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.

VL - 48 IS - 10 ER - TY - JOUR T1 - Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis. JF - Circ Cardiovasc Genet Y1 - 2016 A1 - Natarajan, Pradeep A1 - Bis, Joshua C A1 - Bielak, Lawrence F A1 - Cox, Amanda J A1 - Dörr, Marcus A1 - Feitosa, Mary F A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Hwang, Shih-Jen A1 - Isaacs, Aaron A1 - Jhun, Min A A1 - Kavousi, Maryam A1 - Li-Gao, Ruifang A1 - Lyytikäinen, Leo-Pekka A1 - Marioni, Riccardo E A1 - Schminke, Ulf A1 - Stitziel, Nathan O A1 - Tada, Hayato A1 - van Setten, Jessica A1 - Smith, Albert V A1 - Vojinovic, Dina A1 - Yanek, Lisa R A1 - Yao, Jie A1 - Yerges-Armstrong, Laura M A1 - Amin, Najaf A1 - Baber, Usman A1 - Borecki, Ingrid B A1 - Carr, J Jeffrey A1 - Chen, Yii-Der Ida A1 - Cupples, L Adrienne A1 - de Jong, Pim A A1 - de Koning, Harry A1 - de Vos, Bob D A1 - Demirkan, Ayse A1 - Fuster, Valentin A1 - Franco, Oscar H A1 - Goodarzi, Mark O A1 - Harris, Tamara B A1 - Heckbert, Susan R A1 - Heiss, Gerardo A1 - Hoffmann, Udo A1 - Hofman, Albert A1 - Išgum, Ivana A1 - Jukema, J Wouter A1 - Kähönen, Mika A1 - Kardia, Sharon L R A1 - Kral, Brian G A1 - Launer, Lenore J A1 - Massaro, Joseph A1 - Mehran, Roxana A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - de Mutsert, Renée A1 - Newman, Anne B A1 - Nguyen, Khanh-Dung A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Oudkerk, Matthijs A1 - Pankow, James S A1 - Peloso, Gina M A1 - Post, Wendy A1 - Province, Michael A A1 - Raffield, Laura M A1 - Raitakari, Olli T A1 - Reilly, Dermot F A1 - Rivadeneira, Fernando A1 - Rosendaal, Frits A1 - Sartori, Samantha A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Trompet, Stella A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - Vaidya, Dhananjay A1 - van der Lugt, Aad A1 - Völker, Uwe A1 - Wardlaw, Joanna M A1 - Wassel, Christina L A1 - Weiss, Stefan A1 - Wojczynski, Mary K A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Boerwinkle, Eric A1 - Bowden, Donald W A1 - Deary, Ian J A1 - Dehghan, Abbas A1 - Felix, Stephan B A1 - Gudnason, Vilmundur A1 - Lehtimäki, Terho A1 - Mathias, Rasika A1 - Mook-Kanamori, Dennis O A1 - Psaty, Bruce M A1 - Rader, Daniel J A1 - Rotter, Jerome I A1 - Wilson, James G A1 - van Duijn, Cornelia M A1 - Völzke, Henry A1 - Kathiresan, Sekar A1 - Peyser, Patricia A A1 - O'Donnell, Christopher J AB -**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 = 3×10(-10)). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P = 1×10(-12)) and 1.4% reduced CIMT (P = 4×10(-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 = 1×10(-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.

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.

ER - TY - JOUR T1 - Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. JF - Nat Genet Y1 - 2017 A1 - Christophersen, Ingrid E A1 - Rienstra, Michiel A1 - Roselli, Carolina A1 - Yin, Xiaoyan A1 - Geelhoed, Bastiaan A1 - Barnard, John A1 - Lin, Honghuang A1 - Arking, Dan E A1 - Smith, Albert V A1 - Albert, Christine M A1 - Chaffin, Mark A1 - Tucker, Nathan R A1 - Li, Molong A1 - Klarin, Derek A1 - Bihlmeyer, Nathan A A1 - Low, Siew-Kee A1 - Weeke, Peter E A1 - Müller-Nurasyid, Martina A1 - Smith, J Gustav A1 - Brody, Jennifer A A1 - Niemeijer, Maartje N A1 - Dörr, Marcus A1 - Trompet, Stella A1 - Huffman, Jennifer A1 - Gustafsson, Stefan A1 - Schurmann, Claudia A1 - Kleber, Marcus E A1 - Lyytikäinen, Leo-Pekka A1 - Seppälä, Ilkka A1 - Malik, Rainer A1 - Horimoto, Andrea R V R A1 - Perez, Marco A1 - Sinisalo, Juha A1 - Aeschbacher, Stefanie A1 - Thériault, Sébastien A1 - Yao, Jie A1 - Radmanesh, Farid A1 - Weiss, Stefan A1 - Teumer, Alexander A1 - Choi, Seung Hoan A1 - Weng, Lu-Chen A1 - Clauss, Sebastian A1 - Deo, Rajat A1 - Rader, Daniel J A1 - Shah, Svati H A1 - Sun, Albert A1 - Hopewell, Jemma C A1 - Debette, Stephanie A1 - Chauhan, Ganesh A1 - Yang, Qiong A1 - Worrall, Bradford B A1 - Paré, Guillaume A1 - Kamatani, Yoichiro A1 - Hagemeijer, Yanick P A1 - Verweij, Niek A1 - Siland, Joylene E A1 - Kubo, Michiaki A1 - Smith, Jonathan D A1 - Van Wagoner, David R A1 - Bis, Joshua C A1 - Perz, Siegfried A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Magnani, Jared W A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Shoemaker, M Benjamin A1 - Padmanabhan, Sandosh A1 - Haessler, Jeffrey A1 - Bartz, Traci M A1 - Waldenberger, Melanie A1 - Lichtner, Peter A1 - Arendt, Marina A1 - Krieger, Jose E A1 - Kähönen, Mika A1 - Risch, Lorenz A1 - Mansur, Alfredo J A1 - Peters, Annette A1 - Smith, Blair H A1 - Lind, Lars A1 - Scott, Stuart A A1 - Lu, Yingchang A1 - Bottinger, Erwin B A1 - Hernesniemi, Jussi A1 - Lindgren, Cecilia M A1 - Wong, Jorge A A1 - Huang, Jie A1 - Eskola, Markku A1 - Morris, Andrew P A1 - Ford, Ian A1 - Reiner, Alex P A1 - Delgado, Graciela A1 - Chen, Lin Y A1 - Chen, Yii-Der Ida A1 - Sandhu, Roopinder K A1 - Li, Man A1 - Boerwinkle, Eric A1 - Eisele, Lewin A1 - Lannfelt, Lars A1 - Rost, Natalia A1 - Anderson, Christopher D A1 - Taylor, Kent D A1 - Campbell, Archie A1 - Magnusson, Patrik K A1 - Porteous, David A1 - Hocking, Lynne J A1 - Vlachopoulou, Efthymia A1 - Pedersen, Nancy L A1 - Nikus, Kjell A1 - Orho-Melander, Marju A1 - Hamsten, Anders A1 - Heeringa, Jan A1 - Denny, Joshua C A1 - Kriebel, Jennifer A1 - Darbar, Dawood A1 - Newton-Cheh, Christopher A1 - Shaffer, Christian A1 - Macfarlane, Peter W A1 - Heilmann-Heimbach, Stefanie A1 - Almgren, Peter A1 - Huang, Paul L A1 - Sotoodehnia, Nona A1 - Soliman, Elsayed Z A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Franco, Oscar H A1 - Völker, Uwe A1 - Jöckel, Karl-Heinz A1 - Sinner, Moritz F A1 - Lin, Henry J A1 - Guo, Xiuqing A1 - Dichgans, Martin A1 - Ingelsson, Erik A1 - Kooperberg, Charles A1 - Melander, Olle A1 - Loos, Ruth J F A1 - Laurikka, Jari A1 - Conen, David A1 - Rosand, Jonathan A1 - van der Harst, Pim A1 - Lokki, Marja-Liisa A1 - Kathiresan, Sekar A1 - Pereira, Alexandre A1 - Jukema, J Wouter A1 - Hayward, Caroline A1 - Rotter, Jerome I A1 - März, Winfried A1 - Lehtimäki, Terho A1 - Stricker, Bruno H A1 - Chung, Mina K A1 - Felix, Stephan B A1 - Gudnason, Vilmundur A1 - Alonso, Alvaro A1 - Roden, Dan M A1 - Kääb, Stefan A1 - Chasman, Daniel I A1 - Heckbert, Susan R A1 - Benjamin, Emelia J A1 - Tanaka, Toshihiro A1 - Lunetta, Kathryn L A1 - Lubitz, Steven A A1 - Ellinor, Patrick T AB -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.

