@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 {6155, title = {Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.}, journal = {Circulation}, volume = {128}, year = {2013}, month = {2013 Sep 17}, pages = {1310-24}, abstract = {

BACKGROUND: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34\% to 50\%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2\%) of its variation.

METHODS AND RESULTS: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5{\texttimes}10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7\% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism.

CONCLUSIONS: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

}, keywords = {Adolescent, Adult, African Continental Ancestry Group, Aged, Aged, 80 and over, Cardiovascular Diseases, Coronary Artery Disease, European Continental Ancestry Group, Female, Fibrinogen, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Hispanic Americans, Humans, Male, Middle Aged, Myocardial Infarction, Polymorphism, Single Nucleotide, Risk Factors, Stroke, Venous Thromboembolism, Young Adult}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.113.002251}, author = {Sabater-Lleal, Maria and Huang, Jie and Chasman, Daniel and Naitza, Silvia and Dehghan, Abbas and Johnson, Andrew D and Teumer, Alexander and Reiner, Alex P and Folkersen, Lasse and Basu, Saonli and Rudnicka, Alicja R and Trompet, Stella and M{\"a}larstig, Anders and Baumert, Jens and Bis, Joshua C and Guo, Xiuqing and Hottenga, Jouke J and Shin, So-Youn and Lopez, Lorna M and Lahti, Jari and Tanaka, Toshiko and Yanek, Lisa R and Oudot-Mellakh, Tiphaine and Wilson, James F and Navarro, Pau and Huffman, Jennifer E and Zemunik, Tatijana and Redline, Susan and Mehra, Reena and Pulanic, Drazen and Rudan, Igor and Wright, Alan F and Kolcic, Ivana and Polasek, Ozren and Wild, Sarah H and Campbell, Harry and Curb, J David and Wallace, Robert and Liu, Simin and Eaton, Charles B and Becker, Diane M and Becker, Lewis C and Bandinelli, Stefania and R{\"a}ikk{\"o}nen, Katri and Widen, Elisabeth and Palotie, Aarno and Fornage, Myriam and Green, David and Gross, Myron and Davies, Gail and Harris, Sarah E and Liewald, David C and Starr, John M and Williams, Frances M K and Grant, Peter J and Spector, Timothy D and Strawbridge, Rona J and Silveira, Angela and Sennblad, Bengt and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Hofman, Albert and van Dongen, Jenny and Willemsen, Gonneke and Boomsma, Dorret I and Yao, Jie and Swords Jenny, Nancy and Haritunians, Talin and McKnight, Barbara and Lumley, Thomas and Taylor, Kent D and Rotter, Jerome I and Psaty, Bruce M and Peters, Annette and Gieger, Christian and Illig, Thomas and Grotevendt, Anne and Homuth, Georg and V{\"o}lzke, Henry and Kocher, Thomas and Goel, Anuj and Franzosi, Maria Grazia and Seedorf, Udo and Clarke, Robert and Steri, Maristella and Tarasov, Kirill V and Sanna, Serena and Schlessinger, David and Stott, David J and Sattar, Naveed and Buckley, Brendan M and Rumley, Ann and Lowe, Gordon D and McArdle, Wendy L and Chen, Ming-Huei and Tofler, Geoffrey H and Song, Jaejoon and Boerwinkle, Eric and Folsom, Aaron R and Rose, Lynda M and Franco-Cereceda, Anders and Teichert, Martina and Ikram, M Arfan and Mosley, Thomas H and Bevan, Steve and Dichgans, Martin and Rothwell, Peter M and Sudlow, Cathie L M and Hopewell, Jemma C and Chambers, John C and Saleheen, Danish and Kooner, Jaspal S and Danesh, John and Nelson, Christopher P and Erdmann, Jeanette and Reilly, Muredach P and Kathiresan, Sekar and Schunkert, Heribert and Morange, Pierre-Emmanuel and Ferrucci, Luigi and Eriksson, Johan G and Jacobs, David and Deary, Ian J and Soranzo, Nicole and Witteman, Jacqueline C M and de Geus, Eco J C and Tracy, Russell P and Hayward, Caroline and Koenig, Wolfgang and Cucca, Francesco and Jukema, J Wouter and Eriksson, Per and Seshadri, Sudha and Markus, Hugh S and Watkins, Hugh and Samani, Nilesh J and Wallaschofski, Henri and Smith, Nicholas L and Tregouet, David and Ridker, Paul M and Tang, Weihong and Strachan, David P and Hamsten, Anders and O{\textquoteright}Donnell, Christopher J} } @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 {7136, title = {General Framework for Meta-Analysis of Haplotype Association Tests.}, journal = {Genet Epidemiol}, volume = {40}, year = {2016}, month = {2016 Apr}, pages = {244-52}, abstract = {

For complex traits, most associated single nucleotide variants (SNV) discovered to date have a small effect, and detection of association is only possible with large sample sizes. Because of patient confidentiality concerns, it is often not possible to pool genetic data from multiple cohorts, and meta-analysis has emerged as the method of choice to combine results from multiple studies. Many meta-analysis methods are available for single SNV analyses. As new approaches allow the capture of low frequency and rare genetic variation, it is of interest to jointly consider multiple variants to improve power. However, for the analysis of haplotypes formed by multiple SNVs, meta-analysis remains a challenge, because different haplotypes may be observed across studies. We propose a two-stage meta-analysis approach to combine haplotype analysis results. In the first stage, each cohort estimate haplotype effect sizes in a regression framework, accounting for relatedness among observations if appropriate. For the second stage, we use a multivariate generalized least square meta-analysis approach to combine haplotype effect estimates from multiple cohorts. Haplotype-specific association tests and a global test of independence between haplotypes and traits are obtained within our framework. We demonstrate through simulation studies that we control the type-I error rate, and our approach is more powerful than inverse variance weighted meta-analysis of single SNV analysis when haplotype effects are present. We replicate a published haplotype association between fasting glucose-associated locus (G6PC2) and fasting glucose in seven studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and we provide more precise haplotype effect estimates.

}, issn = {1098-2272}, doi = {10.1002/gepi.21959}, author = {Wang, Shuai and Zhao, Jing Hua and An, Ping and Guo, Xiuqing and Jensen, Richard A and Marten, Jonathan and Huffman, Jennifer E and Meidtner, Karina and Boeing, Heiner and Campbell, Archie and Rice, Kenneth M and Scott, Robert A and Yao, Jie and Schulze, Matthias B and Wareham, Nicholas J and Borecki, Ingrid B and Province, Michael A and Rotter, Jerome I and Hayward, Caroline and Goodarzi, Mark O and Meigs, James B and Dupuis, Jos{\'e}e} } @article {7264, title = {Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci.}, journal = {Nat Genet}, volume = {48}, year = {2016}, month = {2016 Oct}, pages = {1162-70}, abstract = {

Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

}, issn = {1546-1718}, doi = {10.1038/ng.3660}, author = {Liu, Chunyu and Kraja, Aldi T and Smith, Jennifer A and Brody, Jennifer A and Franceschini, Nora and Bis, Joshua C and Rice, Kenneth and Morrison, Alanna C and Lu, Yingchang and Weiss, Stefan and Guo, Xiuqing and Palmas, Walter and Martin, Lisa W and Chen, Yii-Der Ida and Surendran, Praveen and Drenos, Fotios and Cook, James P and Auer, Paul L and Chu, Audrey Y and Giri, Ayush and Zhao, Wei and Jakobsdottir, Johanna and Lin, Li-An and Stafford, Jeanette M and Amin, Najaf and Mei, Hao and Yao, Jie and Voorman, Arend and Larson, Martin G and Grove, Megan L and Smith, Albert V and Hwang, Shih-Jen and Chen, Han and Huan, Tianxiao and Kosova, Gulum and Stitziel, Nathan O and Kathiresan, Sekar and Samani, Nilesh and Schunkert, Heribert and Deloukas, Panos and Li, Man and Fuchsberger, Christian and Pattaro, Cristian and Gorski, Mathias and Kooperberg, Charles and Papanicolaou, George J and Rossouw, Jacques E and Faul, Jessica D and Kardia, Sharon L R and Bouchard, Claude and Raffel, Leslie J and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Vasan, Ramachandran S and O{\textquoteright}Donnell, Christopher J and Taylor, Kent D and Liu, Kiang and Bottinger, Erwin P and Gottesman, Omri and Daw, E Warwick and Giulianini, Franco and Ganesh, Santhi and Salfati, Elias and Harris, Tamara B and Launer, Lenore J and D{\"o}rr, Marcus and Felix, Stephan B and Rettig, Rainer and V{\"o}lzke, Henry and Kim, Eric and Lee, Wen-Jane and Lee, I-Te and Sheu, Wayne H-H and Tsosie, Krystal S and Edwards, Digna R Velez and Liu, Yongmei and Correa, Adolfo and Weir, David R and V{\"o}lker, Uwe and Ridker, Paul M and Boerwinkle, Eric and Gudnason, Vilmundur and Reiner, Alexander P and van Duijn, Cornelia M and Borecki, Ingrid B and Edwards, Todd L and Chakravarti, Aravinda and Rotter, Jerome I and Psaty, Bruce M and Loos, Ruth J F and Fornage, Myriam and Ehret, Georg B and Newton-Cheh, Christopher and Levy, Daniel and Chasman, Daniel I} } @article {6936, title = {A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration.}, journal = {Hum Mol Genet}, volume = {25}, year = {2016}, month = {2016 Jan 15}, pages = {358-70}, abstract = {

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including \~{}120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3\% of the variance in plasma fibrinogen concentration.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddv454}, author = {de Vries, Paul S and Chasman, Daniel I and Sabater-Lleal, Maria and Chen, Ming-Huei and Huffman, Jennifer E and Steri, Maristella and Tang, Weihong and Teumer, Alexander and Marioni, Riccardo E and Grossmann, Vera and Hottenga, Jouke J and Trompet, Stella and M{\"u}ller-Nurasyid, Martina and Zhao, Jing Hua and Brody, Jennifer A and Kleber, Marcus E and Guo, Xiuqing and Wang, Jie Jin and Auer, Paul L and Attia, John R and Yanek, Lisa R and Ahluwalia, Tarunveer S and Lahti, Jari and Venturini, Cristina and Tanaka, Toshiko and Bielak, Lawrence F and Joshi, Peter K and Rocanin-Arjo, Ares and Kolcic, Ivana and Navarro, Pau and Rose, Lynda M and Oldmeadow, Christopher and Riess, Helene and Mazur, Johanna and Basu, Saonli and Goel, Anuj and Yang, Qiong and Ghanbari, Mohsen and Willemsen, Gonneke and Rumley, Ann and Fiorillo, Edoardo and de Craen, Anton J M and Grotevendt, Anne and Scott, Robert and Taylor, Kent D and Delgado, Graciela E and Yao, Jie and Kifley, Annette and Kooperberg, Charles and Qayyum, Rehan and Lopez, Lorna M and Berentzen, Tina L and R{\"a}ikk{\"o}nen, Katri and Mangino, Massimo and Bandinelli, Stefania and Peyser, Patricia A and Wild, Sarah and Tr{\'e}gou{\"e}t, David-Alexandre and Wright, Alan F and Marten, Jonathan and Zemunik, Tatijana and Morrison, Alanna C and Sennblad, Bengt and Tofler, Geoffrey and de Maat, Moniek P M and de Geus, Eco J C and Lowe, Gordon D and Zoledziewska, Magdalena and Sattar, Naveed and Binder, Harald and V{\"o}lker, Uwe and Waldenberger, Melanie and Khaw, Kay-Tee and McKnight, Barbara and Huang, Jie and Jenny, Nancy S and Holliday, Elizabeth G and Qi, Lihong and Mcevoy, Mark G and Becker, Diane M and Starr, John M and Sarin, Antti-Pekka and Hysi, Pirro G and Hernandez, Dena G and Jhun, Min A and Campbell, Harry and Hamsten, Anders and Rivadeneira, Fernando and McArdle, Wendy L and Slagboom, P Eline and Zeller, Tanja and Koenig, Wolfgang and Psaty, Bruce M and Haritunians, Talin and Liu, Jingmin and Palotie, Aarno and Uitterlinden, Andr{\'e} G and Stott, David J and Hofman, Albert and Franco, Oscar H and Polasek, Ozren and Rudan, Igor and Morange, Pierre-Emmanuel and Wilson, James F and Kardia, Sharon L R and Ferrucci, Luigi and Spector, Tim D and Eriksson, Johan G and Hansen, Torben and Deary, Ian J and Becker, Lewis C and Scott, Rodney J and Mitchell, Paul and M{\"a}rz, Winfried and Wareham, Nick J and Peters, Annette and Greinacher, Andreas and Wild, Philipp S and Jukema, J Wouter and Boomsma, Dorret I and Hayward, Caroline and Cucca, Francesco and Tracy, Russell and Watkins, Hugh and Reiner, Alex P and Folsom, Aaron R and Ridker, Paul M and O{\textquoteright}Donnell, Christopher J and Smith, Nicholas L and Strachan, David P and Dehghan, Abbas} } @article {7257, title = {Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis.}, journal = {Circ Cardiovasc Genet}, year = {2016}, month = {2016 Nov 21}, abstract = {

BACKGROUND: -The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease (CHD). We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent CHD.

METHODS AND RESULTS: -We studied a total of 25,109 European ancestry and African-American participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52,869 with common carotid intima media thickness (CIMT) measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Participants were genotyped for 247,870 DNA sequence variants (231,539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and CIMT. APOB p.Arg3527Gln was associated with four-fold excess CAC (P = 3{\texttimes}10(-10)). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3\% reduced CAC (P = 1{\texttimes}10(-12)) and 1.4\% reduced CIMT (P = 4{\texttimes}10(-14)) in carriers compared with non-carriers. In secondary analyses conditioning on LDL cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for CHD (OR 0.77; P = 1{\texttimes}10(-11)).

CONCLUSIONS: -Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities as well as clinical CHD.

}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.116.001572}, author = {Natarajan, Pradeep and Bis, Joshua C and Bielak, Lawrence F and Cox, Amanda J and D{\"o}rr, Marcus and Feitosa, Mary F and Franceschini, Nora and Guo, Xiuqing and Hwang, Shih-Jen and Isaacs, Aaron and Jhun, Min A and Kavousi, Maryam and Li-Gao, Ruifang and Lyytik{\"a}inen, Leo-Pekka and Marioni, Riccardo E and Schminke, Ulf and Stitziel, Nathan O and Tada, Hayato and van Setten, Jessica and Smith, Albert V and Vojinovic, Dina and Yanek, Lisa R and Yao, Jie and Yerges-Armstrong, Laura M and Amin, Najaf and Baber, Usman and Borecki, Ingrid B and Carr, J Jeffrey and Chen, Yii-Der Ida and Cupples, L Adrienne and de Jong, Pim A and de Koning, Harry and de Vos, Bob D and Demirkan, Ayse and Fuster, Valentin and Franco, Oscar H and Goodarzi, Mark O and Harris, Tamara B and Heckbert, Susan R and Heiss, Gerardo and Hoffmann, Udo and Hofman, Albert and I{\v s}gum, Ivana and Jukema, J Wouter and K{\"a}h{\"o}nen, Mika and Kardia, Sharon L R and Kral, Brian G and Launer, Lenore J and Massaro, Joseph and Mehran, Roxana and Mitchell, Braxton D and Mosley, Thomas H and de Mutsert, Ren{\'e}e and Newman, Anne B and Nguyen, Khanh-Dung and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Oudkerk, Matthijs and Pankow, James S and Peloso, Gina M and Post, Wendy and Province, Michael A and Raffield, Laura M and Raitakari, Olli T and Reilly, Dermot F and Rivadeneira, Fernando and Rosendaal, Frits and Sartori, Samantha and Taylor, Kent D and Teumer, Alexander and Trompet, Stella and Turner, Stephen T and Uitterlinden, Andr{\'e} G and Vaidya, Dhananjay and van der Lugt, Aad and V{\"o}lker, Uwe and Wardlaw, Joanna M and Wassel, Christina L and Weiss, Stefan and Wojczynski, Mary K and Becker, Diane M and Becker, Lewis C and Boerwinkle, Eric and Bowden, Donald W and Deary, Ian J and Dehghan, Abbas and Felix, Stephan B and Gudnason, Vilmundur and Lehtim{\"a}ki, Terho and Mathias, Rasika and Mook-Kanamori, Dennis O and Psaty, Bruce M and Rader, Daniel J and Rotter, Jerome I and Wilson, James G and van Duijn, Cornelia M and V{\"o}lzke, Henry and Kathiresan, Sekar and Peyser, Patricia A and O{\textquoteright}Donnell, Christopher J} } @article {7141, title = {Trans-ethnic Meta-analysis and Functional Annotation Illuminates the~Genetic Architecture of Fasting Glucose and Insulin.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Jul 7}, pages = {56-75}, abstract = {

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.05.006}, author = {Liu, Ching-Ti and Raghavan, Sridharan and Maruthur, Nisa and Kabagambe, Edmond Kato and Hong, Jaeyoung and Ng, Maggie C Y and Hivert, Marie-France and Lu, Yingchang and An, Ping and Bentley, Amy R and Drolet, Anne M and Gaulton, Kyle J and Guo, Xiuqing and Armstrong, Loren L and Irvin, Marguerite R and Li, Man and Lipovich, Leonard and Rybin, Denis V and Taylor, Kent D and Agyemang, Charles and Palmer, Nicholette D and Cade, Brian E and Chen, Wei-Min and Dauriz, Marco and Delaney, Joseph A C and Edwards, Todd L and Evans, Daniel S and Evans, Michele K and Lange, Leslie A and Leong, Aaron and Liu, Jingmin and Liu, Yongmei and Nayak, Uma and Patel, Sanjay R and Porneala, Bianca C and Rasmussen-Torvik, Laura J and Snijder, Marieke B and Stallings, Sarah C and Tanaka, Toshiko and Yanek, Lisa R and Zhao, Wei and Becker, Diane M and Bielak, Lawrence F and Biggs, Mary L and Bottinger, Erwin P and Bowden, Donald W and Chen, Guanjie and Correa, Adolfo and Couper, David J and Crawford, Dana C and Cushman, Mary and Eicher, John D and Fornage, Myriam and Franceschini, Nora and Fu, Yi-Ping and Goodarzi, Mark O and Gottesman, Omri and Hara, Kazuo and Harris, Tamara B and Jensen, Richard A and Johnson, Andrew D and Jhun, Min A and Karter, Andrew J and Keller, Margaux F and Kho, Abel N and Kizer, Jorge R and Krauss, Ronald M and Langefeld, Carl D and Li, Xiaohui and Liang, Jingling and Liu, Simin and Lowe, William L and Mosley, Thomas H and North, Kari E and Pacheco, Jennifer A and Peyser, Patricia A and Patrick, Alan L and Rice, Kenneth M and Selvin, Elizabeth and Sims, Mario and Smith, Jennifer A and Tajuddin, Salman M and Vaidya, Dhananjay and Wren, Mary P and Yao, Jie and Zhu, Xiaofeng and Ziegler, Julie T and Zmuda, Joseph M and Zonderman, Alan B and Zwinderman, Aeilko H and Adeyemo, Adebowale and Boerwinkle, Eric and Ferrucci, Luigi and Hayes, M Geoffrey and Kardia, Sharon L R and Miljkovic, Iva and Pankow, James S and Rotimi, Charles N and Sale, Mich{\`e}le M and Wagenknecht, Lynne E and Arnett, Donna K and Chen, Yii-Der Ida and Nalls, Michael A and Province, Michael A and Kao, W H Linda and Siscovick, David S and Psaty, Bruce M and Wilson, James G and Loos, Ruth J F and Dupuis, Jos{\'e}e and Rich, Stephen S and Florez, Jose C and Rotter, Jerome I and Morris, Andrew P and Meigs, James B} } @article {7328, title = {Detection of genetic loci associated with plasma fetuin-A: A meta-analysis of genome-wide association studies from the CHARGE Consortium.}, journal = {Hum Mol Genet}, year = {2017}, month = {2017 Apr 03}, abstract = {

Plasma fetuin-A is associated with type 2 diabetes, and AHSG, the gene encoding fetuin-A, has been identified as a susceptibility locus for diabetes and metabolic syndrome. Thus far, unbiased investigations of the genetic determinants of plasma fetuin-A concentrations have not been conducted. We searched for single nucleotide polymorphisms (SNPs) related to fetuin-A concentrations by a genome-wide association study in six population-based studies.We examined the association of fetuin-A levels with \~{} 2.5 million genotyped and imputed SNPs in 9,055 participants of European descent and 2,119 African Americans. In both ethnicities, strongest associations were centered in a region with a high degree of LD near the AHSG locus. Among 136 genome-wide significant (p < 0.05x10-8) SNPs near the AHSG locus, the top SNP was rs4917 (p = 1.27x10-303), a known coding SNP in exon 6 that is associated with a 0.06 g/L (\~{}13\%) lower fetuin-A level. This variant alone explained 14\% of the variation in fetuin-A levels. Analyses conditioned on rs4917 indicated that the strong association with the AHSG locus stems from additional independent associations of multiple variants among European Americans. In conclusion, levels of fetuin-A in plasma are strongly associated with SNPs in its encoding gene, AHSG, but not elsewhere in the genome. Given the strength of the associations observed for multiple independent SNPs, the AHSG gene is an example of a candidate locus suitable for additional investigations including fine mapping to elucidate the biological basis of the findings and further functional experiments to clarify AHSG as a potential therapeutic target.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddx091}, author = {Jensen, Majken K and Jensen, Richard A and Mukamal, Kenneth J and Guo, Xiuqing and Yao, Jie and Sun, Qi and Cornelis, Marilyn and Liu, Yongmei and Chen, Ming-Huei and Kizer, Jorge R and Djouss{\'e}, Luc and Siscovick, David S and Psaty, Bruce M and Zmuda, Joseph M and Rotter, Jerome I and Garcia, Melissa and Harris, Tamara and Chen, Ida and Goodarzi, Mark O and Nalls, Michael A and Keller, Margaux and Arnold, Alice M and Newman, Anne and Hoogeeven, Ron C and Rexrode, Kathryn M and Rimm, Eric B and Hu, Frank B and Vasan, Ramachandran S and Katz, Ronit and Pankow, James S and Ix, Joachim H} } @article {7352, title = {Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African ancestry anthropometry genetics consortium.}, journal = {PLoS Genet}, volume = {13}, year = {2017}, month = {2017 Apr 21}, pages = {e1006719}, abstract = {

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5{\texttimes}10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5\%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained <= 20 variants in the credible sets that jointly account for 99\% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.

}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006719}, author = {Ng, Maggie C Y and Graff, Mariaelisa and Lu, Yingchang and Justice, Anne E and Mudgal, Poorva and Liu, Ching-Ti and Young, Kristin and Yanek, Lisa R and Feitosa, Mary F and Wojczynski, Mary K and Rand, Kristin and Brody, Jennifer A and Cade, Brian E and Dimitrov, Latchezar and Duan, Qing and Guo, Xiuqing and Lange, Leslie A and Nalls, Michael A and Okut, Hayrettin and Tajuddin, Salman M and Tayo, Bamidele O and Vedantam, Sailaja and Bradfield, Jonathan P and Chen, Guanjie and Chen, Wei-Min and Chesi, Alessandra and Irvin, Marguerite R and Padhukasahasram, Badri and Smith, Jennifer A and Zheng, Wei and Allison, Matthew A and Ambrosone, Christine B and Bandera, Elisa V and Bartz, Traci M and Berndt, Sonja I and Bernstein, Leslie and Blot, William J and Bottinger, Erwin P and Carpten, John and Chanock, Stephen J and Chen, Yii-Der Ida and Conti, David V and Cooper, Richard S and Fornage, Myriam and Freedman, Barry I and Garcia, Melissa and Goodman, Phyllis J and Hsu, Yu-Han H and Hu, Jennifer and Huff, Chad D and Ingles, Sue A and John, Esther M and Kittles, Rick and Klein, Eric and Li, Jin and McKnight, Barbara and Nayak, Uma and Nemesure, Barbara and Ogunniyi, Adesola and Olshan, Andrew and Press, Michael F and Rohde, Rebecca and Rybicki, Benjamin A and Salako, Babatunde and Sanderson, Maureen and Shao, Yaming and Siscovick, David S and Stanford, Janet L and Stevens, Victoria L and Stram, Alex and Strom, Sara S and Vaidya, Dhananjay and Witte, John S and Yao, Jie and Zhu, Xiaofeng and Ziegler, Regina G and Zonderman, Alan B and Adeyemo, Adebowale and Ambs, Stefan and Cushman, Mary and Faul, Jessica D and Hakonarson, Hakon and Levin, Albert M and Nathanson, Katherine L and Ware, Erin B and Weir, David R and Zhao, Wei and Zhi, Degui and Arnett, Donna K and Grant, Struan F A and Kardia, Sharon L R and Oloapde, Olufunmilayo I and Rao, D C and Rotimi, Charles N and Sale, Mich{\`e}le M and Williams, L Keoki and Zemel, Babette S and Becker, Diane M and Borecki, Ingrid B and Evans, Michele K and Harris, Tamara B and Hirschhorn, Joel N and Li, Yun and Patel, Sanjay R and Psaty, Bruce M and Rotter, Jerome I and Wilson, James G and Bowden, Donald W and Cupples, L Adrienne and Haiman, Christopher A and Loos, Ruth J F and North, Kari E} } @article {7363, title = {Discovery of novel heart rate-associated loci using the Exome Chip.}, journal = {Hum Mol Genet}, year = {2017}, month = {2017 Apr 03}, abstract = {

Background Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. GWAS analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9\% of the variation.Aim To discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Methods Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104,452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134,251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.Results We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2, SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long range regulatory chromatin interactions in heart tissue (SCD, SLF2, MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Conclusion Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddx113}, author = {van den Berg, Marten E and Warren, Helen R and Cabrera, Claudia P and Verweij, Niek and Mifsud, Borbala and Haessler, Jeffrey and Bihlmeyer, Nathan A and Fu, Yi-Ping and Weiss, Stefan and Lin, Henry J and Grarup, Niels and Li-Gao, Ruifang and Pistis, Giorgio and Shah, Nabi and Brody, Jennifer A and M{\"u}ller-Nurasyid, Martina and Lin, Honghuang and Mei, Hao and Smith, Albert V and Lyytik{\"a}inen, Leo-Pekka and Hall, Leanne M and van Setten, Jessica and Trompet, Stella and Prins, Bram P and Isaacs, Aaron and Radmanesh, Farid and Marten, Jonathan and Entwistle, Aiman and Kors, Jan A and Silva, Claudia T and Alonso, Alvaro and Bis, Joshua C and de Boer, Rudolf and de Haan, Hugoline G and de Mutsert, Ren{\'e}e and Dedoussis, George and Dominiczak, Anna F and Doney, Alex S F and Ellinor, Patrick T and Eppinga, Ruben N and Felix, Stephan B and Guo, Xiuqing and Hagemeijer, Yanick and Hansen, Torben and Harris, Tamara B and Heckbert, Susan R and Huang, Paul L and Hwang, Shih-Jen and K{\"a}h{\"o}nen, Mika and Kanters, J{\o}rgen K and Kolcic, Ivana and Launer, Lenore J and Li, Man and Yao, Jie and Linneberg, Allan and Liu, Simin and Macfarlane, Peter W and Mangino, Massimo and Morris, Andrew D and Mulas, Antonella and Murray, Alison D and Nelson, Christopher P and Orr{\`u}, Marco and Padmanabhan, Sandosh and Peters, Annette and Porteous, David J and Poulter, Neil and Psaty, Bruce M and Qi, Lihong and Raitakari, Olli T and Rivadeneira, Fernando and Roselli, Carolina and Rudan, Igor and Sattar, Naveed and Sever, Peter and Sinner, Moritz F and Soliman, Elsayed Z and Spector, Timothy D and Stanton, Alice V and Stirrups, Kathleen E and Taylor, Kent D and Tobin, Martin D and Uitterlinden, Andre and Vaartjes, Ilonca and Hoes, Arno W and van der Meer, Peter and V{\"o}lker, Uwe and Waldenberger, Melanie and Xie, Zhijun and Zoledziewska, Magdalena and Tinker, Andrew and Polasek, Ozren and Rosand, Jonathan and Jamshidi, Yalda and van Duijn, Cornelia M and Zeggini, Eleftheria and Wouter Jukema, J and Asselbergs, Folkert W and Samani, Nilesh J and Lehtim{\"a}ki, Terho and Gudnason, Vilmundur and Wilson, James and Lubitz, Steven A and K{\"a}{\"a}b, Stefan and Sotoodehnia, Nona and Caulfield, Mark J and Palmer, Colin N A and Sanna, Serena and Mook-Kanamori, Dennis O and Deloukas, Panos and Pedersen, Oluf and Rotter, Jerome I and D{\"o}rr, Marcus and O{\textquoteright}Donnell, Chris J and Hayward, Caroline and Arking, Dan E and Kooperberg, Charles and van der Harst, Pim and Eijgelsheim, Mark and Stricker, Bruno H and Munroe, Patricia B} } @article {7595, title = {Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium.}, journal = {Sci Rep}, volume = {7}, year = {2017}, month = {2017 Sep 12}, pages = {11303}, abstract = {

It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects <= 65 years of age than among those > 65 years (interaction p-value = 4.0 {\texttimes} 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 {\texttimes} 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.

