%0 Journal Article %J Hum Mol Genet %D 2022 %T Whole-exome sequencing of 14 389 individuals from the ESP and CHARGE consortia identifies novel rare variation associated with hemostatic factors. %A Pankratz, Nathan %A Wei, Peng %A Brody, Jennifer A %A Chen, Ming-Huei %A de Vries, Paul S %A Huffman, Jennifer E %A Stimson, Mary Rachel %A Auer, Paul L %A Eric Boerwinkle %A Cushman, Mary %A de Maat, Moniek P M %A Folsom, Aaron R %A Franco, Oscar H %A Richard A Gibbs %A Haagenson, Kelly K %A Hofman, Albert %A Johnsen, Jill M %A Kovar, Christie L %A Kraaij, Robert %A McKnight, Barbara %A Ginger A Metcalf %A Donna M Muzny %A Psaty, Bruce M %A Tang, Weihong %A Uitterlinden, André G %A van Rooij, Jeroen G J %A Dehghan, Abbas %A O'Donnell, Christopher J %A Reiner, Alex P %A Morrison, Alanna C %A Smith, Nicholas L %K Exome Sequencing %K Factor VII %K Factor VIII %K Fibrinogen %K Hemostatics %K Humans %K Polymorphism, Single Nucleotide %K von Willebrand Factor %X

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.

