@article {6179, title = {Impact of ancestry and common genetic variants on QT interval in African Americans.}, journal = {Circ Cardiovasc Genet}, volume = {5}, year = {2012}, month = {2012 Dec}, pages = {647-55}, abstract = {

BACKGROUND: Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval.

METHODS AND RESULTS: First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12,097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13,105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5 {\texttimes} 10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2 {\texttimes} 10(-15)) and ATP1B1 (rs1320976, P=2 {\texttimes} 10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values (P<10(-5)) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF, and PLN.

CONCLUSIONS: We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of African ancestry.

}, keywords = {Adult, African Americans, Aged, Electrocardiography, European Continental Ancestry Group, Female, Genealogy and Heraldry, Genetic Variation, Genome, Human, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.112.962787}, author = {Smith, J Gustav and Avery, Christy L and Evans, Daniel S and Nalls, Michael A and Meng, Yan A and Smith, Erin N and Palmer, Cameron and Tanaka, Toshiko and Mehra, Reena and Butler, Anne M and Young, Taylor and Buxbaum, Sarah G and Kerr, Kathleen F and Berenson, Gerald S and Schnabel, Renate B and Li, Guo and Ellinor, Patrick T and Magnani, Jared W and Chen, Wei and Bis, Joshua C and Curb, J David and Hsueh, Wen-Chi and Rotter, Jerome I and Liu, Yongmei and Newman, Anne B and Limacher, Marian C and North, Kari E and Reiner, Alexander P and Quibrera, P Miguel and Schork, Nicholas J and Singleton, Andrew B and Psaty, Bruce M and Soliman, Elsayed Z and Solomon, Allen J and Srinivasan, Sathanur R and Alonso, Alvaro and Wallace, Robert and Redline, Susan and Zhang, Zhu-Ming and Post, Wendy S and Zonderman, Alan B and Taylor, Herman A and Murray, Sarah S and Ferrucci, Luigi and Arking, Dan E and Evans, Michele K and Fox, Ervin R and Sotoodehnia, Nona and Heckbert, Susan R and Whitsel, Eric A and Newton-Cheh, Christopher} } @article {1383, title = {Meta-analysis identifies six new susceptibility loci for atrial fibrillation.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Apr 29}, pages = {670-5}, abstract = {

Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 {\texttimes} 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Asian Continental Ancestry Group, Atrial Fibrillation, Child, Child, Preschool, European Continental Ancestry Group, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Infant, Infant, Newborn, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Young Adult}, issn = {1546-1718}, doi = {10.1038/ng.2261}, author = {Ellinor, Patrick T and Lunetta, Kathryn L and Albert, Christine M and Glazer, Nicole L and Ritchie, Marylyn D and Smith, Albert V and Arking, Dan E and M{\"u}ller-Nurasyid, Martina and Krijthe, Bouwe P and Lubitz, Steven A and Bis, Joshua C and Chung, Mina K and D{\"o}rr, Marcus and Ozaki, Kouichi and Roberts, Jason D and Smith, J Gustav and Pfeufer, Arne and Sinner, Moritz F and Lohman, Kurt and Ding, Jingzhong and Smith, Nicholas L and Smith, Jonathan D and Rienstra, Michiel and Rice, Kenneth M and Van Wagoner, David R and Magnani, Jared W and Wakili, Reza and Clauss, Sebastian and Rotter, Jerome I and Steinbeck, Gerhard and Launer, Lenore J and Davies, Robert W and Borkovich, Matthew and Harris, Tamara B and Lin, Honghuang and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Milan, David J and Hofman, Albert and Boerwinkle, Eric and Chen, Lin Y and Soliman, Elsayed Z and Voight, Benjamin F and Li, Guo and Chakravarti, Aravinda and Kubo, Michiaki and Tedrow, Usha B and Rose, Lynda M and Ridker, Paul M and Conen, David and Tsunoda, Tatsuhiko and Furukawa, Tetsushi and Sotoodehnia, Nona and Xu, Siyan and Kamatani, Naoyuki and Levy, Daniel and Nakamura, Yusuke and Parvez, Babar and Mahida, Saagar and Furie, Karen L and Rosand, Jonathan and Muhammad, Raafia and Psaty, Bruce M and Meitinger, Thomas and Perz, Siegfried and Wichmann, H-Erich and Witteman, Jacqueline C M and Kao, W H Linda and Kathiresan, Sekar and Roden, Dan M and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and McKnight, Barbara and Sj{\"o}gren, Marketa and Newman, Anne B and Liu, Yongmei and Gollob, Michael H and Melander, Olle and Tanaka, Toshihiro and Stricker, Bruno H Ch and Felix, Stephan B and Alonso, Alvaro and Darbar, Dawood and Barnard, John and Chasman, Daniel I and Heckbert, Susan R and Benjamin, Emelia J and Gudnason, Vilmundur and K{\"a}{\"a}b, Stefan} } @article {6084, title = {Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts.}, journal = {Circ Cardiovasc Genet}, volume = {5}, year = {2012}, month = {2012 Dec}, pages = {639-46}, abstract = {

