TY - JOUR T1 - Time trends in the use of beta-blockers and other pharmacotherapies in older adults with congestive heart failure. JF - Am Heart J Y1 - 2004 A1 - Smith, Nicholas L A1 - Chan, Jeannie D A1 - Rea, Thomas D A1 - Wiggins, Kerri L A1 - Gottdiener, John S A1 - Lumley, Thomas A1 - Psaty, Bruce M KW - Adrenergic beta-Antagonists KW - Aged KW - Angiotensin II Type 1 Receptor Blockers KW - Angiotensin-Converting Enzyme Inhibitors KW - Cohort Studies KW - Drug Therapy KW - Drug Therapy, Combination KW - Female KW - Heart Failure KW - Humans KW - Male KW - Multivariate Analysis KW - Prevalence AB -

BACKGROUND: Evidence supporting pharmacotherapy of congestive heart failure (CHF) has grown substantially over the past decade and includes large, placebo-controlled trials with mortality end points. We describe beta-blocker and other medication temporal treatment trends of CHF in the Cardiovascular Health Study, a community-based cohort study of 5888 adults > or =65 years of age.

METHODS: Prescription medication data were collected from hospital discharge summaries for incident CHF events and at in-study annual clinic visits for prevalent CHF cases from 1989 to 2000. Change in use of agents over time was estimated by using generalized estimating equations while adjusting for potential confounding factors of age, sex, race, and cardiovascular and pulmonary comorbidities.

RESULTS: Among 1033 incident CHF events, beta-blocker use after diagnosis increased an average of 2.4 percentage points annually (95% CI, 1.5 to 3.4 points) from 1989 to 2000. The increasing trend was consistent throughout follow-up. Among participants with coronary disease and/or hypertension and among those with low ejection fractions (<45%), beta-blocker use remained flat from 1989 to 1994 and increased 4.7 points annually (2.5 to 6.9) and 10.0 points annually (6.1 to 13.8), respectively, from 1995 to 2000. Among participants without coronary disease or hypertension, there was no overall increase in use. Use of renin-angiotensin system inhibitors increased 2.3 points annually (1.0 to 3.5), digoxin use decreased 2.4 points annually (-3.6 to -1.1), and loop diuretic use remained flat between 1989 and 2000. In general, treatment trends were similar for prevalent CHF.

CONCLUSIONS: Treatment of CHF has changed gradually in the 1990s and may in part reflect the influence of CHF clinical trial evidence.

VL - 148 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15459605?dopt=Abstract ER - TY - JOUR T1 - Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo. JF - PLoS Genet Y1 - 2010 A1 - Ikram, M Kamran A1 - Sim, Xueling A1 - Xueling, Sim A1 - Jensen, Richard A A1 - Cotch, Mary Frances A1 - Hewitt, Alex W A1 - Ikram, M Arfan A1 - Wang, Jie Jin A1 - Klein, Ronald A1 - Klein, Barbara E K A1 - Breteler, Monique M B A1 - Cheung, Ning A1 - Liew, Gerald A1 - Mitchell, Paul A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Hofman, Albert A1 - de Jong, Paulus T V M A1 - van Duijn, Cornelia M A1 - Kao, Linda A1 - Cheng, Ching-Yu A1 - Smith, Albert Vernon A1 - Glazer, Nicole L A1 - Lumley, Thomas A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - Jonasson, Fridbert A1 - Eiriksdottir, Gudny A1 - Aspelund, Thor A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Taylor, Kent D A1 - Li, Xiaohui A1 - Iyengar, Sudha K A1 - Xi, Quansheng A1 - Sivakumaran, Theru A A1 - Mackey, David A A1 - Macgregor, Stuart A1 - Martin, Nicholas G A1 - Young, Terri L A1 - Bis, Josh C A1 - Wiggins, Kerri L A1 - Heckbert, Susan R A1 - Hammond, Christopher J A1 - Andrew, Toby A1 - Fahy, Samantha A1 - Attia, John A1 - Holliday, Elizabeth G A1 - Scott, Rodney J A1 - Islam, F M Amirul A1 - Rotter, Jerome I A1 - McAuley, Annie K A1 - Boerwinkle, Eric A1 - Tai, E Shyong A1 - Gudnason, Vilmundur A1 - Siscovick, David S A1 - Vingerling, Johannes R A1 - Wong, Tien Y KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Child KW - Child, Preschool KW - Chromosomes, Human, Pair 12 KW - Chromosomes, Human, Pair 19 KW - Chromosomes, Human, Pair 5 KW - Chromosomes, Human, Pair 6 KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Microcirculation KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Retinal Vessels KW - Young Adult AB -

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n  =  6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p  =  1.61×10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25×10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p  =  2.15×10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.

VL - 6 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21060863?dopt=Abstract ER - TY - JOUR T1 - Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. JF - Circulation Y1 - 2010 A1 - Smith, Nicholas L A1 - Chen, Ming-Huei A1 - Dehghan, Abbas A1 - Strachan, David P A1 - Basu, Saonli A1 - Soranzo, Nicole A1 - Hayward, Caroline A1 - Rudan, Igor A1 - Sabater-Lleal, Maria A1 - Bis, Joshua C A1 - de Maat, Moniek P M A1 - Rumley, Ann A1 - Kong, Xiaoxiao A1 - Yang, Qiong A1 - Williams, Frances M K A1 - Vitart, Veronique A1 - Campbell, Harry A1 - Mälarstig, Anders A1 - Wiggins, Kerri L A1 - van Duijn, Cornelia M A1 - McArdle, Wendy L A1 - Pankow, James S A1 - Johnson, Andrew D A1 - Silveira, Angela A1 - McKnight, Barbara A1 - Uitterlinden, André G A1 - Aleksic, Nena A1 - Meigs, James B A1 - Peters, Annette A1 - Koenig, Wolfgang A1 - Cushman, Mary A1 - Kathiresan, Sekar A1 - Rotter, Jerome I A1 - Bovill, Edwin G A1 - Hofman, Albert A1 - Boerwinkle, Eric A1 - Tofler, Geoffrey H A1 - Peden, John F A1 - Psaty, Bruce M A1 - Leebeek, Frank A1 - Folsom, Aaron R A1 - Larson, Martin G A1 - Spector, Timothy D A1 - Wright, Alan F A1 - Wilson, James F A1 - Hamsten, Anders A1 - Lumley, Thomas A1 - Witteman, Jacqueline C M A1 - Tang, Weihong A1 - O'Donnell, Christopher J KW - Adult KW - Factor VII KW - Factor VIII KW - Female KW - Genome-Wide Association Study KW - Hemostasis KW - Humans KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Thrombosis KW - von Willebrand Factor AB -

BACKGROUND: Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels.

METHODS AND RESULTS: The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0x10(-8) and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2x10(-24)), 4q25 (3.6x10(-12)), 11q12 (2.0x10(-10)), 13q34 (9.0x10(-259)), and 20q11.2 (5.7x10(-37)). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2x10(-22)), 8p21 (1.3x10(-16)), 9q34 (<5.0x10(-324)), 12p13 (1.7x10(-32)), 12q23 (7.3x10(-10)), 12q24.3 (3.8x10(-11)), 14q32 (2.3x10(-10)), and 19p13.2 (1.3x10(-9)). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings were replicated.

CONCLUSIONS: New genetic associations were discovered outside previously known biological pathways and may point to novel prevention and treatment targets of hemostasis disorders.

VL - 121 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20231535?dopt=Abstract ER - TY - JOUR T1 - Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. JF - Nature Y1 - 2011 A1 - Ehret, Georg B A1 - Munroe, Patricia B A1 - Rice, Kenneth M A1 - Bochud, Murielle A1 - Johnson, Andrew D A1 - Chasman, Daniel I A1 - Smith, Albert V A1 - Tobin, Martin D A1 - Verwoert, Germaine C A1 - Hwang, Shih-Jen A1 - Pihur, Vasyl A1 - Vollenweider, Peter A1 - O'Reilly, Paul F A1 - Amin, Najaf A1 - Bragg-Gresham, Jennifer L A1 - Teumer, Alexander A1 - Glazer, Nicole L A1 - Launer, Lenore A1 - Zhao, Jing Hua A1 - Aulchenko, Yurii A1 - Heath, Simon A1 - Sõber, Siim A1 - Parsa, Afshin A1 - Luan, Jian'an A1 - Arora, Pankaj A1 - Dehghan, Abbas A1 - Zhang, Feng A1 - Lucas, Gavin A1 - Hicks, Andrew A A1 - Jackson, Anne U A1 - Peden, John F A1 - Tanaka, Toshiko A1 - Wild, Sarah H A1 - Rudan, Igor A1 - Igl, Wilmar A1 - Milaneschi, Yuri A1 - Parker, Alex N A1 - Fava, Cristiano A1 - Chambers, John C A1 - Fox, Ervin R A1 - Kumari, Meena A1 - Go, Min Jin A1 - van der Harst, Pim A1 - Kao, Wen Hong Linda A1 - Sjögren, Marketa A1 - Vinay, D G A1 - Alexander, Myriam A1 - Tabara, Yasuharu A1 - Shaw-Hawkins, Sue A1 - Whincup, Peter H A1 - Liu, Yongmei A1 - Shi, Gang A1 - Kuusisto, Johanna A1 - Tayo, Bamidele A1 - Seielstad, Mark A1 - Sim, Xueling A1 - Nguyen, Khanh-Dung Hoang A1 - Lehtimäki, Terho A1 - Matullo, Giuseppe A1 - Wu, Ying A1 - Gaunt, Tom R A1 - Onland-Moret, N Charlotte A1 - Cooper, Matthew N A1 - Platou, Carl G P A1 - Org, Elin A1 - Hardy, Rebecca A1 - Dahgam, Santosh A1 - Palmen, Jutta A1 - Vitart, Veronique A1 - Braund, Peter S A1 - Kuznetsova, Tatiana A1 - Uiterwaal, Cuno S P M A1 - Adeyemo, Adebowale A1 - Palmas, Walter A1 - Campbell, Harry A1 - Ludwig, Barbara A1 - Tomaszewski, Maciej A1 - Tzoulaki, Ioanna A1 - Palmer, Nicholette D A1 - Aspelund, Thor A1 - Garcia, Melissa A1 - Chang, Yen-Pei C A1 - O'Connell, Jeffrey R A1 - Steinle, Nanette I A1 - Grobbee, Diederick E A1 - Arking, Dan E A1 - Kardia, Sharon L A1 - Morrison, Alanna C A1 - Hernandez, Dena A1 - Najjar, Samer A1 - McArdle, Wendy L A1 - Hadley, David A1 - Brown, Morris J A1 - Connell, John M A1 - Hingorani, Aroon D A1 - Day, Ian N M A1 - Lawlor, Debbie A A1 - Beilby, John P A1 - Lawrence, Robert W A1 - Clarke, Robert A1 - Hopewell, Jemma C A1 - Ongen, Halit A1 - Dreisbach, Albert W A1 - Li, Yali A1 - Young, J Hunter A1 - Bis, Joshua C A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Adair, Linda S A1 - Lee, Nanette R A1 - Chen, Ming-Huei A1 - Olden, Matthias A1 - Pattaro, Cristian A1 - Bolton, Judith A Hoffman A1 - Köttgen, Anna A1 - Bergmann, Sven A1 - Mooser, Vincent A1 - Chaturvedi, Nish A1 - Frayling, Timothy M A1 - Islam, Muhammad A1 - Jafar, Tazeen H A1 - Erdmann, Jeanette A1 - Kulkarni, Smita R A1 - Bornstein, Stefan R A1 - Grässler, Jürgen A1 - Groop, Leif A1 - Voight, Benjamin F A1 - Kettunen, Johannes A1 - Howard, Philip A1 - Taylor, Andrew A1 - Guarrera, Simonetta A1 - Ricceri, Fulvio A1 - Emilsson, Valur A1 - Plump, Andrew A1 - Barroso, Inês A1 - Khaw, Kay-Tee A1 - Weder, Alan B A1 - Hunt, Steven C A1 - Sun, Yan V A1 - Bergman, Richard N A1 - Collins, Francis S A1 - Bonnycastle, Lori L A1 - Scott, Laura J A1 - Stringham, Heather M A1 - Peltonen, Leena A1 - Perola, Markus A1 - Vartiainen, Erkki A1 - Brand, Stefan-Martin A1 - Staessen, Jan A A1 - Wang, Thomas J A1 - Burton, Paul R A1 - Soler Artigas, Maria A1 - Dong, Yanbin A1 - Snieder, Harold A1 - Wang, Xiaoling A1 - Zhu, Haidong A1 - Lohman, Kurt K A1 - Rudock, Megan E A1 - Heckbert, Susan R A1 - Smith, Nicholas L A1 - Wiggins, Kerri L A1 - Doumatey, Ayo A1 - Shriner, Daniel A1 - Veldre, Gudrun A1 - Viigimaa, Margus A1 - Kinra, Sanjay A1 - Prabhakaran, Dorairaj A1 - Tripathy, Vikal A1 - Langefeld, Carl D A1 - Rosengren, Annika A1 - Thelle, Dag S A1 - Corsi, Anna Maria A1 - Singleton, Andrew A1 - Forrester, Terrence A1 - Hilton, Gina A1 - McKenzie, Colin A A1 - Salako, Tunde A1 - Iwai, Naoharu A1 - Kita, Yoshikuni A1 - Ogihara, Toshio A1 - Ohkubo, Takayoshi A1 - Okamura, Tomonori A1 - Ueshima, Hirotsugu A1 - Umemura, Satoshi A1 - Eyheramendy, Susana A1 - Meitinger, Thomas A1 - Wichmann, H-Erich A1 - Cho, Yoon Shin A1 - Kim, Hyung-Lae A1 - Lee, Jong-Young A1 - Scott, James A1 - Sehmi, Joban S A1 - Zhang, Weihua A1 - Hedblad, Bo A1 - Nilsson, Peter A1 - Smith, George Davey A1 - Wong, Andrew A1 - Narisu, Narisu A1 - Stančáková, Alena A1 - Raffel, Leslie J A1 - Yao, Jie A1 - Kathiresan, Sekar A1 - O'Donnell, Christopher J A1 - Schwartz, Stephen M A1 - Ikram, M Arfan A1 - Longstreth, W T A1 - Mosley, Thomas H A1 - Seshadri, Sudha A1 - Shrine, Nick R G A1 - Wain, Louise V A1 - Morken, Mario A A1 - Swift, Amy J A1 - Laitinen, Jaana A1 - Prokopenko, Inga A1 - Zitting, Paavo A1 - Cooper, Jackie A A1 - Humphries, Steve E A1 - Danesh, John A1 - Rasheed, Asif A1 - Goel, Anuj A1 - Hamsten, Anders A1 - Watkins, Hugh A1 - Bakker, Stephan J L A1 - van Gilst, Wiek H A1 - Janipalli, Charles S A1 - Mani, K Radha A1 - Yajnik, Chittaranjan S A1 - Hofman, Albert A1 - Mattace-Raso, Francesco U S A1 - Oostra, Ben A A1 - Demirkan, Ayse A1 - Isaacs, Aaron A1 - Rivadeneira, Fernando A1 - Lakatta, Edward G A1 - Orrù, Marco A1 - Scuteri, Angelo A1 - Ala-Korpela, Mika A1 - Kangas, Antti J A1 - Lyytikäinen, Leo-Pekka A1 - Soininen, Pasi A1 - Tukiainen, Taru A1 - Würtz, Peter A1 - Ong, Rick Twee-Hee A1 - Dörr, Marcus A1 - Kroemer, Heyo K A1 - Völker, Uwe A1 - Völzke, Henry A1 - Galan, Pilar A1 - Hercberg, Serge A1 - Lathrop, Mark A1 - Zelenika, Diana A1 - Deloukas, Panos A1 - Mangino, Massimo A1 - Spector, Tim D A1 - Zhai, Guangju A1 - Meschia, James F A1 - Nalls, Michael A A1 - Sharma, Pankaj A1 - Terzic, Janos A1 - Kumar, M V Kranthi A1 - Denniff, Matthew A1 - Zukowska-Szczechowska, Ewa A1 - Wagenknecht, Lynne E A1 - Fowkes, F Gerald R A1 - Charchar, Fadi J A1 - Schwarz, Peter E H A1 - Hayward, Caroline A1 - Guo, Xiuqing A1 - Rotimi, Charles A1 - Bots, Michiel L A1 - Brand, Eva A1 - Samani, Nilesh J A1 - Polasek, Ozren A1 - Talmud, Philippa J A1 - Nyberg, Fredrik A1 - Kuh, Diana A1 - Laan, Maris A1 - Hveem, Kristian A1 - Palmer, Lyle J A1 - van der Schouw, Yvonne T A1 - Casas, Juan P A1 - Mohlke, Karen L A1 - Vineis, Paolo A1 - Raitakari, Olli A1 - Ganesh, Santhi K A1 - Wong, Tien Y A1 - Tai, E Shyong A1 - Cooper, Richard S A1 - Laakso, Markku A1 - Rao, Dabeeru C A1 - Harris, Tamara B A1 - Morris, Richard W A1 - Dominiczak, Anna F A1 - Kivimaki, Mika A1 - Marmot, Michael G A1 - Miki, Tetsuro A1 - Saleheen, Danish A1 - Chandak, Giriraj R A1 - Coresh, Josef A1 - Navis, Gerjan A1 - Salomaa, Veikko A1 - Han, Bok-Ghee A1 - Zhu, Xiaofeng A1 - Kooner, Jaspal S A1 - Melander, Olle A1 - Ridker, Paul M A1 - Bandinelli, Stefania A1 - Gyllensten, Ulf B A1 - Wright, Alan F A1 - Wilson, James F A1 - Ferrucci, Luigi A1 - Farrall, Martin A1 - Tuomilehto, Jaakko A1 - Pramstaller, Peter P A1 - Elosua, Roberto A1 - Soranzo, Nicole A1 - Sijbrands, Eric J G A1 - Altshuler, David A1 - Loos, Ruth J F A1 - Shuldiner, Alan R A1 - Gieger, Christian A1 - Meneton, Pierre A1 - Uitterlinden, André G A1 - Wareham, Nicholas J A1 - Gudnason, Vilmundur A1 - Rotter, Jerome I A1 - Rettig, Rainer A1 - Uda, Manuela A1 - Strachan, David P A1 - Witteman, Jacqueline C M A1 - Hartikainen, Anna-Liisa A1 - Beckmann, Jacques S A1 - Boerwinkle, Eric A1 - Vasan, Ramachandran S A1 - Boehnke, Michael A1 - Larson, Martin G A1 - Jarvelin, Marjo-Riitta A1 - Psaty, Bruce M A1 - Abecasis, Goncalo R A1 - Chakravarti, Aravinda A1 - Elliott, Paul A1 - van Duijn, Cornelia M A1 - Newton-Cheh, Christopher A1 - Levy, Daniel A1 - Caulfield, Mark J A1 - Johnson, Toby KW - Africa KW - Asia KW - Blood Pressure KW - Cardiovascular Diseases KW - Coronary Artery Disease KW - Europe KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Kidney Diseases KW - Polymorphism, Single Nucleotide KW - Stroke AB -

