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51. Common variation in fatty acid metabolic genes and risk of incident sudden cardiac arrest

Author

Lemaitre, Rozenn N, Johnson, Catherine O, Hesselson, Stephanie, Sotoodhenia, Nona, McKnight, Barbara, Sitlani, Colleen M, Rea, Thomas D, King, Irena B, Kwok, Pui-Yan, Mak, Angel, Li, Guo, Brody, Jennifer, Larson, Eric, Mozaffarian, Dariush, Psaty, Bruce M, Huertas-Vazquez, Adriana, Tardif, Jean-Claude, Albert, Christine M, Lyytikäinen, Leo-Pekka, Arking, Dan E, Kääb, Stefan, Huikuri, Heikki V, Krijthe, Bouwe P, Eijgelsheim, Mark, Wang, Ying A, Reinier, Kyndaron, Lehtimäki, Terho, Pulit, Sara L, Brugada, Ramon, Müller-Nurasyid, Martina, Newton-Cheh, Chris H, Karhunen, Pekka J, Stricker, Bruno H, Goyette, Philippe, Rotter, Jerome I, Chugh, Sumeet S, Chakravarti, Aravinda, Jouven, Xavier, and Siscovick, David S

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Cardiovascular, Clinical Research, Prevention, Genetics, Aetiology, 2.1 Biological and endogenous factors, 1-Acylglycerophosphocholine O-Acyltransferase, Aged, Algorithms, Alleles, Case-Control Studies, Death, Sudden, Cardiac, Fatty Acids, Female, Genetic Predisposition to Disease, Genetic Variation, Genotype, Humans, Male, Polymorphism, Single Nucleotide, Risk Factors, Death, Sudden, Genetic epidemiology, Biomedical Engineering, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

BackgroundThere is limited information on genetic factors associated with sudden cardiac arrest (SCA).ObjectiveTo assess the association of common variation in genes in fatty acid pathways with SCA risk.MethodsWe selected 85 candidate genes and 1155 single nucleotide polymorphisms (SNPs) tagging common variation in each gene. We investigated the SNP associations with SCA in a population-based case-control study. Cases (n = 2160) were from a repository of SCA in the greater Seattle area. Controls (n = 2615), frequency-matched on age and sex, were from the same area. We used linear logistic regression to examine SNP associations with SCA. We performed permutation-based p-min tests to account for multiple comparisons within each gene. The SNP associations with a corrected P value of

Published
2014

52. Gene expression in thiazide diuretic or statin users in relation to incident type 2 diabetes.

Author

Suchy-Dicey, Astrid, Heckbert, Susan R, Smith, Nicholas L, McKnight, Barbara, Rotter, Jerome I, Chen, Yd Ida, Psaty, Bruce M, and Enquobahrie, Daniel A

Subjects
Biological Sciences, Genetics, Diabetes, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Cardiovascular, Type 2 diabetes, statins, thiazide diuretics, whole blood, gene expression, microarray, supervised normalization, surrogate variable analysis, chemokine ligand 14, zinc finger proteins, Public Health and Health Services, Epidemiology
Abstract

Thiazide diuretics and statins are used to improve cardiovascular outcomes, but may also cause type 2 diabetes (T2DM), although mechanisms are unknown. Gene expression studies may facilitate understanding of these associations. Participants from ongoing population-based studies were sampled for these longitudinal studies of peripheral blood microarray gene expression, and followed to incident diabetes. All sampled subjects were statin or thiazide users. Those who developed diabetes during follow-up comprised cases (44 thiazide users; 19 statin users), and were matched to drug-using controls who did not develop diabetes on several factors. Supervised normalization, surrogate variable analyses removed technical bias and confounding. Differentially-expressed genes were those with a false discovery rate Q-value

Published
2014

53. A genome-wide association study of early menopause and the combined impact of identified variants

Author

Perry, John RB, Corre, Tanguy, Esko, Tõnu, Chasman, Daniel I, Fischer, Krista, Franceschini, Nora, He, Chunyan, Kutalik, Zoltan, Mangino, Massimo, Rose, Lynda M, Smith, Albert Vernon, Stolk, Lisette, Sulem, Patrick, Weedon, Michael N, Zhuang, Wei V, Arnold, Alice, Ashworth, Alan, Bergmann, Sven, Buring, Julie E, Burri, Andrea, Chen, Constance, Cornelis, Marilyn C, Couper, David J, Goodarzi, Mark O, Gudnason, Vilmundur, Harris, Tamara, Hofman, Albert, Jones, Michael, Kraft, Peter, Launer, Lenore, Laven, Joop SE, Li, Guo, McKnight, Barbara, Masciullo, Corrado, Milani, Lili, Orr, Nicholas, Psaty, Bruce M, Ridker, Paul M, Rivadeneira, Fernando, Sala, Cinzia, Salumets, Andres, Schoemaker, Minouk, Traglia, Michela, Waeber, Gérard, Chanock, Stephen J, Demerath, Ellen W, Garcia, Melissa, Hankinson, Susan E, Hu, Frank B, Hunter, David J, Lunetta, Kathryn L, Metspalu, Andres, Montgomery, Grant W, Murabito, Joanne M, Newman, Anne B, Ong, Ken K, Spector, Tim D, Stefansson, Kari, Swerdlow, Anthony J, Thorsteinsdottir, Unnur, Van Dam, Rob M, Uitterlinden, André G, Visser, Jenny A, Vollenweider, Peter, Toniolo, Daniela, and Murray, Anna

Subjects
Biotechnology, Contraception/Reproduction, Infertility, Genetics, Human Genome, Aging, Estrogen, Prevention, Aetiology, 2.1 Biological and endogenous factors, Reproductive health and childbirth, Good Health and Well Being, Case-Control Studies, Female, Gene Frequency, Genome-Wide Association Study, Humans, Menopause, Premature, Polymorphism, Single Nucleotide, Primary Ovarian Insufficiency, Quantitative Trait Loci, Risk, ReproGen Consortium, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.

Published
2013

54. Genome-Wide Association Study of Retinopathy in Individuals without Diabetes

Author

Jensen, Richard A, Sim, Xueling, Li, Xiaohui, Cotch, Mary Frances, Ikram, M Kamran, Holliday, Elizabeth G, Eiriksdottir, Gudny, Harris, Tamara B, Jonasson, Fridbert, Klein, Barbara EK, Launer, Lenore J, Smith, Albert Vernon, Boerwinkle, Eric, Cheung, Ning, Hewitt, Alex W, Liew, Gerald, Mitchell, Paul, Wang, Jie Jin, Attia, John, Scott, Rodney, Glazer, Nicole L, Lumley, Thomas, McKnight, Barbara, Psaty, Bruce M, Taylor, Kent, Hofman, Albert, de Jong, Paulus TVM, Rivadeneira, Fernando, Uitterlinden, Andre G, Tay, Wan-Ting, Teo, Yik Ying, Seielstad, Mark, Liu, Jianjun, Cheng, Ching-Yu, Saw, Seang-Mei, Aung, Tin, Ganesh, Santhi K, O'Donnell, Christopher J, Nalls, Mike A, Wiggins, Kerri L, Kuo, Jane Z, team, The Blue Mountains Eye Study GWAS, Consortium, CKDGen, van Duijn, Cornelia M, Gudnason, Vilmundur, Klein, Ronald, Siscovick, David S, Rotter, Jerome I, Tai, E Shong, Vingerling, Johannes, and Wong, Tien Y

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Human Genome, Hypertension, Diabetes, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Cardiovascular, Aged, Aged, 80 and over, Female, Genome-Wide Association Study, Genotype, Histone Deacetylases, Humans, Male, Polymorphism, Single Nucleotide, Repressor Proteins, Retinal Diseases, Blue Mountains Eye Study GWAS Team, CKDGen Consortium, General Science & Technology
Abstract

BackgroundMild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes.MethodsA working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy.ResultsNo SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3±0.23 (beta ± standard error), p = 6.6×10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r(2) ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension.ConclusionsThis GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.

