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1,211 results on '"McKnight, Barbara"'

1. Whole-exome sequence analysis of anthropometric traits illustrates challenges in identifying effects of rare genetic variants

Author: Young, Kristin L, Fisher, Virginia, Deng, Xuan, Brody, Jennifer A, Graff, Misa, Lim, Elise, Lin, Bridget M, Xu, Hanfei, Amin, Najaf, An, Ping, Aslibekyan, Stella, Fohner, Alison E, Hidalgo, Bertha, Lenzini, Petra, Kraaij, Robert, Medina-Gomez, Carolina, Prokić, Ivana, Rivadeneira, Fernando, Sitlani, Colleen, Tao, Ran, van Rooij, Jeroen, Zhang, Di, Broome, Jai G, Buth, Erin J, Heavner, Benjamin D, Jain, Deepti, Smith, Albert V, Barnes, Kathleen, Boorgula, Meher Preethi, Chavan, Sameer, Darbar, Dawood, De Andrade, Mariza, Guo, Xiuqing, Haessler, Jeffrey, Irvin, Marguerite R, Kalyani, Rita R, Kardia, Sharon LR, Kooperberg, Charles, Kim, Wonji, Mathias, Rasika A, McDonald, Merry-Lynn, Mitchell, Braxton D, Peyser, Patricia A, Regan, Elizabeth A, Redline, Susan, Reiner, Alexander P, Rich, Stephen S, Rotter, Jerome I, Smith, Jennifer A, Weiss, Scott, Wiggins, Kerri L, Yanek, Lisa R, Arnett, Donna, Heard-Costa, Nancy L, Leal, Suzanne, Lin, Danyu, McKnight, Barbara, Province, Michael, van Duijn, Cornelia M, North, Kari E, Cupples, L Adrienne, and Liu, Ching-Ti
Subjects: Biological Sciences, Genetics, Clinical Research, Biotechnology, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Generic health relevance, Good Health and Well Being, Humans, Genome-Wide Association Study, Exome, Body Mass Index, Quantitative Trait Loci, Anthropometry, Intercellular Signaling Peptides and Proteins, Cell Cycle Proteins, body mass index, central obesity, exome sequencing, height
Abstract: Anthropometric traits, measuring body size and shape, are highly heritable and significant clinical risk factors for cardiometabolic disorders. These traits have been extensively studied in genome-wide association studies (GWASs), with hundreds of genome-wide significant loci identified. We performed a whole-exome sequence analysis of the genetics of height, body mass index (BMI) and waist/hip ratio (WHR). We meta-analyzed single-variant and gene-based associations of whole-exome sequence variation with height, BMI, and WHR in up to 22,004 individuals, and we assessed replication of our findings in up to 16,418 individuals from 10 independent cohorts from Trans-Omics for Precision Medicine (TOPMed). We identified four trait associations with single-nucleotide variants (SNVs; two for height and two for BMI) and replicated the LECT2 gene association with height. Our expression quantitative trait locus (eQTL) analysis within previously reported GWAS loci implicated CEP63 and RFT1 as potential functional genes for known height loci. We further assessed enrichment of SNVs, which were monogenic or syndromic variants within loci associated with our three traits. This led to the significant enrichment results for height, whereas we observed no Bonferroni-corrected significance for all SNVs. With a sample size of ∼20,000 whole-exome sequences in our discovery dataset, our findings demonstrate the importance of genomic sequencing in genetic association studies, yet they also illustrate the challenges in identifying effects of rare genetic variants.
Published: 2023

2. Dietary Meat, Trimethylamine N-Oxide-Related Metabolites, and Incident Cardiovascular Disease Among Older Adults: The Cardiovascular Health Study.

Author: Wang, Meng, Wang, Zeneng, Lee, Yujin, Lai, Heidi, de Oliveira Otto, Marcia, Lemaitre, Rozenn, Fretts, Amanda, Sotoodehnia, Nona, DiDonato, Joseph, McKnight, Barbara, Tang, W, Psaty, Bruce, Siscovick, David, Hazen, Stanley, Mozaffarian, Dariush, and Budoff, Matthew
Subjects: cardiovascular diseases, microbiome, myocardial infarction, red meat, stroke, trimethylamine N-oxide, Animals, Atherosclerosis, Cardiovascular Diseases, Carnitine, Humans, Meat, Methylamines, Risk Factors
Abstract: BACKGROUND: Effects of animal source foods (ASF) on atherosclerotic cardiovascular disease (ASCVD) and underlying mechanisms remain controversial. We investigated prospective associations of different ASF with incident ASCVD and potential mediation by gut microbiota-generated trimethylamine N-oxide, its L-carnitine-derived intermediates γ-butyrobetaine and crotonobetaine, and traditional ASCVD risk pathways. METHODS: Among 3931 participants from a community-based US cohort aged 65+ years, ASF intakes and trimethylamine N-oxide-related metabolites were measured serially over time. Incident ASCVD (myocardial infarction, fatal coronary heart disease, stroke, other atherosclerotic death) was adjudicated over 12.5 years median follow-up. Cox proportional hazards models with time-varying exposures and covariates examined ASF-ASCVD associations; and additive hazard models, mediation proportions by different risk pathways. RESULTS: After multivariable-adjustment, higher intakes of unprocessed red meat, total meat, and total ASF associated with higher ASCVD risk, with hazard ratios (95% CI) per interquintile range of 1.15 (1.01-1.30), 1.22 (1.07-1.39), and 1.18 (1.03-1.34), respectively. Trimethylamine N-oxide-related metabolites together significantly mediated these associations, with mediation proportions (95% CI) of 10.6% (1.0-114.5), 7.8% (1.0-32.7), and 9.2% (2.2-44.5), respectively. Processed meat intake associated with a nonsignificant trend toward higher ASCVD (1.11 [0.98-1.25]); intakes of fish, poultry, and eggs were not significantly associated. Among other risk pathways, blood glucose, insulin, and C-reactive protein, but not blood pressure or blood cholesterol, each significantly mediated the total meat-ASCVD association. CONCLUSIONS: In this large, community-based cohort, higher meat intake associated with incident ASCVD, partly mediated by microbiota-derived metabolites of L-carnitine, abundant in red meat. These novel findings support biochemical links between dietary meat, gut microbiome pathways, and ASCVD.
Published: 2022

3. Transcriptome-wide association study and Mendelian randomization in pancreatic cancer identifies susceptibility genes and causal relationships with type 2 diabetes and venous thromboembolism

Author: Lindstrom, Sara, Wang, Lu, Smith, Erin, Gordon, William, Van Hylckama Vlieg, Astrid, De Andrade, Mariza, Brody, Jennifer, Pattee, Jack, Haessler, Jeffrey, Brumpton, Ben, Chasman, Daniel, Suchon, Pierre, Chen, Ming-Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri, MacDonald, James, Braekkan, Sigrid, Armasu, Sebastian, Pankratz, Nathan, Jackson, Rabecca, Nielsen, Jonas, Giulianini, Franco, Puurunen, Marja, Ibrahim, Manal, Heckbert, Susan, Bammler, Theo, Frazer, Kelly, McCauley, Bryan, Taylor, Kent, Pankow, James, Reiner, Alexander, Gabrielsen, Maiken, Deleuze, Jean-François, O'Donnell, Chris, Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John-Bjarne, Rosendaal, Frits, Heit, John, Psaty, Bruce, Tang, Weihong, Kooperberg, Charles, Hveem, Kristian, Ridker, Paul, Morange, Pierre-Emmanuel, Johnson, Andrew, Kabrhel, Christopher, Trégouët, David-Alexandre, Smith, Nicholas, Tan, Marcus C.B., Isom, Chelsea A., Liu, Yangzi, Wu, Lang, Zhou, Dan, and Gamazon, Eric R.
Published: 2024
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4. Multi‐phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations

Author: Temprano‐Sagrera, Gerard, Sitlani, Colleen M, Bone, William P, Martin‐Bornez, Miguel, Voight, Benjamin F, Morrison, Alanna C, Damrauer, Scott M, de Vries, Paul S, Smith, Nicholas L, Sabater‐Lleal, Maria, Dehghan, Abbas, Heath, Adam S, Reiner, Alex P, Johnson, Andrew, Richmond, Anne, Peters, Annette, van Hylckama Vlieg, Astrid, McKnight, Barbara, Psaty, Bruce M, Hayward, Caroline, Ward‐Caviness, Cavin, O’Donnell, Christopher, Chasman, Daniel, Strachan, David P, Tregouet, David A, Mook‐Kanamori, Dennis, Gill, Dipender, Thibord, Florian, Asselbergs, Folkert W, Leebeek, Frank WG, Rosendaal, Frits R, Davies, Gail, Homuth, Georg, Temprano, Gerard, Campbell, Harry, Taylor, Herman A, Bressler, Jan, Huffman, Jennifer E, Rotter, Jerome I, Yao, Jie, Wilson, James F, Bis, Joshua C, Hahn, Julie M, Desch, Karl C, Wiggins, Kerri L, Raffield, Laura M, Bielak, Lawrence F, Yanek, Lisa R, Kleber, Marcus E, Mueller, Martina, Kavousi, Maryam, Mangino, Massimo, Liu, Melissa, Brown, Michael R, Conomos, Matthew P, Jhun, Min‐A, Chen, Ming‐Huei, de Maat, Moniek PM, Pankratz, Nathan, Peyser, Patricia A, Elliot, Paul, Wei, Peng, Wild, Philipp S, Morange, Pierre E, van der Harst, Pim, Yang, Qiong, Le, Ngoc‐Quynh, Marioni, Riccardo, Li, Ruifang, Cox, Simon R, Trompet, Stella, Felix, Stephan B, Völker, Uwe, Tang, Weihong, Koenig, Wolfgang, Jukema, J Wouter, Guo, Xiuqing, Lindstrom, Sara, Wang, Lu, Smith, Erin N, Gordon, William, de Andrade, Mariza, Brody, Jennifer A, Pattee, Jack W, Haessler, Jeffrey, Brumpton, Ben M, Chasman, Daniel I, Suchon, Pierre, Turman, Constance, Germain, Marine, MacDonald, James, and Braekkan, Sigrid K
Subjects: Genetics, Biotechnology, Human Genome, Atherosclerosis, Prevention, Cardiovascular, Hematology, 2.1 Biological and endogenous factors, Aetiology, Cardiovascular Diseases, Factor XI, Genetic Predisposition to Disease, Genome-Wide Association Study, Hemostasis, Hemostatics, Humans, Phenotype, Polymorphism, Single Nucleotide, Tissue Plasminogen Activator, blood coagulation, cardiovascular diseases, genetic pleiotropy, genome-wide association study, hemostasis, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology
Abstract: BackgroundMulti-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes.ObjectivesTo discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events.MethodsSummary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10-9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27).ResultsAcross the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes.ConclusionsThe discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.
Published: 2022