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

VL - 478 IS - 7367 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21909115?dopt=Abstract ER - TY - JOUR T1 - New gene functions in megakaryopoiesis and platelet formation. JF - Nature Y1 - 2011 A1 - Gieger, Christian A1 - Radhakrishnan, Aparna A1 - Cvejic, Ana A1 - Tang, Weihong A1 - Porcu, Eleonora A1 - Pistis, Giorgio A1 - Serbanovic-Canic, Jovana A1 - Elling, Ulrich A1 - Goodall, Alison H A1 - Labrune, Yann A1 - Lopez, Lorna M A1 - Mägi, Reedik A1 - Meacham, Stuart A1 - Okada, Yukinori A1 - Pirastu, Nicola A1 - Sorice, Rossella A1 - Teumer, Alexander A1 - Voss, Katrin A1 - Zhang, Weihua A1 - Ramirez-Solis, Ramiro A1 - Bis, Joshua C A1 - Ellinghaus, David A1 - Gögele, Martin A1 - Hottenga, Jouke-Jan A1 - Langenberg, Claudia A1 - Kovacs, Peter A1 - O'Reilly, Paul F A1 - Shin, So-Youn A1 - Esko, Tõnu A1 - Hartiala, Jaana A1 - Kanoni, Stavroula A1 - Murgia, Federico A1 - Parsa, Afshin A1 - Stephens, Jonathan A1 - van der Harst, Pim A1 - Ellen van der Schoot, C A1 - Allayee, Hooman A1 - Attwood, Antony A1 - Balkau, Beverley A1 - Bastardot, François A1 - Basu, Saonli A1 - Baumeister, Sebastian E A1 - Biino, Ginevra A1 - Bomba, Lorenzo A1 - Bonnefond, Amélie A1 - Cambien, Francois A1 - Chambers, John C A1 - Cucca, Francesco A1 - D'Adamo, Pio A1 - Davies, Gail A1 - de Boer, Rudolf A A1 - de Geus, Eco J C A1 - Döring, Angela A1 - Elliott, Paul A1 - Erdmann, Jeanette A1 - Evans, David M A1 - Falchi, Mario A1 - Feng, Wei A1 - Folsom, Aaron R A1 - Frazer, Ian H A1 - Gibson, Quince D A1 - Glazer, Nicole L A1 - Hammond, Chris A1 - Hartikainen, Anna-Liisa A1 - Heckbert, Susan R A1 - Hengstenberg, Christian A1 - Hersch, Micha A1 - Illig, Thomas A1 - Loos, Ruth J F A1 - Jolley, Jennifer A1 - Khaw, Kay Tee A1 - Kuhnel, Brigitte A1 - Kyrtsonis, Marie-Christine A1 - Lagou, Vasiliki A1 - Lloyd-Jones, Heather A1 - Lumley, Thomas A1 - Mangino, Massimo A1 - Maschio, Andrea A1 - Mateo Leach, Irene A1 - McKnight, Barbara A1 - Memari, Yasin A1 - Mitchell, Braxton D A1 - Montgomery, Grant W A1 - Nakamura, Yusuke A1 - Nauck, Matthias A1 - Navis, Gerjan A1 - Nöthlings, Ute A1 - Nolte, Ilja M A1 - Porteous, David J A1 - Pouta, Anneli A1 - Pramstaller, Peter P A1 - Pullat, Janne A1 - Ring, Susan M A1 - Rotter, Jerome I A1 - Ruggiero, Daniela A1 - Ruokonen, Aimo A1 - Sala, Cinzia A1 - Samani, Nilesh J A1 - Sambrook, Jennifer A1 - Schlessinger, David A1 - Schreiber, Stefan A1 - Schunkert, Heribert A1 - Scott, James A1 - Smith, Nicholas L A1 - Snieder, Harold A1 - Starr, John M A1 - Stumvoll, Michael A1 - Takahashi, Atsushi A1 - Tang, W H Wilson A1 - Taylor, Kent A1 - Tenesa, Albert A1 - Lay Thein, Swee A1 - Tönjes, Anke A1 - Uda, Manuela A1 - Ulivi, Sheila A1 - van Veldhuisen, Dirk J A1 - Visscher, Peter M A1 - Völker, Uwe A1 - Wichmann, H-Erich A1 - Wiggins, Kerri L A1 - Willemsen, Gonneke A1 - Yang, Tsun-Po A1 - Hua Zhao, Jing A1 - Zitting, Paavo A1 - Bradley, John R A1 - Dedoussis, George V A1 - Gasparini, Paolo A1 - Hazen, Stanley L A1 - Metspalu, Andres A1 - Pirastu, Mario A1 - Shuldiner, Alan R A1 - Joost van Pelt, L A1 - Zwaginga, Jaap-Jan A1 - Boomsma, Dorret I A1 - Deary, Ian J A1 - Franke, Andre A1 - Froguel, Philippe A1 - Ganesh, Santhi K A1 - Jarvelin, Marjo-Riitta A1 - Martin, Nicholas G A1 - Meisinger, Christa A1 - Psaty, Bruce M A1 - Spector, Timothy D A1 - Wareham, Nicholas J A1 - Akkerman, Jan-Willem N A1 - Ciullo, Marina A1 - Deloukas, Panos A1 - Greinacher, Andreas A1 - Jupe, Steve A1 - Kamatani, Naoyuki A1 - Khadake, Jyoti A1 - Kooner, Jaspal S A1 - Penninger, Josef A1 - Prokopenko, Inga A1 - Stemple, Derek A1 - Toniolo, Daniela A1 - Wernisch, Lorenz A1 - Sanna, Serena A1 - Hicks, Andrew A A1 - Rendon, Augusto A1 - Ferreira, Manuel A A1 - Ouwehand, Willem H A1 - Soranzo, Nicole KW - Animals KW - Blood Platelets KW - Cell Size KW - Drosophila melanogaster KW - Drosophila Proteins KW - Europe KW - Gene Expression Profiling KW - Gene Silencing KW - Genome, Human KW - Genome-Wide Association Study KW - Hematopoiesis KW - Humans KW - Megakaryocytes KW - Platelet Count KW - Protein Interaction Maps KW - Transcription, Genetic KW - Zebrafish KW - Zebrafish Proteins AB -

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.

VL - 480 IS - 7376 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22139419?dopt=Abstract ER - TY - JOUR T1 - Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies. JF - Lancet Neurol Y1 - 2012 A1 - Traylor, Matthew A1 - Farrall, Martin A1 - Holliday, Elizabeth G A1 - Sudlow, Cathie A1 - Hopewell, Jemma C A1 - Cheng, Yu-Ching A1 - Fornage, Myriam A1 - Ikram, M Arfan A1 - Malik, Rainer A1 - Bevan, Steve A1 - Thorsteinsdottir, Unnur A1 - Nalls, Mike A A1 - Longstreth, Wt A1 - Wiggins, Kerri L A1 - Yadav, Sunaina A1 - Parati, Eugenio A A1 - DeStefano, Anita L A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Khan, Muhammad Saleem A1 - Reiner, Alex P A1 - Helgadottir, Anna A1 - Achterberg, Sefanja A1 - Fernandez-Cadenas, Israel A1 - Abboud, Sherine A1 - Schmidt, Reinhold A1 - Walters, Matthew A1 - Chen, Wei-Min A1 - Ringelstein, E Bernd A1 - O'Donnell, Martin A1 - Ho, Weang Kee A1 - Pera, Joanna A1 - Lemmens, Robin A1 - Norrving, Bo A1 - Higgins, Peter A1 - Benn, Marianne A1 - Sale, Michele A1 - Kuhlenbäumer, Gregor A1 - Doney, Alexander S F A1 - Vicente, Astrid M A1 - Delavaran, Hossein A1 - Algra, Ale A1 - Davies, Gail A1 - Oliveira, Sofia A A1 - Palmer, Colin N A A1 - Deary, Ian A1 - Schmidt, Helena A1 - Pandolfo, Massimo A1 - Montaner, Joan A1 - Carty, Cara A1 - de Bakker, Paul I W A1 - Kostulas, Konstantinos A1 - Ferro, Jose M A1 - van Zuydam, Natalie R A1 - Valdimarsson, Einar A1 - Nordestgaard, Børge G A1 - Lindgren, Arne A1 - Thijs, Vincent A1 - Slowik, Agnieszka A1 - Saleheen, Danish A1 - Paré, Guillaume A1 - Berger, Klaus A1 - Thorleifsson, Gudmar A1 - Hofman, Albert A1 - Mosley, Thomas H A1 - Mitchell, Braxton D A1 - Furie, Karen A1 - Clarke, Robert A1 - Levi, Christopher A1 - Seshadri, Sudha A1 - Gschwendtner, Andreas A1 - Boncoraglio, Giorgio B A1 - Sharma, Pankaj A1 - Bis, Joshua C A1 - Gretarsdottir, Solveig A1 - Psaty, Bruce M A1 - Rothwell, Peter M A1 - Rosand, Jonathan A1 - Meschia, James F A1 - Stefansson, Kari A1 - Dichgans, Martin A1 - Markus, Hugh S KW - Brain Ischemia KW - Databases, Genetic KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Risk Factors KW - Stroke AB -

BACKGROUND: Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.

METHODS: We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.

FINDINGS: We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10(-16)) and ZFHX3 (p=2·28×10(-8)), and for large-vessel stroke at a 9p21 locus (p=3·32×10(-5)) and HDAC9 (p=2·03×10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10(-6). However, we were unable to replicate any of these novel associations in the replication cohort.

INTERPRETATION: Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.

FUNDING: Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).

VL - 11 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23041239?dopt=Abstract ER - TY - JOUR T1 - Genetic loci for retinal arteriolar microcirculation. JF - PLoS One Y1 - 2013 A1 - Sim, Xueling A1 - Jensen, Richard A A1 - Ikram, M Kamran A1 - Cotch, Mary Frances A1 - Li, Xiaohui A1 - Macgregor, Stuart A1 - Xie, Jing A1 - Smith, Albert Vernon A1 - Boerwinkle, Eric A1 - Mitchell, Paul A1 - Klein, Ronald A1 - Klein, Barbara E K A1 - Glazer, Nicole L A1 - Lumley, Thomas A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - de Jong, Paulus T V M A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Harris, Tamara B A1 - Jonasson, Fridbert A1 - Launer, Lenore J A1 - Attia, John A1 - Baird, Paul N A1 - Harrap, Stephen A1 - Holliday, Elizabeth G A1 - Inouye, Michael A1 - Rochtchina, Elena A1 - Scott, Rodney J A1 - Viswanathan, Ananth A1 - Li, Guo A1 - Smith, Nicholas L A1 - Wiggins, Kerri L A1 - Kuo, Jane Z A1 - Taylor, Kent D A1 - Hewitt, Alex W A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - Sun, Cong A1 - Young, Terri L A1 - Mackey, David A A1 - van Zuydam, Natalie R A1 - Doney, Alex S F A1 - Palmer, Colin N A A1 - Morris, Andrew D A1 - Rotter, Jerome I A1 - Tai, E Shyong A1 - Gudnason, Vilmundur A1 - Vingerling, Johannes R A1 - Siscovick, David S A1 - Wang, Jie Jin A1 - Wong, Tien Y KW - Aged KW - Aged, 80 and over KW - Arterioles KW - Chromosomes, Human, Pair 5 KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - MEF2 Transcription Factors KW - Microcirculation KW - Middle Aged KW - Models, Genetic KW - Retinal Vessels AB -

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.

VL - 8 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23776548?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study of retinopathy in individuals without diabetes. JF - PLoS One Y1 - 2013 A1 - Jensen, Richard A A1 - Sim, Xueling A1 - Li, Xiaohui A1 - Cotch, Mary Frances A1 - Ikram, M Kamran A1 - Holliday, Elizabeth G A1 - Eiriksdottir, Gudny A1 - Harris, Tamara B A1 - Jonasson, Fridbert A1 - Klein, Barbara E K A1 - Launer, Lenore J A1 - Smith, Albert Vernon A1 - Boerwinkle, Eric A1 - Cheung, Ning A1 - Hewitt, Alex W A1 - Liew, Gerald A1 - Mitchell, Paul A1 - Wang, Jie Jin A1 - Attia, John A1 - Scott, Rodney A1 - Glazer, Nicole L A1 - Lumley, Thomas A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - Taylor, Kent A1 - Hofman, Albert A1 - de Jong, Paulus T V M A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Tay, Wan-Ting A1 - Teo, Yik Ying A1 - Seielstad, Mark A1 - Liu, Jianjun A1 - Cheng, Ching-Yu A1 - Saw, Seang-Mei A1 - Aung, Tin A1 - Ganesh, Santhi K A1 - O'Donnell, Christopher J A1 - Nalls, Mike A A1 - Wiggins, Kerri L A1 - Kuo, Jane Z A1 - van Duijn, Cornelia M A1 - Gudnason, Vilmundur A1 - Klein, Ronald A1 - Siscovick, David S A1 - Rotter, Jerome I A1 - Tai, E Shong A1 - Vingerling, Johannes A1 - Wong, Tien Y KW - Aged KW - Aged, 80 and over KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Histone Deacetylases KW - Humans KW - Hypertension KW - Male KW - Polymorphism, Single Nucleotide KW - Repressor Proteins KW - Retinal Diseases AB -

BACKGROUND: Mild 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.

METHODS: A 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.

RESULTS: No 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.

CONCLUSIONS: This 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.

VL - 8 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23393555?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study of L-arginine and dimethylarginines reveals novel metabolic pathway for symmetric dimethylarginine. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - Lüneburg, Nicole A1 - Lieb, Wolfgang A1 - Zeller, Tanja A1 - Chen, Ming-Huei A1 - Maas, Renke A1 - Carter, Angela M A1 - Xanthakis, Vanessa A1 - Glazer, Nicole L A1 - Schwedhelm, Edzard A1 - Seshadri, Sudha A1 - Ikram, Mohammad Arfan A1 - Longstreth, William T A1 - Fornage, Myriam A1 - König, Inke R A1 - Loley, Christina A1 - Ojeda, Francisco M A1 - Schillert, Arne A1 - Wang, Thomas J A1 - Sticht, Heinrich A1 - Kittel, Anja A1 - König, Jörg A1 - Benjamin, Emelia J A1 - Sullivan, Lisa M A1 - Bernges, Isabel A1 - Anderssohn, Maike A1 - Ziegler, Andreas A1 - Gieger, Christian A1 - Illig, Thomas A1 - Meisinger, Christa A1 - Wichmann, H-Erich A1 - Wild, Philipp S A1 - Schunkert, Heribert A1 - Psaty, Bruce M A1 - Wiggins, Kerri L A1 - Heckbert, Susan R A1 - Smith, Nicholas A1 - Lackner, Karl A1 - Lunetta, Kathryn L A1 - Blankenberg, Stefan A1 - Erdmann, Jeanette A1 - Münzel, Thomas A1 - Grant, Peter J A1 - Vasan, Ramachandran S A1 - Böger, Rainer H KW - Adult KW - Aged KW - Amidohydrolases KW - Arginine KW - Binding Sites KW - Cohort Studies KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - HEK293 Cells KW - Humans KW - Male KW - Mediator Complex KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Protein Structure, Tertiary KW - Risk Factors KW - Stroke KW - Substrate Specificity KW - Transaminases AB -

BACKGROUND: Dimethylarginines (DMA) interfere with nitric oxide formation by inhibiting nitric oxide synthase (asymmetrical DMA [ADMA]) and l-arginine uptake into the cell (ADMA and symmetrical DMA [SDMA]). In prospective clinical studies, ADMA has been characterized as a cardiovascular risk marker, whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterize the environmental and genetic contributions to interindividual variability of these biomarkers.

METHODS AND RESULTS: This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (Framingham Heart Study [FHS; n=2992], Gutenberg Health Study [GHS; n=4354], and Multinational Monitoring of Trends and Determinants in Cardiovascular Disease Study [MONICA]/Cooperative Health Research in the Augsburg Area, Augsburg, Bavaria, Germany [KORA] F3 [n=581]) and identified replicated loci (DDAH1, MED23, Arg1, and AGXT2) associated with the interindividual variability in ADMA, l-arginine, and SDMA. Experimental in silico and in vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants, and various cardiometabolic risk factors. AGXT2 variants were not associated with poststroke survival in the Leeds study or were they associated with incident stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

CONCLUSIONS: These genome-wide association study support the importance of DDAH1 and MED23/Arg1 in regulating ADMA and l-arginine metabolism, respectively, and identify a novel regulatory renal pathway for SDMA by AGXT2. AGXT2 variants might explain part of the pathogenic link between SDMA, renal function, and outcome. An association between AGXT2 variants and stroke is unclear and warrants further investigation.

VL - 7 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25245031?dopt=Abstract ER - TY - JOUR T1 - Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins. JF - Nat Commun Y1 - 2014 A1 - Postmus, Iris A1 - Trompet, Stella A1 - Deshmukh, Harshal A A1 - Barnes, Michael R A1 - Li, Xiaohui A1 - Warren, Helen R A1 - Chasman, Daniel I A1 - Zhou, Kaixin A1 - Arsenault, Benoit J A1 - Donnelly, Louise A A1 - Wiggins, Kerri L A1 - Avery, Christy L A1 - Griffin, Paula A1 - Feng, QiPing A1 - Taylor, Kent D A1 - Li, Guo A1 - Evans, Daniel S A1 - Smith, Albert V A1 - de Keyser, Catherine E A1 - Johnson, Andrew D A1 - de Craen, Anton J M A1 - Stott, David J A1 - Buckley, Brendan M A1 - Ford, Ian A1 - Westendorp, Rudi G J A1 - Slagboom, P Eline A1 - Sattar, Naveed A1 - Munroe, Patricia B A1 - Sever, Peter A1 - Poulter, Neil A1 - Stanton, Alice A1 - Shields, Denis C A1 - O'Brien, Eoin A1 - Shaw-Hawkins, Sue A1 - Chen, Y-D Ida A1 - Nickerson, Deborah A A1 - Smith, Joshua D A1 - Dubé, Marie Pierre A1 - Boekholdt, S Matthijs A1 - Hovingh, G Kees A1 - Kastelein, John J P A1 - McKeigue, Paul M A1 - Betteridge, John A1 - Neil, Andrew A1 - Durrington, Paul N A1 - Doney, Alex A1 - Carr, Fiona A1 - Morris, Andrew A1 - McCarthy, Mark I A1 - Groop, Leif A1 - Ahlqvist, Emma A1 - Bis, Joshua C A1 - Rice, Kenneth A1 - Smith, Nicholas L A1 - Lumley, Thomas A1 - Whitsel, Eric A A1 - Stürmer, Til A1 - Boerwinkle, Eric A1 - Ngwa, Julius S A1 - O'Donnell, Christopher J A1 - Vasan, Ramachandran S A1 - Wei, Wei-Qi A1 - Wilke, Russell A A1 - Liu, Ching-Ti A1 - Sun, Fangui A1 - Guo, Xiuqing A1 - Heckbert, Susan R A1 - Post, Wendy A1 - Sotoodehnia, Nona A1 - Arnold, Alice M A1 - Stafford, Jeanette M A1 - Ding, Jingzhong A1 - Herrington, David M A1 - Kritchevsky, Stephen B A1 - Eiriksdottir, Gudny A1 - Launer, Leonore J A1 - Harris, Tamara B A1 - Chu, Audrey Y A1 - Giulianini, Franco A1 - MacFadyen, Jean G A1 - Barratt, Bryan J A1 - Nyberg, Fredrik A1 - Stricker, Bruno H A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Emilsson, Valur A1 - Franco, Oscar H A1 - Ridker, Paul M A1 - Gudnason, Vilmundur A1 - Liu, Yongmei A1 - Denny, Joshua C A1 - Ballantyne, Christie M A1 - Rotter, Jerome I A1 - Adrienne Cupples, L A1 - Psaty, Bruce M A1 - Palmer, Colin N A A1 - Tardif, Jean-Claude A1 - Colhoun, Helen M A1 - Hitman, Graham A1 - Krauss, Ronald M A1 - Wouter Jukema, J A1 - Caulfield, Mark J KW - Cholesterol, LDL KW - Genome-Wide Association Study KW - Humans KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors KW - Pharmacogenetics KW - Polymorphism, Single Nucleotide AB -

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

VL - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25350695?dopt=Abstract ER - TY - JOUR T1 - Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium. JF - PLoS One Y1 - 2015 A1 - Bis, Joshua C A1 - Sitlani, Colleen A1 - Irvin, Ryan A1 - Avery, Christy L A1 - Smith, Albert Vernon A1 - Sun, Fangui A1 - Evans, Daniel S A1 - Musani, Solomon K A1 - Li, Xiaohui A1 - Trompet, Stella A1 - Krijthe, Bouwe P A1 - Harris, Tamara B A1 - Quibrera, P Miguel A1 - Brody, Jennifer A A1 - Demissie, Serkalem A1 - Davis, Barry R A1 - Wiggins, Kerri L A1 - Tranah, Gregory J A1 - Lange, Leslie A A1 - Sotoodehnia, Nona A1 - Stott, David J A1 - Franco, Oscar H A1 - Launer, Lenore J A1 - Stürmer, Til A1 - Taylor, Kent D A1 - Cupples, L Adrienne A1 - Eckfeldt, John H A1 - Smith, Nicholas L A1 - Liu, Yongmei A1 - Wilson, James G A1 - Heckbert, Susan R A1 - Buckley, Brendan M A1 - Ikram, M Arfan A1 - Boerwinkle, Eric A1 - Chen, Yii-Der Ida A1 - de Craen, Anton J M A1 - Uitterlinden, André G A1 - Rotter, Jerome I A1 - Ford, Ian A1 - Hofman, Albert A1 - Sattar, Naveed A1 - Slagboom, P Eline A1 - Westendorp, Rudi G J A1 - Gudnason, Vilmundur A1 - Vasan, Ramachandran S A1 - Lumley, Thomas A1 - Cummings, Steven R A1 - Taylor, Herman A A1 - Post, Wendy A1 - Jukema, J Wouter A1 - Stricker, Bruno H A1 - Whitsel, Eric A A1 - Psaty, Bruce M A1 - Arnett, Donna KW - African Americans KW - Aged KW - Antihypertensive Agents KW - Cardiovascular Diseases KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Incidence KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Treatment Outcome AB -

BACKGROUND: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.