%B Hum Mol Genet %V 31 %P 3120-3132 %8 2022 Sep 10 %G eng %N 18 %1 https://www.ncbi.nlm.nih.gov/pubmed/35552711?dopt=Abstract %R 10.1093/hmg/ddac100 %0 Journal Article %J Nature %D 2021 %T Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. %A Taliun, Daniel %A Harris, Daniel N %A Kessler, Michael D %A Carlson, Jedidiah %A Szpiech, Zachary A %A Torres, Raul %A Taliun, Sarah A Gagliano %A Corvelo, André %A Gogarten, Stephanie M %A Kang, Hyun Min %A Pitsillides, Achilleas N %A LeFaive, Jonathon %A Lee, Seung-Been %A Tian, Xiaowen %A Browning, Brian L %A Das, Sayantan %A Emde, Anne-Katrin %A Clarke, Wayne E %A Loesch, Douglas P %A Shetty, Amol C %A Blackwell, Thomas W %A Smith, Albert V %A Wong, Quenna %A Liu, Xiaoming %A Conomos, Matthew P %A Bobo, Dean M %A Aguet, Francois %A Albert, Christine %A Alonso, Alvaro %A Ardlie, Kristin G %A Arking, Dan E %A Aslibekyan, Stella %A Auer, Paul L %A Barnard, John %A Barr, R Graham %A Barwick, Lucas %A Becker, Lewis C %A Beer, Rebecca L %A Benjamin, Emelia J %A Bielak, Lawrence F %A Blangero, John %A Boehnke, Michael %A Bowden, Donald W %A Brody, Jennifer A %A Burchard, Esteban G %A Cade, Brian E %A Casella, James F %A Chalazan, Brandon %A Chasman, Daniel I %A Chen, Yii-Der Ida %A Cho, Michael H %A Choi, Seung Hoan %A Chung, Mina K %A Clish, Clary B %A Correa, Adolfo %A Curran, Joanne E %A Custer, Brian %A Darbar, Dawood %A Daya, Michelle %A de Andrade, Mariza %A DeMeo, Dawn L %A Dutcher, Susan K %A Ellinor, Patrick T %A Emery, Leslie S %A Eng, Celeste %A Fatkin, Diane %A Fingerlin, Tasha %A Forer, Lukas %A Fornage, Myriam %A Franceschini, Nora %A Fuchsberger, Christian %A Fullerton, Stephanie M %A Germer, Soren %A Gladwin, Mark T %A Gottlieb, Daniel J %A Guo, Xiuqing %A Hall, Michael E %A He, Jiang %A Heard-Costa, Nancy L %A Heckbert, Susan R %A Irvin, Marguerite R %A Johnsen, Jill M %A Johnson, Andrew D %A Kaplan, Robert %A Kardia, Sharon L R %A Kelly, Tanika %A Kelly, Shannon %A Kenny, Eimear E %A Kiel, Douglas P %A Klemmer, Robert %A Konkle, Barbara A %A Kooperberg, Charles %A Köttgen, Anna %A Lange, Leslie A %A Lasky-Su, Jessica %A Levy, Daniel %A Lin, Xihong %A Lin, Keng-Han %A Liu, Chunyu %A Loos, Ruth J F %A Garman, Lori %A Gerszten, Robert %A Lubitz, Steven A %A Lunetta, Kathryn L %A Mak, Angel C Y %A Manichaikul, Ani %A Manning, Alisa K %A Mathias, Rasika A %A McManus, David D %A McGarvey, Stephen T %A Meigs, James B %A Meyers, Deborah A %A Mikulla, Julie L %A Minear, Mollie A %A Mitchell, Braxton D %A Mohanty, Sanghamitra %A Montasser, May E %A Montgomery, Courtney %A Morrison, Alanna C %A Murabito, Joanne M %A Natale, Andrea %A Natarajan, Pradeep %A Nelson, Sarah C %A North, Kari E %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Pankratz, Nathan %A Peloso, Gina M %A Peyser, Patricia A %A Pleiness, Jacob %A Post, Wendy S %A Psaty, Bruce M %A Rao, D C %A Redline, Susan %A Reiner, Alexander P %A Roden, Dan %A Rotter, Jerome I %A Ruczinski, Ingo %A Sarnowski, Chloe %A Schoenherr, Sebastian %A Schwartz, David A %A Seo, Jeong-Sun %A Seshadri, Sudha %A Sheehan, Vivien A %A Sheu, Wayne H %A Shoemaker, M Benjamin %A Smith, Nicholas L %A Smith, Jennifer A %A Sotoodehnia, Nona %A Stilp, Adrienne M %A Tang, Weihong %A Taylor, Kent D %A Telen, Marilyn %A Thornton, Timothy A %A Tracy, Russell P %A Van Den Berg, David J %A Vasan, Ramachandran S %A Viaud-Martinez, Karine A %A Vrieze, Scott %A Weeks, Daniel E %A Weir, Bruce S %A Weiss, Scott T %A Weng, Lu-Chen %A Willer, Cristen J %A Zhang, Yingze %A Zhao, Xutong %A Arnett, Donna K %A Ashley-Koch, Allison E %A Barnes, Kathleen C %A Eric Boerwinkle %A Gabriel, Stacey %A Richard A Gibbs %A Rice, Kenneth M %A Rich, Stephen S %A Silverman, Edwin K %A Qasba, Pankaj %A Gan, Weiniu %A Papanicolaou, George J %A Nickerson, Deborah A %A Browning, Sharon R %A Zody, Michael C %A Zöllner, Sebastian %A Wilson, James G %A Cupples, L Adrienne %A Laurie, Cathy C %A Jaquish, Cashell E %A Hernandez, Ryan D %A O'Connor, Timothy D %A Abecasis, Gonçalo R %K Cytochrome P-450 CYP2D6 %K Genetic Variation %K Genome, Human %K Genomics %K Haplotypes %K Heterozygote %K Humans %K INDEL Mutation %K Loss of Function Mutation %K Mutagenesis %K National Heart, Lung, and Blood Institute (U.S.) %K Phenotype %K Polymorphism, Single Nucleotide %K Population Density %K Precision Medicine %K Quality Control %K Sample Size %K United States %K Whole Genome Sequencing %X