BACKGROUND: The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans.

METHODS AND RESULTS: We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 {\texttimes} 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 {\texttimes} 10(-8)).

CONCLUSIONS: This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.

}, keywords = {Adult, African Americans, Cohort Studies, Electrocardiography, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.112.963991}, author = {Butler, Anne M and Yin, Xiaoyan and Evans, Daniel S and Nalls, Michael A and Smith, Erin N and Tanaka, Toshiko and Li, Guo and Buxbaum, Sarah G and Whitsel, Eric A and Alonso, Alvaro and Arking, Dan E and Benjamin, Emelia J and Berenson, Gerald S and Bis, Josh C and Chen, Wei and Deo, Rajat and Ellinor, Patrick T and Heckbert, Susan R and Heiss, Gerardo and Hsueh, Wen-Chi and Keating, Brendan J and Kerr, Kathleen F and Li, Yun and Limacher, Marian C and Liu, Yongmei and Lubitz, Steven A and Marciante, Kristin D and Mehra, Reena and Meng, Yan A and Newman, Anne B and Newton-Cheh, Christopher and North, Kari E and Palmer, Cameron D and Psaty, Bruce M and Quibrera, P Miguel and Redline, Susan and Reiner, Alex P and Rotter, Jerome I and Schnabel, Renate B and Schork, Nicholas J and Singleton, Andrew B and Smith, J Gustav and Soliman, Elsayed Z and Srinivasan, Sathanur R and Zhang, Zhu-Ming and Zonderman, Alan B and Ferrucci, Luigi and Murray, Sarah S and Evans, Michele K and Sotoodehnia, Nona and Magnani, Jared W and Avery, Christy L} } @article {6570, title = {A common SCN5A variant is associated with PR interval and atrial fibrillation among African Americans.}, journal = {J Cardiovasc Electrophysiol}, volume = {25}, year = {2014}, month = {2014 Nov}, pages = {1150-7}, abstract = {

OBJECTIVE: We examined the association of rs7626962 (S1103Y) or rs7629265, a variant in high linkage disequilibrium with S1103Y (r(2) = 0.87 - 1), with sudden cardiac death (SCD) and atrial fibrillation (AF) among African Americans.

BACKGROUND: The SCN5A missense variant S1103Y has been associated with SCD among African Americans in small case-control studies, but larger population-based studies are needed to validate these findings. The association of this variant with AF has not been fully explored.

METHODS: Using genotyping data on over 7,000 African Americans from 5 cohorts (Atherosclerosis Risk in Communities [ARIC], Cleveland Family Study [CFS], Jackson Heart Study [JHS], Multi-Ethnic Study of Atherosclerosis [MESA], Cardiovascular Health Study [CHS]), we examined the association of rs7629265 with electrocardiographic PR, QRS, and QT intervals, and with incident AF and SCD. We examined association of S1103Y (rs7626962) with SCD using a population-based case-control study of SCD Cardiac Arrest Blood Study (CABS).