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

Author: Abe, Namiko, Abecasis, Gonçalo, Aguet, Francois, Albert, Christine, Almasy, Laura, Alonso, Alvaro, Ament, Seth, Anderson, Peter, Anugu, Pramod, Applebaum-Bowden, Deborah, Ardlie, Kristin, Arking, Dan, Arnett, Donna K, Ashley-Koch, Allison, Aslibekyan, Stella, Assimes, Tim, Auer, Paul, Avramopoulos, Dimitrios, Ayas, Najib, Balasubramanian, Adithya, Barnard, John, Barnes, Kathleen, Barr, R. Graham, Barron-Casella, Emily, Barwick, Lucas, Beaty, Terri, Beck, Gerald, Becker, Diane, Becker, Lewis, Beer, Rebecca, Beitelshees, Amber, Benjamin, Emelia, Benos, Takis, Bezerra, Marcos, Bielak, Larry, Bis, Joshua, Blackwell, Thomas, Blangero, John, Blue, Nathan, Boerwinkle, Eric, Bowden, Donald W., Bowler, Russell, Brody, Jennifer, Broeckel, Ulrich, Broome, Jai, Brown, Deborah, Bunting, Karen, Burchard, Esteban, Bustamante, Carlos, Buth, Erin, Cade, Brian, Cardwell, Jonathan, Carey, Vincent, Carrier, Julie, Carson, April P., Carty, Cara, Casaburi, Richard, Casas Romero, Juan P, Casella, James, Castaldi, Peter, Chaffin, Mark, Chang, Christy, Chang, Yi-Cheng, Chasman, Daniel, Chavan, Sameer, Chen, Bo-Juen, Chen, Wei-Min, Ida Chen, Yii-Der, Cho, Michael, Choi, Seung Hoan, Chuang, Lee-Ming, Chung, Mina, Chung, Ren-Hua, Clish, Clary, Comhair, Suzy, Conomos, Matthew, Cornell, Elaine, Correa, Adolfo, Crandall, Carolyn, Crapo, James, Cupples, L. Adrienne, Curran, Joanne, Curtis, Jeffrey, Custer, Brian, Damcott, Coleen, Darbar, Dawood, David, Sean, Davis, Colleen, Daya, Michelle, de Andrade, Mariza, de las Fuentes, Lisa, de Vries, Paul, DeBaun, Michael, Deka, Ranjan, DeMeo, Dawn, Devine, Scott, Dinh, Huyen, Doddapaneni, Harsha, Duan, Qing, Dugan-Perez, Shannon, Duggirala, Ravi, Durda, Jon Peter, Dutcher, Susan K., Eaton, Charles, Ekunwe, Lynette, El Boueiz, Adel, Ellinor, Patrick, Emery, Leslie, Erzurum, Serpil, Farber, Charles, Farek, Jesse, Fingerlin, Tasha, Flickinger, Matthew, Fornage, Myriam, Franceschini, Nora, Frazar, Chris, Fu, Mao, Fullerton, Stephanie M., Fulton, Lucinda, Gabriel, Stacey, Gan, Weiniu, Gao, Shanshan, Gao, Yan, Gass, Margery, Geiger, Heather, Gelb, Bruce, Geraci, Mark, Germer, Soren, Gerszten, Robert, Ghosh, Auyon, Gibbs, Richard, Gignoux, Chris, Gladwin, Mark, Glahn, David, Gogarten, Stephanie, Gong, Da-Wei, Goring, Harald, Graw, Sharon, Gray, Kathryn J., Grine, Daniel, Gross, Colin, Gu, C. Charles, Guan, Yue, Guo, Xiuqing, Gupta, Namrata, Haessler, Jeff, Hall, Michael, Han, Yi, Hanly, Patrick, Harris, Daniel, Hawley, Nicola L., He, Jiang, Heavner, Ben, Heckbert, Susan, Hernandez, Ryan, Herrington, David, Hersh, Craig, Hidalgo, Bertha, Hixson, James, Hobbs, Brian, Hokanson, John, Hong, Elliott, Hoth, Karin, Hsiung, Chao (Agnes), Hu, Jianhong, Hung, Yi-Jen, Huston, Haley, Hwu, Chii Min, Irvin, Marguerite Ryan, Jackson, Rebecca, Jain, Deepti, Jaquish, Cashell, Johnsen, Jill, Johnson, Andrew, Johnson, Craig, Johnston, Rich, Jones, Kimberly, Kang, Hyun Min, Kaplan, Robert, Kardia, Sharon, Kelly, Shannon, Kenny, Eimear, Kessler, Michael, Khan, Alyna, Khan, Ziad, Kim, Wonji, Kimoff, John, Kinney, Greg, Konkle, Barbara, Kooperberg, Charles, Kramer, Holly, Lange, Christoph, Lange, Ethan, Lange, Leslie, Laurie, Cathy, Laurie, Cecelia, LeBoff, Meryl, Lee, Jiwon, Lee, Sandra, Lee, Wen-Jane, LeFaive, Jonathon, Levine, David, Levy, Dan, Lewis, Joshua, Li, Xiaohui, Li, Yun, Lin, Henry, Lin, Honghuang, Lin, Xihong, Liu, Simin, Liu, Yongmei, Liu, Yu, Loos, Ruth J. F., Lubitz, Steven, Lunetta, Kathryn, Luo, James, Magalang, Ulysses, Mahaney, Michael, Make, Barry, Manichaikul, Ani, Manning, Alisa, Manson, JoAnn, Martin, Lisa, Marton, Melissa, Mathai, Susan, Mathias, Rasika, May, Susanne, McArdle, Patrick, McDonald, Merry-Lynn, McFarland, Sean, McGarvey, Stephen, McGoldrick, Daniel, McHugh, Caitlin, McNeil, Becky, Mei, Hao, Meigs, James, Menon, Vipin, Mestroni, Luisa, Metcalf, Ginger, Meyers, Deborah A, Mignot, Emmanuel, Mikulla, Julie, Min, Nancy, Minear, Mollie, Minster, Ryan L, Mitchell, Braxton D., Moll, Matt, Momin, Zeineen, Montasser, May E., Montgomery, Courtney, Muzny, Donna, Mychaleckyj, Josyf C, Nadkarni, Girish, Naik, Rakhi, Naseri, Take, Natarajan, Pradeep, Nekhai, Sergei, Nelson, Sarah C., Neltner, Bonnie, Nessner, Caitlin, Nickerson, Deborah, Nkechinyere, Osuji, North, Kari, O'Connell, Jeff, O'Connor, Tim, Ochs-Balcom, Heather, Okwuonu, Geoffrey, Pack, Allan, Paik, David T., Palmer, Nicholette, Pankow, James, Papanicolaou, George, Parker, Cora, Peloso, Gina, Peralta, Juan Manuel, Perez, Marco, Perry, James, Peters, Ulrike, Peyser, Patricia, Phillips, Lawrence S, Pleiness, Jacob, Pollin, Toni, Post, Wendy, Becker, Julia Powers, Boorgula, Meher Preethi, Preuss, Michael, Psaty, Bruce, Qasba, Pankaj, Qiao, Dandi, Qin, Zhaohui, Rafaels, Nicholas, Raffield, Laura, Rajendran, Mahitha, Ramachandran, Vasan S., Rao, D. C., Rasmussen-Torvik, Laura, Ratan, Aakrosh, Redline, Susan, Reed, Robert, Reeves, Catherine, Regan, Elizabeth, Reiner, Alex, Reupena, Muagututi‘a Sefuiva, Rice, Ken, Rich, Stephen, Robillard, Rebecca, Robine, Nicolas, Roden, Dan, Roselli, Carolina, Rotter, Jerome, Ruczinski, Ingo, Runnels, Alexi, Russell, Pamela, Ruuska, Sarah, Ryan, Kathleen, Sabino, Ester Cerdeira, Saleheen, Danish, Salimi, Shabnam, Salvi, Sejal, Salzberg, Steven, Sandow, Kevin, Sankaran, Vijay G., Santibanez, Jireh, Schwander, Karen, Schwartz, David, Sciurba, Frank, Seidman, Christine, Seidman, Jonathan, Sériès, Frédéric, Sheehan, Vivien, Sherman, Stephanie L., Shetty, Amol, Shetty, Aniket, Hui-Heng Sheu, Wayne, Shoemaker, M. Benjamin, Silver, Brian, Silverman, Edwin, Skomro, Robert, Smith, Albert Vernon, Smith, Jennifer, Smith, Josh, Smith, Nicholas, Smith, Tanja, Smoller, Sylvia, Snively, Beverly, Snyder, Michael, Sofer, Tamar, Sotoodehnia, Nona, Stilp, Adrienne M., Storm, Garrett, Streeten, Elizabeth, Su, Jessica Lasky, Sung, Yun Ju, Sylvia, Jody, Szpiro, Adam, Taliun, Daniel, Tang, Hua, Taub, Margaret, Taylor, Kent D., Taylor, Matthew, Taylor, Simeon, Telen, Marilyn, Thornton, Timothy A., Threlkeld, Machiko, Tinker, Lesley, Tirschwell, David, Tishkoff, Sarah, Tiwari, Hemant, Tong, Catherine, Tracy, Russell, Tsai, Michael, Vaidya, Dhananjay, Van Den Berg, David, VandeHaar, Peter, Vrieze, Scott, Walker, Tarik, Wallace, Robert, Walts, Avram, Wang, Fei Fei, Wang, Heming, Wang, Jiongming, Watson, Karol, Watt, Jennifer, Weeks, Daniel E., Weinstock, Joshua, Weir, Bruce, Weiss, Scott T, Weng, Lu-Chen, Wessel, Jennifer, Willer, Cristen, Williams, Kayleen, Williams, L. Keoki, Wilson, Carla, Wilson, James, Winterkorn, Lara, Wong, Quenna, Wu, Joseph, Xu, Huichun, Yanek, Lisa, Yang, Ivana, Yu, Ketian, Zekavat, Seyedeh Maryam, Zhang, Yingze, Zhao, Snow Xueyan, Zhao, Wei, Zhu, Xiaofeng, Ziv, Elad, Zody, Michael, Zoellner, Sebastian, Lindstrom, Sara, Wang, Lu, Smith, Erin N., Gordon, William, van Hylckama Vlieg, Astrid, Brody, Jennifer A., Pattee, Jack W., Haessler, Jeffrey, Brumpton, Ben M., Chasman, Daniel I., Suchon, Pierre, Chen, Ming-Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri L., MacDonald, James, Braekkan, Sigrid K., Armasu, Sebastian M., Pankratz, Nathan, Jackson, Rabecca D., Nielsen, Jonas B., Giulianini, Franco, Puurunen, Marja K., Ibrahim, Manal, Heckbert, Susan R., Bammler, Theo K., Frazer, Kelly A., McCauley, Bryan M., Taylor, Kent, Pankow, James S., Reiner, Alexander P., Gabrielsen, Maiken E., Deleuze, Jean-François, O'Donnell, Chris J., Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John-Bjarne, Rosendaal, Frits R., Heit, John A., Psaty, Bruce M., Tang, Weihong, Hveem, Kristian, Ridker, Paul M., Morange, Pierre-Emmanuel, Johnson, Andrew D., Kabrhel, Christopher, AlexandreTrégouët, David, Smith, Nicholas L., de Vries, Paul S., Reventun, Paula, Brown, Michael R., Heath, Adam S., Huffman, Jennifer E., Le, Ngoc-Quynh, Bebo, Allison, Temprano-Sagrera, Gerard, Raffield, Laura M., Ozel, Ayse Bilge, Thibord, Florian, Lewis, Joshua P., Rodriguez, Benjamin A. T., Polasek, Ozren, Yanek, Lisa R., Carrasquilla, German D., Marioni, Riccardo E., Kleber, Marcus E., Trégouët, David-Alexandre, Yao, Jie, Li-Gao, Ruifang, Joshi, Peter K., Trompet, Stella, Martinez-Perez, Angel, Ghanbari, Mohsen, Howard, Tom E., Reiner, Alex P., Arvanitis, Marios, Ryan, Kathleen A., Bartz, Traci M., Rudan, Igor, Faraday, Nauder, Linneberg, Allan, Davies, Gail, Delgado, Graciela E., Klaric, Lucija, Noordam, Raymond, van Rooij, Frank, Curran, Joanne E., Wheeler, Marsha M., Osburn, William O., O'Connell, Jeffrey R., Beswick, Andrew, Kolcic, Ivana, Souto, Juan Carlos, Becker, Lewis C., Hansen, Torben, Doyle, Margaret F., Harris, Sarah E., Moissl, Angela P., Rich, Stephen S., Campbell, Harry, Stott, David J., Soria, Jose Manuel, de Maat, Moniek P. M., Brody, Lawrence C., Auer, Paul L., Ben-Shlomo, Yoav, Hayward, Caroline, Mathias, Rasika A., Kilpeläinen, Tuomas O., Lange, Leslie A., Cox, Simon R., März, Winfried, Rotter, Jerome I., Mook-Kanamori, Dennis O., Wilson, James F., van der Harst, Pim, Jukema, J. Wouter, Ikram, M. Arfan, Desch, Karl C., Sabater-Lleal, Maria, Lowenstein, Charles J., and Morrison, Alanna C.
Published: 2024
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6. A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment

Author: Dehghan, Abbas, Heath, Adam S., Morrison, Alanna C., Reiner, Alex P., Johnson, Andrew, Richmond, Anne, Peters, Annette, van Hylckama Vlieg, Astrid, McKnight, Barbara, Psaty, Bruce M., Hayward, Caroline, Ward-Caviness, Cavin, O’Donnell, Christopher, Chasman, Daniel, Strachan, David P., Tregouet, David A., Mook-Kanamori, Dennis, Gill, Dipender, Thibord, Florian, Asselbergs, Folkert W., Leebeek, Frank W.G., Rosendaal, Frits R., Davies, Gail, Homuth, Georg, Temprano, Gerard, Campbell, Harry, Taylor, Herman A., Bressler, Jan, Huffman, Jennifer E., Rotter, Jerome I., Yao, Jie, Wilson, James F., Bis, Joshua C., Hahn, Julie M., Desch, Karl C., Wiggins, Kerri L., Díez-Ahijado, Laia, Raffield, Laura M., Bielak, Lawrence F., Yanek, Lisa R., Kleber, Marcus E., Sabater-Lleal, Maria, Mueller, Martina, Kavousi, Maryam, Mangino, Massimo, Conomos, Matthew P., Liu, Melissa, Brown, Michael R., Jhun, Min-A, Chen, Ming-Huei, de Maat, Moniek P.M., Pankratz, Nathan, Smith, Nicholas L., Peyser, Patricia A., Elliot, Paul, de Vries, Paul S., Wei, Peng, Wild, Philipp S., Morange, Pierre E., van der Harst, Pim, Yang, Qiong, Marioni, Riccardo, Li, Ruifang, Damrauer, Scott M., Cox, Simon R., Trompet, Stella, Felix, Stephan B., Völker, Uwe, Tang, Weihong, Koenig, Wolfgang, Jukema, J. Wouter, Guo, Xiuqing, Gallego-Fabrega, Cristina, Temprano-Sagrera, Gerard, Cárcel-Márquez, Jara, Muiño, Elena, Cullell, Natalia, Lledós, Miquel, Llucià-Carol, Laia, Martin-Campos, Jesús M., Sobrino, Tomás, Castillo, José, Millán, Mònica, Muñoz-Narbona, Lucía, López-Cancio, Elena, Ribó, Marc, Alvarez-Sabin, Jose, Jiménez-Conde, Jordi, Roquer, Jaume, Tur, Silvia, Obach, Victor, Arenillas, Juan F., Segura, Tomas, Serrano-Heras, Gemma, Marti-Fabregas, Joan, Freijo-Guerrero, Marimar, Moniche, Francisco, Castellanos, Maria del Mar, and Fernández-Cadenas, Israel
Published: 2024
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7. Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data

Author: Wainschtein, Pierrick, Jain, Deepti, Zheng, Zhili, Cupples, L Adrienne, Shadyab, Aladdin H, McKnight, Barbara, Shoemaker, Benjamin M, Mitchell, Braxton D, Psaty, Bruce M, Kooperberg, Charles, Liu, Ching-Ti, Albert, Christine M, Roden, Dan, Chasman, Daniel I, Darbar, Dawood, Lloyd-Jones, Donald M, Arnett, Donna K, Regan, Elizabeth A, Boerwinkle, Eric, Rotter, Jerome I, O’Connell, Jeffrey R, Yanek, Lisa R, de Andrade, Mariza, Allison, Matthew A, McDonald, Merry-Lynn N, Chung, Mina K, Fornage, Myriam, Chami, Nathalie, Smith, Nicholas L, Ellinor, Patrick T, Vasan, Ramachandran S, Mathias, Rasika A, Loos, Ruth JF, Rich, Stephen S, Lubitz, Steven A, Heckbert, Susan R, Redline, Susan, Guo, Xiuqing, Chen, Y-D Ida, Laurie, Cecelia A, Hernandez, Ryan D, McGarvey, Stephen T, Goddard, Michael E, Laurie, Cathy C, North, Kari E, Lange, Leslie A, Weir, Bruce S, Yengo, Loic, Yang, Jian, and Visscher, Peter M
Subjects: Human Genome, Genetics, 2.1 Biological and endogenous factors, Aetiology, Generic health relevance, Alleles, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Multifactorial Inheritance, Polymorphism, Single Nucleotide, TOPMed Anthropometry Working Group, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract: Analyses of data from genome-wide association studies on unrelated individuals have shown that, for human traits and diseases, approximately one-third to two-thirds of heritability is captured by common SNPs. However, it is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular whether the causal variants are rare, or whether it is overestimated due to bias in inference from pedigree data. Here we estimated heritability for height and body mass index (BMI) from whole-genome sequence data on 25,465 unrelated individuals of European ancestry. The estimated heritability was 0.68 (standard error 0.10) for height and 0.30 (standard error 0.10) for body mass index. Low minor allele frequency variants in low linkage disequilibrium (LD) with neighboring variants were enriched for heritability, to a greater extent for protein-altering variants, consistent with negative selection. Our results imply that rare variants, in particular those in regions of low linkage disequilibrium, are a major source of the still missing heritability of complex traits and disease.
Published: 2022

8. Longitudinal Plasma Measures of Trimethylamine N‐Oxide and Risk of Atherosclerotic Cardiovascular Disease Events in Community‐Based Older Adults