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

%B Nature %V 590 %P 290-299 %8 2021 Feb %G eng %N 7845 %1 https://www.ncbi.nlm.nih.gov/pubmed/33568819?dopt=Abstract %R 10.1038/s41586-021-03205-y %0 Journal Article %J Am J Hum Genet %D 2020 %T Allelic Heterogeneity at the CRP Locus Identified by Whole-Genome Sequencing in Multi-ancestry Cohorts. %A Raffield, Laura M %A Iyengar, Apoorva K %A Wang, Biqi %A Gaynor, Sheila M %A Spracklen, Cassandra N %A Zhong, Xue %A Kowalski, Madeline H %A Salimi, Shabnam %A Polfus, Linda M %A Benjamin, Emelia J %A Bis, Joshua C %A Bowler, Russell %A Cade, Brian E %A Choi, Won Jung %A Comellas, Alejandro P %A Correa, Adolfo %A Cruz, Pedro %A Harshavardhan Doddapaneni %A Durda, Peter %A Gogarten, Stephanie M %A Jain, Deepti %A Kim, Ryan W %A Kral, Brian G %A Lange, Leslie A %A Larson, Martin G %A Laurie, Cecelia %A Lee, Jiwon %A Lee, Seonwook %A Lewis, Joshua P %A Ginger A Metcalf %A Mitchell, Braxton D %A Momin, Zeineen %A Donna M Muzny %A Pankratz, Nathan %A Park, Cheol Joo %A Rich, Stephen S %A Rotter, Jerome I %A Ryan, Kathleen %A Seo, Daekwan %A Tracy, Russell P %A Viaud-Martinez, Karine A %A Yanek, Lisa R %A Zhao, Lue Ping %A Lin, Xihong %A Li, Bingshan %A Li, Yun %A Dupuis, Josée %A Reiner, Alexander P %A Mohlke, Karen L %A Auer, Paul L %K Asian People %K Black People %K C-Reactive Protein %K Cohort Studies %K Gene Frequency %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Polymorphism, Single Nucleotide %K White People %K Whole Genome Sequencing %X

Whole-genome sequencing (WGS) can improve assessment of low-frequency and rare variants, particularly in non-European populations that have been underrepresented in existing genomic studies. The genetic determinants of C-reactive protein (CRP), a biomarker of chronic inflammation, have been extensively studied, with existing genome-wide association studies (GWASs) conducted in >200,000 individuals of European ancestry. In order to discover novel loci associated with CRP levels, we examined a multi-ancestry population (n = 23,279) with WGS (∼38× coverage) from the Trans-Omics for Precision Medicine (TOPMed) program. We found evidence for eight distinct associations at the CRP locus, including two variants that have not been identified previously (rs11265259 and rs181704186), both of which are non-coding and more common in individuals of African ancestry (∼10% and ∼1% minor allele frequency, respectively, and rare or monomorphic in 1000 Genomes populations of East Asian, South Asian, and European ancestry). We show that the minor (G) allele of rs181704186 is associated with lower CRP levels and decreased transcriptional activity and protein binding in vitro, providing a plausible molecular mechanism for this African ancestry-specific signal. The individuals homozygous for rs181704186-G have a mean CRP level of 0.23 mg/L, in contrast to individuals heterozygous for rs181704186 with mean CRP of 2.97 mg/L and major allele homozygotes with mean CRP of 4.11 mg/L. This study demonstrates the utility of WGS in multi-ethnic populations to drive discovery of complex trait associations of large effect and to identify functional alleles in noncoding regulatory regions.