METHODS: Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).

RESULTS: Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.

VL - 10 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26516778?dopt=Abstract ER - TY - JOUR T1 - Genetic overlap between diagnostic subtypes of ischemic stroke. JF - Stroke Y1 - 2015 A1 - Holliday, Elizabeth G A1 - Traylor, Matthew A1 - Malik, Rainer A1 - Bevan, Steve A1 - Falcone, Guido A1 - Hopewell, Jemma C A1 - Cheng, Yu-Ching A1 - Cotlarciuc, Ioana A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Boncoraglio, Giorgio B A1 - Clarke, Robert A1 - Cole, John W A1 - Fornage, Myriam A1 - Furie, Karen L A1 - Ikram, M Arfan A1 - Jannes, Jim A1 - Kittner, Steven J A1 - Lincz, Lisa F A1 - Maguire, Jane M A1 - Meschia, James F A1 - Mosley, Thomas H A1 - Nalls, Mike A A1 - Oldmeadow, Christopher A1 - Parati, Eugenio A A1 - Psaty, Bruce M A1 - Rothwell, Peter M A1 - Seshadri, Sudha A1 - Scott, Rodney J A1 - Sharma, Pankaj A1 - Sudlow, Cathie A1 - Wiggins, Kerri L A1 - Worrall, Bradford B A1 - Rosand, Jonathan A1 - Mitchell, Braxton D A1 - Dichgans, Martin A1 - Markus, Hugh S A1 - Levi, Christopher A1 - Attia, John A1 - Wray, Naomi R KW - Alleles KW - Atherosclerosis KW - Cerebral Small Vessel Diseases KW - Cohort Studies KW - Data Interpretation, Statistical KW - Embolism KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Ischemia KW - Linear Models KW - Meta-Analysis as Topic KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Stroke AB -

BACKGROUND AND PURPOSE: Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses.

METHODS: Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles.

RESULTS: High genetic correlation was identified between LAA and SVD using linear mixed models (rg=0.96, SE=0.47, P=9×10(-4)) and profile scores (rg=0.72; 95% confidence interval, 0.52-0.93). Between LAA and cardioembolism and SVD and cardioembolism, correlation was moderate using linear mixed models but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association (P=1×10(-7)) for single nucleotide polymorphisms near the opioid receptor μ1 (OPRM1) gene.

CONCLUSIONS: Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes.

VL - 46 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25613305?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism. JF - Am J Hum Genet Y1 - 2015 A1 - Germain, Marine A1 - Chasman, Daniel I A1 - de Haan, Hugoline A1 - Tang, Weihong A1 - Lindström, Sara A1 - Weng, Lu-Chen A1 - de Andrade, Mariza A1 - de Visser, Marieke C H A1 - Wiggins, Kerri L A1 - Suchon, Pierre A1 - Saut, Noémie A1 - Smadja, David M A1 - Le Gal, Grégoire A1 - van Hylckama Vlieg, Astrid A1 - Di Narzo, Antonio A1 - Hao, Ke A1 - Nelson, Christopher P A1 - Rocanin-Arjo, Ares A1 - Folkersen, Lasse A1 - Monajemi, Ramin A1 - Rose, Lynda M A1 - Brody, Jennifer A A1 - Slagboom, Eline A1 - Aïssi, Dylan A1 - Gagnon, France A1 - Deleuze, Jean-Francois A1 - Deloukas, Panos A1 - Tzourio, Christophe A1 - Dartigues, Jean-François A1 - Berr, Claudine A1 - Taylor, Kent D A1 - Civelek, Mete A1 - Eriksson, Per A1 - Psaty, Bruce M A1 - Houwing-Duitermaat, Jeanine A1 - Goodall, Alison H A1 - Cambien, Francois A1 - Kraft, Peter A1 - Amouyel, Philippe A1 - Samani, Nilesh J A1 - Basu, Saonli A1 - Ridker, Paul M A1 - Rosendaal, Frits R A1 - Kabrhel, Christopher A1 - Folsom, Aaron R A1 - Heit, John A1 - Reitsma, Pieter H A1 - Trégouët, David-Alexandre A1 - Smith, Nicholas L A1 - Morange, Pierre-Emmanuel KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Membrane Glycoproteins KW - Membrane Transport Proteins KW - Odds Ratio KW - Tetraspanins KW - Venous Thromboembolism AB -

Venous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE. Nine loci reached the genome-wide significance level of 5 × 10(-8) including six already known to associate with VTE (ABO, F2, F5, F11, FGG, and PROCR) and three unsuspected loci. SNPs mapping to these latter were selected for replication in three independent case-control studies totaling 3,009 VTE-affected individuals and 2,586 control subjects. This strategy led to the identification and replication of two VTE-associated loci, TSPAN15 and SLC44A2, with lead risk alleles associated with odds ratio for disease of 1.31 (p = 1.67 × 10(-16)) and 1.21 (p = 2.75 × 10(-15)), respectively. The lead SNP at the TSPAN15 locus is the intronic rs78707713 and the lead SLC44A2 SNP is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury. We further showed that these two variants did not associate with known hemostatic plasma markers. TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers. Our findings uncovered unexpected actors of VTE etiology and pave the way for novel mechanistic concepts of VTE pathophysiology.

VL - 96 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25772935?dopt=Abstract ER - TY - JOUR T1 - Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF. JF - Blood Y1 - 2015 A1 - Huffman, Jennifer E A1 - de Vries, Paul S A1 - Morrison, Alanna C A1 - Sabater-Lleal, Maria A1 - Kacprowski, Tim A1 - Auer, Paul L A1 - Brody, Jennifer A A1 - Chasman, Daniel I A1 - Chen, Ming-Huei A1 - Guo, Xiuqing A1 - Lin, Li-An A1 - Marioni, Riccardo E A1 - Müller-Nurasyid, Martina A1 - Yanek, Lisa R A1 - Pankratz, Nathan A1 - Grove, Megan L A1 - de Maat, Moniek P M A1 - Cushman, Mary A1 - Wiggins, Kerri L A1 - Qi, Lihong A1 - Sennblad, Bengt A1 - Harris, Sarah E A1 - Polasek, Ozren A1 - Riess, Helene A1 - Rivadeneira, Fernando A1 - Rose, Lynda M A1 - Goel, Anuj A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Uitterlinden, André G A1 - Vaidya, Dhananjay A1 - Yao, Jie A1 - Tang, Weihong A1 - Levy, Daniel A1 - Waldenberger, Melanie A1 - Becker, Diane M A1 - Folsom, Aaron R A1 - Giulianini, Franco A1 - Greinacher, Andreas A1 - Hofman, Albert A1 - Huang, Chiang-Ching A1 - Kooperberg, Charles A1 - Silveira, Angela A1 - Starr, John M A1 - Strauch, Konstantin A1 - Strawbridge, Rona J A1 - Wright, Alan F A1 - McKnight, Barbara A1 - Franco, Oscar H A1 - Zakai, Neil A1 - Mathias, Rasika A A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Tofler, Geoffrey H A1 - Völker, Uwe A1 - Watkins, Hugh A1 - Fornage, Myriam A1 - Hamsten, Anders A1 - Deary, Ian J A1 - Boerwinkle, Eric A1 - Koenig, Wolfgang A1 - Rotter, Jerome I A1 - Hayward, Caroline A1 - Dehghan, Abbas A1 - Reiner, Alex P A1 - O'Donnell, Christopher J A1 - Smith, Nicholas L KW - Cohort Studies KW - Factor VII KW - Factor VIII KW - Fibrinogen KW - Gene Frequency KW - Genetic Association Studies KW - Genetic Variation KW - Humans KW - Nerve Tissue Proteins KW - Polymorphism, Single Nucleotide KW - Potassium Channels KW - von Willebrand Factor AB -

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.

VL - 126 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26105150?dopt=Abstract ER - TY - JOUR T1 - Variation in resting heart rate over 4 years and the risks of myocardial infarction and death among older adults. JF - Heart Y1 - 2015 A1 - Floyd, James S A1 - Sitlani, Colleen M A1 - Wiggins, Kerri L A1 - Wallace, Erin A1 - Suchy-Dicey, Astrid A1 - Abbasi, Siddique A A1 - Carnethon, Mercedes R A1 - Siscovick, David S A1 - Sotoodehnia, Nona A1 - Heckbert, Susan R A1 - McKnight, Barbara A1 - Rice, Kenneth M A1 - Psaty, Bruce M KW - Aged KW - Aged, 80 and over KW - Cause of Death KW - Electrocardiography KW - Female KW - Follow-Up Studies KW - Heart Rate KW - Humans KW - Incidence KW - Linear Models KW - Male KW - Myocardial Infarction KW - Outcome Assessment (Health Care) KW - Prognosis KW - Proportional Hazards Models KW - Prospective Studies KW - Rest KW - Risk Factors KW - Time KW - Washington AB -

OBJECTIVE: Resting heart rate (RHR) is an established predictor of myocardial infarction (MI) and mortality, but the relationship between variation in RHR over a period of several years and health outcomes is unclear. We evaluated the relationship between long-term variation in RHR and the risks of incident MI and mortality among older adults.

METHODS: 1991 subjects without cardiovascular disease from the Cardiovascular Health Study were included. RHR was taken from resting ECGs at the first five annual study visits. RHR mean, trend and variation were estimated with linear regression. Subjects were followed for incident MI and death until December 2010. HRs for RHR mean, trend and variation are reported for differences of 10 bpm, 2 bpm/year and 2 bpm, respectively.

RESULTS: 262 subjects had an incident MI event (13%) and 1326 died (67%) during 12 years of median follow-up. In primary analyses adjusted for cardiovascular risk factors, RHR mean (HR 1.12; 95% CI 1.05 to 1.20) and variation (HR 1.08; 95% CI 1.03 to 1.13) were associated with the risk of death while trend was not. None of the RHR variables were significantly associated with the risk of incident MI events; however, CIs were wide and the MI associations with RHR variables were not significantly different from the mortality associations. Adjusting for additional variables did not affect estimates, and there were no significant interactions with sex.

CONCLUSIONS: Variation in RHR over a period of several years represents a potential predictor of long-term mortality among older persons free of cardiovascular disease.

VL - 101 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25214500?dopt=Abstract ER - TY - JOUR T1 - DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. JF - Genome Biol Y1 - 2016 A1 - Ligthart, Symen A1 - Marzi, Carola A1 - Aslibekyan, Stella A1 - Mendelson, Michael M A1 - Conneely, Karen N A1 - Tanaka, Toshiko A1 - Colicino, Elena A1 - Waite, Lindsay L A1 - Joehanes, Roby A1 - Guan, Weihua A1 - Brody, Jennifer A A1 - Elks, Cathy A1 - Marioni, Riccardo A1 - Jhun, Min A A1 - Agha, Golareh A1 - Bressler, Jan A1 - Ward-Caviness, Cavin K A1 - Chen, Brian H A1 - Huan, Tianxiao A1 - Bakulski, Kelly A1 - Salfati, Elias L A1 - Fiorito, Giovanni A1 - Wahl, Simone A1 - Schramm, Katharina A1 - Sha, Jin A1 - Hernandez, Dena G A1 - Just, Allan C A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Pilling, Luke C A1 - Pankow, James S A1 - Tsao, Phil S A1 - Liu, Chunyu A1 - Zhao, Wei A1 - Guarrera, Simonetta A1 - Michopoulos, Vasiliki J A1 - Smith, Alicia K A1 - Peters, Marjolein J A1 - Melzer, David A1 - Vokonas, Pantel A1 - Fornage, Myriam A1 - Prokisch, Holger A1 - Bis, Joshua C A1 - Chu, Audrey Y A1 - Herder, Christian A1 - Grallert, Harald A1 - Yao, Chen A1 - Shah, Sonia A1 - McRae, Allan F A1 - Lin, Honghuang A1 - Horvath, Steve A1 - Fallin, Daniele A1 - Hofman, Albert A1 - Wareham, Nicholas J A1 - Wiggins, Kerri L A1 - Feinberg, Andrew P A1 - Starr, John M A1 - Visscher, Peter M A1 - Murabito, Joanne M A1 - Kardia, Sharon L R A1 - Absher, Devin M A1 - Binder, Elisabeth B A1 - Singleton, Andrew B A1 - Bandinelli, Stefania A1 - Peters, Annette A1 - Waldenberger, Melanie A1 - Matullo, Giuseppe A1 - Schwartz, Joel D A1 - Demerath, Ellen W A1 - Uitterlinden, André G A1 - van Meurs, Joyce B J A1 - Franco, Oscar H A1 - Chen, Yii-Der Ida A1 - Levy, Daniel A1 - Turner, Stephen T A1 - Deary, Ian J A1 - Ressler, Kerry J A1 - Dupuis, Josée A1 - Ferrucci, Luigi A1 - Ong, Ken K A1 - Assimes, Themistocles L A1 - Boerwinkle, Eric A1 - Koenig, Wolfgang A1 - Arnett, Donna K A1 - Baccarelli, Andrea A A1 - Benjamin, Emelia J A1 - Dehghan, Abbas AB -

BACKGROUND: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.

RESULTS: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10(-7)) in the discovery panel of European ancestry and replicated (P < 2.29 × 10(-4)) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10(-5)), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10(-3)), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10(-5)). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.

CONCLUSION: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.

VL - 17 IS - 1 ER - TY - JOUR T1 - Meta-analysis of genome-wide association studies of HDL cholesterol response to statins. JF - J Med Genet Y1 - 2016 A1 - Postmus, Iris A1 - Warren, Helen R A1 - Trompet, Stella A1 - Arsenault, Benoit J A1 - Avery, Christy L A1 - Bis, Joshua C A1 - Chasman, Daniel I A1 - de Keyser, Catherine E A1 - Deshmukh, Harshal A A1 - Evans, Daniel S A1 - Feng, QiPing A1 - Li, Xiaohui A1 - Smit, Roelof A J A1 - Smith, Albert V A1 - Sun, Fangui A1 - Taylor, Kent D A1 - Arnold, Alice M A1 - Barnes, Michael R A1 - Barratt, Bryan J A1 - Betteridge, John A1 - Boekholdt, S Matthijs A1 - Boerwinkle, Eric A1 - Buckley, Brendan M A1 - Chen, Y-D Ida A1 - de Craen, Anton J M A1 - Cummings, Steven R A1 - Denny, Joshua C A1 - Dubé, Marie Pierre A1 - Durrington, Paul N A1 - Eiriksdottir, Gudny A1 - Ford, Ian A1 - Guo, Xiuqing A1 - Harris, Tamara B A1 - Heckbert, Susan R A1 - Hofman, Albert A1 - Hovingh, G Kees A1 - Kastelein, John J P A1 - Launer, Leonore J A1 - Liu, Ching-Ti A1 - Liu, Yongmei A1 - Lumley, Thomas A1 - McKeigue, Paul M A1 - Munroe, Patricia B A1 - Neil, Andrew A1 - Nickerson, Deborah A A1 - Nyberg, Fredrik A1 - O'Brien, Eoin A1 - O'Donnell, Christopher J A1 - Post, Wendy A1 - Poulter, Neil A1 - Vasan, Ramachandran S A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Rivadeneira, Fernando A1 - Sattar, Naveed A1 - Sever, Peter A1 - Shaw-Hawkins, Sue A1 - Shields, Denis C A1 - Slagboom, P Eline A1 - Smith, Nicholas L A1 - Smith, Joshua D A1 - Sotoodehnia, Nona A1 - Stanton, Alice A1 - Stott, David J A1 - Stricker, Bruno H A1 - Stürmer, Til A1 - Uitterlinden, André G A1 - Wei, Wei-Qi A1 - Westendorp, Rudi G J A1 - Whitsel, Eric A A1 - Wiggins, Kerri L A1 - Wilke, Russell A A1 - Ballantyne, Christie M A1 - Colhoun, Helen M A1 - Cupples, L Adrienne A1 - Franco, Oscar H A1 - Gudnason, Vilmundur A1 - Hitman, Graham A1 - Palmer, Colin N A A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Stafford, Jeanette M A1 - Stein, Charles M A1 - Tardif, Jean-Claude A1 - Caulfield, Mark J A1 - Jukema, J Wouter A1 - Rotter, Jerome I A1 - Krauss, Ronald M AB -

BACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.

METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1×10(-4) from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5×10(-8)) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment.

CONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.

VL - 53 IS - 12 ER - TY - JOUR T1 - A genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. JF - J Med Genet Y1 - 2017 A1 - Noordam, Raymond A1 - Sitlani, Colleen M A1 - Avery, Christy L A1 - Stewart, James D A1 - Gogarten, Stephanie M A1 - Wiggins, Kerri L A1 - Trompet, Stella A1 - Warren, Helen R A1 - Sun, Fangui A1 - Evans, Daniel S A1 - Li, Xiaohui A1 - Li, Jin A1 - Smith, Albert V A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Busch, Evan L A1 - Caulfield, Mark J A1 - Chen, Yii-der I A1 - Cummings, Steven R A1 - Cupples, L Adrienne A1 - Duan, Qing A1 - Franco, Oscar H A1 - Méndez-Giráldez, Rául A1 - Harris, Tamara B A1 - Heckbert, Susan R A1 - van Heemst, Diana A1 - Hofman, Albert A1 - Floyd, James S A1 - Kors, Jan A A1 - Launer, Lenore J A1 - Li, Yun A1 - Li-Gao, Ruifang A1 - Lange, Leslie A A1 - Lin, Henry J A1 - de Mutsert, Renée A1 - Napier, Melanie D A1 - Newton-Cheh, Christopher A1 - Poulter, Neil A1 - Reiner, Alexander P A1 - Rice, Kenneth M A1 - Roach, Jeffrey A1 - Rodriguez, Carlos J A1 - Rosendaal, Frits R A1 - Sattar, Naveed A1 - Sever, Peter A1 - Seyerle, Amanda A A1 - Slagboom, P Eline A1 - Soliman, Elsayed Z A1 - Sotoodehnia, Nona A1 - Stott, David J A1 - Stürmer, Til A1 - Taylor, Kent D A1 - Thornton, Timothy A A1 - Uitterlinden, André G A1 - Wilhelmsen, Kirk C A1 - Wilson, James G A1 - Gudnason, Vilmundur A1 - Jukema, J Wouter A1 - Laurie, Cathy C A1 - Liu, Yongmei A1 - Mook-Kanamori, Dennis O A1 - Munroe, Patricia B A1 - Rotter, Jerome I A1 - Vasan, Ramachandran S A1 - Psaty, Bruce M A1 - Stricker, Bruno H A1 - Whitsel, Eric A AB -

BACKGROUND: Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals.

