@article {807, title = {Time trends in the use of beta-blockers and other pharmacotherapies in older adults with congestive heart failure.}, journal = {Am Heart J}, volume = {148}, year = {2004}, month = {2004 Oct}, pages = {710-7}, abstract = {

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.

}, keywords = {Adrenergic beta-Antagonists, Aged, Angiotensin II Type 1 Receptor Blockers, Angiotensin-Converting Enzyme Inhibitors, Cohort Studies, Drug Therapy, Drug Therapy, Combination, Female, Heart Failure, Humans, Male, Multivariate Analysis, Prevalence}, issn = {1097-6744}, doi = {10.1016/j.ahj.2004.04.002}, author = {Smith, Nicholas L and Chan, Jeannie D and Rea, Thomas D and Wiggins, Kerri L and Gottdiener, John S and Lumley, Thomas and Psaty, Bruce M} } @article {1243, title = {Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo.}, journal = {PLoS Genet}, volume = {6}, year = {2010}, month = {2010 Oct 28}, pages = {e1001184}, abstract = {

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{\texttimes}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{\texttimes}10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25{\texttimes}10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p  =  2.15{\texttimes}10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32{\texttimes}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.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Child, Child, Preschool, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 6, Cohort Studies, European Continental Ancestry Group, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Microcirculation, Middle Aged, Polymorphism, Single Nucleotide, Retinal Vessels, Young Adult}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1001184}, author = {Ikram, M Kamran and Sim, Xueling and Xueling, Sim and Jensen, Richard A and Cotch, Mary Frances and Hewitt, Alex W and Ikram, M Arfan and Wang, Jie Jin and Klein, Ronald and Klein, Barbara E K and Breteler, Monique M B and Cheung, Ning and Liew, Gerald and Mitchell, Paul and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Hofman, Albert and de Jong, Paulus T V M and van Duijn, Cornelia M and Kao, Linda and Cheng, Ching-Yu and Smith, Albert Vernon and Glazer, Nicole L and Lumley, Thomas and McKnight, Barbara and Psaty, Bruce M and Jonasson, Fridbert and Eiriksdottir, Gudny and Aspelund, Thor and Harris, Tamara B and Launer, Lenore J and Taylor, Kent D and Li, Xiaohui and Iyengar, Sudha K and Xi, Quansheng and Sivakumaran, Theru A and Mackey, David A and Macgregor, Stuart and Martin, Nicholas G and Young, Terri L and Bis, Josh C and Wiggins, Kerri L and Heckbert, Susan R and Hammond, Christopher J and Andrew, Toby and Fahy, Samantha and Attia, John and Holliday, Elizabeth G and Scott, Rodney J and Islam, F M Amirul and Rotter, Jerome I and McAuley, Annie K and Boerwinkle, Eric and Tai, E Shyong and Gudnason, Vilmundur and Siscovick, David S and Vingerling, Johannes R and Wong, Tien Y} } @article {1176, title = {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.}, journal = {Circulation}, volume = {121}, year = {2010}, month = {2010 Mar 30}, pages = {1382-92}, abstract = {

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.

}, keywords = {Adult, Factor VII, Factor VIII, Female, Genome-Wide Association Study, Hemostasis, Humans, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Thrombosis, von Willebrand Factor}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.109.869156}, author = {Smith, Nicholas L and Chen, Ming-Huei and Dehghan, Abbas and Strachan, David P and Basu, Saonli and Soranzo, Nicole and Hayward, Caroline and Rudan, Igor and Sabater-Lleal, Maria and Bis, Joshua C and de Maat, Moniek P M and Rumley, Ann and Kong, Xiaoxiao and Yang, Qiong and Williams, Frances M K and Vitart, Veronique and Campbell, Harry and M{\"a}larstig, Anders and Wiggins, Kerri L and van Duijn, Cornelia M and McArdle, Wendy L and Pankow, James S and Johnson, Andrew D and Silveira, Angela and McKnight, Barbara and Uitterlinden, Andr{\'e} G and Aleksic, Nena and Meigs, James B and Peters, Annette and Koenig, Wolfgang and Cushman, Mary and Kathiresan, Sekar and Rotter, Jerome I and Bovill, Edwin G and Hofman, Albert and Boerwinkle, Eric and Tofler, Geoffrey H and Peden, John F and Psaty, Bruce M and Leebeek, Frank and Folsom, Aaron R and Larson, Martin G and Spector, Timothy D and Wright, Alan F and Wilson, James F and Hamsten, Anders and Lumley, Thomas and Witteman, Jacqueline C M and Tang, Weihong and O{\textquoteright}Donnell, Christopher J} } @article {1325, title = {Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.}, journal = {Nature}, volume = {478}, year = {2011}, month = {2011 Sep 11}, pages = {103-9}, abstract = {

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.

