew, Davey Smith, George, Launer, Lenore J., Nyberg, Lars, Jönsson, Erik G., Crespo-Facorro, Benedicto, Koen, Nastassja, Greve, Douglas N., Uitterlinden, André G., Weinberger, Daniel R., Steen, Vidar M., Fedko, Iryna O., Groenewold, Nynke A., Niessen, Wiro J., Toro, Roberto, Tzourio, Christophe, Longstreth, William T., Ikram, M. Kamran, Smoller, Jordan W., van Tol, Marie-Jose, Sussmann, Jessika E., Paus, Tomas, Lemaître, Hervé, Schroeter, Matthias L., Mazoyer, Bernard, Andreassen, Ole A., Holsboer, Florian, Depondt, Chantal, Veltman, Dick J., Turner, Jessica A., Pausova, Zdenka, Schumann, Gunter, van Rooij, Daan, Djurovic, Srdjan, Deary, Ian J., McMahon, Katie L., Müller-Myhsok, Bertram, Brouwer, Rachel M., Soininen, Hilkka, Pandolfo, Massimo, Wassink, Thomas H., Cheung, Joshua W., Wolfers, Thomas, Martinot, Jean-Luc, Zwiers, Marcel P., Nauck, Matthias, Melle, Ingrid, Martin, Nicholas G., Kanai, Ryota, Westman, Eric, Kahn, René S., Sisodiya, Sanjay M., White, Tonya, Saremi, Arvin, van Bokhoven, Hans, Brunner, Han G., Völzke, Henry, Wright, Margaret J., van ‘t Ent, Dennis, Nöthen, Markus M., Ophoff, Roel A., Buitelaar, Jan K., Fernández, Guillén, Sachdev, Perminder S., Rietschel, Marcella, van Haren, Neeltje E. M., Fisher, Simon E., Beiser, Alexa S., Francks, Clyde, Saykin, Andrew J., Mather, Karen A., Romanczuk-Seiferth, Nina, Hartman, Catharina A., DeStefano, Anita L., Heslenfeld, Dirk J., Weiner, Michael W., Walter, Henrik, Hoekstra, Pieter J., Nyquist, Paul A., Franke, Barbara, Bennett, David A., Grabe, Hans J., Johnson, Andrew D., Chen, Christopher, van Duijn, Cornelia M., Lopez, Oscar L., Fornage, Myriam, Wardlaw, Joanna M., Schmidt, Reinhold, DeCarli, Charles, De Jager, Philip L., Villringer, Arno, Debette, Stéphanie, Gudnason, Vilmundur, Medland, Sarah E., Shulman, Joshua M., Thompson, Paul M., Seshadri, Sudha, and Ikram, M. Arfan

Abstract

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophilaorthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Published
2019
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3. A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology

Author

de Vries, Paul S., Sabater-Lleal, Maria, Huffman, Jennifer E., Marten, Jonathan, Song, Ci, Pankratz, Nathan, Bartz, Traci M., de Haan, Hugoline G., Delgado, Graciela E., Eicher, John D., Martinez-Perez, Angel, Ward-Caviness, Cavin K., Brody, Jennifer A., Chen, Ming-Huei, de Maat, Moniek P. M., Frånberg, Mattias, Gill, Dipender, Kleber, Marcus E., Rivadeneira, Fernando, Soria, José Manuel, Tang, Weihong, Tofler, Geoffrey H., Uitterlinden, André G., van Hylckama Vlieg, Astrid, Seshadri, Sudha, Boerwinkle, Eric, Davies, Neil M., Giese, Anne-Katrin, Ikram, M. Kamran, Kittner, Steven J., McKnight, Barbara, Psaty, Bruce M., Reiner, Alex P., Sargurupremraj, Muralidharan, Taylor, Kent D., Fornage, Myriam, Hamsten, Anders, März, Winfried, Rosendaal, Frits R., Souto, Juan Carlos, Dehghan, Abbas, Johnson, Andrew D., Morrison, Alanna C., O'Donnell, Christopher J., and Smith, Nicholas L.