Author: Lee, Yujin, Nemet, Ina, Wang, Zeneng, Lai, Heidi TM, de Oliveira Otto, Marcia C, Lemaitre, Rozenn N, Fretts, Amanda M, Sotoodehnia, Nona, Budoff, Matthew, DiDonato, Joseph A, McKnight, Barbara, Tang, WH Wilson, Psaty, Bruce M, Siscovick, David S, Hazen, Stanley L, and Mozaffarian, Dariush
Subjects: Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Aging, Nutrition, Cardiovascular, Clinical Research, Heart Disease - Coronary Heart Disease, Prevention, Kidney Disease, Heart Disease, Atherosclerosis, Good Health and Well Being, Aged, Biomarkers, Cardiovascular Diseases, Humans, Methylamines, Middle Aged, Prospective Studies, Risk Factors, animal food, atherosclerotic cardiovascular disease, renal function, trimethylamine N-oxide, trimethylamine N‐oxide, Cardiorespiratory Medicine and Haematology, Cardiovascular medicine and haematology
Abstract: Background Trimethylamine N-oxide (TMAO) is a gut microbiota-dependent metabolite of dietary choline, L-carnitine, and phosphatidylcholine-rich foods. On the basis of experimental studies and patients with prevalent disease, elevated plasma TMAO may increase risk of atherosclerotic cardiovascular disease (ASCVD). TMAO is also renally cleared and may interact with and causally contribute to renal dysfunction. Yet, how serial TMAO levels relate to incident and recurrent ASCVD in community-based populations and the potential mediating or modifying role of renal function are not established. Methods and Results We investigated associations of serial measures of plasma TMAO, assessed at baseline and 7 years, with incident and recurrent ASCVD in a community-based cohort of 4131 (incident) and 1449 (recurrent) older US adults. TMAO was measured using stable isotope dilution liquid chromatography-tandem mass spectrometry (laboratory coefficient of variation,
Published: 2021

9. FGL1 as a modulator of plasma D‐dimer levels: Exome‐wide marker analysis of plasma tPA, PAI‐1, and D‐dimer

Author: Thibord, Florian, Song, Ci, Pattee, Jack, Rodriguez, Benjamin AT, Chen, Ming‐Huei, O’Donnell, Christopher J, Kleber, Marcus E, Delgado, Graciela E, Guo, Xiuqing, Yao, Jie, Taylor, Kent D, Ozel, Ayse Bilge, Brody, Jennifer A, McKnight, Barbara, Gyorgy, Beata, Simonsick, Eleanor, Leonard, Hampton L, Carrasquilla, Germán D, Guindo‐Martinez, Marta, Silveira, Angela, Temprano‐Sagrera, Gerard, Yanek, Lisa R, Becker, Diane M, Mathias, Rasika A, Becker, Lewis C, Raffield, Laura M, Kilpeläinen, Tuomas O, Grarup, Niels, Pedersen, Oluf, Hansen, Torben, Linneberg, Allan, Hamsten, Anders, Watkins, Hugh, Sabater‐Lleal, Maria, Nalls, Mike A, Trégouët, David‐Alexandre, Morange, Pierre‐Emmanuel, Psaty, Bruce M, Tracy, Russel P, Smith, Nicholas L, Desch, Karl C, Cushman, Mary, Rotter, Jerome I, de Vries, Paul S, Pankratz, Nathan D, Folsom, Aaron R, Morrison, Alanna C, März, Winfried, Tang, Weihong, and Johnson, Andrew D
Subjects: Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Clinical Research, Hematology, Genetics, Human Genome, Prevention, Exome, Fibrin Fibrinogen Degradation Products, Fibrinogen, Fibrinolysis, Humans, Plasminogen Activator Inhibitor 1, Tissue Plasminogen Activator, computational biology, exome, fibrinogen, fibrinolysis, genetic association study, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract: BackgroundUse of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA, and D-dimer.ObjectivesWe sought to discover new genetic loci contributing to variation in these traits using an exome-array approach.MethodsCohort-level analyses and fixed effects meta-analyses of PAI-1 (n = 15 603), tPA (n = 6876,) and D-dimer (n = 19 306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing.ResultsFive variants located in NME7, FGL1, and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P
Published: 2021

10. Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity

Author: Yaghootkar, Hanieh, Zhang, Yiying, Spracklen, Cassandra N, Karaderi, Tugce, Huang, Lam Opal, Bradfield, Jonathan, Schurmann, Claudia, Fine, Rebecca S, Preuss, Michael H, Kutalik, Zoltan, Wittemans, Laura BL, Lu, Yingchang, Metz, Sophia, Willems, Sara M, Li-Gao, Ruifang, Grarup, Niels, Wang, Shuai, Molnos, Sophie, Sandoval-Zárate, América A, Nalls, Mike A, Lange, Leslie A, Haesser, Jeffrey, Guo, Xiuqing, Lyytikäinen, Leo-Pekka, Feitosa, Mary F, Sitlani, Colleen M, Venturini, Cristina, Mahajan, Anubha, Kacprowski, Tim, Wang, Carol A, Chasman, Daniel I, Amin, Najaf, Broer, Linda, Robertson, Neil, Young, Kristin L, Allison, Matthew, Auer, Paul L, Blüher, Matthias, Borja, Judith B, Bork-Jensen, Jette, Carrasquilla, Germán D, Christofidou, Paraskevi, Demirkan, Ayse, Doege, Claudia A, Garcia, Melissa E, Graff, Mariaelisa, Guo, Kaiying, Hakonarson, Hakon, Hong, Jaeyoung, Ida Chen, Yii-Der, Jackson, Rebecca, Jakupović, Hermina, Jousilahti, Pekka, Justice, Anne E, Kähönen, Mika, Kizer, Jorge R, Kriebel, Jennifer, LeDuc, Charles A, Li, Jin, Lind, Lars, Luan, Jian'an, Mackey, David A, Mangino, Massimo, Männistö, Satu, Martin Carli, Jayne F, Medina-Gomez, Carolina, Mook-Kanamori, Dennis O, Morris, Andrew P, de Mutsert, Renée, Nauck, Matthias, Prokic, Ivana, Pennell, Craig E, Pradhan, Arund D, Psaty, Bruce M, Raitakari, Olli T, Scott, Robert A, Skaaby, Tea, Strauch, Konstantin, Taylor, Kent D, Teumer, Alexander, Uitterlinden, Andre G, Wu, Ying, Yao, Jie, Walker, Mark, North, Kari E, Kovacs, Peter, Ikram, M Arfan, van Duijn, Cornelia M, Ridker, Paul M, Lye, Stephen, Homuth, Georg, Ingelsson, Erik, Spector, Tim D, McKnight, Barbara, Province, Michael A, Lehtimäki, Terho, Adair, Linda S, Rotter, Jerome I, Reiner, Alexander P, and Wilson, James G
Subjects: Genetics, Nutrition, Prevention, Obesity, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Metabolic and endocrine, Cardiovascular, Stroke, Cancer, Adiposity, Gene Expression Regulation, Developmental, Genetic Variation, Genotype, Humans, Leptin, Models, Molecular, Protein Conformation, Racial Groups, Medical and Health Sciences, Endocrinology & Metabolism
Abstract: Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
Published: 2020

11. Proteomics and Population Biology in the Cardiovascular Health Study (CHS): design of a study with mentored access and active data sharing

Author: Austin, Thomas R., McHugh, Caitlin P., Brody, Jennifer A., Bis, Joshua C., Sitlani, Colleen M., Bartz, Traci M., Biggs, Mary L., Bansal, Nisha, Buzkova, Petra, Carr, Steven A., deFilippi, Christopher R., Elkind, Mitchell S. V., Fink, Howard A., Floyd, James S., Fohner, Alison E., Gerszten, Robert E., Heckbert, Susan R., Katz, Daniel H., Kizer, Jorge R., Lemaitre, Rozenn N., Longstreth, W. T., McKnight, Barbara, Mei, Hao, Mukamal, Kenneth J., Newman, Anne B., Ngo, Debby, Odden, Michelle C., Vasan, Ramachandran S., Shojaie, Ali, Simon, Noah, Smith, George Davey, Davies, Neil M., Siscovick, David S., Sotoodehnia, Nona, Tracy, Russell P., Wiggins, Kerri L., Zheng, Jie, and Psaty, Bruce M.
Published: 2022
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12. Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology

Author: Spracklen, Cassandra N, Karaderi, Tugce, Yaghootkar, Hanieh, Schurmann, Claudia, Fine, Rebecca S, Kutalik, Zoltan, Preuss, Michael H, Lu, Yingchang, Wittemans, Laura BL, Adair, Linda S, Allison, Matthew, Amin, Najaf, Auer, Paul L, Bartz, Traci M, Blüher, Matthias, Boehnke, Michael, Borja, Judith B, Bork-Jensen, Jette, Broer, Linda, Chasman, Daniel I, Chen, Yii-Der Ida, Chirstofidou, Paraskevi, Demirkan, Ayse, van Duijn, Cornelia M, Feitosa, Mary F, Garcia, Melissa E, Graff, Mariaelisa, Grallert, Harald, Grarup, Niels, Guo, Xiuqing, Haesser, Jeffrey, Hansen, Torben, Harris, Tamara B, Highland, Heather M, Hong, Jaeyoung, Ikram, M Arfan, Ingelsson, Erik, Jackson, Rebecca, Jousilahti, Pekka, Kähönen, Mika, Kizer, Jorge R, Kovacs, Peter, Kriebel, Jennifer, Laakso, Markku, Lange, Leslie A, Lehtimäki, Terho, Li, Jin, Li-Gao, Ruifang, Lind, Lars, Luan, Jian'an, Lyytikäinen, Leo-Pekka, MacGregor, Stuart, Mackey, David A, Mahajan, Anubha, Mangino, Massimo, Männistö, Satu, McCarthy, Mark I, McKnight, Barbara, Medina-Gomez, Carolina, Meigs, James B, Molnos, Sophie, Mook-Kanamori, Dennis, Morris, Andrew P, de Mutsert, Renee, Nalls, Mike A, Nedeljkovic, Ivana, North, Kari E, Pennell, Craig E, Pradhan, Aruna D, Province, Michael A, Raitakari, Olli T, Raulerson, Chelsea K, Reiner, Alex P, Ridker, Paul M, Ripatti, Samuli, Roberston, Neil, Rotter, Jerome I, Salomaa, Veikko, Sandoval-Zárate, America A, Sitlani, Colleen M, Spector, Tim D, Strauch, Konstantin, Stumvoll, Michael, Taylor, Kent D, Thuesen, Betina, Tönjes, Anke, Uitterlinden, Andre G, Venturini, Cristina, Walker, Mark, Wang, Carol A, Wang, Shuai, Wareham, Nicholas J, Willems, Sara M, Willems van Dijk, Ko, Wilson, James G, Wu, Ying, Yao, Jie, Young, Kristin L, Langenberg, Claudia, and Frayling, Timothy M
Subjects: Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Nutrition, Obesity, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Cardiovascular, Adiponectin, Adipose Tissue, Adolescent, Adult, Black or African American, Aged, Aged, 80 and over, Exome, Female, Genetic Predisposition to Disease, Hispanic or Latino, Humans, Lipids, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, White People, Young Adult, adiponectin, cardio metabolic traits, exome, genetics, genome-wide association study, lipids, obesity, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract: Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10-7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r2 > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10-4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.
Published: 2019

13. A large‐scale exome array analysis of venous thromboembolism

Author: Lindström, Sara, Brody, Jennifer A, Turman, Constance, Germain, Marine, Bartz, Traci M, Smith, Erin N, Chen, Ming‐Huei, Puurunen, Marja, Chasman, Daniel, Hassler, Jeffrey, Pankratz, Nathan, Basu, Saonli, Guan, Weihua, Gyorgy, Beata, Ibrahim, Manal, Empana, Jean‐Philippe, Olaso, Robert, Jackson, Rebecca, Brækkan, Sigrid K, McKnight, Barbara, Deleuze, Jean‐Francois, O’Donnell, Cristopher J, Jouven, Xavier, Frazer, Kelly A, Psaty, Bruce M, Wiggins, Kerri L, Taylor, Kent, Reiner, Alexander P, Heckbert, Susan R, Kooperberg, Charles, Ridker, Paul, Hansen, John‐Bjarne, Tang, Weihong, Johnson, Andrew D, Morange, Pierre‐Emmanuel, Trégouët, David A, Kraft, Peter, Smith, Nicholas L, Kabrhel, Christopher, and Consortium, on behalf of the INVENT
Subjects: Prevention, Clinical Research, Biotechnology, Human Genome, Genetics, 2.1 Biological and endogenous factors, Aetiology, Black or African American, Alleles, Case-Control Studies, Exome, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, High-Throughput Nucleotide Sequencing, Humans, Male, Microarray Analysis, Odds Ratio, Polymorphism, Single Nucleotide, Sample Size, Venous Thromboembolism, exome, genetic association, venous thromboembolism, INVENT Consortium, Public Health and Health Services, Epidemiology
Abstract: Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.
Published: 2019

14. Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels

Author: Sabater-Lleal, Maria, Huffman, Jennifer E, de Vries, Paul S, Marten, Jonathan, Mastrangelo, Michael A, Song, Ci, Pankratz, Nathan, Ward-Caviness, Cavin K, Yanek, Lisa R, Trompet, Stella, Delgado, Graciela E, Guo, Xiuqing, Bartz, Traci M, Martinez-Perez, Angel, Germain, Marine, de Haan, Hugoline G, Ozel, Ayse B, Polasek, Ozren, Smith, Albert V, Eicher, John D, Reiner, Alex P, Tang, Weihong, Davies, Neil M, Stott, David J, Rotter, Jerome I, Tofler, Geoffrey H, Boerwinkle, Eric, de Maat, Moniek PM, Kleber, Marcus E, Welsh, Paul, Brody, Jennifer A, Chen, Ming-Huei, Vaidya, Dhananjay, Soria, José Manuel, Suchon, Pierre, van Hylckama Vlieg, Astrid, Desch, Karl C, Kolcic, Ivana, Joshi, Peter K, Launer, Lenore J, Harris, Tamara B, Campbell, Harry, Rudan, Igor, Becker, Diane M, Li, Jun Z, Rivadeneira, Fernando, Uitterlinden, André G, Hofman, Albert, Franco, Oscar H, Cushman, Mary, Psaty, Bruce M, Morange, Pierre-Emmanuel, McKnight, Barbara, Chong, Michael R, Fernandez-Cadenas, Israel, Rosand, Jonathan, Lindgren, Arne, Consortium, INVENT Consortium MEGASTROKE Consortium of the International Stroke Genetics, Gudnason, Vilmundur, Wilson, James F, Hayward, Caroline, Ginsburg, David, Fornage, Myriam, Rosendaal, Frits R, Souto, Juan Carlos, Becker, Lewis C, Jenny, Nancy S, März, Winfried, Jukema, J Wouter, Dehghan, Abbas, Trégouët, David-Alexandre, Morrison, Alanna C, Johnson, Andrew D, O’Donnell, Christopher J, Strachan, David P, Lowenstein, Charles J, and Smith, Nicholas L
Subjects: Epidemiology, Health Sciences, Hematology, Biotechnology, Rare Diseases, Genetics, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Blood, Cardiovascular, Arterial Occlusive Diseases, Biomarkers, Blood Coagulation, Blood Coagulation Disorders, Inherited, Factor VIII, Genetic Loci, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Phenotype, Ribosomal Protein L3, Risk Factors, Venous Thrombosis, von Willebrand Factor, cardiovascular diseases, factor VIII, genome-wide association studies, genetics, risk factors, von Willebrand factor, INVENT Consortium, MEGASTROKE Consortium of the International Stroke Genetics Consortium, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Public Health and Health Services, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences, Sports science and exercise
Abstract: BackgroundFactor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.MethodsWe meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.ResultsWe identified 13 novel genome-wide significant ( P≤2.5×10-8) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.ConclusionsThe meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.
Published: 2019

15. Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease

Author: Ward-Caviness, Cavin K, de Vries, Paul S, Wiggins, Kerri L, Huffman, Jennifer E, Yanek, Lisa R, Bielak, Lawrence F, Giulianini, Franco, Guo, Xiuqing, Kleber, Marcus E, Kacprowski, Tim, Groß, Stefan, Petersman, Astrid, Smith, George Davey, Hartwig, Fernando P, Bowden, Jack, Hemani, Gibran, Müller-Nuraysid, Martina, Strauch, Konstantin, Koenig, Wolfgang, Waldenberger, Melanie, Meitinger, Thomas, Pankratz, Nathan, Boerwinkle, Eric, Tang, Weihong, Fu, Yi-Ping, Johnson, Andrew D, Song, Ci, de Maat, Moniek PM, Uitterlinden, André G, Franco, Oscar H, Brody, Jennifer A, McKnight, Barbara, Chen, Yii-Der Ida, Psaty, Bruce M, Mathias, Rasika A, Becker, Diane M, Peyser, Patricia A, Smith, Jennifer A, Bielinski, Suzette J, Ridker, Paul M, Taylor, Kent D, Yao, Jie, Tracy, Russell, Delgado, Graciela, Trompet, Stella, Sattar, Naveed, Jukema, J Wouter, Becker, Lewis C, Kardia, Sharon LR, Rotter, Jerome I, März, Winfried, Dörr, Marcus, Chasman, Daniel I, Dehghan, Abbas, O’Donnell, Christopher J, Smith, Nicholas L, Peters, Annette, and Morrison, Alanna C
Subjects: Epidemiology, Biological Sciences, Health Sciences, Genetics, Heart Disease, Cardiovascular, Prevention, Human Genome, Heart Disease - Coronary Heart Disease, Alleles, Coronary Disease, Fibrinogen, Genetic Pleiotropy, Genetic Variation, Genome-Wide Association Study, Humans, Incidence, Mendelian Randomization Analysis, Models, Genetic, Multivariate Analysis, Myocardial Infarction, Odds Ratio, General Science & Technology
Abstract: BackgroundFibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.Methods and findingsWe evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.ConclusionsA small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.
Published: 2019

16. GWAS of QRS duration identifies new loci specific to Hispanic/Latino populations

Author: Swenson, Brenton R, Louie, Tin, Lin, Henry J, Méndez-Giráldez, Raúl, Below, Jennifer E, Laurie, Cathy C, Kerr, Kathleen F, Highland, Heather, Thornton, Timothy A, Ryckman, Kelli K, Kooperberg, Charles, Soliman, Elsayed Z, Seyerle, Amanda A, Guo, Xiuqing, Taylor, Kent D, Yao, Jie, Heckbert, Susan R, Darbar, Dawood, Petty, Lauren E, McKnight, Barbara, Cheng, Susan, Bello, Natalie A, Whitsel, Eric A, Hanis, Craig L, Nalls, Mike A, Evans, Daniel S, Rotter, Jerome I, Sofer, Tamar, Avery, Christy L, and Sotoodehnia, Nona
Subjects: Epidemiology, Biological Sciences, Health Sciences, Genetics, Cardiovascular, Human Genome, Heart Disease, Good Health and Well Being, Electrocardiography, Genetic Loci, Genome-Wide Association Study, Hispanic or Latino, Humans, Middle Aged, Molecular Sequence Annotation, Phenotype, Polymorphism, Single Nucleotide, General Science & Technology
Abstract: BackgroundThe electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored.MethodsWe performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n = 15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis.ResultsWe identified six loci associated with QRS (P
Published: 2019

17. A comprehensive evaluation of the genetic architecture of sudden cardiac arrest

Author: Ashar, Foram N, Mitchell, Rebecca N, Albert, Christine M, Newton-Cheh, Christopher, Brody, Jennifer A, Müller-Nurasyid, Martina, Moes, Anna, Meitinger, Thomas, Mak, Angel, Huikuri, Heikki, Junttila, M Juhani, Goyette, Philippe, Pulit, Sara L, Pazoki, Raha, Tanck, Michael W, Blom, Marieke T, Zhao, XiaoQing, Havulinna, Aki S, Jabbari, Reza, Glinge, Charlotte, Tragante, Vinicius, Escher, Stefan A, Chakravarti, Aravinda, Ehret, Georg, Coresh, Josef, Li, Man, Prineas, Ronald J, Franco, Oscar H, Kwok, Pui-Yan, Lumley, Thomas, Dumas, Florence, McKnight, Barbara, Rotter, Jerome I, Lemaitre, Rozenn N, Heckbert, Susan R, O’Donnell, Christopher J, Hwang, Shih-Jen, Tardif, Jean-Claude, VanDenburgh, Martin, Uitterlinden, André G, Hofman, Albert, Stricker, Bruno HC, de Bakker, Paul IW, Franks, Paul W, Jansson, Jan-Hakan, Asselbergs, Folkert W, Halushka, Marc K, Maleszewski, Joseph J, Tfelt-Hansen, Jacob, Engstrøm, Thomas, Salomaa, Veikko, Virmani, Renu, Kolodgie, Frank, Wilde, Arthur AM, Tan, Hanno L, Bezzina, Connie R, Eijgelsheim, Mark, Rioux, John D, Jouven, Xavier, Kääb, Stefan, Psaty, Bruce M, Siscovick, David S, Arking, Dan E, and Sotoodehnia, Nona
Subjects: Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Prevention, Heart Disease, Human Genome, Genetics, Clinical Research, Heart Disease - Coronary Heart Disease, Cardiovascular, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Arrhythmias, Cardiac, Body Mass Index, Coronary Artery Disease, Death, Sudden, Cardiac, Female, Genome-Wide Association Study, Heart Conduction System, Humans, Male, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Sex Factors, Sudden cardiac arrest, Genome-wide association study, Mendelian randomization, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract: AimsSudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA.Methods and resultsWe carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk.ConclusionsOur findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.
Published: 2018

18. Plasma epoxyeicosatrienoic acids and diabetes-related cardiovascular disease: The cardiovascular health study

Author: Lemaitre, Rozenn N., Jensen, Paul N., Zeigler, Maxwell, Fretts, Amanda M., Umans, Jason G., Howard, Barbara V., Sitlani, Colleen M., McKnight, Barbara, Gharib, Sina A., King, Irena B., Siscovick, David S., Psaty, Bruce M., Sotoodehnia, Nona, and Totah, Rheem A.
Published: 2022
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19. Incident thrombus location and predicting risk of recurrent venous thromboembolism

Author: Lidstrom, Sara C., Wiggins, Kerri L., Harrington, Laura B., McKnight, Barbara, Blondon, Marc, and Smith, Nicholas L.
Published: 2022
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20. Circulating ceramides and sphingomyelins and the risk of incident cardiovascular disease among people with diabetes: the strong heart study

Author: Jensen, Paul N., Fretts, Amanda M., Hoofnagle, Andrew N., McKnight, Barbara, Howard, Barbara V., Umans, Jason G., Sitlani, Colleen M., Siscovick, David S., King, Irena B., Sotoodehnia, Nona, and Lemaitre, Rozenn N.
Published: 2022
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21. Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease

Author: Song, Ci, Burgess, Stephen, Eicher, John D, O'Donnell, Christopher J, Johnson, Andrew D, Huang, Jie, Sabater‐Lleal, Maria, Asselbergs, Folkert W, Tregouet, David, Shin, So‐Youn, Ding, Jingzhong, Baumert, Jens, Oudot‐Mellakh, Tiphaine, Folkersen, Lasse, Smith, Nicholas L, Williams, Scott M, Ikram, Mohammad A, Kleber, Marcus E, Becker, Diane M, Truong, Vinh, Mychaleckyj, Josyf C, Tang, Weihong, Yang, Qiong, Sennblad, Bengt, Moore, Jason H, Williams, Frances MK, Dehghan, Abbas, Silbernagel, Günther, Schrijvers, Elisabeth MC, Smith, Shelly, Karakas, Mahir, Tofler, Geoffrey H, Silveira, Angela, Navis, Gerjan J, Lohman, Kurt, Chen, Ming‐Huei, Peters, Annette, Goel, Anuj, Hopewell, Jemma C, Chambers, John C, Saleheen, Danish, Lundmark, Per, Psaty, Bruce M, Strawbridge, Rona J, Boehm, Bernhard O, Carter, Angela M, Meisinger, Christa, Peden, John F, Bis, Joshua C, McKnight, Barbara, Öhrvik, John, Taylor, Kent, Franzosi, Maria Grazia, Seedorf, Udo, Collins, Rory, Franco‐Cereceda, Anders, Syvänen, Ann‐Christine, Goodall, Alison H, Yanek, Lisa R, Cushman, Mary, Müller‐Nurasyid, Martina, Folsom, Aaron R, Basu, Saonli, Matijevic, Nena, van Gilst, Wiek H, Kooner, Jaspal S, Hofman, Albert, Danesh, John, Clarke, Robert, Meigs, James B, Kathiresan, Sekar, Reilly, Muredach P, Klopp, Norman, Harris, Tamara B, Winkelmann, Bernhard R, Grant, Peter J, Hillege, Hans L, Watkins, Hugh, Spector, Timothy D, Becker, Lewis C, Tracy, Russell P, März, Winfried, Uitterlinden, Andre G, Eriksson, Per, Cambien, Francois, Morange, Pierre‐Emmanuel, Koenig, Wolfgang, Soranzo, Nicole, van der Harst, Pim, Liu, Yongmei, Hamsten, Anders, Ehret, Georg B, Munroe, Patricia B, Rice, Kenneth M, Bochud, Murielle, Chasman, Daniel I, Smith, Albert V, Tobin, Martin D, and Verwoert, Germaine C
Subjects: Clinical Research, Heart Disease - Coronary Heart Disease, Cardiovascular, Heart Disease, Aging, Biomarkers, Blood Glucose, Coronary Disease, Fibrinolysis, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Incidence, Lipoproteins, HDL, Mendelian Randomization Analysis, Multivariate Analysis, Observational Studies as Topic, Odds Ratio, Plasminogen Activator Inhibitor 1, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, coronary heart disease, genome-wide association study, Mendelian randomization, plasminogen activator inhibitor type 1, single nucleotide polymorphism, genome‐wide association study, Cardiorespiratory Medicine and Haematology
Abstract: Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction.
Published: 2017

22. Plasma epoxyeicosatrienoic acids and dihydroxyeicosatrieonic acids, insulin, glucose and risk of diabetes: The strong heart study

Author: Lemaitre, Rozenn N., Jensen, Paul N, Zeigler, Maxwell, Denham, Julie, Fretts, Amanda M., Umans, Jason G., Howard, Barbara V., Sitlani, Colleen M., McKnight, Barbara, Gharib, Sina A., King, Irena B., Siscovick, David S., Psaty, Bruce M, Sotoodehnia, Nona, and Totah, Rheem A.
Published: 2021
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23. Erratum: Genetic loci associated with heart rate variability and their effects on cardiac disease risk.

Author: Nolte, Ilja, Munoz, M, Tragante, Vinicius, Amare, Azmeraw, Jansen, Rick, Vaez, Ahmad, von der Heyde, Benedikt, Avery, Christy, Bis, Joshua, Dierckx, Bram, van Dongen, Jenny, Gogarten, Stephanie, Goyette, Philippe, Hernesniemi, Jussi, Huikari, Ville, Hwang, Shih-Jen, Jaju, Deepali, Kerr, Kathleen, Kluttig, Alexander, Krijthe, Bouwe, Kumar, Jitender, van der Laan, Sander, Lyytikäinen, Leo-Pekka, Maihofer, Adam, Minassian, Arpi, van der Most, Peter, Müller-Nurasyid, Martina, Nivard, Michel, Salvi, Erika, Stewart, James, Thayer, Julian, Verweij, Niek, Wong, Andrew, Zabaneh, Delilah, Zafarmand, Mohammad, Abdellaoui, Abdel, Albarwani, Sulayma, Albert, Christine, Alonso, Alvaro, Ashar, Foram, Auvinen, Juha, Axelsson, Tomas, Baker, Dewleen, de Bakker, Paul, Barcella, Matteo, Bayoumi, Riad, Bieringa, Rob, Boomsma, Dorret, Boucher, Gabrielle, Britton, Annie, Christophersen, Ingrid, Dietrich, Andrea, Ehret, George, Ellinor, Patrick, Eskola, Markku, Felix, Janine, Floras, John, Franco, Oscar, Friberg, Peter, Gademan, Maaike, Geyer, Mark, Giedraitis, Vilmantas, Hartman, Catharina, Hemerich, Daiane, Hofman, Albert, Hottenga, Jouke-Jan, Huikuri, Heikki, Hutri-Kähönen, Nina, Jouven, Xavier, Junttila, Juhani, Juonala, Markus, Kiviniemi, Antti, Kors, Jan, Kumari, Meena, Kuznetsova, Tatiana, Laurie, Cathy, Lefrandt, Joop, Li, Yong, Li, Yun, Liao, Duanping, Limacher, Marian, Lin, Henry, Lindgren, Cecilia, Lubitz, Steven, Mahajan, Anubha, McKnight, Barbara, Zu Schwabedissen, Henriette, Milaneschi, Yuri, Mononen, Nina, Morris, Andrew, Nalls, Mike, Navis, Gerjan, Neijts, Melanie, Nikus, Kjell, North, Kari, OConnor, Daniel, Ormel, Johan, Perz, Siegfried, Peters, Annette, and Psaty, Bruce
Abstract: This corrects the article DOI: 10.1038/ncomms15805.
Published: 2017