}, keywords = {Africa, Asia, Blood Pressure, Cardiovascular Diseases, Coronary Artery Disease, Europe, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hypertension, Kidney Diseases, Polymorphism, Single Nucleotide, Stroke}, issn = {1476-4687}, doi = {10.1038/nature10405}, author = {Ehret, Georg B and Munroe, Patricia B and Rice, Kenneth M and Bochud, Murielle and Johnson, Andrew D and Chasman, Daniel I and Smith, Albert V and Tobin, Martin D and Verwoert, Germaine C and Hwang, Shih-Jen and Pihur, Vasyl and Vollenweider, Peter and O{\textquoteright}Reilly, Paul F and Amin, Najaf and Bragg-Gresham, Jennifer L and Teumer, Alexander and Glazer, Nicole L and Launer, Lenore and Zhao, Jing Hua and Aulchenko, Yurii and Heath, Simon and S{\~o}ber, Siim and Parsa, Afshin and Luan, Jian{\textquoteright}an and Arora, Pankaj and Dehghan, Abbas and Zhang, Feng and Lucas, Gavin and Hicks, Andrew A and Jackson, Anne U and Peden, John F and Tanaka, Toshiko and Wild, Sarah H and Rudan, Igor and Igl, Wilmar and Milaneschi, Yuri and Parker, Alex N and Fava, Cristiano and Chambers, John C and Fox, Ervin R and Kumari, Meena and Go, Min Jin and van der Harst, Pim and Kao, Wen Hong Linda and Sj{\"o}gren, Marketa and Vinay, D G and Alexander, Myriam and Tabara, Yasuharu and Shaw-Hawkins, Sue and Whincup, Peter H and Liu, Yongmei and Shi, Gang and Kuusisto, Johanna and Tayo, Bamidele and Seielstad, Mark and Sim, Xueling and Nguyen, Khanh-Dung Hoang and Lehtim{\"a}ki, Terho and Matullo, Giuseppe and Wu, Ying and Gaunt, Tom R and Onland-Moret, N Charlotte and Cooper, Matthew N and Platou, Carl G P and Org, Elin and Hardy, Rebecca and Dahgam, Santosh and Palmen, Jutta and Vitart, Veronique and Braund, Peter S and Kuznetsova, Tatiana and Uiterwaal, Cuno S P M and Adeyemo, Adebowale and Palmas, Walter and Campbell, Harry and Ludwig, Barbara and Tomaszewski, Maciej and Tzoulaki, Ioanna and Palmer, Nicholette D and Aspelund, Thor and Garcia, Melissa and Chang, Yen-Pei C and O{\textquoteright}Connell, Jeffrey R and Steinle, Nanette I and Grobbee, Diederick E and Arking, Dan E and Kardia, Sharon L and Morrison, Alanna C and Hernandez, Dena and Najjar, Samer and McArdle, Wendy L and Hadley, David and Brown, Morris J and Connell, John M and Hingorani, Aroon D and Day, Ian N M and Lawlor, Debbie A and Beilby, John P and Lawrence, Robert W and Clarke, Robert and Hopewell, Jemma C and Ongen, Halit and Dreisbach, Albert W and Li, Yali and Young, J Hunter and Bis, Joshua C and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Adair, Linda S and Lee, Nanette R and Chen, Ming-Huei and Olden, Matthias and Pattaro, Cristian and Bolton, Judith A Hoffman and K{\"o}ttgen, Anna and Bergmann, Sven and Mooser, Vincent and Chaturvedi, Nish and Frayling, Timothy M and Islam, Muhammad and Jafar, Tazeen H and Erdmann, Jeanette and Kulkarni, Smita R and Bornstein, Stefan R and Gr{\"a}ssler, J{\"u}rgen and Groop, Leif and Voight, Benjamin F and Kettunen, Johannes and Howard, Philip and Taylor, Andrew and Guarrera, Simonetta and Ricceri, Fulvio and Emilsson, Valur and Plump, Andrew and Barroso, In{\^e}s and Khaw, Kay-Tee and Weder, Alan B and Hunt, Steven C and Sun, Yan V and Bergman, Richard N and Collins, Francis S and Bonnycastle, Lori L and Scott, Laura J and Stringham, Heather M and Peltonen, Leena and Perola, Markus and Vartiainen, Erkki and Brand, Stefan-Martin and Staessen, Jan A and Wang, Thomas J and Burton, Paul R and Soler Artigas, Maria and Dong, Yanbin and Snieder, Harold and Wang, Xiaoling and Zhu, Haidong and Lohman, Kurt K and Rudock, Megan E and Heckbert, Susan R and Smith, Nicholas L and Wiggins, Kerri L and Doumatey, Ayo and Shriner, Daniel and Veldre, Gudrun and Viigimaa, Margus and Kinra, Sanjay and Prabhakaran, Dorairaj and Tripathy, Vikal and Langefeld, Carl D and Rosengren, Annika and Thelle, Dag S and Corsi, Anna Maria and Singleton, Andrew and Forrester, Terrence and Hilton, Gina and McKenzie, Colin A and Salako, Tunde and Iwai, Naoharu and Kita, Yoshikuni and Ogihara, Toshio and Ohkubo, Takayoshi and Okamura, Tomonori and Ueshima, Hirotsugu and Umemura, Satoshi and Eyheramendy, Susana and Meitinger, Thomas and Wichmann, H-Erich and Cho, Yoon Shin and Kim, Hyung-Lae and Lee, Jong-Young and Scott, James and Sehmi, Joban S and Zhang, Weihua and Hedblad, Bo and Nilsson, Peter and Smith, George Davey and Wong, Andrew and Narisu, Narisu and Stan{\v c}{\'a}kov{\'a}, Alena and Raffel, Leslie J and Yao, Jie and Kathiresan, Sekar and O{\textquoteright}Donnell, Christopher J and Schwartz, Stephen M and Ikram, M Arfan and Longstreth, W T and Mosley, Thomas H and Seshadri, Sudha and Shrine, Nick R G and Wain, Louise V and Morken, Mario A and Swift, Amy J and Laitinen, Jaana and Prokopenko, Inga and Zitting, Paavo and Cooper, Jackie A and Humphries, Steve E and Danesh, John and Rasheed, Asif and Goel, Anuj and Hamsten, Anders and Watkins, Hugh and Bakker, Stephan J L and van Gilst, Wiek H and Janipalli, Charles S and Mani, K Radha and Yajnik, Chittaranjan S and Hofman, Albert and Mattace-Raso, Francesco U S and Oostra, Ben A and Demirkan, Ayse and Isaacs, Aaron and Rivadeneira, Fernando and Lakatta, Edward G and Orr{\`u}, Marco and Scuteri, Angelo and Ala-Korpela, Mika and Kangas, Antti J and Lyytik{\"a}inen, Leo-Pekka and Soininen, Pasi and Tukiainen, Taru and W{\"u}rtz, Peter and Ong, Rick Twee-Hee and D{\"o}rr, Marcus and Kroemer, Heyo K and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Galan, Pilar and Hercberg, Serge and Lathrop, Mark and Zelenika, Diana and Deloukas, Panos and Mangino, Massimo and Spector, Tim D and Zhai, Guangju and Meschia, James F and Nalls, Michael A and Sharma, Pankaj and Terzic, Janos and Kumar, M V Kranthi and Denniff, Matthew and Zukowska-Szczechowska, Ewa and Wagenknecht, Lynne E and Fowkes, F Gerald R and Charchar, Fadi J and Schwarz, Peter E H and Hayward, Caroline and Guo, Xiuqing and Rotimi, Charles and Bots, Michiel L and Brand, Eva and Samani, Nilesh J and Polasek, Ozren and Talmud, Philippa J and Nyberg, Fredrik and Kuh, Diana and Laan, Maris and Hveem, Kristian and Palmer, Lyle J and van der Schouw, Yvonne T and Casas, Juan P and Mohlke, Karen L and Vineis, Paolo and Raitakari, Olli and Ganesh, Santhi K and Wong, Tien Y and Tai, E Shyong and Cooper, Richard S and Laakso, Markku and Rao, Dabeeru C and Harris, Tamara B and Morris, Richard W and Dominiczak, Anna F and Kivimaki, Mika and Marmot, Michael G and Miki, Tetsuro and Saleheen, Danish and Chandak, Giriraj R and Coresh, Josef and Navis, Gerjan and Salomaa, Veikko and Han, Bok-Ghee and Zhu, Xiaofeng and Kooner, Jaspal S and Melander, Olle and Ridker, Paul M and Bandinelli, Stefania and Gyllensten, Ulf B and Wright, Alan F and Wilson, James F and Ferrucci, Luigi and Farrall, Martin and Tuomilehto, Jaakko and Pramstaller, Peter P and Elosua, Roberto and Soranzo, Nicole and Sijbrands, Eric J G and Altshuler, David and Loos, Ruth J F and Shuldiner, Alan R and Gieger, Christian and Meneton, Pierre and Uitterlinden, Andr{\'e} G and Wareham, Nicholas J and Gudnason, Vilmundur and Rotter, Jerome I and Rettig, Rainer and Uda, Manuela and Strachan, David P and Witteman, Jacqueline C M and Hartikainen, Anna-Liisa and Beckmann, Jacques S and Boerwinkle, Eric and Vasan, Ramachandran S and Boehnke, Michael and Larson, Martin G and Jarvelin, Marjo-Riitta and Psaty, Bruce M and Abecasis, Goncalo R and Chakravarti, Aravinda and Elliott, Paul and van Duijn, Cornelia M and Newton-Cheh, Christopher and Levy, Daniel and Caulfield, Mark J and Johnson, Toby} } @article {1355, title = {New gene functions in megakaryopoiesis and platelet formation.}, journal = {Nature}, volume = {480}, year = {2011}, month = {2011 Nov 30}, pages = {201-8}, abstract = {

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.