METHODS AND RESULTS: We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, pinteraction=3.9e(-9)) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e(-8)). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, pinteraction=2.55e(-8)). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (pinteraction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries.

CONCLUSIONS: Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.

VL - 54 IS - 5 ER - TY - JOUR T1 - PCSK9 Loss-of-Function Variants, Low-Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke: Data From 9 Studies of Blacks and Whites. JF - Circ Cardiovasc Genet Y1 - 2017 A1 - Kent, Shia T A1 - Rosenson, Robert S A1 - Avery, Christy L A1 - Chen, Yii-der I A1 - Correa, Adolfo A1 - Cummings, Steven R A1 - Cupples, L Adrienne A1 - Cushman, Mary A1 - Evans, Daniel S A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Howard, George A1 - Irvin, Marguerite R A1 - Judd, Suzanne E A1 - Jukema, J Wouter A1 - Lange, Leslie A1 - Levitan, Emily B A1 - Li, Xiaohui A1 - Liu, Yongmei A1 - Post, Wendy S A1 - Postmus, Iris A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Safford, Monika M A1 - Sitlani, Colleen M A1 - Smith, Albert V A1 - Stewart, James D A1 - Trompet, Stella A1 - Sun, Fangui A1 - Vasan, Ramachandran S A1 - Woolley, J Michael A1 - Whitsel, Eric A A1 - Wiggins, Kerri L A1 - Wilson, James G A1 - Muntner, Paul AB -

BACKGROUND: PCSK9 loss-of-function (LOF) variants allow for the examination of the effects of lifetime reduced low-density lipoprotein cholesterol (LDL-C) on cardiovascular events. We examined the association of PCSK9 LOF variants with LDL-C and incident coronary heart disease and stroke through a meta-analysis of data from 8 observational cohorts and 1 randomized trial of statin therapy.

METHODS AND RESULTS: These 9 studies together included 17 459 blacks with 403 (2.3%) having at least 1 Y142X or C679X variant and 31 306 whites with 955 (3.1%) having at least 1 R46L variant. Unadjusted odds ratios for associations between PCSK9 LOF variants and incident coronary heart disease (851 events in blacks and 2662 events in whites) and stroke (523 events in blacks and 1660 events in whites) were calculated using pooled Mantel-Haenszel estimates with continuity correction factors. Pooling results across studies using fixed-effects inverse-variance-weighted models, PCSK9 LOF variants were associated with 35 mg/dL (95% confidence interval [CI], 32-39) lower LDL-C in blacks and 13 mg/dL (95% CI, 11-16) lower LDL-C in whites. PCSK9 LOF variants were associated with a pooled odds ratio for coronary heart disease of 0.51 (95% CI, 0.28-0.92) in blacks and 0.82 (95% CI, 0.63-1.06) in whites. PCSK9 LOF variants were not associated with incident stroke (odds ratio, 0.84; 95% CI, 0.48-1.47 in blacks and odds ratio, 1.06; 95% CI, 0.80-1.41 in whites).

CONCLUSIONS: PCSK9 LOF variants were associated with lower LDL-C and coronary heart disease incidence. PCSK9 LOF variants were not associated with stroke risk.

VL - 10 IS - 4 ER - TY - JOUR T1 - Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations. JF - PLoS Genet Y1 - 2017 A1 - Liang, Jingjing A1 - Le, Thu H A1 - Edwards, Digna R Velez A1 - Tayo, Bamidele O A1 - Gaulton, Kyle J A1 - Smith, Jennifer A A1 - Lu, Yingchang A1 - Jensen, Richard A A1 - Chen, Guanjie A1 - Yanek, Lisa R A1 - Schwander, Karen A1 - Tajuddin, Salman M A1 - Sofer, Tamar A1 - Kim, Wonji A1 - Kayima, James A1 - McKenzie, Colin A A1 - Fox, Ervin A1 - Nalls, Michael A A1 - Young, J Hunter A1 - Sun, Yan V A1 - Lane, Jacqueline M A1 - Cechova, Sylvia A1 - Zhou, Jie A1 - Tang, Hua A1 - Fornage, Myriam A1 - Musani, Solomon K A1 - Wang, Heming A1 - Lee, Juyoung A1 - Adeyemo, Adebowale A1 - Dreisbach, Albert W A1 - Forrester, Terrence A1 - Chu, Pei-Lun A1 - Cappola, Anne A1 - Evans, Michele K A1 - Morrison, Alanna C A1 - Martin, Lisa W A1 - Wiggins, Kerri L A1 - Hui, Qin A1 - Zhao, Wei A1 - Jackson, Rebecca D A1 - Ware, Erin B A1 - Faul, Jessica D A1 - Reiner, Alex P A1 - Bray, Michael A1 - Denny, Joshua C A1 - Mosley, Thomas H A1 - Palmas, Walter A1 - Guo, Xiuqing A1 - Papanicolaou, George J A1 - Penman, Alan D A1 - Polak, Joseph F A1 - Rice, Kenneth A1 - Taylor, Ken D A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Liu, Kiang A1 - Risch, Neil A1 - Hunt, Steven C A1 - Kooperberg, Charles A1 - Zonderman, Alan B A1 - Laurie, Cathy C A1 - Becker, Diane M A1 - Cai, Jianwen A1 - Loos, Ruth J F A1 - Psaty, Bruce M A1 - Weir, David R A1 - Kardia, Sharon L R A1 - Arnett, Donna K A1 - Won, Sungho A1 - Edwards, Todd L A1 - Redline, Susan A1 - Cooper, Richard S A1 - Rao, D C A1 - Rotter, Jerome I A1 - Rotimi, Charles A1 - Levy, Daniel A1 - Chakravarti, Aravinda A1 - Zhu, Xiaofeng A1 - Franceschini, Nora KW - African Americans KW - Animals KW - Basic Helix-Loop-Helix Transcription Factors KW - Blood Pressure KW - Cadherins KW - Case-Control Studies KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Male KW - Membrane Proteins KW - Mice KW - Multifactorial Inheritance KW - Polymorphism, Single Nucleotide AB -

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

VL - 13 IS - 5 ER - TY - JOUR T1 - Atrial fibrillation in an African-American cohort: The Jackson Heart Study. JF - Clin Cardiol Y1 - 2018 A1 - Austin, Thomas R A1 - Wiggins, Kerri L A1 - Blackshear, Chad A1 - Yang, Yi A1 - Benjamin, Emelia J A1 - Curtis, Lesley H A1 - Sotoodehnia, Nona A1 - Correa, Adolfo A1 - Heckbert, Susan R AB -

BACKGROUND: Atrial fibrillation (AF) is an important public health problem across race/ethnic groups. Data from US cohort studies initiated in the 1980s suggest a higher prevalence of AF risk factors among African-Americans (AAs) than whites, but lower AF incidence. The Jackson Heart Study (JHS) is a community-based study of 5306 AAs recruited starting in 2000.

HYPOTHESIS: Demographic, anthropometric, cardiovascular, and/or electrocardiographic factors are associated with AF incidence in JHS.

METHODS: Using baseline participant characteristics and incident AF identified through hospital surveillance, study electrocardiogram, and Medicare claims, we estimated age- and sex-specific AF incidence rates, compared them with rates in AA participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and Cardiovascular Health Study (CHS), and examined associations of cardiovascular risk factors with AF.

RESULTS: A total of 66 participants had prevalent AF at baseline. Over an average follow-up of 8.5 years, 242 cases of incident AF were identified. Age- and sex-specific AF incidence rates in JHS were similar to those among AAs in MESA and appeared slightly lower than those among AAs in CHS. In an age- and sex-adjusted model, associations with incident AF were observed for modifiable risk factors: high body weight (HR = 1.23 per 15 kg, 95%CI 1.13-1.35), systolic blood pressure (HR = 1.29 per 20 mmHg, 95%CI 1.13-1.47), and current smoking (HR = 1.80, 95%CI 1.27-2.55). Risk estimates associated with these risk factors were only slightly attenuated after multivariable adjustments.

CONCLUSIONS: These findings underscore the potential additional benefits of interventions for weight management, control of hypertension, and smoking cessation for the prevention of AF among AAs.

ER - TY - JOUR T1 - DNA methylation age is associated with an altered hemostatic profile in a multi-ethnic meta-analysis. JF - Blood Y1 - 2018 A1 - Ward-Caviness, Cavin K A1 - Huffman, Jennifer E A1 - Evertt, Karl A1 - Germain, Marine A1 - van Dongen, Jenny A1 - Hill, W David A1 - Jhun, Min A A1 - Brody, Jennifer A A1 - Ghanbari, Mohsen A1 - Du, Lei A1 - Roetker, Nicholas S A1 - de Vries, Paul S A1 - Waldenberger, Melanie A1 - Gieger, Christian A1 - Wolf, Petra A1 - Prokisch, Holger A1 - Koenig, Wolfgang A1 - O'Donnell, Christopher J A1 - Levy, Daniel A1 - Liu, Chunyu A1 - Truong, Vinh A1 - Wells, Philip S A1 - Trégouët, David-Alexandre A1 - Tang, Weihong A1 - Morrison, Alanna C A1 - Boerwinkle, Eric A1 - Wiggins, Kerri L A1 - McKnight, Barbara A1 - Guo, Xiuqing A1 - Psaty, Bruce M A1 - Sotoodenia, Nona A1 - Boomsa, Dorret I A1 - Willemsen, Gonneke A1 - Ligthart, Lannie A1 - Deary, Ian J A1 - Zhao, Wei A1 - Ware, Erin B A1 - Kardia, Sharon L R A1 - van Meurs, Joyce B J A1 - Uitterlinden, André G A1 - Franco, Oscar H A1 - Eriksson, Per A1 - Franco-Cereceda, Anders A1 - Pankow, James S A1 - Johnson, Andrew D A1 - Gagnon, France A1 - Morange, Pierre-Emmanuel A1 - de Geus, Eco J C A1 - Starr, John M A1 - Smith, Jennifer A A1 - Dehghan, Abbas A1 - Björck, Hanna M A1 - Smith, Nicholas L A1 - Peters, Annette AB -

Many hemostatic factors are associated with age and age-related diseases, however much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we used European and African-ancestry participants who were meta-analyzed separately and combined via a random effects meta-analysis. All other measures only included participants of European-ancestry. We found that 1-year higher extrinsic epigenetic age as compared to chronological age was associated with higher fibrinogen (0.004 g/L per year; 95% CI: 0.001, 0.007; P = 0.01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL per year; 95% CI: 0.07, 0.20; P = 6.6x10-5) concentrations as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the three fibrinogen subunit-encoding genes (FGA, FGG, and FGB), in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a pro-coagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

ER - TY - JOUR T1 - Genome-wide meta-analysis of SNP-by9-ACEI/ARB and SNP-by-thiazide diuretic and effect on serum potassium in cohorts of European and African ancestry. JF - Pharmacogenomics J Y1 - 2018 A1 - Irvin, Marguerite R A1 - Sitlani, Colleen M A1 - Noordam, Raymond A1 - Avery, Christie L A1 - Bis, Joshua C A1 - Floyd, James S A1 - Li, Jin A1 - Limdi, Nita A A1 - Srinivasasainagendra, Vinodh A1 - Stewart, James A1 - de Mutsert, Renée A1 - Mook-Kanamori, Dennis O A1 - Lipovich, Leonard A1 - Kleinbrink, Erica L A1 - Smith, Albert A1 - Bartz, Traci M A1 - Whitsel, Eric A A1 - Uitterlinden, André G A1 - Wiggins, Kerri L A1 - Wilson, James G A1 - Zhi, Degui A1 - Stricker, Bruno H A1 - Rotter, Jerome I A1 - Arnett, Donna K A1 - Psaty, Bruce M A1 - Lange, Leslie A AB -

We evaluated interactions of SNP-by-ACE-I/ARB and SNP-by-TD on serum potassium (K+) among users of antihypertensive treatments (anti-HTN). Our study included seven European-ancestry (EA) (N = 4835) and four African-ancestry (AA) cohorts (N = 2016). We performed race-stratified, fixed-effect, inverse-variance-weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates; race-combined meta-analysis; and trans-ethnic fine-mapping. Among EAs, we identified 11 significant SNPs (P < 5 × 10) for SNP-ACE-I/ARB interactions on serum K+ that were located between NR2F1-AS1 and ARRDC3-AS1 on chromosome 5 (top SNP rs6878413 P = 1.7 × 10; ratio of serum K+ in ACE-I/ARB exposed compared to unexposed is 1.0476, 1.0280, 1.0088 for the TT, AT, and AA genotypes, respectively). Trans-ethnic fine mapping identified the same group of SNPs on chromosome 5 as genome-wide significant for the ACE-I/ARB analysis. In conclusion, SNP-by-ACE-I /ARB interaction analyses uncovered loci that, if replicated, could have future implications for the prevention of arrhythmias due to anti-HTN treatment-related hyperkalemia. Before these loci can be identified as clinically relevant, future validation studies of equal or greater size in comparison to our discovery effort are needed.