24. Genetic loci associated with heart rate variability and their effects on cardiac disease risk.

Author: Nolte, Ilja M, Munoz, M Loretto, Tragante, Vinicius, Amare, Azmeraw T, Jansen, Rick, Vaez, Ahmad, von der Heyde, Benedikt, Avery, Christy L, Bis, Joshua C, Dierckx, Bram, van Dongen, Jenny, Gogarten, Stephanie M, Goyette, Philippe, Hernesniemi, Jussi, Huikari, Ville, Hwang, Shih-Jen, Jaju, Deepali, Kerr, Kathleen F, Kluttig, Alexander, Krijthe, Bouwe P, Kumar, Jitender, van der Laan, Sander W, Lyytikäinen, Leo-Pekka, Maihofer, Adam X, Minassian, Arpi, van der Most, Peter J, Müller-Nurasyid, Martina, Nivard, Michel, Salvi, Erika, Stewart, James D, Thayer, Julian F, Verweij, Niek, Wong, Andrew, Zabaneh, Delilah, Zafarmand, Mohammad H, Abdellaoui, Abdel, Albarwani, Sulayma, Albert, Christine, Alonso, Alvaro, Ashar, Foram, Auvinen, Juha, Axelsson, Tomas, Baker, Dewleen G, de Bakker, Paul IW, Barcella, Matteo, Bayoumi, Riad, Bieringa, Rob J, Boomsma, Dorret, Boucher, Gabrielle, Britton, Annie R, Christophersen, Ingrid, Dietrich, Andrea, Ehret, George B, Ellinor, Patrick T, Eskola, Markku, Felix, Janine F, Floras, John S, Franco, Oscar H, Friberg, Peter, Gademan, Maaike GJ, Geyer, Mark A, Giedraitis, Vilmantas, Hartman, Catharina A, Hemerich, Daiane, Hofman, Albert, Hottenga, Jouke-Jan, Huikuri, Heikki, Hutri-Kähönen, Nina, Jouven, Xavier, Junttila, Juhani, Juonala, Markus, Kiviniemi, Antti M, Kors, Jan A, Kumari, Meena, Kuznetsova, Tatiana, Laurie, Cathy C, Lefrandt, Joop D, Li, Yong, Li, Yun, Liao, Duanping, Limacher, Marian C, Lin, Henry J, Lindgren, Cecilia M, Lubitz, Steven A, Mahajan, Anubha, McKnight, Barbara, Zu Schwabedissen, Henriette Meyer, Milaneschi, Yuri, Mononen, Nina, Morris, Andrew P, Nalls, Mike A, Navis, Gerjan, Neijts, Melanie, Nikus, Kjell, North, Kari E, O'Connor, Daniel T, Ormel, Johan, Perz, Siegfried, Peters, Annette, and Psaty, Bruce M
Subjects: Humans, Heart Diseases, Genetic Predisposition to Disease, RGS Proteins, Potassium Channels, Muscle Proteins, Risk Factors, Cohort Studies, Blood Pressure, Heart Rate, Polymorphism, Single Nucleotide, Quantitative Trait Loci, European Continental Ancestry Group, Genome-Wide Association Study, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Cardiovascular, Genetics, Heart Disease
Abstract: Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74g
Published: 2017

25. Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms

Author: Rusu, Victor, Hoch, Eitan, Mercader, Josep M, Tenen, Danielle E, Gymrek, Melissa, Hartigan, Christina R, DeRan, Michael, von Grotthuss, Marcin, Fontanillas, Pierre, Spooner, Alexandra, Guzman, Gaelen, Deik, Amy A, Pierce, Kerry A, Dennis, Courtney, Clish, Clary B, Carr, Steven A, Wagner, Bridget K, Schenone, Monica, Ng, Maggie CY, Chen, Brian H, Consortium, MEDIA, Shriner, Daniel, Li, Jiang, Chen, Wei-Min, Guo, Xiuqing, Liu, Jiankang, Bielinski, Suzette J, Yanek, Lisa R, Nalls, Michael A, Comeau, Mary E, Rasmussen-Torvik, Laura J, Jensen, Richard A, Evans, Daniel S, Sun, Yan V, An, Ping, Patel, Sanjay R, Lu, Yingchang, Long, Jirong, Armstrong, Loren L, Wagenknecht, Lynne, Yang, Lingyao, Snively, Beverly M, Palmer, Nicholette D, Mudgal, Poorva, Langefeld, Carl D, Keene, Keith L, Freedman, Barry I, Mychaleckyj, Josyf C, Nayak, Uma, Raffel, Leslie J, Goodarzi, Mark O, Chen, Y-D Ida, Taylor, Herman A, Correa, Adolfo, Sims, Mario, Couper, David, Pankow, James S, Boerwinkle, Eric, Adeyemo, Adebowale, Doumatey, Ayo, Chen, Guanjie, Mathias, Rasika A, Vaidya, Dhananjay, Singleton, Andrew B, Zonderman, Alan B, Igo, Robert P, Sedor, John R, Consortium, the FIND, Kabagambe, Edmond K, Siscovick, David S, McKnight, Barbara, Rice, Kenneth, Liu, Yongmei, Hsueh, Wen-Chi, Zhao, Wei, Bielak, Lawrence F, Kraja, Aldi, Province, Michael A, Bottinger, Erwin P, Gottesman, Omri, Cai, Qiuyin, Zheng, Wei, Blot, William J, Lowe, William L, Pacheco, Jennifer A, Crawford, Dana C, Consortium, the eMERGE, Consortium, the DIAGRAM, Grundberg, Elin, Consortium, the MuTHER, Rich, Stephen S, Hayes, M Geoffrey, Shu, Xiao-Ou, Loos, Ruth JF, Borecki, Ingrid B, Peyser, Patricia A, Cummings, Steven R, and Psaty, Bruce M
Subjects: Biological Sciences, Genetics, Clinical Research, Diabetes, Digestive Diseases, Liver Disease, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Basigin, Cell Membrane, Chromosomes, Human, Pair 17, Diabetes Mellitus, Type 2, Gene Knockdown Techniques, Haplotypes, Hepatocytes, Heterozygote, Histone Code, Humans, Liver, Models, Molecular, Monocarboxylic Acid Transporters, MEDIA Consortium, SIGMA T2D Consortium, MCT11, SLC16A11, disease mechanism, fatty acid metabolism, genetics, lipid metabolism, monocarboxylates, precision medicine, solute carrier, type 2 diabetes, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract: Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. VIDEO ABSTRACT.
Published: 2017

26. Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium.

Author: Ng, Maggie CY, Graff, Mariaelisa, Lu, Yingchang, Justice, Anne E, Mudgal, Poorva, Liu, Ching-Ti, Young, Kristin, Yanek, Lisa R, Feitosa, Mary F, Wojczynski, Mary K, Rand, Kristin, Brody, Jennifer A, Cade, Brian E, Dimitrov, Latchezar, Duan, Qing, Guo, Xiuqing, Lange, Leslie A, Nalls, Michael A, Okut, Hayrettin, Tajuddin, Salman M, Tayo, Bamidele O, Vedantam, Sailaja, Bradfield, Jonathan P, Chen, Guanjie, Chen, Wei-Min, Chesi, Alessandra, Irvin, Marguerite R, Padhukasahasram, Badri, Smith, Jennifer A, Zheng, Wei, Allison, Matthew A, Ambrosone, Christine B, Bandera, Elisa V, Bartz, Traci M, Berndt, Sonja I, Bernstein, Leslie, Blot, William J, Bottinger, Erwin P, Carpten, John, Chanock, Stephen J, Chen, Yii-Der Ida, Conti, David V, Cooper, Richard S, Fornage, Myriam, Freedman, Barry I, Garcia, Melissa, Goodman, Phyllis J, Hsu, Yu-Han H, Hu, Jennifer, Huff, Chad D, Ingles, Sue A, John, Esther M, Kittles, Rick, Klein, Eric, Li, Jin, McKnight, Barbara, Nayak, Uma, Nemesure, Barbara, Ogunniyi, Adesola, Olshan, Andrew, Press, Michael F, Rohde, Rebecca, Rybicki, Benjamin A, Salako, Babatunde, Sanderson, Maureen, Shao, Yaming, Siscovick, David S, Stanford, Janet L, Stevens, Victoria L, Stram, Alex, Strom, Sara S, Vaidya, Dhananjay, Witte, John S, Yao, Jie, Zhu, Xiaofeng, Ziegler, Regina G, Zonderman, Alan B, Adeyemo, Adebowale, Ambs, Stefan, Cushman, Mary, Faul, Jessica D, Hakonarson, Hakon, Levin, Albert M, Nathanson, Katherine L, Ware, Erin B, Weir, David R, Zhao, Wei, Zhi, Degui, Bone Mineral Density in Childhood Study (BMDCS) Group, Arnett, Donna K, Grant, Struan FA, Kardia, Sharon LR, Oloapde, Olufunmilayo I, Rao, DC, Rotimi, Charles N, Sale, Michele M, Williams, L Keoki, Zemel, Babette S, Becker, Diane M, and Borecki, Ingrid B
Subjects: Bone Mineral Density in Childhood Study (BMDCS) Group, Humans, Obesity, Genetic Predisposition to Disease, Serine Endopeptidases, Anthropometry, Body Mass Index, Waist-Hip Ratio, Chromosome Mapping, Gene Frequency, Linkage Disequilibrium, Polymorphism, Single Nucleotide, African Continental Ancestry Group, European Continental Ancestry Group, Female, Male, Adiposity, Genome-Wide Association Study, Transcription Factor 7-Like 2 Protein, Genetics, Human Genome, 2.1 Biological and endogenous factors, Developmental Biology
Abstract: Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (
Published: 2017

27. The cross-sectional association between vasomotor symptoms and hemostatic parameter levels in postmenopausal women

Author: Harrington, Laura B, Blondon, Marc, Cushman, Mary, Kaunitz, Andrew M, Rossouw, Jacques E, Allison, Matthew A, Martin, Lisa W, Johnson, Karen C, Rosing, Jan, Woods, Nancy F, LaCroix, Andrea Z, Heckbert, Susan R, McKnight, Barbara, and Smith, Nicholas L
Subjects: Reproductive Medicine, Biomedical and Clinical Sciences, Cardiovascular, Hematology, Aging, Contraception/Reproduction, Aged, Antigens, Antithrombin Proteins, Cross-Sectional Studies, Female, Fibrin Fibrinogen Degradation Products, Hemostasis, Hot Flashes, Humans, Lipoproteins, Middle Aged, Plasminogen Activator Inhibitor 1, Postmenopause, Protein C, Protein S, Severity of Illness Index, Sweating, Symptom Assessment, Thrombin, Epidemiology, Hot flashes, Menopause, Medical and Health Sciences, Obstetrics & Reproductive Medicine, Biomedical and clinical sciences, Health sciences, Psychology
Abstract: ObjectiveVasomotor symptoms (VMS) may be a marker of cardiovascular risk. We aimed to evaluate the cross-sectional association of VMS presence and severity with hemostatic parameter levels measured at baseline among Women's Health Initiative (WHI) Hormone Therapy trial postmenopausal participants.MethodsThis cross-sectional analysis included 2,148 postmenopausal women with measures of VMS presence and severity reported in the 4 weeks before WHI baseline, who were not using warfarin or hormone therapy and for whom the following baseline hemostatic parameters were measured within the WHI Cardiovascular Disease Biomarker Case-Control Study: antithrombin, plasminogen activator inhibitor-1, protein C antigen, total and free protein S antigen, total and free tissue factor pathway inhibitor, D-dimer, normalized activated protein C sensitivity ratio, and thrombin generation. Using multiple linear regression, we estimated the adjusted average difference in each hemostatic parameter associated with VMS presence and severity. A multiple comparisons-corrected P value was computed using the P-min procedure to determine statistical significance of our smallest observed P value.ResultsWomen were 67 years of age on average and 33% reported VMS presence at baseline. There was some suggestion that VMS presence may be associated with a -0.34 adjusted difference in normalized activated protein C sensitivity ratio compared with no VMS (95% CI, -0.60 to -0.087; P = 0.009), but this association was not significant after correction for multiple comparisons (P = 0.073). VMS presence or severity was not significantly associated with the other hemostatic parameters.ConclusionsWe found no convincing evidence that VMS presence or severity was associated with levels of hemostatic parameters among postmenopausal women.
Published: 2017

28. Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study

Author: de Vries, Paul S, Sabater-Lleal, Maria, Chasman, Daniel I, Trompet, Stella, Ahluwalia, Tarunveer S, Teumer, Alexander, Kleber, Marcus E, Chen, Ming-Huei, Wang, Jie Jin, Attia, John R, Marioni, Riccardo E, Steri, Maristella, Weng, Lu-Chen, Pool, Rene, Grossmann, Vera, Brody, Jennifer A, Venturini, Cristina, Tanaka, Toshiko, Rose, Lynda M, Oldmeadow, Christopher, Mazur, Johanna, Basu, Saonli, Frånberg, Mattias, Yang, Qiong, Ligthart, Symen, Hottenga, Jouke J, Rumley, Ann, Mulas, Antonella, de Craen, Anton JM, Grotevendt, Anne, Taylor, Kent D, Delgado, Graciela E, Kifley, Annette, Lopez, Lorna M, Berentzen, Tina L, Mangino, Massimo, Bandinelli, Stefania, Morrison, Alanna C, Hamsten, Anders, Tofler, Geoffrey, de Maat, Moniek PM, Draisma, Harmen HM, Lowe, Gordon D, Zoledziewska, Magdalena, Sattar, Naveed, Lackner, Karl J, Völker, Uwe, McKnight, Barbara, Huang, Jie, Holliday, Elizabeth G, McEvoy, Mark A, Starr, John M, Hysi, Pirro G, Hernandez, Dena G, Guan, Weihua, Rivadeneira, Fernando, McArdle, Wendy L, Slagboom, P Eline, Zeller, Tanja, Psaty, Bruce M, Uitterlinden, André G, de Geus, Eco JC, Stott, David J, Binder, Harald, Hofman, Albert, Franco, Oscar H, Rotter, Jerome I, Ferrucci, Luigi, Spector, Tim D, Deary, Ian J, März, Winfried, Greinacher, Andreas, Wild, Philipp S, Cucca, Francesco, Boomsma, Dorret I, Watkins, Hugh, Tang, Weihong, Ridker, Paul M, Jukema, Jan W, Scott, Rodney J, Mitchell, Paul, Hansen, Torben, O'Donnell, Christopher J, Smith, Nicholas L, Strachan, David P, and Dehghan, Abbas
Subjects: Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Genome-Wide Association Study, HapMap Project, Humans, General Science & Technology
Abstract: An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.
Published: 2017

29. A Mendelian randomization of γ′ and total fibrinogen levels in relation to venous thromboembolism and ischemic stroke

Author: Maners, Jillian, Gill, Dipender, Pankratz, Nathan, Laffan, Michael A., Wolberg, Alisa S., de Maat, Moniek P.M., Ligthart, Symen, Tang, Weihong, Ward-Caviness, Cavin K., Fornage, Myriam, Debette, Stephanie, Dichgans, Martin, McKnight, Barbara, Boerwinkle, Eric, CHARGE Inflammation Working Group, INVENT Consortium, MEGASTROKE consortium of the International Stroke Genetics Consortium (ISGC), Smith, Nicholas L., Morrison, Alanna C., Dehghan, Abbas, and de Vries, Paul S.
Published: 2020
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30. In the Wrong Place with the Wrong SNP

