04917nas a2201453 4500008004100000022001400041245008200055210006900137260001600206300001000222490000700232520088500239653001501124653001001139653000901149653002201158653003701180653002401217653001001241653002101251653004001272653001101312653001701323653003801340653003401378653001101412653001101423653002001434653000901454653001601463653003601479653001701515653001601532100002401548700002401572700002501596700002201621700002401643700002101667700001901688700003001707700002201737700002201759700001901781700001901800700001801819700001901837700002201856700001801878700001801896700002201914700001701936700002001953700002301973700002301996700002202019700002102041700002602062700002202088700001702110700002202127700002202149700002302171700002202194700002202216700002302238700002202261700001902283700001702302700001902319700002002338700001902358700002102377700001702398700002402415700002402439700001202463700002602475700001902501700002002520700001902540700002002559700001702579700002302596700002302619700002202642700001402664700002202678700001702700700002102717700001802738700001902756700002002775700002102795700002102816700002002837700002202857700002002879700002202899700003002921700002002951700002202971700001802993700002803011700002603039700002203065700002203087700002003109700001703129700002303146700001903169700002203188700002603210700002203236700001903258700001903277700001803296700002303314700002303337700002403360700002403384700001903408856003603427 2012 eng d a1546-171800aMeta-analysis identifies six new susceptibility loci for atrial fibrillation.0 aMetaanalysis identifies six new susceptibility loci for atrial f c2012 Apr 29 a670-50 v443 a
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 × 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.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aAsian Continental Ancestry Group10aAtrial Fibrillation10aChild10aChild, Preschool10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aInfant10aInfant, Newborn10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors10aYoung Adult1 aEllinor, Patrick, T1 aLunetta, Kathryn, L1 aAlbert, Christine, M1 aGlazer, Nicole, L1 aRitchie, Marylyn, D1 aSmith, Albert, V1 aArking, Dan, E1 aMüller-Nurasyid, Martina1 aKrijthe, Bouwe, P1 aLubitz, Steven, A1 aBis, Joshua, C1 aChung, Mina, K1 aDörr, Marcus1 aOzaki, Kouichi1 aRoberts, Jason, D1 aSmith, Gustav1 aPfeufer, Arne1 aSinner, Moritz, F1 aLohman, Kurt1 aDing, Jingzhong1 aSmith, Nicholas, L1 aSmith, Jonathan, D1 aRienstra, Michiel1 aRice, Kenneth, M1 aVan Wagoner, David, R1 aMagnani, Jared, W1 aWakili, Reza1 aClauss, Sebastian1 aRotter, Jerome, I1 aSteinbeck, Gerhard1 aLauner, Lenore, J1 aDavies, Robert, W1 aBorkovich, Matthew1 aHarris, Tamara, B1 aLin, Honghuang1 aVölker, Uwe1 aVölzke, Henry1 aMilan, David, J1 aHofman, Albert1 aBoerwinkle, Eric1 aChen, Lin, Y1 aSoliman, Elsayed, Z1 aVoight, Benjamin, F1 aLi, Guo1 aChakravarti, Aravinda1 aKubo, Michiaki1 aTedrow, Usha, B1 aRose, Lynda, M1 aRidker, Paul, M1 aConen, David1 aTsunoda, Tatsuhiko1 aFurukawa, Tetsushi1 aSotoodehnia, Nona1 aXu, Siyan1 aKamatani, Naoyuki1 aLevy, Daniel1 aNakamura, Yusuke1 aParvez, Babar1 aMahida, Saagar1 aFurie, Karen, L1 aRosand, Jonathan1 aMuhammad, Raafia1 aPsaty, Bruce, M1 aMeitinger, Thomas1 aPerz, Siegfried1 aWichmann, H-Erich1 aWitteman, Jacqueline, C M1 aKao, Linda, W H1 aKathiresan, Sekar1 aRoden, Dan, M1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aMcKnight, Barbara1 aSjögren, Marketa1 aNewman, Anne, B1 aLiu, Yongmei1 aGollob, Michael, H1 aMelander, Olle1 aTanaka, Toshihiro1 aStricker, Bruno, H Ch1 aFelix, Stephan, B1 aAlonso, Alvaro1 aDarbar, Dawood1 aBarnard, John1 aChasman, Daniel, I1 aHeckbert, Susan, R1 aBenjamin, Emelia, J1 aGudnason, Vilmundur1 aKääb, Stefan uhttps://chs-nhlbi.org/node/138304246nas a2200769 4500008004100000022001400041245015300055210006900208260001300277300001000290490000600300520206100306653002202367653000902389653001902398653001302417653002102430653004002451653001102491653003402502653001302536653001002549653001102559653000902570653001602579653001402595653003602609653001202645100001802657700002302675700001902698700001902717700001302736700002402749700002302773700002102796700002202817700001902839700002002858700002102878700002302899700002502922700002202947700002302969700001602992700002103008700001903029700001303048700001803061700002503079700002003104700002903124700002103153700002403174700002203198700002403220700001903244700001803263700002203281700002203303700002203325700002003347700002303367700002303390700002703413856003603440 2013 eng d a1942-326800aGenome-wide association study of cardiac structure and systolic function in African Americans: the Candidate Gene Association Resource (CARe) study.0 aGenomewide association study of cardiac structure and systolic f c2013 Feb a37-460 v63 aBACKGROUND: Using data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study.