}, keywords = {Animals, Blood Platelets, Cell Size, Drosophila melanogaster, Drosophila Proteins, Europe, Gene Expression Profiling, Gene Silencing, Genome, Human, Genome-Wide Association Study, Hematopoiesis, Humans, Megakaryocytes, Platelet Count, Protein Interaction Maps, Transcription, Genetic, Zebrafish, Zebrafish Proteins}, issn = {1476-4687}, doi = {10.1038/nature10659}, author = {Gieger, Christian and Radhakrishnan, Aparna and Cvejic, Ana and Tang, Weihong and Porcu, Eleonora and Pistis, Giorgio and Serbanovic-Canic, Jovana and Elling, Ulrich and Goodall, Alison H and Labrune, Yann and Lopez, Lorna M and M{\"a}gi, Reedik and Meacham, Stuart and Okada, Yukinori and Pirastu, Nicola and Sorice, Rossella and Teumer, Alexander and Voss, Katrin and Zhang, Weihua and Ramirez-Solis, Ramiro and Bis, Joshua C and Ellinghaus, David and G{\"o}gele, Martin and Hottenga, Jouke-Jan and Langenberg, Claudia and Kovacs, Peter and O{\textquoteright}Reilly, Paul F and Shin, So-Youn and Esko, T{\~o}nu and Hartiala, Jaana and Kanoni, Stavroula and Murgia, Federico and Parsa, Afshin and Stephens, Jonathan and van der Harst, Pim and Ellen van der Schoot, C and Allayee, Hooman and Attwood, Antony and Balkau, Beverley and Bastardot, Fran{\c c}ois and Basu, Saonli and Baumeister, Sebastian E and Biino, Ginevra and Bomba, Lorenzo and Bonnefond, Am{\'e}lie and Cambien, Francois and Chambers, John C and Cucca, Francesco and D{\textquoteright}Adamo, Pio and Davies, Gail and de Boer, Rudolf A and de Geus, Eco J C and D{\"o}ring, Angela and Elliott, Paul and Erdmann, Jeanette and Evans, David M and Falchi, Mario and Feng, Wei and Folsom, Aaron R and Frazer, Ian H and Gibson, Quince D and Glazer, Nicole L and Hammond, Chris and Hartikainen, Anna-Liisa and Heckbert, Susan R and Hengstenberg, Christian and Hersch, Micha and Illig, Thomas and Loos, Ruth J F and Jolley, Jennifer and Khaw, Kay Tee and Kuhnel, Brigitte and Kyrtsonis, Marie-Christine and Lagou, Vasiliki and Lloyd-Jones, Heather and Lumley, Thomas and Mangino, Massimo and Maschio, Andrea and Mateo Leach, Irene and McKnight, Barbara and Memari, Yasin and Mitchell, Braxton D and Montgomery, Grant W and Nakamura, Yusuke and Nauck, Matthias and Navis, Gerjan and N{\"o}thlings, Ute and Nolte, Ilja M and Porteous, David J and Pouta, Anneli and Pramstaller, Peter P and Pullat, Janne and Ring, Susan M and Rotter, Jerome I and Ruggiero, Daniela and Ruokonen, Aimo and Sala, Cinzia and Samani, Nilesh J and Sambrook, Jennifer and Schlessinger, David and Schreiber, Stefan and Schunkert, Heribert and Scott, James and Smith, Nicholas L and Snieder, Harold and Starr, John M and Stumvoll, Michael and Takahashi, Atsushi and Tang, W H Wilson and Taylor, Kent and Tenesa, Albert and Lay Thein, Swee and T{\"o}njes, Anke and Uda, Manuela and Ulivi, Sheila and van Veldhuisen, Dirk J and Visscher, Peter M and V{\"o}lker, Uwe and Wichmann, H-Erich and Wiggins, Kerri L and Willemsen, Gonneke and Yang, Tsun-Po and Hua Zhao, Jing and Zitting, Paavo and Bradley, John R and Dedoussis, George V and Gasparini, Paolo and Hazen, Stanley L and Metspalu, Andres and Pirastu, Mario and Shuldiner, Alan R and Joost van Pelt, L and Zwaginga, Jaap-Jan and Boomsma, Dorret I and Deary, Ian J and Franke, Andre and Froguel, Philippe and Ganesh, Santhi K and Jarvelin, Marjo-Riitta and Martin, Nicholas G and Meisinger, Christa and Psaty, Bruce M and Spector, Timothy D and Wareham, Nicholas J and Akkerman, Jan-Willem N and Ciullo, Marina and Deloukas, Panos and Greinacher, Andreas and Jupe, Steve and Kamatani, Naoyuki and Khadake, Jyoti and Kooner, Jaspal S and Penninger, Josef and Prokopenko, Inga and Stemple, Derek and Toniolo, Daniela and Wernisch, Lorenz and Sanna, Serena and Hicks, Andrew A and Rendon, Augusto and Ferreira, Manuel A and Ouwehand, Willem H and Soranzo, Nicole} } @article {5863, title = {Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies.}, journal = {Lancet Neurol}, volume = {11}, year = {2012}, month = {2012 Nov}, pages = {951-62}, abstract = {

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{\textperiodcentered}8{\texttimes}10(-16)) and ZFHX3 (p=2{\textperiodcentered}28{\texttimes}10(-8)), and for large-vessel stroke at a 9p21 locus (p=3{\textperiodcentered}32{\texttimes}10(-5)) and HDAC9 (p=2{\textperiodcentered}03{\texttimes}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{\texttimes}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).

}, keywords = {Brain Ischemia, Databases, Genetic, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Risk Factors, Stroke}, issn = {1474-4465}, doi = {10.1016/S1474-4422(12)70234-X}, author = {Traylor, Matthew and Farrall, Martin and Holliday, Elizabeth G and Sudlow, Cathie and Hopewell, Jemma C and Cheng, Yu-Ching and Fornage, Myriam and Ikram, M Arfan and Malik, Rainer and Bevan, Steve and Thorsteinsdottir, Unnur and Nalls, Mike A and Longstreth, Wt and Wiggins, Kerri L and Yadav, Sunaina and Parati, Eugenio A and DeStefano, Anita L and Worrall, Bradford B and Kittner, Steven J and Khan, Muhammad Saleem and Reiner, Alex P and Helgadottir, Anna and Achterberg, Sefanja and Fernandez-Cadenas, Israel and Abboud, Sherine and Schmidt, Reinhold and Walters, Matthew and Chen, Wei-Min and Ringelstein, E Bernd and O{\textquoteright}Donnell, Martin and Ho, Weang Kee and Pera, Joanna and Lemmens, Robin and Norrving, Bo and Higgins, Peter and Benn, Marianne and Sale, Michele and Kuhlenb{\"a}umer, Gregor and Doney, Alexander S F and Vicente, Astrid M and Delavaran, Hossein and Algra, Ale and Davies, Gail and Oliveira, Sofia A and Palmer, Colin N A and Deary, Ian and Schmidt, Helena and Pandolfo, Massimo and Montaner, Joan and Carty, Cara and de Bakker, Paul I W and Kostulas, Konstantinos and Ferro, Jose M and van Zuydam, Natalie R and Valdimarsson, Einar and Nordestgaard, B{\o}rge G and Lindgren, Arne and Thijs, Vincent and Slowik, Agnieszka and Saleheen, Danish and Par{\'e}, Guillaume and Berger, Klaus and Thorleifsson, Gudmar and Hofman, Albert and Mosley, Thomas H and Mitchell, Braxton D and Furie, Karen and Clarke, Robert and Levi, Christopher and Seshadri, Sudha and Gschwendtner, Andreas and Boncoraglio, Giorgio B and Sharma, Pankaj and Bis, Joshua C and Gretarsdottir, Solveig and Psaty, Bruce M and Rothwell, Peter M and Rosand, Jonathan and Meschia, James F and Stefansson, Kari and Dichgans, Martin and Markus, Hugh S} } @article {6027, title = {Genetic loci for retinal arteriolar microcirculation.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e65804}, abstract = {

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{\texttimes}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{\texttimes}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.