VL - 49 IS - 6 ER - TY - JOUR T1 - New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals. JF - Circ Cardiovasc Genet Y1 - 2017 A1 - Kraja, Aldi T A1 - Cook, James P A1 - Warren, Helen R A1 - Surendran, Praveen A1 - Liu, Chunyu A1 - Evangelou, Evangelos A1 - Manning, Alisa K A1 - Grarup, Niels A1 - Drenos, Fotios A1 - Sim, Xueling A1 - Smith, Albert Vernon A1 - Amin, Najaf A1 - Blakemore, Alexandra I F A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Farmaki, Aliki-Eleni A1 - Fava, Cristiano A1 - Ferreira, Teresa A1 - Herzig, Karl-Heinz A1 - Giri, Ayush A1 - Giulianini, Franco A1 - Grove, Megan L A1 - Guo, Xiuqing A1 - Harris, Sarah E A1 - Have, Christian T A1 - Havulinna, Aki S A1 - Zhang, He A1 - Jørgensen, Marit E A1 - Käräjämäki, AnneMari A1 - Kooperberg, Charles A1 - Linneberg, Allan A1 - Little, Louis A1 - Liu, Yongmei A1 - Bonnycastle, Lori L A1 - Lu, Yingchang A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Malerba, Giovanni A1 - Marioni, Riccardo E A1 - Mei, Hao A1 - Menni, Cristina A1 - Morrison, Alanna C A1 - Padmanabhan, Sandosh A1 - Palmas, Walter A1 - Poveda, Alaitz A1 - Rauramaa, Rainer A1 - Rayner, Nigel William A1 - Riaz, Muhammad A1 - Rice, Ken A1 - Richard, Melissa A A1 - Smith, Jennifer A A1 - Southam, Lorraine A1 - Stančáková, Alena A1 - Stirrups, Kathleen E A1 - Tragante, Vinicius A1 - Tuomi, Tiinamaija A1 - Tzoulaki, Ioanna A1 - Varga, Tibor V A1 - Weiss, Stefan A1 - Yiorkas, Andrianos M A1 - Young, Robin A1 - Zhang, Weihua A1 - Barnes, Michael R A1 - Cabrera, Claudia P A1 - Gao, He A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Chambers, John C A1 - Connell, John M A1 - Christensen, Cramer K A1 - de Boer, Rudolf A A1 - Deary, Ian J A1 - Dedoussis, George A1 - Deloukas, Panos A1 - Dominiczak, Anna F A1 - Dörr, Marcus A1 - Joehanes, Roby A1 - Edwards, Todd L A1 - Esko, Tõnu A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Franks, Paul W A1 - Gambaro, Giovanni A1 - Groop, Leif A1 - Hallmans, Göran A1 - Hansen, Torben A1 - Hayward, Caroline A1 - Heikki, Oksa A1 - Ingelsson, Erik A1 - Tuomilehto, Jaakko A1 - Jarvelin, Marjo-Riitta A1 - Kardia, Sharon L R A1 - Karpe, Fredrik A1 - Kooner, Jaspal S A1 - Lakka, Timo A A1 - Langenberg, Claudia A1 - Lind, Lars A1 - Loos, Ruth J F A1 - Laakso, Markku A1 - McCarthy, Mark I A1 - Melander, Olle A1 - Mohlke, Karen L A1 - Morris, Andrew P A1 - Palmer, Colin N A A1 - Pedersen, Oluf A1 - Polasek, Ozren A1 - Poulter, Neil R A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Sever, Peter J A1 - Skaaby, Tea A1 - Stafford, Jeanette M A1 - Starr, John M A1 - van der Harst, Pim A1 - van der Meer, Peter A1 - van Duijn, Cornelia M A1 - Vergnaud, Anne-Claire A1 - Gudnason, Vilmundur A1 - Wareham, Nicholas J A1 - Wilson, James G A1 - Willer, Cristen J A1 - Witte, Daniel R A1 - Zeggini, Eleftheria A1 - Saleheen, Danish A1 - Butterworth, Adam S A1 - Danesh, John A1 - Asselbergs, Folkert W A1 - Wain, Louise V A1 - Ehret, Georg B A1 - Chasman, Daniel I A1 - Caulfield, Mark J A1 - Elliott, Paul A1 - Lindgren, Cecilia M A1 - Levy, Daniel A1 - Newton-Cheh, Christopher A1 - Munroe, Patricia B A1 - Howson, Joanna M M AB -**BACKGROUND: **Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.