Abstract

Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27?495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a trans-ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring F7 messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel (REEP3 and JAZF1-AS1) and 6 known loci associated with FVII activity, explaining 19.0% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing REEP3 in HuH7 cells upregulated FVII, whereas silencing JAZF1 downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at REEP3 and JAZF1 contribute to FVII activity by regulating F7 expression levels. FVII activity appears to contribute to the etiology of IS in the general population.

Published
2019
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4. A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology

Author

de Vries, Paul S., Sabater-Lleal, Maria, Huffman, Jennifer E., Marten, Jonathan, Song, Ci, Pankratz, Nathan, Bartz, Traci M., de Haan, Hugoline G., Delgado, Graciela E., Eicher, John D., Martinez-Perez, Angel, Ward-Caviness, Cavin K., Brody, Jennifer A., Chen, Ming-Huei, de Maat, Moniek P.M., Frånberg, Mattias, Gill, Dipender, Kleber, Marcus E., Rivadeneira, Fernando, Soria, José Manuel, Tang, Weihong, Tofler, Geoffrey H., Uitterlinden, André G., van Hylckama Vlieg, Astrid, Seshadri, Sudha, Boerwinkle, Eric, Davies, Neil M., Giese, Anne-Katrin, Ikram, M. Kamran, Kittner, Steven J., McKnight, Barbara, Psaty, Bruce M., Reiner, Alex P., Sargurupremraj, Muralidharan, Taylor, Kent D., Fornage, Myriam, Hamsten, Anders, März, Winfried, Rosendaal, Frits R., Souto, Juan Carlos, Dehghan, Abbas, Johnson, Andrew D., Morrison, Alanna C., O’Donnell, Christopher J., and Smith, Nicholas L.

Abstract

Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27 495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a trans-ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring F7messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel (REEP3and JAZF1-AS1) and 6 known loci associated with FVII activity, explaining 19.0% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing REEP3in HuH7 cells upregulated FVII, whereas silencing JAZF1downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at REEP3and JAZF1contribute to FVII activity by regulating F7expression levels. FVII activity appears to contribute to the etiology of IS in the general population.

Published
2019
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5. Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Author

Howson, Joanna M M, Zhao, Wei, Barnes, Daniel R, Ho, Weang-Kee, Young, Robin, Paul, Dirk S, Waite, Lindsay L, Freitag, Daniel F, Fauman, Eric B, Salfati, Elias L, Sun, Benjamin B, Eicher, John D, Johnson, Andrew D, Sheu, Wayne H H, Nielsen, Sune F, Lin, Wei-Yu, Surendran, Praveen, Malarstig, Anders, Wilk, Jemma B, Tybjærg-Hansen, Anne, Rasmussen, Katrine L, Kamstrup, Pia R, Deloukas, Panos, Erdmann, Jeanette, Kathiresan, Sekar, Samani, Nilesh J, Schunkert, Heribert, Watkins, Hugh, Do, Ron, Rader, Daniel J, Johnson, Julie A, Hazen, Stanley L, Quyyumi, Arshed A, Spertus, John A, Pepine, Carl J, Franceschini, Nora, Justice, Anne, Reiner, Alex P, Buyske, Steven, Hindorff, Lucia A, Carty, Cara L, North, Kari E, Kooperberg, Charles, Boerwinkle, Eric, Young, Kristin, Graff, Mariaelisa, Peters, Ulrike, Absher, Devin, Hsiung, Chao A, Lee, Wen-Jane, Taylor, Kent D, Chen, Ying-Hsiang, Lee, I-Te, Guo, Xiuqing, Chung, Ren-Hua, Hung, Yi-Jen, Rotter, Jerome I, Juang, Jyh-Ming J, Quertermous, Thomas, Wang, Tzung-Dau, Rasheed, Asif, Frossard, Philippe, Alam, Dewan S, Majumder, Abdulla al Shafi, Di Angelantonio, Emanuele, Chowdhury, Rajiv, Chen, Yii-Der Ida, Nordestgaard, Børge G, Assimes, Themistocles L, Danesh, John, Butterworth, Adam S, and Saleheen, Danish

Abstract

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP–CAD associations (P < 5 × 10−8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

Published
2017
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6. Whole exome sequencing in the Framingham Heart Study identifies rare variation in HYAL2 that influences platelet aggregation

Author

Eicher, John D., Chen, Ming-Huei, Pitsillides, Achilleas N., Lin, Honghuang, Veeraraghavan, Narayanan, Brody, Jennifer A., Metcalf, Ginger A., Muzny, Donna M., Gibbs, Richard A., Becker, Diane M., Becker, Lewis C., Faraday, Nauder, Mathias, Rasika A., Yanek, Lisa R., Boerwinkle, Eric, Adrienne Cupples, L., and Johnson, Andrew D.