METHODS AND RESULTS: Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10(-7)). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10(-7)) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10(-7)) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10(-8)) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10(-7)) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN.
CONCLUSIONS: In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.
10aAfrican Americans10aAged10aCohort Studies10aDiastole10aEchocardiography10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aGenotype10aHeart10aHumans10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aSystole1 aFox, Ervin, R1 aMusani, Solomon, K1 aBarbalic, Maja1 aLin, Honghuang1 aYu, Bing1 aOgunyankin, Kofo, O1 aSmith, Nicholas, L1 aKutlar, Abdullah1 aGlazer, Nicole, L1 aPost, Wendy, S1 aPaltoo, Dina, N1 aDries, Daniel, L1 aFarlow, Deborah, N1 aDuarte, Christine, W1 aKardia, Sharon, L1 aMeyers, Kristin, J1 aSun, Yan, V1 aArnett, Donna, K1 aPatki, Amit, A1 aSha, Jin1 aCui, Xiangqui1 aSamdarshi, Tandaw, E1 aPenman, Alan, D1 aBibbins-Domingo, Kirsten1 aBůzková, Petra1 aBenjamin, Emelia, J1 aBluemke, David, A1 aMorrison, Alanna, C1 aHeiss, Gerardo1 aCarr, Jeffrey1 aTracy, Russell, P1 aMosley, Thomas, H1 aTaylor, Herman, A1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aCappola, Thomas, P1 aVasan, Ramachandran, S uhttps://chs-nhlbi.org/node/663204762nas a2201117 4500008004100000022001400041245011700055210006900172260001500241300001200256490000800268520162700276653000901903653001201912653002401924653002301948653001601971653001101987653001101998653003002009653001702039653003802056653001302094653002502107653001102132653001002143653000902153653001602162653002002178653002102198653002802219653002302247653002602270653002602296653003002322653001402352653002302366100002202389700002202411700002402433700001902457700001802476700002002494700001902514700001902533700001902552700002202571700002202593700002202615700002202637700001902659700002302678700002302701700003002724700002002754700002002774700002102794700001902815700002302834700002002857700002302877700001902900700002302919700002502942700001802967700002302985700002503008700002203033700001903055700001803074700002103092700002403113700001903137700002803156700002403184700002003208700001803228700002103246700002103267700002603288700002403314700002003338700001903358700002303377700001403400700001703414700001803431700002203449700002503471700002203496700001903518700002403537710002603561710002103587856003603608 2014 eng d a1524-453900aIntegrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation.0 aIntegrating genetic transcriptional and functional analyses to i c2014 Oct 7 a1225-350 v1303 aBACKGROUND: 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=6.5×10(-16)), GJA1 (rs13216675; RR=1.10; 95% CI, 1.06-1.14; P=2.2×10(-8)), TBX5 (rs10507248; RR=1.12; 95% CI, 1.08-1.16; P=5.7×10(-11)), and CAND2 (rs4642101; RR=1.10; 95% CI, 1.06-1.14; P=9.8×10(-9)). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95% CI, 1.26-1.39; P=2.0×10(-25)) and CUX2 (rs6490029; RR=1.12; 95% CI, 1.08-1.16; P=3.9×10(-9)). The top single-nucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6×10(-19)), GJA1 (P=2.66×10(-6)), and TBX5 (P=1.36×10(-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.