Author: Mooney, Stephen J, Grady, Stephanie T, Sotoodehnia, Nona, Lemaitre, Rozenn N, Wallace, Erin R, Mohanty, April F, Yee, Jean, Siscovick, David S, Rea, Thomas D, McKnight, Barbara, Kwok, Pui-Yan, Mak, Angel CY, Hesselson, Stephanie, and Lovasi, Gina S
Subjects: Epidemiology, Public Health, Health Sciences, Heart Disease, Basic Behavioral and Social Science, Clinical Research, Cardiovascular, Behavioral and Social Science, Mental Health, Genetics, 2.1 Biological and endogenous factors, Aetiology, Adult, Aged, Aged, 80 and over, Female, Gene-Environment Interaction, Genotype, Humans, Male, Middle Aged, Out-of-Hospital Cardiac Arrest, Polymorphism, Single Nucleotide, Receptors, Adrenergic, beta-2, Residence Characteristics, Socioeconomic Factors, Washington, White People, Statistics, Public Health and Health Services, Public health
Abstract: BackgroundSudden cardiac arrest has been linked independently both to stressful neighborhood conditions and to polymorphisms in the ADRB2 gene. The ADRB2 gene mediates sympathetic activation in response to stress. Therefore, if neighborhood conditions cause cardiac arrest through the stress pathway, the ADRB2 variant may modify the association between neighborhood conditions, such as socioeconomic deprivation and incidence of cardiac arrest.MethodsThe Cardiac Arrest Blood Study Repository is a population-based repository of specimens and other data from adult cardiac arrest patients residing in King County, Washington. Cases (n = 1,539) were 25- to 100-year-old individuals of European descent who experienced out-of-hospital cardiac arrest from 1988 to 2004. Interactions between neighborhood conditions and the ADRB2 genotype on cardiac arrest risk were assessed in a case-only study design. Gene-environment independence was assessed in blood samples obtained from King County residents initially contacted by random-digit dialing.ResultsFewer than 4% of study subjects resided in socioeconomically deprived neighborhoods. Nonetheless, the case-only analysis indicated the presence of supramultiplicative interaction of socioeconomic deprivation and the homozygous Gln27Glu variant (case-only odds ratio: 1.8 [95% confidence interval: 1.0, 2.9]). Interactions between population density and the homozygous Gln27Glu variant were weaker (case-only odds ratio: 1.2 [95% confidence interval: 0.97, 1.5]).ConclusionsFindings support a supramultiplicative interaction between the Gln27Glu ADRB2 variant and socioeconomic deprivation among individuals of European descent. This result is consistent with the hypothesis that the elevation in cardiac arrest risk associated with socioeconomic deprivation operates through the stress pathway.
Published: 2016

31. Novel Genetic Loci Associated With Retinal Microvascular Diameter

Author: Jensen, Richard A, Sim, Xueling, Smith, Albert Vernon, Li, Xiaohui, Jakobsdóttir, Jóhanna, Cheng, Ching-Yu, Brody, Jennifer A, Cotch, Mary Frances, Mcknight, Barbara, Klein, Ronald, Wang, Jie Jin, Kifley, Annette, Harris, Tamara B, Launer, Lenore J, Taylor, Kent D, Klein, Barbara EK, Raffel, Leslie J, Li, Xiang, Ikram, M Arfan, Klaver, Caroline C, van der Lee, Sven J, Mutlu, Unal, Hofman, Albert, Uitterlinden, André G, Liu, Chunyu, Kraja, Aldi T, Mitchell, Paul, Gudnason, Vilmundur, Rotter, Jerome I, Boerwinkle, Eric, van Duijn, Cornelia M, Psaty, Bruce M, and Wong, Tien Y
Subjects: Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Genetics, Eye Disease and Disorders of Vision, Clinical Research, Human Genome, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Adult, Aged, Aged, 80 and over, Alleles, Arterioles, DNA-Binding Proteins, Female, Gene Frequency, Genetic Loci, Humans, Male, Middle Aged, Nuclear Proteins, Polymorphism, Single Nucleotide, Retinal Artery, Retinal Vein, TEA Domain Transcription Factors, Tetraspanins, Transcription Factors, Venules, meta-analysis, genetics, microcirculation, exome, retina, CHARGE Exome Chip Blood Pressure Consortium, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract: BackgroundThere is increasing evidence that retinal microvascular diameters are associated with cardiovascular and cerebrovascular conditions. The shared genetic effects of these associations are currently unknown. The aim of this study was to increase our understanding of the genetic factors that mediate retinal vessel size.Methods and resultsThis study extends previous genome-wide association study results using 24 000+ multiethnic participants from 7 discovery cohorts and 5000+ subjects of European ancestry from 2 replication cohorts. Using the Illumina HumanExome BeadChip, we investigate the association of single-nucleotide polymorphisms and variants collectively across genes with summary measures of retinal vessel diameters, referred to as the central retinal venule equivalent and the central retinal arteriole equivalent. We report 4 new loci associated with central retinal venule equivalent, one of which is also associated with central retinal arteriole equivalent. The 4 single-nucleotide polymorphisms are rs7926971 in TEAD1 (P=3.1×10(-) (11); minor allele frequency=0.43), rs201259422 in TSPAN10 (P=4.4×10(-9); minor allele frequency=0.27), rs5442 in GNB3 (P=7.0×10(-10); minor allele frequency=0.05), and rs1800407 in OCA2 (P=3.4×10(-8); minor allele frequency=0.05). The latter single-nucleotide polymorphism, rs1800407, was also associated with central retinal arteriole equivalent (P=6.5×10(-12)). Results from the gene-based burden tests were null. In phenotype look-ups, single-nucleotide polymorphism rs201255422 was associated with both systolic (P=0.001) and diastolic blood pressures (P=8.3×10(-04)).ConclusionsOur study expands the understanding of genetic factors influencing the size of the retinal microvasculature. These findings may also provide insight into the relationship between retinal and systemic microvascular disease.
Published: 2016

32. Prior hysterectomy and oophorectomy and incident venous thrombosis risk among postmenopausal women

Author: Harrington, Laura B, Weiss, Noel S, Wiggins, Kerri L, Heckbert, Susan R, McKnight, Barbara, Blondon, Marc, Woods, Nancy F, LaCroix, Andrea Z, Psaty, Bruce M, and Smith, Nicholas L
Subjects: Reproductive Medicine, Biomedical and Clinical Sciences, Contraception/Reproduction, Clinical Research, Prevention, Aging, Estrogen, Case-Control Studies, Causality, Confidence Intervals, Estrogen Replacement Therapy, Female, Humans, Hysterectomy, Logistic Models, Middle Aged, Odds Ratio, Ovariectomy, Postmenopause, Risk Factors, Salpingectomy, Venous Thrombosis, Cardiovascular diseases, Hormones, Thrombosis, Women, Medical and Health Sciences, Obstetrics & Reproductive Medicine, Biomedical and clinical sciences, Health sciences, Psychology
Abstract: ObjectiveHysterectomy and bilateral salpingo-oophorectomy (BSO) are associated with changes in endogenous hormone levels, yet the risk of venous thrombosis (VT) associated with hysterectomy and BSO is incompletely characterized. This study evaluated the risk of incident VT among postmenopausal women associated with combined prior hysterectomy/oophorectomy status and current use of hormone therapy (HT).MethodsIn a case-control study, we identified incident VT cases (n = 1,623) among postmenopausal Group Health Cooperative enrollees without reproductive cancer, defining their "index date" as their VT diagnosis date (1995-2010). Matched controls had not experienced a prior VT (n = 4,480). Multiple logistic regression models estimated adjusted relative risks for VT associated with combinations of prior hysterectomy/oophorectomy status and HT use at the index date.ResultsCompared with women with an intact uterus who were not using HT, there was no suggestion of greater VT risk in women with prior hysterectomy without BSO, whether they were (adjusted odds ratio [aOR] = 0.80 [95% CI: 0.57, 1.12]) or were not using HT (aOR = 1.09 [95% CI: 0.89, 1.35]). Women with prior hysterectomy and BSO who were using HT were not at a greater VT risk (OR = 1.00 [95% CI: 0.78, 1.27]), but there was evidence of a 25% greater risk associated with prior hysterectomy with BSO and no current HT use (OR = 1.25 [95% CI: 1.05, 1.49]).ConclusionsCollectively, these and prior data do not suggest a substantial impact of hysterectomy, with or without BSO, on the risk of VT among postmenopausal women.
Published: 2016

33. Prior hysterectomy and oophorectomy and incident venous thrombosis risk among postmenopausal women: a population-based, case-control study.

Author: Harrington, Laura B, Weiss, Noel S, Wiggins, Kerri L, Heckbert, Susan R, McKnight, Barbara, Blondon, Marc, Woods, Nancy F, LaCroix, Andrea Z, Psaty, Bruce M, and Smith, Nicholas L
Subjects: Humans, Venous Thrombosis, Estrogen Replacement Therapy, Ovariectomy, Hysterectomy, Confidence Intervals, Logistic Models, Odds Ratio, Risk Factors, Case-Control Studies, Causality, Postmenopause, Middle Aged, Female, Salpingectomy, Clinical Research, Aging, Contraception/Reproduction, Estrogen, Prevention, Medical And Health Sciences, Obstetrics & Reproductive Medicine, Medical and Health Sciences
Abstract: ObjectiveHysterectomy and bilateral salpingo-oophorectomy (BSO) are associated with changes in endogenous hormone levels, yet the risk of venous thrombosis (VT) associated with hysterectomy and BSO is incompletely characterized. This study evaluated the risk of incident VT among postmenopausal women associated with combined prior hysterectomy/oophorectomy status and current use of hormone therapy (HT).MethodsIn a case-control study, we identified incident VT cases (n = 1,623) among postmenopausal Group Health Cooperative enrollees without reproductive cancer, defining their "index date" as their VT diagnosis date (1995-2010). Matched controls had not experienced a prior VT (n = 4,480). Multiple logistic regression models estimated adjusted relative risks for VT associated with combinations of prior hysterectomy/oophorectomy status and HT use at the index date.ResultsCompared with women with an intact uterus who were not using HT, there was no suggestion of greater VT risk in women with prior hysterectomy without BSO, whether they were (adjusted odds ratio [aOR] = 0.80 [95% CI: 0.57, 1.12]) or were not using HT (aOR = 1.09 [95% CI: 0.89, 1.35]). Women with prior hysterectomy and BSO who were using HT were not at a greater VT risk (OR = 1.00 [95% CI: 0.78, 1.27]), but there was evidence of a 25% greater risk associated with prior hysterectomy with BSO and no current HT use (OR = 1.25 [95% CI: 1.05, 1.49]).ConclusionsCollectively, these and prior data do not suggest a substantial impact of hysterectomy, with or without BSO, on the risk of VT among postmenopausal women.
Published: 2016

34. A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration

Author: de Vries, Paul S, Chasman, Daniel I, Sabater-Lleal, Maria, Chen, Ming-Huei, Huffman, Jennifer E, Steri, Maristella, Tang, Weihong, Teumer, Alexander, Marioni, Riccardo E, Grossmann, Vera, Hottenga, Jouke J, Trompet, Stella, Müller-Nurasyid, Martina, Zhao, Jing Hua, Brody, Jennifer A, Kleber, Marcus E, Guo, Xiuqing, Wang, Jie Jin, Auer, Paul L, Attia, John R, Yanek, Lisa R, Ahluwalia, Tarunveer S, Lahti, Jari, Venturini, Cristina, Tanaka, Toshiko, Bielak, Lawrence F, Joshi, Peter K, Rocanin-Arjo, Ares, Kolcic, Ivana, Navarro, Pau, Rose, Lynda M, Oldmeadow, Christopher, Riess, Helene, Mazur, Johanna, Basu, Saonli, Goel, Anuj, Yang, Qiong, Ghanbari, Mohsen, Willemsen, Gonneke, Rumley, Ann, Fiorillo, Edoardo, de Craen, Anton JM, Grotevendt, Anne, Scott, Robert, Taylor, Kent D, Delgado, Graciela E, Yao, Jie, Kifley, Annette, Kooperberg, Charles, Qayyum, Rehan, Lopez, Lorna M, Berentzen, Tina L, Räikkönen, Katri, Mangino, Massimo, Bandinelli, Stefania, Peyser, Patricia A, Wild, Sarah, Trégouët, David-Alexandre, Wright, Alan F, Marten, Jonathan, Zemunik, Tatijana, Morrison, Alanna C, Sennblad, Bengt, Tofler, Geoffrey, de Maat, Moniek PM, de Geus, Eco JC, Lowe, Gordon D, Zoledziewska, Magdalena, Sattar, Naveed, Binder, Harald, Völker, Uwe, Waldenberger, Melanie, Khaw, Kay-Tee, Mcknight, Barbara, Huang, Jie, Jenny, Nancy S, Holliday, Elizabeth G, Qi, Lihong, Mcevoy, Mark G, Becker, Diane M, Starr, John M, Sarin, Antti-Pekka, Hysi, Pirro G, Hernandez, Dena G, Jhun, Min A, Campbell, Harry, Hamsten, Anders, Rivadeneira, Fernando, Mcardle, Wendy L, Slagboom, P Eline, Zeller, Tanja, Koenig, Wolfgang, Psaty, Bruce M, Haritunians, Talin, Liu, Jingmin, Palotie, Aarno, Uitterlinden, André G, Stott, David J, Hofman, Albert, and Franco, Oscar H
Subjects: Biological Sciences, Genetics, Human Genome, Adult, Aged, Aged, 80 and over, Female, Fibrinogen, Genetic Loci, Genome-Wide Association Study, Humans, INDEL Mutation, Male, Middle Aged, Polymorphism, Single Nucleotide, White People, Medical and Health Sciences, Genetics & Heredity
Abstract: Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.
Published: 2016

35. Circulating n-3 fatty acids and trans-fatty acids, PLA2G2A gene variation and sudden cardiac arrest

Author: Lemaitre, Rozenn N, Bartz, Traci M, King, Irena B, Brody, Jennifer A, McKnight, Barbara, Sotoodehnia, Nona, Rea, Thomas D, Johnson, Catherine O, Mozaffarian, Dariush, Hesselson, Stephanie, Kwok, Pui-Yan, and Siscovick, David S
Subjects: Epidemiology, Biomedical and Clinical Sciences, Nutrition and Dietetics, Health Sciences, Prevention, Cardiovascular, Nutrition, Genetics, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Sudden cardiac arrest, Fatty acids, SCA, sudden cardiac arrest, sPLA2, secretory phospholipase A2, Nutrition and dietetics
Abstract: Whether genetic factors influence the associations of fatty acids with the risk of sudden cardiac arrest (SCA) is largely unknown. To investigate possible gene-fatty acid interactions on SCA risk, we used a case-only approach and measured fatty acids in erythrocyte samples from 1869 SCA cases in a population-based repository with genetic data. We selected 191 SNP in ENCODE-identified regulatory regions of fifty-five candidate genes in fatty acid metabolic pathways. Using linear regression and additive genetic models, we investigated the association of the selected SNP with erythrocyte levels of fatty acids, including DHA, EPA and trans-fatty acids among the SCA cases. The assumption of no association in non-cases was supported by analysis of publicly available datasets containing over 8000 samples. None of the SNP-fatty acid associations tested among the cases reached statistical significance after correction for multiple comparisons. One SNP, rs4654990 near PLA2G2A, with an allele frequency of 0·33, was nominally associated with lower levels of DHA and EPA and higher levels of trans-fatty acids. The strongest association was with DHA levels (exponentiated coefficient for one unit (1 % of total fatty acids), 0·90, 95 % CI 0·85, 0·97; P = 0·003), indicating that for subjects with a coded allele, the OR of SCA associated with one unit higher DHA is about 90 % what it is for subjects with one fewer coded allele. These findings suggest that the associations of circulating n-3 and trans-fatty acids with SCA risk may be more pronounced in carriers of the rs4654990 G allele.
Published: 2016

36. Plasma Ceramides and Sphingomyelins and Sudden Cardiac Death in the Cardiovascular Health Study

Author: Bockus, Lee B., primary, Jensen, Paul N., additional, Fretts, Amanda M., additional, Hoofnagle, Andrew N., additional, McKnight, Barbara, additional, Sitlani, Colleen M., additional, Siscovick, David S., additional, King, Irena B., additional, Psaty, Bruce M., additional, Sotoodehnia, Nona, additional, and Lemaitre, Rozenn N., additional
Published: 2023
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37. Parent-of-Origin Effects of the APOB Gene on Adiposity in Young Adults.