}, issn = {2045-2322}, doi = {10.1038/s41598-017-09396-7}, author = {Weng, Lu-Chen and Lunetta, Kathryn L and M{\"u}ller-Nurasyid, Martina and Smith, Albert Vernon and Th{\'e}riault, S{\'e}bastien and Weeke, Peter E and Barnard, John and Bis, Joshua C and Lyytik{\"a}inen, Leo-Pekka and Kleber, Marcus E and Martinsson, Andreas and Lin, Henry J and Rienstra, Michiel and Trompet, Stella and Krijthe, Bouwe P and D{\"o}rr, Marcus and Klarin, Derek and Chasman, Daniel I and Sinner, Moritz F and Waldenberger, Melanie and Launer, Lenore J and Harris, Tamara B and Soliman, Elsayed Z and Alonso, Alvaro and Par{\'e}, Guillaume and Teixeira, Pedro L and Denny, Joshua C and Shoemaker, M Benjamin and Van Wagoner, David R and Smith, Jonathan D and Psaty, Bruce M and Sotoodehnia, Nona and Taylor, Kent D and K{\"a}h{\"o}nen, Mika and Nikus, Kjell and Delgado, Graciela E and Melander, Olle and Engstr{\"o}m, Gunnar and Yao, Jie and Guo, Xiuqing and Christophersen, Ingrid E and Ellinor, Patrick T and Geelhoed, Bastiaan and Verweij, Niek and Macfarlane, Peter and Ford, Ian and Heeringa, Jan and Franco, Oscar H and Uitterlinden, Andr{\'e} G and V{\"o}lker, Uwe and Teumer, Alexander and Rose, Lynda M and K{\"a}{\"a}b, Stefan and Gudnason, Vilmundur and Arking, Dan E and Conen, David and Roden, Dan M and Chung, Mina K and Heckbert, Susan R and Benjamin, Emelia J and Lehtim{\"a}ki, Terho and M{\"a}rz, Winfried and Smith, J Gustav and Rotter, Jerome I and van der Harst, Pim and Jukema, J Wouter and Stricker, Bruno H and Felix, Stephan B and Albert, Christine M and Lubitz, Steven A} } @article {7571, title = {Genome-Wide Association Study Meta-Analysis of Long-Term Average Blood Pressure in East Asians.}, journal = {Circ Cardiovasc Genet}, volume = {10}, year = {2017}, month = {2017 Apr}, pages = {e001527}, abstract = {

BACKGROUND: Genome-wide single marker and gene-based meta-analyses of long-term average (LTA) blood pressure (BP) phenotypes may reveal novel findings for BP.

METHODS AND RESULTS: We conducted genome-wide analysis among 18 422 East Asian participants (stage 1) followed by replication study of <=46 629 participants of European ancestry (stage 2). Significant single-nucleotide polymorphisms and genes were determined by a P<5.0{\texttimes}10-8 and 2.5{\texttimes}10-6, respectively, in joint analyses of stage-1 and stage-2 data. We identified 1 novel ARL3 variant, rs4919669 at 10q24.32, influencing LTA systolic BP (stage-1 P=5.03{\texttimes}10-8, stage-2 P=8.64{\texttimes}10-3, joint P=2.63{\texttimes}10-8) and mean arterial pressure (stage-1 P=3.59{\texttimes}10-9, stage-2 P=2.35{\texttimes}10-2, joint P=2.64{\texttimes}10-8). Three previously reported BP loci (WBP1L, NT5C2, and ATP2B1) were also identified for all BP phenotypes. Gene-based analysis provided the first robust evidence for association of KCNJ11 with LTA systolic BP (stage-1 P=8.55{\texttimes}10-6, stage-2 P=1.62{\texttimes}10-5, joint P=3.28{\texttimes}10-9) and mean arterial pressure (stage-1 P=9.19{\texttimes}10-7, stage-2 P=9.69{\texttimes}10-5, joint P=2.15{\texttimes}10-9) phenotypes. Fourteen genes (TMEM180, ACTR1A, SUFU, ARL3, SFXN2, WBP1L, CYP17A1, C10orf32, C10orf32-ASMT, AS3MT, CNNM2, and NT5C2 at 10q24.32; ATP2B1 at 12q21.33; and NCR3LG1 at 11p15.1) implicated by previous genome-wide association study meta-analyses were also identified. Among the loci identified by the previous genome-wide association study meta-analysis of LTA BP, we transethnically replicated associations of the KCNK3 marker rs1275988 at 2p23.3 with LTA systolic BP and mean arterial pressure phenotypes (P=1.27{\texttimes}10-4 and 3.30{\texttimes}10-4, respectively).

CONCLUSIONS: We identified 1 novel variant and 1 novel gene and present the first direct evidence of relevance of the KCNK3 locus for LTA BP among East Asians.

}, keywords = {Asian Continental Ancestry Group, Blood Pressure, Far East, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Phenotype, Polymorphism, Single Nucleotide}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.116.001527}, author = {Li, Changwei and Kim, Yun Kyoung and Dorajoo, Rajkumar and Li, Huaixing and Lee, I-Te and Cheng, Ching-Yu and He, Meian and Sheu, Wayne H-H and Guo, Xiuqing and Ganesh, Santhi K and He, Jiang and Lee, Juyoung and Liu, Jianjun and Hu, Yao and Rao, Dabeeru C and Tsai, Fuu-Jen and Koh, Jia Yu and Hu, Hua and Liang, Kae-Woei and Palmas, Walter and Hixson, James E and Han, Sohee and Teo, Yik-Ying and Wang, Yiqin and Chen, Jing and Lu, Chieh Hsiang and Zheng, Yingfeng and Gui, Lixuan and Lee, Wen-Jane and Yao, Jie and Gu, Dongfeng and Han, Bok-Ghee and Sim, Xueling and Sun, Liang and Zhao, Jinying and Chen, Chien-Hsiun and Kumari, Neelam and He, Yunfeng and Taylor, Kent D and Raffel, Leslie J and Moon, Sanghoon and Rotter, Jerome I and Ida Chen, Yii-Der and Wu, Tangchun and Wong, Tien Yin and Wu, Jer-Yuarn and Lin, Xu and Tai, E-Shyong and Kim, Bong-Jo and Kelly, Tanika N} } @article {7596, title = {Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.}, journal = {PLoS Med}, volume = {14}, year = {2017}, month = {2017 Sep}, pages = {e1002383}, abstract = {

BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.

METHODS \& FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95\% CI 1.04-1.06, per HbA1c-raising allele, p = 3 {\texttimes} 10-29); whereas GS-E was not (OR = 1.00, 95\% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11\%) was associated with an absolute decrease in HbA1c of 0.81\%-units (95\% CI 0.66-0.96) per allele in hemizygous men, and 0.68\%-units (95\% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2\% (N = 0.65 million, 95\% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.

CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

}, keywords = {Diabetes Mellitus, Type 2, Genetic Variation, Genome-Wide Association Study, Glycated Hemoglobin A, Humans, Phenotype, Risk}, issn = {1549-1676}, doi = {10.1371/journal.pmed.1002383}, author = {Wheeler, Eleanor and Leong, Aaron and Liu, Ching-Ti and Hivert, Marie-France and Strawbridge, Rona J and Podmore, Clara and Li, Man and Yao, Jie and Sim, Xueling and Hong, Jaeyoung and Chu, Audrey Y and Zhang, Weihua and Wang, Xu and Chen, Peng and Maruthur, Nisa M and Porneala, Bianca C and Sharp, Stephen J and Jia, Yucheng and Kabagambe, Edmond K and Chang, Li-Ching and Chen, Wei-Min and Elks, Cathy E and Evans, Daniel S and Fan, Qiao and Giulianini, Franco and Go, Min Jin and Hottenga, Jouke-Jan and Hu, Yao and Jackson, Anne U and Kanoni, Stavroula and Kim, Young Jin and Kleber, Marcus E and Ladenvall, Claes and Lecoeur, C{\'e}cile and Lim, Sing-Hui and Lu, Yingchang and Mahajan, Anubha and Marzi, Carola and Nalls, Mike A and Navarro, Pau and Nolte, Ilja M and Rose, Lynda M and Rybin, Denis V and Sanna, Serena and Shi, Yuan and Stram, Daniel O and Takeuchi, Fumihiko and Tan, Shu Pei and van der Most, Peter J and van Vliet-Ostaptchouk, Jana V and Wong, Andrew and Yengo, Loic and Zhao, Wanting and Goel, Anuj and Martinez Larrad, Maria Teresa and Radke, D{\"o}rte and Salo, Perttu and Tanaka, Toshiko and van Iperen, Erik P A and Abecasis, Goncalo and Afaq, Saima and Alizadeh, Behrooz Z and Bertoni, Alain G and Bonnefond, Am{\'e}lie and B{\"o}ttcher, Yvonne and Bottinger, Erwin P and Campbell, Harry and Carlson, Olga D and Chen, Chien-Hsiun and Cho, Yoon Shin and Garvey, W Timothy and Gieger, Christian and Goodarzi, Mark O and Grallert, Harald and Hamsten, Anders and Hartman, Catharina A and Herder, Christian and Hsiung, Chao Agnes and Huang, Jie and Igase, Michiya and Isono, Masato and Katsuya, Tomohiro and Khor, Chiea-Chuen and Kiess, Wieland and Kohara, Katsuhiko and Kovacs, Peter and Lee, Juyoung and Lee, Wen-Jane and Lehne, Benjamin and Li, Huaixing and Liu, Jianjun and Lobbens, Stephane and Luan, Jian{\textquoteright}an and Lyssenko, Valeriya and Meitinger, Thomas and Miki, Tetsuro and Miljkovic, Iva and Moon, Sanghoon and Mulas, Antonella and M{\"u}ller, Gabriele and M{\"u}ller-Nurasyid, Martina and Nagaraja, Ramaiah and Nauck, Matthias and Pankow, James S and Polasek, Ozren and Prokopenko, Inga and Ramos, Paula S and Rasmussen-Torvik, Laura and Rathmann, Wolfgang and Rich, Stephen S and Robertson, Neil R and Roden, Michael and Roussel, Ronan and Rudan, Igor and Scott, Robert A and Scott, William R and Sennblad, Bengt and Siscovick, David S and Strauch, Konstantin and Sun, Liang and Swertz, Morris and Tajuddin, Salman M and Taylor, Kent D and Teo, Yik-Ying and Tham, Yih Chung and T{\"o}njes, Anke and Wareham, Nicholas J and Willemsen, Gonneke and Wilsgaard, Tom and Hingorani, Aroon D and Egan, Josephine and Ferrucci, Luigi and Hovingh, G Kees and Jula, Antti and Kivimaki, Mika and Kumari, Meena and Nj{\o}lstad, Inger and Palmer, Colin N A and Serrano R{\'\i}os, Manuel and Stumvoll, Michael and Watkins, Hugh and Aung, Tin and Bl{\"u}her, Matthias and Boehnke, Michael and Boomsma, Dorret I and Bornstein, Stefan R and Chambers, John C and Chasman, Daniel I and Chen, Yii-Der Ida and Chen, Yduan-Tsong and Cheng, Ching-Yu and Cucca, Francesco and de Geus, Eco J C and Deloukas, Panos and Evans, Michele K and Fornage, Myriam and Friedlander, Yechiel and Froguel, Philippe and Groop, Leif and Gross, Myron D and Harris, Tamara B and Hayward, Caroline and Heng, Chew-Kiat and Ingelsson, Erik and Kato, Norihiro and Kim, Bong-Jo and Koh, Woon-Puay and Kooner, Jaspal S and K{\"o}rner, Antje and Kuh, Diana and Kuusisto, Johanna and Laakso, Markku and Lin, Xu and Liu, Yongmei and Loos, Ruth J F and Magnusson, Patrik K E and M{\"a}rz, Winfried and McCarthy, Mark I and Oldehinkel, Albertine J and Ong, Ken K and Pedersen, Nancy L and Pereira, Mark A and Peters, Annette and Ridker, Paul M and Sabanayagam, Charumathi and Sale, Michele and Saleheen, Danish and Saltevo, Juha and Schwarz, Peter Eh and Sheu, Wayne H H and Snieder, Harold and Spector, Timothy D and Tabara, Yasuharu and Tuomilehto, Jaakko and van Dam, Rob M and Wilson, James G and Wilson, James F and Wolffenbuttel, Bruce H R and Wong, Tien Yin and Wu, Jer-Yuarn and Yuan, Jian-Min and Zonderman, Alan B and Soranzo, Nicole and Guo, Xiuqing and Roberts, David J and Florez, Jose C and Sladek, Robert and Dupuis, Jos{\'e}e and Morris, Andrew P and Tai, E-Shyong and Selvin, Elizabeth and Rotter, Jerome I and Langenberg, Claudia and Barroso, In{\^e}s and Meigs, James B} } @article {7396, title = {Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Jun}, pages = {946-952}, abstract = {

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.

}, issn = {1546-1718}, doi = {10.1038/ng.3843}, author = {Christophersen, Ingrid E and Rienstra, Michiel and Roselli, Carolina and Yin, Xiaoyan and Geelhoed, Bastiaan and Barnard, John and Lin, Honghuang and Arking, Dan E and Smith, Albert V and Albert, Christine M and Chaffin, Mark and Tucker, Nathan R and Li, Molong and Klarin, Derek and Bihlmeyer, Nathan A and Low, Siew-Kee and Weeke, Peter E and M{\"u}ller-Nurasyid, Martina and Smith, J Gustav and Brody, Jennifer A and Niemeijer, Maartje N and D{\"o}rr, Marcus and Trompet, Stella and Huffman, Jennifer and Gustafsson, Stefan and Schurmann, Claudia and Kleber, Marcus E and Lyytik{\"a}inen, Leo-Pekka and Sepp{\"a}l{\"a}, Ilkka and Malik, Rainer and Horimoto, Andrea R V R and Perez, Marco and Sinisalo, Juha and Aeschbacher, Stefanie and Th{\'e}riault, S{\'e}bastien and Yao, Jie and Radmanesh, Farid and Weiss, Stefan and Teumer, Alexander and Choi, Seung Hoan and Weng, Lu-Chen and Clauss, Sebastian and Deo, Rajat and Rader, Daniel J and Shah, Svati H and Sun, Albert and Hopewell, Jemma C and Debette, Stephanie and Chauhan, Ganesh and Yang, Qiong and Worrall, Bradford B and Par{\'e}, Guillaume and Kamatani, Yoichiro and Hagemeijer, Yanick P and Verweij, Niek and Siland, Joylene E and Kubo, Michiaki and Smith, Jonathan D and Van Wagoner, David R and Bis, Joshua C and Perz, Siegfried and Psaty, Bruce M and Ridker, Paul M and Magnani, Jared W and Harris, Tamara B and Launer, Lenore J and Shoemaker, M Benjamin and Padmanabhan, Sandosh and Haessler, Jeffrey and Bartz, Traci M and Waldenberger, Melanie and Lichtner, Peter and Arendt, Marina and Krieger, Jose E and K{\"a}h{\"o}nen, Mika and Risch, Lorenz and Mansur, Alfredo J and Peters, Annette and Smith, Blair H and Lind, Lars and Scott, Stuart A and Lu, Yingchang and Bottinger, Erwin B and Hernesniemi, Jussi and Lindgren, Cecilia M and Wong, Jorge A and Huang, Jie and Eskola, Markku and Morris, Andrew P and Ford, Ian and Reiner, Alex P and Delgado, Graciela and Chen, Lin Y and Chen, Yii-Der Ida and Sandhu, Roopinder K and Li, Man and Boerwinkle, Eric and Eisele, Lewin and Lannfelt, Lars and Rost, Natalia and Anderson, Christopher D and Taylor, Kent D and Campbell, Archie and Magnusson, Patrik K and Porteous, David and Hocking, Lynne J and Vlachopoulou, Efthymia and Pedersen, Nancy L and Nikus, Kjell and Orho-Melander, Marju and Hamsten, Anders and Heeringa, Jan and Denny, Joshua C and Kriebel, Jennifer and Darbar, Dawood and Newton-Cheh, Christopher and Shaffer, Christian and Macfarlane, Peter W and Heilmann-Heimbach, Stefanie and Almgren, Peter and Huang, Paul L and Sotoodehnia, Nona and Soliman, Elsayed Z and Uitterlinden, Andr{\'e} G and Hofman, Albert and Franco, Oscar H and V{\"o}lker, Uwe and J{\"o}ckel, Karl-Heinz and Sinner, Moritz F and Lin, Henry J and Guo, Xiuqing and Dichgans, Martin and Ingelsson, Erik and Kooperberg, Charles and Melander, Olle and Loos, Ruth J F and Laurikka, Jari and Conen, David and Rosand, Jonathan and van der Harst, Pim and Lokki, Marja-Liisa and Kathiresan, Sekar and Pereira, Alexandre and Jukema, J Wouter and Hayward, Caroline and Rotter, Jerome I and M{\"a}rz, Winfried and Lehtim{\"a}ki, Terho and Stricker, Bruno H and Chung, Mina K and Felix, Stephan B and Gudnason, Vilmundur and Alonso, Alvaro and Roden, Dan M and K{\"a}{\"a}b, Stefan and Chasman, Daniel I and Heckbert, Susan R and Benjamin, Emelia J and Tanaka, Toshihiro and Lunetta, Kathryn L and Lubitz, Steven A and Ellinor, Patrick T} } @article {7492, title = {Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.}, journal = {Hypertension}, year = {2017}, month = {2017 Jul 24}, abstract = {

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

}, issn = {1524-4563}, doi = {10.1161/HYPERTENSIONAHA.117.09438}, author = {Wain, Louise V and Vaez, Ahmad and Jansen, Rick and Joehanes, Roby and van der Most, Peter J and Erzurumluoglu, A Mesut and O{\textquoteright}Reilly, Paul F and Cabrera, Claudia P and Warren, Helen R and Rose, Lynda M and Verwoert, Germaine C and Hottenga, Jouke-Jan and Strawbridge, Rona J and Esko, T{\~o}nu and Arking, Dan E and Hwang, Shih-Jen and Guo, Xiuqing and Kutalik, Zolt{\'a}n and Trompet, Stella and Shrine, Nick and Teumer, Alexander and Ried, Janina S and Bis, Joshua C and Smith, Albert V and Amin, Najaf and Nolte, Ilja M and Lyytik{\"a}inen, Leo-Pekka and Mahajan, Anubha and Wareham, Nicholas J and Hofer, Edith and Joshi, Peter K and Kristiansson, Kati and Traglia, Michela and Havulinna, Aki S and Goel, Anuj and Nalls, Mike A and S{\~o}ber, Siim and Vuckovic, Dragana and Luan, Jian{\textquoteright}an and del Greco M, Fabiola and Ayers, Kristin L and Marrugat, Jaume and Ruggiero, Daniela and Lopez, Lorna M and Niiranen, Teemu and Enroth, Stefan and Jackson, Anne U and Nelson, Christopher P and Huffman, Jennifer E and Zhang, Weihua and Marten, Jonathan and Gandin, Ilaria and Harris, Sarah E and Zemunik, Tatijana and Lu, Yingchang and Evangelou, Evangelos and Shah, Nabi and de Borst, Martin H and Mangino, Massimo and Prins, Bram P and Campbell, Archie and Li-Gao, Ruifang and Chauhan, Ganesh and Oldmeadow, Christopher and Abecasis, Goncalo and Abedi, Maryam and Barbieri, Caterina M and Barnes, Michael R and Batini, Chiara and Beilby, John and Blake, Tineka and Boehnke, Michael and Bottinger, Erwin P and Braund, Peter S and Brown, Morris and Brumat, Marco and Campbell, Harry and Chambers, John C and Cocca, Massimiliano and Collins, Francis and Connell, John and Cordell, Heather J and Damman, Jeffrey J and Davies, Gail and de Geus, Eco J and de Mutsert, Ren{\'e}e and Deelen, Joris and Demirkale, Yusuf and Doney, Alex S F and D{\"o}rr, Marcus and Farrall, Martin and Ferreira, Teresa and Fr{\r a}nberg, Mattias and Gao, He and Giedraitis, Vilmantas and Gieger, Christian and Giulianini, Franco and Gow, Alan J and Hamsten, Anders and Harris, Tamara B and Hofman, Albert and Holliday, Elizabeth G and Hui, Jennie and Jarvelin, Marjo-Riitta and Johansson, Asa and Johnson, Andrew D and Jousilahti, Pekka and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kathiresan, Sekar and Khaw, Kay-Tee and Kolcic, Ivana and Koskinen, Seppo and Langenberg, Claudia and Larson, Marty and Launer, Lenore J and Lehne, Benjamin and Liewald, David C M and Lin, Li and Lind, Lars and Mach, Fran{\c c}ois and Mamasoula, Chrysovalanto and Menni, Cristina and Mifsud, Borbala and Milaneschi, Yuri and Morgan, Anna and Morris, Andrew D and Morrison, Alanna C and Munson, Peter J and Nandakumar, Priyanka and Nguyen, Quang Tri and Nutile, Teresa and Oldehinkel, Albertine J and Oostra, Ben A and Org, Elin and Padmanabhan, Sandosh and Palotie, Aarno and Par{\'e}, Guillaume and Pattie, Alison and Penninx, Brenda W J H and Poulter, Neil and Pramstaller, Peter P and Raitakari, Olli T and Ren, Meixia and Rice, Kenneth and Ridker, Paul M and Riese, Harri{\"e}tte and Ripatti, Samuli and Robino, Antonietta and Rotter, Jerome I and Rudan, Igor and Saba, Yasaman and Saint Pierre, Aude and Sala, Cinzia F and Sarin, Antti-Pekka and Schmidt, Reinhold and Scott, Rodney and Seelen, Marc A and Shields, Denis C and Siscovick, David and Sorice, Rossella and Stanton, Alice and Stott, David J and Sundstr{\"o}m, Johan and Swertz, Morris and Taylor, Kent D and Thom, Simon and Tzoulaki, Ioanna and Tzourio, Christophe and Uitterlinden, Andr{\'e} G and V{\"o}lker, Uwe and Vollenweider, Peter and Wild, Sarah and Willemsen, Gonneke and Wright, Alan F and Yao, Jie and Th{\'e}riault, S{\'e}bastien and Conen, David and Attia, John and Sever, Peter and Debette, Stephanie and Mook-Kanamori, Dennis O and Zeggini, Eleftheria and Spector, Tim D and van der Harst, Pim and Palmer, Colin N A and Vergnaud, Anne-Claire and Loos, Ruth J F and Polasek, Ozren and Starr, John M and Girotto, Giorgia and Hayward, Caroline and Kooner, Jaspal S and Lindgren, Cecila M and Vitart, Veronique and Samani, Nilesh J and Tuomilehto, Jaakko and Gyllensten, Ulf and Knekt, Paul and Deary, Ian J and Ciullo, Marina and Elosua, Roberto and Keavney, Bernard D and Hicks, Andrew A and Scott, Robert A and Gasparini, Paolo and Laan, Maris and Liu, Yongmei and Watkins, Hugh and Hartman, Catharina A and Salomaa, Veikko and Toniolo, Daniela and Perola, Markus and Wilson, James F and Schmidt, Helena and Zhao, Jing Hua and Lehtim{\"a}ki, Terho and van Duijn, Cornelia M and Gudnason, Vilmundur and Psaty, Bruce M and Peters, Annette and Rettig, Rainer and James, Alan and Jukema, J Wouter and Strachan, David P and Palmas, Walter and Metspalu, Andres and Ingelsson, Erik and Boomsma, Dorret I and Franco, Oscar H and Bochud, Murielle and Newton-Cheh, Christopher and Munroe, Patricia B and Elliott, Paul and Chasman, Daniel I and Chakravarti, Aravinda and Knight, Joanne and Morris, Andrew P and Levy, Daniel and Tobin, Martin D and Snieder, Harold and Caulfield, Mark J and Ehret, Georg B} } @article {7801, title = {Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval.}, journal = {Circ Genom Precis Med}, volume = {11}, year = {2018}, month = {2018 May}, pages = {e002037}, abstract = {

BACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability.

METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval.

RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (<1.2{\texttimes}10), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at (=5.9{\texttimes}10) and (=1.1{\texttimes}10) were associated with PR interval. locus also was implicated in the common variant analysis, whereas was a novel locus.

CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.117.002037}, author = {Lin, Honghuang and van Setten, Jessica and Smith, Albert V and Bihlmeyer, Nathan A and Warren, Helen R and Brody, Jennifer A and Radmanesh, Farid and Hall, Leanne and Grarup, Niels and M{\"u}ller-Nurasyid, Martina and Boutin, Thibaud and Verweij, Niek and Lin, Henry J and Li-Gao, Ruifang and van den Berg, Marten E and Marten, Jonathan and Weiss, Stefan and Prins, Bram P and Haessler, Jeffrey and Lyytik{\"a}inen, Leo-Pekka and Mei, Hao and Harris, Tamara B and Launer, Lenore J and Li, Man and Alonso, Alvaro and Soliman, Elsayed Z and Connell, John M and Huang, Paul L and Weng, Lu-Chen and Jameson, Heather S and Hucker, William and Hanley, Alan and Tucker, Nathan R and Chen, Yii-Der Ida and Bis, Joshua C and Rice, Kenneth M and Sitlani, Colleen M and Kors, Jan A and Xie, Zhijun and Wen, Chengping and Magnani, Jared W and Nelson, Christopher P and Kanters, J{\o}rgen K and Sinner, Moritz F and Strauch, Konstantin and Peters, Annette and Waldenberger, Melanie and Meitinger, Thomas and Bork-Jensen, Jette and Pedersen, Oluf and Linneberg, Allan and Rudan, Igor and de Boer, Rudolf A and van der Meer, Peter and Yao, Jie and Guo, Xiuqing and Taylor, Kent D and Sotoodehnia, Nona and Rotter, Jerome I and Mook-Kanamori, Dennis O and Trompet, Stella and Rivadeneira, Fernando and Uitterlinden, Andre and Eijgelsheim, Mark and Padmanabhan, Sandosh and Smith, Blair H and V{\"o}lzke, Henry and Felix, Stephan B and Homuth, Georg and V{\"o}lker, Uwe and Mangino, Massimo and Spector, Timothy D and Bots, Michiel L and Perez, Marco and K{\"a}h{\"o}nen, Mika and Raitakari, Olli T and Gudnason, Vilmundur and Arking, Dan E and Munroe, Patricia B and Psaty, Bruce M and van Duijn, Cornelia M and Benjamin, Emelia J and Rosand, Jonathan and Samani, Nilesh J and Hansen, Torben and K{\"a}{\"a}b, Stefan and Polasek, Ozren and van der Harst, Pim and Heckbert, Susan R and Jukema, J Wouter and Stricker, Bruno H and Hayward, Caroline and D{\"o}rr, Marcus and Jamshidi, Yalda and Asselbergs, Folkert W and Kooperberg, Charles and Lehtim{\"a}ki, Terho and Wilson, James G and Ellinor, Patrick T and Lubitz, Steven A and Isaacs, Aaron} } @article {7784, title = {ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals.}, journal = {Circ Genom Precis Med}, volume = {11}, year = {2018}, month = {2018 Jan}, pages = {e001758}, abstract = {

BACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest.

METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci.

CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.117.001758}, author = {Bihlmeyer, Nathan A and Brody, Jennifer A and Smith, Albert Vernon and Warren, Helen R and Lin, Honghuang and Isaacs, Aaron and Liu, Ching-Ti and Marten, Jonathan and Radmanesh, Farid and Hall, Leanne M and Grarup, Niels and Mei, Hao and M{\"u}ller-Nurasyid, Martina and Huffman, Jennifer E and Verweij, Niek and Guo, Xiuqing and Yao, Jie and Li-Gao, Ruifang and van den Berg, Marten and Weiss, Stefan and Prins, Bram P and van Setten, Jessica and Haessler, Jeffrey and Lyytik{\"a}inen, Leo-Pekka and Li, Man and Alonso, Alvaro and Soliman, Elsayed Z and Bis, Joshua C and Austin, Tom and Chen, Yii-Der Ida and Psaty, Bruce M and Harrris, Tamara B and Launer, Lenore J and Padmanabhan, Sandosh and Dominiczak, Anna and Huang, Paul L and Xie, Zhijun and Ellinor, Patrick T and Kors, Jan A and Campbell, Archie and Murray, Alison D and Nelson, Christopher P and Tobin, Martin D and Bork-Jensen, Jette and Hansen, Torben and Pedersen, Oluf and Linneberg, Allan and Sinner, Moritz F and Peters, Annette and Waldenberger, Melanie and Meitinger, Thomas and Perz, Siegfried and Kolcic, Ivana and Rudan, Igor and de Boer, Rudolf A and van der Meer, Peter and Lin, Henry J and Taylor, Kent D and de Mutsert, Ren{\'e}e and Trompet, Stella and Jukema, J Wouter and Maan, Arie C and Stricker, Bruno H C and Rivadeneira, Fernando and Uitterlinden, Andre and V{\"o}lker, Uwe and Homuth, Georg and V{\"o}lzke, Henry and Felix, Stephan B and Mangino, Massimo and Spector, Timothy D and Bots, Michiel L and Perez, Marco and Raitakari, Olli T and K{\"a}h{\"o}nen, Mika and Mononen, Nina and Gudnason, Vilmundur and Munroe, Patricia B and Lubitz, Steven A and van Duijn, Cornelia M and Newton-Cheh, Christopher H and Hayward, Caroline and Rosand, Jonathan and Samani, Nilesh J and Kanters, J{\o}rgen K and Wilson, James G and K{\"a}{\"a}b, Stefan and Polasek, Ozren and van der Harst, Pim and Heckbert, Susan R and Rotter, Jerome I and Mook-Kanamori, Dennis O and Eijgelsheim, Mark and D{\"o}rr, Marcus and Jamshidi, Yalda and Asselbergs, Folkert W and Kooperberg, Charles and Lehtim{\"a}ki, Terho and Arking, Dan E and Sotoodehnia, Nona} } @article {7845, title = {Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Oct}, pages = {1412-1425}, abstract = {

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0205-x}, author = {Evangelou, Evangelos and Warren, Helen R and Mosen-Ansorena, David and Mifsud, Borbala and Pazoki, Raha and Gao, He and Ntritsos, Georgios and Dimou, Niki and Cabrera, Claudia P and Karaman, Ibrahim and Ng, Fu Liang and Evangelou, Marina and Witkowska, Katarzyna and Tzanis, Evan and Hellwege, Jacklyn N and Giri, Ayush and Velez Edwards, Digna R and Sun, Yan V and Cho, Kelly and Gaziano, J Michael and Wilson, Peter W F and Tsao, Philip S and Kovesdy, Csaba P and Esko, T{\~o}nu and M{\"a}gi, Reedik and Milani, Lili and Almgren, Peter and Boutin, Thibaud and Debette, Stephanie and Ding, Jun and Giulianini, Franco and Holliday, Elizabeth G and Jackson, Anne U and Li-Gao, Ruifang and Lin, Wei-Yu and Luan, Jian{\textquoteright}an and Mangino, Massimo and Oldmeadow, Christopher and Prins, Bram Peter and Qian, Yong and Sargurupremraj, Muralidharan and Shah, Nabi and Surendran, Praveen and Th{\'e}riault, S{\'e}bastien and Verweij, Niek and Willems, Sara M and Zhao, Jing-Hua and Amouyel, Philippe and Connell, John and de Mutsert, Ren{\'e}e and Doney, Alex S F and Farrall, Martin and Menni, Cristina and Morris, Andrew D and Noordam, Raymond and Par{\'e}, Guillaume and Poulter, Neil R and Shields, Denis C and Stanton, Alice and Thom, Simon and Abecasis, Goncalo and Amin, Najaf and Arking, Dan E and Ayers, Kristin L and Barbieri, Caterina M and Batini, Chiara and Bis, Joshua C and Blake, Tineka and Bochud, Murielle and Boehnke, Michael and Boerwinkle, Eric and Boomsma, Dorret I and Bottinger, Erwin P and Braund, Peter S and Brumat, Marco and Campbell, Archie and Campbell, Harry and Chakravarti, Aravinda and Chambers, John C and Chauhan, Ganesh and Ciullo, Marina and Cocca, Massimiliano and Collins, Francis and Cordell, Heather J and Davies, Gail and Borst, Martin H de and Geus, Eco J de and Deary, Ian J and Deelen, Joris and del Greco M, Fabiola and Demirkale, Cumhur Yusuf and D{\"o}rr, Marcus and Ehret, Georg B and Elosua, Roberto and Enroth, Stefan and Erzurumluoglu, A Mesut and Ferreira, Teresa and Fr{\r a}nberg, Mattias and Franco, Oscar H and Gandin, Ilaria and Gasparini, Paolo and Giedraitis, Vilmantas and Gieger, Christian and Girotto, Giorgia and Goel, Anuj and Gow, Alan J and Gudnason, Vilmundur and Guo, Xiuqing and Gyllensten, Ulf and Hamsten, Anders and Harris, Tamara B and Harris, Sarah E and Hartman, Catharina A and Havulinna, Aki S and Hicks, Andrew A and Hofer, Edith and Hofman, Albert and Hottenga, Jouke-Jan and Huffman, Jennifer E and Hwang, Shih-Jen and Ingelsson, Erik and James, Alan and Jansen, Rick and Jarvelin, Marjo-Riitta and Joehanes, Roby and Johansson, Asa and Johnson, Andrew D and Joshi, Peter K and Jousilahti, Pekka and Jukema, J Wouter and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kathiresan, Sekar and Keavney, Bernard D and Khaw, Kay-Tee and Knekt, Paul and Knight, Joanne and Kolcic, Ivana and Kooner, Jaspal S and Koskinen, Seppo and Kristiansson, Kati and Kutalik, Zolt{\'a}n and Laan, Maris and Larson, Marty and Launer, Lenore J and Lehne, Benjamin and Lehtim{\"a}ki, Terho and Liewald, David C M and Lin, Li and Lind, Lars and Lindgren, Cecilia M and Liu, Yongmei and Loos, Ruth J F and Lopez, Lorna M and Lu, Yingchang and Lyytik{\"a}inen, Leo-Pekka and Mahajan, Anubha and Mamasoula, Chrysovalanto and Marrugat, Jaume and Marten, Jonathan and Milaneschi, Yuri and Morgan, Anna and Morris, Andrew P and Morrison, Alanna C and Munson, Peter J and Nalls, Mike A and Nandakumar, Priyanka and Nelson, Christopher P and Niiranen, Teemu and Nolte, Ilja M and Nutile, Teresa and Oldehinkel, Albertine J and Oostra, Ben A and O{\textquoteright}Reilly, Paul F and Org, Elin and Padmanabhan, Sandosh and Palmas, Walter and Palotie, Aarno and Pattie, Alison and Penninx, Brenda W J H and Perola, Markus and Peters, Annette and Polasek, Ozren and Pramstaller, Peter P and Nguyen, Quang Tri and Raitakari, Olli T and Ren, Meixia and Rettig, Rainer and Rice, Kenneth and Ridker, Paul M and Ried, Janina S and Riese, Harri{\"e}tte and Ripatti, Samuli and Robino, Antonietta and Rose, Lynda M and Rotter, Jerome I and Rudan, Igor and Ruggiero, Daniela and Saba, Yasaman and Sala, Cinzia F and Salomaa, Veikko and Samani, Nilesh J and Sarin, Antti-Pekka and Schmidt, Reinhold and Schmidt, Helena and Shrine, Nick and Siscovick, David and Smith, Albert V and Snieder, Harold and S{\~o}ber, Siim and Sorice, Rossella and Starr, John M and Stott, David J and Strachan, David P and Strawbridge, Rona J and Sundstr{\"o}m, Johan and Swertz, Morris A and Taylor, Kent D and Teumer, Alexander and Tobin, Martin D and Tomaszewski, Maciej and Toniolo, Daniela and Traglia, Michela and Trompet, Stella and Tuomilehto, Jaakko and Tzourio, Christophe and Uitterlinden, Andr{\'e} G and Vaez, Ahmad and van der Most, Peter J and van Duijn, Cornelia M and Vergnaud, Anne-Claire and Verwoert, Germaine C and Vitart, Veronique and V{\"o}lker, Uwe and Vollenweider, Peter and Vuckovic, Dragana and Watkins, Hugh and Wild, Sarah H and Willemsen, Gonneke and Wilson, James F and Wright, Alan F and Yao, Jie and Zemunik, Tatijana and Zhang, Weihua and Attia, John R and Butterworth, Adam S and Chasman, Daniel I and Conen, David and Cucca, Francesco and Danesh, John and Hayward, Caroline and Howson, Joanna M M and Laakso, Markku and Lakatta, Edward G and Langenberg, Claudia and Melander, Olle and Mook-Kanamori, Dennis O and Palmer, Colin N A and Risch, Lorenz and Scott, Robert A and Scott, Rodney J and Sever, Peter and Spector, Tim D and van der Harst, Pim and Wareham, Nicholas J and Zeggini, Eleftheria and Levy, Daniel and Munroe, Patricia B and Newton-Cheh, Christopher and Brown, Morris J and Metspalu, Andres and Hung, Adriana M and O{\textquoteright}Donnell, Christopher J and Edwards, Todd L and Psaty, Bruce M and Tzoulaki, Ioanna and Barnes, Michael R and Wain, Louise V and Elliott, Paul and Caulfield, Mark J} } @article {7669, title = {Genome-wide association study and meta-analysis identify loci associated with ventricular and supraventricular ectopy.}, journal = {Sci Rep}, volume = {8}, year = {2018}, month = {2018 Apr 04}, pages = {5675}, abstract = {

The genetic basis of supraventricular and ventricular ectopy (SVE, VE) remains largely uncharacterized, despite established genetic mechanisms of arrhythmogenesis. To identify novel genetic variants associated with SVE/VE in ancestrally diverse human populations, we conducted a genome-wide association study of electrocardiographically~identified SVE and VE in five cohorts including approximately 43,000 participants of African, European and Hispanic/Latino ancestry. In thirteen ancestry-stratified subgroups, we tested multivariable-adjusted associations of SVE and VE with single nucleotide polymorphism (SNP) dosage. We combined subgroup-specific association estimates in inverse variance-weighted, fixed-effects and Bayesian meta-analyses. We also combined fixed-effects meta-analytic t-test statistics for SVE and VE in multi-trait SNP association analyses. No loci reached genome-wide significance in trans-ethnic meta-analyses. However, we found genome-wide significant SNPs intronic to an apoptosis-enhancing gene previously associated with QRS interval duration (FAF1; lead SNP rs7545860; effect allele frequency = 0.02; P = 2.0 {\texttimes} 10) in multi-trait analysis among European ancestry participants and near a locus encoding calcium-dependent glycoproteins (DSC3; lead SNP rs8086068; effect allele frequency = 0.17) in meta-analysis of SVE (P = 4.0 {\texttimes} 10) and multi-trait analysis (P = 2.9 {\texttimes} 10) among African ancestry participants. The novel findings suggest several mechanisms by which genetic variation may predispose to ectopy in humans and highlight the potential value of leveraging pleiotropy in future studies of ectopy-related phenotypes.

}, issn = {2045-2322}, doi = {10.1038/s41598-018-23843-z}, author = {Napier, Melanie D and Franceschini, Nora and Gondalia, Rahul and Stewart, James D and M{\'e}ndez-Gir{\'a}ldez, R{\'a}ul and Sitlani, Colleen M and Seyerle, Amanda A and Highland, Heather M and Li, Yun and Wilhelmsen, Kirk C and Yan, Song and Duan, Qing and Roach, Jeffrey and Yao, Jie and Guo, Xiuqing and Taylor, Kent D and Heckbert, Susan R and Rotter, Jerome I and North, Kari E and Reiner, Alexander P and Zhang, Zhu-Ming and Tinker, Lesley F and Liao, Duanping and Laurie, Cathy C and Gogarten, Stephanie M and Lin, Henry J and Brody, Jennifer A and Bartz, Traci M and Psaty, Bruce M and Sotoodehnia, Nona and Soliman, Elsayed Z and Avery, Christy L and Whitsel, Eric A} } @article {7686, title = {A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 Mar 01}, pages = {375-400}, abstract = {

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined \~{}18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5~{\texttimes} 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5~{\texttimes} 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.01.015}, author = {Sung, Yun J and Winkler, Thomas W and de Las Fuentes, Lisa and Bentley, Amy R and Brown, Michael R and Kraja, Aldi T and Schwander, Karen and Ntalla, Ioanna and Guo, Xiuqing and Franceschini, Nora and Lu, Yingchang and Cheng, Ching-Yu and Sim, Xueling and Vojinovic, Dina and Marten, Jonathan and Musani, Solomon K and Li, Changwei and Feitosa, Mary F and Kilpel{\"a}inen, Tuomas O and Richard, Melissa A and Noordam, Raymond and Aslibekyan, Stella and Aschard, Hugues and Bartz, Traci M and Dorajoo, Rajkumar and Liu, Yongmei and Manning, Alisa K and Rankinen, Tuomo and Smith, Albert Vernon and Tajuddin, Salman M and Tayo, Bamidele O and Warren, Helen R and Zhao, Wei and Zhou, Yanhua and Matoba, Nana and Sofer, Tamar and Alver, Maris and Amini, Marzyeh and Boissel, Mathilde and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Gandin, Ilaria and Gao, Chuan and Giulianini, Franco and Goel, Anuj and Harris, Sarah E and Hartwig, Fernando Pires and Horimoto, Andrea R V R and Hsu, Fang-Chi and Jackson, Anne U and K{\"a}h{\"o}nen, Mika and Kasturiratne, Anuradhani and Kuhnel, Brigitte and Leander, Karin and Lee, Wen-Jane and Lin, Keng-Hung and {\textquoteright}an Luan, Jian and McKenzie, Colin A and Meian, He and Nelson, Christopher P and Rauramaa, Rainer and Schupf, Nicole and Scott, Robert A and Sheu, Wayne H H and Stan{\v c}{\'a}kov{\'a}, Alena and Takeuchi, Fumihiko and van der Most, Peter J and Varga, Tibor V and Wang, Heming and Wang, Yajuan and Ware, Erin B and Weiss, Stefan and Wen, Wanqing and Yanek, Lisa R and Zhang, Weihua and Zhao, Jing Hua and Afaq, Saima and Alfred, Tamuno and Amin, Najaf and Arking, Dan and Aung, Tin and Barr, R Graham and Bielak, Lawrence F and Boerwinkle, Eric and Bottinger, Erwin P and Braund, Peter S and Brody, Jennifer A and Broeckel, Ulrich and Cabrera, Claudia P and Cade, Brian and Caizheng, Yu and Campbell, Archie and Canouil, Micka{\"e}l and Chakravarti, Aravinda and Chauhan, Ganesh and Christensen, Kaare and Cocca, Massimiliano and Collins, Francis S and Connell, John M and de Mutsert, Ren{\'e}e and de Silva, H Janaka and Debette, Stephanie and D{\"o}rr, Marcus and Duan, Qing and Eaton, Charles B and Ehret, Georg and Evangelou, Evangelos and Faul, Jessica D and Fisher, Virginia A and Forouhi, Nita G and Franco, Oscar H and Friedlander, Yechiel and Gao, He and Gigante, Bruna and Graff, Misa and Gu, C Charles and Gu, Dongfeng and Gupta, Preeti and Hagenaars, Saskia P and Harris, Tamara B and He, Jiang and Heikkinen, Sami and Heng, Chew-Kiat and Hirata, Makoto and Hofman, Albert and Howard, Barbara V and Hunt, Steven and Irvin, Marguerite R and Jia, Yucheng and Joehanes, Roby and Justice, Anne E and Katsuya, Tomohiro and Kaufman, Joel and Kerrison, Nicola D and Khor, Chiea Chuen and Koh, Woon-Puay and Koistinen, Heikki A and Komulainen, Pirjo and Kooperberg, Charles and Krieger, Jose E and Kubo, Michiaki and Kuusisto, Johanna and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lehne, Benjamin and Lewis, Cora E and Li, Yize and Lim, Sing Hui and Lin, Shiow and Liu, Ching-Ti and Liu, Jianjun and Liu, Jingmin and Liu, Kiang and Liu, Yeheng and Loh, Marie and Lohman, Kurt K and Long, Jirong and Louie, Tin and M{\"a}gi, Reedik and Mahajan, Anubha and Meitinger, Thomas and Metspalu, Andres and Milani, Lili and Momozawa, Yukihide and Morris, Andrew P and Mosley, Thomas H and Munson, Peter and Murray, Alison D and Nalls, Mike A and Nasri, Ubaydah and Norris, Jill M and North, Kari and Ogunniyi, Adesola and Padmanabhan, Sandosh and Palmas, Walter R and Palmer, Nicholette D and Pankow, James S and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Polasek, Ozren and Raitakari, Olli T and Renstrom, Frida and Rice, Treva K and Ridker, Paul M and Robino, Antonietta and Robinson, Jennifer G and Rose, Lynda M and Rudan, Igor and Sabanayagam, Charumathi and Salako, Babatunde L and Sandow, Kevin and Schmidt, Carsten O and Schreiner, Pamela J and Scott, William R and Seshadri, Sudha and Sever, Peter and Sitlani, Colleen M and Smith, Jennifer A and Snieder, Harold and Starr, John M and Strauch, Konstantin and Tang, Hua and Taylor, Kent D and Teo, Yik Ying and Tham, Yih Chung and Uitterlinden, Andr{\'e} G and Waldenberger, Melanie and Wang, Lihua and Wang, Ya X and Wei, Wen Bin and Williams, Christine and Wilson, Gregory and Wojczynski, Mary K and Yao, Jie and Yuan, Jian-Min and Zonderman, Alan B and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and Chambers, John C and Chen, Yii-Der Ida and de Faire, Ulf and Deary, Ian J and Esko, T{\~o}nu and Farrall, Martin and Forrester, Terrence and Franks, Paul W and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Horta, Bernardo Lessa and Hung, Yi-Jen and Jonas, Jost B and Kato, Norihiro and Kooner, Jaspal S and Laakso, Markku and Lehtim{\"a}ki, Terho and Liang, Kae-Woei and Magnusson, Patrik K E and Newman, Anne B and Oldehinkel, Albertine J and Pereira, Alexandre C and Redline, Susan and Rettig, Rainer and Samani, Nilesh J and Scott, James and Shu, Xiao-Ou and van der Harst, Pim and Wagenknecht, Lynne E and Wareham, Nicholas J and Watkins, Hugh and Weir, David R and Wickremasinghe, Ananda R and Wu, Tangchun and Zheng, Wei and Kamatani, Yoichiro and Laurie, Cathy C and Bouchard, Claude and Cooper, Richard S and Evans, Michele K and Gudnason, Vilmundur and Kardia, Sharon L R and Kritchevsky, Stephen B and Levy, Daniel and O{\textquoteright}Connell, Jeff R and Psaty, Bruce M and van Dam, Rob M and Sims, Mario and Arnett, Donna K and Mook-Kanamori, Dennis O and Kelly, Tanika N and Fox, Ervin R and Hayward, Caroline and Fornage, Myriam and Rotimi, Charles N and Province, Michael A and van Duijn, Cornelia M and Tai, E Shyong and Wong, Tien Yin and Loos, Ruth J F and Reiner, Alex P and Rotter, Jerome I and Zhu, Xiaofeng and Bierut, Laura J and Gauderman, W James and Caulfield, Mark J and Elliott, Paul and Rice, Kenneth and Munroe, Patricia B and Morrison, Alanna C and Cupples, L Adrienne and Rao, Dabeeru C and Chasman, Daniel I} } @article {7811, title = {Multi-ethnic genome-wide association study for atrial fibrillation.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Sep}, pages = {1225-1233}, abstract = {

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

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0133-9}, author = {Roselli, Carolina and Chaffin, Mark D and Weng, Lu-Chen and Aeschbacher, Stefanie and Ahlberg, Gustav and Albert, Christine M and Almgren, Peter and Alonso, Alvaro and Anderson, Christopher D and Aragam, Krishna G and Arking, Dan E and Barnard, John and Bartz, Traci M and Benjamin, Emelia J and Bihlmeyer, Nathan A and Bis, Joshua C and Bloom, Heather L and Boerwinkle, Eric and Bottinger, Erwin B and Brody, Jennifer A and Calkins, Hugh and Campbell, Archie and Cappola, Thomas P and Carlquist, John and Chasman, Daniel I and Chen, Lin Y and Chen, Yii-Der Ida and Choi, Eue-Keun and Choi, Seung Hoan and Christophersen, Ingrid E and Chung, Mina K and Cole, John W and Conen, David and Cook, James and Crijns, Harry J and Cutler, Michael J and Damrauer, Scott M and Daniels, Brian R and Darbar, Dawood and Delgado, Graciela and Denny, Joshua C and Dichgans, Martin and D{\"o}rr, Marcus and Dudink, Elton A and Dudley, Samuel C and Esa, Nada and Esko, T{\~o}nu and Eskola, Markku and Fatkin, Diane and Felix, Stephan B and Ford, Ian and Franco, Oscar H and Geelhoed, Bastiaan and Grewal, Raji P and Gudnason, Vilmundur and Guo, Xiuqing and Gupta, Namrata and Gustafsson, Stefan and Gutmann, Rebecca and Hamsten, Anders and Harris, Tamara B and Hayward, Caroline and Heckbert, Susan R and Hernesniemi, Jussi and Hocking, Lynne J and Hofman, Albert and Horimoto, Andrea R V R and Huang, Jie and Huang, Paul L and Huffman, Jennifer and Ingelsson, Erik and Ipek, Esra Gucuk and Ito, Kaoru and Jimenez-Conde, Jordi and Johnson, Renee and Jukema, J Wouter and K{\"a}{\"a}b, Stefan and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kane, John P and Kastrati, Adnan and Kathiresan, Sekar and Katschnig-Winter, Petra and Kavousi, Maryam and Kessler, Thorsten and Kietselaer, Bas L and Kirchhof, Paulus and Kleber, Marcus E and Knight, Stacey and Krieger, Jose E and Kubo, Michiaki and Launer, Lenore J and Laurikka, Jari and Lehtim{\"a}ki, Terho and Leineweber, Kirsten and Lemaitre, Rozenn N and Li, Man and Lim, Hong Euy and Lin, Henry J and Lin, Honghuang and Lind, Lars and Lindgren, Cecilia M and Lokki, Marja-Liisa and London, Barry and Loos, Ruth J F and Low, Siew-Kee and Lu, Yingchang and Lyytik{\"a}inen, Leo-Pekka and Macfarlane, Peter W and Magnusson, Patrik K and Mahajan, Anubha and Malik, Rainer and Mansur, Alfredo J and Marcus, Gregory M and Margolin, Lauren and Margulies, Kenneth B and M{\"a}rz, Winfried and McManus, David D and Melander, Olle and Mohanty, Sanghamitra and Montgomery, Jay A and Morley, Michael P and Morris, Andrew P and M{\"u}ller-Nurasyid, Martina and Natale, Andrea and Nazarian, Saman and Neumann, Benjamin and Newton-Cheh, Christopher and Niemeijer, Maartje N and Nikus, Kjell and Nilsson, Peter and Noordam, Raymond and Oellers, Heidi and Olesen, Morten S and Orho-Melander, Marju and Padmanabhan, Sandosh and Pak, Hui-Nam and Par{\'e}, Guillaume and Pedersen, Nancy L and Pera, Joanna and Pereira, Alexandre and Porteous, David and Psaty, Bruce M and Pulit, Sara L and Pullinger, Clive R and Rader, Daniel J and Refsgaard, Lena and Ribas{\'e}s, Marta and Ridker, Paul M and Rienstra, Michiel and Risch, Lorenz and Roden, Dan M and Rosand, Jonathan and Rosenberg, Michael A and Rost, Natalia and Rotter, Jerome I and Saba, Samir and Sandhu, Roopinder K and Schnabel, Renate B and Schramm, Katharina and Schunkert, Heribert and Schurman, Claudia and Scott, Stuart A and Sepp{\"a}l{\"a}, Ilkka and Shaffer, Christian and Shah, Svati and Shalaby, Alaa A and Shim, Jaemin and Shoemaker, M Benjamin and Siland, Joylene E and Sinisalo, Juha and Sinner, Moritz F and Slowik, Agnieszka and Smith, Albert V and Smith, Blair H and Smith, J Gustav and Smith, Jonathan D and Smith, Nicholas L and Soliman, Elsayed Z and Sotoodehnia, Nona and Stricker, Bruno H and Sun, Albert and Sun, Han and Svendsen, Jesper H and Tanaka, Toshihiro and Tanriverdi, Kahraman and Taylor, Kent D and Teder-Laving, Maris and Teumer, Alexander and Th{\'e}riault, S{\'e}bastien and Trompet, Stella and Tucker, Nathan R and Tveit, Arnljot and Uitterlinden, Andr{\'e} G and van der Harst, Pim and Van Gelder, Isabelle C and Van Wagoner, David R and Verweij, Niek and Vlachopoulou, Efthymia and V{\"o}lker, Uwe and Wang, Biqi and Weeke, Peter E and Weijs, Bob and Weiss, Raul and Weiss, Stefan and Wells, Quinn S and Wiggins, Kerri L and Wong, Jorge A and Woo, Daniel and Worrall, Bradford B and Yang, Pil-Sung and Yao, Jie and Yoneda, Zachary T and Zeller, Tanja and Zeng, Lingyao and Lubitz, Steven A and Lunetta, Kathryn L and Ellinor, Patrick T} } @article {7792, title = {Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0198166}, abstract = {