**METHODS AND RESULTS: **Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.

**CONCLUSIONS: **We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

**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 (<1.2×10), 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 (=5.9×10) and (=1.1×10) 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.

**BACKGROUND: **Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear.

**RESULTS: **Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction.

**CONCLUSIONS: **Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.

**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.

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 × 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 × 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).

VL - 102 IS - 3 ER - TY - JOUR T1 - Meta-analysis of exome array data identifies six novel genetic loci for lung function. JF - Wellcome Open Res Y1 - 2018 A1 - Jackson, Victoria E A1 - Latourelle, Jeanne C A1 - Wain, Louise V A1 - Smith, Albert V A1 - Grove, Megan L A1 - Bartz, Traci M A1 - Obeidat, Ma'en A1 - Province, Michael A A1 - Gao, Wei A1 - Qaiser, Beenish A1 - Porteous, David J A1 - Cassano, Patricia A A1 - Ahluwalia, Tarunveer S A1 - Grarup, Niels A1 - Li, Jin A1 - Altmaier, Elisabeth A1 - Marten, Jonathan A1 - Harris, Sarah E A1 - Manichaikul, Ani A1 - Pottinger, Tess D A1 - Li-Gao, Ruifang A1 - Lind-Thomsen, Allan A1 - Mahajan, Anubha A1 - Lahousse, Lies A1 - Imboden, Medea A1 - Teumer, Alexander A1 - Prins, Bram A1 - Lyytikäinen, Leo-Pekka A1 - Eiriksdottir, Gudny A1 - Franceschini, Nora A1 - Sitlani, Colleen M A1 - Brody, Jennifer A A1 - Bossé, Yohan A1 - Timens, Wim A1 - Kraja, Aldi A1 - Loukola, Anu A1 - Tang, Wenbo A1 - Liu, Yongmei A1 - Bork-Jensen, Jette A1 - Justesen, Johanne M A1 - Linneberg, Allan A1 - Lange, Leslie A A1 - Rawal, Rajesh A1 - Karrasch, Stefan A1 - Huffman, Jennifer E A1 - Smith, Blair H A1 - Davies, Gail A1 - Burkart, Kristin M A1 - Mychaleckyj, Josyf C A1 - Bonten, Tobias N A1 - Enroth, Stefan A1 - Lind, Lars A1 - Brusselle, Guy G A1 - Kumar, Ashish A1 - Stubbe, Beate A1 - Kähönen, Mika A1 - Wyss, Annah B A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Hao, Ke A1 - Rantanen, Taina A1 - Kritchevsky, Stephen B A1 - Lohman, Kurt A1 - Skaaby, Tea A1 - Pisinger, Charlotta A1 - Hansen, Torben A1 - Schulz, Holger A1 - Polasek, Ozren A1 - Campbell, Archie A1 - Starr, John M A1 - Rich, Stephen S A1 - Mook-Kanamori, Dennis O A1 - Johansson, Asa A1 - Ingelsson, Erik A1 - Uitterlinden, André G A1 - Weiss, Stefan A1 - Raitakari, Olli T A1 - Gudnason, Vilmundur A1 - North, Kari E A1 - Gharib, Sina A A1 - Sin, Don D A1 - Taylor, Kent D A1 - O'Connor, George T A1 - Kaprio, Jaakko A1 - Harris, Tamara B A1 - Pederson, Oluf A1 - Vestergaard, Henrik A1 - Wilson, James G A1 - Strauch, Konstantin A1 - Hayward, Caroline A1 - Kerr, Shona A1 - Deary, Ian J A1 - Barr, R Graham A1 - de Mutsert, Renée A1 - Gyllensten, Ulf A1 - Morris, Andrew P A1 - Ikram, M Arfan A1 - Probst-Hensch, Nicole A1 - Gläser, Sven A1 - Zeggini, Eleftheria A1 - Lehtimäki, Terho A1 - Strachan, David P A1 - Dupuis, Josée A1 - Morrison, Alanna C A1 - Hall, Ian P A1 - Tobin, Martin D A1 - London, Stephanie J AB -Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV ), forced vital capacity (FVC) and the ratio of FEV to FVC (FEV /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. We identified significant (P<2·8x10 ) associations with six SNPs: a nonsynonymous variant in , which is predicted to be damaging, three intronic SNPs ( and ) and two intergenic SNPs near to and Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including and . Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