ER - TY - JOUR T1 - Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. JF - Nat Genet Y1 - 2018 A1 - Malik, Rainer A1 - Chauhan, Ganesh A1 - Traylor, Matthew A1 - Sargurupremraj, Muralidharan A1 - Okada, Yukinori A1 - Mishra, Aniket A1 - Rutten-Jacobs, Loes A1 - Giese, Anne-Katrin A1 - van der Laan, Sander W A1 - Gretarsdottir, Solveig A1 - Anderson, Christopher D A1 - Chong, Michael A1 - Adams, Hieab H H A1 - Ago, Tetsuro A1 - Almgren, Peter A1 - Amouyel, Philippe A1 - Ay, Hakan A1 - Bartz, Traci M A1 - Benavente, Oscar R A1 - Bevan, Steve A1 - Boncoraglio, Giorgio B A1 - Brown, Robert D A1 - Butterworth, Adam S A1 - Carrera, Caty A1 - Carty, Cara L A1 - Chasman, Daniel I A1 - Chen, Wei-Min A1 - Cole, John W A1 - Correa, Adolfo A1 - Cotlarciuc, Ioana A1 - Cruchaga, Carlos A1 - Danesh, John A1 - de Bakker, Paul I W A1 - DeStefano, Anita L A1 - den Hoed, Marcel A1 - Duan, Qing A1 - Engelter, Stefan T A1 - Falcone, Guido J A1 - Gottesman, Rebecca F A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Haessler, Jeffrey A1 - Harris, Tamara B A1 - Hassan, Ahamad A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Holliday, Elizabeth G A1 - Howard, George A1 - Hsu, Fang-Chi A1 - Hyacinth, Hyacinth I A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Irvin, Marguerite R A1 - Jian, Xueqiu A1 - Jimenez-Conde, Jordi A1 - Johnson, Julie A A1 - Jukema, J Wouter A1 - Kanai, Masahiro A1 - Keene, Keith L A1 - Kissela, Brett M A1 - Kleindorfer, Dawn O A1 - Kooperberg, Charles A1 - Kubo, Michiaki A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lee, Jin-Moo A1 - Lemmens, Robin A1 - Leys, Didier A1 - Lewis, Cathryn M A1 - Lin, Wei-Yu A1 - Lindgren, Arne G A1 - Lorentzen, Erik A1 - Magnusson, Patrik K A1 - Maguire, Jane A1 - Manichaikul, Ani A1 - McArdle, Patrick F A1 - Meschia, James F A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - Nalls, Michael A A1 - Ninomiya, Toshiharu A1 - O'Donnell, Martin J A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Rannikmae, Kristiina A1 - Reiner, Alexander P A1 - Rexrode, Kathryn M A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rost, Natalia S A1 - Rothwell, Peter M A1 - Rotter, Jerome I A1 - Rundek, Tatjana A1 - Sacco, Ralph L A1 - Sakaue, Saori A1 - Sale, Michèle M A1 - Salomaa, Veikko A1 - Sapkota, Bishwa R A1 - Schmidt, Reinhold A1 - Schmidt, Carsten O A1 - Schminke, Ulf A1 - Sharma, Pankaj A1 - Slowik, Agnieszka A1 - Sudlow, Cathie L M A1 - Tanislav, Christian A1 - Tatlisumak, Turgut A1 - Taylor, Kent D A1 - Thijs, Vincent N S A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tiedt, Steffen A1 - Trompet, Stella A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Walters, Matthew A1 - Wareham, Nicholas J A1 - Wassertheil-Smoller, Sylvia A1 - Wilson, James G A1 - Wiggins, Kerri L A1 - Yang, Qiong A1 - Yusuf, Salim A1 - Bis, Joshua C A1 - Pastinen, Tomi A1 - Ruusalepp, Arno A1 - Schadt, Eric E A1 - Koplev, Simon A1 - Björkegren, Johan L M A1 - Codoni, Veronica A1 - Civelek, Mete A1 - Smith, Nicholas L A1 - Trégouët, David A A1 - Christophersen, Ingrid E A1 - Roselli, Carolina A1 - Lubitz, Steven A A1 - Ellinor, Patrick T A1 - Tai, E Shyong A1 - Kooner, Jaspal S A1 - Kato, Norihiro A1 - He, Jiang A1 - van der Harst, Pim A1 - Elliott, Paul A1 - Chambers, John C A1 - Takeuchi, Fumihiko A1 - Johnson, Andrew D A1 - Sanghera, Dharambir K A1 - Melander, Olle A1 - Jern, Christina A1 - Strbian, Daniel A1 - Fernandez-Cadenas, Israel A1 - Longstreth, W T A1 - Rolfs, Arndt A1 - Hata, Jun A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Paré, Guillaume A1 - Hopewell, Jemma C A1 - Saleheen, Danish A1 - Stefansson, Kari A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Seshadri, Sudha A1 - Fornage, Myriam A1 - Markus, Hugh S A1 - Howson, Joanna M M A1 - Kamatani, Yoichiro A1 - Debette, Stephanie A1 - Dichgans, Martin A1 - Malik, Rainer A1 - Chauhan, Ganesh A1 - Traylor, Matthew A1 - Sargurupremraj, Muralidharan A1 - Okada, Yukinori A1 - Mishra, Aniket A1 - Rutten-Jacobs, Loes A1 - Giese, Anne-Katrin A1 - van der Laan, Sander W A1 - Gretarsdottir, Solveig A1 - Anderson, Christopher D A1 - Chong, Michael A1 - Adams, Hieab H H A1 - Ago, Tetsuro A1 - Almgren, Peter A1 - Amouyel, Philippe A1 - Ay, Hakan A1 - Bartz, Traci M A1 - Benavente, Oscar R A1 - Bevan, Steve A1 - Boncoraglio, Giorgio B A1 - Brown, Robert D A1 - Butterworth, Adam S A1 - Carrera, Caty A1 - Carty, Cara L A1 - Chasman, Daniel I A1 - Chen, Wei-Min A1 - Cole, John W A1 - Correa, Adolfo A1 - Cotlarciuc, Ioana A1 - Cruchaga, Carlos A1 - Danesh, John A1 - de Bakker, Paul I W A1 - DeStefano, Anita L A1 - Hoed, Marcel den A1 - Duan, Qing A1 - Engelter, Stefan T A1 - Falcone, Guido J A1 - Gottesman, Rebecca F A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Haessler, Jeffrey A1 - Harris, Tamara B A1 - Hassan, Ahamad A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Holliday, Elizabeth G A1 - Howard, George A1 - Hsu, Fang-Chi A1 - Hyacinth, Hyacinth I A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Irvin, Marguerite R A1 - Jian, Xueqiu A1 - Jimenez-Conde, Jordi A1 - Johnson, Julie A A1 - Jukema, J Wouter A1 - Kanai, Masahiro A1 - Keene, Keith L A1 - Kissela, Brett M A1 - Kleindorfer, Dawn O A1 - Kooperberg, Charles A1 - Kubo, Michiaki A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lee, Jin-Moo A1 - Lemmens, Robin A1 - Leys, Didier A1 - Lewis, Cathryn M A1 - Lin, Wei-Yu A1 - Lindgren, Arne G A1 - Lorentzen, Erik A1 - Magnusson, Patrik K A1 - Maguire, Jane A1 - Manichaikul, Ani A1 - McArdle, Patrick F A1 - Meschia, James F A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - Nalls, Michael A A1 - Ninomiya, Toshiharu A1 - O'Donnell, Martin J A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Rannikmae, Kristiina A1 - Reiner, Alexander P A1 - Rexrode, Kathryn M A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rost, Natalia S A1 - Rothwell, Peter M A1 - Rotter, Jerome I A1 - Rundek, Tatjana A1 - Sacco, Ralph L A1 - Sakaue, Saori A1 - Sale, Michèle M A1 - Salomaa, Veikko A1 - Sapkota, Bishwa R A1 - Schmidt, Reinhold A1 - Schmidt, Carsten O A1 - Schminke, Ulf A1 - Sharma, Pankaj A1 - Slowik, Agnieszka A1 - Sudlow, Cathie L M A1 - Tanislav, Christian A1 - Tatlisumak, Turgut A1 - Taylor, Kent D A1 - Thijs, Vincent N S A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tiedt, Steffen A1 - Trompet, Stella A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Walters, Matthew A1 - Wareham, Nicholas J A1 - Wassertheil-Smoller, Sylvia A1 - Wilson, James G A1 - Wiggins, Kerri L A1 - Yang, Qiong A1 - Yusuf, Salim A1 - Amin, Najaf A1 - Aparicio, Hugo S A1 - Arnett, Donna K A1 - Attia, John A1 - Beiser, Alexa S A1 - Berr, Claudine A1 - Buring, Julie E A1 - Bustamante, Mariana A1 - Caso, Valeria A1 - Cheng, Yu-Ching A1 - Choi, Seung Hoan A1 - Chowhan, Ayesha A1 - Cullell, Natalia A1 - Dartigues, Jean-François A1 - Delavaran, Hossein A1 - Delgado, Pilar A1 - Dörr, Marcus A1 - Engström, Gunnar A1 - Ford, Ian A1 - Gurpreet, Wander S A1 - Hamsten, Anders A1 - Heitsch, Laura A1 - Hozawa, Atsushi A1 - Ibanez, Laura A1 - Ilinca, Andreea A1 - Ingelsson, Martin A1 - Iwasaki, Motoki A1 - Jackson, Rebecca D A1 - Jood, Katarina A1 - Jousilahti, Pekka A1 - Kaffashian, Sara A1 - Kalra, Lalit A1 - Kamouchi, Masahiro A1 - Kitazono, Takanari A1 - Kjartansson, Olafur A1 - Kloss, Manja A1 - Koudstaal, Peter J A1 - Krupinski, Jerzy A1 - Labovitz, Daniel L A1 - Laurie, Cathy C A1 - Levi, Christopher R A1 - Li, Linxin A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Lioutas, Vasileios A1 - Liu, Yong Mei A1 - Lopez, Oscar L A1 - Makoto, Hirata A1 - Martinez-Majander, Nicolas A1 - Matsuda, Koichi A1 - Minegishi, Naoko A1 - Montaner, Joan A1 - Morris, Andrew P A1 - Muiño, Elena A1 - Müller-Nurasyid, Martina A1 - Norrving, Bo A1 - Ogishima, Soichi A1 - Parati, Eugenio A A1 - Peddareddygari, Leema Reddy A1 - Pedersen, Nancy L A1 - Pera, Joanna A1 - Perola, Markus A1 - Pezzini, Alessandro A1 - Pileggi, Silvana A1 - Rabionet, Raquel A1 - Riba-Llena, Iolanda A1 - Ribasés, Marta A1 - Romero, Jose R A1 - Roquer, Jaume A1 - Rudd, Anthony G A1 - Sarin, Antti-Pekka A1 - Sarju, Ralhan A1 - Sarnowski, Chloe A1 - Sasaki, Makoto A1 - Satizabal, Claudia L A1 - Satoh, Mamoru A1 - Sattar, Naveed A1 - Sawada, Norie A1 - Sibolt, Gerli A1 - Sigurdsson, Ásgeir A1 - Smith, Albert A1 - Sobue, Kenji A1 - Soriano-Tárraga, Carolina A1 - Stanne, Tara A1 - Stine, O Colin A1 - Stott, David J A1 - Strauch, Konstantin A1 - Takai, Takako A1 - Tanaka, Hideo A1 - Tanno, Kozo A1 - Teumer, Alexander A1 - Tomppo, Liisa A1 - Torres-Aguila, Nuria P A1 - Touze, Emmanuel A1 - Tsugane, Shoichiro A1 - Uitterlinden, André G A1 - Valdimarsson, Einar M A1 - van der Lee, Sven J A1 - Völzke, Henry A1 - Wakai, Kenji A1 - Weir, David A1 - Williams, Stephen R A1 - Wolfe, Charles D A A1 - Wong, Quenna A1 - Xu, Huichun A1 - Yamaji, Taiki A1 - Sanghera, Dharambir K A1 - Melander, Olle A1 - Jern, Christina A1 - Strbian, Daniel A1 - Fernandez-Cadenas, Israel A1 - Longstreth, W T A1 - Rolfs, Arndt A1 - Hata, Jun A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Paré, Guillaume A1 - Hopewell, Jemma C A1 - Saleheen, Danish A1 - Stefansson, Kari A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Seshadri, Sudha A1 - Fornage, Myriam A1 - Markus, Hugh S A1 - Howson, Joanna M M A1 - Kamatani, Yoichiro A1 - Debette, Stephanie A1 - Dichgans, Martin AB -

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

VL - 50 IS - 4 ER - TY - JOUR T1 - Multi-ethnic genome-wide association study for atrial fibrillation. JF - Nat Genet Y1 - 2018 A1 - Roselli, Carolina A1 - Chaffin, Mark D A1 - Weng, Lu-Chen A1 - Aeschbacher, Stefanie A1 - Ahlberg, Gustav A1 - Albert, Christine M A1 - Almgren, Peter A1 - Alonso, Alvaro A1 - Anderson, Christopher D A1 - Aragam, Krishna G A1 - Arking, Dan E A1 - Barnard, John A1 - Bartz, Traci M A1 - Benjamin, Emelia J A1 - Bihlmeyer, Nathan A A1 - Bis, Joshua C A1 - Bloom, Heather L A1 - Boerwinkle, Eric A1 - Bottinger, Erwin B A1 - Brody, Jennifer A A1 - Calkins, Hugh A1 - Campbell, Archie A1 - Cappola, Thomas P A1 - Carlquist, John A1 - Chasman, Daniel I A1 - Chen, Lin Y A1 - Chen, Yii-Der Ida A1 - Choi, Eue-Keun A1 - Choi, Seung Hoan A1 - Christophersen, Ingrid E A1 - Chung, Mina K A1 - Cole, John W A1 - Conen, David A1 - Cook, James A1 - Crijns, Harry J A1 - Cutler, Michael J A1 - Damrauer, Scott M A1 - Daniels, Brian R A1 - Darbar, Dawood A1 - Delgado, Graciela A1 - Denny, Joshua C A1 - Dichgans, Martin A1 - Dörr, Marcus A1 - Dudink, Elton A A1 - Dudley, Samuel C A1 - Esa, Nada A1 - Esko, Tõnu A1 - Eskola, Markku A1 - Fatkin, Diane A1 - Felix, Stephan B A1 - Ford, Ian A1 - Franco, Oscar H A1 - Geelhoed, Bastiaan A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Guo, Xiuqing A1 - Gupta, Namrata A1 - Gustafsson, Stefan A1 - Gutmann, Rebecca A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Heckbert, Susan R A1 - Hernesniemi, Jussi A1 - Hocking, Lynne J A1 - Hofman, Albert A1 - Horimoto, Andrea R V R A1 - Huang, Jie A1 - Huang, Paul L A1 - Huffman, Jennifer A1 - Ingelsson, Erik A1 - Ipek, Esra Gucuk A1 - Ito, Kaoru A1 - Jimenez-Conde, Jordi A1 - Johnson, Renee A1 - Jukema, J Wouter A1 - Kääb, Stefan A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kane, John P A1 - Kastrati, Adnan A1 - Kathiresan, Sekar A1 - Katschnig-Winter, Petra A1 - Kavousi, Maryam A1 - Kessler, Thorsten A1 - Kietselaer, Bas L A1 - Kirchhof, Paulus A1 - Kleber, Marcus E A1 - Knight, Stacey A1 - Krieger, Jose E A1 - Kubo, Michiaki A1 - Launer, Lenore J A1 - Laurikka, Jari A1 - Lehtimäki, Terho A1 - Leineweber, Kirsten A1 - Lemaitre, Rozenn N A1 - Li, Man A1 - Lim, Hong Euy A1 - Lin, Henry J A1 - Lin, Honghuang A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Lokki, Marja-Liisa A1 - London, Barry A1 - Loos, Ruth J F A1 - Low, Siew-Kee A1 - Lu, Yingchang A1 - Lyytikäinen, Leo-Pekka A1 - Macfarlane, Peter W A1 - Magnusson, Patrik K A1 - Mahajan, Anubha A1 - Malik, Rainer A1 - Mansur, Alfredo J A1 - Marcus, Gregory M A1 - Margolin, Lauren A1 - Margulies, Kenneth B A1 - März, Winfried A1 - McManus, David D A1 - Melander, Olle A1 - Mohanty, Sanghamitra A1 - Montgomery, Jay A A1 - Morley, Michael P A1 - Morris, Andrew P A1 - Müller-Nurasyid, Martina A1 - Natale, Andrea A1 - Nazarian, Saman A1 - Neumann, Benjamin A1 - Newton-Cheh, Christopher A1 - Niemeijer, Maartje N A1 - Nikus, Kjell A1 - Nilsson, Peter A1 - Noordam, Raymond A1 - Oellers, Heidi A1 - Olesen, Morten S A1 - Orho-Melander, Marju A1 - Padmanabhan, Sandosh A1 - Pak, Hui-Nam A1 - Paré, Guillaume A1 - Pedersen, Nancy L A1 - Pera, Joanna A1 - Pereira, Alexandre A1 - Porteous, David A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Pullinger, Clive R A1 - Rader, Daniel J A1 - Refsgaard, Lena A1 - Ribasés, Marta A1 - Ridker, Paul M A1 - Rienstra, Michiel A1 - Risch, Lorenz A1 - Roden, Dan M A1 - Rosand, Jonathan A1 - Rosenberg, Michael A A1 - Rost, Natalia A1 - Rotter, Jerome I A1 - Saba, Samir A1 - Sandhu, Roopinder K A1 - Schnabel, Renate B A1 - Schramm, Katharina A1 - Schunkert, Heribert A1 - Schurman, Claudia A1 - Scott, Stuart A A1 - Seppälä, Ilkka A1 - Shaffer, Christian A1 - Shah, Svati A1 - Shalaby, Alaa A A1 - Shim, Jaemin A1 - Shoemaker, M Benjamin A1 - Siland, Joylene E A1 - Sinisalo, Juha A1 - Sinner, Moritz F A1 - Slowik, Agnieszka A1 - Smith, Albert V A1 - Smith, Blair H A1 - Smith, J Gustav A1 - Smith, Jonathan D A1 - Smith, Nicholas L A1 - Soliman, Elsayed Z A1 - Sotoodehnia, Nona A1 - Stricker, Bruno H A1 - Sun, Albert A1 - Sun, Han A1 - Svendsen, Jesper H A1 - Tanaka, Toshihiro A1 - Tanriverdi, Kahraman A1 - Taylor, Kent D A1 - Teder-Laving, Maris A1 - Teumer, Alexander A1 - Thériault, Sébastien A1 - Trompet, Stella A1 - Tucker, Nathan R A1 - Tveit, Arnljot A1 - Uitterlinden, André G A1 - van der Harst, Pim A1 - Van Gelder, Isabelle C A1 - Van Wagoner, David R A1 - Verweij, Niek A1 - Vlachopoulou, Efthymia A1 - Völker, Uwe A1 - Wang, Biqi A1 - Weeke, Peter E A1 - Weijs, Bob A1 - Weiss, Raul A1 - Weiss, Stefan A1 - Wells, Quinn S A1 - Wiggins, Kerri L A1 - Wong, Jorge A A1 - Woo, Daniel A1 - Worrall, Bradford B A1 - Yang, Pil-Sung A1 - Yao, Jie A1 - Yoneda, Zachary T A1 - Zeller, Tanja A1 - Zeng, Lingyao A1 - Lubitz, Steven A A1 - Lunetta, Kathryn L A1 - Ellinor, Patrick T AB -

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

VL - 50 IS - 9 ER - TY - JOUR T1 - Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease. JF - Circulation Y1 - 2019 A1 - Agha, Golareh A1 - Mendelson, Michael M A1 - Ward-Caviness, Cavin K A1 - Joehanes, Roby A1 - Huan, Tianxiao A1 - Gondalia, Rahul A1 - Salfati, Elias A1 - Brody, Jennifer A A1 - Fiorito, Giovanni A1 - Bressler, Jan A1 - Chen, Brian H A1 - Ligthart, Symen A1 - Guarrera, Simonetta A1 - Colicino, Elena A1 - Just, Allan C A1 - Wahl, Simone A1 - Gieger, Christian A1 - Vandiver, Amy R A1 - Tanaka, Toshiko A1 - Hernandez, Dena G A1 - Pilling, Luke C A1 - Singleton, Andrew B A1 - Sacerdote, Carlotta A1 - Krogh, Vittorio A1 - Panico, Salvatore A1 - Tumino, Rosario A1 - Li, Yun A1 - Zhang, Guosheng A1 - Stewart, James D A1 - Floyd, James S A1 - Wiggins, Kerri L A1 - Rotter, Jerome I A1 - Multhaup, Michael A1 - Bakulski, Kelly A1 - Horvath, Steven A1 - Tsao, Philip S A1 - Absher, Devin M A1 - Vokonas, Pantel A1 - Hirschhorn, Joel A1 - Fallin, M Daniele A1 - Liu, Chunyu A1 - Bandinelli, Stefania A1 - Boerwinkle, Eric A1 - Dehghan, Abbas A1 - Schwartz, Joel D A1 - Psaty, Bruce M A1 - Feinberg, Andrew P A1 - Hou, Lifang A1 - Ferrucci, Luigi A1 - Sotoodehnia, Nona A1 - Matullo, Giuseppe A1 - Peters, Annette A1 - Fornage, Myriam A1 - Assimes, Themistocles L A1 - Whitsel, Eric A A1 - Levy, Daniel A1 - Baccarelli, Andrea A KW - Adult KW - Aged KW - Cohort Studies KW - Coronary Disease KW - CpG Islands KW - DNA Methylation KW - Europe KW - Female KW - Genome-Wide Association Study KW - Humans KW - Incidence KW - Leukocytes KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Population Groups KW - Prognosis KW - Prospective Studies KW - Risk KW - United States AB -

BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts.

METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.

RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts.

CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.

VL - 140 IS - 8 ER - TY - JOUR T1 - Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group. JF - Am J Hypertens Y1 - 2019 A1 - Irvin, Marguerite R A1 - Sitlani, Colleen M A1 - Floyd, James S A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Wiggins, Kerri L A1 - Whitsel, Eric A A1 - Stürmer, Til A1 - Stewart, James A1 - Raffield, Laura A1 - Sun, Fangui A1 - Liu, Ching-Ti A1 - Xu, Hanfei A1 - Cupples, Adrienne L A1 - Tanner, Rikki M A1 - Rossing, Peter A1 - Smith, Albert A1 - Zilhão, Nuno R A1 - Launer, Lenore J A1 - Noordam, Raymond A1 - Rotter, Jerome I A1 - Yao, Jie A1 - Li, Xiaohui A1 - Guo, Xiuqing A1 - Limdi, Nita A1 - Sundaresan, Aishwarya A1 - Lange, Leslie A1 - Correa, Adolfo A1 - Stott, David J A1 - Ford, Ian A1 - Jukema, J Wouter A1 - Gudnason, Vilmundur A1 - Mook-Kanamori, Dennis O A1 - Trompet, Stella A1 - Palmas, Walter A1 - Warren, Helen R A1 - Hellwege, Jacklyn N A1 - Giri, Ayush A1 - O'donnell, Christopher A1 - Hung, Adriana M A1 - Edwards, Todd L A1 - Ahluwalia, Tarunveer S A1 - Arnett, Donna K A1 - Avery, Christy L KW - Aged KW - Antihypertensive Agents KW - Black or African American KW - Blood Pressure KW - Case-Control Studies KW - DNA (Cytosine-5-)-Methyltransferases KW - DNA Methyltransferase 3A KW - DNA-Binding Proteins KW - Drug Resistance KW - Dystrophin-Associated Proteins KW - Europe KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Myosin Heavy Chains KW - Myosin Type V KW - Neuropeptides KW - Pharmacogenetics KW - Pharmacogenomic Variants KW - Polymorphism, Single Nucleotide KW - Risk Assessment KW - Risk Factors KW - Transcription Factors KW - United States KW - White People AB -

BACKGROUND: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.

METHODS: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL.

RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls.

CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.

VL - 32 IS - 12 ER - TY - JOUR T1 - Genome-wide meta-analysis of SNP and antihypertensive medication interactions on left ventricular traits in African Americans. JF - Mol Genet Genomic Med Y1 - 2019 A1 - Do, Anh N A1 - Zhao, Wei A1 - Baldridge, Abigail S A1 - Raffield, Laura M A1 - Wiggins, Kerri L A1 - Shah, Sanjiv J A1 - Aslibekyan, Stella A1 - Tiwari, Hemant K A1 - Limdi, Nita A1 - Zhi, Degui A1 - Sitlani, Colleen M A1 - Taylor, Kent D A1 - Psaty, Bruce M A1 - Sotoodehnia, Nona A1 - Brody, Jennifer A A1 - Rasmussen-Torvik, Laura J A1 - Lloyd-Jones, Donald A1 - Lange, Leslie A A1 - Wilson, James G A1 - Smith, Jennifer A A1 - Kardia, Sharon L R A1 - Mosley, Thomas H A1 - Vasan, Ramachandran S A1 - Arnett, Donna K A1 - Irvin, Marguerite R KW - African Americans KW - Angiotensin-Converting Enzyme Inhibitors KW - Antihypertensive Agents KW - Calcium Channel Blockers KW - Humans KW - Observational Studies as Topic KW - Pharmacogenomic Variants KW - Polymorphism, Single Nucleotide KW - Sodium Chloride Symporter Inhibitors KW - Ventricular Dysfunction, Left AB -

BACKGROUND: Left ventricular (LV) hypertrophy affects up to 43% of African Americans (AAs). Antihypertensive treatment reduces LV mass (LVM). However, interindividual variation in LV traits in response to antihypertensive treatments exists. We hypothesized that genetic variants may modify the association of antihypertensive treatment class with LV traits measured by echocardiography.