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0198166}, author = {Feitosa, Mary F and Kraja, Aldi T and Chasman, Daniel I and Sung, Yun J and Winkler, Thomas W and Ntalla, Ioanna and Guo, Xiuqing and Franceschini, Nora and Cheng, Ching-Yu and Sim, Xueling and Vojinovic, Dina and Marten, Jonathan and Musani, Solomon K and Li, Changwei and Bentley, Amy R and Brown, Michael R and Schwander, Karen and Richard, Melissa A and Noordam, Raymond and Aschard, Hugues and Bartz, Traci M and Bielak, Lawrence F and Dorajoo, Rajkumar and Fisher, Virginia and Hartwig, Fernando P and Horimoto, Andrea R V R and Lohman, Kurt K and Manning, Alisa K and Rankinen, Tuomo and Smith, Albert V and Tajuddin, Salman M and Wojczynski, Mary K and Alver, Maris and Boissel, Mathilde and Cai, Qiuyin and Campbell, Archie and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Gao, Chuan and Goel, Anuj and Hagemeijer, Yanick and Harris, Sarah E and He, Meian and Hsu, Fang-Chi and Jackson, Anne U and K{\"a}h{\"o}nen, Mika and Kasturiratne, Anuradhani and Komulainen, Pirjo and Kuhnel, Brigitte and Laguzzi, Federica and Luan, Jian{\textquoteright}an and Matoba, Nana and Nolte, Ilja M and Padmanabhan, Sandosh and Riaz, Muhammad and Rueedi, Rico and Robino, Antonietta and Said, M Abdullah and Scott, Robert A and Sofer, Tamar and Stan{\v c}{\'a}kov{\'a}, Alena and Takeuchi, Fumihiko and Tayo, Bamidele O and van der Most, Peter J and Varga, Tibor V and Vitart, Veronique and Wang, Yajuan and Ware, Erin B and Warren, Helen R and Weiss, Stefan and Wen, Wanqing and Yanek, Lisa R and Zhang, Weihua and Zhao, Jing Hua and Afaq, Saima and Amin, Najaf and Amini, Marzyeh and Arking, Dan E and Aung, Tin and Boerwinkle, Eric and Borecki, Ingrid and Broeckel, Ulrich and Brown, Morris and Brumat, Marco and Burke, Gregory L and Canouil, Micka{\"e}l and Chakravarti, Aravinda and Charumathi, Sabanayagam and Ida Chen, Yii-Der and Connell, John M and Correa, Adolfo and de Las Fuentes, Lisa and de Mutsert, Ren{\'e}e and de Silva, H Janaka and Deng, Xuan and Ding, Jingzhong and Duan, Qing and Eaton, Charles B and Ehret, Georg and Eppinga, Ruben N and Evangelou, Evangelos and Faul, Jessica D and Felix, Stephan B and Forouhi, Nita G and Forrester, Terrence and Franco, Oscar H and Friedlander, Yechiel and Gandin, Ilaria and Gao, He and Ghanbari, Mohsen and Gigante, Bruna and Gu, C Charles and Gu, Dongfeng and Hagenaars, Saskia P and Hallmans, G{\"o}ran and Harris, Tamara B and He, Jiang and Heikkinen, Sami and Heng, Chew-Kiat and Hirata, Makoto and Howard, Barbara V and Ikram, M Arfan and John, Ulrich and Katsuya, Tomohiro and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Krieger, Jose E and Kritchevsky, Stephen B and Kubo, Michiaki and Kuusisto, Johanna and Lakka, Timo A and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lehne, Benjamin and Lewis, Cora E and Li, Yize and Lin, Shiow and Liu, Jianjun and Liu, Jingmin and Loh, Marie and Louie, Tin and M{\"a}gi, Reedik and McKenzie, Colin A and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Milani, Lili and Mohlke, Karen L and Momozawa, Yukihide and Nalls, Mike A and Nelson, Christopher P and Sotoodehnia, Nona and Norris, Jill M and O{\textquoteright}Connell, Jeff R and Palmer, Nicholette D and Perls, Thomas and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Poulter, Neil and Raffel, Leslie J and Raitakari, Olli T and Roll, Kathryn and Rose, Lynda M and Rosendaal, Frits R and Rotter, Jerome I and Schmidt, Carsten O and Schreiner, Pamela J and Schupf, Nicole and Scott, William R and Sever, Peter S and Shi, Yuan and Sidney, Stephen and Sims, Mario and Sitlani, Colleen M and Smith, Jennifer A and Snieder, Harold and Starr, John M and Strauch, Konstantin and Stringham, Heather M and Tan, Nicholas Y Q and Tang, Hua and Taylor, Kent D and Teo, Yik Ying and Tham, Yih Chung and Turner, Stephen T and Uitterlinden, Andr{\'e} G and Vollenweider, Peter and Waldenberger, Melanie and Wang, Lihua and Wang, Ya Xing and Wei, Wen Bin and Williams, Christine and Yao, Jie and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Zonderman, Alan B and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and Chambers, John C and Deary, Ian J and Esko, T{\~o}nu and Farrall, Martin and Franks, Paul W and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Jonas, Jost Bruno and Kamatani, Yoichiro and Kato, Norihiro and Kooner, Jaspal S and Kutalik, Zolt{\'a}n and Laakso, Markku and Laurie, Cathy C and Leander, Karin and Lehtim{\"a}ki, Terho and Study, Lifelines Cohort and Magnusson, Patrik K E and Oldehinkel, Albertine J and Penninx, Brenda W J H and Polasek, Ozren and Porteous, David J and Rauramaa, Rainer and Samani, Nilesh J and Scott, James and Shu, Xiao-Ou and van der Harst, Pim and Wagenknecht, Lynne E and Wareham, Nicholas J and Watkins, Hugh and Weir, David R and Wickremasinghe, Ananda R and Wu, Tangchun and Zheng, Wei and Bouchard, Claude and Christensen, Kaare and Evans, Michele K and Gudnason, Vilmundur and Horta, Bernardo L and Kardia, Sharon L R and Liu, Yongmei and Pereira, Alexandre C and Psaty, Bruce M and Ridker, Paul M and van Dam, Rob M and Gauderman, W James and Zhu, Xiaofeng and Mook-Kanamori, Dennis O and Fornage, Myriam and Rotimi, Charles N and Cupples, L Adrienne and Kelly, Tanika N and Fox, Ervin R and Hayward, Caroline and van Duijn, Cornelia M and Tai, E Shyong and Wong, Tien Yin and Kooperberg, Charles and Palmas, Walter and Rice, Kenneth and Morrison, Alanna C and Elliott, Paul and Caulfield, Mark J and Munroe, Patricia B and Rao, Dabeeru C and Province, Michael A and Levy, Daniel} } @article {7668, title = {Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Apr}, pages = {559-571}, abstract = {

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 {\texttimes} 10); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio <=1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent {\textquoteright}false leads{\textquoteright} with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0084-1}, author = {Mahajan, Anubha and Wessel, Jennifer and Willems, Sara M and Zhao, Wei and Robertson, Neil R and Chu, Audrey Y and Gan, Wei and Kitajima, Hidetoshi and Taliun, Daniel and Rayner, N William and Guo, Xiuqing and Lu, Yingchang and Li, Man and Jensen, Richard A and Hu, Yao and Huo, Shaofeng and Lohman, Kurt K and Zhang, Weihua and Cook, James P and Prins, Bram Peter and Flannick, Jason and Grarup, Niels and Trubetskoy, Vassily Vladimirovich and Kravic, Jasmina and Kim, Young Jin and Rybin, Denis V and Yaghootkar, Hanieh and M{\"u}ller-Nurasyid, Martina and Meidtner, Karina and Li-Gao, Ruifang and Varga, Tibor V and Marten, Jonathan and Li, Jin and Smith, Albert Vernon and An, Ping and Ligthart, Symen and Gustafsson, Stefan and Malerba, Giovanni and Demirkan, Ayse and Tajes, Juan Fernandez and Steinthorsdottir, Valgerdur and Wuttke, Matthias and Lecoeur, C{\'e}cile and Preuss, Michael and Bielak, Lawrence F and Graff, Marielisa and Highland, Heather M and Justice, Anne E and Liu, Dajiang J and Marouli, Eirini and Peloso, Gina Marie and Warren, Helen R and Afaq, Saima and Afzal, Shoaib and Ahlqvist, Emma and Almgren, Peter and Amin, Najaf and Bang, Lia B and Bertoni, Alain G and Bombieri, Cristina and Bork-Jensen, Jette and Brandslund, Ivan and Brody, Jennifer A and Burtt, Noel P and Canouil, Micka{\"e}l and Chen, Yii-Der Ida and Cho, Yoon Shin and Christensen, Cramer and Eastwood, Sophie V and Eckardt, Kai-Uwe and Fischer, Krista and Gambaro, Giovanni and Giedraitis, Vilmantas and Grove, Megan L and de Haan, Hugoline G and Hackinger, Sophie and Hai, Yang and Han, Sohee and Tybj{\ae}rg-Hansen, Anne and Hivert, Marie-France and Isomaa, Bo and J{\"a}ger, Susanne and J{\o}rgensen, Marit E and J{\o}rgensen, Torben and K{\"a}r{\"a}j{\"a}m{\"a}ki, AnneMari and Kim, Bong-Jo and Kim, Sung Soo and Koistinen, Heikki A and Kovacs, Peter and Kriebel, Jennifer and Kronenberg, Florian and L{\"a}ll, Kristi and Lange, Leslie A and Lee, Jung-Jin and Lehne, Benjamin and Li, Huaixing and Lin, Keng-Hung and Linneberg, Allan and Liu, Ching-Ti and Liu, Jun and Loh, Marie and M{\"a}gi, Reedik and Mamakou, Vasiliki and McKean-Cowdin, Roberta and Nadkarni, Girish and Neville, Matt and Nielsen, Sune F and Ntalla, Ioanna and Peyser, Patricia A and Rathmann, Wolfgang and Rice, Kenneth and Rich, Stephen S and Rode, Line and Rolandsson, Olov and Sch{\"o}nherr, Sebastian and Selvin, Elizabeth and Small, Kerrin S and Stan{\v c}{\'a}kov{\'a}, Alena and Surendran, Praveen and Taylor, Kent D and Teslovich, Tanya M and Thorand, Barbara and Thorleifsson, Gudmar and Tin, Adrienne and T{\"o}njes, Anke and Varbo, Anette and Witte, Daniel R and Wood, Andrew R and Yajnik, Pranav and Yao, Jie and Yengo, Loic and Young, Robin and Amouyel, Philippe and Boeing, Heiner and Boerwinkle, Eric and Bottinger, Erwin P and Chowdhury, Rajiv and Collins, Francis S and Dedoussis, George and Dehghan, Abbas and Deloukas, Panos and Ferrario, Marco M and Ferrieres, Jean and Florez, Jose C and Frossard, Philippe and Gudnason, Vilmundur and Harris, Tamara B and Heckbert, Susan R and Howson, Joanna M M and Ingelsson, Martin and Kathiresan, Sekar and Kee, Frank and Kuusisto, Johanna and Langenberg, Claudia and Launer, Lenore J and Lindgren, Cecilia M and M{\"a}nnist{\"o}, Satu and Meitinger, Thomas and Melander, Olle and Mohlke, Karen L and Moitry, Marie and Morris, Andrew D and Murray, Alison D and de Mutsert, Ren{\'e}e and Orho-Melander, Marju and Owen, Katharine R and Perola, Markus and Peters, Annette and Province, Michael A and Rasheed, Asif and Ridker, Paul M and Rivadineira, Fernando and Rosendaal, Frits R and Rosengren, Anders H and Salomaa, Veikko and Sheu, Wayne H-H and Sladek, Rob and Smith, Blair H and Strauch, Konstantin and Uitterlinden, Andr{\'e} G and Varma, Rohit and Willer, Cristen J and Bl{\"u}her, Matthias and Butterworth, Adam S and Chambers, John Campbell and Chasman, Daniel I and Danesh, John and van Duijn, Cornelia and Dupuis, Jos{\'e}e and Franco, Oscar H and Franks, Paul W and Froguel, Philippe and Grallert, Harald and Groop, Leif and Han, Bok-Ghee and Hansen, Torben and Hattersley, Andrew T and Hayward, Caroline and Ingelsson, Erik and Kardia, Sharon L R and Karpe, Fredrik and Kooner, Jaspal Singh and K{\"o}ttgen, Anna and Kuulasmaa, Kari and Laakso, Markku and Lin, Xu and Lind, Lars and Liu, Yongmei and Loos, Ruth J F and Marchini, Jonathan and Metspalu, Andres and Mook-Kanamori, Dennis and Nordestgaard, B{\o}rge G and Palmer, Colin N A and Pankow, James S and Pedersen, Oluf and Psaty, Bruce M and Rauramaa, Rainer and Sattar, Naveed and Schulze, Matthias B and Soranzo, Nicole and Spector, Timothy D and Stefansson, Kari and Stumvoll, Michael and Thorsteinsdottir, Unnur and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Wareham, Nicholas J and Wilson, James G and Zeggini, Eleftheria and Scott, Robert A and Barroso, In{\^e}s and Frayling, Timothy M and Goodarzi, Mark O and Meigs, James B and Boehnke, Michael and Saleheen, Danish and Morris, Andrew P and Rotter, Jerome I and McCarthy, Mark I} } @article {8198, title = {Associations of autozygosity with a broad range of human phenotypes.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 Oct 31}, pages = {4957}, abstract = {

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55\% decrease [95\% CI 44-66\%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.

}, issn = {2041-1723}, doi = {10.1038/s41467-019-12283-6}, author = {Clark, David W and Okada, Yukinori and Moore, Kristjan H S and Mason, Dan and Pirastu, Nicola and Gandin, Ilaria and Mattsson, Hannele and Barnes, Catriona L K and Lin, Kuang and Zhao, Jing Hua and Deelen, Patrick and Rohde, Rebecca and Schurmann, Claudia and Guo, Xiuqing and Giulianini, Franco and Zhang, Weihua and Medina-G{\'o}mez, Carolina and Karlsson, Robert and Bao, Yanchun and Bartz, Traci M and Baumbach, Clemens and Biino, Ginevra and Bixley, Matthew J and Brumat, Marco and Chai, Jin-Fang and Corre, Tanguy and Cousminer, Diana L and Dekker, Annelot M and Eccles, David A and van Eijk, Kristel R and Fuchsberger, Christian and Gao, He and Germain, Marine and Gordon, Scott D and de Haan, Hugoline G and Harris, Sarah E and Hofer, Edith and Huerta-Chagoya, Alicia and Igartua, Catherine and Jansen, Iris E and Jia, Yucheng and Kacprowski, Tim and Karlsson, Torgny and Kleber, Marcus E and Li, Shengchao Alfred and Li-Gao, Ruifang and Mahajan, Anubha and Matsuda, Koichi and Meidtner, Karina and Meng, Weihua and Montasser, May E and van der Most, Peter J and Munz, Matthias and Nutile, Teresa and Palviainen, Teemu and Prasad, Gauri and Prasad, Rashmi B and Priyanka, Tallapragada Divya Sri and Rizzi, Federica and Salvi, Erika and Sapkota, Bishwa R and Shriner, Daniel and Skotte, Line and Smart, Melissa C and Smith, Albert Vernon and van der Spek, Ashley and Spracklen, Cassandra N and Strawbridge, Rona J and Tajuddin, Salman M and Trompet, Stella and Turman, Constance and Verweij, Niek and Viberti, Clara and Wang, Lihua and Warren, Helen R and Wootton, Robyn E and Yanek, Lisa R and Yao, Jie and Yousri, Noha A and Zhao, Wei and Adeyemo, Adebowale A and Afaq, Saima and Aguilar-Salinas, Carlos Alberto and Akiyama, Masato and Albert, Matthew L and Allison, Matthew A and Alver, Maris and Aung, Tin and Azizi, Fereidoun and Bentley, Amy R and Boeing, Heiner and Boerwinkle, Eric and Borja, Judith B and de Borst, Gert J and Bottinger, Erwin P and Broer, Linda and Campbell, Harry and Chanock, Stephen and Chee, Miao-Li and Chen, Guanjie and Chen, Yii-der I and Chen, Zhengming and Chiu, Yen-Feng and Cocca, Massimiliano and Collins, Francis S and Concas, Maria Pina and Corley, Janie and Cugliari, Giovanni and van Dam, Rob M and Damulina, Anna and Daneshpour, Maryam S and Day, Felix R and Delgado, Graciela E and Dhana, Klodian and Doney, Alexander S F and D{\"o}rr, Marcus and Doumatey, Ayo P and Dzimiri, Nduna and Ebenesersd{\'o}ttir, S Sunna and Elliott, Joshua and Elliott, Paul and Ewert, Ralf and Felix, Janine F and Fischer, Krista and Freedman, Barry I and Girotto, Giorgia and Goel, Anuj and G{\"o}gele, Martin and Goodarzi, Mark O and Graff, Mariaelisa and Granot-Hershkovitz, Einat and Grodstein, Francine and Guarrera, Simonetta and Gudbjartsson, Daniel F and Guity, Kamran and Gunnarsson, Bjarni and Guo, Yu and Hagenaars, Saskia P and Haiman, Christopher A and Halevy, Avner and Harris, Tamara B and Hedayati, Mehdi and van Heel, David A and Hirata, Makoto and H{\"o}fer, Imo and Hsiung, Chao Agnes and Huang, Jinyan and Hung, Yi-Jen and Ikram, M Arfan and Jagadeesan, Anuradha and Jousilahti, Pekka and Kamatani, Yoichiro and Kanai, Masahiro and Kerrison, Nicola D and Kessler, Thorsten and Khaw, Kay-Tee and Khor, Chiea Chuen and de Kleijn, Dominique P V and Koh, Woon-Puay and Kolcic, Ivana and Kraft, Peter and Kr{\"a}mer, Bernhard K and Kutalik, Zolt{\'a}n and Kuusisto, Johanna and Langenberg, Claudia and Launer, Lenore J and Lawlor, Deborah A and Lee, I-Te and Lee, Wen-Jane and Lerch, Markus M and Li, Liming and Liu, Jianjun and Loh, Marie and London, Stephanie J and Loomis, Stephanie and Lu, Yingchang and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Manichaikul, Ani W and Manunta, Paolo and M{\'a}sson, G{\'\i}sli and Matoba, Nana and Mei, Xue W and Meisinger, Christa and Meitinger, Thomas and Mezzavilla, Massimo and Milani, Lili and Millwood, Iona Y and Momozawa, Yukihide and Moore, Amy and Morange, Pierre-Emmanuel and Moreno-Macias, Hortensia and Mori, Trevor A and Morrison, Alanna C and Muka, Taulant and Murakami, Yoshinori and Murray, Alison D and de Mutsert, Ren{\'e}e and Mychaleckyj, Josyf C and Nalls, Mike A and Nauck, Matthias and Neville, Matt J and Nolte, Ilja M and Ong, Ken K and Orozco, Lorena and Padmanabhan, Sandosh and P{\'a}lsson, Gunnar and Pankow, James S and Pattaro, Cristian and Pattie, Alison and Polasek, Ozren and Poulter, Neil and Pramstaller, Peter P and Quintana-Murci, Lluis and R{\"a}ikk{\"o}nen, Katri and Ralhan, Sarju and Rao, Dabeeru C and van Rheenen, Wouter and Rich, Stephen S and Ridker, Paul M and Rietveld, Cornelius A and Robino, Antonietta and van Rooij, Frank J A and Ruggiero, Daniela and Saba, Yasaman and Sabanayagam, Charumathi and Sabater-Lleal, Maria and Sala, Cinzia Felicita and Salomaa, Veikko and Sandow, Kevin and Schmidt, Helena and Scott, Laura J and Scott, William R and Sedaghati-Khayat, Bahareh and Sennblad, Bengt and van Setten, Jessica and Sever, Peter J and Sheu, Wayne H-H and Shi, Yuan and Shrestha, Smeeta and Shukla, Sharvari Rahul and Sigurdsson, Jon K and Sikka, Timo Tonis and Singh, Jai Rup and Smith, Blair H and Stan{\v c}{\'a}kov{\'a}, Alena and Stanton, Alice and Starr, John M and Stefansdottir, Lilja and Straker, Leon and Sulem, Patrick and Sveinbjornsson, Gardar and Swertz, Morris A and Taylor, Adele M and Taylor, Kent D and Terzikhan, Natalie and Tham, Yih-Chung and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tillander, Annika and Tracy, Russell P and Tusi{\'e}-Luna, Teresa and Tzoulaki, Ioanna and Vaccargiu, Simona and Vangipurapu, Jagadish and Veldink, Jan H and Vitart, Veronique and V{\"o}lker, Uwe and Vuoksimaa, Eero and Wakil, Salma M and Waldenberger, Melanie and Wander, Gurpreet S and Wang, Ya Xing and Wareham, Nicholas J and Wild, Sarah and Yajnik, Chittaranjan S and Yuan, Jian-Min and Zeng, Lingyao and Zhang, Liang and Zhou, Jie and Amin, Najaf and Asselbergs, Folkert W and Bakker, Stephan J L and Becker, Diane M and Lehne, Benjamin and Bennett, David A and van den Berg, Leonard H and Berndt, Sonja I and Bharadwaj, Dwaipayan and Bielak, Lawrence F and Bochud, Murielle and Boehnke, Mike and Bouchard, Claude and Bradfield, Jonathan P and Brody, Jennifer A and Campbell, Archie and Carmi, Shai and Caulfield, Mark J and Cesarini, David and Chambers, John C and Chandak, Giriraj Ratan and Cheng, Ching-Yu and Ciullo, Marina and Cornelis, Marilyn and Cusi, Daniele and Smith, George Davey and Deary, Ian J and Dorajoo, Rajkumar and van Duijn, Cornelia M and Ellinghaus, David and Erdmann, Jeanette and Eriksson, Johan G and Evangelou, Evangelos and Evans, Michele K and Faul, Jessica D and Feenstra, Bjarke and Feitosa, Mary and Foisy, Sylvain and Franke, Andre and Friedlander, Yechiel and Gasparini, Paolo and Gieger, Christian and Gonzalez, Clicerio and Goyette, Philippe and Grant, Struan F A and Griffiths, Lyn R and Groop, Leif and Gudnason, Vilmundur and Gyllensten, Ulf and Hakonarson, Hakon and Hamsten, Anders and van der Harst, Pim and Heng, Chew-Kiat and Hicks, Andrew A and Hochner, Hagit and Huikuri, Heikki and Hunt, Steven C and Jaddoe, Vincent W V and De Jager, Philip L and Johannesson, Magnus and Johansson, Asa and Jonas, Jost B and Jukema, J Wouter and Junttila, Juhani and Kaprio, Jaakko and Kardia, Sharon L R and Karpe, Fredrik and Kumari, Meena and Laakso, Markku and van der Laan, Sander W and Lahti, Jari and Laudes, Matthias and Lea, Rodney A and Lieb, Wolfgang and Lumley, Thomas and Martin, Nicholas G and M{\"a}rz, Winfried and Matullo, Giuseppe and McCarthy, Mark I and Medland, Sarah E and Merriman, Tony R and Metspalu, Andres and Meyer, Brian F and Mohlke, Karen L and Montgomery, Grant W and Mook-Kanamori, Dennis and Munroe, Patricia B and North, Kari E and Nyholt, Dale R and O{\textquoteright}Connell, Jeffery R and Ober, Carole and Oldehinkel, Albertine J and Palmas, Walter and Palmer, Colin and Pasterkamp, Gerard G and Patin, Etienne and Pennell, Craig E and Perusse, Louis and Peyser, Patricia A and Pirastu, Mario and Polderman, Tinca J C and Porteous, David J and Posthuma, Danielle and Psaty, Bruce M and Rioux, John D and Rivadeneira, Fernando and Rotimi, Charles and Rotter, Jerome I and Rudan, Igor and den Ruijter, Hester M and Sanghera, Dharambir K and Sattar, Naveed and Schmidt, Reinhold and Schulze, Matthias B and Schunkert, Heribert and Scott, Robert A and Shuldiner, Alan R and Sim, Xueling and Small, Neil and Smith, Jennifer A and Sotoodehnia, Nona and Tai, E-Shyong and Teumer, Alexander and Timpson, Nicholas J and Toniolo, Daniela and Tr{\'e}gou{\"e}t, David-Alexandre and Tuomi, Tiinamaija and Vollenweider, Peter and Wang, Carol A and Weir, David R and Whitfield, John B and Wijmenga, Cisca and Wong, Tien-Yin and Wright, John and Yang, Jingyun and Yu, Lei and Zemel, Babette S and Zonderman, Alan B and Perola, Markus and Magnusson, Patrik K E and Uitterlinden, Andr{\'e} G and Kooner, Jaspal S and Chasman, Daniel I and Loos, Ruth J F and Franceschini, Nora and Franke, Lude and Haley, Chris S and Hayward, Caroline and Walters, Robin G and Perry, John R B and Esko, T{\~o}nu and Helgason, Agnar and Stefansson, Kari and Joshi, Peter K and Kubo, Michiaki and Wilson, James F} } @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 {8050, title = {Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease.}, journal = {PLoS One}, volume = {14}, year = {2019}, month = {2019}, pages = {e0216222}, abstract = {

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

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

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

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0216222}, author = {Ward-Caviness, Cavin K and de Vries, Paul S and Wiggins, Kerri L and Huffman, Jennifer E and Yanek, Lisa R and Bielak, Lawrence F and Giulianini, Franco and Guo, Xiuqing and Kleber, Marcus E and Kacprowski, Tim and Gro{\ss}, Stefan and Petersman, Astrid and Davey Smith, George and Hartwig, Fernando P and Bowden, Jack and Hemani, Gibran and M{\"u}ller-Nuraysid, Martina and Strauch, Konstantin and Koenig, Wolfgang and Waldenberger, Melanie and Meitinger, Thomas and Pankratz, Nathan and Boerwinkle, Eric and Tang, Weihong and Fu, Yi-Ping and Johnson, Andrew D and Song, Ci and de Maat, Moniek P M and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Brody, Jennifer A and McKnight, Barbara and Chen, Yii-Der Ida and Psaty, Bruce M and Mathias, Rasika A and Becker, Diane M and Peyser, Patricia A and Smith, Jennifer A and Bielinski, Suzette J and Ridker, Paul M and Taylor, Kent D and Yao, Jie and Tracy, Russell and Delgado, Graciela and Trompet, Stella and Sattar, Naveed and Jukema, J Wouter and Becker, Lewis C and Kardia, Sharon L R and Rotter, Jerome I and M{\"a}rz, Winfried and D{\"o}rr, Marcus and Chasman, Daniel I and Dehghan, Abbas and O{\textquoteright}Donnell, Christopher J and Smith, Nicholas L and Peters, Annette and Morrison, Alanna C} } @article {7970, title = {Multi-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.}, journal = {Am J Epidemiol}, year = {2019}, month = {2019 Jan 29}, abstract = {

An individual{\textquoteright}s lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P~<~1~{\texttimes}~10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P~<~5~{\texttimes}~10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.