10aAged10aAnimals10aAtrial Fibrillation10aChromosome Mapping10aConnexin 4310aEurope10aFemale10aGene Knockdown Techniques10aGenetic Loci10aGenetic Predisposition to Disease10aGenotype10aHomeodomain Proteins10aHumans10aJapan10aMale10aMiddle Aged10aMuscle Proteins10aNuclear Proteins10aQuantitative Trait Loci10aRepressor Proteins10aT-Box Domain Proteins10aTranscription Factors10aUbiquitin-Protein Ligases10aZebrafish10aZebrafish Proteins1 aSinner, Moritz, F1 aTucker, Nathan, R1 aLunetta, Kathryn, L1 aOzaki, Kouichi1 aSmith, Gustav1 aTrompet, Stella1 aBis, Joshua, C1 aLin, Honghuang1 aChung, Mina, K1 aNielsen, Jonas, B1 aLubitz, Steven, A1 aKrijthe, Bouwe, P1 aMagnani, Jared, W1 aYe, Jiangchuan1 aGollob, Michael, H1 aTsunoda, Tatsuhiko1 aMüller-Nurasyid, Martina1 aLichtner, Peter1 aPeters, Annette1 aDolmatova, Elena1 aKubo, Michiaki1 aSmith, Jonathan, D1 aPsaty, Bruce, M1 aSmith, Nicholas, L1 aJukema, Wouter1 aChasman, Daniel, I1 aAlbert, Christine, M1 aEbana, Yusuke1 aFurukawa, Tetsushi1 aMacfarlane, Peter, W1 aHarris, Tamara, B1 aDarbar, Dawood1 aDörr, Marcus1 aHolst, Anders, G1 aSvendsen, Jesper, H1 aHofman, Albert1 aUitterlinden, André, G1 aGudnason, Vilmundur1 aIsobe, Mitsuaki1 aMalik, Rainer1 aDichgans, Martin1 aRosand, Jonathan1 aVan Wagoner, David, R1 aBenjamin, Emelia, J1 aMilan, David, J1 aMelander, Olle1 aHeckbert, Susan, R1 aFord, Ian1 aLiu, Yongmei1 aBarnard, John1 aOlesen, Morten, S1 aStricker, Bruno, H C1 aTanaka, Toshihiro1 aKääb, Stefan1 aEllinor, Patrick, T1 aMETASTROKE Consortium1 aAFGen Consortium uhttps://chs-nhlbi.org/node/660003736nas a2200577 4500008004100000022001400041245014100055210006900196260001300265490000600278520210100284653001002385653000902395653002802404653001802432653001002450653001102460653001302471653001102484653001802495653002002513653000902533653002502542653001602567653004002583653004002623653001202663653001502675653003602690653001402726653001702740653002702757100002402784700001102808700001802819700001902837700002502856700002102881700002002902700002102922700001902943700001702962700002002979700002202999700001903021700002003040700002303060700001803083700002103101856003603122 2014 eng d a2047-998000aA low-frequency variant in MAPK14 provides mechanistic evidence of a link with myeloperoxidase: a prognostic cardiovascular risk marker.0 alowfrequency variant in MAPK14 provides mechanistic evidence of c2014 Aug0 v33 aBACKGROUND: Genetics can be used to predict drug effects and generate hypotheses around alternative indications. To support Losmapimod, a p38 mitogen-activated protein kinase inhibitor in development for acute coronary syndrome, we characterized gene variation in MAPK11/14 genes by exome sequencing and follow-up genotyping or imputation in participants well-phenotyped for cardiovascular and metabolic traits.
METHODS AND RESULTS: Investigation of genetic variation in MAPK11 and MAPK14 genes using additive genetic models in linear or logistic regression with cardiovascular, metabolic, and biomarker phenotypes highlighted an association of RS2859144 in MAPK14 with myeloperoxidase in a dyslipidemic population (Genetic Epidemiology of Metabolic Syndrome Study), P=2.3×10(-6)). This variant (or proxy) was consistently associated with myeloperoxidase in the Framingham Heart Study and Cardiovascular Health Study studies (replication meta-P=0.003), leading to a meta-P value of 9.96×10(-7) in the 3 dyslipidemic groups. The variant or its proxy was then profiled in additional population-based cohorts (up to a total of 58 930 subjects) including Cohorte Lausannoise, Ely, Fenland, European Prospective Investigation of Cancer, London Life Sciences Prospective Population Study, and the Genetics of Obesity Associations study obesity case-control for up to 40 cardiovascular and metabolic traits. Overall analysis identified the same single nucleotide polymorphisms to be nominally associated consistently with glomerular filtration rate (P=0.002) and risk of obesity (body mass index ≥30 kg/m(2), P=0.004).
CONCLUSIONS: As myeloperoxidase is a prognostic marker of coronary events, the MAPK14 variant may provide a mechanistic link between p38 map kinase and these events, providing information consistent with current indication of Losmapimod for acute coronary syndrome. If replicated, the association with glomerular filtration rate, along with previous biological findings, also provides support for kidney diseases as alternative indications.