VL - 3 ER - TY - JOUR T1 - Multi-ethnic genome-wide association study for atrial fibrillation. JF - Nat Genet Y1 - 2018 A1 - Roselli, Carolina A1 - Chaffin, Mark D A1 - Weng, Lu-Chen A1 - Aeschbacher, Stefanie A1 - Ahlberg, Gustav A1 - Albert, Christine M A1 - Almgren, Peter A1 - Alonso, Alvaro A1 - Anderson, Christopher D A1 - Aragam, Krishna G A1 - Arking, Dan E A1 - Barnard, John A1 - Bartz, Traci M A1 - Benjamin, Emelia J A1 - Bihlmeyer, Nathan A A1 - Bis, Joshua C A1 - Bloom, Heather L A1 - Boerwinkle, Eric A1 - Bottinger, Erwin B A1 - Brody, Jennifer A A1 - Calkins, Hugh A1 - Campbell, Archie A1 - Cappola, Thomas P A1 - Carlquist, John A1 - Chasman, Daniel I A1 - Chen, Lin Y A1 - Chen, Yii-Der Ida A1 - Choi, Eue-Keun A1 - Choi, Seung Hoan A1 - Christophersen, Ingrid E A1 - Chung, Mina K A1 - Cole, John W A1 - Conen, David A1 - Cook, James A1 - Crijns, Harry J A1 - Cutler, Michael J A1 - Damrauer, Scott M A1 - Daniels, Brian R A1 - Darbar, Dawood A1 - Delgado, Graciela A1 - Denny, Joshua C A1 - Dichgans, Martin A1 - Dörr, Marcus A1 - Dudink, Elton A A1 - Dudley, Samuel C A1 - Esa, Nada A1 - Esko, Tõnu A1 - Eskola, Markku A1 - Fatkin, Diane A1 - Felix, Stephan B A1 - Ford, Ian A1 - Franco, Oscar H A1 - Geelhoed, Bastiaan A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Guo, Xiuqing A1 - Gupta, Namrata A1 - Gustafsson, Stefan A1 - Gutmann, Rebecca A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Heckbert, Susan R A1 - Hernesniemi, Jussi A1 - Hocking, Lynne J A1 - Hofman, Albert A1 - Horimoto, Andrea R V R A1 - Huang, Jie A1 - Huang, Paul L A1 - Huffman, Jennifer A1 - Ingelsson, Erik A1 - Ipek, Esra Gucuk A1 - Ito, Kaoru A1 - Jimenez-Conde, Jordi A1 - Johnson, Renee A1 - Jukema, J Wouter A1 - Kääb, Stefan A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kane, John P A1 - Kastrati, Adnan A1 - Kathiresan, Sekar A1 - Katschnig-Winter, Petra A1 - Kavousi, Maryam A1 - Kessler, Thorsten A1 - Kietselaer, Bas L A1 - Kirchhof, Paulus A1 - Kleber, Marcus E A1 - Knight, Stacey A1 - Krieger, Jose E A1 - Kubo, Michiaki A1 - Launer, Lenore J A1 - Laurikka, Jari A1 - Lehtimäki, Terho A1 - Leineweber, Kirsten A1 - Lemaitre, Rozenn N A1 - Li, Man A1 - Lim, Hong Euy A1 - Lin, Henry J A1 - Lin, Honghuang A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Lokki, Marja-Liisa A1 - London, Barry A1 - Loos, Ruth J F A1 - Low, Siew-Kee A1 - Lu, Yingchang A1 - Lyytikäinen, Leo-Pekka A1 - Macfarlane, Peter W A1 - Magnusson, Patrik K A1 - Mahajan, Anubha A1 - Malik, Rainer A1 - Mansur, Alfredo J A1 - Marcus, Gregory M A1 - Margolin, Lauren A1 - Margulies, Kenneth B A1 - März, Winfried A1 - McManus, David D A1 - Melander, Olle A1 - Mohanty, Sanghamitra A1 - Montgomery, Jay A A1 - Morley, Michael P A1 - Morris, Andrew P A1 - Müller-Nurasyid, Martina A1 - Natale, Andrea A1 - Nazarian, Saman A1 - Neumann, Benjamin A1 - Newton-Cheh, Christopher A1 - Niemeijer, Maartje N A1 - Nikus, Kjell A1 - Nilsson, Peter A1 - Noordam, Raymond A1 - Oellers, Heidi A1 - Olesen, Morten S A1 - Orho-Melander, Marju A1 - Padmanabhan, Sandosh A1 - Pak, Hui-Nam A1 - Paré, Guillaume A1 - Pedersen, Nancy L A1 - Pera, Joanna A1 - Pereira, Alexandre A1 - Porteous, David A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Pullinger, Clive R A1 - Rader, Daniel J A1 - Refsgaard, Lena A1 - Ribasés, Marta A1 - Ridker, Paul M A1 - Rienstra, Michiel A1 - Risch, Lorenz A1 - Roden, Dan M A1 - Rosand, Jonathan A1 - Rosenberg, Michael A A1 - Rost, Natalia A1 - Rotter, Jerome I A1 - Saba, Samir A1 - Sandhu, Roopinder K A1 - Schnabel, Renate B A1 - Schramm, Katharina A1 - Schunkert, Heribert A1 - Schurman, Claudia A1 - Scott, Stuart A A1 - Seppälä, Ilkka A1 - Shaffer, Christian A1 - Shah, Svati A1 - Shalaby, Alaa A A1 - Shim, Jaemin A1 - Shoemaker, M Benjamin A1 - Siland, Joylene E A1 - Sinisalo, Juha A1 - Sinner, Moritz F A1 - Slowik, Agnieszka A1 - Smith, Albert V A1 - Smith, Blair H A1 - Smith, J Gustav A1 - Smith, Jonathan D A1 - Smith, Nicholas L A1 - Soliman, Elsayed Z A1 - Sotoodehnia, Nona A1 - Stricker, Bruno H A1 - Sun, Albert A1 - Sun, Han A1 - Svendsen, Jesper H A1 - Tanaka, Toshihiro A1 - Tanriverdi, Kahraman A1 - Taylor, Kent D A1 - Teder-Laving, Maris A1 - Teumer, Alexander A1 - Thériault, Sébastien A1 - Trompet, Stella A1 - Tucker, Nathan R A1 - Tveit, Arnljot A1 - Uitterlinden, André G A1 - van der Harst, Pim A1 - Van Gelder, Isabelle C A1 - Van Wagoner, David R A1 - Verweij, Niek A1 - Vlachopoulou, Efthymia A1 - Völker, Uwe A1 - Wang, Biqi A1 - Weeke, Peter E A1 - Weijs, Bob A1 - Weiss, Raul A1 - Weiss, Stefan A1 - Wells, Quinn S A1 - Wiggins, Kerri L A1 - Wong, Jorge A A1 - Woo, Daniel A1 - Worrall, Bradford B A1 - Yang, Pil-Sung A1 - Yao, Jie A1 - Yoneda, Zachary T A1 - Zeller, Tanja A1 - Zeng, Lingyao A1 - Lubitz, Steven A A1 - Lunetta, Kathryn L A1 - Ellinor, Patrick T AB -Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