}, issn = {1476-6256}, doi = {10.1093/aje/kwz005}, author = {de Vries, Paul S and Brown, Michael R and Bentley, Amy R and Sung, Yun J and Winkler, Thomas W and Ntalla, Ioanna and Schwander, Karen and Kraja, Aldi T and Guo, Xiuqing and Franceschini, Nora and Cheng, Ching-Yu and Sim, Xueling and Vojinovic, Dina and Huffman, Jennifer E and Musani, Solomon K and Li, Changwei and Feitosa, Mary F and Richard, Melissa A and Noordam, Raymond and Aschard, Hugues and Bartz, Traci M and Bielak, Lawrence F and Deng, Xuan and Dorajoo, Rajkumar and Lohman, Kurt K and Manning, Alisa K and Rankinen, Tuomo and Smith, Albert V and Tajuddin, Salman M and Evangelou, Evangelos and Graff, Mariaelisa and Alver, Maris and Boissel, Mathilde and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Gandin, Ilaria and Gao, Chuan and Goel, Anuj and Hagemeijer, Yanick and Harris, Sarah E and Hartwig, Fernando P and He, Meian and Horimoto, Andrea R V R and Hsu, Fang-Chi and Jackson, Anne U and Kasturiratne, Anuradhani and Komulainen, Pirjo and Kuhnel, Brigitte and Laguzzi, Federica and Lee, Joseph H and Luan, Jian{\textquoteright}an and Lyytik{\"a}inen, Leo-Pekka and Matoba, Nana and Nolte, Ilja M and Pietzner, Maik and Riaz, Muhammad and Said, M Abdullah and Scott, Robert A and Sofer, Tamar and Stan{\v c}{\'a}kov{\'a}, Alena and Takeuchi, Fumihiko and Tayo, Bamidele O and van der Most, Peter J and Varga, Tibor V and Wang, Yajuan and Ware, Erin B and Wen, Wanqing and Yanek, Lisa R and Zhang, Weihua and Zhao, Jing Hua and Afaq, Saima and Amin, Najaf and Amini, Marzyeh and Arking, Dan E and Aung, Tin and Ballantyne, Christie and Boerwinkle, Eric and Broeckel, Ulrich and Campbell, Archie and Canouil, Micka{\"e}l and Charumathi, Sabanayagam and Chen, Yii-Der Ida and Connell, John M and de Faire, Ulf and de Las Fuentes, Lisa and de Mutsert, Ren{\'e}e and de Silva, H Janaka and Ding, Jingzhong and Dominiczak, Anna F and Duan, Qing and Eaton, Charles B and Eppinga, Ruben N and Faul, Jessica D and Fisher, Virginia and Forrester, Terrence and Franco, Oscar H and Friedlander, Yechiel and Ghanbari, Mohsen and Giulianini, Franco and Grabe, Hans J and Grove, Megan L and Gu, C Charles and Harris, Tamara B and Heikkinen, Sami and Heng, Chew-Kiat and Hirata, Makoto and Hixson, James E and Howard, Barbara V and Ikram, M Arfan and Jacobs, David R and Johnson, Craig and Jonas, Jost Bruno and Kammerer, Candace M and Katsuya, Tomohiro and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Koistinen, Heikki A and Kolcic, Ivana and Kooperberg, Charles and Krieger, Jose E and Kritchevsky, Steve B and Kubo, Michiaki and Kuusisto, Johanna and Lakka, Timo A and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lehne, Benjamin and Lemaitre, Rozenn N and Li, Yize and Liang, Jingjing and Liu, Jianjun and Liu, Kiang and Loh, Marie and Louie, Tin and M{\"a}gi, Reedik and Manichaikul, Ani W and McKenzie, Colin A and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Milani, Lili and Mohlke, Karen L and Mosley, Thomas H and Mukamal, Kenneth J and Nalls, Mike A and Nauck, Matthias and Nelson, Christopher P and Sotoodehnia, Nona and O{\textquoteright}Connell, Jeff R and Palmer, Nicholette D and Pazoki, Raha and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Polasek, Ozren and Poulter, Neil and Raffel, Leslie J and Raitakari, Olli T and Reiner, Alex P and Rice, Treva K and Rich, Stephen S and Robino, Antonietta and Robinson, Jennifer G and Rose, Lynda M and Rudan, Igor and Schmidt, Carsten O and Schreiner, Pamela J and Scott, William R and Sever, Peter and Shi, Yuan and Sidney, Stephen and Sims, Mario and Smith, Blair H and Smith, Jennifer A and Snieder, Harold and Starr, John M and Strauch, Konstantin and Tan, Nicholas and Taylor, Kent D and Teo, Yik Ying and Tham, Yih Chung and Uitterlinden, Andr{\'e} G and van Heemst, Diana and Vuckovic, Dragana and Waldenberger, Melanie and Wang, Lihua and Wang, Yujie and Wang, Zhe and Wei, Wen Bin and Williams, Christine and Wilson, Gregory and Wojczynski, Mary K and Yao, Jie and Yu, Bing and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Zonderman, Alan B and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and Chambers, John C and Deary, Ian J and Esko, T{\~o}nu and Farrall, Martin and Franks, Paul W and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Horta, Bernardo L and Kamatani, Yoichiro and Kato, Norihiro and Kooner, Jaspal S and Laakso, Markku and Leander, Karin and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and Penninx, Brenda and Pereira, Alexandre C and Rauramaa, Rainer and Samani, Nilesh J and Scott, James and Shu, Xiao-Ou and van der Harst, Pim and Wagenknecht, Lynne E and Wang, Ya Xing and Wareham, Nicholas J and Watkins, Hugh and Weir, David R and Wickremasinghe, Ananda R and Zheng, Wei and Elliott, Paul and North, Kari E and Bouchard, Claude and Evans, Michele K and Gudnason, Vilmundur and Liu, Ching-Ti and Liu, Yongmei and Psaty, Bruce M and Ridker, Paul M and van Dam, Rob M and Kardia, Sharon L R and Zhu, Xiaofeng and Rotimi, Charles N and Mook-Kanamori, Dennis O and Fornage, Myriam and Kelly, Tanika N and Fox, Ervin R and Hayward, Caroline and van Duijn, Cornelia M and Tai, E Shyong and Wong, Tien Yin and Liu, Jingmin and Rotter, Jerome I and Gauderman, W James and Province, Michael A and Munroe, Patricia B and Rice, Kenneth and Chasman, Daniel I and Cupples, L Adrienne and Rao, Dabeeru C and Morrison, Alanna C} } @article {8005, title = {Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 Apr}, pages = {636-648}, abstract = {

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.

}, issn = {1546-1718}, doi = {10.1038/s41588-019-0378-y}, author = {Bentley, Amy R and Sung, Yun J and Brown, Michael R and Winkler, Thomas W and Kraja, Aldi T and Ntalla, Ioanna and Schwander, Karen and Chasman, Daniel I and Lim, Elise and Deng, Xuan and Guo, Xiuqing and Liu, Jingmin and Lu, Yingchang and Cheng, Ching-Yu and Sim, Xueling and Vojinovic, Dina and Huffman, Jennifer E and Musani, Solomon K and Li, Changwei and Feitosa, Mary F and Richard, Melissa A and Noordam, Raymond and Baker, Jenna and Chen, Guanjie and Aschard, Hugues and Bartz, Traci M and Ding, Jingzhong and Dorajoo, Rajkumar and Manning, Alisa K and Rankinen, Tuomo and Smith, Albert V and Tajuddin, Salman M and Zhao, Wei and Graff, Mariaelisa and Alver, Maris and Boissel, Mathilde and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Evangelou, Evangelos and Gao, Chuan and Goel, Anuj and Hagemeijer, Yanick and Harris, Sarah E and Hartwig, Fernando P and He, Meian and Horimoto, Andrea R V R and Hsu, Fang-Chi and Hung, Yi-Jen and Jackson, Anne U and Kasturiratne, Anuradhani and Komulainen, Pirjo and Kuhnel, Brigitte and Leander, Karin and Lin, Keng-Hung and Luan, Jian{\textquoteright}an and Lyytik{\"a}inen, Leo-Pekka and Matoba, Nana and Nolte, Ilja M and Pietzner, Maik and Prins, Bram and Riaz, Muhammad and Robino, Antonietta and Said, M Abdullah and Schupf, Nicole and Scott, Robert A and Sofer, Tamar and Stan{\v c}{\'a}kov{\'a}, Alena and Takeuchi, Fumihiko and Tayo, Bamidele O and van der Most, Peter J and Varga, Tibor V and Wang, Tzung-Dau and Wang, Yajuan and Ware, Erin B and Wen, Wanqing and Xiang, Yong-Bing and Yanek, Lisa R and Zhang, Weihua and Zhao, Jing Hua and Adeyemo, Adebowale and Afaq, Saima and Amin, Najaf and Amini, Marzyeh and Arking, Dan E and Arzumanyan, Zorayr and Aung, Tin and Ballantyne, Christie and Barr, R Graham and Bielak, Lawrence F and Boerwinkle, Eric and Bottinger, Erwin P and Broeckel, Ulrich and Brown, Morris and Cade, Brian E and Campbell, Archie and Canouil, Micka{\"e}l and Charumathi, Sabanayagam and Chen, Yii-Der Ida and Christensen, Kaare and Concas, Maria Pina and Connell, John M and de Las Fuentes, Lisa and de Silva, H Janaka and de Vries, Paul S and Doumatey, Ayo and Duan, Qing and Eaton, Charles B and Eppinga, Ruben N and Faul, Jessica D and Floyd, James S and Forouhi, Nita G and Forrester, Terrence and Friedlander, Yechiel and Gandin, Ilaria and Gao, He and Ghanbari, Mohsen and Gharib, Sina A and Gigante, Bruna and Giulianini, Franco and Grabe, Hans J and Gu, C Charles and Harris, Tamara B and Heikkinen, Sami and Heng, Chew-Kiat and Hirata, Makoto and Hixson, James E and Ikram, M Arfan and Jia, Yucheng and Joehanes, Roby and Johnson, Craig and Jonas, Jost Bruno and Justice, Anne E and Katsuya, Tomohiro and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Kolcic, Ivana and Kooperberg, Charles and Krieger, Jose E and Kritchevsky, Stephen B and Kubo, Michiaki and Kuusisto, Johanna and Lakka, Timo A and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lehne, Benjamin and Lewis, Cora E and Li, Yize and Liang, Jingjing and Lin, Shiow and Liu, Ching-Ti and Liu, Jianjun and Liu, Kiang and Loh, Marie and Lohman, Kurt K and Louie, Tin and Luzzi, Anna and M{\"a}gi, Reedik and Mahajan, Anubha and Manichaikul, Ani W and McKenzie, Colin A and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Milani, Lili and Mohlke, Karen L and Momozawa, Yukihide and Morris, Andrew P and Murray, Alison D and Nalls, Mike A and Nauck, Matthias and Nelson, Christopher P and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Papanicolau, George J and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Polasek, Ozren and Poulter, Neil and Raitakari, Olli T and Reiner, Alex P and Renstrom, Frida and Rice, Treva K and Rich, Stephen S and Robinson, Jennifer G and Rose, Lynda M and Rosendaal, Frits R and Rudan, Igor and Schmidt, Carsten O and Schreiner, Pamela J and Scott, William R and Sever, Peter and Shi, Yuan and Sidney, Stephen and Sims, Mario and Smith, Jennifer A and Snieder, Harold and Starr, John M and Strauch, Konstantin and Stringham, Heather M and Tan, Nicholas Y Q and Tang, Hua and Taylor, Kent D and Teo, Yik Ying and Tham, Yih Chung and Tiemeier, Henning and Turner, Stephen T and Uitterlinden, Andr{\'e} G and van Heemst, Diana and Waldenberger, Melanie and Wang, Heming and Wang, Lan and Wang, Lihua and Wei, Wen Bin and Williams, Christine A and Wilson, Gregory and Wojczynski, Mary K and Yao, Jie and Young, Kristin and Yu, Caizheng and Yuan, Jian-Min and Zhou, Jie and Zonderman, Alan B and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and Chambers, John C and Cooper, Richard S and de Faire, Ulf and Deary, Ian J and Elliott, Paul and Esko, T{\~o}nu and Farrall, Martin and Franks, Paul W and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Horta, Bernardo L and Juang, Jyh-Ming Jimmy and Kamatani, Yoichiro and Kammerer, Candace M and Kato, Norihiro and Kooner, Jaspal S and Laakso, Markku and Laurie, Cathy C and Lee, I-Te and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and Oldehinkel, Albertine J and Penninx, Brenda W J H and Pereira, Alexandre C and Rauramaa, Rainer and Redline, Susan and Samani, Nilesh J and Scott, James and Shu, Xiao-Ou and van der Harst, Pim and Wagenknecht, Lynne E and Wang, Jun-Sing and Wang, Ya Xing and Wareham, Nicholas J and Watkins, Hugh and Weir, David R and Wickremasinghe, Ananda R and Wu, Tangchun and Zeggini, Eleftheria and Zheng, Wei and Bouchard, Claude and Evans, Michele K and Gudnason, Vilmundur and Kardia, Sharon L R and Liu, Yongmei and Psaty, Bruce M and Ridker, Paul M and van Dam, Rob M and Mook-Kanamori, Dennis O and Fornage, Myriam and Province, Michael A and Kelly, Tanika N and Fox, Ervin R and Hayward, Caroline and van Duijn, Cornelia M and Tai, E Shyong and Wong, Tien Yin and Loos, Ruth J F and Franceschini, Nora and Rotter, Jerome I and Zhu, Xiaofeng and Bierut, Laura J and Gauderman, W James and Rice, Kenneth and Munroe, Patricia B and Morrison, Alanna C and Rao, Dabeeru C and Rotimi, Charles N and Cupples, L Adrienne} } @article {7976, title = {Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 01 22}, pages = {376}, abstract = {

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

}, keywords = {Adolescent, Adult, African Continental Ancestry Group, Aged, Aged, 80 and over, Asian Continental Ancestry Group, Brazil, Calcium-Binding Proteins, Cholesterol, Cholesterol, HDL, Cholesterol, LDL, European Continental Ancestry Group, Exercise, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Hispanic Americans, Humans, LIM-Homeodomain Proteins, Lipid Metabolism, Lipids, Male, Membrane Proteins, Microtubule-Associated Proteins, Middle Aged, Muscle Proteins, Nerve Tissue Proteins, Transcription Factors, Triglycerides, Young Adult}, issn = {2041-1723}, doi = {10.1038/s41467-018-08008-w}, author = {Kilpel{\"a}inen, Tuomas O and Bentley, Amy R and Noordam, Raymond and Sung, Yun Ju and Schwander, Karen and Winkler, Thomas W and Jakupovi{\'c}, Hermina and Chasman, Daniel I and Manning, Alisa and Ntalla, Ioanna and Aschard, Hugues and Brown, Michael R and de Las Fuentes, Lisa and Franceschini, Nora and Guo, Xiuqing and Vojinovic, Dina and Aslibekyan, Stella and Feitosa, Mary F and Kho, Minjung and Musani, Solomon K and Richard, Melissa and Wang, Heming and Wang, Zhe and Bartz, Traci M and Bielak, Lawrence F and Campbell, Archie and Dorajoo, Rajkumar and Fisher, Virginia and Hartwig, Fernando P and Horimoto, Andrea R V R and Li, Changwei and Lohman, Kurt K and Marten, Jonathan and Sim, Xueling and Smith, Albert V and Tajuddin, Salman M and Alver, Maris and Amini, Marzyeh and Boissel, Mathilde and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Evangelou, Evangelos and Gao, Chuan and Graff, Mariaelisa and Harris, Sarah E and He, Meian and Hsu, Fang-Chi and Jackson, Anne U and Zhao, Jing Hua and Kraja, Aldi T and Kuhnel, Brigitte and Laguzzi, Federica and Lyytik{\"a}inen, Leo-Pekka and Nolte, Ilja M and Rauramaa, Rainer and Riaz, Muhammad and Robino, Antonietta and Rueedi, Rico and Stringham, Heather M and Takeuchi, Fumihiko and van der Most, Peter J and Varga, Tibor V and Verweij, Niek and Ware, Erin B and Wen, Wanqing and Li, Xiaoyin and Yanek, Lisa R and Amin, Najaf and Arnett, Donna K and Boerwinkle, Eric and Brumat, Marco and Cade, Brian and Canouil, Micka{\"e}l and Chen, Yii-Der Ida and Concas, Maria Pina and Connell, John and de Mutsert, Ren{\'e}e and de Silva, H Janaka and de Vries, Paul S and Demirkan, Ayse and Ding, Jingzhong and Eaton, Charles B and Faul, Jessica D and Friedlander, Yechiel and Gabriel, Kelley P and Ghanbari, Mohsen and Giulianini, Franco and Gu, Chi Charles and Gu, Dongfeng and Harris, Tamara B and He, Jiang and Heikkinen, Sami and Heng, Chew-Kiat and Hunt, Steven C and Ikram, M Arfan and Jonas, Jost B and Koh, Woon-Puay and Komulainen, Pirjo and Krieger, Jose E and Kritchevsky, Stephen B and Kutalik, Zolt{\'a}n and Kuusisto, Johanna and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Leander, Karin and Lemaitre, Rozenn N and Lewis, Cora E and Liang, Jingjing and Liu, Jianjun and M{\"a}gi, Reedik and Manichaikul, Ani and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Mohlke, Karen L and Mosley, Thomas H and Murray, Alison D and Nalls, Mike A and Nang, Ei-Ei Khaing and Nelson, Christopher P and Nona, Sotoodehnia and Norris, Jill M and Nwuba, Chiamaka Vivian and O{\textquoteright}Connell, Jeff and Palmer, Nicholette D and Papanicolau, George J and Pazoki, Raha and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Polasek, Ozren and Porteous, David J and Poveda, Alaitz and Raitakari, Olli T and Rich, Stephen S and Risch, Neil and Robinson, Jennifer G and Rose, Lynda M and Rudan, Igor and Schreiner, Pamela J and Scott, Robert A and Sidney, Stephen S and Sims, Mario and Smith, Jennifer A and Snieder, Harold and Sofer, Tamar and Starr, John M and Sternfeld, Barbara and Strauch, Konstantin and Tang, Hua and Taylor, Kent D and Tsai, Michael Y and Tuomilehto, Jaakko and Uitterlinden, Andr{\'e} G and van der Ende, M Yldau and van Heemst, Diana and Voortman, Trudy and Waldenberger, Melanie and Wennberg, Patrik and Wilson, Gregory and Xiang, Yong-Bing and Yao, Jie and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Zonderman, Alan B and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and de Faire, Ulf and Deary, Ian J and Elliott, Paul and Esko, T{\~o}nu and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Kato, Norihiro and Laakso, Markku and Lakka, Timo A and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and Oldehinkel, Albertine J and Penninx, Brenda W J H and Samani, Nilesh J and Shu, Xiao-Ou and van der Harst, Pim and van Vliet-Ostaptchouk, Jana V and Vollenweider, Peter and Wagenknecht, Lynne E and Wang, Ya X and Wareham, Nicholas J and Weir, David R and Wu, Tangchun and Zheng, Wei and Zhu, Xiaofeng and Evans, Michele K and Franks, Paul W and Gudnason, Vilmundur and Hayward, Caroline and Horta, Bernardo L and Kelly, Tanika N and Liu, Yongmei and North, Kari E and Pereira, Alexandre C and Ridker, Paul M and Tai, E Shyong and van Dam, Rob M and Fox, Ervin R and Kardia, Sharon L R and Liu, Ching-Ti and Mook-Kanamori, Dennis O and Province, Michael A and Redline, Susan and van Duijn, Cornelia M and Rotter, Jerome I and Kooperberg, Charles B and Gauderman, W James and Psaty, Bruce M and Rice, Kenneth and Munroe, Patricia B and Fornage, Myriam and Cupples, L Adrienne and Rotimi, Charles N and Morrison, Alanna C and Rao, Dabeeru C and Loos, Ruth J F} } @article {8381, title = {Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.}, journal = {Mol Psychiatry}, year = {2020}, month = {2020 May 05}, abstract = {

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 {\texttimes} 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

}, issn = {1476-5578}, doi = {10.1038/s41380-020-0719-3}, author = {de Las Fuentes, Lisa and Sung, Yun Ju and Noordam, Raymond and Winkler, Thomas and Feitosa, Mary F and Schwander, Karen and Bentley, Amy R and Brown, Michael R and Guo, Xiuqing and Manning, Alisa and Chasman, Daniel I and Aschard, Hugues and Bartz, Traci M and Bielak, Lawrence F and Campbell, Archie and Cheng, Ching-Yu and Dorajoo, Rajkumar and Hartwig, Fernando P and Horimoto, A R V R and Li, Changwei and Li-Gao, Ruifang and Liu, Yongmei and Marten, Jonathan and Musani, Solomon K and Ntalla, Ioanna and Rankinen, Tuomo and Richard, Melissa and Sim, Xueling and Smith, Albert V and Tajuddin, Salman M and Tayo, Bamidele O and Vojinovic, Dina and Warren, Helen R and Xuan, Deng and Alver, Maris and Boissel, Mathilde and Chai, Jin-Fang and Chen, Xu and Christensen, Kaare and Divers, Jasmin and Evangelou, Evangelos and Gao, Chuan and Girotto, Giorgia and Harris, Sarah E and He, Meian and Hsu, Fang-Chi and Kuhnel, Brigitte and Laguzzi, Federica and Li, Xiaoyin and Lyytik{\"a}inen, Leo-Pekka and Nolte, Ilja M and Poveda, Alaitz and Rauramaa, Rainer and Riaz, Muhammad and Rueedi, Rico and Shu, Xiao-Ou and Snieder, Harold and Sofer, Tamar and Takeuchi, Fumihiko and Verweij, Niek and Ware, Erin B and Weiss, Stefan and Yanek, Lisa R and Amin, Najaf and Arking, Dan E and Arnett, Donna K and Bergmann, Sven and Boerwinkle, Eric and Brody, Jennifer A and Broeckel, Ulrich and Brumat, Marco and Burke, Gregory and Cabrera, Claudia P and Canouil, Micka{\"e}l and Chee, Miao Li and Chen, Yii-Der Ida and Cocca, Massimiliano and Connell, John and de Silva, H Janaka and de Vries, Paul S and Eiriksdottir, Gudny and Faul, Jessica D and Fisher, Virginia and Forrester, Terrence and Fox, Ervin F and Friedlander, Yechiel and Gao, He and Gigante, Bruna and Giulianini, Franco and Gu, Chi Charles and Gu, Dongfeng and Harris, Tamara B and He, Jiang and Heikkinen, Sami and Heng, Chew-Kiat and Hunt, Steven and Ikram, M Arfan and Irvin, Marguerite R and K{\"a}h{\"o}nen, Mika and Kavousi, Maryam and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Komulainen, Pirjo and Kraja, Aldi T and Krieger, J E and Langefeld, Carl D and Li, Yize and Liang, Jingjing and Liewald, David C M and Liu, Ching-Ti and Liu, Jianjun and Lohman, Kurt K and M{\"a}gi, Reedik and McKenzie, Colin A and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Milani, Lili and Mook-Kanamori, Dennis O and Nalls, Mike A and Nelson, Christopher P and Norris, Jill M and O{\textquoteright}Connell, Jeff and Ogunniyi, Adesola and Padmanabhan, Sandosh and Palmer, Nicholette D and Pedersen, Nancy L and Perls, Thomas and Peters, Annette and Petersmann, Astrid and Peyser, Patricia A and Polasek, Ozren and Porteous, David J and Raffel, Leslie J and Rice, Treva K and Rotter, Jerome I and Rudan, Igor and Rueda-Ochoa, Oscar-Leonel and Sabanayagam, Charumathi and Salako, Babatunde L and Schreiner, Pamela J and Shikany, James M and Sidney, Stephen S and Sims, Mario and Sitlani, Colleen M and Smith, Jennifer A and Starr, John M and Strauch, Konstantin and Swertz, Morris A and Teumer, Alexander and Tham, Yih Chung and Uitterlinden, Andr{\'e} G and Vaidya, Dhananjay and van der Ende, M Yldau and Waldenberger, Melanie and Wang, Lihua and Wang, Ya-Xing and Wei, Wen-Bin and Weir, David R and Wen, Wanqing and Yao, Jie and Yu, Bing and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Zonderman, Alan B and Becker, Diane M and Bowden, Donald W and Deary, Ian J and D{\"o}rr, Marcus and Esko, T{\~o}nu and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Jonas, Jost Bruno and Kammerer, Candace M and Kato, Norihiro and Lakka, Timo A and Leander, Karin and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and Marques-Vidal, Pedro and Penninx, Brenda W J H and Samani, Nilesh J and van der Harst, Pim and Wagenknecht, Lynne E and Wu, Tangchun and Zheng, Wei and Zhu, Xiaofeng and Bouchard, Claude and Cooper, Richard S and Correa, Adolfo and Evans, Michele K and Gudnason, Vilmundur and Hayward, Caroline and Horta, Bernardo L and Kelly, Tanika N and Kritchevsky, Stephen B and Levy, Daniel and Palmas, Walter R and Pereira, A C and Province, Michael M and Psaty, Bruce M and Ridker, Paul M and Rotimi, Charles N and Tai, E Shyong and van Dam, Rob M and van Duijn, Cornelia M and Wong, Tien Yin and Rice, Kenneth and Gauderman, W James and Morrison, Alanna C and North, Kari E and Kardia, Sharon L R and Caulfield, Mark J and Elliott, Paul and Munroe, Patricia B and Franks, Paul W and Rao, Dabeeru C and Fornage, Myriam} } @article {8625, title = {Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.}, journal = {PLoS One}, volume = {15}, year = {2020}, month = {2020}, pages = {e0230035}, abstract = {

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

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

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

}, keywords = {Aging, Coronary Artery Disease, Cross-Sectional Studies, Europe, European Continental Ancestry Group, Genetic Loci, Genome-Wide Association Study, Humans, Myocardial Infarction, Polymorphism, Single Nucleotide, Prospective Studies}, issn = {1932-6203}, doi = {10.1371/journal.pone.0230035}, author = {Hahn, Julie and Fu, Yi-Ping and Brown, Michael R and Bis, Joshua C and de Vries, Paul S and Feitosa, Mary F and Yanek, Lisa R and Weiss, Stefan and Giulianini, Franco and Smith, Albert Vernon and Guo, Xiuqing and Bartz, Traci M and Becker, Diane M and Becker, Lewis C and Boerwinkle, Eric and Brody, Jennifer A and Chen, Yii-Der Ida and Franco, Oscar H and Grove, Megan and Harris, Tamara B and Hofman, Albert and Hwang, Shih-Jen and Kral, Brian G and Launer, Lenore J and Markus, Marcello R P and Rice, Kenneth M and Rich, Stephen S and Ridker, Paul M and Rivadeneira, Fernando and Rotter, Jerome I and Sotoodehnia, Nona and Taylor, Kent D and Uitterlinden, Andr{\'e} G and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Yao, Jie and Chasman, Daniel I and D{\"o}rr, Marcus and Gudnason, Vilmundur and Mathias, Rasika A and Post, Wendy and Psaty, Bruce M and Dehghan, Abbas and O{\textquoteright}Donnell, Christopher J and Morrison, Alanna C} } @article {8491, title = {Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.}, journal = {Diabetes}, year = {2020}, month = {2020 Sep 11}, abstract = {

Leptin influences food intake by informing the brain about the status of body fat stores. Rare mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in , and , and one intergenic variant near The missense variant Val94Met (rs17151919) in was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10, n=3,901). Using analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.