Published
2013

55. Genome-wide association of body fat distribution in African ancestry populations suggests new loci.

Author

Liu, Ching-Ti, Monda, Keri L, Taylor, Kira C, Lange, Leslie, Demerath, Ellen W, Palmas, Walter, Wojczynski, Mary K, Ellis, Jaclyn C, Vitolins, Mara Z, Liu, Simin, Papanicolaou, George J, Irvin, Marguerite R, Xue, Luting, Griffin, Paula J, Nalls, Michael A, Adeyemo, Adebowale, Liu, Jiankang, Li, Guo, Ruiz-Narvaez, Edward A, Chen, Wei-Min, Chen, Fang, Henderson, Brian E, Millikan, Robert C, Ambrosone, Christine B, Strom, Sara S, Guo, Xiuqing, Andrews, Jeanette S, Sun, Yan V, Mosley, Thomas H, Yanek, Lisa R, Shriner, Daniel, Haritunians, Talin, Rotter, Jerome I, Speliotes, Elizabeth K, Smith, Megan, Rosenberg, Lynn, Mychaleckyj, Josyf, Nayak, Uma, Spruill, Ida, Garvey, W Timothy, Pettaway, Curtis, Nyante, Sarah, Bandera, Elisa V, Britton, Angela F, Zonderman, Alan B, Rasmussen-Torvik, Laura J, Chen, Yii-Der Ida, Ding, Jingzhong, Lohman, Kurt, Kritchevsky, Stephen B, Zhao, Wei, Peyser, Patricia A, Kardia, Sharon LR, Kabagambe, Edmond, Broeckel, Ulrich, Chen, Guanjie, Zhou, Jie, Wassertheil-Smoller, Sylvia, Neuhouser, Marian L, Rampersaud, Evadnie, Psaty, Bruce, Kooperberg, Charles, Manson, Joann E, Kuller, Lewis H, Ochs-Balcom, Heather M, Johnson, Karen C, Sucheston, Lara, Ordovas, Jose M, Palmer, Julie R, Haiman, Christopher A, McKnight, Barbara, Howard, Barbara V, Becker, Diane M, Bielak, Lawrence F, Liu, Yongmei, Allison, Matthew A, Grant, Struan FA, Burke, Gregory L, Patel, Sanjay R, Schreiner, Pamela J, Borecki, Ingrid B, Evans, Michele K, Taylor, Herman, Sale, Michele M, Howard, Virginia, Carlson, Christopher S, Rotimi, Charles N, Cushman, Mary, Harris, Tamara B, Reiner, Alexander P, Cupples, L Adrienne, North, Kari E, and Fox, Caroline S

Subjects
Humans, Obesity, Waist-Hip Ratio, Polymorphism, Single Nucleotide, African Continental Ancestry Group, European Continental Ancestry Group, Female, Male, Adiposity, Body Fat Distribution, Genome-Wide Association Study, Genetic Loci, Polymorphism, Single Nucleotide, Developmental Biology, Genetics
Abstract

Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values

Published
2013

56. Common Variation in Fatty Acid Genes and Resuscitation From Sudden Cardiac Arrest

Author

Johnson, Catherine O, Lemaitre, Rozenn N, Fahrenbruch, Carol E, Hesselson, Stephanie, Sotoodehnia, Nona, McKnight, Barbara, Rice, Kenneth M, Kwok, Pui-Yan, Siscovick, David S, and Rea, Thomas D

Subjects
Heart Disease, Genetics, Cardiovascular, Clinical Research, Physical Injury - Accidents and Adverse Effects, Aetiology, 2.1 Biological and endogenous factors, Aged, Cardiopulmonary Resuscitation, Death, Sudden, Cardiac, Fatty Acids, Female, Genetic Association Studies, Genetic Variation, Humans, Lipid Metabolism, Male, Polymorphism, Single Nucleotide, Survival Analysis, epidemiology, fatty acids, genetics, heart arrest, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology
Abstract

BackgroundFatty acids provide energy and structural substrates for the heart and brain and may influence resuscitation from sudden cardiac arrest (SCA). We investigated whether genetic variation in fatty acid metabolism pathways was associated with SCA survival.Methods and resultsSubjects (mean age, 67 years; 80% male, white) were out-of-hospital SCA patients found in ventricular fibrillation in King County, WA. We compared subjects who survived to hospital admission (n=664) with those who did not (n=689), and subjects who survived to hospital discharge (n=334) with those who did not (n=1019). Associations between survival and genetic variants were assessed using logistic regression adjusting for age, sex, location, time to arrival of paramedics, whether the event was witnessed, and receipt of bystander cardiopulmonary resuscitation. Within-gene permutation tests were used to correct for multiple comparisons. Variants in 5 genes were significantly associated with SCA survival. After correction for multiple comparisons, single-nucleotide polymorphisms in ACSL1 and ACSL3 were significantly associated with survival to hospital admission. Single-nucleotide polymorphisms in ACSL3, AGPAT3, MLYCD, and SLC27A6 were significantly associated with survival to hospital discharge.ConclusionsOur findings indicate that variants in genes important in fatty acid metabolism are associated with SCA survival in this population.

Published
2012

58. Hundreds of variants clustered in genomic loci and biological pathways affect human height

Author

Lango Allen, Hana, Estrada, Karol, Lettre, Guillaume, Berndt, Sonja I, Weedon, Michael N, Rivadeneira, Fernando, Willer, Cristen J, Jackson, Anne U, Vedantam, Sailaja, Raychaudhuri, Soumya, Ferreira, Teresa, Wood, Andrew R, Weyant, Robert J, Segrè, Ayellet V, Speliotes, Elizabeth K, Wheeler, Eleanor, Soranzo, Nicole, Park, Ju-Hyun, Yang, Jian, Gudbjartsson, Daniel, Heard-Costa, Nancy L, Randall, Joshua C, Qi, Lu, Vernon Smith, Albert, Mägi, Reedik, Pastinen, Tomi, Liang, Liming, Heid, Iris M, Luan, Jian’an, Thorleifsson, Gudmar, Winkler, Thomas W, Goddard, Michael E, Sin Lo, Ken, Palmer, Cameron, Workalemahu, Tsegaselassie, Aulchenko, Yurii S, Johansson, Åsa, Carola Zillikens, M, Feitosa, Mary F, Esko, Tõnu, Johnson, Toby, Ketkar, Shamika, Kraft, Peter, Mangino, Massimo, Prokopenko, Inga, Absher, Devin, Albrecht, Eva, Ernst, Florian, Glazer, Nicole L, Hayward, Caroline, Hottenga, Jouke-Jan, Jacobs, Kevin B, Knowles, Joshua W, Kutalik, Zoltán, Monda, Keri L, Polasek, Ozren, Preuss, Michael, Rayner, Nigel W, Robertson, Neil R, Steinthorsdottir, Valgerdur, Tyrer, Jonathan P, Voight, Benjamin F, Wiklund, Fredrik, Xu, Jianfeng, Hua Zhao, Jing, Nyholt, Dale R, Pellikka, Niina, Perola, Markus, Perry, John RB, Surakka, Ida, Tammesoo, Mari-Liis, Altmaier, Elizabeth L, Amin, Najaf, Aspelund, Thor, Bhangale, Tushar, Boucher, Gabrielle, Chasman, Daniel I, Chen, Constance, Coin, Lachlan, Cooper, Matthew N, Dixon, Anna L, Gibson, Quince, Grundberg, Elin, Hao, Ke, Juhani Junttila, M, Kaplan, Lee M, Kettunen, Johannes, König, Inke R, Kwan, Tony, Lawrence, Robert W, Levinson, Douglas F, Lorentzon, Mattias, McKnight, Barbara, Morris, Andrew P, Müller, Martina, Suh Ngwa, Julius, Purcell, Shaun, Rafelt, Suzanne, Salem, Rany M, and Salvi, Erika

Subjects
Biological Sciences, Genetics, Health Sciences, Mathematical Sciences, Statistics, Human Genome, Clinical Research, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Body Height, Chromosomes, Human, Pair 3, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Metabolic Networks and Pathways, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide, General Science & Technology
Abstract

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P

Published
2010

59. 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 L.R., 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, Liu, Ching Ti, 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 L.R., 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

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

62. Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality: An Individual-Level Pooled Analysis of 30 Cohort Studies

Author

Marklund, Matti, Wu, Jason H.Y., Imamura, Fumiaki, Del Gobbo, Liana C., Fretts, Amanda, de Goede, Janette, Shi, Peilin, Tintle, Nathan, Wennberg, Maria, Aslibekyan, Stella, Chen, Tzu-An, de Oliveira Otto, Marcia C., Hirakawa, Yoichiro, Eriksen, Helle Højmark, Kröger, Janine, Laguzzi, Federica, Lankinen, Maria, Murphy, Rachel A., Prem, Kiesha, Samieri, Cécilia, Virtanen, Jyrki, Wood, Alexis C., Wong, Kerry, Yang, Wei-Sin, Zhou, Xia, Baylin, Ana, Boer, Jolanda M.A., Brouwer, Ingeborg A., Campos, Hannia, Chaves, Paulo H. M., Chien, Kuo-Liong, de Faire, Ulf, Djoussé, Luc, Eiriksdottir, Gudny, El-Abbadi, Naglaa, Forouhi, Nita G., Gaziano, J. Michael, Geleijnse, Johanna M., Gigante, Bruna, Giles, Graham, Guallar, Eliseo, Gudnason, Vilmundur, Harris, Tamara, Harris, William S., Helmer, Catherine, Hellenius, Mai-Lis, Hodge, Allison, Hu, Frank B., Jacques, Paul F., Jansson, Jan-Håkan, Kalsbeek, Anya, Khaw, Kay-Tee, Koh, Woon-Puay, Laakso, Markku, Leander, Karin, Lin, Hung-Ju, Lind, Lars, Luben, Robert, Luo, Juhua, McKnight, Barbara, Mursu, Jaakko, Ninomiya, Toshiharu, Overvad, Kim, Psaty, Bruce M., Rimm, Eric, Schulze, Matthias B., Siscovick, David, Skjelbo Nielsen, Michael, Smith, Albert V., Steffen, Brian T., Steffen, Lyn, Sun, Qi, Sundström, Johan, Tsai, Michael Y., Tunstall-Pedoe, Hugh, Uusitupa, Matti I. J., van Dam, Rob M., Veenstra, Jenna, Verschuren, W.M. Monique, Wareham, Nick, Willett, Walter, Woodward, Mark, Yuan, Jian-Min, Micha, Renata, Lemaitre, Rozenn N, Mozaffarian, Dariush, and Risérus, Ulf