VL - 50 IS - 9 ER - TY - JOUR T1 - Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries. JF - PLoS One Y1 - 2018 A1 - Feitosa, Mary F A1 - Kraja, Aldi T A1 - Chasman, Daniel I A1 - Sung, Yun J A1 - Winkler, Thomas W A1 - Ntalla, Ioanna A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Li, Changwei A1 - Bentley, Amy R A1 - Brown, Michael R A1 - Schwander, Karen A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Dorajoo, Rajkumar A1 - Fisher, Virginia A1 - Hartwig, Fernando P A1 - Horimoto, Andrea R V R A1 - Lohman, Kurt K A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Wojczynski, Mary K A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Cai, Qiuyin A1 - Campbell, Archie A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Gao, Chuan A1 - Goel, Anuj A1 - Hagemeijer, Yanick A1 - Harris, Sarah E A1 - He, Meian A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Kähönen, Mika A1 - Kasturiratne, Anuradhani A1 - Komulainen, Pirjo A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Luan, Jian'an A1 - Matoba, Nana A1 - Nolte, Ilja M A1 - Padmanabhan, Sandosh A1 - Riaz, Muhammad A1 - Rueedi, Rico A1 - Robino, Antonietta A1 - Said, M Abdullah A1 - Scott, Robert A A1 - Sofer, Tamar A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Vitart, Veronique A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Warren, Helen R A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Afaq, Saima A1 - Amin, Najaf A1 - Amini, Marzyeh A1 - Arking, Dan E A1 - Aung, Tin A1 - Boerwinkle, Eric A1 - Borecki, Ingrid A1 - Broeckel, Ulrich A1 - Brown, Morris A1 - Brumat, Marco A1 - Burke, Gregory L A1 - Canouil, Mickaël A1 - Chakravarti, Aravinda A1 - Charumathi, Sabanayagam A1 - Ida Chen, Yii-Der A1 - Connell, John M A1 - Correa, Adolfo A1 - de Las Fuentes, Lisa A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - Deng, Xuan A1 - Ding, Jingzhong A1 - Duan, Qing A1 - Eaton, Charles B A1 - Ehret, Georg A1 - Eppinga, Ruben N A1 - Evangelou, Evangelos A1 - Faul, Jessica D A1 - Felix, Stephan B A1 - Forouhi, Nita G A1 - Forrester, Terrence A1 - Franco, Oscar H A1 - Friedlander, Yechiel A1 - Gandin, Ilaria A1 - Gao, He A1 - Ghanbari, Mohsen A1 - Gigante, Bruna A1 - Gu, C Charles A1 - Gu, Dongfeng A1 - Hagenaars, Saskia P A1 - Hallmans, Göran A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Howard, Barbara V A1 - Ikram, M Arfan A1 - John, Ulrich A1 - Katsuya, Tomohiro A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Krieger, Jose E A1 - Kritchevsky, Stephen B A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lewis, Cora E A1 - Li, Yize A1 - Lin, Shiow A1 - Liu, Jianjun A1 - Liu, Jingmin A1 - Loh, Marie A1 - Louie, Tin A1 - Mägi, Reedik A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Milani, Lili A1 - Mohlke, Karen L A1 - Momozawa, Yukihide A1 - Nalls, Mike A A1 - Nelson, Christopher P A1 - Sotoodehnia, Nona A1 - Norris, Jill M A1 - O'Connell, Jeff R A1 - Palmer, Nicholette D A1 - Perls, Thomas A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Poulter, Neil A1 - Raffel, Leslie J A1 - Raitakari, Olli T A1 - Roll, Kathryn A1 - Rose, Lynda M A1 - Rosendaal, Frits R A1 - Rotter, Jerome I A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Schupf, Nicole A1 - Scott, William R A1 - Sever, Peter S A1 - Shi, Yuan A1 - Sidney, Stephen A1 - Sims, Mario A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Tan, Nicholas Y Q A1 - Tang, Hua A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - Vollenweider, Peter A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Ya Xing A1 - Wei, Wen Bin A1 - Williams, Christine A1 - Yao, Jie A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Deary, Ian J A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Jonas, Jost Bruno A1 - Kamatani, Yoichiro A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Kutalik, Zoltán A1 - Laakso, Markku A1 - Laurie, Cathy C A1 - Leander, Karin A1 - Lehtimäki, Terho A1 - Study, Lifelines Cohort A1 - Magnusson, Patrik K E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Polasek, Ozren A1 - Porteous, David J A1 - Rauramaa, Rainer A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Bouchard, Claude A1 - Christensen, Kaare A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Horta, Bernardo L A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Pereira, Alexandre C A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - van Dam, Rob M A1 - Gauderman, W James A1 - Zhu, Xiaofeng A1 - Mook-Kanamori, Dennis O A1 - Fornage, Myriam A1 - Rotimi, Charles N A1 - Cupples, L Adrienne A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Kooperberg, Charles A1 - Palmas, Walter A1 - Rice, Kenneth A1 - Morrison, Alanna C A1 - Elliott, Paul A1 - Caulfield, Mark J A1 - Munroe, Patricia B A1 - Rao, Dabeeru C A1 - Province, Michael A A1 - Levy, Daniel AB -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.

VL - 13 IS - 6 ER - TY - JOUR T1 - Assessment of the Relationship Between Genetic Determinants of Thyroid Function and Atrial Fibrillation: A Mendelian Randomization Study. JF - JAMA Cardiol Y1 - 2019 A1 - Ellervik, Christina A1 - Roselli, Carolina A1 - Christophersen, Ingrid E A1 - Alonso, Alvaro A1 - Pietzner, Maik A1 - Sitlani, Collen M A1 - Trompet, Stella A1 - Arking, Dan E A1 - Geelhoed, Bastiaan A1 - Guo, Xiuqing A1 - Kleber, Marcus E A1 - Lin, Henry J A1 - Lin, Honghuang A1 - Macfarlane, Peter A1 - Selvin, Elizabeth A1 - Shaffer, Christian A1 - Smith, Albert V A1 - Verweij, Niek A1 - Weiss, Stefan A1 - Cappola, Anne R A1 - Dörr, Marcus A1 - Gudnason, Vilmundur A1 - Heckbert, Susan A1 - Mooijaart, Simon A1 - März, Winfried A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Roden, Dan A1 - Stott, David J A1 - Völzke, Henry A1 - Benjamin, Emelia J A1 - Delgado, Graciela A1 - Ellinor, Patrick A1 - Homuth, Georg A1 - Köttgen, Anna A1 - Jukema, Johan W A1 - Lubitz, Steven A A1 - Mora, Samia A1 - Rienstra, Michiel A1 - Rotter, Jerome I A1 - Shoemaker, M Benjamin A1 - Sotoodehnia, Nona A1 - Taylor, Kent D A1 - van der Harst, Pim A1 - Albert, Christine M A1 - Chasman, Daniel I AB -**Importance: **Increased free thyroxine (FT4) and decreased thyrotropin are associated with increased risk of atrial fibrillation (AF) in observational studies, but direct involvement is unclear.