Published
2017
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7. Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation

Author

Chu, Audrey Y, Deng, Xuan, Fisher, Virginia A, Drong, Alexander, Zhang, Yang, Feitosa, Mary F, Liu, Ching-Ti, Weeks, Olivia, Choh, Audrey C, Duan, Qing, Dyer, Thomas D, Eicher, John D, Guo, Xiuqing, Heard-Costa, Nancy L, Kacprowski, Tim, Kent, Jack W, Lange, Leslie A, Liu, Xinggang, Lohman, Kurt, Lu, Lingyi, Mahajan, Anubha, O'Connell, Jeffrey R, Parihar, Ankita, Peralta, Juan M, Smith, Albert V, Zhang, Yi, Homuth, Georg, Kissebah, Ahmed H, Kullberg, Joel, Laqua, René, Launer, Lenore J, Nauck, Matthias, Olivier, Michael, Peyser, Patricia A, Terry, James G, Wojczynski, Mary K, Yao, Jie, Bielak, Lawrence F, Blangero, John, Borecki, Ingrid B, Bowden, Donald W, Carr, John Jeffrey, Czerwinski, Stefan A, Ding, Jingzhong, Friedrich, Nele, Gudnason, Vilmunder, Harris, Tamara B, Ingelsson, Erik, Johnson, Andrew D, Kardia, Sharon L R, Langefeld, Carl D, Lind, Lars, Liu, Yongmei, Mitchell, Braxton D, Morris, Andrew P, Mosley, Thomas H, Rotter, Jerome I, Shuldiner, Alan R, Towne, Bradford, Völzke, Henry, Wallaschofski, Henri, Wilson, James G, Allison, Matthew, Lindgren, Cecilia M, Goessling, Wolfram, Cupples, L Adrienne, Steinhauser, Matthew L, and Fox, Caroline S

Abstract

Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10−8; false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.

Published
2017
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8. Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance

Author

Lotta, Luca A, Gulati, Pawan, Day, Felix R, Payne, Felicity, Ongen, Halit, van de Bunt, Martijn, Gaulton, Kyle J, Eicher, John D, Sharp, Stephen J, Luan, Jian'an, De Lucia Rolfe, Emanuella, Stewart, Isobel D, Wheeler, Eleanor, Willems, Sara M, Adams, Claire, Yaghootkar, Hanieh, Forouhi, Nita G, Khaw, Kay-Tee, Johnson, Andrew D, Semple, Robert K, Frayling, Timothy, Perry, John R B, Dermitzakis, Emmanouil, McCarthy, Mark I, Barroso, Inês, Wareham, Nicholas J, Savage, David B, Langenberg, Claudia, O'Rahilly, Stephen, and Scott, Robert A

Abstract

Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms in common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.

Published
2017
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9. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