Published
2019
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64. Modeling Temporal Aspects of an Exposure

Author

Hsieh, Chung-cheng, Lambe, Mats, Lan, Shou-Jen, Robertson, Chris, Boyle, Peter, Cummings, Peter, McKnight, Barbara, Weiss, Noel S., Stanford, Janet L., and Thompson, W. Douglas

Published
1998

69. Interaction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies and methylation analysis of 3 studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium

Author

Ma, Yiyi, Follis, Jack L, Smith, Caren E, Tanaka, Toshiko, Manichaikul, Ani W, Chu, Audrey Y, Samieri, Cecilia, Zhou, Xia, Guan, Weihua, Wang, Lu, Biggs, Mary L, Chen, Yii-Der I, Hernandez, Dena G, Borecki, Ingrid, Chasman, Daniel I, Rich, Stephen S, Ferrucci, Luigi, Irvin, Marguerite Ryan, Aslibekyan, Stella, Zhi, Degui, Tiwari, Hemant K, Claas, Steven A, Sha, Jin, Kabagambe, Edmond K, Lai, Chao-Qiang, Parnell, Laurence D, Lee, Yu-Chi, Amouyel, Philippe, Lambert, Jean-Charles, Psaty, Bruce M, King, Irena B, Mozaffarian, Dariush, McKnight, Barbara, Bandinelli, Stefania, Tsai, Michael Y, Ridker, Paul M, Ding, Jingzhong, Mstat, Kurt Lohmant, Liu, Yongmei, Sotoodehnia, Nona, Barberger-Gateau, Pascale, Steffen, Lyn M, Siscovick, David S, Absher, Devin, Arnett, Donna K, Ordovás, José M, and Lemaitre, Rozenn N

Published
2016
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70. Challenges posed by non‐random missing quality of life data in an advanced‐stage colorectal cancer clinical trial

Author

Moinpour, Carol M, Triplett, Julia Sawyers, McKnight, Barbara, Lovato, Laura C, Upchurch, Christine, Leichman, Cynthia G, Muggia, Franco M, Tanaka, Leora, James, Wendy A, Lennard, Martha, and Meyskens, Frank L

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Cancer, Behavioral and Social Science, Colo-Rectal Cancer, Clinical Research, Clinical Trials and Supportive Activities, Digestive Diseases, Adult, Aged, Aged, 80 and over, Antimetabolites, Antineoplastic, Bias, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Colorectal Neoplasms, Cross-Sectional Studies, Data Collection, Data Interpretation, Statistical, Female, Fluorouracil, Humans, Longitudinal Studies, Male, Middle Aged, Neoplasm Staging, Quality of Life, Randomized Controlled Trials as Topic, Reproducibility of Results, Research Design, Surveys and Questionnaires, Oncology and Carcinogenesis, Psychology, Oncology & Carcinogenesis, Biomedical and clinical sciences
Abstract

Effects of variations in agent, dose, and route of treatment administration on patient reported quality of life (QOL) were examined for 279 patients enrolled on a seven-arm randomized clinical trial (S8905) of 5-FU and its modulation for advanced colorectal cancer. Patients completed QOL questionnaires at randomization and weeks 6, 11, and 21 post-randomization with five QOL endpoints considered primary: three treatment-specific symptoms (stomatitis, diarrhea, and hand/foot sensitivity); physical functioning; and emotional functioning. Patient compliance with the QOL assessment schedule was good, supporting the feasibility of including QOL measures in cooperative group trials. However, death and deteriorating health produced substantial missing data. Cross-sectional analyses indicated that the seven therapeutic arms did not differ in their impact on QOL. Unfortunately, longitudinal analyses of the QOL data were inappropriate given non-random missing data. Graphical presentation of non-random missing data identified the seriousness of this problem and its effect on potential conclusions about QOL during treatment. This problem appears to be particularly challenging in the context of advanced-stage disease. Failure to recognize the presence of non-random missing data can lead to serious overestimates of patient QOL over time.

Published
2000

72. A study of reproductive function in patients with seminoma treated with radiotherapy and orchidectomy: (SWOG-8711)

Author

Gordon, William, Siegmund, Kimberly, Stanisic, Thomas H, McKnight, Barbara, Harris, Irene T, Carroll, Peter R, Paradelo, Jorge C, Meyers, Frederick J, Chapman, Robert A, and Meyskens, Frank L

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Cancer, Infertility, Contraception/Reproduction, 6.5 Radiotherapy and other non-invasive therapies, Evaluation of treatments and therapeutic interventions, Reproductive health and childbirth, Adult, Biomarkers, Follicle Stimulating Hormone, Humans, Male, Orchiectomy, Prospective Studies, Reproduction, Seminoma, Sex, Sperm Count, Testicular Neoplasms, radiotherapy, seminoma, semen, follicle-stimulating hormone, testicular injury, Other Physical Sciences, Clinical Sciences, Oncology & Carcinogenesis, Oncology and carcinogenesis, Theoretical and computational chemistry, Medical and biological physics
Abstract

PurposeThe results of Southwest Oncology Group Study 8711 (Group 2B) are presented. The objective was to evaluate the natural history of sperm concentration and selected hormonal parameters in patients with testicular cancer treated with orchiectomy and radiotherapy.Methods and materialsOf a total of 207 patients enrolled on SWOG 8711, 53 pure seminoma patients were identified who were treated with orchiectomy and radiotherapy only. Sperm concentration, follicle-stimulating hormone (FSH) levels, and sexual satisfaction scores were the main parameters followed.ResultsA fraction of the patients were infertile prior to receiving radiotherapy. Our analysis indicates that incidental radiation dose to the remaining testicle affects time to recovery of fertility, and at an aggregate level, changes in FSH mirror changes in sperm concentration over time. This phenomenon is the same as that described in patients free from testicular cancer. These men evaluated their sexual activity as good after orchidectomy.ConclusionOur data support the use of clamshell-type testicular shields as a means of providing maximum protection to the remaining testicle.

Published
1997

73. Estrogen Replacement Therapy and Prognosis after First Myocardial Infarction

Author

Newton, Katherine M, LaCroix, Andrea Z, McKnight, Barbara, Knopp, Robert H, Siscovick, David S, Heckbert, Susan R, and Weiss, Noel S

Subjects
Epidemiology, Health Sciences, Aging, Heart Disease - Coronary Heart Disease, Estrogen, Cardiovascular, Heart Disease, Clinical Research, Patient Safety, Prevention, Good Health and Well Being, Adult, Aged, Cohort Studies, Confidence Intervals, Contraindications, Estrogen Replacement Therapy, Female, Humans, Middle Aged, Myocardial Infarction, Prognosis, Recurrence, Retrospective Studies, Risk, Survival Analysis, Mathematical Sciences, Medical and Health Sciences
Abstract

The effects of estrogen replacement therapy on prognosis in women with established coronary disease remain uncertain. The authors conducted a retrospective cohort study of 726 women (mean age, 66.2 years) who survived first myocardial infarction to hospital discharge from 1980 through 1991, while enrolled at Group Health Cooperative of Puget Sound in western Washington State. Estrogen replacement therapy after myocardial infarction (122 women) was ascertained from computerized pharmacy records. Reinfarctions (n = 135) and deaths (n = 183) through 1993 were identified, and relative risks were calculated. The relative risk for reinfarction associated with current estrogen replacement therapy after myocardial infarction, adjusting for age and time since infarction, was 0.64 (95% confidence interval (CI) 0.32-1.30), and that for past estrogen replacement therapy was 0.90 (95% CI 0.62-1.31). The relative risk for all-cause mortality associated with current estrogen replacement therapy was 0.50 (95% CI 0.25-1.00), and that for past estrogen replacement therapy was 0.79 (95% CI 0.56-1.09). While estrogen users were less likely than nonusers to have a history of diabetes or congestive heart failure, adjustment for these and additional prognostic factors altered risk estimates only slightly. Estrogen replacement therapy after first myocardial infarction was not associated with increased risk of reinfarction or mortality. This study provides reassurance regarding the safety of estrogen replacement therapy after myocardial infarction in women.