%B Am J Hum Genet %V 106 %P 112-120 %8 2020 Jan 02 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31883642?dopt=Abstract %R 10.1016/j.ajhg.2019.12.002 %0 Journal Article %J Blood %D 2019 %T A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology. %A de Vries, Paul S %A Sabater-Lleal, Maria %A Huffman, Jennifer E %A Marten, Jonathan %A Song, Ci %A Pankratz, Nathan %A Bartz, Traci M %A de Haan, Hugoline G %A Delgado, Graciela E %A Eicher, John D %A Martinez-Perez, Angel %A Ward-Caviness, Cavin K %A Brody, Jennifer A %A Chen, Ming-Huei %A de Maat, Moniek P M %A Frånberg, Mattias %A Gill, Dipender %A Kleber, Marcus E %A Rivadeneira, Fernando %A Soria, José Manuel %A Tang, Weihong %A Tofler, Geoffrey H %A Uitterlinden, André G %A van Hylckama Vlieg, Astrid %A Seshadri, Sudha %A Eric Boerwinkle %A Davies, Neil M %A Giese, Anne-Katrin %A Ikram, M Kamran %A Kittner, Steven J %A McKnight, Barbara %A Psaty, Bruce M %A Reiner, Alex P %A Sargurupremraj, Muralidharan %A Taylor, Kent D %A Fornage, Myriam %A Hamsten, Anders %A Marz, Winfried %A Rosendaal, Frits R %A Souto, Juan Carlos %A Dehghan, Abbas %A Johnson, Andrew D %A Morrison, Alanna C %A O'Donnell, Christopher J %A Smith, Nicholas L %K Brain Ischemia %K Co-Repressor Proteins %K Cohort Studies %K Coronary Artery Disease %K DNA-Binding Proteins %K Factor VII %K Female %K Follow-Up Studies %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Membrane Transport Proteins %K Mendelian Randomization Analysis %K Middle Aged %K Neoplasm Proteins %K Phenotype %K Polymorphism, Single Nucleotide %K Prognosis %K Stroke %K Venous Thromboembolism %X

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

%B Blood %V 133 %P 967-977 %8 2019 Feb 28 %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/30642921?dopt=Abstract %R 10.1182/blood-2018-05-849240 %0 Journal Article %J Hum Mol Genet %D 2015 %T Association of exome sequences with plasma C-reactive protein levels in >9000 participants. %A Schick, Ursula M %A Auer, Paul L %A Bis, Joshua C %A Lin, Honghuang %A Wei, Peng %A Pankratz, Nathan %A Lange, Leslie A %A Brody, Jennifer %A Stitziel, Nathan O %A Kim, Daniel S %A Carlson, Christopher S %A Fornage, Myriam %A Haessler, Jeffery %A Hsu, Li %A Jackson, Rebecca D %A Kooperberg, Charles %A Leal, Suzanne M %A Psaty, Bruce M %A Boerwinkle, Eric %A Tracy, Russell %A Ardissino, Diego %A Shah, Svati %A Willer, Cristen %A Loos, Ruth %A Melander, Olle %A McPherson, Ruth %A Hovingh, Kees %A Reilly, Muredach %A Watkins, Hugh %A Girelli, Domenico %A Fontanillas, Pierre %A Chasman, Daniel I %A Gabriel, Stacey B %A Gibbs, Richard %A Nickerson, Deborah A %A Kathiresan, Sekar %A Peters, Ulrike %A Dupuis, Josée %A Wilson, James G %A Rich, Stephen S %A Morrison, Alanna C %A Benjamin, Emelia J %A Gross, Myron D %A Reiner, Alex P %K Adult %K Black or African American %K C-Reactive Protein %K Cardiovascular Diseases %K Cohort Studies %K Exome %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Hepatocyte Nuclear Factor 1-alpha %K Humans %K Male %K Plasma %K Polymorphism, Single Nucleotide %K Receptors, Interleukin-6 %K Risk Factors %K White People %X

C-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in ∼25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 × 10(-6)). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 × 10(-15)). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-ε2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 × 10(-8)), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In gene-based tests, a burden of rare/lower frequency variation in CRP in EAs (P ≤ 6.8 × 10(-4)) and in retinoic acid receptor-related orphan receptor α (RORA) in AAs (P = 1.7 × 10(-3)) were associated with CRP levels at the candidate gene level (P < 2.0 × 10(-3)). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels.