Author

Ehret, Georg B, Ferreira, Teresa, Chasman, Daniel I, Jackson, Anne U, Schmidt, Ellen M, Johnson, Toby, Thorleifsson, Gudmar, Luan, Jian'an, Donnelly, Louise A, Kanoni, Stavroula, Petersen, Ann-Kristin, Pihur, Vasyl, Strawbridge, Rona J, Shungin, Dmitry, Hughes, Maria F, Meirelles, Osorio, Kaakinen, Marika, Bouatia-Naji, Nabila, Kristiansson, Kati, Shah, Sonia, Kleber, Marcus E, Guo, Xiuqing, Lyytikäinen, Leo-Pekka, Fava, Cristiano, Eriksson, Niclas, Nolte, Ilja M, Magnusson, Patrik K, Salfati, Elias L, Rallidis, Loukianos S, Theusch, Elizabeth, Smith, Andrew J P, Folkersen, Lasse, Witkowska, Kate, Pers, Tune H, Joehanes, Roby, Kim, Stuart K, Lataniotis, Lazaros, Jansen, Rick, Johnson, Andrew D, Warren, Helen, Kim, Young Jin, Zhao, Wei, Wu, Ying, Tayo, Bamidele O, Bochud, Murielle, Absher, Devin, Adair, Linda S, Amin, Najaf, Arking, Dan E, Axelsson, Tomas, Baldassarre, Damiano, Balkau, Beverley, Bandinelli, Stefania, Barnes, Michael R, Barroso, Inês, Bevan, Stephen, Bis, Joshua C, Bjornsdottir, Gyda, Boehnke, Michael, Boerwinkle, Eric, Bonnycastle, Lori L, Boomsma, Dorret I, Bornstein, Stefan R, Brown, Morris J, Burnier, Michel, Cabrera, Claudia P, Chambers, John C, Chang, I-Shou, Cheng, Ching-Yu, Chines, Peter S, Chung, Ren-Hua, Collins, Francis S, Connell, John M, Döring, Angela, Dallongeville, Jean, Danesh, John, de Faire, Ulf, Delgado, Graciela, Dominiczak, Anna F, Doney, Alex S F, Drenos, Fotios, Edkins, Sarah, Eicher, John D, Elosua, Roberto, Enroth, Stefan, Erdmann, Jeanette, Eriksson, Per, Esko, Tonu, Evangelou, Evangelos, Evans, Alun, Fall, Tove, Farrall, Martin, Felix, Janine F, Ferrières, Jean, Ferrucci, Luigi, Fornage, Myriam, Forrester, Terrence, Franceschini, Nora, Franco, Oscar H, Franco-Cereceda, Anders, Fraser, Ross M, Ganesh, Santhi K, Gao, He, Gertow, Karl, Gianfagna, Francesco, Gigante, Bruna, Giulianini, Franco, Goel, Anuj, Goodall, Alison H, Goodarzi, Mark O, Gorski, Mathias, Gräßler, Jürgen, Groves, Christopher J, Gudnason, Vilmundur, Gyllensten, Ulf, Hallmans, Göran, Hartikainen, Anna-Liisa, Hassinen, Maija, Havulinna, Aki S, Hayward, Caroline, Hercberg, Serge, Herzig, Karl-Heinz, Hicks, Andrew A, Hingorani, Aroon D, Hirschhorn, Joel N, Hofman, Albert, Holmen, Jostein, Holmen, Oddgeir Lingaas, Hottenga, Jouke-Jan, Howard, Phil, Hsiung, Chao A, Hunt, Steven C, Ikram, M Arfan, Illig, Thomas, Iribarren, Carlos, Jensen, Richard A, Kähönen, Mika, Kang, Hyun Min, Kathiresan, Sekar, Keating, Brendan J, Khaw, Kay-Tee, Kim, Yun Kyoung, Kim, Eric, Kivimaki, Mika, Klopp, Norman, Kolovou, Genovefa, Komulainen, Pirjo, Kooner, Jaspal S, Kosova, Gulum, Krauss, Ronald M, Kuh, Diana, Kutalik, Zoltan, Kuusisto, Johanna, Kvaløy, Kirsti, Lakka, Timo A, Lee, Nanette