Published
1997

79. Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels

Author

Tin, Adrienne, Li, Yong, Brody, Jennifer A., Nutile, Teresa, Chu, Audrey Y., Huffman, Jennifer E., Yang, Qiong, Chen, Ming-Huei, Robinson-Cohen, Cassianne, Macé, Aurélien, Liu, Jun, Demirkan, Ayşe, Sorice, Rossella, Sedaghat, Sanaz, Swen, Melody, Yu, Bing, Ghasemi, Sahar, Teumer, Alexanda, Vollenweider, Peter, Ciullo, Marina, Li, Meng, Uitterlinden, André G., Kraaij, Robert, Amin, Najaf, van Rooij, Jeroen, Kutalik, Zoltán, Dehghan, Abbas, McKnight, Barbara, van Duijn, Cornelia M., Morrison, Alanna, Psaty, Bruce M., Boerwinkle, Eric, Fox, Caroline S., Woodward, Owen M., and Köttgen, Anna

Published
2018
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81. Genetic loci associated with circulating phospholipid trans fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium

Author

Mozaffarian, Dariush, Kabagambe, Edmond K, Johnson, Catherine O, Lemaitre, Rozenn N, Manichaikul, Ani, Sun, Qi, Foy, Millennia, Wang, Lu, Wiener, Howard, Irvin, Marguerite R, Rich, Stephen S, Wu, Hongyu, Jensen, Majken K, Chasman, Daniel I, Chu, Audrey Y, Fornage, Myriam, Steffen, Lyn, King, Irena B, McKnight, Barbara, Psaty, Bruce M, Djoussé, Luc, Chen, Ida Y-D, Wu, Jason HY, Siscovick, David S, Ridker, Paul M, Tsai, Michael Y, Rimm, Eric B, Hu, Frank B, and Arnett, Donna K

Published
2015
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82. Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus

Author

Stacey, David, Chen, Lingyan, Stanczyk, Paulina J, Howson, Joanna MM, Mason, Amy M, Burgess, Stephen, MacDonald, Stephen, Langdown, Jonathan, McKinney, Harriett, Downes, Kate, Farahi, Neda, Peters, James E, Basu, Saonli, Pankow, James S, Tang, Weihong, Pankratz, Nathan, Sabater-Lleal, Maria, De Vries, Paul S, Smith, Nicholas L, 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 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, Conomos, Matthew P, Liu, Melissa, Brown, Michael R, Jhun, Min-A, Chen, Ming-Huei, De Maat, Moniek PM, 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, Damrauer, Scott M, Cox, Simon R, Trompet, Stella, Felix, Stephan B, Völker, Uwe, Koenig, Wolfgang, Jukema, J Wouter, Guo, Xiuqing, Gelinas, Amy D, Schneider, Daniel J, Janjic, Nebojsa, Samani, Nilesh J, Ye, Shu, Summers, Charlotte, Chilvers, Edwin R, Danesh, John, Paul, Dirk S, Chen, Lingyan [0000-0003-3750-6761], Howson, Joanna MM [0000-0001-7618-0050], Mason, Amy M [0000-0002-8019-0777], Burgess, Stephen [0000-0001-5365-8760], Peters, James E [0000-0002-9415-3440], Pankow, James S [0000-0001-7076-483X], Pankratz, Nathan [0000-0001-5958-693X], Sabater-Lleal, Maria [0000-0002-0128-379X], Schneider, Daniel J [0000-0001-6830-0905], Samani, Nilesh J [0000-0002-3286-8133], Ye, Shu [0000-0002-4126-4278], Summers, Charlotte [0000-0002-7269-2873], Chilvers, Edwin R [0000-0002-4230-9677], Paul, Dirk S [0000-0002-8230-0116], and Apollo - University of Cambridge Repository

Subjects
13/31, 13/1, 692/4019/592/2727, 45/43, article, 631/208/212/2301, 45/88, 13/106
Abstract

Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte–endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations.

Published
2022

83. Fatty acids in the de novo lipogenesis pathway and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies

Author

Imamura, Fumiaki, Fretts, Amanda M., Marklund, Matti, Ardisson Korat, Andres V., Yang, Wei-Sin, Lankinen, Maria, Qureshi, Waqas, Helmer, Catherine, Chen, Tzu-An, Virtanen, Jyrki K., Wong, Kerry, Bassett, Julie K., Murphy, Rachel, Tintle, Nathan, Yu, Chaoyu Ian, Brouwer, Ingeborg A., Chien, Kuo-Liong, Chen, Yun-yu, Wood, Alexis C., del Gobbo, Liana C., Djousse, Luc, Geleijnse, Johanna M., Giles, Graham G., de Goede, Janette, Gudnason, Vilmundur, Harris, William S., Hodge, Allison, Hu, Frank, Koulman, Albert, Laakso, Markku, Lind, Lars, Lin, Hung-Ju, McKnight, Barbara, Rajaobelina, Kalina, Riserus, Ulf, Robinson, Jennifer G., Samieri, Cecilia, Senn, Mackenzie, Siscovick, David S., Soedamah-Muthu, Sabita S., Sotoodehnia, Nona, Sun, Qi, Tsai, Michael Y., Tuomainen, Tomi-Pekka, Uusitupa, Matti, Wagenknecht, Lynne E., Wareham, Nick J., Wu, Jason H. Y., Micha, Renata, Lemaitre, Rozenn N., Mozaffarian, Dariush, and Forouhi, Nita G.

Subjects
Fatty acids -- Analysis, Type 2 diabetes -- Analysis, Exercise -- Analysis, Triglycerides -- Analysis, Biological sciences
Abstract

Background De novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D). Methods and findings Seventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970-1973 to 2006-2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3-75.5 years; % women = 20.4%-62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41-1.66; p < 0.001) for 16:0, 1.40 (1.33-1.48; p < 0.001) for 16:1n-7, 1.14 (1.05-1.22; p = 0.001) for 18:0, and 1.16 (1.07-1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I.sup.2 = 51.1%-73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94-1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors. Conclusions Concentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D., Author(s): Fumiaki Imamura 1,*, Amanda M. Fretts 2, Matti Marklund 3,4,5, Andres V. Ardisson Korat 6,7, Wei-Sin Yang 8, Maria Lankinen 9, Waqas Qureshi 10, Catherine Helmer 11, Tzu-An Chen [...]

Published
2020
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84. Genetically predicted cortisol levels and risk of venous thromboembolism

Author

Allarai, Elias, Lee, Wei-Hsuan, Burgess, Stephen, Larsson, Susanna C., Lindstrom, 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 Michael, Chasman, Daniel I., Suchon, Pierre, Chen, Ming-Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri L., Macdonald, James, Brækkan, Sigrid Kufaas, 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 Elvestad, Deleuze, Jean-Francois, O'Donnell, Chris J., Kim, Jihye, Mcknight, Barbara, Kraft, Peter, Hansen, John Bjarne, Rosendaal, Frits Richard, Heit, John A., Psaty, Bruce M., Tang, Weihong, Kooperberg, Charles, Hveem, Kristian, Ridker, Paul M., Morange, Pierre-Emmanuel, Johnson, Andrew D., Kabrhel, Christopher, Alexandretrégouët, David, Smith, Nicholas L., Allara, Elias [0000-0002-1634-8330], Burgess, Stephen [0000-0001-5365-8760], and Apollo - University of Cambridge Repository

Subjects
Medicine and health sciences, Multidisciplinary, Kardiologi, Hydrocortisone, Biology and life sciences, FOS: Social sciences, Venous Thromboembolism, Mendelian Randomization Analysis, Endocrinology and Diabetes, Social sciences, Risk Factors, Endokrinologi och diabetes, Humans, Cardiac and Cardiovascular Systems, Pulmonary Embolism, Medical Genetics, Medicinsk genetik, Research Article
Abstract

Introduction In observational studies, venous thromboembolism (VTE) has been associated with Cushing’s syndrome and with persistent mental stress, two conditions associated with higher cortisol levels. However, it remains unknown whether high cortisol levels within the usual range are causally associated with VTE risk. We aimed to assess the association between plasma cortisol levels and VTE risk using Mendelian randomization. Methods Three genetic variants in the SERPINA1/SERPINA6 locus (rs12589136, rs11621961 and rs2749527) were used to proxy plasma cortisol. The associations of the cortisol-associated genetic variants with VTE were acquired from the INVENT (28 907 cases and 157 243 non-cases) and FinnGen (6913 cases and 169 986 non-cases) consortia. Corresponding data for VTE subtypes were available from the FinnGen consortium and UK Biobank. Two-sample Mendelian randomization analyses (inverse-variance weighted method) were performed. Results Genetic predisposition to higher plasma cortisol levels was associated with a reduced risk of VTE (odds ratio [OR] per one standard deviation increment 0.73, 95% confidence interval [CI] 0.62–0.87, p Conclusions This study provides evidence that genetically predicted plasma cortisol levels in the high end of the normal range are associated with a decreased risk of VTE and that this association may be mediated by blood pressure. This study has implications for the planning of observational studies of cortisol and VTE, suggesting that blood pressure traits should be measured and accounted for.

Published
2022

87. Erratum: 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 I. W., 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 G. J., 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, Psaty, Bruce M., Raitakari, Olli T., Risbrough, Victoria B., Sinner, Moritz F., Siscovick, David, Smit, Johannes H., Smith, Nicholas L., Soliman, Elsayed Z., Sotoodehnia, Nona, Staessen, Jan A., Stein, Phyllis K., Stilp, Adrienne M., Stolarz-Skrzypek, Katarzyna, Strauch, Konstantin, Sundström, Johan, Swenne, Cees A., Syvänen, Ann-Christine, Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thornton, Timothy A., Tinker, Lesley E., Uitterlinden, André G., van Setten, Jessica, Voss, Andreas, Waldenberger, Melanie, Wilhelmsen, Kirk C., Willemsen, Gonneke, Wong, Quenna, Zhang, Zhu-Ming, Zonderman, Alan B, Cusi, Daniele, Evans, Michele K., Greiser, Halina K., van der Harst, Pim, Hassan, Mohammad, Ingelsson, Erik, Järvelin, Marjo-Riitta, Kääb, Stefan, Kähönen, Mika, Kivimaki, Mika, Kooperberg, Charles, Kuh, Diana, Lehtimäki, Terho, Lind, Lars, Nievergelt, Caroline M., O'Donnell, Chris J., Oldehinkel, Albertine J., Penninx, Brenda, Reiner, Alexander P., Riese, Harriëtte, van Roon, Arie M., Rioux, John D., Rotter, Jerome I., Sofer, Tamar, Stricker, Bruno H., Tiemeier, Henning, Vrijkotte, Tanja G. M., Asselbergs, Folkert W., Brundel, Bianca J. J.M, Heckbert, Susan R., Whitsel, Eric A., den Hoed, Marcel, Snieder, Harold, and de Geus, Eco J. C.