**Objective: **To evaluate the potential direct involvement of thyroid traits on AF.

**Design, Setting, and Participants: **Study-level mendelian randomization (MR) included 11 studies, and summary-level MR included 55 114 AF cases and 482 295 referents, all of European ancestry.

**Exposures: **Genomewide significant variants were used as instruments for standardized FT4 and thyrotropin levels within the reference range, standardized triiodothyronine (FT3):FT4 ratio, hypothyroidism, standardized thyroid peroxidase antibody levels, and hyperthyroidism. Mendelian randomization used genetic risk scores in study-level analysis or individual single-nucleotide polymorphisms in 2-sample MR for the summary-level data.

**Main Outcomes and Measures: **Prevalent and incident AF.

**Results: **The study-level analysis included 7679 individuals with AF and 49 233 referents (mean age [standard error], 62 [3] years; 15 859 men [29.7%]). In study-level random-effects meta-analysis, the pooled hazard ratio of FT4 levels (nanograms per deciliter) for incident AF was 1.55 (95% CI, 1.09-2.20; P = .02; I2 = 76%) and the pooled odds ratio (OR) for prevalent AF was 2.80 (95% CI, 1.41-5.54; P = .003; I2 = 64%) in multivariable-adjusted analyses. The FT4 genetic risk score was associated with an increase in FT4 by 0.082 SD (standard error, 0.007; P < .001) but not with incident AF (risk ratio, 0.84; 95% CI, 0.62-1.14; P = .27) or prevalent AF (OR, 1.32; 95% CI, 0.64-2.73; P = .46). Similarly, in summary-level inverse-variance weighted random-effects MR, gene-based FT4 within the reference range was not associated with AF (OR, 1.01; 95% CI, 0.89-1.14; P = .88). However, gene-based increased FT3:FT4 ratio, increased thyrotropin within the reference range, and hypothyroidism were associated with AF with inverse-variance weighted random-effects OR of 1.33 (95% CI, 1.08-1.63; P = .006), 0.88 (95% CI, 0.84-0.92; P < .001), and 0.94 (95% CI, 0.90-0.99; P = .009), respectively, and robust to tests of horizontal pleiotropy. However, the subset of hypothyroidism single-nucleotide polymorphisms involved in autoimmunity and thyroid peroxidase antibodies levels were not associated with AF. Gene-based hyperthyroidism was associated with AF with MR-Egger OR of 1.31 (95% CI, 1.05-1.63; P = .02) with evidence of horizontal pleiotropy (P = .045).

**Conclusions and Relevance: **Genetically increased FT3:FT4 ratio and hyperthyroidism, but not FT4 within the reference range, were associated with increased AF, and increased thyrotropin within the reference range and hypothyroidism were associated with decreased AF, supporting a pathway involving the pituitary-thyroid-cardiac axis.

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.

VL - 10 IS - 1 ER - TY - JOUR T1 - Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci. JF - Mol Psychiatry Y1 - 2020 A1 - de Las Fuentes, Lisa A1 - Sung, Yun Ju A1 - Noordam, Raymond A1 - Winkler, Thomas A1 - Feitosa, Mary F A1 - Schwander, Karen A1 - Bentley, Amy R A1 - Brown, Michael R A1 - Guo, Xiuqing A1 - Manning, Alisa A1 - Chasman, Daniel I A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Campbell, Archie A1 - Cheng, Ching-Yu A1 - Dorajoo, Rajkumar A1 - Hartwig, Fernando P A1 - Horimoto, A R V R A1 - Li, Changwei A1 - Li-Gao, Ruifang A1 - Liu, Yongmei A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Ntalla, Ioanna A1 - Rankinen, Tuomo A1 - Richard, Melissa A1 - Sim, Xueling A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Tayo, Bamidele O A1 - Vojinovic, Dina A1 - Warren, Helen R A1 - Xuan, Deng A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Chai, Jin-Fang A1 - Chen, Xu A1 - Christensen, Kaare A1 - Divers, Jasmin A1 - Evangelou, Evangelos A1 - Gao, Chuan A1 - Girotto, Giorgia A1 - Harris, Sarah E A1 - He, Meian A1 - Hsu, Fang-Chi A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Li, Xiaoyin A1 - Lyytikäinen, Leo-Pekka A1 - Nolte, Ilja M A1 - Poveda, Alaitz A1 - Rauramaa, Rainer A1 - Riaz, Muhammad A1 - Rueedi, Rico A1 - Shu, Xiao-Ou A1 - Snieder, Harold A1 - Sofer, Tamar A1 - Takeuchi, Fumihiko A1 - Verweij, Niek A1 - Ware, Erin B A1 - Weiss, Stefan A1 - Yanek, Lisa R A1 - Amin, Najaf A1 - Arking, Dan E A1 - Arnett, Donna K A1 - Bergmann, Sven A1 - Boerwinkle, Eric A1 - Brody, Jennifer A A1 - Broeckel, Ulrich A1 - Brumat, Marco A1 - Burke, Gregory A1 - Cabrera, Claudia P A1 - Canouil, Mickaël A1 - Chee, Miao Li A1 - Chen, Yii-Der Ida A1 - Cocca, Massimiliano A1 - Connell, John A1 - de Silva, H Janaka A1 - de Vries, Paul S A1 - Eiriksdottir, Gudny A1 - Faul, Jessica D A1 - Fisher, Virginia A1 - Forrester, Terrence A1 - Fox, Ervin F A1 - Friedlander, Yechiel A1 - Gao, He A1 - Gigante, Bruna A1 - Giulianini, Franco A1 - Gu, Chi Charles A1 - Gu, Dongfeng A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hunt, Steven A1 - Ikram, M Arfan A1 - Irvin, Marguerite R A1 - Kähönen, Mika A1 - Kavousi, Maryam A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Komulainen, Pirjo A1 - Kraja, Aldi T A1 - Krieger, J E A1 - Langefeld, Carl D A1 - Li, Yize A1 - Liang, Jingjing A1 - Liewald, David C M A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Lohman, Kurt K A1 - Mägi, Reedik A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Milani, Lili A1 - Mook-Kanamori, Dennis O A1 - Nalls, Mike A A1 - Nelson, Christopher P A1 - Norris, Jill M A1 - O'Connell, Jeff A1 - Ogunniyi, Adesola A1 - Padmanabhan, Sandosh A1 - Palmer, Nicholette D A1 - Pedersen, Nancy L A1 - Perls, Thomas A1 - Peters, Annette A1 - Petersmann, Astrid A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Porteous, David J A1 - Raffel, Leslie J A1 - Rice, Treva K A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Rueda-Ochoa, Oscar-Leonel A1 - Sabanayagam, Charumathi A1 - Salako, Babatunde L A1 - Schreiner, Pamela J A1 - Shikany, James M A1 - Sidney, Stephen S A1 - Sims, Mario A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Starr, John M A1 - Strauch, Konstantin A1 - Swertz, Morris A A1 - Teumer, Alexander A1 - Tham, Yih Chung A1 - Uitterlinden, André G A1 - Vaidya, Dhananjay A1 - van der Ende, M Yldau A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Ya-Xing A1 - Wei, Wen-Bin A1 - Weir, David R A1 - Wen, Wanqing A1 - Yao, Jie A1 - Yu, Bing A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Bowden, Donald W A1 - Deary, Ian J A1 - Dörr, Marcus A1 - Esko, Tõnu A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Jonas, Jost Bruno A1 - Kammerer, Candace M A1 - Kato, Norihiro A1 - Lakka, Timo A A1 - Leander, Karin A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - Marques-Vidal, Pedro A1 - Penninx, Brenda W J H A1 - Samani, Nilesh J A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Zhu, Xiaofeng A1 - Bouchard, Claude A1 - Cooper, Richard S A1 - Correa, Adolfo A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Hayward, Caroline A1 - Horta, Bernardo L A1 - Kelly, Tanika N A1 - Kritchevsky, Stephen B A1 - Levy, Daniel A1 - Palmas, Walter R A1 - Pereira, A C A1 - Province, Michael M A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Rotimi, Charles N A1 - Tai, E Shyong A1 - van Dam, Rob M A1 - van Duijn, Cornelia M A1 - Wong, Tien Yin A1 - Rice, Kenneth A1 - Gauderman, W James A1 - Morrison, Alanna C A1 - North, Kari E A1 - Kardia, Sharon L R A1 - Caulfield, Mark J A1 - Elliott, Paul A1 - Munroe, Patricia B A1 - Franks, Paul W A1 - Rao, Dabeeru C A1 - Fornage, Myriam AB -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 × 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.