10aAdult10aAged10aCardiovascular Diseases10aDyslipidemias10aExome10aFemale10aGenotype10aHumans10aLinear Models10aLogistic Models10aMale10aMetabolic Syndrome X10aMiddle Aged10aMitogen-Activated Protein Kinase 1110aMitogen-Activated Protein Kinase 1410aObesity10aPeroxidase10aPolymorphism, Single Nucleotide10aPrognosis10aRisk Factors10aSequence Analysis, DNA1 aWaterworth, Dawn, M1 aLi, Li1 aScott, Robert1 aWarren, Liling1 aGillson, Christopher1 aAponte, Jennifer1 aSarov-Blat, Lea1 aSprecher, Dennis1 aDupuis, Josée1 aReiner, Alex1 aPsaty, Bruce, M1 aTracy, Russell, P1 aLin, Honghuang1 aMcPherson, Ruth1 aChissoe, Stephanie1 aWareham, Nick1 aEhm, Margaret, G uhttps://chs-nhlbi.org/node/661004953nas a2201105 4500008004100000022001400041245009300055210006900148260001500217300001200232490000700244520183400251653001002085653000902095653002202104653003702126653002402163653002302187653003102210653001102241653004002252653001102292653002002303653003802323653002502361653001102386653001002397653000902407653001602416653003602432653002602468100002202494700002402516700001902540700001902559700002002578700001202598700002202610700002302632700001802655700002202673700001802695700001902713700002102732700003002753700001902783700002202802700001902824700002302843700001702866700002402883700001402907700002102921700002202942700001902964700001902983700001903002700002203021700001903043700002203062700002503084700002203109700002203131700002203153700002003175700002003195700001903215700002203234700002603256700002303282700002203305700002003327700002003347700002403367700002303391700002803414700002603442700001703468700001903485700002403504700002203528700002403550700002203574700002003596700001603616700002503632700002303657700002203680700002303702700001903725700001903744700002403763700002403787856003603811 2014 eng d a1558-359700aNovel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.0 aNovel genetic markers associate with atrial fibrillation risk in c2014 Apr 1 a1200-100 v633 aOBJECTIVES: This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.
BACKGROUND: AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.
METHODS: We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).
RESULTS: We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.
CONCLUSIONS: The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.
10aAdult10aAged10aAged, 80 and over10aAsian Continental Ancestry Group10aAtrial Fibrillation10aChromosome Mapping10aChromosomes, Human, Pair 410aEurope10aEuropean Continental Ancestry Group10aFemale10aGenetic Markers10aGenetic Predisposition to Disease10aHomeodomain Proteins10aHumans10aJapan10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aTranscription Factors1 aLubitz, Steven, A1 aLunetta, Kathryn, L1 aLin, Honghuang1 aArking, Dan, E1 aTrompet, Stella1 aLi, Guo1 aKrijthe, Bouwe, P1 aChasman, Daniel, I1 aBarnard, John1 aKleber, Marcus, E1 aDörr, Marcus1 aOzaki, Kouichi1 aSmith, Albert, V1 aMüller-Nurasyid, Martina1 aWalter, Stefan1 aAgarwal, Sunil, K1 aBis, Joshua, C1 aBrody, Jennifer, A1 aChen, Lin, Y1 aEverett, Brendan, M1 aFord, Ian1 aFranco, Oscar, H1 aHarris, Tamara, B1 aHofman, Albert1 aKääb, Stefan1 aMahida, Saagar1 aKathiresan, Sekar1 aKubo, Michiaki1 aLauner, Lenore, J1 aMacfarlane, Peter, W1 aMagnani, Jared, W1 aMcKnight, Barbara1 aMcManus, David, D1 aPeters, Annette1 aPsaty, Bruce, M1 aRose, Lynda, M1 aRotter, Jerome, I1 aSilbernagel, Guenther1 aSmith, Jonathan, D1 aSotoodehnia, Nona1 aStott, David, J1 aTaylor, Kent, D1 aTomaschitz, Andreas1 aTsunoda, Tatsuhiko1 aUitterlinden, André, G1 aVan Wagoner, David, R1 aVölker, Uwe1 aVölzke, Henry1 aMurabito, Joanne, M1 aSinner, Moritz, F1 aGudnason, Vilmundur1 aFelix, Stephan, B1 aMärz, Winfried1 aChung, Mina1 aAlbert, Christine, M1 aStricker, Bruno, H1 aTanaka, Toshihiro1 aHeckbert, Susan, R1 aJukema, Wouter1 aAlonso, Alvaro1 aBenjamin, Emelia, J1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/682003673nas a2200529 4500008004100000022001400041245019500055210006900250260001300319300001100332490000600343520199700349653000902346653002202355653001002377653002002387653004302407653001902450653004002469653001102509653002202520653003402542653001302576653001102589653000902600653001602609653003602625653002702661653005202688100001902740700002202759700002302781700002002804700002002824700001702844700002202861700001902883700001802902700001902920700002102939700002002960700001902980700002502999700003003024710005303054856003603107 2014 eng d a1942-326800aSequencing of 2 subclinical atherosclerosis candidate regions in 3669 individuals: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.0 aSequencing of 2 subclinical atherosclerosis candidate regions in c2014 Jun a359-640 v73 aBACKGROUND: Atherosclerosis, the precursor to coronary heart disease and stroke, is characterized by an accumulation of fatty cells in the arterial intimal-medial layers. Common carotid intima media thickness (cIMT) and plaque are subclinical atherosclerosis measures that predict cardiovascular disease events. Previously, genome-wide association studies demonstrated evidence for association with cIMT (SLC17A4) and plaque (PIK3CG).