RESULTS: Meta-analyses across 5 cohorts demonstrated that rs7629265 was significantly associated with PR duration (β = -4.1 milliseconds; P = 2.2{\texttimes}10(-6) ), but not significantly associated with QRS or QT intervals. In meta-analyses of prospectively followed ARIC and CHS participants (n = 3,656), rs7629265 was associated with increased AF risk (n = 299 AF cases; HR = 1.74, P = 1.9 {\texttimes} 10(-4) ). By contrast, rs7629265 was not significantly associated with SCD risk in ARIC (n = 83 SCD cases; P = 0.30) or CHS (n = 54 SCD cases; P = 0.47). Similarly, S1103Y was not significantly associated with SCD risk in CABS (n = 225 SCD cases; P = 0.29).

CONCLUSION: The common SCN5A variant, rs7629265, is associated with increased AF risk and shorter PR interval among African Americans. In contrast to prior reports, we found no evidence of association of rs7629265 or rs7626962 (S1103Y) with SCD risk in the general population.

}, keywords = {Adult, African Americans, Aged, Aged, 80 and over, Atrial Fibrillation, Case-Control Studies, Cohort Studies, Death, Sudden, Cardiac, Female, Genetic Variation, Humans, Male, Middle Aged, NAV1.5 Voltage-Gated Sodium Channel, Prospective Studies, Risk Factors, Single-Blind Method}, issn = {1540-8167}, doi = {10.1111/jce.12483}, author = {Ilkhanoff, Leonard and Arking, Dan E and Lemaitre, Rozenn N and Alonso, Alvaro and Chen, Lin Y and Durda, Peter and Hesselson, Stephanie E and Kerr, Kathleen F and Magnani, Jared W and Marcus, Gregory M and Schnabel, Renate B and Smith, J Gustav and Soliman, Elsayed Z and Reiner, Alexander P and Sotoodehnia, Nona} } @article {6544, title = {Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Aug}, pages = {826-36}, abstract = {

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain \~{}8-10\% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