Published
2017
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88. Whole-exome sequencing of 14 389 individuals from the ESP and CHARGE consortia identifies novel rare variation associated with hemostatic factors

Author

Pankratz, Nathan, Wei, Peng, Brody, Jennifer A., Chen, Ming Huei, de Vries, Paul S., Huffman, Jennifer E., Stimson, Mary Rachel, Auer, Paul L., Boerwinkle, Eric, Cushman, Mary, de Maat, Moniek P.M., Folsom, Aaron R., Franco, Oscar H., Gibbs, Richard A., Haagenson, Kelly K., Hofman, Albert, Johnsen, Jill M., Kovar, Christie L., Kraaij, Robert, McKnight, Barbara, Metcalf, Ginger A., Muzny, Donna, Psaty, Bruce M., Tang, Weihong, Uitterlinden, André G., van Rooij, Jeroen G.J., Dehghan, Abbas, O'Donnell, Christopher J., Reiner, Alex P., Morrison, Alanna C., Smith, Nicholas L., Pankratz, Nathan, Wei, Peng, Brody, Jennifer A., Chen, Ming Huei, de Vries, Paul S., Huffman, Jennifer E., Stimson, Mary Rachel, Auer, Paul L., Boerwinkle, Eric, Cushman, Mary, de Maat, Moniek P.M., Folsom, Aaron R., Franco, Oscar H., Gibbs, Richard A., Haagenson, Kelly K., Hofman, Albert, Johnsen, Jill M., Kovar, Christie L., Kraaij, Robert, McKnight, Barbara, Metcalf, Ginger A., Muzny, Donna, Psaty, Bruce M., Tang, Weihong, Uitterlinden, André G., van Rooij, Jeroen G.J., Dehghan, Abbas, O'Donnell, Christopher J., Reiner, Alex P., Morrison, Alanna C., and Smith, Nicholas L.

Abstract

Plasma levels of fibrinogen, coagulation factors VII and VIII and von Willebrand factor (vWF) are four intermediate phenotypes that are heritable and have been associated with the risk of clinical thrombotic events. To identify rare and low-frequency variants associated with these hemostatic factors, we conducted whole-exome sequencing in 10 860 individuals of European ancestry (EA) and 3529 African Americans (AAs) from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and the National Heart, Lung and Blood Institute's Exome Sequencing Project. Gene-based tests demonstrated significant associations with rare variation (minor allele frequency < 5%) in fibrinogen gamma chain (FGG) (with fibrinogen, P = 9.1 × 10-13), coagulation factor VII (F7) (with factor VII, P = 1.3 × 10-72; seven novel variants) and VWF (with factor VIII and vWF; P = 3.2 × 10-14; one novel variant). These eight novel rare variant associations were independent of the known common variants at these loci and tended to have much larger effect sizes. In addition, one of the rare novel variants in F7 was significantly associated with an increased risk of venous thromboembolism in AAs (Ile200Ser; rs141219108; P = 4.2 × 10-5). After restricting gene-based analyses to only loss-of-function variants, a novel significant association was detected and replicated between factor VIII levels and a stop-gain mutation exclusive to AAs (rs3211938) in CD36 molecule (CD36). This variant has previously been linked to dyslipidemia but not with the levels of a hemostatic factor. These efforts represent the largest integration of whole-exome sequence data from two national projects to identify genetic variation associated with plasma hemostatic factors.