R, Lee, I-Te, Lee, Wen-Jane, Levy, Daniel, Li, Xiaohui, Liang, Kae-Woei, Lin, Honghuang, Lin, Li, Lindström, Jaana, Lobbens, Stéphane, Männistö, Satu, Müller, Gabriele, Müller-Nurasyid, Martina, Mach, François, Markus, Hugh S, Marouli, Eirini, McCarthy, Mark I, McKenzie, Colin A, Meneton, Pierre, Menni, Cristina, Metspalu, Andres, Mijatovic, Vladan, Moilanen, Leena, Montasser, May E, Morris, Andrew D, Morrison, Alanna C, Mulas, Antonella, Nagaraja, Ramaiah, Narisu, Narisu, Nikus, Kjell, O'Donnell, Christopher J, O'Reilly, Paul F, Ong, Ken K, Paccaud, Fred, Palmer, Cameron D, Parsa, Afshin, Pedersen, Nancy L, Penninx, Brenda W, Perola, Markus, Peters, Annette, Poulter, Neil, Pramstaller, Peter P, Psaty, Bruce M, Quertermous, Thomas, Rao, Dabeeru C, Rasheed, Asif, Rayner, N William, Renström, Frida, Rettig, Rainer, Rice, Kenneth M, Roberts, Robert, Rose, Lynda M, Rossouw, Jacques, Samani, Nilesh J, Sanna, Serena, Saramies, Jouko, Schunkert, Heribert, Sebert, Sylvain, Sheu, Wayne H-H, Shin, Young-Ah, Sim, Xueling, Smit, Johannes H, Smith, Albert V, Sosa, Maria X, Spector, Tim D, Stančáková, Alena, Stanton, Alice V, Stirrups, Kathleen E, Stringham, Heather M, Sundstrom, Johan, Swift, Amy J, Syvänen, Ann-Christine, Tai, E-Shyong, Tanaka, Toshiko, Tarasov, Kirill V, Teumer, Alexander, Thorsteinsdottir, Unnur, Tobin, Martin D, Tremoli, Elena, Uitterlinden, Andre G, Uusitupa, Matti, Vaez, Ahmad, Vaidya, Dhananjay, van Duijn, Cornelia M, van Iperen, Erik P A, Vasan, Ramachandran S, Verwoert, Germaine C, Virtamo, Jarmo, Vitart, Veronique, Voight, Benjamin F, Vollenweider, Peter, Wagner, Aline, Wain, Louise V, Wareham, Nicholas J, Watkins, Hugh, Weder, Alan B, Westra, Harm-Jan, Wilks, Rainford, Wilsgaard, Tom, Wilson, James F, Wong, Tien Y, Yang, Tsun-Po, Yao, Jie, Yengo, Loic, Zhang, Weihua, Zhao, Jing Hua, Zhu, Xiaofeng, Bovet, Pascal, Cooper, Richard S, Mohlke, Karen L, Saleheen, Danish, Lee, Jong-Young, Elliott, Paul, Gierman, Hinco J, Willer, Cristen J, Franke, Lude, Hovingh, G Kees, Taylor, Kent D, Dedoussis, George, Sever, Peter, Wong, Andrew, Lind, Lars, Assimes, Themistocles L, Njølstad, Inger, Schwarz, Peter E H, Langenberg, Claudia, Snieder, Harold, Caulfield, Mark J, Melander, Olle, Laakso, Markku, Saltevo, Juha, Rauramaa, Rainer, Tuomilehto, Jaakko, Ingelsson, Erik, Lehtimäki, Terho, Hveem, Kristian, Palmas, Walter, März, Winfried, Kumari, Meena, Salomaa, Veikko, Chen, Yii-Der I, Rotter, Jerome I, Froguel, Philippe, Jarvelin, Marjo-Riitta, Lakatta, Edward G, Kuulasmaa, Kari, Franks, Paul W, Hamsten, Anders, Wichmann, H-Erich, Palmer, Colin N A, Stefansson, Kari, Ridker, Paul M, Loos, Ruth J F, Chakravarti, Aravinda, Deloukas, Panos, Morris, Andrew P, Newton-Cheh, Christopher, and Munroe, Patricia B