}, keywords = {Adult, Aged, Arrhythmias, Cardiac, Calcium Signaling, Death, Sudden, Cardiac, Electrocardiography, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Long QT Syndrome, Male, Middle Aged, Myocardium, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.3014}, author = {Arking, Dan E and Pulit, Sara L and Crotti, Lia and van der Harst, Pim and Munroe, Patricia B and Koopmann, Tamara T and Sotoodehnia, Nona and Rossin, Elizabeth J and Morley, Michael and Wang, Xinchen and Johnson, Andrew D and Lundby, Alicia and Gudbjartsson, Daniel F and Noseworthy, Peter A and Eijgelsheim, Mark and Bradford, Yuki and Tarasov, Kirill V and D{\"o}rr, Marcus and M{\"u}ller-Nurasyid, Martina and Lahtinen, Annukka M and Nolte, Ilja M and Smith, Albert Vernon and Bis, Joshua C and Isaacs, Aaron and Newhouse, Stephen J and Evans, Daniel S and Post, Wendy S and Waggott, Daryl and Lyytik{\"a}inen, Leo-Pekka and Hicks, Andrew A and Eisele, Lewin and Ellinghaus, David and Hayward, Caroline and Navarro, Pau and Ulivi, Sheila and Tanaka, Toshiko and Tester, David J and Chatel, St{\'e}phanie and Gustafsson, Stefan and Kumari, Meena and Morris, Richard W and Naluai, {\r A}sa T and Padmanabhan, Sandosh and Kluttig, Alexander and Strohmer, Bernhard and Panayiotou, Andrie G and Torres, Maria and Knoflach, Michael and Hubacek, Jaroslav A and Slowikowski, Kamil and Raychaudhuri, Soumya and Kumar, Runjun D and Harris, Tamara B and Launer, Lenore J and Shuldiner, Alan R and Alonso, Alvaro and Bader, Joel S and Ehret, Georg and Huang, Hailiang and Kao, W H Linda and Strait, James B and Macfarlane, Peter W and Brown, Morris and Caulfield, Mark J and Samani, Nilesh J and Kronenberg, Florian and Willeit, Johann and Smith, J Gustav and Greiser, Karin H and Meyer Zu Schwabedissen, Henriette and Werdan, Karl and Carella, Massimo and Zelante, Leopoldo and Heckbert, Susan R and Psaty, Bruce M and Rotter, Jerome I and Kolcic, Ivana and Polasek, Ozren and Wright, Alan F and Griffin, Maura and Daly, Mark J and Arnar, David O and Holm, Hilma and Thorsteinsdottir, Unnur and Denny, Joshua C and Roden, Dan M and Zuvich, Rebecca L and Emilsson, Valur and Plump, Andrew S and Larson, Martin G and O{\textquoteright}Donnell, Christopher J and Yin, Xiaoyan and Bobbo, Marco and D{\textquoteright}Adamo, Adamo P and Iorio, Annamaria and Sinagra, Gianfranco and Carracedo, Angel and Cummings, Steven R and Nalls, Michael A and Jula, Antti and Kontula, Kimmo K and Marjamaa, Annukka and Oikarinen, Lasse and Perola, Markus and Porthan, Kimmo and Erbel, Raimund and Hoffmann, Per and J{\"o}ckel, Karl-Heinz and K{\"a}lsch, Hagen and N{\"o}then, Markus M and den Hoed, Marcel and Loos, Ruth J F and Thelle, Dag S and Gieger, Christian and Meitinger, Thomas and Perz, Siegfried and Peters, Annette and Prucha, Hanna and Sinner, Moritz F and Waldenberger, Melanie and de Boer, Rudolf A and Franke, Lude and van der Vleuten, Pieter A and Beckmann, Britt Maria and Martens, Eimo and Bardai, Abdennasser and Hofman, Nynke and Wilde, Arthur A M and Behr, Elijah R and Dalageorgou, Chrysoula and Giudicessi, John R and Medeiros-Domingo, Argelia and Barc, Julien and Kyndt, Florence and Probst, Vincent and Ghidoni, Alice and Insolia, Roberto and Hamilton, Robert M and Scherer, Stephen W and Brandimarto, Jeffrey and Margulies, Kenneth and Moravec, Christine E and del Greco M, Fabiola and Fuchsberger, Christian and O{\textquoteright}Connell, Jeffrey R and Lee, Wai K and Watt, Graham C M and Campbell, Harry and Wild, Sarah H and El Mokhtari, Nour E and Frey, Norbert and Asselbergs, Folkert W and Mateo Leach, Irene and Navis, Gerjan and van den Berg, Maarten P and van Veldhuisen, Dirk J and Kellis, Manolis and Krijthe, Bouwe P and Franco, Oscar H and Hofman, Albert and Kors, Jan A and Uitterlinden, Andr{\'e} G and Witteman, Jacqueline C M and Kedenko, Lyudmyla and Lamina, Claudia and Oostra, Ben A and Abecasis, Goncalo R and Lakatta, Edward G and Mulas, Antonella and Orr{\`u}, Marco and Schlessinger, David and Uda, Manuela and Markus, Marcello R P and V{\"o}lker, Uwe and Snieder, Harold and Spector, Timothy D and Arnl{\"o}v, Johan and Lind, Lars and Sundstr{\"o}m, Johan and Syv{\"a}nen, Ann-Christine and Kivimaki, Mika and K{\"a}h{\"o}nen, Mika and Mononen, Nina and Raitakari, Olli T and Viikari, Jorma S and Adamkova, Vera and Kiechl, Stefan and Brion, Maria and Nicolaides, Andrew N and Paulweber, Bernhard and Haerting, Johannes and Dominiczak, Anna F and Nyberg, Fredrik and Whincup, Peter H and Hingorani, Aroon D and Schott, Jean-Jacques and Bezzina, Connie R and Ingelsson, Erik and Ferrucci, Luigi and Gasparini, Paolo and Wilson, James F and Rudan, Igor and Franke, Andre and M{\"u}hleisen, Thomas W and Pramstaller, Peter P and Lehtim{\"a}ki, Terho J and Paterson, Andrew D and Parsa, Afshin and Liu, Yongmei and van Duijn, Cornelia M and Siscovick, David S and Gudnason, Vilmundur and Jamshidi, Yalda and Salomaa, Veikko and Felix, Stephan B and Sanna, Serena and Ritchie, Marylyn D and Stricker, Bruno H and Stefansson, Kari and Boyer, Laurie A and Cappola, Thomas P and Olsen, Jesper V and Lage, Kasper and Schwartz, Peter J and K{\"a}{\"a}b, Stefan and Chakravarti, Aravinda and Ackerman, Michael J and Pfeufer, Arne and de Bakker, Paul I W and Newton-Cheh, Christopher} } @article {6600, title = {Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation.}, journal = {Circulation}, volume = {130}, year = {2014}, month = {2014 Oct 7}, pages = {1225-35}, abstract = {

BACKGROUND: Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood.