METHODS: We evaluated the main effects of the three most common antihypertensive treatments for AAs as well as the single nucleotide polymorphism (SNP)-by-drug interaction on LVM and relative wall thickness (RWT) in 2,068 participants across five community-based cohorts. Treatments included thiazide diuretics (TDs), angiotensin converting enzyme inhibitors (ACE-Is), and dihydropyridine calcium channel blockers (dCCBs) and were compared in a pairwise manner. We performed fixed effects inverse variance weighted meta-analyses of main effects of drugs and 2.5 million SNP-by-drug interaction estimates.

RESULTS: We observed that dCCBs versus TDs were associated with higher LVM after adjusting for covariates (p = 0.001). We report three SNPs at a single locus on chromosome 20 that modified the association between RWT and treatment when comparing dCCBs to ACE-Is with consistent effects across cohorts (smallest p = 4.7 × 10 , minor allele frequency range 0.09-0.12). This locus has been linked to LV hypertrophy in a previous study. A marginally significant locus in BICD1 (rs326641) was validated in an external population.

CONCLUSIONS: Our study identified one locus having genome-wide significant SNP-by-drug interaction effect on RWT among dCCB users in comparison to ACE-I users. Upon additional validation in future studies, our findings can enhance the precision of medical approaches in hypertension treatment.

VL - 7 IS - 10 ER - TY - JOUR T1 - Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism. JF - Blood Y1 - 2019 A1 - Lindström, Sara A1 - Wang, Lu A1 - Smith, Erin N A1 - Gordon, William A1 - van Hylckama Vlieg, Astrid A1 - de Andrade, Mariza A1 - Brody, Jennifer A A1 - Pattee, Jack W A1 - Haessler, Jeffrey A1 - Brumpton, Ben M A1 - Chasman, Daniel I A1 - Suchon, Pierre A1 - Chen, Ming-Huei A1 - Turman, Constance A1 - Germain, Marine A1 - Wiggins, Kerri L A1 - MacDonald, James A1 - Braekkan, Sigrid K A1 - Armasu, Sebastian M A1 - Pankratz, Nathan A1 - Jackson, Rebecca D A1 - Nielsen, Jonas B A1 - Giulianini, Franco A1 - Puurunen, Marja K A1 - Ibrahim, Manal A1 - Heckbert, Susan R A1 - Damrauer, Scott M A1 - Natarajan, Pradeep A1 - Klarin, Derek A1 - de Vries, Paul S A1 - Sabater-Lleal, Maria A1 - Huffman, Jennifer E A1 - Bammler, Theo K A1 - Frazer, Kelly A A1 - McCauley, Bryan M A1 - Taylor, Kent A1 - Pankow, James S A1 - Reiner, Alexander P A1 - Gabrielsen, Maiken E A1 - Deleuze, Jean-Francois A1 - O'Donnell, Chris J A1 - Kim, Jihye A1 - McKnight, Barbara A1 - Kraft, Peter A1 - Hansen, John-Bjarne A1 - Rosendaal, Frits R A1 - Heit, John A A1 - Psaty, Bruce M A1 - Tang, Weihong A1 - Kooperberg, Charles A1 - Hveem, Kristian A1 - Ridker, Paul M A1 - Morange, Pierre-Emmanuel A1 - Johnson, Andrew D A1 - Kabrhel, Christopher A1 - Trégouët, David-Alexandre A1 - Smith, Nicholas L AB -

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

VL - 134 IS - 19 ER - TY - JOUR T1 - A large-scale exome array analysis of venous thromboembolism. JF - Genet Epidemiol Y1 - 2019 A1 - Lindström, Sara A1 - Brody, Jennifer A A1 - Turman, Constance A1 - Germain, Marine A1 - Bartz, Traci M A1 - Smith, Erin N A1 - Chen, Ming-Huei A1 - Puurunen, Marja A1 - Chasman, Daniel A1 - Hassler, Jeffrey A1 - Pankratz, Nathan A1 - Basu, Saonli A1 - Guan, Weihua A1 - Gyorgy, Beata A1 - Ibrahim, Manal A1 - Empana, Jean-Philippe A1 - Olaso, Robert A1 - Jackson, Rebecca A1 - Braekkan, Sigrid K A1 - McKnight, Barbara A1 - Deleuze, Jean-Francois A1 - O'Donnell, Cristopher J A1 - Jouven, Xavier A1 - Frazer, Kelly A A1 - Psaty, Bruce M A1 - Wiggins, Kerri L A1 - Taylor, Kent A1 - Reiner, Alexander P A1 - Heckbert, Susan R A1 - Kooperberg, Charles A1 - Ridker, Paul A1 - Hansen, John-Bjarne A1 - Tang, Weihong A1 - Johnson, Andrew D A1 - Morange, Pierre-Emmanuel A1 - Trégouët, David A A1 - Kraft, Peter A1 - Smith, Nicholas L A1 - Kabrhel, Christopher AB -

Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.

ER - TY - JOUR T1 - Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease. JF - PLoS One Y1 - 2019 A1 - Ward-Caviness, Cavin K A1 - de Vries, Paul S A1 - Wiggins, Kerri L A1 - Huffman, Jennifer E A1 - Yanek, Lisa R A1 - Bielak, Lawrence F A1 - Giulianini, Franco A1 - Guo, Xiuqing A1 - Kleber, Marcus E A1 - Kacprowski, Tim A1 - Groß, Stefan A1 - Petersman, Astrid A1 - Davey Smith, George A1 - Hartwig, Fernando P A1 - Bowden, Jack A1 - Hemani, Gibran A1 - Müller-Nuraysid, Martina A1 - Strauch, Konstantin A1 - Koenig, Wolfgang A1 - Waldenberger, Melanie A1 - Meitinger, Thomas A1 - Pankratz, Nathan A1 - Boerwinkle, Eric A1 - Tang, Weihong A1 - Fu, Yi-Ping A1 - Johnson, Andrew D A1 - Song, Ci A1 - de Maat, Moniek P M A1 - Uitterlinden, André G A1 - Franco, Oscar H A1 - Brody, Jennifer A A1 - McKnight, Barbara A1 - Chen, Yii-Der Ida A1 - Psaty, Bruce M A1 - Mathias, Rasika A A1 - Becker, Diane M A1 - Peyser, Patricia A A1 - Smith, Jennifer A A1 - Bielinski, Suzette J A1 - Ridker, Paul M A1 - Taylor, Kent D A1 - Yao, Jie A1 - Tracy, Russell A1 - Delgado, Graciela A1 - Trompet, Stella A1 - Sattar, Naveed A1 - Jukema, J Wouter A1 - Becker, Lewis C A1 - Kardia, Sharon L R A1 - Rotter, Jerome I A1 - März, Winfried A1 - Dörr, Marcus A1 - Chasman, Daniel I A1 - Dehghan, Abbas A1 - O'Donnell, Christopher J A1 - Smith, Nicholas L A1 - Peters, Annette A1 - Morrison, Alanna C AB -

BACKGROUND: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.

METHODS AND FINDINGS: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.

CONCLUSIONS: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.

VL - 14 IS - 5 ER - TY - JOUR T1 - Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing. JF - PLoS One Y1 - 2019 A1 - Floyd, James S A1 - Bloch, Katarzyna M A1 - Brody, Jennifer A A1 - Maroteau, Cyrielle A1 - Siddiqui, Moneeza K A1 - Gregory, Richard A1 - Carr, Daniel F A1 - Molokhia, Mariam A1 - Liu, Xiaoming A1 - Bis, Joshua C A1 - Ahmed, Ammar A1 - Liu, Xuan A1 - Hallberg, Pär A1 - Yue, Qun-Ying A1 - Magnusson, Patrik K E A1 - Brisson, Diane A1 - Wiggins, Kerri L A1 - Morrison, Alanna C A1 - Khoury, Etienne A1 - McKeigue, Paul A1 - Stricker, Bruno H A1 - Lapeyre-Mestre, Maryse A1 - Heckbert, Susan R A1 - Gallagher, Arlene M A1 - Chinoy, Hector A1 - Gibbs, Richard A A1 - Bondon-Guitton, Emmanuelle A1 - Tracy, Russell A1 - Boerwinkle, Eric A1 - Gaudet, Daniel A1 - Conforti, Anita A1 - van Staa, Tjeerd A1 - Sitlani, Colleen M A1 - Rice, Kenneth M A1 - Maitland-van der Zee, Anke-Hilse A1 - Wadelius, Mia A1 - Morris, Andrew P A1 - Pirmohamed, Munir A1 - Palmer, Colin A N A1 - Psaty, Bruce M A1 - Alfirevic, Ana AB -

AIMS: Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM.

METHODS AND RESULTS: SRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance.

CONCLUSIONS: In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.

VL - 14 IS - 6 ER - TY - JOUR T1 - Association of mitochondrial DNA copy number with cardiometabolic diseases. JF - Cell Genom Y1 - 2021 A1 - Liu, Xue A1 - Longchamps, Ryan J A1 - Wiggins, Kerri L A1 - Raffield, Laura M A1 - Bielak, Lawrence F A1 - Zhao, Wei A1 - Pitsillides, Achilleas A1 - Blackwell, Thomas W A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Kurniansyah, Nuzulul A1 - Thyagarajan, Bharat A1 - Pankratz, Nathan A1 - Rich, Stephen S A1 - Taylor, Kent D A1 - Peyser, Patricia A A1 - Heckbert, Susan R A1 - Seshadri, Sudha A1 - Cupples, L Adrienne A1 - Boerwinkle, Eric A1 - Grove, Megan L A1 - Larson, Nicholas B A1 - Smith, Jennifer A A1 - Vasan, Ramachandran S A1 - Sofer, Tamar A1 - Fitzpatrick, Annette L A1 - Fornage, Myriam A1 - Ding, Jun A1 - Correa, Adolfo A1 - Abecasis, Goncalo A1 - Psaty, Bruce M A1 - Wilson, James G A1 - Levy, Daniel A1 - Rotter, Jerome I A1 - Bis, Joshua C A1 - Satizabal, Claudia L A1 - Arking, Dan E A1 - Liu, Chunyu AB -

Mitochondrial DNA (mtDNA) is present in multiple copies in human cells. We evaluated cross-sectional associations of whole blood mtDNA copy number (CN) with several cardiometabolic disease traits in 408,361 participants of multiple ancestries in TOPMed and UK Biobank. Age showed a threshold association with mtDNA CN: among younger participants (<65 years of age), each additional 10 years of age was associated with 0.03 standard deviation (s.d.) higher level of mtDNA CN ( = 0.0014) versus a 0.14 s.d. lower level of mtDNA CN ( = 1.82 × 10) among older participants (≥65 years). At lower mtDNA CN levels, we found age-independent associations with increased odds of obesity ( = 5.6 × 10), hypertension ( = 2.8 × 10), diabetes ( = 3.6 × 10), and hyperlipidemia ( = 6.3 × 10). The observed decline in mtDNA CN after 65 years of age may be a key to understanding age-related diseases.

VL - 1 IS - 1 ER - TY - JOUR T1 - A System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. JF - Am J Epidemiol Y1 - 2021 A1 - Stilp, Adrienne M A1 - Emery, Leslie S A1 - Broome, Jai G A1 - Buth, Erin J A1 - Khan, Alyna T A1 - Laurie, Cecelia A A1 - Wang, Fei Fei A1 - Wong, Quenna A1 - Chen, Dongquan A1 - D'Augustine, Catherine M A1 - Heard-Costa, Nancy L A1 - Hohensee, Chancellor R A1 - Johnson, William Craig A1 - Juarez, Lucia D A1 - Liu, Jingmin A1 - Mutalik, Karen M A1 - Raffield, Laura M A1 - Wiggins, Kerri L A1 - de Vries, Paul S A1 - Kelly, Tanika N A1 - Kooperberg, Charles A1 - Natarajan, Pradeep A1 - Peloso, Gina M A1 - Peyser, Patricia A A1 - Reiner, Alex P A1 - Arnett, Donna K A1 - Aslibekyan, Stella A1 - Barnes, Kathleen C A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Cade, Brian E A1 - Chen, Ming-Huei A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - de Andrade, Mariza A1 - Ellinor, Patrick T A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Gan, Weiniu A1 - Ganesh, Santhi K A1 - Graffelman, Jan A1 - Grove, Megan L A1 - Guo, Xiuqing A1 - Hawley, Nicola L A1 - Hsu, Wan-Ling A1 - Jackson, Rebecca D A1 - Jaquish, Cashell E A1 - Johnson, Andrew D A1 - Kardia, Sharon L R A1 - Kelly, Shannon A1 - Lee, Jiwon A1 - Mathias, Rasika A A1 - McGarvey, Stephen T A1 - Mitchell, Braxton D A1 - Montasser, May E A1 - Morrison, Alanna C A1 - North, Kari E A1 - Nouraie, Seyed Mehdi A1 - Oelsner, Elizabeth C A1 - Pankratz, Nathan A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Smith, Jennifer A A1 - Taylor, Kent D A1 - Vasan, Ramachandran S A1 - Weeks, Daniel E A1 - Weiss, Scott T A1 - Wilson, Carla G A1 - Yanek, Lisa R A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Laurie, Cathy C AB -

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.

ER - TY - JOUR T1 - Associations of Pulmonary Function with MRI Brain Volumes: A Coordinated Multi-Study Analysis. JF - J Alzheimers Dis Y1 - 2022 A1 - Frenzel, Stefan A1 - Bis, Josh C A1 - Gudmundsson, Elias F A1 - O'Donnell, Adrienne A1 - Simino, Jeannette A1 - Yaqub, Amber A1 - Bartz, Traci M A1 - Brusselle, Guy G O A1 - Bülow, Robin A1 - DeCarli, Charles S A1 - Ewert, Ralf A1 - Gharib, Sina A A1 - Ghosh, Saptaparni A1 - Gireud-Goss, Monica A1 - Gottesman, Rebecca F A1 - Ikram, M Arfan A1 - Knopman, David S A1 - Launer, Lenore J A1 - London, Stephanie J A1 - Longstreth, W T A1 - Lopez, Oscar L A1 - Melo van Lent, Debora A1 - O'Connor, George A1 - Satizabal, Claudia L A1 - Shrestha, Srishti A1 - Sigurdsson, Sigurdur A1 - Stubbe, Beate A1 - Talluri, Rajesh A1 - Vasan, Ramachandran S A1 - Vernooij, Meike W A1 - Völzke, Henry A1 - Wiggins, Kerri L A1 - Yu, Bing A1 - Beiser, Alexa S A1 - Gudnason, Vilmundur A1 - Mosley, Thomas A1 - Psaty, Bruce M A1 - Wolters, Frank J A1 - Grabe, Hans J A1 - Seshadri, Sudha AB -

BACKGROUND: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent.

OBJECTIVE: To study the cross-sectional associations of pulmonary function with structural brain variables.

METHODS: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses.

RESULTS: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume.

CONCLUSION: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.

ER - TY - JOUR T1 - Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors. JF - Circulation Y1 - 2022 A1 - Thibord, Florian A1 - Klarin, Derek A1 - Brody, Jennifer A A1 - Chen, Ming-Huei A1 - Levin, Michael G A1 - Chasman, Daniel I A1 - Goode, Ellen L A1 - Hveem, Kristian A1 - Teder-Laving, Maris A1 - Martinez-Perez, Angel A1 - Aïssi, Dylan A1 - Daian-Bacq, Delphine A1 - Ito, Kaoru A1 - Natarajan, Pradeep A1 - Lutsey, Pamela L A1 - Nadkarni, Girish N A1 - de Vries, Paul S A1 - Cuellar-Partida, Gabriel A1 - Wolford, Brooke N A1 - Pattee, Jack W A1 - Kooperberg, Charles A1 - Braekkan, Sigrid K A1 - Li-Gao, Ruifang A1 - Saut, Noémie A1 - Sept, Corriene A1 - Germain, Marine A1 - Judy, Renae L A1 - Wiggins, Kerri L A1 - Ko, Darae A1 - O'Donnell, Christopher J A1 - Taylor, Kent D A1 - Giulianini, Franco A1 - de Andrade, Mariza A1 - Nøst, Therese H A1 - Boland, Anne A1 - Empana, Jean-Philippe A1 - Koyama, Satoshi A1 - Gilliland, Thomas A1 - Do, Ron A1 - Huffman, Jennifer E A1 - Wang, Xin A1 - Zhou, Wei A1 - Manuel Soria, Jose A1 - Carlos Souto, Juan A1 - Pankratz, Nathan A1 - Haessler, Jeffery A1 - Hindberg, Kristian A1 - Rosendaal, Frits R A1 - Turman, Constance A1 - Olaso, Robert A1 - Kember, Rachel L A1 - Bartz, Traci M A1 - Lynch, Julie A A1 - Heckbert, Susan R A1 - Armasu, Sebastian M A1 - Brumpton, Ben A1 - Smadja, David M A1 - Jouven, Xavier A1 - Komuro, Issei A1 - Clapham, Katharine R A1 - Loos, Ruth J F A1 - Willer, Cristen J A1 - Sabater-Lleal, Maria A1 - Pankow, James S A1 - Reiner, Alexander P A1 - Morelli, Vania M A1 - Ridker, Paul M A1 - Vlieg, Astrid van Hylckama A1 - Deleuze, Jean-Francois A1 - Kraft, Peter A1 - Rader, Daniel J A1 - Min Lee, Kyung A1 - Psaty, Bruce M A1 - Heidi Skogholt, Anne A1 - Emmerich, Joseph A1 - Suchon, Pierre A1 - Rich, Stephen S A1 - Vy, Ha My T A1 - Tang, Weihong A1 - Jackson, Rebecca D A1 - Hansen, John-Bjarne A1 - Morange, Pierre-Emmanuel A1 - Kabrhel, Christopher A1 - Trégouët, David-Alexandre A1 - Damrauer, Scott M A1 - Johnson, Andrew D A1 - Smith, Nicholas L KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genomics KW - Humans KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Thrombosis KW - Venous Thromboembolism AB -

BACKGROUND: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources.

METHODS: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations.

RESULTS: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis.

CONCLUSIONS: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

VL - 146 IS - 16 ER - TY - JOUR T1 - A multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood. JF - Nat Commun Y1 - 2022 A1 - Kurniansyah, Nuzulul A1 - Goodman, Matthew O A1 - Kelly, Tanika N A1 - Elfassy, Tali A1 - Wiggins, Kerri L A1 - Bis, Joshua C A1 - Guo, Xiuqing A1 - Palmas, Walter A1 - Taylor, Kent D A1 - Lin, Henry J A1 - Haessler, Jeffrey A1 - Gao, Yan A1 - Shimbo, Daichi A1 - Smith, Jennifer A A1 - Yu, Bing A1 - Feofanova, Elena V A1 - Smit, Roelof A J A1 - Wang, Zhe A1 - Hwang, Shih-Jen A1 - Liu, Simin A1 - Wassertheil-Smoller, Sylvia A1 - Manson, JoAnn E A1 - Lloyd-Jones, Donald M A1 - Rich, Stephen S A1 - Loos, Ruth J F A1 - Redline, Susan A1 - Correa, Adolfo A1 - Kooperberg, Charles A1 - Fornage, Myriam A1 - Kaplan, Robert C A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Arnett, Donna K A1 - Morrison, Alanna C A1 - Franceschini, Nora A1 - Levy, Daniel A1 - Sofer, Tamar KW - Adult KW - Diabetes Mellitus, Type 2 KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Multifactorial Inheritance KW - Prevalence KW - Risk Factors AB -

In a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS is selected by optimizing the coefficient of variation (CV) across estimated effect sizes from multiple potential PRS using the same GWAS, after which the 3 trait-specific PRSs are combined via an unweighted sum called "PRSsum", forming the HTN-PRS. The HTN-PRS is associated with both prevalent and incident hypertension at 4-6 years of follow up. This association is further confirmed in age-stratified analysis. In an independent biobank of 40,201 individuals, the HTN-PRS is confirmed to be predictive of increased risk for coronary artery disease, ischemic stroke, type 2 diabetes, and chronic kidney disease.