}, issn = {1939-327X}, doi = {10.2337/db20-0070}, author = {Yaghootkar, Hanieh and Zhang, Yiying and Spracklen, Cassandra N and Karaderi, Tugce and Huang, Lam Opal and Bradfield, Jonathan and Schurmann, Claudia and Fine, Rebecca S and Preuss, Michael H and Kutalik, Zolt{\'a}n and Wittemans, Laura Bl and Lu, Yingchang and Metz, Sophia and Willems, Sara M and Li-Gao, Ruifang and Grarup, Niels and Wang, Shuai and Molnos, Sophie and Sandoval-Z{\'a}rate, Am{\'e}rica A and Nalls, Mike A and Lange, Leslie A and Haesser, Jeffrey and Guo, Xiuqing and Lyytik{\"a}inen, Leo-Pekka and Feitosa, Mary F and Sitlani, Colleen M and Venturini, Cristina and Mahajan, Anubha and Kacprowski, Tim and Wang, Carol A and Chasman, Daniel I and Amin, Najaf and Broer, Linda and Robertson, Neil and Young, Kristin L and Allison, Matthew and Auer, Paul L and Bl{\"u}her, Matthias and Borja, Judith B and Bork-Jensen, Jette and Carrasquilla, Germ{\'a}n D and Christofidou, Paraskevi and Demirkan, Ayse and Doege, Claudia A and Garcia, Melissa E and Graff, Mariaelisa and Guo, Kaiying and Hakonarson, Hakon and Hong, Jaeyoung and Ida Chen, Yii-Der and Jackson, Rebecca and Jakupovi{\'c}, Hermina and Jousilahti, Pekka and Justice, Anne E and K{\"a}h{\"o}nen, Mika and Kizer, Jorge R and Kriebel, Jennifer and LeDuc, Charles A and Li, Jin and Lind, Lars and Luan, Jian{\textquoteright}an and Mackey, David and Mangino, Massimo and M{\"a}nnist{\"o}, Satu and Martin Carli, Jayne F and Medina-G{\'o}mez, Carolina and Mook-Kanamori, Dennis O and Morris, Andrew P and de Mutsert, Ren{\'e}e and Nauck, Matthias and Nedeljkovic, Ivana and Pennell, Craig E and Pradhan, Arund D and Psaty, Bruce M and Raitakari, Olli T and Scott, Robert A and Skaaby, Tea and Strauch, Konstantin and Taylor, Kent D and Teumer, Alexander and Uitterlinden, Andr{\'e} G and Wu, Ying and Yao, Jie and Walker, Mark and North, Kari E and Kovacs, Peter and Ikram, M Arfan and van Duijn, Cornelia M and Ridker, Paul M and Lye, Stephen and Homuth, Georg and Ingelsson, Erik and Spector, Tim D and McKnight, Barbara and Province, Michael A and Lehtim{\"a}ki, Terho and Adair, Linda S and Rotter, Jerome I and Reiner, Alexander P and Wilson, James G and Harris, Tamara B and Ripatti, Samuli and Grallert, Harald and Meigs, James B and Salomaa, Veikko and Hansen, Torben and Willems van Dijk, Ko and Wareham, Nicholas J and Grant, Struan Fa and Langenberg, Claudia and Frayling, Timothy M and Lindgren, Cecilia M and Mohlke, Karen L and Leibel, Rudolph L and Loos, Ruth Jf and Kilpel{\"a}inen, Tuomas O} } @article {8368, title = {Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 May 21}, pages = {2542}, abstract = {

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5\% to 62.6\%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

}, issn = {2041-1723}, doi = {10.1038/s41467-020-15706-x}, author = {Ntalla, Ioanna and Weng, Lu-Chen and Cartwright, James H and Hall, Amelia Weber and Sveinbjornsson, Gardar and Tucker, Nathan R and Choi, Seung Hoan and Chaffin, Mark D and Roselli, Carolina and Barnes, Michael R and Mifsud, Borbala and Warren, Helen R and Hayward, Caroline and Marten, Jonathan and Cranley, James J and Concas, Maria Pina and Gasparini, Paolo and Boutin, Thibaud and Kolcic, Ivana and Polasek, Ozren and Rudan, Igor and Araujo, Nathalia M and Lima-Costa, Maria Fernanda and Ribeiro, Antonio Luiz P and Souza, Renan P and Tarazona-Santos, Eduardo and Giedraitis, Vilmantas and Ingelsson, Erik and Mahajan, Anubha and Morris, Andrew P and del Greco M, Fabiola and Foco, Luisa and G{\"o}gele, Martin and Hicks, Andrew A and Cook, James P and Lind, Lars and Lindgren, Cecilia M and Sundstr{\"o}m, Johan and Nelson, Christopher P and Riaz, Muhammad B and Samani, Nilesh J and Sinagra, Gianfranco and Ulivi, Sheila and K{\"a}h{\"o}nen, Mika and Mishra, Pashupati P and Mononen, Nina and Nikus, Kjell and Caulfield, Mark J and Dominiczak, Anna and Padmanabhan, Sandosh and Montasser, May E and O{\textquoteright}Connell, Jeff R and Ryan, Kathleen and Shuldiner, Alan R and Aeschbacher, Stefanie and Conen, David and Risch, Lorenz and Th{\'e}riault, S{\'e}bastien and Hutri-K{\"a}h{\"o}nen, Nina and Lehtim{\"a}ki, Terho and Lyytik{\"a}inen, Leo-Pekka and Raitakari, Olli T and Barnes, Catriona L K and Campbell, Harry and Joshi, Peter K and Wilson, James F and Isaacs, Aaron and Kors, Jan A and van Duijn, Cornelia M and Huang, Paul L and Gudnason, Vilmundur and Harris, Tamara B and Launer, Lenore J and Smith, Albert V and Bottinger, Erwin P and Loos, Ruth J F and Nadkarni, Girish N and Preuss, Michael H and Correa, Adolfo and Mei, Hao and Wilson, James and Meitinger, Thomas and M{\"u}ller-Nurasyid, Martina and Peters, Annette and Waldenberger, Melanie and Mangino, Massimo and Spector, Timothy D and Rienstra, Michiel and van de Vegte, Yordi J and van der Harst, Pim and Verweij, Niek and K{\"a}{\"a}b, Stefan and Schramm, Katharina and Sinner, Moritz F and Strauch, Konstantin and Cutler, Michael J and Fatkin, Diane and London, Barry and Olesen, Morten and Roden, Dan M and Benjamin Shoemaker, M and Gustav Smith, J and Biggs, Mary L and Bis, Joshua C and Brody, Jennifer A and Psaty, Bruce M and Rice, Kenneth and Sotoodehnia, Nona and De Grandi, Alessandro and Fuchsberger, Christian and Pattaro, Cristian and Pramstaller, Peter P and Ford, Ian and Wouter Jukema, J and Macfarlane, Peter W and Trompet, Stella and D{\"o}rr, Marcus and Felix, Stephan B and V{\"o}lker, Uwe and Weiss, Stefan and Havulinna, Aki S and Jula, Antti and S{\"a}{\"a}ksj{\"a}rvi, Katri and Salomaa, Veikko and Guo, Xiuqing and Heckbert, Susan R and Lin, Henry J and Rotter, Jerome I and Taylor, Kent D and Yao, Jie and de Mutsert, Ren{\'e}e and Maan, Arie C and Mook-Kanamori, Dennis O and Noordam, Raymond and Cucca, Francesco and Ding, Jun and Lakatta, Edward G and Qian, Yong and Tarasov, Kirill V and Levy, Daniel and Lin, Honghuang and Newton-Cheh, Christopher H and Lunetta, Kathryn L and Murray, Alison D and Porteous, David J and Smith, Blair H and Stricker, Bruno H and Uitterlinden, Andre and van den Berg, Marten E and Haessler, Jeffrey and Jackson, Rebecca D and Kooperberg, Charles and Peters, Ulrike and Reiner, Alexander P and Whitsel, Eric A and Alonso, Alvaro and Arking, Dan E and Boerwinkle, Eric and Ehret, Georg B and Soliman, Elsayed Z and Avery, Christy L and Gogarten, Stephanie M and Kerr, Kathleen F and Laurie, Cathy C and Seyerle, Amanda A and Stilp, Adrienne and Assa, Solmaz and Abdullah Said, M and Yldau van der Ende, M and Lambiase, Pier D and Orini, Michele and Ramirez, Julia and Van Duijvenboden, Stefan and Arnar, David O and Gudbjartsson, Daniel F and Holm, Hilma and Sulem, Patrick and Thorleifsson, Gudmar and Thorolfsdottir, Rosa B and Thorsteinsdottir, Unnur and Benjamin, Emelia J and Tinker, Andrew and Stefansson, Kari and Ellinor, Patrick T and Jamshidi, Yalda and Lubitz, Steven A and Munroe, Patricia B} } @article {8407, title = {Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels.}, journal = {Circ Genom Precis Med}, volume = {13}, year = {2020}, month = {2020 Aug}, pages = {e002772}, abstract = {

BACKGROUND: Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.

METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, <=5\%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered.

RESULTS: We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (, , , , , , , and ) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (=6.65{\texttimes}10 for the interaction test) and replicated at nominal significance level (=0.013) in .

CONCLUSIONS: In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.119.002772}, author = {Wang, Zhe and Chen, Han and Bartz, Traci M and Bielak, Lawrence F and Chasman, Daniel I and Feitosa, Mary F and Franceschini, Nora and Guo, Xiuqing and Lim, Elise and Noordam, Raymond and Richard, Melissa A and Wang, Heming and Cade, Brian and Cupples, L Adrienne and de Vries, Paul S and Giulanini, Franco and Lee, Jiwon and Lemaitre, Rozenn N and Martin, Lisa W and Reiner, Alex P and Rich, Stephen S and Schreiner, Pamela J and Sidney, Stephen and Sitlani, Colleen M and Smith, Jennifer A and Willems van Dijk, Ko and Yao, Jie and Zhao, Wei and Fornage, Myriam and Kardia, Sharon L R and Kooperberg, Charles and Liu, Ching-Ti and Mook-Kanamori, Dennis O and Province, Michael A and Psaty, Bruce M and Redline, Susan and Ridker, Paul M and Rotter, Jerome I and Boerwinkle, Eric and Morrison, Alanna C} } @article {8997, title = {Association of mitochondrial DNA copy number with cardiometabolic diseases.}, journal = {Cell Genom}, volume = {1}, year = {2021}, month = {2021 Oct 13}, abstract = {

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

}, issn = {2666-979X}, doi = {10.1016/j.xgen.2021.100006}, author = {Liu, Xue and Longchamps, Ryan J and Wiggins, Kerri L and Raffield, Laura M and Bielak, Lawrence F and Zhao, Wei and Pitsillides, Achilleas and Blackwell, Thomas W and Yao, Jie and Guo, Xiuqing and Kurniansyah, Nuzulul and Thyagarajan, Bharat and Pankratz, Nathan and Rich, Stephen S and Taylor, Kent D and Peyser, Patricia A and Heckbert, Susan R and Seshadri, Sudha and Cupples, L Adrienne and Boerwinkle, Eric and Grove, Megan L and Larson, Nicholas B and Smith, Jennifer A and Vasan, Ramachandran S and Sofer, Tamar and Fitzpatrick, Annette L and Fornage, Myriam and Ding, Jun and Correa, Adolfo and Abecasis, Goncalo and Psaty, Bruce M and Wilson, James G and Levy, Daniel and Rotter, Jerome I and Bis, Joshua C and Satizabal, Claudia L and Arking, Dan E and Liu, Chunyu} } @article {8705, title = {Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 Apr 01}, pages = {564-582}, abstract = {

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5\%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained <=20 variants in the credible sets that jointly account for 99\% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.02.011}, author = {Graff, Mariaelisa and Justice, Anne E and Young, Kristin L and Marouli, Eirini and Zhang, Xinruo and Fine, Rebecca S and Lim, Elise and Buchanan, Victoria and Rand, Kristin and Feitosa, Mary F and Wojczynski, Mary K and Yanek, Lisa R and Shao, Yaming and Rohde, Rebecca and Adeyemo, Adebowale A and Aldrich, Melinda C and Allison, Matthew A and Ambrosone, Christine B and Ambs, Stefan and Amos, Christopher and Arnett, Donna K and Atwood, Larry and Bandera, Elisa V and Bartz, Traci and Becker, Diane M and Berndt, Sonja I and Bernstein, Leslie and Bielak, Lawrence F and Blot, William J and Bottinger, Erwin P and Bowden, Donald W and Bradfield, Jonathan P and Brody, Jennifer A and Broeckel, Ulrich and Burke, Gregory and Cade, Brian E and Cai, Qiuyin and Caporaso, Neil and Carlson, Chris and Carpten, John and Casey, Graham and Chanock, Stephen J and Chen, Guanjie and Chen, Minhui and Chen, Yii-der I and Chen, Wei-Min and Chesi, Alessandra and Chiang, Charleston W K and Chu, Lisa and Coetzee, Gerry A and Conti, David V and Cooper, Richard S and Cushman, Mary and Demerath, Ellen and Deming, Sandra L and Dimitrov, Latchezar and Ding, Jingzhong and Diver, W Ryan and Duan, Qing and Evans, Michele K and Falusi, Adeyinka G and Faul, Jessica D and Fornage, Myriam and Fox, Caroline and Freedman, Barry I and Garcia, Melissa and Gillanders, Elizabeth M and Goodman, Phyllis and Gottesman, Omri and Grant, Struan F A and Guo, Xiuqing and Hakonarson, Hakon and Haritunians, Talin and Harris, Tamara B and Harris, Curtis C and Henderson, Brian E and Hennis, Anselm and Hernandez, Dena G and Hirschhorn, Joel N and McNeill, Lorna Haughton and Howard, Timothy D and Howard, Barbara and Hsing, Ann W and Hsu, Yu-Han H and Hu, Jennifer J and Huff, Chad D and Huo, Dezheng and Ingles, Sue A and Irvin, Marguerite R and John, Esther M and Johnson, Karen C and Jordan, Joanne M and Kabagambe, Edmond K and Kang, Sun J and Kardia, Sharon L and Keating, Brendan J and Kittles, Rick A and Klein, Eric A and Kolb, Suzanne and Kolonel, Laurence N and Kooperberg, Charles and Kuller, Lewis and Kutlar, Abdullah and Lange, Leslie and Langefeld, Carl D and Le Marchand, Lo{\"\i}c and Leonard, Hampton and Lettre, Guillaume and Levin, Albert M and Li, Yun and Li, Jin and Liu, Yongmei and Liu, Youfang and Liu, Simin and Lohman, Kurt and Lotay, Vaneet and Lu, Yingchang and Maixner, William and Manson, JoAnn E and McKnight, Barbara and Meng, Yan and Monda, Keri L and Monroe, Kris and Moore, Jason H and Mosley, Thomas H and Mudgal, Poorva and Murphy, Adam B and Nadukuru, Rajiv and Nalls, Mike A and Nathanson, Katherine L and Nayak, Uma and N{\textquoteright}diaye, Amidou and Nemesure, Barbara and Neslund-Dudas, Christine and Neuhouser, Marian L and Nyante, Sarah and Ochs-Balcom, Heather and Ogundiran, Temidayo O and Ogunniyi, Adesola and Ojengbede, Oladosu and Okut, Hayrettin and Olopade, Olufunmilayo I and Olshan, Andrew and Padhukasahasram, Badri and Palmer, Julie and Palmer, Cameron D and Palmer, Nicholette D and Papanicolaou, George and Patel, Sanjay R and Pettaway, Curtis A and Peyser, Patricia A and Press, Michael F and Rao, D C and Rasmussen-Torvik, Laura J and Redline, Susan and Reiner, Alex P and Rhie, Suhn K and Rodriguez-Gil, Jorge L and Rotimi, Charles N and Rotter, Jerome I and Ruiz-Narvaez, Edward A and Rybicki, Benjamin A and Salako, Babatunde and Sale, Mich{\`e}le M and Sanderson, Maureen and Schadt, Eric and Schreiner, Pamela J and Schurmann, Claudia and Schwartz, Ann G and Shriner, Daniel A and Signorello, Lisa B and Singleton, Andrew B and Siscovick, David S and Smith, Jennifer A and Smith, Shad and Speliotes, Elizabeth and Spitz, Margaret and Stanford, Janet L and Stevens, Victoria L and Stram, Alex and Strom, Sara S and Sucheston, Lara and Sun, Yan V and Tajuddin, Salman M and Taylor, Herman and Taylor, Kira and Tayo, Bamidele O and Thun, Michael J and Tucker, Margaret A and Vaidya, Dhananjay and Van Den Berg, David J and Vedantam, Sailaja and Vitolins, Mara and Wang, Zhaoming and Ware, Erin B and Wassertheil-Smoller, Sylvia and Weir, David R and Wiencke, John K and Williams, Scott M and Williams, L Keoki and Wilson, James G and Witte, John S and Wrensch, Margaret and Wu, Xifeng and Yao, Jie and Zakai, Neil and Zanetti, Krista and Zemel, Babette S and Zhao, Wei and Zhao, Jing Hua and Zheng, Wei and Zhi, Degui and Zhou, Jie and Zhu, Xiaofeng and Ziegler, Regina G and Zmuda, Joe and Zonderman, Alan B and Psaty, Bruce M and Borecki, Ingrid B and Cupples, L Adrienne and Liu, Ching-Ti and Haiman, Christopher A and Loos, Ruth and Ng, Maggie C Y and North, Kari E} } @article {8791, title = {FGL1 as a modulator of plasma D-dimer levels: Exome-wide marker analysis of plasma tPA, PAI-1, and D-dimer.}, journal = {J Thromb Haemost}, year = {2021}, month = {2021 Apr 20}, abstract = {

BACKGROUND: Use of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA, and D-dimer.

OBJECTIVES: We sought to discover new genetic loci contributing to variation in these traits using an exome-array approach.

METHODS: Cohort-level analyses and fixed effects meta-analyses of PAI-1 (n~=~15~603), tPA (n~=~6876,) and D-dimer (n~=~19~306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing.

RESULTS: Five variants located in NME7, FGL1, and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P~<~5~{\texttimes}~10 ). Replication was sought for these 5 variants, as well as 45 well-imputed variants with P~<~1~{\texttimes}~10 in the discovery using an independent cohort. Replication was observed for three out of the five significant associations, including a novel and uncommon (0.013 allele frequency) coding variant p.Trp256Leu in FGL1 (fibrinogen-like-1) with increased plasma D-dimer levels. Additionally, a candidate-gene approach revealed a suggestive association for a coding variant (rs143202684-C) in SERPINB2, and suggestive associations with consistent effect in the replication analysis include an intronic variant (rs11057830-A) in SCARB1 associated with increased D-dimer levels.

CONCLUSION: This work provides new evidence for a role of FGL1 in hemostasis.

}, issn = {1538-7836}, doi = {10.1111/jth.15345}, author = {Thibord, Florian and Song, Ci and Pattee, Jack and Rodriguez, Benjamin A T and Chen, Ming-Huei and O{\textquoteright}Donnell, Christopher J and Kleber, Marcus E and Delgado, Graciela E and Guo, Xiuqing and Yao, Jie and Taylor, Kent D and Ozel, Ayse Bilge and Brody, Jennifer A and McKnight, Barbara and Gyorgy, Beata and Simonsick, Eleanor and Leonard, Hampton L and Carrasquilla, Germ{\'a}n D and Guindo-Martinez, Marta and Silveira, Angela and Temprano-Sagrera, Gerard and Yanek, Lisa R and Becker, Diane M and Mathias, Rasika A and Becker, Lewis C and Raffield, Laura M and Kilpel{\"a}inen, Tuomas O and Grarup, Niels and Pedersen, Oluf and Hansen, Torben and Linneberg, Allan and Hamsten, Anders and Watkins, Hugh and Sabater-Lleal, Maria and Nalls, Mike A and Tr{\'e}gou{\"e}t, David-Alexandre and Morange, Pierre-Emmanuel and Psaty, Bruce M and Tracy, Russel P and Smith, Nicholas L and Desch, Karl C and Cushman, Mary and Rotter, Jerome I and de Vries, Paul S and Pankratz, Nathan D and Folsom, Aaron R and Morrison, Alanna C and M{\"a}rz, Winfried and Tang, Weihong and Johnson, Andrew D} } @article {9007, title = {Identification of Functional Genetic Determinants of Cardiac Troponin T and I in a Multiethnic Population and Causal Associations With Atrial Fibrillation.}, journal = {Circ Genom Precis Med}, volume = {14}, year = {2021}, month = {2021 12}, pages = {e003460}, abstract = {

BACKGROUND: Elevated cardiac troponin levels in blood are associated with increased risk of cardiovascular diseases and mortality. Cardiac troponin levels are heritable, but their genetic architecture remains elusive.

METHODS: We conducted a transethnic genome-wide association analysis on high-sensitivity cTnT (cardiac troponin T; hs-cTnT) and high-sensitivity cTnI (cardiac troponin I; hs-cTnI) levels in 24 617 and 14 336 participants free of coronary heart disease and heart failure from 6 population-based cohorts, followed by a series of bioinformatic analyses to decipher the genetic architecture of hs-cTnT and hs-cTnI.

RESULTS: We identified 4 genome-wide significant loci for hs-cTnT including a novel locus rs3737882 in and 3 previously reported loci at , , and . One known locus at was replicated for hs-cTnI. One copy of C allele for rs3737882 was associated with a 6\% increase in hs-cTnT levels (minor allele frequency, 0.18; =2.80{\texttimes}10). We observed pleiotropic loci located at and . The proportions of variances explained by single-nucleotide polymorphisms were 10.15\% and 7.74\% for hs-cTnT and hs-cTnI, respectively. Single-nucleotide polymorphisms were colocalized with expression in heart tissues and hs-cTnT and with expression in artery, heart tissues, and whole blood and both troponins. Mendelian randomization analyses showed that genetically increased hs-cTnT and hs-cTnI levels were associated with higher odds of atrial fibrillation (odds ratio, 1.38 [95\% CI, 1.25-1.54] for hs-cTnT and 1.21 [95\% CI, 1.06-1.37] for hs-cTnI).

CONCLUSIONS: We identified a novel genetic locus associated with hs-cTnT in a multiethnic population and found that genetically regulated troponin levels were associated with atrial fibrillation.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.121.003460}, author = {Yang, Yunju and Bartz, Traci M and Brown, Michael R and Guo, Xiuqing and Zilh{\~a}o, Nuno R and Trompet, Stella and Weiss, Stefan and Yao, Jie and Brody, Jennifer A and deFilippi, Christopher R and Hoogeveen, Ron C and Lin, Henry J and Gudnason, Vilmundur and Ballantyne, Christie M and D{\"o}rr, Marcus and Jukema, J Wouter and Petersmann, Astrid and Psaty, Bruce M and Rotter, Jerome I and Boerwinkle, Eric and Fornage, Myriam and Jun, Goo and Yu, Bing} } @article {9005, title = {Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits.}, journal = {HGG Adv}, volume = {2}, year = {2021}, month = {2021 Jan 14}, abstract = {

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (), synaptic function and neurotransmission (), as well as genes previously implicated in neuropsychiatric or stress-related disorders (). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

}, issn = {2666-2477}, doi = {10.1016/j.xhgg.2020.100013}, author = {Sun, Daokun and Richard, Melissa and Musani, Solomon K and Sung, Yun Ju and Winkler, Thomas W and Schwander, Karen and Chai, Jin Fang and Guo, Xiuqing and Kilpel{\"a}inen, Tuomas O and Vojinovic, Dina and Aschard, Hugues and Bartz, Traci M and Bielak, Lawrence F and Brown, Michael R and Chitrala, Kumaraswamy and Hartwig, Fernando P and Horimoto, Andrea R V R and Liu, Yongmei and Manning, Alisa K and Noordam, Raymond and Smith, Albert V and Harris, Sarah E and Kuhnel, Brigitte and Lyytik{\"a}inen, Leo-Pekka and Nolte, Ilja M and Rauramaa, Rainer and van der Most, Peter J and Wang, Rujia and Ware, Erin B and Weiss, Stefan and Wen, Wanqing and Yanek, Lisa R and Arking, Dan E and Arnett, Donna K and Barac, Ana and Boerwinkle, Eric and Broeckel, Ulrich and Chakravarti, Aravinda and Chen, Yii-Der Ida and Cupples, L Adrienne and Davigulus, Martha L and de Las Fuentes, Lisa and de Mutsert, Ren{\'e}e and de Vries, Paul S and Delaney, Joseph A C and Roux, Ana V Diez and D{\"o}rr, Marcus and Faul, Jessica D and Fretts, Amanda M and Gallo, Linda C and Grabe, Hans J{\"o}rgen and Gu, C Charles and Harris, Tamara B and Hartman, Catharina C A and Heikkinen, Sami and Ikram, M Arfan and Isasi, Carmen and Johnson, W Craig and Jonas, Jost Bruno and Kaplan, Robert C and Komulainen, Pirjo and Krieger, Jose E and Levy, Daniel and Liu, Jianjun and Lohman, Kurt and Luik, Annemarie I and Martin, Lisa W and Meitinger, Thomas and Milaneschi, Yuri and O{\textquoteright}Connell, Jeff R and Palmas, Walter R and Peters, Annette and Peyser, Patricia A and Pulkki-R{\r a}back, Laura and Raffel, Leslie J and Reiner, Alex P and Rice, Kenneth and Robinson, Jennifer G and Rosendaal, Frits R and Schmidt, Carsten Oliver and Schreiner, Pamela J and Schwettmann, Lars and Shikany, James M and Shu, Xiao-Ou and Sidney, Stephen and Sims, Mario and Smith, Jennifer A and Sotoodehnia, Nona and Strauch, Konstantin and Tai, E Shyong and Taylor, Kent and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Waldenberger, Melanie and Wee, Hwee-Lin and Wei, Wen-Bin and Wilson, Gregory and Xuan, Deng and Yao, Jie and Zeng, Donglin and Zhao, Wei and Zhu, Xiaofeng and Zonderman, Alan B and Becker, Diane M and Deary, Ian J and Gieger, Christian and Lakka, Timo A and Lehtim{\"a}ki, Terho and North, Kari E and Oldehinkel, Albertine J and Penninx, Brenda W J H and Snieder, Harold and Wang, Ya-Xing and Weir, David R and Zheng, Wei and Evans, Michele K and Gauderman, W James and Gudnason, Vilmundur and Horta, Bernardo L and Liu, Ching-Ti and Mook-Kanamori, Dennis O and Morrison, Alanna C and Pereira, Alexandre C and Psaty, Bruce M and Amin, Najaf and Fox, Ervin R and Kooperberg, Charles and Sim, Xueling and Bierut, Laura and Rotter, Jerome I and Kardia, Sharon L R and Franceschini, Nora and Rao, Dabeeru C and Fornage, Myriam} } @article {8714, title = {Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.}, journal = {Mol Psychiatry}, year = {2021}, month = {2021 Apr 15}, abstract = {

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 {\texttimes} 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 {\texttimes} 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 {\texttimes} 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

}, issn = {1476-5578}, doi = {10.1038/s41380-021-01087-0}, author = {Wang, Heming and Noordam, Raymond and Cade, Brian E and Schwander, Karen and Winkler, Thomas W and Lee, Jiwon and Sung, Yun Ju and Bentley, Amy R and Manning, Alisa K and Aschard, Hugues and Kilpel{\"a}inen, Tuomas O and Ilkov, Marjan and Brown, Michael R and Horimoto, Andrea R and Richard, Melissa and Bartz, Traci M and Vojinovic, Dina and Lim, Elise and Nierenberg, Jovia L and Liu, Yongmei and Chitrala, Kumaraswamynaidu and Rankinen, Tuomo and Musani, Solomon K and Franceschini, Nora and Rauramaa, Rainer and Alver, Maris and Zee, Phyllis C and Harris, Sarah E and van der Most, Peter J and Nolte, Ilja M and Munroe, Patricia B and Palmer, Nicholette D and Kuhnel, Brigitte and Weiss, Stefan and Wen, Wanqing and Hall, Kelly A and Lyytik{\"a}inen, Leo-Pekka and O{\textquoteright}Connell, Jeff and Eiriksdottir, Gudny and Launer, Lenore J and de Vries, Paul S and Arking, Dan E and Chen, Han and Boerwinkle, Eric and Krieger, Jose E and Schreiner, Pamela J and Sidney, Stephen and Shikany, James M and Rice, Kenneth and Chen, Yii-Der Ida and Gharib, Sina A and Bis, Joshua C and Luik, Annemarie I and Ikram, M Arfan and Uitterlinden, Andr{\'e} G and Amin, Najaf and Xu, Hanfei and Levy, Daniel and He, Jiang and Lohman, Kurt K and Zonderman, Alan B and Rice, Treva K and Sims, Mario and Wilson, Gregory and Sofer, Tamar and Rich, Stephen S and Palmas, Walter and Yao, Jie and Guo, Xiuqing and Rotter, Jerome I and Biermasz, Nienke R and Mook-Kanamori, Dennis O and Martin, Lisa W and Barac, Ana and Wallace, Robert B and Gottlieb, Daniel J and Komulainen, Pirjo and Heikkinen, Sami and M{\"a}gi, Reedik and Milani, Lili and Metspalu, Andres and Starr, John M and Milaneschi, Yuri and Waken, R J and Gao, Chuan and Waldenberger, Melanie and Peters, Annette and Strauch, Konstantin and Meitinger, Thomas and Roenneberg, Till and V{\"o}lker, Uwe and D{\"o}rr, Marcus and Shu, Xiao-Ou and Mukherjee, Sutapa and Hillman, David R and K{\"a}h{\"o}nen, Mika and Wagenknecht, Lynne E and Gieger, Christian and Grabe, Hans J and Zheng, Wei and Palmer, Lyle J and Lehtim{\"a}ki, Terho and Gudnason, Vilmundur and Morrison, Alanna C and Pereira, Alexandre C and Fornage, Myriam and Psaty, Bruce M and van Duijn, Cornelia M and Liu, Ching-Ti and Kelly, Tanika N and Evans, Michele K and Bouchard, Claude and Fox, Ervin R and Kooperberg, Charles and Zhu, Xiaofeng and Lakka, Timo A and Esko, T{\~o}nu and North, Kari E and Deary, Ian J and Snieder, Harold and Penninx, Brenda W J H and Gauderman, W James and Rao, Dabeeru C and Redline, Susan and van Heemst, Diana} } @article {8832, title = {Multiethnic Genome-Wide Association Study of Subclinical Atherosclerosis in Individuals With Type 2 Diabetes.}, journal = {Circ Genom Precis Med}, volume = {14}, year = {2021}, month = {2021 Aug}, pages = {e003258}, abstract = {

BACKGROUND: Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis.