METHODS AND RESULTS: To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501; relative risk [RR]=1.18; 95\% confidence interval [CI], 1.13-1.23; P=6.5{\texttimes}10(-16)), GJA1 (rs13216675; RR=1.10; 95\% CI, 1.06-1.14; P=2.2{\texttimes}10(-8)), TBX5 (rs10507248; RR=1.12; 95\% CI, 1.08-1.16; P=5.7{\texttimes}10(-11)), and CAND2 (rs4642101; RR=1.10; 95\% CI, 1.06-1.14; P=9.8{\texttimes}10(-9)). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95\% CI, 1.26-1.39; P=2.0{\texttimes}10(-25)) and CUX2 (rs6490029; RR=1.12; 95\% CI, 1.08-1.16; P=3.9{\texttimes}10(-9)). The top single-nucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6{\texttimes}10(-19)), GJA1 (P=2.66{\texttimes}10(-6)), and TBX5 (P=1.36{\texttimes}10(-5)). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17\% and 45\%, respectively).

CONCLUSIONS: We have identified 5 novel loci for AF. Our results expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.

}, keywords = {Aged, Animals, Atrial Fibrillation, Chromosome Mapping, Connexin 43, Europe, Female, Gene Knockdown Techniques, Genetic Loci, Genetic Predisposition to Disease, Genotype, Homeodomain Proteins, Humans, Japan, Male, Middle Aged, Muscle Proteins, Nuclear Proteins, Quantitative Trait Loci, Repressor Proteins, T-Box Domain Proteins, Transcription Factors, Ubiquitin-Protein Ligases, Zebrafish, Zebrafish Proteins}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.114.009892}, author = {Sinner, Moritz F and Tucker, Nathan R and Lunetta, Kathryn L and Ozaki, Kouichi and Smith, J Gustav and Trompet, Stella and Bis, Joshua C and Lin, Honghuang and Chung, Mina K and Nielsen, Jonas B and Lubitz, Steven A and Krijthe, Bouwe P and Magnani, Jared W and Ye, Jiangchuan and Gollob, Michael H and Tsunoda, Tatsuhiko and M{\"u}ller-Nurasyid, Martina and Lichtner, Peter and Peters, Annette and Dolmatova, Elena and Kubo, Michiaki and Smith, Jonathan D and Psaty, Bruce M and Smith, Nicholas L and Jukema, J Wouter and Chasman, Daniel I and Albert, Christine M and Ebana, Yusuke and Furukawa, Tetsushi and Macfarlane, Peter W and Harris, Tamara B and Darbar, Dawood and D{\"o}rr, Marcus and Holst, Anders G and Svendsen, Jesper H and Hofman, Albert and Uitterlinden, Andr{\'e} G and Gudnason, Vilmundur and Isobe, Mitsuaki and Malik, Rainer and Dichgans, Martin and Rosand, Jonathan and Van Wagoner, David R and Benjamin, Emelia J and Milan, David J and Melander, Olle and Heckbert, Susan R and Ford, Ian and Liu, Yongmei and Barnard, John and Olesen, Morten S and Stricker, Bruno H C and Tanaka, Toshihiro and K{\"a}{\"a}b, Stefan and Ellinor, Patrick T} } @article {7144, title = {Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure.}, journal = {PLoS Genet}, volume = {12}, year = {2016}, month = {2016 May}, pages = {e1006034}, abstract = {

Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36\% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.