}, keywords = {Aged, Aged, 80 and over, Arterioles, Chromosomes, Human, Pair 5, European Continental Ancestry Group, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Male, MEF2 Transcription Factors, Microcirculation, Middle Aged, Models, Genetic, Retinal Vessels}, issn = {1932-6203}, doi = {10.1371/journal.pone.0065804}, author = {Sim, Xueling and Jensen, Richard A and Ikram, M Kamran and Cotch, Mary Frances and Li, Xiaohui and Macgregor, Stuart and Xie, Jing and Smith, Albert Vernon and Boerwinkle, Eric and Mitchell, Paul and Klein, Ronald and Klein, Barbara E K and Glazer, Nicole L and Lumley, Thomas and McKnight, Barbara and Psaty, Bruce M and de Jong, Paulus T V M and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Aspelund, Thor and Eiriksdottir, Gudny and Harris, Tamara B and Jonasson, Fridbert and Launer, Lenore J and Attia, John and Baird, Paul N and Harrap, Stephen and Holliday, Elizabeth G and Inouye, Michael and Rochtchina, Elena and Scott, Rodney J and Viswanathan, Ananth and Li, Guo and Smith, Nicholas L and Wiggins, Kerri L and Kuo, Jane Z and Taylor, Kent D and Hewitt, Alex W and Martin, Nicholas G and Montgomery, Grant W and Sun, Cong and Young, Terri L and Mackey, David A and van Zuydam, Natalie R and Doney, Alex S F and Palmer, Colin N A and Morris, Andrew D and Rotter, Jerome I and Tai, E Shyong and Gudnason, Vilmundur and Vingerling, Johannes R and Siscovick, David S and Wang, Jie Jin and Wong, Tien Y} } @article {6072, title = {Genome-wide association study of retinopathy in individuals without diabetes.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e54232}, abstract = {

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{\textpm}0.23 (beta {\textpm} standard error), p = 6.6{\texttimes}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.

}, keywords = {Aged, Aged, 80 and over, Female, Genome-Wide Association Study, Genotype, Histone Deacetylases, Humans, Hypertension, Male, Polymorphism, Single Nucleotide, Repressor Proteins, Retinal Diseases}, issn = {1932-6203}, doi = {10.1371/journal.pone.0054232}, author = {Jensen, Richard A and Sim, Xueling and Li, Xiaohui and Cotch, Mary Frances and Ikram, M Kamran and Holliday, Elizabeth G and Eiriksdottir, Gudny and Harris, Tamara B and Jonasson, Fridbert and Klein, Barbara E K and Launer, Lenore J and Smith, Albert Vernon and Boerwinkle, Eric and Cheung, Ning and Hewitt, Alex W and Liew, Gerald and Mitchell, Paul and Wang, Jie Jin and Attia, John and Scott, Rodney and Glazer, Nicole L and Lumley, Thomas and McKnight, Barbara and Psaty, Bruce M and Taylor, Kent and Hofman, Albert and de Jong, Paulus T V M and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Tay, Wan-Ting and Teo, Yik Ying and Seielstad, Mark and Liu, Jianjun and Cheng, Ching-Yu and Saw, Seang-Mei and Aung, Tin and Ganesh, Santhi K and O{\textquoteright}Donnell, Christopher J and Nalls, Mike A and Wiggins, Kerri L and Kuo, Jane Z and van Duijn, Cornelia M and Gudnason, Vilmundur and Klein, Ronald and Siscovick, David S and Rotter, Jerome I and Tai, E Shong and Vingerling, Johannes and Wong, Tien Y} } @article {6819, title = {Genome-wide association study of L-arginine and dimethylarginines reveals novel metabolic pathway for symmetric dimethylarginine.}, journal = {Circ Cardiovasc Genet}, volume = {7}, year = {2014}, month = {2014 Dec}, pages = {864-72}, abstract = {

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.

}, keywords = {Adult, Aged, Amidohydrolases, Arginine, Binding Sites, Cohort Studies, Female, Genetic Loci, Genome-Wide Association Study, Genotype, HEK293 Cells, Humans, Male, Mediator Complex, Middle Aged, Polymorphism, Single Nucleotide, Protein Structure, Tertiary, Risk Factors, Stroke, Substrate Specificity, Transaminases}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.113.000264}, author = {L{\"u}neburg, Nicole and Lieb, Wolfgang and Zeller, Tanja and Chen, Ming-Huei and Maas, Renke and Carter, Angela M and Xanthakis, Vanessa and Glazer, Nicole L and Schwedhelm, Edzard and Seshadri, Sudha and Ikram, Mohammad Arfan and Longstreth, William T and Fornage, Myriam and K{\"o}nig, Inke R and Loley, Christina and Ojeda, Francisco M and Schillert, Arne and Wang, Thomas J and Sticht, Heinrich and Kittel, Anja and K{\"o}nig, J{\"o}rg and Benjamin, Emelia J and Sullivan, Lisa M and Bernges, Isabel and Anderssohn, Maike and Ziegler, Andreas and Gieger, Christian and Illig, Thomas and Meisinger, Christa and Wichmann, H-Erich and Wild, Philipp S and Schunkert, Heribert and Psaty, Bruce M and Wiggins, Kerri L and Heckbert, Susan R and Smith, Nicholas and Lackner, Karl and Lunetta, Kathryn L and Blankenberg, Stefan and Erdmann, Jeanette and M{\"u}nzel, Thomas and Grant, Peter J and Vasan, Ramachandran S and B{\"o}ger, Rainer H} } @article {6591, title = {Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.}, journal = {Nat Commun}, volume = {5}, year = {2014}, month = {2014 Oct 28}, pages = {5068}, abstract = {

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.

}, keywords = {Cholesterol, LDL, Genome-Wide Association Study, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Pharmacogenetics, Polymorphism, Single Nucleotide}, issn = {2041-1723}, doi = {10.1038/ncomms6068}, author = {Postmus, Iris and Trompet, Stella and Deshmukh, Harshal A and Barnes, Michael R and Li, Xiaohui and Warren, Helen R and Chasman, Daniel I and Zhou, Kaixin and Arsenault, Benoit J and Donnelly, Louise A and Wiggins, Kerri L and Avery, Christy L and Griffin, Paula and Feng, QiPing and Taylor, Kent D and Li, Guo and Evans, Daniel S and Smith, Albert V and de Keyser, Catherine E and Johnson, Andrew D and de Craen, Anton J M and Stott, David J and Buckley, Brendan M and Ford, Ian and Westendorp, Rudi G J and Slagboom, P Eline and Sattar, Naveed and Munroe, Patricia B and Sever, Peter and Poulter, Neil and Stanton, Alice and Shields, Denis C and O{\textquoteright}Brien, Eoin and Shaw-Hawkins, Sue and Chen, Y-D Ida and Nickerson, Deborah A and Smith, Joshua D and Dub{\'e}, Marie Pierre and Boekholdt, S Matthijs and Hovingh, G Kees and Kastelein, John J P and McKeigue, Paul M and Betteridge, John and Neil, Andrew and Durrington, Paul N and Doney, Alex and Carr, Fiona and Morris, Andrew and McCarthy, Mark I and Groop, Leif and Ahlqvist, Emma and Bis, Joshua C and Rice, Kenneth and Smith, Nicholas L and Lumley, Thomas and Whitsel, Eric A and St{\"u}rmer, Til and Boerwinkle, Eric and Ngwa, Julius S and O{\textquoteright}Donnell, Christopher J and Vasan, Ramachandran S and Wei, Wei-Qi and Wilke, Russell A and Liu, Ching-Ti and Sun, Fangui and Guo, Xiuqing and Heckbert, Susan R and Post, Wendy and Sotoodehnia, Nona and Arnold, Alice M and Stafford, Jeanette M and Ding, Jingzhong and Herrington, David M and Kritchevsky, Stephen B and Eiriksdottir, Gudny and Launer, Leonore J and Harris, Tamara B and Chu, Audrey Y and Giulianini, Franco and MacFadyen, Jean G and Barratt, Bryan J and Nyberg, Fredrik and Stricker, Bruno H and Uitterlinden, Andr{\'e} G and Hofman, Albert and Rivadeneira, Fernando and Emilsson, Valur and Franco, Oscar H and Ridker, Paul M and Gudnason, Vilmundur and Liu, Yongmei and Denny, Joshua C and Ballantyne, Christie M and Rotter, Jerome I and Adrienne Cupples, L and Psaty, Bruce M and Palmer, Colin N A and Tardif, Jean-Claude and Colhoun, Helen M and Hitman, Graham and Krauss, Ronald M and Wouter Jukema, J and Caulfield, Mark J} } @article {6875, title = {Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium.}, journal = {PLoS One}, volume = {10}, year = {2015}, month = {2015}, pages = {e0140496}, abstract = {

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{\texttimes}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.