Published
2022

89. Stroke genetics informs drug discovery and risk prediction across ancestries

Author

Mishra, Aniket, Malik, Rainer, Hachiya, Tsuyoshi, Jurgenson, Tuuli, Namba, Shinichi, Posner, Daniel C, Kamanu, Frederick K, Koido, Masaru, Le Grand, Quentin, Shi, Mingyang, He, Yunye, Georgakis, Marios K, Caro, Ilana, Krebs, Kristi, Liaw, Yi-Ching, Vaura, Felix C, Lin, Kuang, Winsvold, Bendik Slagsvold, Srinivasasainagendra, Vinodh, Parodi, Livia, Bae, Hee-Joon, Chauhan, Ganesh, Chong, Michael R, Tomppo, Liisa, Akinyemi, Rufus, Roshchupkin, Gennady V, Habib, Naomi, Jee, Yon Ho, Thomassen, Jesper Qvist, Abedi, Vida, Carcel-Marquez, Jara, Nygaard, Marianne, Leonard, Hampton L, Yang, Chaojie, Yonova-Doing, Ekaterina, Knol, Maria J, Lewis, Adam J, Judy, Renae L, Ago, Tetsuro, Amouyel, Philippe, Armstrong, Nicole D, Bakker, Mark K, Bartz, Traci M, Bennett, David A, Bis, Joshua C, Bordes, Constance, Borte, Sigrid, Cain, Anael, Ridker, Paul M, Cho, Kelly, Chen, Zhengming, Cruchaga, Carlos, Cole, John W, de Jager, Phil L, de Cid, Rafael, Endres, Matthias, Ferreira, Leslie E, Geerlings, Mirjam I, Gasca, Natalie C, Gudnason, Vilmundur, Hata, Jun, He, Jing, Heath, Alicia K, Ho, Yuk-Lam, Havulinna, Aki S, Hopewell, Jemma C, Hyacinth, Hyacinth I, Inouye, Michael, Jacob, Mina A, Jeon, Christina E, Jern, Christina, Kamouchi, Masahiro, Keene, Keith L, Kitazono, Takanari, Kittner, Steven J, Konuma, Takahiro, Kumar, Amit, Lacaze, Paul, Launer, Lenore J, Lee, Keon-Joo, Lepik, Kaido, Li, Jiang, Li, Liming, Manichaikul, Ani, Markus, Hugh S, Marston, Nicholas A, Meitinger, Thomas, Mitchell, Braxton D, Montellano, Felipe A, Morisaki, Takayuki, Mosley, Thomas H, Nalls, Mike A, Nordestgaard, Borge G, O'Donnell, Martin J, Okada, Yukinori, Onland-Moret, N Charlotte, Ovbiagele, Bruce, Peters, Annette, Psaty, Bruce M, Rich, Stephen S, Rosand, Jonathan, Sabatine, Marc S, Sacco, Ralph L, Saleheen, Danish, Sandset, Else Charlotte, Salomaa, Veikko, Sargurupremraj, Muralidharan, Sasaki, Makoto, Satizabal, Claudia L, Schmidt, Carsten O, Shimizu, Atsushi, Smith, Nicholas L, Sloane, Kelly L, Sutoh, Yoichi, Sun, Yan V, Tanno, Kozo, Tiedt, Steffen, Tatlisumak, Turgut, Torres-Aguila, Nuria P, Tiwari, Hemant K, Tregouet, David-Alexandre, Trompet, Stella, Tuladhar, Anil Man, Tybjaerg-Hansen, Anne, van Vugt, Marion, Vibo, Riina, Verma, Shefali S, Wiggins, Kerri L, Wennberg, Patrik, Woo, Daniel, Wilson, Peter WF, Xu, Huichun, Yang, Qiong, Yoon, Kyungheon, Lee, Jin-Moo, Cheng, Yu-Ching, Meschia, James F, Chen, Wei Min, Sale, Michele M, Zonderman, Alan B, Evans, Michele K, Wilson, James G, Correa, Adolfo, Traylor, Matthew, Lewis, Cathryn M, Carty, Cara L, Reiner, Alexander, Haessler, Jeffrey, Langefeld, Carl D, Gottesman, Rebecca F, Yaffe, Kristine, Liu, Yong Mei, Kooperberg, Charles, Lange, Leslie A, Furie, Karen L, Arnett, Donna K, Benavente, Oscar R, Grewal, Raji P, Peddareddygari, Leema Reddy, Hveem, Kristian, Lindstrom, Sara, Wang, Lu, Smith, Erin N, Gordon, William, van Hylckama Vlieg, Astrid, de Andrade, Mariza, Brody, Jennifer A, Pattee, Jack W, Brumpton, Ben M, Suchon, Pierre, Chen, Ming-Huei, Frazer, Kelly A, Turman, Constance, Germain, Marine, 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, Bammler, Theo K, McCauley, Bryan M, Taylor, Kent D, Pankow, James S, Reiner, Alexander P, Gabrielsen, Maiken E, Deleuze, Jean-Francois, O'Donnell, Chris J, Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John-Bjarne, Rosendaal, Frits R, Heit, John A, Tang, Weihong, Morange, Pierre-Emmanuel, Johnson, Andrew D, Kabrhel, Christopher, van Dijk, Ewoud J, Koudstaal, Peter J, Luijckx, Gert-Jan, Nederkoorn, Paul J, van Oostenbrugge, Robert J, Visser, Marieke C, Wermer, Marieke JH, Kappelle, L Jaap, Esko, Tonu, Metspalu, Andres, Magi, Reedik, Nelis, Mari, Irvin, Marguerite R, de Leeuw, Frank-Erik, Levi, Christopher R, Maguire, Jane, Jimenez-Conde, Jordi, Sharma, Pankaj, Sudlow, Cathie LM, Rannikmae, Kristiina, Schmidt, Reinhold, Slowik, Agnieszka, Pera, Joanna, Thijs, Vincent NS, Lindgren, Arne G, Ilinca, Andreea, Melander, Olle, Engstrom, Gunnar, Rexrode, Kathryn M, Rothwell, Peter M, Stanne, Tara M, Johnson, Julie A, Danesh, John, Butterworth, Adam S, Heitsch, Laura, Boncoraglio, Giorgio B, Kubo, Michiaki, Pezzini, Alessandro, Rolfs, Arndt, Giese, Anne-Katrin, Weir, David, Ross, Owen A, Lemmons, Robin, Soderholm, Martin, Cushman, Mary, Jood, Katarina, McDonough, Caitrin W, Bell, Steven, Linkohr, Birgit, Lee, Tsong-Hai, Putaala, Jukka, Anderson, Christopher D, Lopez, Oscar L, Jian, Xueqiu, Schminke, Ulf, Cullell, Natalia, Delgado, Pilar, Ibanez, Laura, Krupinski, Jerzy, Lioutas, Vasileios, Matsuda, Koichi, Montaner, Joan, Muino, Elena, Roquer, Jaume, Sarnowski, Chloe, Sattar, Naveed, Sibolt, Gerli, Teumer, Alexander, Rutten-Jacobs, Loes, Kanai, Masahiro, Gretarsdottir, Solveig, Rost, Natalia S, Yusuf, Salim, Almgren, Peter, Ay, Hakan, Bevan, Steve, Brown, Robert D, Carrera, Caty, Buring, Julie E, Chen, Wei-Min, Cotlarciuc, Ioana, de Bakker, Paul IW, DeStefano, Anita L, den Hoed, Marcel, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gustafsson, Stefan, Hassan, Ahamad, Holliday, Elizabeth G, Howard, George, Hsu, Fang-Chi, Ingelsson, Erik, Harris, Tamara B, Kissela, Brett M, Kleindorfer, Dawn O, Langenberg, Claudia, Lemmens, Robin, Leys, Didier, Lin, Wei-Yu, Lorentzen, Erik, Magnusson, Patrik K, McArdle, Patrick F, Pulit, Sara L, Rice, Kenneth, Sakaue, Saori, Sapkota, Bishwa R, Tanislav, Christian, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tzourio, Christophe, van Duijn, Cornelia M, Walters, Matthew, Wareham, Nicholas J, Amin, Najaf, Aparicio, Hugo J, Attia, John, Beiser, Alexa S, Berr, Claudine, Bustamante, Mariana, Caso, Valeria, Choi, Seung Hoan, Chowhan, Ayesha, Dartigues, Jean-Francois, Delavaran, Hossein, Dorr, Marcus, Ford, Ian, Gurpreet, Wander S, Hamsten, Anders, Hozawa, Atsushi, Ingelsson, Martin, Iwasaki, Motoki, Kaffashian, Sara, Kalra, Lalit, Kjartansson, Olafur, Kloss, Manja, Labovitz, Daniel L, Laurie, Cathy C, Li, Linxin, Lind, Lars, Lindgren, Cecilia M, Makoto, Hirata, Minegishi, Naoko, Morris, Andrew P, Muller-Nurasyid, Martina, Norrving, Bo, Ogishima, Soichi, Parati, Eugenio A, Pedersen, Nancy L, Perola, Markus, Jousilahti, Pekka, Pileggi, Silvana, Rabionet, Raquel, Riba-Llena, Iolanda, Ribases, Marta, Romero, Jose R, Rudd, Anthony G, Sarin, Antti-Pekka, Sarju, Ralhan, Satoh, Mamoru, Sawada, Norie, Sigurdsson, Asgeir, Smith, Albert, Stine, O Colin, Stott, David J, Strauch, Konstantin, Takai, Takako, Tanaka, Hideo, Touze, Emmanuel, Tsugane, Shoichiro, Uitterlinden, Andre G, Valdimarsson, Einar M, van der Lee, Sven J, Wakai, Kenji, Williams, Stephen R, Wolfe, Charles DA, Wong, Quenna, Yamaji, Taiki, Sanghera, Dharambir K, Stefansson, Kari, Martinez-Majander, Nicolas, Sobue, Kenji, Soriano-Tarraga, Carolina, Volzke, Henry, Akpa, Onoja, Sarfo, Fred S, Akpalu, Albert, Obiako, Reginald, Wahab, Kolawole, Osaigbovo, Godwin, Owolabi, Lukman, Komolafe, Morenikeji, Jenkins, Carolyn, Arulogun, Oyedunni, Ogbole, Godwin, Adeoye, Abiodun M, Akinyemi, Joshua, Agunloye, Atinuke, Fakunle, Adekunle G, Uvere, Ezinne, Olalere, Abimbola, Adebajo, Olayinka J, Chen, Junshi, Clarke, Robert, Collins, Rory, Guo, Yu, Wang, Chen, Lv, Jun, Peto, Richard, Chen, Yiping, Fairhurst-Hunter, Zammy, Hill, Michael, Pozarickij, Alfred, Schmidt, Dan, Stevens, Becky, Turnbull, Iain, Yu, Canqing, Nagai, Akiko, Murakami, Yoishinori, Shiroma, Eric J, Sigurdsson, Sigurdur, Ghanbari, Mohsen, Boerwinkle, Eric, Fongang, Bernard, Wang, Ruiqi, Ikram, Mohammad K, Volker, Uwe, de Laat, Karlijn F, van Norden, Anouk GW, de Kort, Paul L, Vermeer, Sarah E, Brouwers, Paul JAM, Gons, Rob AR, den Heijer, Tom, van Dijk, Gert W, van Rooij, Frank GW, Aamodt, Anne H, Skogholt, Anne H, Willer, Cristen J, Heuch, Ingrid, Hagen, Knut, Fritsche, Lars G, Pedersen, Linda M, Ellekjaer, Hanne, Zhou, Wei, Martinsen, Amy E, Kristoffersen, Espen S, Thomas, Laurent F, Kleinschnitz, Christoph, Frantz, Stefan, Ungethum, Kathrin, Gallego-Fabrega, Cristina, Lledos, Miquel, Llucia-Carol, Laia, Sobrino, Tomas, Campos, Francisco, Castillo, Jose, Freijo, Marimar, Arenillas, Juan Francisco, Obach, Victor, Alvarez-Sabin, Jose, Molina, Carlos A, Ribo, Marc, Munoz-Narbona, Lucia, Lopez-Cancio, Elena, Millan, Monica, Diaz-Navarro, Rosa, Vives-Bauza, Cristofol, Serrano-Heras, Gemma, Segura, Tomas, Dhar, Rajat, Delgado-Mederos, Raquel, Prats-Sanchez, Luis, Camps-Renom, Pol, Blay, Natalia, Sumoy, Lauro, Marti-Fabregas, Joan, Schnohr, Peter, Jensen, Gorm B, Benn, Marianne, Afzal, Shoaib, Kamstrup, Pia R, van Setten, Jessica, van der Laan, Sander W, Vonk, Jet MJ, Kim, Bong-Jo, Curtze, Sami, Tiainen, Marjaana, Kinnunen, Janne, Menon, Vilas, Sung, Yun Ju, Yang, Chengran, Saillour-Glenisson, Florence, Gravel, Simon, Millwood, Iona Y, Gieger, Christian, Ninomiya, Toshiharu, Grabe, Hans J, Jukema, J Wouter, Rissanen, Ina L, Strbian, Daniel, Kim, Young Jin, Chen, Pei-Hsin, Mayerhofer, Ernst, Howson, Joanna MM, Adams, Hieab, Wassertheil-Smoller, Sylvia, Christensen, Kaare, Ikram, Mohammad A, Rundek, Tatjana, Worrall, Bradford B, Lathrop, G Mark, Riaz, Moeen, Simonsick, Eleanor M, Korv, Janika, Franca, Paulo HC, Zand, Ramin, Prasad, Kameshwar, Frikke-Schmidt, Ruth, Liman, Thomas, Haeusler, Karl Georg, Ruigrok, Ynte M, Heuschmann, Peter Ulrich, Longstreth, WT, Jung, Keum Ji, Bastarache, Lisa, Pare, Guillaume, Damrauer, Scott M, Chasman, Daniel I, Rotter, Jerome I, Zwart, John-Anker, Niiranen, Teemu J, Fornage, Myriam, Liaw, Yung-Po, Seshadri, Sudha, Fernandez-Cadenas, Israel, Walters, Robin G, Ruff, Christian T, Owolabi, Mayowa O, Huffman, Jennifer