Author: Hochner, Hagit, Allard, Catherine, Granot-Hershkovitz, Einat, Chen, Jinbo, Sitlani, Colleen M, Sazdovska, Sandra, Lumley, Thomas, McKnight, Barbara, Rice, Kenneth, Enquobahrie, Daniel A, Meigs, James B, Kwok, Pui, Hivert, Marie-France, Borecki, Ingrid B, Gomez, Felicia, Wang, Ting, van Duijn, Cornelia, Amin, Najaf, Rotter, Jerome I, Stamatoyannopoulos, John, Meiner, Vardiella, Manor, Orly, Dupuis, Josée, Friedlander, Yechiel, and Siscovick, David S
Subjects: Humans, Obesity, Cholesterol, Insulin, Glucose, Body Mass Index, Waist-Hip Ratio, Genomic Imprinting, Polymorphism, Single Nucleotide, Adult, Female, Male, Adiposity, Apolipoprotein B-100, Waist Circumference, Genome-Wide Association Study, Young Adult, Developmental Biology, Genetics
Abstract: Loci identified in genome-wide association studies (GWAS) of cardio-metabolic traits account for a small proportion of the traits' heritability. To date, most association studies have not considered parent-of-origin effects (POEs). Here we report investigation of POEs on adiposity and glycemic traits in young adults. The Jerusalem Perinatal Family Follow-Up Study (JPS), comprising 1250 young adults and their mothers was used for discovery. Focusing on 18 genes identified by previous GWAS as associated with cardio-metabolic traits, we used linear regression to examine the associations of maternally- and paternally-derived offspring minor alleles with body mass index (BMI), waist circumference (WC), fasting glucose and insulin. We replicated and meta-analyzed JPS findings in individuals of European ancestry aged ≤50 belonging to pedigrees from the Framingham Heart Study, Family Heart Study and Erasmus Rucphen Family study (total N≅4800). We considered p0.6). Suggestive maternally-derived associations of rs1367117 were observed with fasting glucose (β = 0.9; 95%CI:0.3,1.5; p = 4.0x10-3) and insulin (ln-transformed, β = 0.06; 95%CI:0.03,0.1; p = 7.4x10-4). Bioinformatic annotation for rs1367117 revealed a variety of regulatory functions in this region in liver and adipose tissues and a 50% methylation pattern in liver only, consistent with allelic-specific methylation, which may indicate tissue-specific POE. Our findings demonstrate a maternal-specific association between a common APOB variant and adiposity, an association that was not previously detected in GWAS. These results provide evidence for the role of regulatory mechanisms, POEs specifically, in adiposity. In addition this study highlights the benefit of utilizing family studies for deciphering the genetic architecture of complex traits.
Published: 2015

38. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Author: Winkler, Thomas W, Justice, Anne E, Graff, Mariaelisa, Barata, Llilda, Feitosa, Mary F, Chu, Su, Czajkowski, Jacek, Esko, Tõnu, Fall, Tove, Kilpeläinen, Tuomas O, Lu, Yingchang, Mägi, Reedik, Mihailov, Evelin, Pers, Tune H, Rüeger, Sina, Teumer, Alexander, Ehret, Georg B, Ferreira, Teresa, Heard-Costa, Nancy L, Karjalainen, Juha, Lagou, Vasiliki, Mahajan, Anubha, Neinast, Michael D, Prokopenko, Inga, Simino, Jeannette, Teslovich, Tanya M, Jansen, Rick, Westra, Harm-Jan, White, Charles C, Absher, Devin, Ahluwalia, Tarunveer S, Ahmad, Shafqat, Albrecht, Eva, Alves, Alexessander Couto, Bragg-Gresham, Jennifer L, de Craen, Anton JM, Bis, Joshua C, Bonnefond, Amélie, Boucher, Gabrielle, Cadby, Gemma, Cheng, Yu-Ching, Chiang, Charleston WK, Delgado, Graciela, Demirkan, Ayse, Dueker, Nicole, Eklund, Niina, Eiriksdottir, Gudny, Eriksson, Joel, Feenstra, Bjarke, Fischer, Krista, Frau, Francesca, Galesloot, Tessel E, Geller, Frank, Goel, Anuj, Gorski, Mathias, Grammer, Tanja B, Gustafsson, Stefan, Haitjema, Saskia, Hottenga, Jouke-Jan, Huffman, Jennifer E, Jackson, Anne U, Jacobs, Kevin B, Johansson, Åsa, Kaakinen, Marika, Kleber, Marcus E, Lahti, Jari, Mateo Leach, Irene, Lehne, Benjamin, Liu, Youfang, Lo, Ken Sin, Lorentzon, Mattias, Luan, Jian'an, Madden, Pamela AF, Mangino, Massimo, McKnight, Barbara, Medina-Gomez, Carolina, Monda, Keri L, Montasser, May E, Müller, Gabriele, Müller-Nurasyid, Martina, Nolte, Ilja M, Panoutsopoulou, Kalliope, Pascoe, Laura, Paternoster, Lavinia, Rayner, Nigel W, Renström, Frida, Rizzi, Federica, Rose, Lynda M, Ryan, Kathy A, Salo, Perttu, Sanna, Serena, Scharnagl, Hubert, Shi, Jianxin, Smith, Albert Vernon, Southam, Lorraine, Stančáková, Alena, Steinthorsdottir, Valgerdur, Strawbridge, Rona J, Sung, Yun Ju, and Tachmazidou, Ioanna
Subjects: CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Humans, Genetic Predisposition to Disease, Body Mass Index, Body Size, Waist-Hip Ratio, Chromosome Mapping, Age Factors, Sex Characteristics, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, European Continental Ancestry Group, Female, Male, Genome-Wide Association Study, Developmental Biology, Genetics
Abstract: Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR
Published: 2015

39. Cooking for Health: a healthy food budgeting, purchasing, and cooking skills randomized controlled trial to improve diet among American Indians with type 2 diabetes

Author: Hawley, Caitlin N., Huber, Corrine M., Best, Lyle G., Howard, Barbara V., Umans, Jason, Beresford, Shirley A. A., McKnight, Barbara, Hager, Arlette, O’Leary, Marcia, Thorndike, Anne N., Ornelas, India J., Brown, Meagan C., and Fretts, Amanda M.
Published: 2021
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40. Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism

Author: Lindström, Sara, Wang, Lu, Smith, Erin N., Gordon, William, van Hylckama Vlieg, Astrid, de Andrade, Mariza, Brody, Jennifer A., Pattee, Jack W., Haessler, Jeffrey, Brumpton, Ben M., Chasman, Daniel I., Suchon, Pierre, Chen, Ming-Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri L., MacDonald, James, Braekkan, Sigrid K., Armasu, Sebastian M., Pankratz, Nathan, Jackson, Rebecca D., Nielsen, Jonas B., Giulianini, Franco, Puurunen, Marja K., Ibrahim, Manal, Heckbert, Susan R., Damrauer, Scott M., Natarajan, Pradeep, Klarin, Derek, de Vries, Paul S., Sabater-Lleal, Maria, Huffman, Jennifer E., Bammler, Theo K., Frazer, Kelly A., McCauley, Bryan M., Taylor, Kent, Pankow, James S., Reiner, Alexander P., Gabrielsen, Maiken E., Deleuze, Jean-François, O'Donnell, Chris J., Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John-Bjarne, Rosendaal, Frits R., Heit, John A., Psaty, Bruce M., Tang, Weihong, Kooperberg, Charles, Hveem, Kristian, Ridker, Paul M., Morange, Pierre-Emmanuel, Johnson, Andrew D., Kabrhel, Christopher, Trégouët, David-Alexandre, and Smith, Nicholas L.
Published: 2019
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41. Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF

Author: Huffman, Jennifer E, de Vries, Paul S, Morrison, Alanna C, Sabater-Lleal, Maria, Kacprowski, Tim, Auer, Paul L, Brody, Jennifer A, Chasman, Daniel I, Chen, Ming-Huei, Guo, Xiuqing, Lin, Li-An, Marioni, Riccardo E, Müller-Nurasyid, Martina, Yanek, Lisa R, Pankratz, Nathan, Grove, Megan L, de Maat, Moniek PM, Cushman, Mary, Wiggins, Kerri L, Qi, Lihong, Sennblad, Bengt, Harris, Sarah E, Polasek, Ozren, Riess, Helene, Rivadeneira, Fernando, Rose, Lynda M, Goel, Anuj, Taylor, Kent D, Teumer, Alexander, Uitterlinden, André G, Vaidya, Dhananjay, Yao, Jie, Tang, Weihong, Levy, Daniel, Waldenberger, Melanie, Becker, Diane M, Folsom, Aaron R, Giulianini, Franco, Greinacher, Andreas, Hofman, Albert, Huang, Chiang-Ching, Kooperberg, Charles, Silveira, Angela, Starr, John M, Strauch, Konstantin, Strawbridge, Rona J, Wright, Alan F, McKnight, Barbara, Franco, Oscar H, Zakai, Neil, Mathias, Rasika A, Psaty, Bruce M, Ridker, Paul M, Tofler, Geoffrey H, Völker, Uwe, Watkins, Hugh, Fornage, Myriam, Hamsten, Anders, Deary, Ian J, Boerwinkle, Eric, Koenig, Wolfgang, Rotter, Jerome I, Hayward, Caroline, Dehghan, Abbas, Reiner, Alex P, O'Donnell, Christopher J, and Smith, Nicholas L
Subjects: Biological Sciences, Genetics, Human Genome, Hematology, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Cardiovascular, Cohort Studies, Factor VII, Factor VIII, Fibrinogen, Gene Frequency, Genetic Association Studies, Genetic Variation, Humans, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Potassium Channels, Potassium Channels, Sodium-Activated, von Willebrand Factor, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Paediatrics and Reproductive Medicine, Immunology, Biochemistry and cell biology, Cardiovascular medicine and haematology, Paediatrics
Abstract: Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] ≥0.01 and
Published: 2015

42. Dietary fatty acids modulate associations between genetic variants and circulating fatty acids in plasma and erythrocyte membranes: Meta‐analysis of nine studies in the CHARGE consortium

Author: Smith, Caren E, Follis, Jack L, Nettleton, Jennifer A, Foy, Millennia, Wu, Jason HY, Ma, Yiyi, Tanaka, Toshiko, Manichakul, Ani W, Wu, Hongyu, Chu, Audrey Y, Steffen, Lyn M, Fornage, Myriam, Mozaffarian, Dariush, Kabagambe, Edmond K, Ferruci, Luigi, Chen, Yii-Der Ida, Rich, Stephen S, Djoussé, Luc, Ridker, Paul M, Tang, Weihong, McKnight, Barbara, Tsai, Michael Y, Bandinelli, Stefania, Rotter, Jerome I, Hu, Frank B, Chasman, Daniel I, Psaty, Bruce M, Arnett, Donna K, King, Irena B, Sun, Qi, Wang, Lu, Lumley, Thomas, Chiuve, Stephanie E, Siscovick, David S, Ordovás, José M, and Lemaitre, Rozenn N
Subjects: Biomedical and Clinical Sciences, Nutrition and Dietetics, Prevention, Complementary and Integrative Health, Nutrition, Genetics, Acetyltransferases, Acyltransferases, Adaptor Proteins, Signal Transducing, Carboxy-Lyases, Delta-5 Fatty Acid Desaturase, Diet, Docosahexaenoic Acids, Eicosapentaenoic Acid, Erythrocyte Membrane, Fatty Acid Desaturases, Fatty Acid Elongases, Fatty Acids, Fatty Acids, Omega-3, Female, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, FADS1, Gene-diet interactions, Meta-analysis, Omega-3 fatty acids, Food Sciences, Public Health and Health Services, Food Science, Nutrition & Dietetics, Food sciences, Nutrition and dietetics
Abstract: ScopeTissue concentrations of omega-3 fatty acids may reduce cardiovascular disease risk, and genetic variants are associated with circulating fatty acids concentrations. Whether dietary fatty acids interact with genetic variants to modify circulating omega-3 fatty acids is unclear. We evaluated interactions between genetic variants and fatty acid intakes for circulating alpha-linoleic acid, eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid.Methods and resultsWe conducted meta-analyses (N = 11 668) evaluating interactions between dietary fatty acids and genetic variants (rs174538 and rs174548 in FADS1 (fatty acid desaturase 1), rs7435 in AGPAT3 (1-acyl-sn-glycerol-3-phosphate), rs4985167 in PDXDC1 (pyridoxal-dependent decarboxylase domain-containing 1), rs780094 in GCKR (glucokinase regulatory protein), and rs3734398 in ELOVL2 (fatty acid elongase 2)). Stratification by measurement compartment (plasma versus erthyrocyte) revealed compartment-specific interactions between FADS1 rs174538 and rs174548 and dietary alpha-linolenic acid and linoleic acid for docosahexaenoic acid and docosapentaenoic acid.ConclusionOur findings reinforce earlier reports that genetically based differences in circulating fatty acids may be partially due to differences in the conversion of fatty acid precursors. Further, fatty acids measurement compartment may modify gene-diet relationships, and considering compartment may improve the detection of gene-fatty acids interactions for circulating fatty acid outcomes.
Published: 2015

43. A comparison of prehospital lactate and systolic blood pressure for predicting the need for resuscitative care in trauma transported by ground.