}, keywords = {African Americans, Aged, Antihypertensive Agents, Cardiovascular Diseases, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Hypertension, Incidence, Male, Middle Aged, Polymorphism, Single Nucleotide, Treatment Outcome}, issn = {1932-6203}, doi = {10.1371/journal.pone.0140496}, author = {Bis, Joshua C and Sitlani, Colleen and Irvin, Ryan and Avery, Christy L and Smith, Albert Vernon and Sun, Fangui and Evans, Daniel S and Musani, Solomon K and Li, Xiaohui and Trompet, Stella and Krijthe, Bouwe P and Harris, Tamara B and Quibrera, P Miguel and Brody, Jennifer A and Demissie, Serkalem and Davis, Barry R and Wiggins, Kerri L and Tranah, Gregory J and Lange, Leslie A and Sotoodehnia, Nona and Stott, David J and Franco, Oscar H and Launer, Lenore J and St{\"u}rmer, Til and Taylor, Kent D and Cupples, L Adrienne and Eckfeldt, John H and Smith, Nicholas L and Liu, Yongmei and Wilson, James G and Heckbert, Susan R and Buckley, Brendan M and Ikram, M Arfan and Boerwinkle, Eric and Chen, Yii-Der Ida and de Craen, Anton J M and Uitterlinden, Andr{\'e} G and Rotter, Jerome I and Ford, Ian and Hofman, Albert and Sattar, Naveed and Slagboom, P Eline and Westendorp, Rudi G J and Gudnason, Vilmundur and Vasan, Ramachandran S and Lumley, Thomas and Cummings, Steven R and Taylor, Herman A and Post, Wendy and Jukema, J Wouter and Stricker, Bruno H and Whitsel, Eric A and Psaty, Bruce M and Arnett, Donna} } @article {6688, title = {Genetic overlap between diagnostic subtypes of ischemic stroke.}, journal = {Stroke}, volume = {46}, year = {2015}, month = {2015 Mar}, pages = {615-9}, abstract = {

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{\texttimes}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{\texttimes}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.

}, keywords = {Alleles, Atherosclerosis, Cerebral Small Vessel Diseases, Cohort Studies, Data Interpretation, Statistical, Embolism, Genome-Wide Association Study, Genotype, Humans, Ischemia, Linear Models, Meta-Analysis as Topic, Phenotype, Polymorphism, Single Nucleotide, Stroke}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.114.007930}, author = {Holliday, Elizabeth G and Traylor, Matthew and Malik, Rainer and Bevan, Steve and Falcone, Guido and Hopewell, Jemma C and Cheng, Yu-Ching and Cotlarciuc, Ioana and Bis, Joshua C and Boerwinkle, Eric and Boncoraglio, Giorgio B and Clarke, Robert and Cole, John W and Fornage, Myriam and Furie, Karen L and Ikram, M Arfan and Jannes, Jim and Kittner, Steven J and Lincz, Lisa F and Maguire, Jane M and Meschia, James F and Mosley, Thomas H and Nalls, Mike A and Oldmeadow, Christopher and Parati, Eugenio A and Psaty, Bruce M and Rothwell, Peter M and Seshadri, Sudha and Scott, Rodney J and Sharma, Pankaj and Sudlow, Cathie and Wiggins, Kerri L and Worrall, Bradford B and Rosand, Jonathan and Mitchell, Braxton D and Dichgans, Martin and Markus, Hugh S and Levi, Christopher and Attia, John and Wray, Naomi R} } @article {6681, title = {Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism.}, journal = {Am J Hum Genet}, volume = {96}, year = {2015}, month = {2015 Apr 2}, pages = {532-42}, abstract = {

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~{\texttimes} 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~{\texttimes} 10(-16)) and 1.21 (p = 2.75~{\texttimes} 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.

}, keywords = {Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Membrane Glycoproteins, Membrane Transport Proteins, Odds Ratio, Tetraspanins, Venous Thromboembolism}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.01.019}, author = {Germain, Marine and Chasman, Daniel I and de Haan, Hugoline and Tang, Weihong and Lindstr{\"o}m, Sara and Weng, Lu-Chen and de Andrade, Mariza and de Visser, Marieke C H and Wiggins, Kerri L and Suchon, Pierre and Saut, No{\'e}mie and Smadja, David M and Le Gal, Gr{\'e}goire and van Hylckama Vlieg, Astrid and Di Narzo, Antonio and Hao, Ke and Nelson, Christopher P and Rocanin-Arjo, Ares and Folkersen, Lasse and Monajemi, Ramin and Rose, Lynda M and Brody, Jennifer A and Slagboom, Eline and A{\"\i}ssi, Dylan and Gagnon, France and Deleuze, Jean-Francois and Deloukas, Panos and Tzourio, Christophe and Dartigues, Jean-Fran{\c c}ois and Berr, Claudine and Taylor, Kent D and Civelek, Mete and Eriksson, Per and Psaty, Bruce M and Houwing-Duitermaat, Jeanine and Goodall, Alison H and Cambien, Francois and Kraft, Peter and Amouyel, Philippe and Samani, Nilesh J and Basu, Saonli and Ridker, Paul M and Rosendaal, Frits R and Kabrhel, Christopher and Folsom, Aaron R and Heit, John and Reitsma, Pieter H and Tr{\'e}gou{\"e}t, David-Alexandre and Smith, Nicholas L and Morange, Pierre-Emmanuel} } @article {6788, title = {Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF.}, journal = {Blood}, volume = {126}, year = {2015}, month = {2015 Sep 10}, pages = {e19-29}, abstract = {

Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] >=0.01 and <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.

}, keywords = {Cohort Studies, Factor VII, Factor VIII, Fibrinogen, Gene Frequency, Genetic Association Studies, Genetic Variation, Humans, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Potassium Channels, von Willebrand Factor}, issn = {1528-0020}, doi = {10.1182/blood-2015-02-624551}, author = {Huffman, Jennifer E and de Vries, Paul S and Morrison, Alanna C and Sabater-Lleal, Maria and Kacprowski, Tim and Auer, Paul L and Brody, Jennifer A and Chasman, Daniel I and Chen, Ming-Huei and Guo, Xiuqing and Lin, Li-An and Marioni, Riccardo E and M{\"u}ller-Nurasyid, Martina and Yanek, Lisa R and Pankratz, Nathan and Grove, Megan L and de Maat, Moniek P M and Cushman, Mary and Wiggins, Kerri L and Qi, Lihong and Sennblad, Bengt and Harris, Sarah E and Polasek, Ozren and Riess, Helene and Rivadeneira, Fernando and Rose, Lynda M and Goel, Anuj and Taylor, Kent D and Teumer, Alexander and Uitterlinden, Andr{\'e} G and Vaidya, Dhananjay and Yao, Jie and Tang, Weihong and Levy, Daniel and Waldenberger, Melanie and Becker, Diane M and Folsom, Aaron R and Giulianini, Franco and Greinacher, Andreas and Hofman, Albert and Huang, Chiang-Ching and Kooperberg, Charles and Silveira, Angela and Starr, John M and Strauch, Konstantin and Strawbridge, Rona J and Wright, Alan F and McKnight, Barbara and Franco, Oscar H and Zakai, Neil and Mathias, Rasika A and Psaty, Bruce M and Ridker, Paul M and Tofler, Geoffrey H and V{\"o}lker, Uwe and Watkins, Hugh and Fornage, Myriam and Hamsten, Anders and Deary, Ian J and Boerwinkle, Eric and Koenig, Wolfgang and Rotter, Jerome I and Hayward, Caroline and Dehghan, Abbas and Reiner, Alex P and O{\textquoteright}Donnell, Christopher J and Smith, Nicholas L} } @article {6561, title = {Variation in resting heart rate over 4 years and the risks of myocardial infarction and death among older adults.}, journal = {Heart}, volume = {101}, year = {2015}, month = {2015 Jan}, pages = {132-8}, abstract = {

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.