}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006034}, author = {Smith, J Gustav and Felix, Janine F and Morrison, Alanna C and Kalogeropoulos, Andreas and Trompet, Stella and Wilk, Jemma B and Gidl{\"o}f, Olof and Wang, Xinchen and Morley, Michael and Mendelson, Michael and Joehanes, Roby and Ligthart, Symen and Shan, Xiaoyin and Bis, Joshua C and Wang, Ying A and Sj{\"o}gren, Marketa and Ngwa, Julius and Brandimarto, Jeffrey and Stott, David J and Aguilar, David and Rice, Kenneth M and Sesso, Howard D and Demissie, Serkalem and Buckley, Brendan M and Taylor, Kent D and Ford, Ian and Yao, Chen and Liu, Chunyu and Sotoodehnia, Nona and van der Harst, Pim and Stricker, Bruno H Ch and Kritchevsky, Stephen B and Liu, Yongmei and Gaziano, J Michael and Hofman, Albert and Moravec, Christine S and Uitterlinden, Andr{\'e} G and Kellis, Manolis and van Meurs, Joyce B and Margulies, Kenneth B and Dehghan, Abbas and Levy, Daniel and Olde, Bj{\"o}rn and Psaty, Bruce M and Cupples, L Adrienne and Jukema, J Wouter and Djouss{\'e}, Luc and Franco, Oscar H and Boerwinkle, Eric and Boyer, Laurie A and Newton-Cheh, Christopher and Butler, Javed and Vasan, Ramachandran S and Cappola, Thomas P and Smith, Nicholas L} } @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 {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 {7373, title = {Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function.}, journal = {J Clin Invest}, volume = {127}, year = {2017}, month = {2017 May 01}, pages = {1798-1812}, abstract = {

BACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function.

METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function.

RESULTS: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue.

CONCLUSION: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.

FUNDING: For detailed information per study, see Acknowledgments.

}, issn = {1558-8238}, doi = {10.1172/JCI84840}, author = {Wild, Philipp S and Felix, Janine F and Schillert, Arne and Teumer, Alexander and Chen, Ming-Huei and Leening, Maarten J G and V{\"o}lker, Uwe and Gro{\ss}mann, Vera and Brody, Jennifer A and Irvin, Marguerite R and Shah, Sanjiv J and Pramana, Setia and Lieb, Wolfgang and Schmidt, Reinhold and Stanton, Alice V and Malzahn, D{\"o}rthe and Smith, Albert Vernon and Sundstr{\"o}m, Johan and Minelli, Cosetta and Ruggiero, Daniela and Lyytik{\"a}inen, Leo-Pekka and Tiller, Daniel and Smith, J Gustav and Monnereau, Claire and Di Tullio, Marco R and Musani, Solomon K and Morrison, Alanna C and Pers, Tune H and Morley, Michael and Kleber, Marcus E and Aragam, Jayashri and Benjamin, Emelia J and Bis, Joshua C and Bisping, Egbert and Broeckel, Ulrich and Cheng, Susan and Deckers, Jaap W and del Greco M, Fabiola and Edelmann, Frank and Fornage, Myriam and Franke, Lude and Friedrich, Nele and Harris, Tamara B and Hofer, Edith and Hofman, Albert and Huang, Jie and Hughes, Alun D and K{\"a}h{\"o}nen, Mika and Investigators, Knhi and Kruppa, Jochen and Lackner, Karl J and Lannfelt, Lars and Laskowski, Rafael and Launer, Lenore J and Leosdottir, Margr{\'e}t and Lin, Honghuang and Lindgren, Cecilia M and Loley, Christina and MacRae, Calum A and Mascalzoni, Deborah and Mayet, Jamil and Medenwald, Daniel and Morris, Andrew P and M{\"u}ller, Christian and M{\"u}ller-Nurasyid, Martina and Nappo, Stefania and Nilsson, Peter M and Nuding, Sebastian and Nutile, Teresa and Peters, Annette and Pfeufer, Arne and Pietzner, Diana and Pramstaller, Peter P and Raitakari, Olli T and Rice, Kenneth M and Rivadeneira, Fernando and Rotter, Jerome I and Ruohonen, Saku T and Sacco, Ralph L and Samdarshi, Tandaw E and Schmidt, Helena and Sharp, Andrew S P and Shields, Denis C and Sorice, Rossella and Sotoodehnia, Nona and Stricker, Bruno H and Surendran, Praveen and Thom, Simon and T{\"o}glhofer, Anna M and Uitterlinden, Andr{\'e} G and Wachter, Rolf and V{\"o}lzke, Henry and Ziegler, Andreas and M{\"u}nzel, Thomas and M{\"a}rz, Winfried and Cappola, Thomas P and Hirschhorn, Joel N and Mitchell, Gary F and Smith, Nicholas L and Fox, Ervin R and Dueker, Nicole D and Jaddoe, Vincent W V and Melander, Olle and Russ, Martin and Lehtim{\"a}ki, Terho and Ciullo, Marina and Hicks, Andrew A and Lind, Lars and Gudnason, Vilmundur and Pieske, Burkert and Barron, Anthony J and Zweiker, Robert and Schunkert, Heribert and Ingelsson, Erik and Liu, Kiang and Arnett, Donna K and Psaty, Bruce M and Blankenberg, Stefan and Larson, Martin G and Felix, Stephan B and Franco, Oscar H and Zeller, Tanja and Vasan, Ramachandran S and D{\"o}rr, Marcus} } @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 {9168, title = {Rare genetic variants explain missing heritability in smoking.}, journal = {Nat Hum Behav}, year = {2022}, month = {2022 Aug 04}, abstract = {