VL - 13 IS - 1 ER - TY - JOUR T1 - Proteomics and Population Biology in the Cardiovascular Health Study (CHS): design of a study with mentored access and active data sharing. JF - Eur J Epidemiol Y1 - 2022 A1 - Austin, Thomas R A1 - McHugh, Caitlin P A1 - Brody, Jennifer A A1 - Bis, Joshua C A1 - Sitlani, Colleen M A1 - Bartz, Traci M A1 - Biggs, Mary L A1 - Bansal, Nisha A1 - Bůzková, Petra A1 - Carr, Steven A A1 - deFilippi, Christopher R A1 - Elkind, Mitchell S V A1 - Fink, Howard A A1 - Floyd, James S A1 - Fohner, Alison E A1 - Gerszten, Robert E A1 - Heckbert, Susan R A1 - Katz, Daniel H A1 - Kizer, Jorge R A1 - Lemaitre, Rozenn N A1 - Longstreth, W T A1 - McKnight, Barbara A1 - Mei, Hao A1 - Mukamal, Kenneth J A1 - Newman, Anne B A1 - Ngo, Debby A1 - Odden, Michelle C A1 - Vasan, Ramachandran S A1 - Shojaie, Ali A1 - Simon, Noah A1 - Smith, George Davey A1 - Davies, Neil M A1 - Siscovick, David S A1 - Sotoodehnia, Nona A1 - Tracy, Russell P A1 - Wiggins, Kerri L A1 - Zheng, Jie A1 - Psaty, Bruce M AB -

BACKGROUND: In the last decade, genomic studies have identified and replicated thousands of genetic associations with measures of health and disease and contributed to the understanding of the etiology of a variety of health conditions. Proteins are key biomarkers in clinical medicine and often drug-therapy targets. Like genomics, proteomics can advance our understanding of biology.

METHODS AND RESULTS: In the setting of the Cardiovascular Health Study (CHS), a cohort study of older adults, an aptamer-based method that has high sensitivity for low-abundance proteins was used to assay 4979 proteins in frozen, stored plasma from 3188 participants (61% women, mean age 74 years). CHS provides active support, including central analysis, for seven phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 early or mid-career scientists. In this setting of mentored access, the proteomic data and analytic methods are widely shared with the WGs and investigators so that they may evaluate associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses. We describe the design of CHS, the CHS Proteomics Study, characteristics of participants, quality control measures, and structural characteristics of the data provided to CHS WGs. We additionally highlight plans for validation and replication of novel proteomic associations.

CONCLUSION: The CHS Proteomics Study offers an opportunity for collaborative data sharing to improve our understanding of the etiology of a variety of health conditions in older adults.

ER - TY - JOUR T1 - Rare genetic variants explain missing heritability in smoking. JF - Nat Hum Behav Y1 - 2022 A1 - Jang, Seon-Kyeong A1 - Evans, Luke A1 - Fialkowski, Allison A1 - Arnett, Donna K A1 - Ashley-Koch, Allison E A1 - Barnes, Kathleen C A1 - Becker, Diane M A1 - Bis, Joshua C A1 - Blangero, John A1 - Bleecker, Eugene R A1 - Boorgula, Meher Preethi A1 - Bowden, Donald W A1 - Brody, Jennifer A A1 - Cade, Brian E A1 - Jenkins, Brenda W Campbell A1 - Carson, April P A1 - Chavan, Sameer A1 - Cupples, L Adrienne A1 - Custer, Brian A1 - Damrauer, Scott M A1 - David, Sean P A1 - de Andrade, Mariza A1 - Dinardo, Carla L A1 - Fingerlin, Tasha E A1 - Fornage, Myriam A1 - Freedman, Barry I A1 - Garrett, Melanie E A1 - Gharib, Sina A A1 - Glahn, David C A1 - Haessler, Jeffrey A1 - Heckbert, Susan R A1 - Hokanson, John E A1 - Hou, Lifang A1 - Hwang, Shih-Jen A1 - Hyman, Matthew C A1 - Judy, Renae A1 - Justice, Anne E A1 - Kaplan, Robert C A1 - Kardia, Sharon L R A1 - Kelly, Shannon A1 - Kim, Wonji A1 - Kooperberg, Charles A1 - Levy, Daniel A1 - Lloyd-Jones, Donald M A1 - Loos, Ruth J F A1 - Manichaikul, Ani W A1 - Gladwin, Mark T A1 - Martin, Lisa Warsinger A1 - Nouraie, Mehdi A1 - Melander, Olle A1 - Meyers, Deborah A A1 - Montgomery, Courtney G A1 - North, Kari E A1 - Oelsner, Elizabeth C A1 - Palmer, Nicholette D A1 - Payton, Marinelle A1 - Peljto, Anna L A1 - Peyser, Patricia A A1 - Preuss, Michael A1 - Psaty, Bruce M A1 - Qiao, Dandi A1 - Rader, Daniel J A1 - Rafaels, Nicholas A1 - Redline, Susan A1 - Reed, Robert M A1 - Reiner, Alexander P A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Schwartz, David A A1 - Shadyab, Aladdin H A1 - Silverman, Edwin K A1 - Smith, Nicholas L A1 - Smith, J Gustav A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Tang, Weihong A1 - Taylor, Kent D A1 - Telen, Marilyn J A1 - Vasan, Ramachandran S A1 - Gordeuk, Victor R A1 - Wang, Zhe A1 - Wiggins, Kerri L A1 - Yanek, Lisa R A1 - Yang, Ivana V A1 - Young, Kendra A A1 - Young, Kristin L A1 - Zhang, Yingze A1 - Liu, Dajiang J A1 - Keller, Matthew C A1 - Vrieze, Scott AB -

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.

ER - TY - JOUR T1 - Stroke genetics informs drug discovery and risk prediction across ancestries. JF - Nature Y1 - 2022 A1 - Mishra, Aniket A1 - Malik, Rainer A1 - Hachiya, Tsuyoshi A1 - Jürgenson, Tuuli A1 - Namba, Shinichi A1 - Posner, Daniel C A1 - Kamanu, Frederick K A1 - Koido, Masaru A1 - Le Grand, Quentin A1 - Shi, Mingyang A1 - He, Yunye A1 - Georgakis, Marios K A1 - Caro, Ilana A1 - Krebs, Kristi A1 - Liaw, Yi-Ching A1 - Vaura, Felix C A1 - Lin, Kuang A1 - Winsvold, Bendik Slagsvold A1 - Srinivasasainagendra, Vinodh A1 - Parodi, Livia A1 - Bae, Hee-Joon A1 - Chauhan, Ganesh A1 - Chong, Michael R A1 - Tomppo, Liisa A1 - Akinyemi, Rufus A1 - Roshchupkin, Gennady V A1 - Habib, Naomi A1 - Jee, Yon Ho A1 - Thomassen, Jesper Qvist A1 - Abedi, Vida A1 - Cárcel-Márquez, Jara A1 - Nygaard, Marianne A1 - Leonard, Hampton L A1 - Yang, Chaojie A1 - Yonova-Doing, Ekaterina A1 - Knol, Maria J A1 - Lewis, Adam J A1 - Judy, Renae L A1 - Ago, Tetsuro A1 - Amouyel, Philippe A1 - Armstrong, Nicole D A1 - Bakker, Mark K A1 - Bartz, Traci M A1 - Bennett, David A A1 - Bis, Joshua C A1 - Bordes, Constance A1 - Børte, Sigrid A1 - Cain, Anael A1 - Ridker, Paul M A1 - Cho, Kelly A1 - Chen, Zhengming A1 - Cruchaga, Carlos A1 - Cole, John W A1 - De Jager, Phil L A1 - de Cid, Rafael A1 - Endres, Matthias A1 - Ferreira, Leslie E A1 - Geerlings, Mirjam I A1 - Gasca, Natalie C A1 - Gudnason, Vilmundur A1 - Hata, Jun A1 - He, Jing A1 - Heath, Alicia K A1 - Ho, Yuk-Lam A1 - Havulinna, Aki S A1 - Hopewell, Jemma C A1 - Hyacinth, Hyacinth I A1 - Inouye, Michael A1 - Jacob, Mina A A1 - Jeon, Christina E A1 - Jern, Christina A1 - Kamouchi, Masahiro A1 - Keene, Keith L A1 - Kitazono, Takanari A1 - Kittner, Steven J A1 - Konuma, Takahiro A1 - Kumar, Amit A1 - Lacaze, Paul A1 - Launer, Lenore J A1 - Lee, Keon-Joo A1 - Lepik, Kaido A1 - Li, Jiang A1 - Li, Liming A1 - Manichaikul, Ani A1 - Markus, Hugh S A1 - Marston, Nicholas A A1 - Meitinger, Thomas A1 - Mitchell, Braxton D A1 - Montellano, Felipe A A1 - Morisaki, Takayuki A1 - Mosley, Thomas H A1 - Nalls, Mike A A1 - Nordestgaard, Børge G A1 - O'Donnell, Martin J A1 - Okada, Yukinori A1 - Onland-Moret, N Charlotte A1 - Ovbiagele, Bruce A1 - Peters, Annette A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Rosand, Jonathan A1 - Sabatine, Marc S A1 - Sacco, Ralph L A1 - Saleheen, Danish A1 - Sandset, Else Charlotte A1 - Salomaa, Veikko A1 - Sargurupremraj, Muralidharan A1 - Sasaki, Makoto A1 - Satizabal, Claudia L A1 - Schmidt, Carsten O A1 - Shimizu, Atsushi A1 - Smith, Nicholas L A1 - Sloane, Kelly L A1 - Sutoh, Yoichi A1 - Sun, Yan V A1 - Tanno, Kozo A1 - Tiedt, Steffen A1 - Tatlisumak, Turgut A1 - Torres-Aguila, Nuria P A1 - Tiwari, Hemant K A1 - Trégouët, David-Alexandre A1 - Trompet, Stella A1 - Tuladhar, Anil Man A1 - Tybjærg-Hansen, Anne A1 - van Vugt, Marion A1 - Vibo, Riina A1 - Verma, Shefali S A1 - Wiggins, Kerri L A1 - Wennberg, Patrik A1 - Woo, Daniel A1 - Wilson, Peter W F A1 - Xu, Huichun A1 - Yang, Qiong A1 - Yoon, Kyungheon A1 - Millwood, Iona Y A1 - Gieger, Christian A1 - Ninomiya, Toshiharu A1 - Grabe, Hans J A1 - Jukema, J Wouter A1 - Rissanen, Ina L A1 - Strbian, Daniel A1 - Kim, Young Jin A1 - Chen, Pei-Hsin A1 - Mayerhofer, Ernst A1 - Howson, Joanna M M A1 - Irvin, Marguerite R A1 - Adams, Hieab A1 - Wassertheil-Smoller, Sylvia A1 - Christensen, Kaare A1 - Ikram, Mohammad A A1 - Rundek, Tatjana A1 - Worrall, Bradford B A1 - Lathrop, G Mark A1 - Riaz, Moeen A1 - Simonsick, Eleanor M A1 - Kõrv, Janika A1 - França, Paulo H C A1 - Zand, Ramin A1 - Prasad, Kameshwar A1 - Frikke-Schmidt, Ruth A1 - de Leeuw, Frank-Erik A1 - Liman, Thomas A1 - Haeusler, Karl Georg A1 - Ruigrok, Ynte M A1 - Heuschmann, Peter Ulrich A1 - Longstreth, W T A1 - Jung, Keum Ji A1 - Bastarache, Lisa A1 - Paré, Guillaume A1 - Damrauer, Scott M A1 - Chasman, Daniel I A1 - Rotter, Jerome I A1 - Anderson, Christopher D A1 - Zwart, John-Anker A1 - Niiranen, Teemu J A1 - Fornage, Myriam A1 - Liaw, Yung-Po A1 - Seshadri, Sudha A1 - Fernandez-Cadenas, Israel A1 - Walters, Robin G A1 - Ruff, Christian T A1 - Owolabi, Mayowa O A1 - Huffman, Jennifer E A1 - Milani, Lili A1 - Kamatani, Yoichiro A1 - Dichgans, Martin A1 - Debette, Stephanie AB -

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry. 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 analysis, 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 approach, 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 ancestry. 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.

ER - TY - JOUR T1 - Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis. JF - Nature Y1 - 2023 A1 - Weinstock, Joshua S A1 - Gopakumar, Jayakrishnan A1 - Burugula, Bala Bharathi A1 - Uddin, Md Mesbah A1 - Jahn, Nikolaus A1 - Belk, Julia A A1 - Bouzid, Hind A1 - Daniel, Bence A1 - Miao, Zhuang A1 - Ly, Nghi A1 - Mack, Taralynn M A1 - Luna, Sofia E A1 - Prothro, Katherine P A1 - Mitchell, Shaneice R A1 - Laurie, Cecelia A A1 - Broome, Jai G A1 - Taylor, Kent D A1 - Guo, Xiuqing A1 - Sinner, Moritz F A1 - von Falkenhausen, Aenne S A1 - Kääb, Stefan A1 - Shuldiner, Alan R A1 - O'Connell, Jeffrey R A1 - Lewis, Joshua P A1 - Boerwinkle, Eric A1 - Barnes, Kathleen C A1 - Chami, Nathalie A1 - Kenny, Eimear E A1 - Loos, Ruth J F A1 - Fornage, Myriam A1 - Hou, Lifang A1 - Lloyd-Jones, Donald M A1 - Redline, Susan A1 - Cade, Brian E A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Silverman, Edwin K A1 - Yun, Jeong H A1 - Qiao, Dandi A1 - Palmer, Nicholette D A1 - Freedman, Barry I A1 - Bowden, Donald W A1 - Cho, Michael H A1 - DeMeo, Dawn L A1 - Vasan, Ramachandran S A1 - Yanek, Lisa R A1 - Becker, Lewis C A1 - Kardia, Sharon L R A1 - Peyser, Patricia A A1 - He, Jiang A1 - Rienstra, Michiel A1 - van der Harst, Pim A1 - Kaplan, Robert A1 - Heckbert, Susan R A1 - Smith, Nicholas L A1 - Wiggins, Kerri L A1 - Arnett, Donna K A1 - Irvin, Marguerite R A1 - Tiwari, Hemant A1 - Cutler, Michael J A1 - Knight, Stacey A1 - Muhlestein, J Brent A1 - Correa, Adolfo A1 - Raffield, Laura M A1 - Gao, Yan A1 - de Andrade, Mariza A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Tracy, Russell P A1 - Konkle, Barbara A A1 - Johnsen, Jill M A1 - Wheeler, Marsha M A1 - Smith, J Gustav A1 - Melander, Olle A1 - Nilsson, Peter M A1 - Custer, Brian S A1 - Duggirala, Ravindranath A1 - Curran, Joanne E A1 - Blangero, John A1 - McGarvey, Stephen A1 - Williams, L Keoki A1 - Xiao, Shujie A1 - Yang, Mao A1 - Gu, C Charles A1 - Chen, Yii-Der Ida A1 - Lee, Wen-Jane A1 - Marcus, Gregory M A1 - Kane, John P A1 - Pullinger, Clive R A1 - Shoemaker, M Benjamin A1 - Darbar, Dawood A1 - Roden, Dan M A1 - Albert, Christine A1 - Kooperberg, Charles A1 - Zhou, Ying A1 - Manson, JoAnn E A1 - Desai, Pinkal A1 - Johnson, Andrew D A1 - Mathias, Rasika A A1 - Blackwell, Thomas W A1 - Abecasis, Goncalo R A1 - Smith, Albert V A1 - Kang, Hyun M A1 - Satpathy, Ansuman T A1 - Natarajan, Pradeep A1 - Kitzman, Jacob O A1 - Whitsel, Eric A A1 - Reiner, Alexander P A1 - Bick, Alexander G A1 - Jaiswal, Siddhartha KW - Alleles KW - Animals KW - Clonal Hematopoiesis KW - Genome-Wide Association Study KW - Hematopoiesis KW - Hematopoietic Stem Cells KW - Humans KW - Mice KW - Mutation KW - Promoter Regions, Genetic AB -

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

VL - 616 IS - 7958 ER - TY - JOUR T1 - Association Between Whole Blood-Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk. JF - J Am Heart Assoc Y1 - 2023 A1 - Liu, Xue A1 - Sun, Xianbang A1 - Zhang, Yuankai A1 - Jiang, Wenqing A1 - Lai, Meng A1 - Wiggins, Kerri L A1 - Raffield, Laura M A1 - Bielak, Lawrence F A1 - Zhao, Wei A1 - Pitsillides, Achilleas A1 - Haessler, Jeffrey A1 - Zheng, Yinan A1 - Blackwell, Thomas W A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Qian, Yong A1 - Thyagarajan, Bharat A1 - Pankratz, Nathan A1 - Rich, Stephen S A1 - Taylor, Kent D A1 - Peyser, Patricia A A1 - Heckbert, Susan R A1 - Seshadri, Sudha A1 - Boerwinkle, Eric A1 - Grove, Megan L A1 - Larson, Nicholas B A1 - Smith, Jennifer A A1 - Vasan, Ramachandran S A1 - Fitzpatrick, Annette L A1 - Fornage, Myriam A1 - Ding, Jun A1 - Carson, April P A1 - Abecasis, Goncalo A1 - Dupuis, Josée A1 - Reiner, Alexander A1 - Kooperberg, Charles A1 - Hou, Lifang A1 - Psaty, Bruce M A1 - Wilson, James G A1 - Levy, Daniel A1 - Rotter, Jerome I A1 - Bis, Joshua C A1 - Satizabal, Claudia L A1 - Arking, Dan E A1 - Liu, Chunyu AB -

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1-SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04-1.12; <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; =0.11) or in the reverse direction (β=-0.012; =0.076). Additional bidirectional Mendelian randomization analyses revealed that low-density lipoprotein cholesterol had a causal effect on mtDNA CN (β=-0.084; <0.001), but the reverse direction was not significant (=0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low-density lipoprotein cholesterol level (=0.52), whereas there was a strong direct causal effect of higher low-density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=-0.092; <0.001). Conclusions Our findings indicate that high low-density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

ER - TY - JOUR T1 - Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts. JF - Neurology Y1 - 2023 A1 - Zhang, Yuankai A1 - Liu, Xue A1 - Wiggins, Kerri L A1 - Kurniansyah, Nuzulul A1 - Guo, Xiuqing A1 - Rodrigue, Amanda L A1 - Zhao, Wei A1 - Yanek, Lisa R A1 - Ratliff, Scott M A1 - Pitsillides, Achilleas A1 - Aguirre Patiño, Juan Sebastian A1 - Sofer, Tamar A1 - Arking, Dan E A1 - Austin, Thomas R A1 - Beiser, Alexa S A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bressler, Jan A1 - Curran, Joanne E A1 - Hou, Lifang A1 - Hughes, Timothy M A1 - Kardia, Sharon L A1 - Launer, Lenore A1 - Levy, Daniel A1 - Mosley, Tom H A1 - Nasrallah, Ilya M A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Seshadri, Sudha A1 - Tarraf, Wassim A1 - González, Kevin A A1 - Ramachandran, Vasan A1 - Yaffe, Kristine A1 - Nyquist, Paul A A1 - Psaty, Bruce M A1 - DeCarli, Charles S A1 - Smith, Jennifer A A1 - Glahn, David C A1 - González, Hector M A1 - Bis, Joshua C A1 - Fornage, Myriam A1 - Heckbert, Susan R A1 - Fitzpatrick, Annette L A1 - Liu, Chunyu A1 - Satizabal, Claudia L AB -

BACKGROUND AND OBJECTIVES: Previous studies suggest lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer's disease (AD) and AD related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.