}, keywords = {Aged, Aged, 80 and over, Cause of Death, Electrocardiography, Female, Follow-Up Studies, Heart Rate, Humans, Incidence, Linear Models, Male, Myocardial Infarction, Outcome Assessment (Health Care), Prognosis, Proportional Hazards Models, Prospective Studies, Rest, Risk Factors, Time, Washington}, issn = {1468-201X}, doi = {10.1136/heartjnl-2014-306046}, author = {Floyd, James S and Sitlani, Colleen M and Wiggins, Kerri L and Wallace, Erin and Suchy-Dicey, Astrid and Abbasi, Siddique A and Carnethon, Mercedes R and Siscovick, David S and Sotoodehnia, Nona and Heckbert, Susan R and McKnight, Barbara and Rice, Kenneth M and Psaty, Bruce M} } @article {7572, title = {Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.}, journal = {PLoS Genet}, volume = {13}, year = {2017}, month = {2017 May}, pages = {e1006728}, abstract = {

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{\texttimes}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.

}, keywords = {African Americans, Animals, Basic Helix-Loop-Helix Transcription Factors, Blood Pressure, Cadherins, Case-Control Studies, Female, Genetic Loci, Genome-Wide Association Study, Humans, Hypertension, Male, Membrane Proteins, Mice, Multifactorial Inheritance, Polymorphism, Single Nucleotide}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006728}, author = {Liang, Jingjing and Le, Thu H and Edwards, Digna R Velez and Tayo, Bamidele O and Gaulton, Kyle J and Smith, Jennifer A and Lu, Yingchang and Jensen, Richard A and Chen, Guanjie and Yanek, Lisa R and Schwander, Karen and Tajuddin, Salman M and Sofer, Tamar and Kim, Wonji and Kayima, James and McKenzie, Colin A and Fox, Ervin and Nalls, Michael A and Young, J Hunter and Sun, Yan V and Lane, Jacqueline M and Cechova, Sylvia and Zhou, Jie and Tang, Hua and Fornage, Myriam and Musani, Solomon K and Wang, Heming and Lee, Juyoung and Adeyemo, Adebowale and Dreisbach, Albert W and Forrester, Terrence and Chu, Pei-Lun and Cappola, Anne and Evans, Michele K and Morrison, Alanna C and Martin, Lisa W and Wiggins, Kerri L and Hui, Qin and Zhao, Wei and Jackson, Rebecca D and Ware, Erin B and Faul, Jessica D and Reiner, Alex P and Bray, Michael and Denny, Joshua C and Mosley, Thomas H and Palmas, Walter and Guo, Xiuqing and Papanicolaou, George J and Penman, Alan D and Polak, Joseph F and Rice, Kenneth and Taylor, Ken D and Boerwinkle, Eric and Bottinger, Erwin P and Liu, Kiang and Risch, Neil and Hunt, Steven C and Kooperberg, Charles and Zonderman, Alan B and Laurie, Cathy C and Becker, Diane M and Cai, Jianwen and Loos, Ruth J F and Psaty, Bruce M and Weir, David R and Kardia, Sharon L R and Arnett, Donna K and Won, Sungho and Edwards, Todd L and Redline, Susan and Cooper, Richard S and Rao, D C and Rotter, Jerome I and Rotimi, Charles and Levy, Daniel and Chakravarti, Aravinda and Zhu, Xiaofeng and Franceschini, Nora} } @article {8507, title = {Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease.}, journal = {Circulation}, volume = {140}, year = {2019}, month = {2019 08 20}, pages = {645-657}, abstract = {

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.

}, keywords = {Adult, Aged, Cohort Studies, Coronary Disease, CpG Islands, DNA Methylation, Europe, Female, Genome-Wide Association Study, Humans, Incidence, Leukocytes, Male, Middle Aged, Myocardial Infarction, Population Groups, Prognosis, Prospective Studies, Risk, United States}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.118.039357}, author = {Agha, Golareh and Mendelson, Michael M and Ward-Caviness, Cavin K and Joehanes, Roby and Huan, Tianxiao and Gondalia, Rahul and Salfati, Elias and Brody, Jennifer A and Fiorito, Giovanni and Bressler, Jan and Chen, Brian H and Ligthart, Symen and Guarrera, Simonetta and Colicino, Elena and Just, Allan C and Wahl, Simone and Gieger, Christian and Vandiver, Amy R and Tanaka, Toshiko and Hernandez, Dena G and Pilling, Luke C and Singleton, Andrew B and Sacerdote, Carlotta and Krogh, Vittorio and Panico, Salvatore and Tumino, Rosario and Li, Yun and Zhang, Guosheng and Stewart, James D and Floyd, James S and Wiggins, Kerri L and Rotter, Jerome I and Multhaup, Michael and Bakulski, Kelly and Horvath, Steven and Tsao, Philip S and Absher, Devin M and Vokonas, Pantel and Hirschhorn, Joel and Fallin, M Daniele and Liu, Chunyu and Bandinelli, Stefania and Boerwinkle, Eric and Dehghan, Abbas and Schwartz, Joel D and Psaty, Bruce M and Feinberg, Andrew P and Hou, Lifang and Ferrucci, Luigi and Sotoodehnia, Nona and Matullo, Giuseppe and Peters, Annette and Fornage, Myriam and Assimes, Themistocles L and Whitsel, Eric A and Levy, Daniel and Baccarelli, Andrea A} } @article {9372, title = {Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group.}, journal = {Am J Hypertens}, volume = {32}, year = {2019}, month = {2019 Nov 15}, pages = {1146-1153}, abstract = {

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 {\texttimes} 10-8) and in the race-combined analysis (P = 1.5 {\texttimes} 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.

}, keywords = {Aged, Antihypertensive Agents, Black or African American, Blood Pressure, Case-Control Studies, DNA (Cytosine-5-)-Methyltransferases, DNA Methyltransferase 3A, DNA-Binding Proteins, Drug Resistance, Dystrophin-Associated Proteins, Europe, Female, Genetic Loci, Genome-Wide Association Study, Humans, Hypertension, Male, Middle Aged, Myosin Heavy Chains, Myosin Type V, Neuropeptides, Pharmacogenetics, Pharmacogenomic Variants, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Transcription Factors, United States, White People}, issn = {1941-7225}, doi = {10.1093/ajh/hpz150}, author = {Irvin, Marguerite R and Sitlani, Colleen M and Floyd, James S and Psaty, Bruce M and Bis, Joshua C and Wiggins, Kerri L and Whitsel, Eric A and St{\"u}rmer, Til and Stewart, James and Raffield, Laura and Sun, Fangui and Liu, Ching-Ti and Xu, Hanfei and Cupples, Adrienne L and Tanner, Rikki M and Rossing, Peter and Smith, Albert and Zilh{\~a}o, Nuno R and Launer, Lenore J and Noordam, Raymond and Rotter, Jerome I and Yao, Jie and Li, Xiaohui and Guo, Xiuqing and Limdi, Nita and Sundaresan, Aishwarya and Lange, Leslie and Correa, Adolfo and Stott, David J and Ford, Ian and Jukema, J Wouter and Gudnason, Vilmundur and Mook-Kanamori, Dennis O and Trompet, Stella and Palmas, Walter and Warren, Helen R and Hellwege, Jacklyn N and Giri, Ayush and O{\textquoteright}donnell, Christopher and Hung, Adriana M and Edwards, Todd L and Ahluwalia, Tarunveer S and Arnett, Donna K and Avery, Christy L} } @article {8511, title = {Genome-wide meta-analysis of SNP and antihypertensive medication interactions on left ventricular traits in African Americans.}, journal = {Mol Genet Genomic Med}, volume = {7}, year = {2019}, month = {2019 10}, pages = {e00788}, abstract = {

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~{\texttimes}~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.