Abstract

To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure–associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure–related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.

Published
2016
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10. Large-Scale Genomic Analyses Link Reproductive Aging to Hypothalamic Signaling, Breast Cancer Susceptibility, and BRCA1-Mediated DNA Repair

Author

Day, Felix R., Ruth, Katherine S., Thompson, Deborah J., Lunetta, Kathryn L., Pervjakova, Natalia, Chasman, Daniel I., Stolk, Lisette, Finucane, Hilary K., Sulem, Patrick, Bulik-Sullivan, Brendan, Esko, Tõnu, Johnson, Andrew D., Elks, Cathy E., Franceschini, Nora, He, Chunyan, Altmaier, Elisabeth, Brody, Jennifer A., Franke, Lude L., Huffman, Jennifer E., Keller, Margaux F., McArdle, Patrick F., Nutile, Teresa, Porcu, Eleonora, Robino, Antonietta, Rose, Lynda M., Schick, Ursula M., Smith, Jennifer A., Teumer, Alexander, Traglia, Michela, Vuckovic, Dragana, Yao, Jie, Zhao, Wei, Albrecht, Eva, Amin, Najaf, Corre, Tanguy, Hottenga, Jouke-Jan, Mangino, Massimo, Smith, Albert V., Tanaka, Toshiko, Abecasis, Gonçalo R., Andrulis, Irene L., Anton-Culver, Hoda, Antoniou, Antonis C., Arndt, Volker, Arnold, Alice M., Barbieri, Caterina, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bernstein, Leslie, Bielinski, Suzette J., Blomqvist, Carl, Boerwinkle, Eric, Bogdanova, Natalia V., Bojesen, Stig E., Bolla, Manjeet K., Borresen-Dale, Anne-Lise, Boutin, Thibaud S., Brauch, Hiltrud, Brenner, Hermann, Brüning, Thomas, Burwinkel, Barbara, Campbell, Archie, Campbell, Harry, Chanock, Stephen J., Chapman, J. Ross, Ida Chen, Yii-Der, Chenevix-Trench, Georgia, Couch, Fergus J., Coviello, Andrea D., Cox, Angela, Czene, Kamila, Darabi, Hatef, De Vivo, Immaculata, Demerath, Ellen W., Dennis, Joe, Devilee, Peter, Dörk, Thilo, dos-Santos-Silva, Isabel, Dunning, Alison M., Eicher, John D., Fasching, Peter A., Faul, Jessica D., Figueroa, Jonine, Flesch-Janys, Dieter, Gandin, Ilaria, Garcia, Melissa E., García-Closas, Montserrat, Giles, Graham G., Girotto, Giorgia G., Goldberg, Mark S., González-Neira, Anna, Goodarzi, Mark O., Grove, Megan L., Gudbjartsson, Daniel F., Guénel, Pascal, Guo, Xiuqing, Haiman, Christopher A., Hall, Per, Hamann, Ute, Henderson, Brian E., Hocking, Lynne J., Hofman, Albert, Homuth, Georg, Hooning, Maartje J., Hopper, John L., Hu, Frank B., Huang, Jinyan, Humphreys, Keith, Hunter, David J., Jakubowska, Anna, Jones, Samuel E., Kabisch, Maria, Karasik, David, Knight, Julia A., Kolcic, Ivana, Kooperberg, Charles, Kosma, Veli-Matti, Kriebel, Jennifer, Kristensen, Vessela, Lambrechts, Diether, Langenberg, Claudia, Li, Jingmei, Li, Xin, Lindström, Sara, Liu, Yongmei, Luan, Jian’an, Lubinski, Jan, Mägi, Reedik, Mannermaa, Arto, Manz, Judith, Margolin, Sara, Marten, Jonathan, Martin, Nicholas G., Masciullo, Corrado, Meindl, Alfons, Michailidou, Kyriaki, Mihailov, Evelin, Milani, Lili, Milne, Roger L., Müller-Nurasyid, Martina, Nalls, Michael, Neale, Benjamin M., Nevanlinna, Heli, Neven, Patrick, Newman, Anne B., Nordestgaard, Børge G., Olson, Janet E., Padmanabhan, Sandosh, Peterlongo, Paolo, Peters, Ulrike, Petersmann, Astrid, Peto, Julian, Pharoah, Paul D. P., Pirastu, Nicola N., Pirie, Ailith, Pistis, Giorgio, Polasek, Ozren, Porteous, David, Psaty, Bruce M., Pylkäs, Katri, Radice, Paolo, Raffel, Leslie J., Rivadeneira, Fernando, Rudan, Igor, Rudolph, Anja, Ruggiero, Daniela, Sala, Cinzia F., Sanna, Serena, Sawyer, Elinor J., Schlessinger, David, Schmidt, Marjanka K., Schmidt, Frank, Schmutzler, Rita K., Schoemaker, Minouk J., Scott, Robert A., Seynaeve, Caroline M., Simard, Jacques, Sorice, Rossella, Southey, Melissa C., Stöckl, Doris, Strauch, Konstantin, Swerdlow, Anthony, Taylor, Kent D., Thorsteinsdottir, Unnur, Toland, Amanda E., Tomlinson, Ian, Truong, Thérèse, Tryggvadottir, Laufey, Turner, Stephen T., Vozzi, Diego, Wang, Qin, Wellons, Melissa, Willemsen, Gonneke, Wilson, James F., Winqvist, Robert, Wolffenbuttel, Bruce B. H. R., Wright, Alan F., Yannoukakos, Drakoulis, Zemunik, Tatijana, Zheng, Wei, Zygmunt, Marek, Bergmann, Sven, Boomsma, Dorret I., Buring, Julie E., Ferrucci, Luigi, Montgomery, Grant W., Gudnason, Vilmundur, Spector, Tim D., van Duijn, Cornelia M., Alizadeh, Behrooz Z., Ciullo, Marina, Crisponi, Laura, Easton, Douglas F., Gasparini, Paolo P., Gieger, Christian, Harris, Tamara B., Hayward, Caroline, Kardia, Sharon L. R., Kraft, Peter, McKnight, Barbara, Metspalu, Andres, Morrison, Alanna C., Reiner, Alex P., Ridker, Paul M., Rotter, Jerome I., Toniolo, Daniela, Uitterlinden, André G., Ulivi, Sheila, Völzke, Henry, Wareham, Nicholas J., Weir, David R., Yerges-Armstrong, Laura M., Price, Alkes L., Stefansson, Kari, Visser, Jenny A., Ong, Ken K., Chang-Claude, Jenny, Murabito, Joanne M., Perry, John R. B., and Murray, Anna