E, Milani, Lili, Kamatani, Yoichiro, Dichgans, Martin, Debette, Stephanie, Mishra, Aniket, Malik, Rainer, Hachiya, Tsuyoshi, Jurgenson, Tuuli, Namba, Shinichi, Posner, Daniel C, Kamanu, Frederick K, Koido, Masaru, Le Grand, Quentin, Shi, Mingyang, He, Yunye, Georgakis, Marios K, Caro, Ilana, Krebs, Kristi, Liaw, Yi-Ching, Vaura, Felix C, Lin, Kuang, Winsvold, Bendik Slagsvold, Srinivasasainagendra, Vinodh, Parodi, Livia, Bae, Hee-Joon, Chauhan, Ganesh, Chong, Michael R, Tomppo, Liisa, Akinyemi, Rufus, Roshchupkin, Gennady V, Habib, Naomi, Jee, Yon Ho, Thomassen, Jesper Qvist, Abedi, Vida, Carcel-Marquez, Jara, Nygaard, Marianne, Leonard, Hampton L, Yang, Chaojie, Yonova-Doing, Ekaterina, Knol, Maria J, Lewis, Adam J, Judy, Renae L, Ago, Tetsuro, Amouyel, Philippe, Armstrong, Nicole D, Bakker, Mark K, Bartz, Traci M, Bennett, David A, Bis, Joshua C, Bordes, Constance, Borte, Sigrid, Cain, Anael, Ridker, Paul M, Cho, Kelly, Chen, Zhengming, Cruchaga, Carlos, Cole, John W, de Jager, Phil L, de Cid, Rafael, Endres, Matthias, Ferreira, Leslie E, Geerlings, Mirjam I, Gasca, Natalie C, Gudnason, Vilmundur, Hata, Jun, He, Jing, Heath, Alicia K, Ho, Yuk-Lam, Havulinna, Aki S, Hopewell, Jemma C, Hyacinth, Hyacinth I, Inouye, Michael, Jacob, Mina A, Jeon, Christina E, Jern, Christina, Kamouchi, Masahiro, Keene, Keith L, Kitazono, Takanari, Kittner, Steven J, Konuma, Takahiro, Kumar, Amit, Lacaze, Paul, Launer, Lenore J, Lee, Keon-Joo, Lepik, Kaido, Li, Jiang, Li, Liming, Manichaikul, Ani, Markus, Hugh S, Marston, Nicholas A, Meitinger, Thomas, Mitchell, Braxton D, Montellano, Felipe A, Morisaki, Takayuki, Mosley, Thomas H, Nalls, Mike A, Nordestgaard, Borge G, O'Donnell, Martin J, Okada, Yukinori, Onland-Moret, N Charlotte, Ovbiagele, Bruce, Peters, Annette, Psaty, Bruce M, Rich, Stephen S, Rosand, Jonathan, Sabatine, Marc S, Sacco, Ralph L, Saleheen, Danish, Sandset, Else Charlotte, Salomaa, Veikko, Sargurupremraj, Muralidharan, Sasaki, Makoto, Satizabal, Claudia L, Schmidt, Carsten O, Shimizu, Atsushi, Smith, Nicholas L, Sloane, Kelly L, Sutoh, Yoichi, Sun, Yan V, Tanno, Kozo, Tiedt, Steffen, Tatlisumak, Turgut, Torres-Aguila, Nuria P, Tiwari, Hemant K, Tregouet, David-Alexandre, Trompet, Stella, Tuladhar, Anil Man, Tybjaerg-Hansen, Anne, van Vugt, Marion, Vibo, Riina, Verma, Shefali S, Wiggins, Kerri L, Wennberg, Patrik, Woo, Daniel, Wilson, Peter WF, Xu, Huichun, Yang, Qiong, Yoon, Kyungheon, Lee, Jin-Moo, Cheng, Yu-Ching, Meschia, James F, Chen, Wei Min, Sale, Michele M, Zonderman, Alan B, Evans, Michele K, Wilson, James G, Correa, Adolfo, Traylor, Matthew, Lewis, Cathryn M, Carty, Cara L, Reiner, Alexander, Haessler, Jeffrey, Langefeld, Carl D, Gottesman, Rebecca F, Yaffe, Kristine, Liu, Yong Mei, Kooperberg, Charles, Lange, Leslie A, Furie, Karen L, Arnett, Donna K, Benavente, Oscar R, Grewal, Raji P, Peddareddygari, Leema Reddy, Hveem, Kristian, Lindstrom, Sara, Wang, Lu, Smith, Erin N, Gordon, William, van Hylckama Vlieg, Astrid, de Andrade, Mariza, Brody, Jennifer A, Pattee, Jack W, Brumpton, Ben M, Suchon, Pierre, Chen, Ming-Huei, Frazer, Kelly A, Turman, Constance, Germain, Marine, 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, Bammler, Theo K, McCauley, Bryan M, Taylor, Kent D, Pankow, James S, Reiner, Alexander P, Gabrielsen, Maiken E, Deleuze, Jean-Francois, O'Donnell, Chris J, Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John-Bjarne, Rosendaal, Frits R, Heit, John A, Tang, Weihong, Morange, Pierre-Emmanuel, Johnson, Andrew D, Kabrhel, Christopher, van Dijk, Ewoud J, Koudstaal, Peter J, Luijckx, Gert-Jan, Nederkoorn, Paul J, van Oostenbrugge, Robert J, Visser, Marieke C, Wermer, Marieke JH, Kappelle, L Jaap, Esko, Tonu, Metspalu, Andres, Magi, Reedik, Nelis, Mari, Irvin, Marguerite R, de Leeuw, Frank-Erik, Levi, Christopher R, Maguire, Jane, Jimenez-Conde, Jordi, Sharma, Pankaj, Sudlow, Cathie LM, Rannikmae, Kristiina, Schmidt, Reinhold, Slowik, Agnieszka, Pera, Joanna, Thijs, Vincent NS, Lindgren, Arne G, Ilinca, Andreea, Melander, Olle, Engstrom, Gunnar, Rexrode, Kathryn M, Rothwell, Peter M, Stanne, Tara M, Johnson, Julie A, Danesh, John, Butterworth, Adam S, Heitsch, Laura, Boncoraglio, Giorgio B, Kubo, Michiaki, Pezzini, Alessandro, Rolfs, Arndt, Giese, Anne-Katrin, Weir, David, Ross, Owen A, Lemmons, Robin, Soderholm, Martin, Cushman, Mary, Jood, Katarina, McDonough, Caitrin W, Bell, Steven, Linkohr, Birgit, Lee, Tsong-Hai, Putaala, Jukka, Anderson, Christopher D, Lopez, Oscar L, Jian, Xueqiu, Schminke, Ulf, Cullell, Natalia, Delgado, Pilar, Ibanez, Laura, Krupinski, Jerzy, Lioutas, Vasileios, Matsuda, Koichi, Montaner, Joan, Muino, Elena, Roquer, Jaume, Sarnowski, Chloe, Sattar, Naveed, Sibolt, Gerli, Teumer, Alexander, Rutten-Jacobs, Loes, Kanai, Masahiro, Gretarsdottir, Solveig, Rost, Natalia S, Yusuf, Salim, Almgren, Peter, Ay, Hakan, Bevan, Steve, Brown, Robert D, Carrera, Caty, Buring, Julie E, Chen, Wei-Min, Cotlarciuc, Ioana, de Bakker, Paul IW, DeStefano, Anita L, den Hoed, Marcel, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gustafsson, Stefan, Hassan, Ahamad, Holliday, Elizabeth G, Howard, George, Hsu, Fang-Chi, Ingelsson, Erik, Harris, Tamara B, Kissela, Brett M, Kleindorfer, Dawn O, Langenberg, Claudia, Lemmens, Robin, Leys, Didier, Lin, Wei-Yu, Lorentzen, Erik, Magnusson, Patrik K, McArdle, Patrick F, Pulit, Sara L, Rice, Kenneth, Sakaue, Saori, Sapkota, Bishwa R, Tanislav, Christian, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tzourio, Christophe, van Duijn, Cornelia M, Walters, Matthew, Wareham, Nicholas J, Amin, Najaf, Aparicio, Hugo J, Attia, John, Beiser, Alexa S, Berr, Claudine, Bustamante, Mariana, Caso, Valeria, Choi, Seung Hoan, Chowhan, Ayesha, Dartigues, Jean-Francois, Delavaran, Hossein, Dorr, Marcus, Ford, Ian, Gurpreet, Wander S, Hamsten, Anders, Hozawa, Atsushi, Ingelsson, Martin, Iwasaki, Motoki, Kaffashian, Sara, Kalra, Lalit, Kjartansson, Olafur, Kloss, Manja, Labovitz, Daniel L, Laurie, Cathy C, Li, Linxin, Lind, Lars, Lindgren, Cecilia M, Makoto, Hirata, Minegishi, Naoko, Morris, Andrew P, Muller-Nurasyid, Martina, Norrving, Bo, Ogishima, Soichi, Parati, Eugenio A, Pedersen, Nancy L, Perola, Markus, Jousilahti, Pekka, Pileggi, Silvana, Rabionet, Raquel, Riba-Llena, Iolanda, Ribases, Marta, Romero, Jose R, Rudd, Anthony G, Sarin, Antti-Pekka, Sarju, Ralhan, Satoh, Mamoru, Sawada, Norie, Sigurdsson, Asgeir, Smith, Albert, Stine, O Colin, Stott, David J, Strauch, Konstantin, Takai, Takako, Tanaka, Hideo, Touze, Emmanuel, Tsugane, Shoichiro, Uitterlinden, Andre G, Valdimarsson, Einar M, van der Lee, Sven J, Wakai, Kenji, Williams, Stephen R, Wolfe, Charles DA, Wong, Quenna, Yamaji, Taiki, Sanghera, Dharambir K, Stefansson, Kari, Martinez-Majander, Nicolas, Sobue, Kenji, Soriano-Tarraga, Carolina, Volzke, Henry, Akpa, Onoja, Sarfo, Fred S, Akpalu, Albert, Obiako, Reginald, Wahab, Kolawole, Osaigbovo, Godwin, Owolabi, Lukman, Komolafe, Morenikeji, Jenkins, Carolyn, Arulogun, Oyedunni, Ogbole, Godwin, Adeoye, Abiodun M, Akinyemi, Joshua, Agunloye, Atinuke, Fakunle, Adekunle G, Uvere, Ezinne, Olalere, Abimbola, Adebajo, Olayinka J, Chen, Junshi, Clarke, Robert, Collins, Rory, Guo, Yu, Wang, Chen, Lv, Jun, Peto, Richard, Chen, Yiping, Fairhurst-Hunter, Zammy, Hill, Michael, Pozarickij, Alfred, Schmidt, Dan, Stevens, Becky, Turnbull, Iain, Yu, Canqing, Nagai, Akiko, Murakami, Yoishinori, Shiroma, Eric J, Sigurdsson, Sigurdur, Ghanbari, Mohsen, Boerwinkle, Eric, Fongang, Bernard, Wang, Ruiqi, Ikram, Mohammad K, Volker, Uwe, de Laat, Karlijn F, van Norden, Anouk GW, de Kort, Paul L, Vermeer, Sarah E, Brouwers, Paul JAM, Gons, Rob AR, den Heijer, Tom, van Dijk, Gert W, van Rooij, Frank GW, Aamodt, Anne H, Skogholt, Anne H, Willer, Cristen J, Heuch, Ingrid, Hagen, Knut, Fritsche, Lars G, Pedersen, Linda M, Ellekjaer, Hanne, Zhou, Wei, Martinsen, Amy E, Kristoffersen, Espen S, Thomas, Laurent F, Kleinschnitz, Christoph, Frantz, Stefan, Ungethum, Kathrin, Gallego-Fabrega, Cristina, Lledos, Miquel, Llucia-Carol, Laia, Sobrino, Tomas, Campos, Francisco, Castillo, Jose, Freijo, Marimar, Arenillas, Juan Francisco, Obach, Victor, Alvarez-Sabin, Jose, Molina, Carlos A, Ribo, Marc, Munoz-Narbona, Lucia, Lopez-Cancio, Elena, Millan, Monica, Diaz-Navarro, Rosa, Vives-Bauza, Cristofol, Serrano-Heras, Gemma, Segura, Tomas, Dhar, Rajat, Delgado-Mederos, Raquel, Prats-Sanchez, Luis, Camps-Renom, Pol, Blay, Natalia, Sumoy, Lauro, Marti-Fabregas, Joan, Schnohr, Peter, Jensen, Gorm B, Benn, Marianne, Afzal, Shoaib, Kamstrup, Pia R, van Setten, Jessica, van der Laan, Sander W, Vonk, Jet MJ, Kim, Bong-Jo, Curtze, Sami, Tiainen, Marjaana, Kinnunen, Janne, Menon, Vilas, Sung, Yun Ju, Yang, Chengran, Saillour-Glenisson, Florence, Gravel, Simon, Millwood, Iona Y, Gieger, Christian, Ninomiya, Toshiharu, Grabe, Hans J, Jukema, J Wouter, Rissanen, Ina L, Strbian, Daniel, Kim, Young Jin, Chen, Pei-Hsin, Mayerhofer, Ernst, Howson, Joanna MM, Adams, Hieab, Wassertheil-Smoller, Sylvia, Christensen, Kaare, Ikram, Mohammad A, Rundek, Tatjana, Worrall, Bradford B, Lathrop, G Mark, Riaz, Moeen, Simonsick, Eleanor M, Korv, Janika, Franca, Paulo HC, Zand, Ramin, Prasad, Kameshwar, Frikke-Schmidt, Ruth, Liman, Thomas, Haeusler, Karl Georg, Ruigrok, Ynte M, Heuschmann, Peter Ulrich, Longstreth, WT, Jung, Keum Ji, Bastarache, Lisa, Pare, Guillaume, Damrauer, Scott M, Chasman, Daniel I, Rotter, Jerome I, Zwart, John-Anker, Niiranen, Teemu J, Fornage, Myriam, Liaw, Yung-Po, Seshadri, Sudha, Fernandez-Cadenas, Israel, Walters, Robin G, Ruff, Christian T, Owolabi, Mayowa O, Huffman, Jennifer E, Milani, Lili, Kamatani, Yoichiro, Dichgans, Martin, and Debette, Stephanie