}, keywords = {African Americans, Angiotensin-Converting Enzyme Inhibitors, Antihypertensive Agents, Calcium Channel Blockers, Humans, Observational Studies as Topic, Pharmacogenomic Variants, Polymorphism, Single Nucleotide, Sodium Chloride Symporter Inhibitors, Ventricular Dysfunction, Left}, issn = {2324-9269}, doi = {10.1002/mgg3.788}, author = {Do, Anh N and Zhao, Wei and Baldridge, Abigail S and Raffield, Laura M and Wiggins, Kerri L and Shah, Sanjiv J and Aslibekyan, Stella and Tiwari, Hemant K and Limdi, Nita and Zhi, Degui and Sitlani, Colleen M and Taylor, Kent D and Psaty, Bruce M and Sotoodehnia, Nona and Brody, Jennifer A and Rasmussen-Torvik, Laura J and Lloyd-Jones, Donald and Lange, Leslie A and Wilson, James G and Smith, Jennifer A and Kardia, Sharon L R and Mosley, Thomas H and Vasan, Ramachandran S and Arnett, Donna K and Irvin, Marguerite R} } @article {9194, title = {Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors.}, journal = {Circulation}, volume = {146}, year = {2022}, month = {2022 Oct 18}, pages = {1225-1242}, abstract = {

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.

}, keywords = {Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Thrombosis, Venous Thromboembolism}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.122.059675}, author = {Thibord, Florian and Klarin, Derek and Brody, Jennifer A and Chen, Ming-Huei and Levin, Michael G and Chasman, Daniel I and Goode, Ellen L and Hveem, Kristian and Teder-Laving, Maris and Martinez-Perez, Angel and A{\"\i}ssi, Dylan and Daian-Bacq, Delphine and Ito, Kaoru and Natarajan, Pradeep and Lutsey, Pamela L and Nadkarni, Girish N and de Vries, Paul S and Cuellar-Partida, Gabriel and Wolford, Brooke N and Pattee, Jack W and Kooperberg, Charles and Braekkan, Sigrid K and Li-Gao, Ruifang and Saut, No{\'e}mie and Sept, Corriene and Germain, Marine and Judy, Renae L and Wiggins, Kerri L and Ko, Darae and O{\textquoteright}Donnell, Christopher J and Taylor, Kent D and Giulianini, Franco and de Andrade, Mariza and N{\o}st, Therese H and Boland, Anne and Empana, Jean-Philippe and Koyama, Satoshi and Gilliland, Thomas and Do, Ron and Huffman, Jennifer E and Wang, Xin and Zhou, Wei and Manuel Soria, Jose and Carlos Souto, Juan and Pankratz, Nathan and Haessler, Jeffery and Hindberg, Kristian and Rosendaal, Frits R and Turman, Constance and Olaso, Robert and Kember, Rachel L and Bartz, Traci M and Lynch, Julie A and Heckbert, Susan R and Armasu, Sebastian M and Brumpton, Ben and Smadja, David M and Jouven, Xavier and Komuro, Issei and Clapham, Katharine R and Loos, Ruth J F and Willer, Cristen J and Sabater-Lleal, Maria and Pankow, James S and Reiner, Alexander P and Morelli, Vania M and Ridker, Paul M and Vlieg, Astrid van Hylckama and Deleuze, Jean-Francois and Kraft, Peter and Rader, Daniel J and Min Lee, Kyung and Psaty, Bruce M and Heidi Skogholt, Anne and Emmerich, Joseph and Suchon, Pierre and Rich, Stephen S and Vy, Ha My T and Tang, Weihong and Jackson, Rebecca D and Hansen, John-Bjarne and Morange, Pierre-Emmanuel and Kabrhel, Christopher and Tr{\'e}gou{\"e}t, David-Alexandre and Damrauer, Scott M and Johnson, Andrew D and Smith, Nicholas L} } @article {9100, title = {A multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood.}, journal = {Nat Commun}, volume = {13}, year = {2022}, month = {2022 Jun 21}, pages = {3549}, abstract = {

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.

}, keywords = {Adult, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hypertension, Multifactorial Inheritance, Prevalence, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-022-31080-2}, author = {Kurniansyah, Nuzulul and Goodman, Matthew O and Kelly, Tanika N and Elfassy, Tali and Wiggins, Kerri L and Bis, Joshua C and Guo, Xiuqing and Palmas, Walter and Taylor, Kent D and Lin, Henry J and Haessler, Jeffrey and Gao, Yan and Shimbo, Daichi and Smith, Jennifer A and Yu, Bing and Feofanova, Elena V and Smit, Roelof A J and Wang, Zhe and Hwang, Shih-Jen and Liu, Simin and Wassertheil-Smoller, Sylvia and Manson, JoAnn E and Lloyd-Jones, Donald M and Rich, Stephen S and Loos, Ruth J F and Redline, Susan and Correa, Adolfo and Kooperberg, Charles and Fornage, Myriam and Kaplan, Robert C and Psaty, Bruce M and Rotter, Jerome I and Arnett, Donna K and Morrison, Alanna C and Franceschini, Nora and Levy, Daniel and Sofer, Tamar} } @article {9387, title = {Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.}, journal = {Nature}, volume = {616}, year = {2023}, month = {2023 Apr}, pages = {755-763}, abstract = {

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.

}, keywords = {Alleles, Animals, Clonal Hematopoiesis, Genome-Wide Association Study, Hematopoiesis, Hematopoietic Stem Cells, Humans, Mice, Mutation, Promoter Regions, Genetic}, issn = {1476-4687}, doi = {10.1038/s41586-023-05806-1}, author = {Weinstock, Joshua S and Gopakumar, Jayakrishnan and Burugula, Bala Bharathi and Uddin, Md Mesbah and Jahn, Nikolaus and Belk, Julia A and Bouzid, Hind and Daniel, Bence and Miao, Zhuang and Ly, Nghi and Mack, Taralynn M and Luna, Sofia E and Prothro, Katherine P and Mitchell, Shaneice R and Laurie, Cecelia A and Broome, Jai G and Taylor, Kent D and Guo, Xiuqing and Sinner, Moritz F and von Falkenhausen, Aenne S and K{\"a}{\"a}b, Stefan and Shuldiner, Alan R and O{\textquoteright}Connell, Jeffrey R and Lewis, Joshua P and Boerwinkle, Eric and Barnes, Kathleen C and Chami, Nathalie and Kenny, Eimear E and Loos, Ruth J F and Fornage, Myriam and Hou, Lifang and Lloyd-Jones, Donald M and Redline, Susan and Cade, Brian E and Psaty, Bruce M and Bis, Joshua C and Brody, Jennifer A and Silverman, Edwin K and Yun, Jeong H and Qiao, Dandi and Palmer, Nicholette D and Freedman, Barry I and Bowden, Donald W and Cho, Michael H and DeMeo, Dawn L and Vasan, Ramachandran S and Yanek, Lisa R and Becker, Lewis C and Kardia, Sharon L R and Peyser, Patricia A and He, Jiang and Rienstra, Michiel and van der Harst, Pim and Kaplan, Robert and Heckbert, Susan R and Smith, Nicholas L and Wiggins, Kerri L and Arnett, Donna K and Irvin, Marguerite R and Tiwari, Hemant and Cutler, Michael J and Knight, Stacey and Muhlestein, J Brent and Correa, Adolfo and Raffield, Laura M and Gao, Yan and de Andrade, Mariza and Rotter, Jerome I and Rich, Stephen S and Tracy, Russell P and Konkle, Barbara A and Johnsen, Jill M and Wheeler, Marsha M and Smith, J Gustav and Melander, Olle and Nilsson, Peter M and Custer, Brian S and Duggirala, Ravindranath and Curran, Joanne E and Blangero, John and McGarvey, Stephen and Williams, L Keoki and Xiao, Shujie and Yang, Mao and Gu, C Charles and Chen, Yii-Der Ida and Lee, Wen-Jane and Marcus, Gregory M and Kane, John P and Pullinger, Clive R and Shoemaker, M Benjamin and Darbar, Dawood and Roden, Dan M and Albert, Christine and Kooperberg, Charles and Zhou, Ying and Manson, JoAnn E and Desai, Pinkal and Johnson, Andrew D and Mathias, Rasika A and Blackwell, Thomas W and Abecasis, Goncalo R and Smith, Albert V and Kang, Hyun M and Satpathy, Ansuman T and Natarajan, Pradeep and Kitzman, Jacob O and Whitsel, Eric A and Reiner, Alexander P and Bick, Alexander G and Jaiswal, Siddhartha} } @article {9379, title = {Evaluating the use of blood pressure polygenic risk scores across race/ethnic background groups.}, journal = {Nat Commun}, volume = {14}, year = {2023}, month = {2023 Jun 02}, pages = {3202}, abstract = {

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.