ER - TY - JOUR T1 - Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction. JF - Nat Commun Y1 - 2020 A1 - Ntalla, Ioanna A1 - Weng, Lu-Chen A1 - Cartwright, James H A1 - Hall, Amelia Weber A1 - Sveinbjornsson, Gardar A1 - Tucker, Nathan R A1 - Choi, Seung Hoan A1 - Chaffin, Mark D A1 - Roselli, Carolina A1 - Barnes, Michael R A1 - Mifsud, Borbala A1 - Warren, Helen R A1 - Hayward, Caroline A1 - Marten, Jonathan A1 - Cranley, James J A1 - Concas, Maria Pina A1 - Gasparini, Paolo A1 - Boutin, Thibaud A1 - Kolcic, Ivana A1 - Polasek, Ozren A1 - Rudan, Igor A1 - Araujo, Nathalia M A1 - Lima-Costa, Maria Fernanda A1 - Ribeiro, Antonio Luiz P A1 - Souza, Renan P A1 - Tarazona-Santos, Eduardo A1 - Giedraitis, Vilmantas A1 - Ingelsson, Erik A1 - Mahajan, Anubha A1 - Morris, Andrew P A1 - del Greco M, Fabiola A1 - Foco, Luisa A1 - Gögele, Martin A1 - Hicks, Andrew A A1 - Cook, James P A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Sundström, Johan A1 - Nelson, Christopher P A1 - Riaz, Muhammad B A1 - Samani, Nilesh J A1 - Sinagra, Gianfranco A1 - Ulivi, Sheila A1 - Kähönen, Mika A1 - Mishra, Pashupati P A1 - Mononen, Nina A1 - Nikus, Kjell A1 - Caulfield, Mark J A1 - Dominiczak, Anna A1 - Padmanabhan, Sandosh A1 - Montasser, May E A1 - O'Connell, Jeff R A1 - Ryan, Kathleen A1 - Shuldiner, Alan R A1 - Aeschbacher, Stefanie A1 - Conen, David A1 - Risch, Lorenz A1 - Thériault, Sébastien A1 - Hutri-Kähönen, Nina A1 - Lehtimäki, Terho A1 - Lyytikäinen, Leo-Pekka A1 - Raitakari, Olli T A1 - Barnes, Catriona L K A1 - Campbell, Harry A1 - Joshi, Peter K A1 - Wilson, James F A1 - Isaacs, Aaron A1 - Kors, Jan A A1 - van Duijn, Cornelia M A1 - Huang, Paul L A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Smith, Albert V A1 - Bottinger, Erwin P A1 - Loos, Ruth J F A1 - Nadkarni, Girish N A1 - Preuss, Michael H A1 - Correa, Adolfo A1 - Mei, Hao A1 - Wilson, James A1 - Meitinger, Thomas A1 - Müller-Nurasyid, Martina A1 - Peters, Annette A1 - Waldenberger, Melanie A1 - Mangino, Massimo A1 - Spector, Timothy D A1 - Rienstra, Michiel A1 - van de Vegte, Yordi J A1 - van der Harst, Pim A1 - Verweij, Niek A1 - Kääb, Stefan A1 - Schramm, Katharina A1 - Sinner, Moritz F A1 - Strauch, Konstantin A1 - Cutler, Michael J A1 - Fatkin, Diane A1 - London, Barry A1 - Olesen, Morten A1 - Roden, Dan M A1 - Benjamin Shoemaker, M A1 - Gustav Smith, J A1 - Biggs, Mary L A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Psaty, Bruce M A1 - Rice, Kenneth A1 - Sotoodehnia, Nona A1 - De Grandi, Alessandro A1 - Fuchsberger, Christian A1 - Pattaro, Cristian A1 - Pramstaller, Peter P A1 - Ford, Ian A1 - Wouter Jukema, J A1 - Macfarlane, Peter W A1 - Trompet, Stella A1 - Dörr, Marcus A1 - Felix, Stephan B A1 - Völker, Uwe A1 - Weiss, Stefan A1 - Havulinna, Aki S A1 - Jula, Antti A1 - Sääksjärvi, Katri A1 - Salomaa, Veikko A1 - Guo, Xiuqing A1 - Heckbert, Susan R A1 - Lin, Henry J A1 - Rotter, Jerome I A1 - Taylor, Kent D A1 - Yao, Jie A1 - de Mutsert, Renée A1 - Maan, Arie C A1 - Mook-Kanamori, Dennis O A1 - Noordam, Raymond A1 - Cucca, Francesco A1 - Ding, Jun A1 - Lakatta, Edward G A1 - Qian, Yong A1 - Tarasov, Kirill V A1 - Levy, Daniel A1 - Lin, Honghuang A1 - Newton-Cheh, Christopher H A1 - Lunetta, Kathryn L A1 - Murray, Alison D A1 - Porteous, David J A1 - Smith, Blair H A1 - Stricker, Bruno H A1 - Uitterlinden, Andre A1 - van den Berg, Marten E A1 - Haessler, Jeffrey A1 - Jackson, Rebecca D A1 - Kooperberg, Charles A1 - Peters, Ulrike A1 - Reiner, Alexander P A1 - Whitsel, Eric A A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Ehret, Georg B A1 - Soliman, Elsayed Z A1 - Avery, Christy L A1 - Gogarten, Stephanie M A1 - Kerr, Kathleen F A1 - Laurie, Cathy C A1 - Seyerle, Amanda A A1 - Stilp, Adrienne A1 - Assa, Solmaz A1 - Abdullah Said, M A1 - Yldau van der Ende, M A1 - Lambiase, Pier D A1 - Orini, Michele A1 - Ramirez, Julia A1 - Van Duijvenboden, Stefan A1 - Arnar, David O A1 - Gudbjartsson, Daniel F A1 - Holm, Hilma A1 - Sulem, Patrick A1 - Thorleifsson, Gudmar A1 - Thorolfsdottir, Rosa B A1 - Thorsteinsdottir, Unnur A1 - Benjamin, Emelia J A1 - Tinker, Andrew A1 - Stefansson, Kari A1 - Ellinor, Patrick T A1 - Jamshidi, Yalda A1 - Lubitz, Steven A A1 - Munroe, Patricia B AB -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.