METHODS: We included dementia-free participants from nine diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5 to 20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs. ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed Mendelian randomization (MR) analyses to assess causality.

RESULTS: We included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (Beta=0.04; 95% CI 0.02, 0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition.

DISCUSSION: Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the US. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.

ER - TY - JOUR T1 - Evaluating the use of blood pressure polygenic risk scores across race/ethnic background groups. JF - Nat Commun Y1 - 2023 A1 - Kurniansyah, Nuzulul A1 - Goodman, Matthew O A1 - Khan, Alyna T A1 - Wang, Jiongming A1 - Feofanova, Elena A1 - Bis, Joshua C A1 - Wiggins, Kerri L A1 - Huffman, Jennifer E A1 - Kelly, Tanika A1 - Elfassy, Tali A1 - Guo, Xiuqing A1 - Palmas, Walter A1 - Lin, Henry J A1 - Hwang, Shih-Jen A1 - Gao, Yan A1 - Young, Kendra A1 - Kinney, Gregory L A1 - Smith, Jennifer A A1 - Yu, Bing A1 - Liu, Simin A1 - Wassertheil-Smoller, Sylvia A1 - Manson, JoAnn E A1 - Zhu, Xiaofeng A1 - Chen, Yii-Der Ida A1 - Lee, I-Te A1 - Gu, C Charles A1 - Lloyd-Jones, Donald M A1 - Zöllner, Sebastian A1 - Fornage, Myriam A1 - Kooperberg, Charles A1 - Correa, Adolfo A1 - Psaty, Bruce M A1 - Arnett, Donna K A1 - Isasi, Carmen R A1 - Rich, Stephen S A1 - Kaplan, Robert C A1 - Redline, Susan A1 - Mitchell, Braxton D A1 - Franceschini, Nora A1 - Levy, Daniel A1 - Rotter, Jerome I A1 - Morrison, Alanna C A1 - Sofer, Tamar KW - Blood Pressure KW - Ethnicity KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Multifactorial Inheritance KW - Population Health KW - Risk Factors AB -

We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare "clumping-and-thresholding" (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs developed from multiple independent GWAS, perform best across all race/ethnic backgrounds. Stratified analysis in All of Us shows that PRSs are better predictive of BP in females compared to males, individuals without obesity, and middle-aged (40-60 years) compared to older and younger individuals.

VL - 14 IS - 1 ER - TY - JOUR T1 - Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease. JF - Nat Commun Y1 - 2023 A1 - Young, William J A1 - Haessler, Jeffrey A1 - Benjamins, Jan-Walter A1 - Repetto, Linda A1 - Yao, Jie A1 - Isaacs, Aaron A1 - Harper, Andrew R A1 - Ramirez, Julia A1 - Garnier, Sophie A1 - Van Duijvenboden, Stefan A1 - Baldassari, Antoine R A1 - Concas, Maria Pina A1 - Duong, ThuyVy A1 - Foco, Luisa A1 - Isaksen, Jonas L A1 - Mei, Hao A1 - Noordam, Raymond A1 - Nursyifa, Casia A1 - Richmond, Anne A1 - Santolalla, Meddly L A1 - Sitlani, Colleen M A1 - Soroush, Negin A1 - Thériault, Sébastien A1 - Trompet, Stella A1 - Aeschbacher, Stefanie A1 - Ahmadizar, Fariba A1 - Alonso, Alvaro A1 - Brody, Jennifer A A1 - Campbell, Archie A1 - Correa, Adolfo A1 - Darbar, Dawood A1 - De Luca, Antonio A1 - Deleuze, Jean-Francois A1 - Ellervik, Christina A1 - Fuchsberger, Christian A1 - Goel, Anuj A1 - Grace, Christopher A1 - Guo, Xiuqing A1 - Hansen, Torben A1 - Heckbert, Susan R A1 - Jackson, Rebecca D A1 - Kors, Jan A A1 - Lima-Costa, Maria Fernanda A1 - Linneberg, Allan A1 - Macfarlane, Peter W A1 - Morrison, Alanna C A1 - Navarro, Pau A1 - Porteous, David J A1 - Pramstaller, Peter P A1 - Reiner, Alexander P A1 - Risch, Lorenz A1 - Schotten, Ulrich A1 - Shen, Xia A1 - Sinagra, Gianfranco A1 - Soliman, Elsayed Z A1 - Stoll, Monika A1 - Tarazona-Santos, Eduardo A1 - Tinker, Andrew A1 - Trajanoska, Katerina A1 - Villard, Eric A1 - Warren, Helen R A1 - Whitsel, Eric A A1 - Wiggins, Kerri L A1 - Arking, Dan E A1 - Avery, Christy L A1 - Conen, David A1 - Girotto, Giorgia A1 - Grarup, Niels A1 - Hayward, Caroline A1 - Jukema, J Wouter A1 - Mook-Kanamori, Dennis O A1 - Olesen, Morten Salling A1 - Padmanabhan, Sandosh A1 - Psaty, Bruce M A1 - Pattaro, Cristian A1 - Ribeiro, Antonio Luiz P A1 - Rotter, Jerome I A1 - Stricker, Bruno H A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Verweij, Niek A1 - Wilson, James G A1 - Orini, Michele A1 - Charron, Philippe A1 - Watkins, Hugh A1 - Kooperberg, Charles A1 - Lin, Henry J A1 - Wilson, James F A1 - Kanters, Jørgen K A1 - Sotoodehnia, Nona A1 - Mifsud, Borbala A1 - Lambiase, Pier D A1 - Tereshchenko, Larisa G A1 - Munroe, Patricia B KW - Arrhythmias, Cardiac KW - Atrioventricular Block KW - Biomarkers KW - Cardiovascular Diseases KW - Electrocardiography KW - Genome-Wide Association Study KW - Humans KW - Risk Factors AB -

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.

VL - 14 IS - 1 ER - TY - JOUR T1 - The genetic determinants of recurrent somatic mutations in 43,693 blood genomes. JF - Sci Adv Y1 - 2023 A1 - Weinstock, Joshua S A1 - Laurie, Cecelia A A1 - Broome, Jai G A1 - Taylor, Kent D A1 - Guo, Xiuqing A1 - Shuldiner, Alan R A1 - O'Connell, Jeffrey R A1 - Lewis, Joshua P A1 - Boerwinkle, Eric A1 - Barnes, Kathleen C A1 - Chami, Nathalie A1 - Kenny, Eimear E A1 - Loos, Ruth J F A1 - Fornage, Myriam A1 - Redline, Susan A1 - Cade, Brian E A1 - Gilliland, Frank D A1 - Chen, Zhanghua A1 - Gauderman, W James A1 - Kumar, Rajesh A1 - Grammer, Leslie A1 - Schleimer, Robert P A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Silverman, Edwin K A1 - Yun, Jeong H A1 - Qiao, Dandi A1 - Weiss, Scott T A1 - Lasky-Su, Jessica A1 - DeMeo, Dawn L A1 - Palmer, Nicholette D A1 - Freedman, Barry I A1 - Bowden, Donald W A1 - Cho, Michael H A1 - Vasan, Ramachandran S A1 - Johnson, Andrew D A1 - Yanek, Lisa R A1 - Becker, Lewis C A1 - Kardia, Sharon A1 - He, Jiang A1 - Kaplan, Robert A1 - Heckbert, Susan R A1 - Smith, Nicholas L A1 - Wiggins, Kerri L A1 - Arnett, Donna K A1 - Irvin, Marguerite R A1 - Tiwari, Hemant A1 - Correa, Adolfo A1 - Raffield, Laura M A1 - Gao, Yan A1 - de Andrade, Mariza A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Manichaikul, Ani W A1 - Konkle, Barbara A A1 - Johnsen, Jill M A1 - Wheeler, Marsha M A1 - Custer, Brian S A1 - Duggirala, Ravindranath A1 - Curran, Joanne E A1 - Blangero, John A1 - Gui, Hongsheng A1 - Xiao, Shujie A1 - Williams, L Keoki A1 - Meyers, Deborah A A1 - Li, Xingnan A1 - Ortega, Victor A1 - McGarvey, Stephen A1 - Gu, C Charles A1 - Chen, Yii-Der Ida A1 - Lee, Wen-Jane A1 - Shoemaker, M Benjamin A1 - Darbar, Dawood A1 - Roden, Dan A1 - Albert, Christine A1 - Kooperberg, Charles A1 - Desai, Pinkal A1 - Blackwell, Thomas W A1 - Abecasis, Goncalo R A1 - Smith, Albert V A1 - Kang, Hyun M A1 - Mathias, Rasika A1 - Natarajan, Pradeep A1 - Jaiswal, Siddhartha A1 - Reiner, Alexander P A1 - Bick, Alexander G KW - Germ-Line Mutation KW - Hematopoiesis KW - Humans KW - Middle Aged KW - Mutation KW - Mutation, Missense KW - Phenotype AB -

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

VL - 9 IS - 17 ER - TY - JOUR T1 - Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus. JF - medRxiv Y1 - 2023 A1 - Kwak, Soo Heon A1 - Hernandez-Cancela, Ryan B A1 - DiCorpo, Daniel A A1 - Condon, David E A1 - Merino, Jordi A1 - Wu, Peitao A1 - Brody, Jennifer A A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Ahmadizar, Fariba A1 - Meyer, Mariah A1 - Sincan, Murat A1 - Mercader, Josep M A1 - Lee, Sujin A1 - Haessler, Jeffrey A1 - Vy, Ha My T A1 - Lin, Zhaotong A1 - Armstrong, Nicole D A1 - Gu, Shaopeng A1 - Tsao, Noah L A1 - Lange, Leslie A A1 - Wang, Ningyuan A1 - Wiggins, Kerri L A1 - Trompet, Stella A1 - Liu, Simin A1 - Loos, Ruth J F A1 - Judy, Renae A1 - Schroeder, Philip H A1 - Hasbani, Natalie R A1 - Bos, Maxime M A1 - Morrison, Alanna C A1 - Jackson, Rebecca D A1 - Reiner, Alexander P A1 - Manson, JoAnn E A1 - Chaudhary, Ninad S A1 - Carmichael, Lynn K A1 - Chen, Yii-Der Ida A1 - Taylor, Kent D A1 - Ghanbari, Mohsen A1 - van Meurs, Joyce A1 - Pitsillides, Achilleas N A1 - Psaty, Bruce M A1 - Noordam, Raymond A1 - Do, Ron A1 - Park, Kyong Soo A1 - Jukema, J Wouter A1 - Kavousi, Maryam A1 - Correa, Adolfo A1 - Rich, Stephen S A1 - Damrauer, Scott M A1 - Hajek, Catherine A1 - Cho, Nam H A1 - Irvin, Marguerite R A1 - Pankow, James S A1 - Nadkarni, Girish N A1 - Sladek, Robert A1 - Goodarzi, Mark O A1 - Florez, Jose C A1 - Chasman, Daniel I A1 - Heckbert, Susan R A1 - Kooperberg, Charles A1 - Dupuis, Josée A1 - Malhotra, Rajeev A1 - de Vries, Paul S A1 - Liu, Ching-Ti A1 - Rotter, Jerome I A1 - Meigs, James B AB -

BACKGROUND: Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD.

METHODS: From 16 studies of the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D.

RESULTS: A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance ( <5.0×10 ): rs147138607 (intergenic variant between and ) with a hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.15 - 1.32, =3.6×10 , rs11444867 (intergenic variant near ) with HR 1.89, 95% CI 1.52 - 2.35, =9.9×10 , and rs335407 (intergenic variant between and ) HR 1.25, 95% CI 1.16 - 1.35, =1.5×10 . Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with <0.05, and 5 were significant after Bonferroni correction ( <0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95% CI 1.12 - 1.16) per 1 standard deviation increase ( =1.0×10 ).

CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

CLINICAL PERSPECTIVE: We conducted a large-scale multi-ancestry time-to-event GWAS to identify genetic variants associated with CVD among people with T2D. Three variants were significantly associated with incident CVD in people with T2D: rs147138607 (intergenic variant between and ), rs11444867 (intergenic variant near ), and rs335407 (intergenic variant between and ). A polygenic score composed of known CAD variants identified in the general population was significantly associated with the risk of CVD in people with T2D. There are genetic risk factors specific to T2D that could at least partially explain the excess risk of CVD in people with T2D.In addition, we show that people with T2D have enrichment of known CAD association signals which could also explain the excess risk of CVD.

ER - TY - JOUR T1 - Whole Genome Analysis of Venous Thromboembolism: the Trans-Omics for Precision Medicine Program. JF - Circ Genom Precis Med Y1 - 2023 A1 - Seyerle, Amanda A A1 - Laurie, Cecelia A A1 - Coombes, Brandon J A1 - Jain, Deepti A1 - Conomos, Matthew P A1 - Brody, Jennifer A1 - Chen, Ming-Huei A1 - Gogarten, Stephanie M A1 - Beutel, Kathleen M A1 - Gupta, Namrata A1 - Heckbert, Susan R A1 - Jackson, Rebecca D A1 - Johnson, Andrew D A1 - Ko, Darae A1 - Manson, JoAnn E A1 - McKnight, Barbara A1 - Metcalf, Ginger A A1 - Morrison, Alanna C A1 - Reiner, Alexander P A1 - Sofer, Tamar A1 - Tang, Weihong A1 - Wiggins, Kerri L A1 - Boerwinkle, Eric A1 - Andrade, Mariza de A1 - Gabriel, Stacey B A1 - Gibbs, Richard A A1 - Laurie, Cathy C A1 - Psaty, Bruce M A1 - Vasan, Ramachandran S A1 - Rice, Ken A1 - Kooperberg, Charles A1 - Pankow, James S A1 - Smith, Nicholas L A1 - Pankratz, Nathan AB -

Background Risk for venous thromboembolism has a strong genetic component. Whole genome sequencingfrom the Trans-Omics for Precision Medicine program allowed us to look for new associations, particularly rare variants missed by standard genome-wide association studies. Methods The 3793 cases and 7834 controls (11.6% of cases were Black, Hispanic/Latino, or Asian American) were analyzed using a single variant approach and an aggregate gene-based approach using our primary filter (included only loss-of-function and missense variants predicted to be deleterious) and our secondary filter (included all missense variants). Results Single variant analyses identified associations at 5 known loci. Aggregate gene-based analyses identified only (odds ratio, 6.2 for carriers of rare variants; =7.4×10) when using our primary filter. Employing our secondary variant filter led to a smaller effect size at (odds ratio, 3.8; =1.6×10), while excluding variants found only in rare isoforms led to a larger one (odds ratio, 7.5). Different filtering strategies improved the signal for 2 other known genes: became significant (minimum =1.8×10 with the secondary filter), while did not (minimum =4.4×10 with minor allele frequency <0.0005). Results were largely the same when restricting the analyses to include only unprovoked cases; however, one novel gene, , became significant (=4.4×10 using all missense variants with minor allele frequency <0.0005). Conclusions Here, we have demonstrated the importance of using multiple variant filtering strategies, as we detected additional genes when filtering variants based on their predicted deleteriousness, frequency, and presence on the most expressed isoforms. Our primary analyses did not identify new candidate loci; thus larger follow-up studies are needed to replicate the novel locus and to identify additional rare variation associated with venous thromboembolism.

ER - TY - JOUR T1 - WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE. JF - medRxiv Y1 - 2023 A1 - Zhang, Xinruo A1 - Brody, Jennifer A A1 - Graff, Mariaelisa A1 - Highland, Heather M A1 - Chami, Nathalie A1 - Xu, Hanfei A1 - Wang, Zhe A1 - Ferrier, Kendra A1 - Chittoor, Geetha A1 - Josyula, Navya S A1 - Li, Xihao A1 - Li, Zilin A1 - Allison, Matthew A A1 - Becker, Diane M A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Boorgula, Meher Preethi A1 - Bowden, Donald W A1 - Broome, Jai G A1 - Buth, Erin J A1 - Carlson, Christopher S A1 - Chang, Kyong-Mi A1 - Chavan, Sameer A1 - Chiu, Yen-Feng A1 - Chuang, Lee-Ming A1 - Conomos, Matthew P A1 - DeMeo, Dawn L A1 - Du, Margaret A1 - Duggirala, Ravindranath A1 - Eng, Celeste A1 - Fohner, Alison E A1 - Freedman, Barry I A1 - Garrett, Melanie E A1 - Guo, Xiuqing A1 - Haiman, Chris A1 - Heavner, Benjamin D A1 - Hidalgo, Bertha A1 - Hixson, James E A1 - Ho, Yuk-Lam A1 - Hobbs, Brian D A1 - Hu, Donglei A1 - Hui, Qin A1 - Hwu, Chii-Min A1 - Jackson, Rebecca D A1 - Jain, Deepti A1 - Kalyani, Rita R A1 - Kardia, Sharon L R A1 - Kelly, Tanika N A1 - Lange, Ethan M A1 - LeNoir, Michael A1 - Li, Changwei A1 - Marchand, Loic Le A1 - McDonald, Merry-Lynn N A1 - McHugh, Caitlin P A1 - Morrison, Alanna C A1 - Naseri, Take A1 - O'Connell, Jeffrey A1 - O'Donnell, Christopher J A1 - Palmer, Nicholette D A1 - Pankow, James S A1 - Perry, James A A1 - Peters, Ulrike A1 - Preuss, Michael H A1 - Rao, D C A1 - Regan, Elizabeth A A1 - Reupena, Sefuiva M A1 - Roden, Dan M A1 - Rodriguez-Santana, Jose A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Tiwari, Hemant K A1 - Vasan, Ramachandran S A1 - Wang, Zeyuan A1 - Weeks, Daniel E A1 - Wessel, Jennifer A1 - Wiggins, Kerri L A1 - Wilkens, Lynne R A1 - Wilson, Peter W F A1 - Yanek, Lisa R A1 - Yoneda, Zachary T A1 - Zhao, Wei A1 - Zöllner, Sebastian A1 - Arnett, Donna K A1 - Ashley-Koch, Allison E A1 - Barnes, Kathleen C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Burchard, Esteban G A1 - Carson, April P A1 - Chasman, Daniel I A1 - Chen, Yii-Der Ida A1 - Curran, Joanne E A1 - Fornage, Myriam A1 - Gordeuk, Victor R A1 - He, Jiang A1 - Heckbert, Susan R A1 - Hou, Lifang A1 - Irvin, Marguerite R A1 - Kooperberg, Charles A1 - Minster, Ryan L A1 - Mitchell, Braxton D A1 - Nouraie, Mehdi A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Reiner, Alexander P A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Shoemaker, M Benjamin A1 - Smith, Nicholas L A1 - Taylor, Kent D A1 - Telen, Marilyn J A1 - Weiss, Scott T A1 - Zhang, Yingze A1 - Costa, Nancy Heard- A1 - Sun, Yan V A1 - Lin, Xihong A1 - Cupples, L Adrienne A1 - Lange, Leslie A A1 - Liu, Ching-Ti A1 - Loos, Ruth J F A1 - North, Kari E A1 - Justice, Anne E AB -

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals ( < 5 × 10 ). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the and loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.

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