Author: Guyette, Francis, Meier, Eric, Newgard, Craig, McKnight, Barbara, Daya, Mohamud, Bulger, Eileen, Powell, Judy, Brasel, Karen, Kerby, Jeffery, Egan, Debra, Sise, Michael, Coimbra, Raul, Fabian, Timothy, and Hoyt, David
Subjects: Adult, Ambulances, Biomarkers, Blood Pressure, Female, Humans, Lactates, Male, Predictive Value of Tests, Prognosis, Prospective Studies, Resuscitation, Sensitivity and Specificity, Systole, Trauma Centers, Triage, Wounds and Injuries
Abstract: BACKGROUND: Reliance on prehospital trauma triage guidelines misses patients with serious injury. Lactate is a biomarker capable of identifying high-risk trauma patients. Our objective was to compare prehospital point-of-care lactate (P-LAC) with systolic blood pressure (SBP) for predicting the need for resuscitative care (RC) in trauma patients transported by ground emergency medical services. METHODS: This is a prospective observational study at nine sites within the Resuscitation Outcomes Consortium conducted from March 2011 to August 2012. Lactate was measured on patients with a prehospital SBP of 100 mm Hg or less who were transported by emergency medical services to a Level I or II trauma center. Patients were followed up for the need for RC, defined as any of the following within 6 hours of emergency department arrival: blood transfusion of 5 U or greater; intervention for hemorrhage including thoracotomy, laparotomy, pelvic fixation, or interventional radiology embolization; or death. RESULTS: A total of 387 patients had a lactate value and presented with SBP between 71 mm Hg and 100 mm Hg, and 70 (18%) required RC. With the use of a P-LAC decision rule (≥2.5 mmol/L) that yielded the same specificity as that of SBP of 90 mm Hg or less (48%), the observed sensitivities for RC were 93% (95% confidence interval [CI], 84-98%) for P-LAC of 2.5 mmol/L or greater and 67% (95% CI, 55-78%) for SBP of 90 mm Hg or less (McNemars test, p < 0.001). P-LAC has an estimated area under the curve of 0.78 (95% CI, 0.73-0.83), which is statistically superior to that of SBP (0.59; 95% CI, 0.53-0.66) and shock index (heart rate / SBP) (0.66; 95% CI, 0.60-0.74). CONCLUSION: P-LAC obtained at the scene is associated with the need for RC. P-LAC is superior to other early surrogates for hypoperfusion (SBP and shock index) in predicting the need for RC in trauma patients with 70 mm Hg < SBP ≤ 100 mm Hg. LEVEL OF EVIDENCE: Prognostic study, level II.
Published: 2015

44. 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.
Published: 2019
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45. Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes.

Author: Ng, Maggie CY, Shriner, Daniel, Chen, Brian H, Li, Jiang, Chen, Wei-Min, Guo, Xiuqing, Liu, Jiankang, Bielinski, Suzette J, Yanek, Lisa R, Nalls, Michael A, Comeau, Mary E, Rasmussen-Torvik, Laura J, Jensen, Richard A, Evans, Daniel S, Sun, Yan V, An, Ping, Patel, Sanjay R, Lu, Yingchang, Long, Jirong, Armstrong, Loren L, Wagenknecht, Lynne, Yang, Lingyao, Snively, Beverly M, Palmer, Nicholette D, Mudgal, Poorva, Langefeld, Carl D, Keene, Keith L, Freedman, Barry I, Mychaleckyj, Josyf C, Nayak, Uma, Raffel, Leslie J, Goodarzi, Mark O, Chen, Y-D Ida, Taylor, Herman A, Correa, Adolfo, Sims, Mario, Couper, David, Pankow, James S, Boerwinkle, Eric, Adeyemo, Adebowale, Doumatey, Ayo, Chen, Guanjie, Mathias, Rasika A, Vaidya, Dhananjay, Singleton, Andrew B, Zonderman, Alan B, Igo, Robert P, Sedor, John R, FIND Consortium, Kabagambe, Edmond K, Siscovick, David S, McKnight, Barbara, Rice, Kenneth, Liu, Yongmei, Hsueh, Wen-Chi, Zhao, Wei, Bielak, Lawrence F, Kraja, Aldi, Province, Michael A, Bottinger, Erwin P, Gottesman, Omri, Cai, Qiuyin, Zheng, Wei, Blot, William J, Lowe, William L, Pacheco, Jennifer A, Crawford, Dana C, eMERGE Consortium, DIAGRAM Consortium, Grundberg, Elin, MuTHER Consortium, Rich, Stephen S, Hayes, M Geoffrey, Shu, Xiao-Ou, Loos, Ruth JF, Borecki, Ingrid B, Peyser, Patricia A, Cummings, Steven R, Psaty, Bruce M, Fornage, Myriam, Iyengar, Sudha K, Evans, Michele K, Becker, Diane M, Kao, WH Linda, Wilson, James G, Rotter, Jerome I, Sale, Michèle M, Liu, Simin, Rotimi, Charles N, Bowden, Donald W, and MEta-analysis of type 2 DIabetes in African Americans Consortium
Subjects: FIND Consortium, eMERGE Consortium, DIAGRAM Consortium, MuTHER Consortium, MEta-analysis of type 2 DIabetes in African Americans Consortium, Humans, Diabetes Mellitus, Type 2, HMGA2 Protein, HLA-B27 Antigen, Polymorphism, Single Nucleotide, African Americans, Mutant Chimeric Proteins, KCNQ1 Potassium Channel, Genome-Wide Association Study, Transcription Factor 7-Like 2 Protein, Human Genome, Diabetes, Genetics, 2.1 Biological and endogenous factors, Metabolic and endocrine, Developmental Biology
Abstract: Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)
Published: 2014

46. Meta-analysis of loci associated with age at natural menopause in African-American women

Author: Chen, Christina TL, Liu, Ching-Ti, Chen, Gary K, Andrews, Jeanette S, Arnold, Alice M, Dreyfus, Jill, Franceschini, Nora, Garcia, Melissa E, Kerr, Kathleen F, Li, Guo, Lohman, Kurt K, Musani, Solomon K, Nalls, Michael A, Raffel, Leslie J, Smith, Jennifer, Ambrosone, Christine B, Bandera, Elisa V, Bernstein, Leslie, Britton, Angela, Brzyski, Robert G, Cappola, Anne, Carlson, Christopher S, Couper, David, Deming, Sandra L, Goodarzi, Mark O, Heiss, Gerardo, John, Esther M, Lu, Xiaoning, Le Marchand, Loic, Marciante, Kristin, Mcknight, Barbara, Millikan, Robert, Nock, Nora L, Olshan, Andrew F, Press, Michael F, Vaiyda, Dhananjay, Woods, Nancy F, Taylor, Herman A, Zhao, Wei, Zheng, Wei, Evans, Michele K, Harris, Tamara B, Henderson, Brian E, Kardia, Sharon LR, Kooperberg, Charles, Liu, Yongmei, Mosley, Thomas H, Psaty, Bruce, Wellons, Melissa, Windham, Beverly G, Zonderman, Alan B, Cupples, L Adrienne, Demerath, Ellen W, Haiman, Christopher, Murabito, Joanne M, and Rajkovic, Aleksandar
Subjects: Contraception/Reproduction, Estrogen, Genetics, Human Genome, Aging, 2.1 Biological and endogenous factors, Aetiology, Reproductive health and childbirth, Black or African American, Age Factors, Chromosomes, Human, Female, Genetic Loci, Genetic Variation, Genome-Wide Association Study, Humans, Menopause, United States, White People, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: Age at menopause marks the end of a woman's reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from 11 studies across the USA. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (P-value < 0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of 14 loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in USA.
Published: 2014

47. Association of Levels of Fasting Glucose and Insulin With Rare Variants at the Chromosome 11p11.2-MADD Locus

Author: Cornes, Belinda K, Brody, Jennifer A, Nikpoor, Naghmeh, Morrison, Alanna C, Chu, Huan, Ahn, Byung Soo, Wang, Shuai, Dauriz, Marco, Barzilay, Joshua I, Dupuis, Josée, Florez, Jose C, Coresh, Josef, Gibbs, Richard A, Kao, WH Linda, Liu, Ching-Ti, McKnight, Barbara, Muzny, Donna, Pankow, James S, Reid, Jeffrey G, White, Charles C, Johnson, Andrew D, Wong, Tien Y, Psaty, Bruce M, Boerwinkle, Eric, Rotter, Jerome I, Siscovick, David S, Sladek, Robert, and Meigs, James B
Subjects: Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Genetics, Human Genome, Diabetes, Aetiology, 1.1 Normal biological development and functioning, Underpinning research, 2.1 Biological and endogenous factors, Metabolic and endocrine, Aged, Aged, 80 and over, Aging, Blood Glucose, Chromosomes, Human, Pair 11, Cohort Studies, Death Domain Receptor Signaling Adaptor Proteins, Diabetes Mellitus, Type 2, Fasting, Female, Gene Frequency, Genetic Variation, Genome-Wide Association Study, Genomics, Guanine Nucleotide Exchange Factors, Heart Diseases, Humans, Insulin, Male, Middle Aged, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, genetic epidemiology, glucose, human genetics, insulin, molecular genetics, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract: BackgroundCommon variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels.Methods and resultsSequencing (mean depth, 38×) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9% of which were rare (minor allele frequency 2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity.ConclusionsSequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity.
Published: 2014

48. Novel Genetic Markers Associate With Atrial Fibrillation Risk in Europeans and Japanese

Author: Lubitz, Steven A, Lunetta, Kathryn L, Lin, Honghuang, Arking, Dan E, Trompet, Stella, Li, Guo, Krijthe, Bouwe P, Chasman, Daniel I, Barnard, John, Kleber, Marcus E, Dörr, Marcus, Ozaki, Kouichi, Smith, Albert V, Müller-Nurasyid, Martina, Walter, Stefan, Agarwal, Sunil K, Bis, Joshua C, Brody, Jennifer A, Chen, Lin Y, Everett, Brendan M, Ford, Ian, Franco, Oscar H, Harris, Tamara B, Hofman, Albert, Kääb, Stefan, Mahida, Saagar, Kathiresan, Sekar, Kubo, Michiaki, Launer, Lenore J, Macfarlane, Peter W, Magnani, Jared W, McKnight, Barbara, McManus, David D, Peters, Annette, Psaty, Bruce M, Rose, Lynda M, Rotter, Jerome I, Silbernagel, Guenther, Smith, Jonathan D, Sotoodehnia, Nona, Stott, David J, Taylor, Kent D, Tomaschitz, Andreas, Tsunoda, Tatsuhiko, Uitterlinden, Andre G, Van Wagoner, David R, Völker, Uwe, Völzke, Henry, Murabito, Joanne M, Sinner, Moritz F, Gudnason, Vilmundur, Felix, Stephan B, März, Winfried, Chung, Mina, Albert, Christine M, Stricker, Bruno H, Tanaka, Toshihiro, Heckbert, Susan R, Jukema, J Wouter, Alonso, Alvaro, Benjamin, Emelia J, and Ellinor, Patrick T
Subjects: Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Genetics, Heart Disease, Cardiovascular, Clinical Research, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Adult, Aged, Aged, 80 and over, Asian People, Atrial Fibrillation, Chromosome Mapping, Chromosomes, Human, Pair 4, Europe, Female, Genetic Markers, Genetic Predisposition to Disease, Homeodomain Proteins, Humans, Japan, Male, Middle Aged, Polymorphism, Single Nucleotide, Transcription Factors, White People, atrial fibrillation, atrial flutter, genetic, prognosis, risk, Cardiorespiratory Medicine and Haematology, Public Health and Health Services, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract: ObjectivesThis study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.BackgroundAF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.MethodsWe performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).ResultsWe observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.ConclusionsThe chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.
Published: 2014

49. DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis

Author: Ward-Caviness, Cavin K., Huffman, Jennifer E., Everett, Karl, Germain, Marine, van Dongen, Jenny, Hill, W. David, Jhun, Min A., Brody, Jennifer A., Ghanbari, Mohsen, Du, Lei, Roetker, Nicholas S., de Vries, Paul S., Waldenberger, Melanie, Gieger, Christian, Wolf, Petra, Prokisch, Holger, Koenig, Wolfgang, O'Donnell, Christopher J., Levy, Daniel, Liu, Chunyu, Truong, Vinh, Wells, Philip S., Trégouët, David-Alexandre, Tang, Weihong, Morrison, Alanna C., Boerwinkle, Eric, Wiggins, Kerri L., McKnight, Barbara, Guo, Xiuqing, Psaty, Bruce M., Sotoodenia, Nona, Boomsma, Dorret I., Willemsen, Gonneke, Ligthart, Lannie, Deary, Ian J., Zhao, Wei, Ware, Erin B., Kardia, Sharon L.R., Van Meurs, Joyce B.J., Uitterlinden, Andre G., Franco, Oscar H., Eriksson, Per, Franco-Cereceda, Anders, Pankow, James S., Johnson, Andrew D., Gagnon, France, Morange, Pierre-Emmanuel, de Geus, Eco J.C., Starr, John M., Smith, Jennifer A., Dehghan, Abbas, Björck, Hanna M., Smith, Nicholas L., and Peters, Annette
Published: 2018
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50. Targeted sequencing in candidate genes for atrial fibrillation: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study

Author: Lin, Honghuang, Sinner, Moritz F, Brody, Jennifer A, Arking, Dan E, Lunetta, Kathryn L, Rienstra, Michiel, Lubitz, Steven A, Magnani, Jared W, Sotoodehnia, Nona, McKnight, Barbara, McManus, David D, Boerwinkle, Eric, Psaty, Bruce M, Rotter, Jerome I, Bis, Joshua C, Gibbs, Richard A, Muzny, Donna, Kovar, Christie L, Morrison, Alanna C, Gupta, Mayetri, Folsom, Aaron R, Kääb, Stefan, Heckbert, Susan R, Alonso, Alvaro, Ellinor, Patrick T, Benjamin, Emelia J, and Group, on behalf of the CHARGE Atrial Fibrillation Working
Subjects: Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Human Genome, Cardiovascular, Biotechnology, Aging, Genetics, Heart Disease, Aetiology, 2.1 Biological and endogenous factors, Aged, Atrial Fibrillation, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Homeodomain Proteins, Humans, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide, Receptors, Interleukin-6, Arrhythmia, Atrial fibrillation, Epidemiology, CHARGE Atrial Fibrillation Working Group, Biomedical Engineering, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract: BackgroundGenome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF.ObjectiveTo study the association of genetic variants with AF at GWAS top loci.MethodsIn the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital.ResultsOne common variant (rs11265611; P = 1.70 × 10(-6)) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r(2) = .69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P = .01).ConclusionsWe identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.
Published: 2014

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