METHODS: We performed meta-analyses of genome-wide association studies in up to 2500 T2D individuals of European ancestry (EA) and 1590 T2D individuals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 individuals of EA and 838 individuals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.

RESULTS: We replicated 2 loci (rs9369640 and rs9349379 near and rs10757278 near ) for CAC and one locus for cIMT (rs7412 and rs445925 near ) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near at 13q13.3) at =2.0{\texttimes}10 in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints , encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations (<3.1{\texttimes}10) for 3 previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near and rs11170820 near for CAC, and rs7412 near for cIMT).

CONCLUSIONS: Our results provide potential biological mechanisms that could link CAC and cIMT to increased cardiovascular disease risk in individuals with T2D.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.120.003258}, author = {Lu, Yingchang and Dimitrov, Latchezar and Chen, Shyh-Huei and Bielak, Lawrence F and Bis, Joshua C and Feitosa, Mary F and Lu, Lingyi and Kavousi, Maryam and Raffield, Laura M and Smith, Albert V and Wang, Lihua and Weiss, Stefan and Yao, Jie and Zhu, Jiaxi and Gudmundsson, Elias F and Gudmundsdottir, Valborg and Bos, Daniel and Ghanbari, Mohsen and Ikram, M Arfan and Hwang, Shih-Jen and Taylor, Kent D and Budoff, Matthew J and Gislason, Gauti K and O{\textquoteright}Donnell, Christopher J and An, Ping and Franceschini, Nora and Freedman, Barry I and Fu, Yi-Ping and Guo, Xiuqing and Heiss, Gerardo and Kardia, Sharon L R and Wilson, James G and Langefeld, Carl D and Schminke, Ulf and Uitterlinden, Andr{\'e} G and Lange, Leslie A and Peyser, Patricia A and Gudnason, Vilmundur G and Psaty, Bruce M and Rotter, Jerome I and Bowden, Donald W and Ng, Maggie C Y} } @article {9104, title = {Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation.}, journal = {Nat Genet}, volume = {54}, year = {2022}, month = {2022 May}, pages = {560-572}, abstract = {

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9\% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 {\texttimes} 10), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4\% of T2D associations to a single variant with >50\% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.

}, keywords = {Diabetes Mellitus, Type 2, Ethnicity, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1546-1718}, doi = {10.1038/s41588-022-01058-3}, author = {Mahajan, Anubha and Spracklen, Cassandra N and Zhang, Weihua and Ng, Maggie C Y and Petty, Lauren E and Kitajima, Hidetoshi and Yu, Grace Z and R{\"u}eger, Sina and Speidel, Leo and Kim, Young Jin and Horikoshi, Momoko and Mercader, Josep M and Taliun, Daniel and Moon, Sanghoon and Kwak, Soo-Heon and Robertson, Neil R and Rayner, Nigel W and Loh, Marie and Kim, Bong-Jo and Chiou, Joshua and Miguel-Escalada, Irene and Della Briotta Parolo, Pietro and Lin, Kuang and Bragg, Fiona and Preuss, Michael H and Takeuchi, Fumihiko and Nano, Jana and Guo, Xiuqing and Lamri, Amel and Nakatochi, Masahiro and Scott, Robert A and Lee, Jung-Jin and Huerta-Chagoya, Alicia and Graff, Mariaelisa and Chai, Jin-Fang and Parra, Esteban J and Yao, Jie and Bielak, Lawrence F and Tabara, Yasuharu and Hai, Yang and Steinthorsdottir, Valgerdur and Cook, James P and Kals, Mart and Grarup, Niels and Schmidt, Ellen M and Pan, Ian and Sofer, Tamar and Wuttke, Matthias and Sarnowski, Chloe and Gieger, Christian and Nousome, Darryl and Trompet, Stella and Long, Jirong and Sun, Meng and Tong, Lin and Chen, Wei-Min and Ahmad, Meraj and Noordam, Raymond and Lim, Victor J Y and Tam, Claudia H T and Joo, Yoonjung Yoonie and Chen, Chien-Hsiun and Raffield, Laura M and Lecoeur, C{\'e}cile and Prins, Bram Peter and Nicolas, Aude and Yanek, Lisa R and Chen, Guanjie and Jensen, Richard A and Tajuddin, Salman and Kabagambe, Edmond K and An, Ping and Xiang, Anny H and Choi, Hyeok Sun and Cade, Brian E and Tan, Jingyi and Flanagan, Jack and Abaitua, Fernando and Adair, Linda S and Adeyemo, Adebowale and Aguilar-Salinas, Carlos A and Akiyama, Masato and Anand, Sonia S and Bertoni, Alain and Bian, Zheng and Bork-Jensen, Jette and Brandslund, Ivan and Brody, Jennifer A and Brummett, Chad M and Buchanan, Thomas A and Canouil, Micka{\"e}l and Chan, Juliana C N and Chang, Li-Ching and Chee, Miao-Li and Chen, Ji and Chen, Shyh-Huei and Chen, Yuan-Tsong and Chen, Zhengming and Chuang, Lee-Ming and Cushman, Mary and Das, Swapan K and de Silva, H Janaka and Dedoussis, George and Dimitrov, Latchezar and Doumatey, Ayo P and Du, Shufa and Duan, Qing and Eckardt, Kai-Uwe and Emery, Leslie S and Evans, Daniel S and Evans, Michele K and Fischer, Krista and Floyd, James S and Ford, Ian and Fornage, Myriam and Franco, Oscar H and Frayling, Timothy M and Freedman, Barry I and Fuchsberger, Christian and Genter, Pauline and Gerstein, Hertzel C and Giedraitis, Vilmantas and Gonz{\'a}lez-Villalpando, Clicerio and Gonzalez-Villalpando, Maria Elena and Goodarzi, Mark O and Gordon-Larsen, Penny and Gorkin, David and Gross, Myron and Guo, Yu and Hackinger, Sophie and Han, Sohee and Hattersley, Andrew T and Herder, Christian and Howard, Annie-Green and Hsueh, Willa and Huang, Mengna and Huang, Wei and Hung, Yi-Jen and Hwang, Mi Yeong and Hwu, Chii-Min and Ichihara, Sahoko and Ikram, Mohammad Arfan and Ingelsson, Martin and Islam, Md Tariqul and Isono, Masato and Jang, Hye-Mi and Jasmine, Farzana and Jiang, Guozhi and Jonas, Jost B and J{\o}rgensen, Marit E and J{\o}rgensen, Torben and Kamatani, Yoichiro and Kandeel, Fouad R and Kasturiratne, Anuradhani and Katsuya, Tomohiro and Kaur, Varinderpal and Kawaguchi, Takahisa and Keaton, Jacob M and Kho, Abel N and Khor, Chiea-Chuen and Kibriya, Muhammad G and Kim, Duk-Hwan and Kohara, Katsuhiko and Kriebel, Jennifer and Kronenberg, Florian and Kuusisto, Johanna and L{\"a}ll, Kristi and Lange, Leslie A and Lee, Myung-Shik and Lee, Nanette R and Leong, Aaron and Li, Liming and Li, Yun and Li-Gao, Ruifang and Ligthart, Symen and Lindgren, Cecilia M and Linneberg, Allan and Liu, Ching-Ti and Liu, Jianjun and Locke, Adam E and Louie, Tin and Luan, Jian{\textquoteright}an and Luk, Andrea O and Luo, Xi and Lv, Jun and Lyssenko, Valeriya and Mamakou, Vasiliki and Mani, K Radha and Meitinger, Thomas and Metspalu, Andres and Morris, Andrew D and Nadkarni, Girish N and Nadler, Jerry L and Nalls, Michael A and Nayak, Uma and Nongmaithem, Suraj S and Ntalla, Ioanna and Okada, Yukinori and Orozco, Lorena and Patel, Sanjay R and Pereira, Mark A and Peters, Annette and Pirie, Fraser J and Porneala, Bianca and Prasad, Gauri and Preissl, Sebastian and Rasmussen-Torvik, Laura J and Reiner, Alexander P and Roden, Michael and Rohde, Rebecca and Roll, Kathryn and Sabanayagam, Charumathi and Sander, Maike and Sandow, Kevin and Sattar, Naveed and Sch{\"o}nherr, Sebastian and Schurmann, Claudia and Shahriar, Mohammad and Shi, Jinxiu and Shin, Dong Mun and Shriner, Daniel and Smith, Jennifer A and So, Wing Yee and Stan{\v c}{\'a}kov{\'a}, Alena and Stilp, Adrienne M and Strauch, Konstantin and Suzuki, Ken and Takahashi, Atsushi and Taylor, Kent D and Thorand, Barbara and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tomlinson, Brian and Torres, Jason M and Tsai, Fuu-Jen and Tuomilehto, Jaakko and Tusi{\'e}-Luna, Teresa and Udler, Miriam S and Valladares-Salgado, Adan and van Dam, Rob M and van Klinken, Jan B and Varma, Rohit and Vujkovic, Marijana and Wacher-Rodarte, Niels and Wheeler, Eleanor and Whitsel, Eric A and Wickremasinghe, Ananda R and van Dijk, Ko Willems and Witte, Daniel R and Yajnik, Chittaranjan S and Yamamoto, Ken and Yamauchi, Toshimasa and Yengo, Loic and Yoon, Kyungheon and Yu, Canqing and Yuan, Jian-Min and Yusuf, Salim and Zhang, Liang and Zheng, Wei and Raffel, Leslie J and Igase, Michiya and Ipp, Eli and Redline, Susan and Cho, Yoon Shin and Lind, Lars and Province, Michael A and Hanis, Craig L and Peyser, Patricia A and Ingelsson, Erik and Zonderman, Alan B and Psaty, Bruce M and Wang, Ya-Xing and Rotimi, Charles N and Becker, Diane M and Matsuda, Fumihiko and Liu, Yongmei and Zeggini, Eleftheria and Yokota, Mitsuhiro and Rich, Stephen S and Kooperberg, Charles and Pankow, James S and Engert, James C and Chen, Yii-Der Ida and Froguel, Philippe and Wilson, James G and Sheu, Wayne H H and Kardia, Sharon L R and Wu, Jer-Yuarn and Hayes, M Geoffrey and Ma, Ronald C W and Wong, Tien-Yin and Groop, Leif and Mook-Kanamori, Dennis O and Chandak, Giriraj R and Collins, Francis S and Bharadwaj, Dwaipayan and Par{\'e}, Guillaume and Sale, Mich{\`e}le M and Ahsan, Habibul and Motala, Ayesha A and Shu, Xiao-Ou and Park, Kyong-Soo and Jukema, J Wouter and Cruz, Miguel and McKean-Cowdin, Roberta and Grallert, Harald and Cheng, Ching-Yu and Bottinger, Erwin P and Dehghan, Abbas and Tai, E-Shyong and Dupuis, Jos{\'e}e and Kato, Norihiro and Laakso, Markku and K{\"o}ttgen, Anna and Koh, Woon-Puay and Palmer, Colin N A and Liu, Simin and Abecasis, Goncalo and Kooner, Jaspal S and Loos, Ruth J F and North, Kari E and Haiman, Christopher A and Florez, Jose C and Saleheen, Danish and Hansen, Torben and Pedersen, Oluf and M{\"a}gi, Reedik and Langenberg, Claudia and Wareham, Nicholas J and Maeda, Shiro and Kadowaki, Takashi and Lee, Juyoung and Millwood, Iona Y and Walters, Robin G and Stefansson, Kari and Myers, Simon R and Ferrer, Jorge and Gaulton, Kyle J and Meigs, James B and Mohlke, Karen L and Gloyn, Anna L and Bowden, Donald W and Below, Jennifer E and Chambers, John C and Sim, Xueling and Boehnke, Michael and Rotter, Jerome I and McCarthy, Mark I and Morris, Andrew P} } @article {9158, title = {Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program.}, journal = {Commun Biol}, volume = {5}, year = {2022}, month = {2022 07 28}, pages = {756}, abstract = {

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI{\textquoteright}s Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.

}, keywords = {Diabetes Mellitus, Type 2, Fasting, Glucose, Humans, Insulin, National Heart, Lung, and Blood Institute (U.S.), Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Precision Medicine, Receptors, Immunologic, United States}, issn = {2399-3642}, doi = {10.1038/s42003-022-03702-4}, author = {DiCorpo, Daniel and Gaynor, Sheila M and Russell, Emily M and Westerman, Kenneth E and Raffield, Laura M and Majarian, Timothy D and Wu, Peitao and Sarnowski, Chloe and Highland, Heather M and Jackson, Anne and Hasbani, Natalie R and de Vries, Paul S and Brody, Jennifer A and Hidalgo, Bertha and Guo, Xiuqing and Perry, James A and O{\textquoteright}Connell, Jeffrey R and Lent, Samantha and Montasser, May E and Cade, Brian E and Jain, Deepti and Wang, Heming and D{\textquoteright}Oliveira Albanus, Ricardo and Varshney, Arushi and Yanek, Lisa R and Lange, Leslie and Palmer, Nicholette D and Almeida, Marcio and Peralta, Juan M and Aslibekyan, Stella and Baldridge, Abigail S and Bertoni, Alain G and Bielak, Lawrence F and Chen, Chung-Shiuan and Chen, Yii-Der Ida and Choi, Won Jung and Goodarzi, Mark O and Floyd, James S and Irvin, Marguerite R and Kalyani, Rita R and Kelly, Tanika N and Lee, Seonwook and Liu, Ching-Ti and Loesch, Douglas and Manson, JoAnn E and Minster, Ryan L and Naseri, Take and Pankow, James S and Rasmussen-Torvik, Laura J and Reiner, Alexander P and Reupena, Muagututi{\textquoteright}a Sefuiva and Selvin, Elizabeth and Smith, Jennifer A and Weeks, Daniel E and Xu, Huichun and Yao, Jie and Zhao, Wei and Parker, Stephen and Alonso, Alvaro and Arnett, Donna K and Blangero, John and Boerwinkle, Eric and Correa, Adolfo and Cupples, L Adrienne and Curran, Joanne E and Duggirala, Ravindranath and He, Jiang and Heckbert, Susan R and Kardia, Sharon L R and Kim, Ryan W and Kooperberg, Charles and Liu, Simin and Mathias, Rasika A and McGarvey, Stephen T and Mitchell, Braxton D and Morrison, Alanna C and Peyser, Patricia A and Psaty, Bruce M and Redline, Susan and Shuldiner, Alan R and Taylor, Kent D and Vasan, Ramachandran S and Viaud-Martinez, Karine A and Florez, Jose C and Wilson, James G and Sladek, Robert and Rich, Stephen S and Rotter, Jerome I and Lin, Xihong and Dupuis, Jos{\'e}e and Meigs, James B and Wessel, Jennifer and Manning, Alisa K} } @article {9502, title = {Association Between Whole Blood-Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk.}, journal = {J Am Heart Assoc}, year = {2023}, month = {2023 Oct 07}, pages = {e029090}, abstract = {

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

}, issn = {2047-9980}, doi = {10.1161/JAHA.122.029090}, author = {Liu, Xue and Sun, Xianbang and Zhang, Yuankai and Jiang, Wenqing and Lai, Meng and Wiggins, Kerri L and Raffield, Laura M and Bielak, Lawrence F and Zhao, Wei and Pitsillides, Achilleas and Haessler, Jeffrey and Zheng, Yinan and Blackwell, Thomas W and Yao, Jie and Guo, Xiuqing and Qian, Yong and Thyagarajan, Bharat and Pankratz, Nathan and Rich, Stephen S and Taylor, Kent D and Peyser, Patricia A and Heckbert, Susan R and Seshadri, Sudha and Boerwinkle, Eric and Grove, Megan L and Larson, Nicholas B and Smith, Jennifer A and Vasan, Ramachandran S and Fitzpatrick, Annette L and Fornage, Myriam and Ding, Jun and Carson, April P and Abecasis, Goncalo and Dupuis, Jos{\'e}e and Reiner, Alexander and Kooperberg, Charles and Hou, Lifang and Psaty, Bruce M and Wilson, James G and Levy, Daniel and Rotter, Jerome I and Bis, Joshua C and Satizabal, Claudia L and Arking, Dan E and Liu, Chunyu} } @article {9535, title = {Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci.}, journal = {Front Genet}, volume = {14}, year = {2023}, month = {2023}, pages = {1235337}, abstract = {

Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant ( < 5 {\texttimes} 10) and suggestive ( < 1 {\texttimes} 10) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (), brain (), and liver () biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

}, issn = {1664-8021}, doi = {10.3389/fgene.2023.1235337}, author = {de Las Fuentes, Lisa and Schwander, Karen L and Brown, Michael R and Bentley, Amy R and Winkler, Thomas W and Sung, Yun Ju and Munroe, Patricia B and Miller, Clint L and Aschard, Hugo and Aslibekyan, Stella and Bartz, Traci M and Bielak, Lawrence F and Chai, Jin Fang and Cheng, Ching-Yu and Dorajoo, Rajkumar and Feitosa, Mary F and Guo, Xiuqing and Hartwig, Fernando P and Horimoto, Andrea and Kolcic, Ivana and Lim, Elise and Liu, Yongmei and Manning, Alisa K and Marten, Jonathan and Musani, Solomon K and Noordam, Raymond and Padmanabhan, Sandosh and Rankinen, Tuomo and Richard, Melissa A and Ridker, Paul M and Smith, Albert V and Vojinovic, Dina and Zonderman, Alan B and Alver, Maris and Boissel, Mathilde and Christensen, Kaare and Freedman, Barry I and Gao, Chuan and Giulianini, Franco and Harris, Sarah E and He, Meian and Hsu, Fang-Chi and Kuhnel, Brigitte and Laguzzi, Federica and Li, Xiaoyin and Lyytik{\"a}inen, Leo-Pekka and Nolte, Ilja M and Poveda, Alaitz and Rauramaa, Rainer and Riaz, Muhammad and Robino, Antonietta and Sofer, Tamar and Takeuchi, Fumihiko and Tayo, Bamidele O and van der Most, Peter J and Verweij, Niek and Ware, Erin B and Weiss, Stefan and Wen, Wanqing and Yanek, Lisa R and Zhan, Yiqiang and Amin, Najaf and Arking, Dan E and Ballantyne, Christie and Boerwinkle, Eric and Brody, Jennifer A and Broeckel, Ulrich and Campbell, Archie and Canouil, Micka{\"e}l and Chai, Xiaoran and Chen, Yii-Der Ida and Chen, Xu and Chitrala, Kumaraswamy Naidu and Concas, Maria Pina and de Faire, Ulf and de Mutsert, Ren{\'e}e and de Silva, H Janaka and de Vries, Paul S and Do, Ahn and Faul, Jessica D and Fisher, Virginia and Floyd, James S and Forrester, Terrence and Friedlander, Yechiel and Girotto, Giorgia and Gu, C Charles and Hallmans, G{\"o}ran and Heikkinen, Sami and Heng, Chew-Kiat and Homuth, Georg and Hunt, Steven and Ikram, M Arfan and Jacobs, David R and Kavousi, Maryam and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Komulainen, Pirjo and Langefeld, Carl D and Liang, Jingjing and Liu, Kiang and Liu, Jianjun and Lohman, Kurt and M{\"a}gi, Reedik and Manichaikul, Ani W and McKenzie, Colin A and Meitinger, Thomas and Milaneschi, Yuri and Nauck, Matthias and Nelson, Christopher P and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Pereira, Alexandre C and Perls, Thomas and Peters, Annette and Polasek, Ozren and Raitakari, Olli T and Rice, Kenneth and Rice, Treva K and Rich, Stephen S and Sabanayagam, Charumathi and Schreiner, Pamela J and Shu, Xiao-Ou and Sidney, Stephen and Sims, Mario and Smith, Jennifer A and Starr, John M and Strauch, Konstantin and Tai, E Shyong and Taylor, Kent D and Tsai, Michael Y and Uitterlinden, Andr{\'e} G and van Heemst, Diana and Waldenberger, Melanie and Wang, Ya-Xing and Wei, Wen-Bin and Wilson, Gregory and Xuan, Deng and Yao, Jie and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Becker, Diane M and Bonnefond, Am{\'e}lie and Bowden, Donald W and Cooper, Richard S and Deary, Ian J and Divers, Jasmin and Esko, T{\~o}nu and Franks, Paul W and Froguel, Philippe and Gieger, Christian and Jonas, Jost B and Kato, Norihiro and Lakka, Timo A and Leander, Karin and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and North, Kari E and Ntalla, Ioanna and Penninx, Brenda and Samani, Nilesh J and Snieder, Harold and Spedicati, Beatrice and van der Harst, Pim and V{\"o}lzke, Henry and Wagenknecht, Lynne E and Weir, David R and Wojczynski, Mary K and Wu, Tangchun and Zheng, Wei and Zhu, Xiaofeng and Bouchard, Claude and Chasman, Daniel I and Evans, Michele K and Fox, Ervin R and Gudnason, Vilmundur and Hayward, Caroline and Horta, Bernardo L and Kardia, Sharon L R and Krieger, Jose Eduardo and Mook-Kanamori, Dennis O and Peyser, Patricia A and Province, Michael M and Psaty, Bruce M and Rudan, Igor and Sim, Xueling and Smith, Blair H and van Dam, Rob M and van Duijn, Cornelia M and Wong, Tien Yin and Arnett, Donna K and Rao, Dabeeru C and Gauderman, James and Liu, Ching-Ti and Morrison, Alanna C and Rotter, Jerome I and Fornage, Myriam} } @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 {9385, title = {Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.}, journal = {medRxiv}, year = {2023}, month = {2023 Mar 31}, abstract = {

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7\% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5{\texttimes}10 ) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.