Abstract

Menopause timing has a major impact on infertility and risk of disease. Younger age at natural (nonsurgical) menopause (ANM) is associated with a higher risk of osteoporosis, cardiovascular disease, and type 2 diabetes and a lower risk of breast cancer. Late menopause is associated with a higher risk of breast cancer. It is well known that the age at which women go through menopause is partly determined by genes, but the underlying mechanisms are poorly understood. Genome-wide association studies have identified 18 common genetic variants associated with ANM. These variants explain less than 5% of the variation in ANM compared with the 21% explained by all common variants on genome-wide association study arrays.This genome-wide association study was the collaborative effort of researchers from 177 institutions worldwide. The study was designed to investigate genetic variants associated with timing of menopause among a population of approximately 70,000 women of European ancestry. A dual strategy was used to identify both common and, for the first time, low-frequency coding variants associated with ANM. The causal relationship between ANM and breast cancer was investigated using a Mendelian randomization approach.Combined analysis identified 1208 single-nucleotide polymorphisms (SNPs) of a total of approximately 2.6 million that reached the genome-wide significance threshold for association with ANM. Forty-four regions with common variants were identified; among these 44 loci were 2 rare low-frequency missense alleles of large effect. A majority of ANM SNPs were enriched in DNA damage response (DDR) genes, including the first common coding variant in BRCA1associated with any complex trait. Mendelian randomization analyses supported a causal relationship between delayed ANM and breast cancer risk; there was approximately 6% increase in risk per year; P= 3 × 10−14); increased risk with delayed menopause appeared to be mediated primarily by prolonged sex hormone exposure in a woman’s lifetime, not DDRmechanisms.This is the first study to confirm the link between early and late menopause and breast cancer risk using genetic information. Age at natural menopause genetic variants influence breast cancer risk primarily through variation in menopause timing. Although carrying higher numbers of ANM-increasing variants and enrichment in DDRgenes are associated with a modest increase in breast cancer risk, the major mechanism for increased risk appears to be prolonged estrogen and/or progesterone exposure due to delayed menopause.

Published
2015
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11. The additive blood pressure lowering effects of exercise intensity on post-exercise hypotension.

Author

Eicher, John D., Maresh, Carl M., Tsongalis, Gregory J., Thompson, Paul D., and Pescatello, Linda S.