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

}, issn = {2397-3374}, doi = {10.1038/s41562-022-01408-5}, author = {Jang, Seon-Kyeong and Evans, Luke and Fialkowski, Allison and Arnett, Donna K and Ashley-Koch, Allison E and Barnes, Kathleen C and Becker, Diane M and Bis, Joshua C and Blangero, John and Bleecker, Eugene R and Boorgula, Meher Preethi and Bowden, Donald W and Brody, Jennifer A and Cade, Brian E and Jenkins, Brenda W Campbell and Carson, April P and Chavan, Sameer and Cupples, L Adrienne and Custer, Brian and Damrauer, Scott M and David, Sean P and de Andrade, Mariza and Dinardo, Carla L and Fingerlin, Tasha E and Fornage, Myriam and Freedman, Barry I and Garrett, Melanie E and Gharib, Sina A and Glahn, David C and Haessler, Jeffrey and Heckbert, Susan R and Hokanson, John E and Hou, Lifang and Hwang, Shih-Jen and Hyman, Matthew C and Judy, Renae and Justice, Anne E and Kaplan, Robert C and Kardia, Sharon L R and Kelly, Shannon and Kim, Wonji and Kooperberg, Charles and Levy, Daniel and Lloyd-Jones, Donald M and Loos, Ruth J F and Manichaikul, Ani W and Gladwin, Mark T and Martin, Lisa Warsinger and Nouraie, Mehdi and Melander, Olle and Meyers, Deborah A and Montgomery, Courtney G and North, Kari E and Oelsner, Elizabeth C and Palmer, Nicholette D and Payton, Marinelle and Peljto, Anna L and Peyser, Patricia A and Preuss, Michael and Psaty, Bruce M and Qiao, Dandi and Rader, Daniel J and Rafaels, Nicholas and Redline, Susan and Reed, Robert M and Reiner, Alexander P and Rich, Stephen S and Rotter, Jerome I and Schwartz, David A and Shadyab, Aladdin H and Silverman, Edwin K and Smith, Nicholas L and Smith, J Gustav and Smith, Albert V and Smith, Jennifer A and Tang, Weihong and Taylor, Kent D and Telen, Marilyn J and Vasan, Ramachandran S and Gordeuk, Victor R and Wang, Zhe and Wiggins, Kerri L and Yanek, Lisa R and Yang, Ivana V and Young, Kendra A and Young, Kristin L and Zhang, Yingze and Liu, Dajiang J and Keller, Matthew C and Vrieze, Scott} } @article {9387, title = {Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.}, journal = {Nature}, volume = {616}, year = {2023}, month = {2023 Apr}, pages = {755-763}, abstract = {

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

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