}, doi = {10.1101/2023.03.31.23287839}, author = {Suzuki, Ken and Hatzikotoulas, Konstantinos and Southam, Lorraine and Taylor, Henry J and Yin, Xianyong and Lorenz, Kim M and Mandla, Ravi and Huerta-Chagoya, Alicia and Rayner, Nigel W and Bocher, Ozvan and Ana Luiza de, S V Arruda and Sonehara, Kyuto and Namba, Shinichi and Lee, Simon S K and Preuss, Michael H and Petty, Lauren E and Schroeder, Philip and Vanderwerff, Brett and Kals, Mart and Bragg, Fiona and Lin, Kuang and Guo, Xiuqing and Zhang, Weihua and Yao, Jie and Kim, Young Jin and Graff, Mariaelisa and Takeuchi, Fumihiko and Nano, Jana and Lamri, Amel and Nakatochi, Masahiro and Moon, Sanghoon and Scott, Robert A and Cook, James P and Lee, Jung-Jin and Pan, Ian and Taliun, Daniel and Parra, Esteban J and Chai, Jin-Fang and Bielak, Lawrence F and Tabara, Yasuharu and Hai, Yang and Thorleifsson, Gudmar and Grarup, Niels and Sofer, Tamar and Wuttke, Matthias and Sarnowski, Chloe and Gieger, Christian and Nousome, Darryl and Trompet, Stella and Kwak, Soo-Heon and Long, Jirong and Sun, Meng and Tong, Lin and Chen, Wei-Min and Nongmaithem, Suraj S and Noordam, Raymond and Lim, Victor J Y and Tam, Claudia H T and Joo, Yoonjung Yoonie and Chen, Chien-Hsiun and Raffield, Laura M and Prins, Bram Peter and Nicolas, Aude and Yanek, Lisa R and Chen, Guanjie and Brody, Jennifer A and Kabagambe, Edmond and An, Ping and Xiang, Anny H and Choi, Hyeok Sun and Cade, Brian E and Tan, Jingyi and Alaine Broadaway, K and Williamson, Alice and Kamali, Zoha and Cui, Jinrui and Adair, Linda S and Adeyemo, Adebowale and Aguilar-Salinas, Carlos A and Ahluwalia, Tarunveer S and Anand, Sonia S and Bertoni, Alain and Bork-Jensen, Jette and Brandslund, Ivan and Buchanan, Thomas A and Burant, Charles F and Butterworth, Adam S and Canouil, Micka{\"e}l and Chan, Juliana C N and Chang, Li-Ching and Chee, Miao-Li and Chen, Ji and Chen, Shyh-Huei and Chen, Yuan-Tsong and Chen, Zhengming and Chuang, Lee-Ming and Cushman, Mary and Danesh, John and Das, Swapan K and Janaka de Silva, H and Dedoussis, George and Dimitrov, Latchezar and Doumatey, Ayo P and Du, Shufa and Duan, Qing and Eckardt, Kai-Uwe and Emery, Leslie S and Evans, Daniel S and Evans, Michele K and Fischer, Krista and Floyd, James S and Ford, Ian and Franco, Oscar H and Frayling, Timothy M and Freedman, Barry I and Genter, Pauline and Gerstein, Hertzel C and Giedraitis, Vilmantas and Gonz{\'a}lez-Villalpando, Clicerio and Gonzalez-Villalpando, Maria Elena and Gordon-Larsen, Penny and Gross, Myron and Guare, Lindsay A and Hackinger, Sophie and Han, Sohee and Hattersley, Andrew T and Herder, Christian and Horikoshi, Momoko and Howard, Annie-Green and Hsueh, Willa and Huang, Mengna and Huang, Wei and Hung, Yi-Jen and Hwang, Mi Yeong and Hwu, Chii-Min and Ichihara, Sahoko and Ikram, Mohammad Arfan and Ingelsson, Martin and Islam, Md Tariqul and Isono, Masato and Jang, Hye-Mi and Jasmine, Farzana and Jiang, Guozhi and Jonas, Jost B and J{\o}rgensen, Torben and Kandeel, Fouad R and Kasturiratne, Anuradhani and Katsuya, Tomohiro and Kaur, Varinderpal and Kawaguchi, Takahisa and Keaton, Jacob M and Kho, Abel N and Khor, Chiea-Chuen and Kibriya, Muhammad G and Kim, Duk-Hwan and Kronenberg, Florian and Kuusisto, Johanna and L{\"a}ll, Kristi and Lange, Leslie A and Lee, Kyung Min and Lee, Myung-Shik and Lee, Nanette R and Leong, Aaron and Li, Liming and Li, Yun and Li-Gao, Ruifang and Lithgart, Symen and Lindgren, Cecilia M and Linneberg, Allan and Liu, Ching-Ti and Liu, Jianjun and Locke, Adam E and Louie, Tin and Luan, Jian{\textquoteright}an and Luk, Andrea O and Luo, Xi and Lv, Jun and Lynch, Julie A and Lyssenko, Valeriya and Maeda, Shiro and Mamakou, Vasiliki and Mansuri, Sohail Rafik and Matsuda, Koichi and Meitinger, Thomas and Metspalu, Andres and Mo, Huan and Morris, Andrew D and Nadler, Jerry L and Nalls, Michael A and Nayak, Uma and Ntalla, Ioanna and Okada, Yukinori and Orozco, Lorena and Patel, Sanjay R and Patil, Snehal and Pei, Pei and Pereira, Mark A and Peters, Annette and Pirie, Fraser J and Polikowsky, Hannah G and Porneala, Bianca and Prasad, Gauri and Rasmussen-Torvik, Laura J and Reiner, Alexander P and Roden, Michael and Rohde, Rebecca and Roll, Katheryn and Sabanayagam, Charumathi and Sandow, Kevin and Sankareswaran, Alagu and Sattar, Naveed and Sch{\"o}nherr, Sebastian and Shahriar, Mohammad and Shen, Botong and Shi, Jinxiu and Shin, Dong Mun and Shojima, Nobuhiro and Smith, Jennifer A and So, Wing Yee and Stan{\v c}{\'a}kov{\'a}, Alena and Steinthorsdottir, Valgerdur and Stilp, Adrienne M and Strauch, Konstantin and Taylor, Kent D and Thorand, Barbara and Thorsteinsdottir, Unnur and Tomlinson, Brian and Tran, Tam C and Tsai, Fuu-Jen and Tuomilehto, Jaakko and Tusi{\'e}-Luna, Teresa and Udler, Miriam S and Valladares-Salgado, Adan and van Dam, Rob M and van Klinken, Jan B and Varma, Rohit and Wacher-Rodarte, Niels and Wheeler, Eleanor and Wickremasinghe, Ananda R and van Dijk, Ko Willems and Witte, Daniel R and Yajnik, Chittaranjan S and Yamamoto, Ken and Yamamoto, Kenichi and Yoon, Kyungheon and Yu, Canqing and Yuan, Jian-Min and Yusuf, Salim and Zawistowski, Matthew and Zhang, Liang and Zheng, Wei and Project, Biobank Japan and BioBank, Penn Medicine and Center, Regeneron Genetics and Consortium, eMERGE and Raffel, Leslie J and Igase, Michiya and Ipp, Eli and Redline, Susan and Cho, Yoon Shin and Lind, Lars and Province, Michael A and Fornage, Myriam and Hanis, Craig L and Ingelsson, Erik and Zonderman, Alan B and Psaty, Bruce M and Wang, Ya-Xing and Rotimi, Charles N and Becker, Diane M and Matsuda, Fumihiko and Liu, Yongmei and Yokota, Mitsuhiro and Kardia, Sharon L R and Peyser, Patricia A and Pankow, James S and Engert, James C and Bonnefond, Am{\'e}lie and Froguel, Philippe and Wilson, James G and Sheu, Wayne H H and Wu, Jer-Yuarn and Geoffrey Hayes, M and Ma, Ronald C W and Wong, Tien-Yin and Mook-Kanamori, Dennis O and Tuomi, Tiinamaija and Chandak, Giriraj R and Collins, Francis S and Bharadwaj, Dwaipayan and Par{\'e}, Guillaume and Sale, Mich{\`e}le M and Ahsan, Habibul and Motala, Ayesha A and Shu, Xiao-Ou and Park, Kyong-Soo and Jukema, J Wouter and Cruz, Miguel and Chen, Yii-Der Ida and Rich, Stephen S and McKean-Cowdin, Roberta and Grallert, Harald and Cheng, Ching-Yu and Ghanbari, Mohsen and Tai, E-Shyong and Dupuis, Jos{\'e}e and Kato, Norihiro and Laakso, Markku and K{\"o}ttgen, Anna and Koh, Woon-Puay and Bowden, Donald W and Palmer, Colin N A and Kooner, Jaspal S and Kooperberg, Charles and Liu, Simin and North, Kari E and Saleheen, Danish and Hansen, Torben and Pedersen, Oluf and Wareham, Nicholas J and Lee, Juyoung and Kim, Bong-Jo and Millwood, Iona Y and Walters, Robin G and Stefansson, Kari and Goodarzi, Mark O and Mohlke, Karen L and Langenberg, Claudia and Haiman, Christopher A and Loos, Ruth J F and Florez, Jose C and Rader, Daniel J and Ritchie, Marylyn D and Z{\"o}llner, Sebastian and M{\"a}gi, Reedik and Denny, Joshua C and Yamauchi, Toshimasa and Kadowaki, Takashi and Chambers, John C and Ng, Maggie C Y and Sim, Xueling and Below, Jennifer E and Tsao, Philip S and Chang, Kyong-Mi and McCarthy, Mark I and Meigs, James B and Mahajan, Anubha and Spracklen, Cassandra N and Mercader, Josep M and Boehnke, Michael and Rotter, Jerome I and Vujkovic, Marijana and Voight, Benjamin F and Morris, Andrew P and Zeggini, Eleftheria} } @article {9450, title = {Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus.}, journal = {medRxiv}, year = {2023}, month = {2023 Jul 28}, abstract = {

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

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

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

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

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

}, doi = {10.1101/2023.07.25.23293180}, author = {Kwak, Soo Heon and Hernandez-Cancela, Ryan B and DiCorpo, Daniel A and Condon, David E and Merino, Jordi and Wu, Peitao and Brody, Jennifer A and Yao, Jie and Guo, Xiuqing and Ahmadizar, Fariba and Meyer, Mariah and Sincan, Murat and Mercader, Josep M and Lee, Sujin and Haessler, Jeffrey and Vy, Ha My T and Lin, Zhaotong and Armstrong, Nicole D and Gu, Shaopeng and Tsao, Noah L and Lange, Leslie A and Wang, Ningyuan and Wiggins, Kerri L and Trompet, Stella and Liu, Simin and Loos, Ruth J F and Judy, Renae and Schroeder, Philip H and Hasbani, Natalie R and Bos, Maxime M and Morrison, Alanna C and Jackson, Rebecca D and Reiner, Alexander P and Manson, JoAnn E and Chaudhary, Ninad S and Carmichael, Lynn K and Chen, Yii-Der Ida and Taylor, Kent D and Ghanbari, Mohsen and van Meurs, Joyce and Pitsillides, Achilleas N and Psaty, Bruce M and Noordam, Raymond and Do, Ron and Park, Kyong Soo and Jukema, J Wouter and Kavousi, Maryam and Correa, Adolfo and Rich, Stephen S and Damrauer, Scott M and Hajek, Catherine and Cho, Nam H and Irvin, Marguerite R and Pankow, James S and Nadkarni, Girish N and Sladek, Robert and Goodarzi, Mark O and Florez, Jose C and Chasman, Daniel I and Heckbert, Susan R and Kooperberg, Charles and Dupuis, Jos{\'e}e and Malhotra, Rajeev and de Vries, Paul S and Liu, Ching-Ti and Rotter, Jerome I and Meigs, James B} } @article {9449, title = {Whole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles.}, journal = {medRxiv}, year = {2023}, month = {2023 Jun 12}, abstract = {

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

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

}, doi = {10.1101/2023.06.07.23291095}, author = {Huffman, Jennifer E and Nicolas, Jayna and Hahn, Julie and Heath, Adam S and Raffield, Laura M and Yanek, Lisa R and Brody, Jennifer A and Thibord, Florian and Almasy, Laura and Bartz, Traci M and Bielak, Lawrence F and Bowler, Russell P and Carrasquilla, Germ{\'a}n D and Chasman, Daniel I and Chen, Ming-Huei and Emmert, David B and Ghanbari, Mohsen and Haessle, Jeffery and Hottenga, Jouke-Jan and Kleber, Marcus E and Le, Ngoc-Quynh and Lee, Jiwon and Lewis, Joshua P and Li-Gao, Ruifang and Luan, Jian{\textquoteright}an and Malmberg, Anni and Mangino, Massimo and Marioni, Riccardo E and Martinez-Perez, Angel and Pankratz, Nathan and Polasek, Ozren and Richmond, Anne and Rodriguez, Benjamin At and Rotter, Jerome I and Steri, Maristella and Suchon, Pierre and Trompet, Stella and Weiss, Stefan and Zare, Marjan and Auer, Paul and Cho, Michael H and Christofidou, Paraskevi and Davies, Gail and de Geus, Eco and Deleuze, Jean-Francois and Delgado, Graciela E and Ekunwe, Lynette and Faraday, Nauder and G{\"o}gele, Martin and Greinacher, Andreas and He, Gao and Howard, Tom and Joshi, Peter K and Kilpel{\"a}inen, Tuomas O and Lahti, Jari and Linneberg, Allan and Naitza, Silvia and Noordam, Raymond and Pa{\"u}ls-Verg{\'e}s, Ferran and Rich, Stephen S and Rosendaal, Frits R and Rudan, Igor and Ryan, Kathleen A and Souto, Juan Carlos and van Rooij, Frank Ja and Wang, Heming and Zhao, Wei and Becker, Lewis C and Beswick, Andrew and Brown, Michael R and Cade, Brian E and Campbell, Harry and Cho, Kelly and Crapo, James D and Curran, Joanne E and de Maat, Moniek Pm and Doyle, Margaret and Elliott, Paul and Floyd, James S and Fuchsberger, Christian and Grarup, Niels and Guo, Xiuqing and Harris, Sarah E and Hou, Lifang and Kolcic, Ivana and Kooperberg, Charles and Menni, Cristina and Nauck, Matthias and O{\textquoteright}Connell, Jeffrey R and Orr{\`u}, Valeria and Psaty, Bruce M and R{\"a}ikk{\"o}nen, Katri and Smith, Jennifer A and Soria, Jos{\'e} Manuel and Stott, David J and van Hylckama Vlieg, Astrid and Watkins, Hugh and Willemsen, Gonneke and Wilson, Peter and Ben-Shlomo, Yoav and Blangero, John and Boomsma, Dorret and Cox, Simon R and Dehghan, Abbas and Eriksson, Johan G and Fiorillo, Edoardo and Fornage, Myriam and Hansen, Torben and Hayward, Caroline and Ikram, M Arfan and Jukema, J Wouter and Kardia, Sharon Lr and Lange, Leslie A and M{\"a}rz, Winfried and Mathias, Rasika A and Mitchell, Braxton D and Mook-Kanamori, Dennis O and Morange, Pierre-Emmanuel and Pedersen, Oluf and Pramstaller, Peter P and Redline, Susan and Reiner, Alexander and Ridker, Paul M and Silverman, Edwin K and Spector, Tim D and V{\"o}lker, Uwe and Wareham, Nick and Wilson, James F and Yao, Jie and Tr{\'e}gou{\"e}t, David-Alexandre and Johnson, Andrew D and Wolberg, Alisa S and de Vries, Paul S and Sabater-Lleal, Maria and Morrison, Alanna C and Smith, Nicholas L} } @article {9619, title = {Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.}, journal = {Nature}, year = {2024}, month = {2024 Feb 19}, abstract = {

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell type. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7\% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 {\texttimes} 10) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

}, issn = {1476-4687}, doi = {10.1038/s41586-024-07019-6}, author = {Suzuki, Ken and Hatzikotoulas, Konstantinos and Southam, Lorraine and Taylor, Henry J and Yin, Xianyong and Lorenz, Kim M and Mandla, Ravi and Huerta-Chagoya, Alicia and Melloni, Giorgio E M and Kanoni, Stavroula and Rayner, Nigel W and Bocher, Ozvan and Arruda, Ana Luiza and Sonehara, Kyuto and Namba, Shinichi and Lee, Simon S K and Preuss, Michael H and Petty, Lauren E and Schroeder, Philip and Vanderwerff, Brett and Kals, Mart and Bragg, Fiona and Lin, Kuang and Guo, Xiuqing and Zhang, Weihua and Yao, Jie and Kim, Young Jin and Graff, Mariaelisa and Takeuchi, Fumihiko and Nano, Jana and Lamri, Amel and Nakatochi, Masahiro and Moon, Sanghoon and Scott, Robert A and Cook, James P and Lee, Jung-Jin and Pan, Ian and Taliun, Daniel and Parra, Esteban J and Chai, Jin-Fang and Bielak, Lawrence F and Tabara, Yasuharu and Hai, Yang and Thorleifsson, Gudmar and Grarup, Niels and Sofer, Tamar and Wuttke, Matthias and Sarnowski, Chloe and Gieger, Christian and Nousome, Darryl and Trompet, Stella and Kwak, Soo-Heon and Long, Jirong and Sun, Meng and Tong, Lin and Chen, Wei-Min and Nongmaithem, Suraj S and Noordam, Raymond and Lim, Victor J Y and Tam, Claudia H T and Joo, Yoonjung Yoonie and Chen, Chien-Hsiun and Raffield, Laura M and Prins, Bram Peter and Nicolas, Aude and Yanek, Lisa R and Chen, Guanjie and Brody, Jennifer A and Kabagambe, Edmond and An, Ping and Xiang, Anny H and Choi, Hyeok Sun and Cade, Brian E and Tan, Jingyi and Broadaway, K Alaine and Williamson, Alice and Kamali, Zoha and Cui, Jinrui and Thangam, Manonanthini and Adair, Linda S and Adeyemo, Adebowale and Aguilar-Salinas, Carlos A and Ahluwalia, Tarunveer S and Anand, Sonia S and Bertoni, Alain and Bork-Jensen, Jette and Brandslund, Ivan and Buchanan, Thomas A and Burant, Charles F and Butterworth, Adam S and Canouil, Micka{\"e}l and Chan, Juliana C N and Chang, Li-Ching and Chee, Miao-Li and Chen, Ji and Chen, Shyh-Huei and Chen, Yuan-Tsong and Chen, Zhengming and Chuang, Lee-Ming and Cushman, Mary and Danesh, John and Das, Swapan K and de Silva, H Janaka and Dedoussis, George and Dimitrov, Latchezar and Doumatey, Ayo P and Du, Shufa and Duan, Qing and Eckardt, Kai-Uwe and Emery, Leslie S and Evans, Daniel S and Evans, Michele K and Fischer, Krista and Floyd, James S and Ford, Ian and Franco, Oscar H and Frayling, Timothy M and Freedman, Barry I and Genter, Pauline and Gerstein, Hertzel C and Giedraitis, Vilmantas and Gonz{\'a}lez-Villalpando, Clicerio and Gonzalez-Villalpando, Maria Elena and Gordon-Larsen, Penny and Gross, Myron and Guare, Lindsay A and Hackinger, Sophie and Hakaste, Liisa and Han, Sohee and Hattersley, Andrew T and Herder, Christian and Horikoshi, Momoko and Howard, Annie-Green and Hsueh, Willa and Huang, Mengna and Huang, Wei and Hung, Yi-Jen and Hwang, Mi Yeong and Hwu, Chii-Min and Ichihara, Sahoko and Ikram, Mohammad Arfan and Ingelsson, Martin and Islam, Md Tariqul and Isono, Masato and Jang, Hye-Mi and Jasmine, Farzana and Jiang, Guozhi and Jonas, Jost B and J{\o}rgensen, Torben and Kamanu, Frederick K and Kandeel, Fouad R and Kasturiratne, Anuradhani and Katsuya, Tomohiro and Kaur, Varinderpal and Kawaguchi, Takahisa and Keaton, Jacob M and Kho, Abel N and Khor, Chiea-Chuen and Kibriya, Muhammad G and Kim, Duk-Hwan and Kronenberg, Florian and Kuusisto, Johanna and L{\"a}ll, Kristi and Lange, Leslie A and Lee, Kyung Min and Lee, Myung-Shik and Lee, Nanette R and Leong, Aaron and Li, Liming and Li, Yun and Li-Gao, Ruifang and Ligthart, Symen and Lindgren, Cecilia M and Linneberg, Allan and Liu, Ching-Ti and Liu, Jianjun and Locke, Adam E and Louie, Tin and Luan, Jian{\textquoteright}an and Luk, Andrea O and Luo, Xi and Lv, Jun and Lynch, Julie A and Lyssenko, Valeriya and Maeda, Shiro and Mamakou, Vasiliki and Mansuri, Sohail Rafik and Matsuda, Koichi and Meitinger, Thomas and Melander, Olle and Metspalu, Andres and Mo, Huan and Morris, Andrew D and Moura, Filipe A and Nadler, Jerry L and Nalls, Michael A and Nayak, Uma and Ntalla, Ioanna and Okada, Yukinori and Orozco, Lorena and Patel, Sanjay R and Patil, Snehal and Pei, Pei and Pereira, Mark A and Peters, Annette and Pirie, Fraser J and Polikowsky, Hannah G and Porneala, Bianca and Prasad, Gauri and Rasmussen-Torvik, Laura J and Reiner, Alexander P and Roden, Michael and Rohde, Rebecca and Roll, Katheryn and Sabanayagam, Charumathi and Sandow, Kevin and Sankareswaran, Alagu and Sattar, Naveed and Sch{\"o}nherr, Sebastian and Shahriar, Mohammad and Shen, Botong and Shi, Jinxiu and Shin, Dong Mun and Shojima, Nobuhiro and Smith, Jennifer A and So, Wing Yee and Stan{\v c}{\'a}kov{\'a}, Alena and Steinthorsdottir, Valgerdur and Stilp, Adrienne M and Strauch, Konstantin and Taylor, Kent D and Thorand, Barbara and Thorsteinsdottir, Unnur and Tomlinson, Brian and Tran, Tam C and Tsai, Fuu-Jen and Tuomilehto, Jaakko and Tusi{\'e}-Luna, Teresa and Udler, Miriam S and Valladares-Salgado, Adan and van Dam, Rob M and van Klinken, Jan B and Varma, Rohit and Wacher-Rodarte, Niels and Wheeler, Eleanor and Wickremasinghe, Ananda R and van Dijk, Ko Willems and Witte, Daniel R and Yajnik, Chittaranjan S and Yamamoto, Ken and Yamamoto, Kenichi and Yoon, Kyungheon and Yu, Canqing and Yuan, Jian-Min and Yusuf, Salim and Zawistowski, Matthew and Zhang, Liang and Zheng, Wei and Raffel, Leslie J and Igase, Michiya and Ipp, Eli and Redline, Susan and Cho, Yoon Shin and Lind, Lars and Province, Michael A and Fornage, Myriam and Hanis, Craig L and Ingelsson, Erik and Zonderman, Alan B and Psaty, Bruce M and Wang, Ya-Xing and Rotimi, Charles N and Becker, Diane M and Matsuda, Fumihiko and Liu, Yongmei and Yokota, Mitsuhiro and Kardia, Sharon L R and Peyser, Patricia A and Pankow, James S and Engert, James C and Bonnefond, Am{\'e}lie and Froguel, Philippe and Wilson, James G and Sheu, Wayne H H and Wu, Jer-Yuarn and Hayes, M Geoffrey and Ma, Ronald C W and Wong, Tien-Yin and Mook-Kanamori, Dennis O and Tuomi, Tiinamaija and Chandak, Giriraj R and Collins, Francis S and Bharadwaj, Dwaipayan and Par{\'e}, Guillaume and Sale, Mich{\`e}le M and Ahsan, Habibul and Motala, Ayesha A and Shu, Xiao-Ou and Park, Kyong-Soo and Jukema, J Wouter and Cruz, Miguel and Chen, Yii-Der Ida and Rich, Stephen S and McKean-Cowdin, Roberta and Grallert, Harald and Cheng, Ching-Yu and Ghanbari, Mohsen and Tai, E-Shyong and Dupuis, Jos{\'e}e and Kato, Norihiro and Laakso, Markku and K{\"o}ttgen, Anna and Koh, Woon-Puay and Bowden, Donald W and Palmer, Colin N A and Kooner, Jaspal S and Kooperberg, Charles and Liu, Simin and North, Kari E and Saleheen, Danish and Hansen, Torben and Pedersen, Oluf and Wareham, Nicholas J and Lee, Juyoung and Kim, Bong-Jo and Millwood, Iona Y and Walters, Robin G and Stefansson, Kari and Ahlqvist, Emma and Goodarzi, Mark O and Mohlke, Karen L and Langenberg, Claudia and Haiman, Christopher A and Loos, Ruth J F and Florez, Jose C and Rader, Daniel J and Ritchie, Marylyn D and Z{\"o}llner, Sebastian and M{\"a}gi, Reedik and Marston, Nicholas A and Ruff, Christian T and van Heel, David A and Finer, Sarah and Denny, Joshua C and Yamauchi, Toshimasa and Kadowaki, Takashi and Chambers, John C and Ng, Maggie C Y and Sim, Xueling and Below, Jennifer E and Tsao, Philip S and Chang, Kyong-Mi and McCarthy, Mark I and Meigs, James B and Mahajan, Anubha and Spracklen, Cassandra N and Mercader, Josep M and Boehnke, Michael and Rotter, Jerome I and Vujkovic, Marijana and Voight, Benjamin F and Morris, Andrew P and Zeggini, Eleftheria} } @article {9642, title = {A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.}, journal = {medRxiv}, year = {2024}, month = {2024 Mar 08}, abstract = {

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to genes involved in neurological, thyroidal, bone metabolism, and hematopoietic pathways. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausibility of distinct influences of both sleep duration extremes in cardiovascular health. With several of our loci reflecting specificity towards population background or sex, our discovery sheds light on the importance of embracing granularity when addressing heterogeneity entangled in gene-environment interactions, and in therapeutic design approaches for blood pressure management.

}, doi = {10.1101/2024.03.07.24303870}, author = {Nagarajan, Pavithra and Winkler, Thomas W and Bentley, Amy R and Miller, Clint L and Kraja, Aldi T and Schwander, Karen and Lee, Songmi and Wang, Wenyi and Brown, Michael R and Morrison, John L and Giri, Ayush and O{\textquoteright}Connell, Jeffrey R and Bartz, Traci M and de Las Fuentes, Lisa and Gudmundsdottir, Valborg and Guo, Xiuqing and Harris, Sarah E and Huang, Zhijie and Kals, Mart and Kho, Minjung and Lefevre, Christophe and Luan, Jian{\textquoteright}an and Lyytik{\"a}inen, Leo-Pekka and Mangino, Massimo and Milaneschi, Yuri and Palmer, Nicholette D and Rao, Varun and Rauramaa, Rainer and Shen, Botong and Stadler, Stefan and Sun, Quan and Tang, Jingxian and Th{\'e}riault, S{\'e}bastien and van der Graaf, Adriaan and van der Most, Peter J and Wang, Yujie and Weiss, Stefan and Westerman, Kenneth E and Yang, Qian and Yasuharu, Tabara and Zhao, Wei and Zhu, Wanying and Altschul, Drew and Ansari, Md Abu Yusuf and Anugu, Pramod and Argoty-Pantoja, Anna D and Arzt, Michael and Aschard, Hugues and Attia, John R and Bazzanno, Lydia and Breyer, Max A and Brody, Jennifer A and Cade, Brian E and Chen, Hung-Hsin and Ida Chen, Yii-Der and Chen, Zekai and de Vries, Paul S and Dimitrov, Latchezar M and Do, Anh and Du, Jiawen and Dupont, Charles T and Edwards, Todd L and Evans, Michele K and Faquih, Tariq and Felix, Stephan B and Fisher-Hoch, Susan P and Floyd, James S and Graff, Mariaelisa and Gu, Charles and Gu, Dongfeng and Hairston, Kristen G and Hanley, Anthony J and Heid, Iris M and Heikkinen, Sami and Highland, Heather M and Hood, Michelle M and K{\"a}h{\"o}nen, Mika and Karvonen-Gutierrez, Carrie A and Kawaguchi, Takahisa and Kazuya, Setoh and Kelly, Tanika N and Komulainen, Pirjo and Levy, Daniel and Lin, Henry J and Liu, Peter Y and Marques-Vidal, Pedro and McCormick, Joseph B and Mei, Hao and Meigs, James B and Menni, Cristina and Nam, Kisung and Nolte, Ilja M and Pacheco, Natasha L and Petty, Lauren E and Polikowsky, Hannah G and Province, Michael A and Psaty, Bruce M and Raffield, Laura M and Raitakari, Olli T and Rich, Stephen S and Riha, Renata L and Risch, Lorenz and Risch, Martin and Ruiz-Narvaez, Edward A and Scott, Rodney J and Sitlani, Colleen M and Smith, Jennifer A and Sofer, Tamar and Teder-Laving, Maris and V{\"o}lker, Uwe and Vollenweider, Peter and Wang, Guanchao and van Dijk, Ko Willems and Wilson, Otis D and Xia, Rui and Yao, Jie and Young, Kristin L and Zhang, Ruiyuan and Zhu, Xiaofeng and Below, Jennifer E and B{\"o}ger, Carsten A and Conen, David and Cox, Simon R and D{\"o}rr, Marcus and Feitosa, Mary F and Fox, Ervin R and Franceschini, Nora and Gharib, Sina A and Gudnason, Vilmundur and Harlow, Sioban D and He, Jiang and Holliday, Elizabeth G and Kutalik, Zolt{\'a}n and Lakka, Timo A and Lawlor, Deborah A and Lee, Seunggeun and Lehtim{\"a}ki, Terho and Li, Changwei and Liu, Ching-Ti and M{\"a}gi, Reedik and Matsuda, Fumihiko and Morrison, Alanna C and Penninx, Brenda Wjh and Peyser, Patricia A and Rotter, Jerome I and Snieder, Harold and Spector, Tim D and Wagenknecht, Lynne E and Wareham, Nicholas J and Zonderman, Alan B and North, Kari E and Fornage, Myriam and Hung, Adriana M and Manning, Alisa K and Gauderman, James and Chen, Han and Munroe, Patricia B and Rao, Dabeeru C and van Heemst, Diana and Redline, Susan and Noordam, Raymond and Wang, Heming} }