Abstract

Background: Evidence contends lower levels of physical exertion reduce blood pressure (BP) as effectively as more rigorous levels. We compared the effects of low (40% peak oxygen consumption, Vo 2peak), moderate (60% Vo 2peak), and vigorous (100% Vo 2peak) exercise intensity on the BP response immediately following aerobic exercise. We also examined clinical correlates of the BP response. Methods: Subjects were 45 men (mean ± SEM, 43.9 ± 1.4 years) with elevated awake ambulatory BP (ABP, 144.5 ± 1.5/85.4 ± 1.2 mm Hg). Men completed four randomly assigned experiments: non-exercise control and three exercise bouts at low, moderate, and vigorous intensity. All experiments began with a baseline period of seated rest. Subjects left the laboratory wearing an ABP monitor. Results: Systolic ABP increased 2.8 ± 1.6 mm Hg less after low, 5.4 ± 1.4 mm Hg less after moderate, and 11.7 ± 1.5 mm Hg less after vigorous than control over 9 h (P < .001). Diastolic ABP decreased 1.5 ± 1.2 mm Hg more after low, 2.0 ± 1.0 mm Hg more after moderate, and 4.9 ± 1.3 mm Hg more after vigorous versus control over 9 h (P < .010). Baseline correlates of the systolic ABP post-exercise response to vigorous were fasting glucose (r = -0.415), C-reactive protein (r = -0.362), renin (r = −0.348), fasting insulin (r = 0.310), and fasting low density lipoprotein (r = −0.298) (R 2 = 0.400, P = .002). Baseline correlates of the diastolic ABP post-exercise response to vigorous were Vo 2peak (r = −0.431), fasting low density lipoprotein (r = -0.431), renin (r = -0.411), fibrinogen (r = 0.369), and fasting glucose (r = −0.326) (R 2 = 0.429, P < .001). Conclusions: The antihypertensive effects of exercise intensity occurred in dose response fashion. Clinicians should weigh the benefits and risks of prescribing vigorous exercise intensity for those with hypertension on an individual basis. [Copyright &y& Elsevier]

Published
2010
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12. Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies.

Author

Joshi, Amit D., Andersson, Charlotte, Buch, Stephan, Stender, Stefan, Noordam, Raymond, Weng, Lu-Chen, Weeke, Peter E., Auer, Paul L., Boehm, Bernhard, Chen, Constance, Choi, Hyon, Curhan, Gary, Denny, Joshua C., De Vivo, Immaculata, Eicher, John D., Ellinghaus, David, Folsom, Aaron R., Fuchs, Charles, Gala, Manish, and Haessler, Jeffrey

Abstract

Background & Aims A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease. Methods We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study-specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls. Results We observed independent associations for 2 single-nucleotide polymorphisms at the ABCG8 locus: rs11887534 (OR, 1.69; 95% confidence interval [CI], 1.54–1.86; P = 2.44 × 10 -60 ) and rs4245791 (OR, 1.27; P = 1.90 × 10 -34 ). We also identified and/or replicated associations for rs9843304 in TM4SF4 (OR, 1.12; 95% CI, 1.08–1.16; P = 6.09 × 10 -11 ), rs2547231 in SULT2A1 (encodes a sulfoconjugation enzyme that acts on hydroxysteroids and cholesterol-derived sterol bile acids) (OR, 1.17; 95% CI, 1.12–1.21; P = 2.24 × 10 -10 ), rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07–1.17; P = 2.55 × 10 -10 ), and rs6471717 near CYP7A1 (encodes an enzyme that catalyzes conversion of cholesterol to primary bile acids) (OR, 1.11; 95% CI, 1.08–1.15; P = 8.84 × 10 -9 ). Among individuals of African American and Hispanic American ancestry, rs11887534 and rs4245791 were associated positively with gallstone disease risk, whereas the association for the rs1260326 variant was inverse. Conclusions In this large-scale GWAS of gallstone disease, we identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydroxysteroids. [ABSTRACT FROM AUTHOR]

Published
2016
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13. Corrigendum: Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance

Author

Lotta, Luca A, Gulati, Pawan, Day, Felix R, Payne, Felicity, Ongen, Halit, van de Bunt, Martijn, Gaulton, Kyle J, Eicher, John D, Sharp, Stephen J, Luan, Jian'an, Rolfe, Emanuella De Lucia, Stewart, Isobel D, Wheeler, Eleanor, Willems, Sara M, Adams, Claire, Yaghootkar, Hanieh, Forouhi, Nita G, Khaw, Kay-Tee, Johnson, Andrew D, Semple, Robert K, Frayling, Timothy, Perry, John R B, Dermitzakis, Emmanouil, McCarthy, Mark I, Barroso, Inês, Wareham, Nicholas J, Savage, David B, Langenberg, Claudia, O'Rahilly, Stephen, and Scott, Robert A

Published
2017
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