%0 Journal Article %J PLoS One %D 2020 %T Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. %A Hahn, Julie %A Fu, Yi-Ping %A Brown, Michael R %A Bis, Joshua C %A de Vries, Paul S %A Feitosa, Mary F %A Yanek, Lisa R %A Weiss, Stefan %A Giulianini, Franco %A Smith, Albert Vernon %A Guo, Xiuqing %A Bartz, Traci M %A Becker, Diane M %A Becker, Lewis C %A Boerwinkle, Eric %A Brody, Jennifer A %A Chen, Yii-Der Ida %A Franco, Oscar H %A Grove, Megan %A Harris, Tamara B %A Hofman, Albert %A Hwang, Shih-Jen %A Kral, Brian G %A Launer, Lenore J %A Markus, Marcello R P %A Rice, Kenneth M %A Rich, Stephen S %A Ridker, Paul M %A Rivadeneira, Fernando %A Rotter, Jerome I %A Sotoodehnia, Nona %A Taylor, Kent D %A Uitterlinden, André G %A Völker, Uwe %A Völzke, Henry %A Yao, Jie %A Chasman, Daniel I %A Dörr, Marcus %A Gudnason, Vilmundur %A Mathias, Rasika A %A Post, Wendy %A Psaty, Bruce M %A Dehghan, Abbas %A O'Donnell, Christopher J %A Morrison, Alanna C %K Aging %K Coronary Artery Disease %K Cross-Sectional Studies %K Europe %K European Continental Ancestry Group %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Prospective Studies %X

BACKGROUND: Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.

METHODS AND RESULTS: Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.

CONCLUSION: This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.

%B PLoS One %V 15 %P e0230035 %8 2020 %G eng %N 11 %R 10.1371/journal.pone.0230035 %0 Journal Article %J medRxiv %D 2023 %T Whole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles. %A Huffman, Jennifer E %A Nicolas, Jayna %A Hahn, Julie %A Heath, Adam S %A Raffield, Laura M %A Yanek, Lisa R %A Brody, Jennifer A %A Thibord, Florian %A Almasy, Laura %A Bartz, Traci M %A Bielak, Lawrence F %A Bowler, Russell P %A Carrasquilla, Germán D %A Chasman, Daniel I %A Chen, Ming-Huei %A Emmert, David B %A Ghanbari, Mohsen %A Haessle, Jeffery %A Hottenga, Jouke-Jan %A Kleber, Marcus E %A Le, Ngoc-Quynh %A Lee, Jiwon %A Lewis, Joshua P %A Li-Gao, Ruifang %A Luan, Jian'an %A Malmberg, Anni %A Mangino, Massimo %A Marioni, Riccardo E %A Martinez-Perez, Angel %A Pankratz, Nathan %A Polasek, Ozren %A Richmond, Anne %A Rodriguez, Benjamin At %A Rotter, Jerome I %A Steri, Maristella %A Suchon, Pierre %A Trompet, Stella %A Weiss, Stefan %A Zare, Marjan %A Auer, Paul %A Cho, Michael H %A Christofidou, Paraskevi %A Davies, Gail %A de Geus, Eco %A Deleuze, Jean-Francois %A Delgado, Graciela E %A Ekunwe, Lynette %A Faraday, Nauder %A Gögele, Martin %A Greinacher, Andreas %A He, Gao %A Howard, Tom %A Joshi, Peter K %A Kilpeläinen, Tuomas O %A Lahti, Jari %A Linneberg, Allan %A Naitza, Silvia %A Noordam, Raymond %A Paüls-Vergés, Ferran %A Rich, Stephen S %A Rosendaal, Frits R %A Rudan, Igor %A Ryan, Kathleen A %A Souto, Juan Carlos %A van Rooij, Frank Ja %A Wang, Heming %A Zhao, Wei %A Becker, Lewis C %A Beswick, Andrew %A Brown, Michael R %A Cade, Brian E %A Campbell, Harry %A Cho, Kelly %A Crapo, James D %A Curran, Joanne E %A de Maat, Moniek Pm %A Doyle, Margaret %A Elliott, Paul %A Floyd, James S %A Fuchsberger, Christian %A Grarup, Niels %A Guo, Xiuqing %A Harris, Sarah E %A Hou, Lifang %A Kolcic, Ivana %A Kooperberg, Charles %A Menni, Cristina %A Nauck, Matthias %A O'Connell, Jeffrey R %A Orrù, Valeria %A Psaty, Bruce M %A Räikkönen, Katri %A Smith, Jennifer A %A Soria, José Manuel %A Stott, David J %A van Hylckama Vlieg, Astrid %A Watkins, Hugh %A Willemsen, Gonneke %A Wilson, Peter %A Ben-Shlomo, Yoav %A Blangero, John %A Boomsma, Dorret %A Cox, Simon R %A Dehghan, Abbas %A Eriksson, Johan G %A Fiorillo, Edoardo %A Fornage, Myriam %A Hansen, Torben %A Hayward, Caroline %A Ikram, M Arfan %A Jukema, J Wouter %A Kardia, Sharon Lr %A Lange, Leslie A %A März, Winfried %A Mathias, Rasika A %A Mitchell, Braxton D %A Mook-Kanamori, Dennis O %A Morange, Pierre-Emmanuel %A Pedersen, Oluf %A Pramstaller, Peter P %A Redline, Susan %A Reiner, Alexander %A Ridker, Paul M %A Silverman, Edwin K %A Spector, Tim D %A Völker, Uwe %A Wareham, Nick %A Wilson, James F %A Yao, Jie %A Trégouët, David-Alexandre %A Johnson, Andrew D %A Wolberg, Alisa S %A de Vries, Paul S %A Sabater-Lleal, Maria %A Morrison, Alanna C %A Smith, Nicholas L %X

UNLABELLED: Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI's Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10% higher in African populations. Three ( , and signals contain predicted deleterious missense variants. Two loci, and , each harbor two conditionally distinct, non-coding variants. The gene region encoding the protein chain subunits ( ), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common (MAF=0.180) in African reference panels but extremely rare (MAF=0.008) in Europeans. Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.

KEY POINTS: Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 conditionally distinct variants (20 novel).Sufficient power achieved to identify signal driven by African population variant.Links to (1) liver enzyme, blood cell and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.

%B medRxiv %8 2023 Jun 12 %G eng %R 10.1101/2023.06.07.23291095