%B Hum Mol Genet %V 24 %P 559-71 %8 2015 Jan 15 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/25187575?dopt=Abstract %R 10.1093/hmg/ddu450 %0 Journal Article %J Blood %D 2015 %T Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF. %A Huffman, Jennifer E %A de Vries, Paul S %A Morrison, Alanna C %A Sabater-Lleal, Maria %A Kacprowski, Tim %A Auer, Paul L %A Brody, Jennifer A %A Chasman, Daniel I %A Chen, Ming-Huei %A Guo, Xiuqing %A Lin, Li-An %A Marioni, Riccardo E %A Müller-Nurasyid, Martina %A Yanek, Lisa R %A Pankratz, Nathan %A Grove, Megan L %A de Maat, Moniek P M %A Cushman, Mary %A Wiggins, Kerri L %A Qi, Lihong %A Sennblad, Bengt %A Harris, Sarah E %A Polasek, Ozren %A Riess, Helene %A Rivadeneira, Fernando %A Rose, Lynda M %A Goel, Anuj %A Taylor, Kent D %A Teumer, Alexander %A Uitterlinden, André G %A Vaidya, Dhananjay %A Yao, Jie %A Tang, Weihong %A Levy, Daniel %A Waldenberger, Melanie %A Becker, Diane M %A Folsom, Aaron R %A Giulianini, Franco %A Greinacher, Andreas %A Hofman, Albert %A Huang, Chiang-Ching %A Kooperberg, Charles %A Silveira, Angela %A Starr, John M %A Strauch, Konstantin %A Strawbridge, Rona J %A Wright, Alan F %A McKnight, Barbara %A Franco, Oscar H %A Zakai, Neil %A Mathias, Rasika A %A Psaty, Bruce M %A Ridker, Paul M %A Tofler, Geoffrey H %A Völker, Uwe %A Watkins, Hugh %A Fornage, Myriam %A Hamsten, Anders %A Deary, Ian J %A Boerwinkle, Eric %A Koenig, Wolfgang %A Rotter, Jerome I %A Hayward, Caroline %A Dehghan, Abbas %A Reiner, Alex P %A O'Donnell, Christopher J %A Smith, Nicholas L %K Cohort Studies %K Factor VII %K Factor VIII %K Fibrinogen %K Gene Frequency %K Genetic Association Studies %K Genetic Variation %K Humans %K Nerve Tissue Proteins %K Polymorphism, Single Nucleotide %K Potassium Channels %K Potassium Channels, Sodium-Activated %K von Willebrand Factor %X

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 <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76,000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n = 2) and rare (n = 10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identified new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information for understanding individual variation in hemostasis pathways.

%B Blood %V 126 %P e19-29 %8 2015 Sep 10 %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/26105150?dopt=Abstract %R 10.1182/blood-2015-02-624551 %0 Journal Article %J Genet Epidemiol %D 2013 %T A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium. %A Tang, Weihong %A Teichert, Martina %A Chasman, Daniel I %A Heit, John A %A Morange, Pierre-Emmanuel %A Li, Guo %A Pankratz, Nathan %A Leebeek, Frank W %A Paré, Guillaume %A de Andrade, Mariza %A Tzourio, Christophe %A Psaty, Bruce M %A Basu, Saonli %A Ruiter, Rikje %A Rose, Lynda %A Armasu, Sebastian M %A Lumley, Thomas %A Heckbert, Susan R %A Uitterlinden, André G %A Lathrop, Mark %A Rice, Kenneth M %A Cushman, Mary %A Hofman, Albert %A Lambert, Jean-Charles %A Glazer, Nicole L %A Pankow, James S %A Witteman, Jacqueline C %A Amouyel, Philippe %A Bis, Joshua C %A Bovill, Edwin G %A Kong, Xiaoxiao %A Tracy, Russell P %A Eric Boerwinkle %A Rotter, Jerome I %A Trégouët, David-Alexandre %A Loth, Daan W %A Stricker, Bruno H Ch %A Ridker, Paul M %A Folsom, Aaron R %A Smith, Nicholas L %K Aged %K Aging %K Case-Control Studies %K Cohort Studies %K Female %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Middle Aged %K Polymorphism, Single Nucleotide %K Regression Analysis %K Risk Factors %K Venous Thromboembolism %X

Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10(-13) for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10(-6) ) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.

%B Genet Epidemiol %V 37 %P 512-521 %8 2013 Jul %G eng %N 5 %R 10.1002/gepi.21731