VL - 11 IS - 1 ER - TY - JOUR T1 - The Polygenic and Monogenic Basis of Blood Traits and Diseases. JF - Cell Y1 - 2020 A1 - Vuckovic, Dragana A1 - Bao, Erik L A1 - Akbari, Parsa A1 - Lareau, Caleb A A1 - Mousas, Abdou A1 - Jiang, Tao A1 - Chen, Ming-Huei A1 - Raffield, Laura M A1 - Tardaguila, Manuel A1 - Huffman, Jennifer E A1 - Ritchie, Scott C A1 - Megy, Karyn A1 - Ponstingl, Hannes A1 - Penkett, Christopher J A1 - Albers, Patrick K A1 - Wigdor, Emilie M A1 - Sakaue, Saori A1 - Moscati, Arden A1 - Manansala, Regina A1 - Lo, Ken Sin A1 - Qian, Huijun A1 - Akiyama, Masato A1 - Bartz, Traci M A1 - Ben-Shlomo, Yoav A1 - Beswick, Andrew A1 - Bork-Jensen, Jette A1 - Bottinger, Erwin P A1 - Brody, Jennifer A A1 - van Rooij, Frank J A A1 - Chitrala, Kumaraswamy N A1 - Wilson, Peter W F A1 - Choquet, Helene A1 - Danesh, John A1 - Di Angelantonio, Emanuele A1 - Dimou, Niki A1 - Ding, Jingzhong A1 - Elliott, Paul A1 - Esko, Tõnu A1 - Evans, Michele K A1 - Felix, Stephan B A1 - Floyd, James S A1 - Broer, Linda A1 - Grarup, Niels A1 - Guo, Michael H A1 - Guo, Qi A1 - Greinacher, Andreas A1 - Haessler, Jeff A1 - Hansen, Torben A1 - Howson, Joanna M M A1 - Huang, Wei A1 - Jorgenson, Eric A1 - Kacprowski, Tim A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kanai, Masahiro A1 - Karthikeyan, Savita A1 - Koskeridis, Fotios A1 - Lange, Leslie A A1 - Lehtimäki, Terho A1 - Linneberg, Allan A1 - Liu, Yongmei A1 - Lyytikäinen, Leo-Pekka A1 - Manichaikul, Ani A1 - Matsuda, Koichi A1 - Mohlke, Karen L A1 - Mononen, Nina A1 - Murakami, Yoshinori A1 - Nadkarni, Girish N A1 - Nikus, Kjell A1 - Pankratz, Nathan A1 - Pedersen, Oluf A1 - Preuss, Michael A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Rich, Stephen S A1 - Rodriguez, Benjamin A T A1 - Rosen, Jonathan D A1 - Rotter, Jerome I A1 - Schubert, Petra A1 - Spracklen, Cassandra N A1 - Surendran, Praveen A1 - Tang, Hua A1 - Tardif, Jean-Claude A1 - Ghanbari, Mohsen A1 - Völker, Uwe A1 - Völzke, Henry A1 - Watkins, Nicholas A A1 - Weiss, Stefan A1 - Cai, Na A1 - Kundu, Kousik A1 - Watt, Stephen B A1 - Walter, Klaudia A1 - Zonderman, Alan B A1 - Cho, Kelly A1 - Li, Yun A1 - Loos, Ruth J F A1 - Knight, Julian C A1 - Georges, Michel A1 - Stegle, Oliver A1 - Evangelou, Evangelos A1 - Okada, Yukinori A1 - Roberts, David J A1 - Inouye, Michael A1 - Johnson, Andrew D A1 - Auer, Paul L A1 - Astle, William J A1 - Reiner, Alexander P A1 - Butterworth, Adam S A1 - Ouwehand, Willem H A1 - Lettre, Guillaume A1 - Sankaran, Vijay G A1 - Soranzo, Nicole AB -Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

VL - 182 IS - 5 ER -