}, keywords = {Blood Pressure, Ethnicity, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Population Health, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-023-38990-9}, author = {Kurniansyah, Nuzulul and Goodman, Matthew O and Khan, Alyna T and Wang, Jiongming and Feofanova, Elena and Bis, Joshua C and Wiggins, Kerri L and Huffman, Jennifer E and Kelly, Tanika and Elfassy, Tali and Guo, Xiuqing and Palmas, Walter and Lin, Henry J and Hwang, Shih-Jen and Gao, Yan and Young, Kendra and Kinney, Gregory L and Smith, Jennifer A and Yu, Bing and Liu, Simin and Wassertheil-Smoller, Sylvia and Manson, JoAnn E and Zhu, Xiaofeng and Chen, Yii-Der Ida and Lee, I-Te and Gu, C Charles and Lloyd-Jones, Donald M and Z{\"o}llner, Sebastian and Fornage, Myriam and Kooperberg, Charles and Correa, Adolfo and Psaty, Bruce M and Arnett, Donna K and Isasi, Carmen R and Rich, Stephen S and Kaplan, Robert C and Redline, Susan and Mitchell, Braxton D and Franceschini, Nora and Levy, Daniel and Rotter, Jerome I and Morrison, Alanna C and Sofer, Tamar} } @article {9322, title = {Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease.}, journal = {Nat Commun}, volume = {14}, year = {2023}, month = {2023 Mar 14}, pages = {1411}, abstract = {

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.

}, keywords = {Arrhythmias, Cardiac, Atrioventricular Block, Biomarkers, Cardiovascular Diseases, Electrocardiography, Genome-Wide Association Study, Humans, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-023-36997-w}, author = {Young, William J and Haessler, Jeffrey and Benjamins, Jan-Walter and Repetto, Linda and Yao, Jie and Isaacs, Aaron and Harper, Andrew R and Ramirez, Julia and Garnier, Sophie and Van Duijvenboden, Stefan and Baldassari, Antoine R and Concas, Maria Pina and Duong, ThuyVy and Foco, Luisa and Isaksen, Jonas L and Mei, Hao and Noordam, Raymond and Nursyifa, Casia and Richmond, Anne and Santolalla, Meddly L and Sitlani, Colleen M and Soroush, Negin and Th{\'e}riault, S{\'e}bastien and Trompet, Stella and Aeschbacher, Stefanie and Ahmadizar, Fariba and Alonso, Alvaro and Brody, Jennifer A and Campbell, Archie and Correa, Adolfo and Darbar, Dawood and De Luca, Antonio and Deleuze, Jean-Francois and Ellervik, Christina and Fuchsberger, Christian and Goel, Anuj and Grace, Christopher and Guo, Xiuqing and Hansen, Torben and Heckbert, Susan R and Jackson, Rebecca D and Kors, Jan A and Lima-Costa, Maria Fernanda and Linneberg, Allan and Macfarlane, Peter W and Morrison, Alanna C and Navarro, Pau and Porteous, David J and Pramstaller, Peter P and Reiner, Alexander P and Risch, Lorenz and Schotten, Ulrich and Shen, Xia and Sinagra, Gianfranco and Soliman, Elsayed Z and Stoll, Monika and Tarazona-Santos, Eduardo and Tinker, Andrew and Trajanoska, Katerina and Villard, Eric and Warren, Helen R and Whitsel, Eric A and Wiggins, Kerri L and Arking, Dan E and Avery, Christy L and Conen, David and Girotto, Giorgia and Grarup, Niels and Hayward, Caroline and Jukema, J Wouter and Mook-Kanamori, Dennis O and Olesen, Morten Salling and Padmanabhan, Sandosh and Psaty, Bruce M and Pattaro, Cristian and Ribeiro, Antonio Luiz P and Rotter, Jerome I and Stricker, Bruno H and van der Harst, Pim and van Duijn, Cornelia M and Verweij, Niek and Wilson, James G and Orini, Michele and Charron, Philippe and Watkins, Hugh and Kooperberg, Charles and Lin, Henry J and Wilson, James F and Kanters, J{\o}rgen K and Sotoodehnia, Nona and Mifsud, Borbala and Lambiase, Pier D and Tereshchenko, Larisa G and Munroe, Patricia B} } @article {9419, title = {The genetic determinants of recurrent somatic mutations in 43,693 blood genomes.}, journal = {Sci Adv}, volume = {9}, year = {2023}, month = {2023 Apr 28}, pages = {eabm4945}, abstract = {

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.

}, keywords = {Germ-Line Mutation, Hematopoiesis, Humans, Middle Aged, Mutation, Mutation, Missense, Phenotype}, issn = {2375-2548}, doi = {10.1126/sciadv.abm4945}, author = {Weinstock, Joshua S and Laurie, Cecelia A and Broome, Jai G and Taylor, Kent D and Guo, Xiuqing and Shuldiner, Alan R and O{\textquoteright}Connell, Jeffrey R and Lewis, Joshua P and Boerwinkle, Eric and Barnes, Kathleen C and Chami, Nathalie and Kenny, Eimear E and Loos, Ruth J F and Fornage, Myriam and Redline, Susan and Cade, Brian E and Gilliland, Frank D and Chen, Zhanghua and Gauderman, W James and Kumar, Rajesh and Grammer, Leslie and Schleimer, Robert P and Psaty, Bruce M and Bis, Joshua C and Brody, Jennifer A and Silverman, Edwin K and Yun, Jeong H and Qiao, Dandi and Weiss, Scott T and Lasky-Su, Jessica and DeMeo, Dawn L and Palmer, Nicholette D and Freedman, Barry I and Bowden, Donald W and Cho, Michael H and Vasan, Ramachandran S and Johnson, Andrew D and Yanek, Lisa R and Becker, Lewis C and Kardia, Sharon and He, Jiang and Kaplan, Robert and Heckbert, Susan R and Smith, Nicholas L and Wiggins, Kerri L and Arnett, Donna K and Irvin, Marguerite R and Tiwari, Hemant and Correa, Adolfo and Raffield, Laura M and Gao, Yan and de Andrade, Mariza and Rotter, Jerome I and Rich, Stephen S and Manichaikul, Ani W and Konkle, Barbara A and Johnsen, Jill M and Wheeler, Marsha M and Custer, Brian S and Duggirala, Ravindranath and Curran, Joanne E and Blangero, John and Gui, Hongsheng and Xiao, Shujie and Williams, L Keoki and Meyers, Deborah A and Li, Xingnan and Ortega, Victor and McGarvey, Stephen and Gu, C Charles and Chen, Yii-Der Ida and Lee, Wen-Jane and Shoemaker, M Benjamin and Darbar, Dawood and Roden, Dan and Albert, Christine and Kooperberg, Charles and Desai, Pinkal and Blackwell, Thomas W and Abecasis, Goncalo R and Smith, Albert V and Kang, Hyun M and Mathias, Rasika and Natarajan, Pradeep and Jaiswal, Siddhartha and Reiner, Alexander P and Bick, Alexander G} }