Abstract

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Published
2022

90. Whole-exome sequencing of 14 389 individuals from the ESP and CHARGE consortia identifies novel rare variation associated with hemostatic factors

Author

Pankratz, Nathan, primary, Wei, Peng, additional, Brody, Jennifer A, additional, Chen, Ming-Huei, additional, de Vries, Paul S, additional, Huffman, Jennifer E, additional, Stimson, Mary Rachel, additional, Auer, Paul L, additional, Boerwinkle, Eric, additional, Cushman, Mary, additional, de Maat, Moniek P M, additional, Folsom, Aaron R, additional, Franco, Oscar H, additional, Gibbs, Richard A, additional, Haagenson, Kelly K, additional, Hofman, Albert, additional, Johnsen, Jill M, additional, Kovar, Christie L, additional, Kraaij, Robert, additional, McKnight, Barbara, additional, Metcalf, Ginger A, additional, Muzny, Donna, additional, Psaty, Bruce M, additional, Tang, Weihong, additional, Uitterlinden, André G, additional, van Rooij, Jeroen G J, additional, Dehghan, Abbas, additional, O'Donnell, Christopher J, additional, Reiner, Alex P, additional, Morrison, Alanna C, additional, and Smith, Nicholas L, additional

Published
2022
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91. Circulating Ceramides and Sphingomyelins and the Risk of Incident Cardiovascular Disease Among People with Diabetes: The Strong Heart Study

Author

Jensen, Paul N., primary, Fretts, Amanda M., additional, Hoofnagle, Andrew N., additional, McKnight, Barbara, additional, Howard, Barbara V., additional, Umans, Jason, additional, Sitlani, Colleen M., additional, Siscovick, David S., additional, King, Irena B., additional, Sotoodehnia, Nona, additional, and Lemaitre, Rozenn N., additional

Published
2022
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92. Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease

Author

van Meurs, Joyce BJ, Pare, Guillaume, Schwartz, Stephen M, Hazra, Aditi, Tanaka, Toshiko, Vermeulen, Sita H, Cotlarciuc, Ioana, Yuan, Xin, Mälarstig, Anders, Bandinelli, Stefania, Bis, Joshua C, Blom, Henk, Brown, Morris J, Chen, Constance, Chen, Yii-Der, Clarke, Robert J, Dehghan, Abbas, Erdmann, Jeanette, Ferrucci, Luigi, Hamsten, Anders, Hofman, Albert, Hunter, David J, Goel, Anuj, Johnson, Andrew D, Kathiresan, Sekar, Kampman, Ellen, Kiel, Douglas P, Kiemeney, Lambertus ALM, Chambers, John C, Kraft, Peter, Lindemans, Jan, McKnight, Barbara, Nelson, Christopher P, O’Donnell, Christopher J, Psaty, Bruce M, Ridker, Paul M, Rivadeneira, Fernando, Rose, Lynda M, Seedorf, Udo, Siscovick, David S, Schunkert, Heribert, Selhub, Jacob, Ueland, Per M, Vollenweider, Peter, Waeber, Gérard, Waterworth, Dawn M, Watkins, Hugh, Witteman, Jacqueline CM, den Heijer, Martin, Jacques, Paul, Uitterlinden, Andre G, Kooner, Jaspal S, Rader, Dan J, Reilly, Muredach P, Mooser, Vincent, Chasman, Daniel I, Samani, Nilesh J, and Ahmadi, Kourosh R

Published
2013
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95. Additional file 1 of 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.

Abstract

Additional file 1: Figure S1. Correlation of Sphingolipid Species in SHFS and SHS.

Published
2022
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96. Additional file 2 of 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.

Abstract

Additional file 2: Table S1. Risk of incident CVD per two-fold higher sphingolipid level in SHFS. Table S2. Odds of incident CVD per two-fold higher sphingolipid level in SHS. Table S3. Sensitivity analysis—associations of sphingolipids with incident CVD risk after adjustment for HDL and Triglycerides, Fibrinogen, and Chronic Kidney Disease.

Published
2022
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98. Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation

Author

Huang, Jie, Sabater-Lleal, Maria, Asselbergs, Folkert W., Tregouet, David, Shin, So-Youn, Ding, Jingzhong, Baumert, Jens, Oudot-Mellakh, Tiphaine, Folkersen, Lasse, Johnson, Andrew D., 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 M.K., Dehghan, Abbas, Silbernagel, Günther, Schrijvers, Elisabeth M.C., 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, O'Donnell, Christopher J., and Hamsten, Anders

Published
2012
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