METHODS AND RESULTS: We sequenced 120 kb around SLC17A4 (6p22.2) and 251 kb around PIK3CG (7q22.3) among 3669 European ancestry participants from the Atherosclerosis Risk in Communities (ARIC) study, Cardiovascular Health Study (CHS), and Framingham Heart Study (FHS) in Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Primary analyses focused on 438 common variants (minor allele frequency ≥1%), which were independently meta-analyzed. A 3' untranslated region CCDC71L variant (rs2286149), upstream from PIK3CG, was the most significant finding in cIMT (P=0.00033) and plaque (P=0.0004) analyses. A SLC17A4 intronic variant was also associated with cIMT (P=0.008). Both were in low linkage disequilibrium with the genome-wide association study single nucleotide polymorphisms. Gene-based tests including T1 count and sequence kernel association test for rare variants (minor allele frequency <1%) did not yield statistically significant associations. However, we observed nominal associations for rare variants in CCDC71L and SLC17A3 with cIMT and of the entire 7q22 region with plaque (P=0.05).
CONCLUSIONS: Common and rare variants in PIK3CG and SLC17A4 regions demonstrated modest association with subclinical atherosclerosis traits. Although not conclusive, these findings may help to understand the genetic architecture of regions previously implicated by genome-wide association studies and identify variants within these regions for further investigation in larger samples.
10aAged10aAged, 80 and over10aAging10aAtherosclerosis10aClass Ib Phosphatidylinositol 3-Kinase10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Variation10aGenome-Wide Association Study10aGenomics10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aSequence Analysis, DNA10aSodium-Phosphate Cotransporter Proteins, Type I1 aBis, Joshua, C1 aWhite, Charles, C1 aFranceschini, Nora1 aBrody, Jennifer1 aZhang, Xiaoling1 aMuzny, Donna1 aSantibanez, Jireh1 aGibbs, Richard1 aLiu, Xiaoming1 aLin, Honghuang1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aNorth, Kari, E1 aCupples, Adrienne, L1 aO'Donnell, Christopher, J1 aCHARGE Subclinical Atherosclerosis Working Group uhttps://chs-nhlbi.org/node/654704324nas a2200793 4500008004100000022001400041245017800055210006900233260001300302300001100315490000600326520200100332653001002333653000902343653002202352653001002374653001902384653001102403653002202414653003402436653001302470653002802483653001902511653001102530653000902541653001602550653004002566653003602606653002702642100002202669700002302691700001902714700001902733700001902752700001702771700001802788700002402806700001602830700002002846700001902866700001902885700002302904700001902927700002402946700002502970700002202995700002403017700001903041700002903060700003003089700002403119700002403143700002003167700002203187700002203209700002203231700002203253700002103275700002003296700002103316700002103337700002103358700002003379700002203399710002203421710004103443710001003484856003603494 2014 eng d a1942-326800aSequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.0 aSequencing of SCN5A identifies rare and common variants associat c2014 Jun a365-730 v73 aBACKGROUND: The cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to characterize further the contribution of rare and common coding variation in SCN5A to cardiac conduction.
METHODS AND RESULTS: In Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study, we performed targeted exonic sequencing of SCN5A (n=3699, European ancestry individuals) and identified 4 common (minor allele frequency >1%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-analysis of European ancestry participants from CHARGE, National Heart, Lung, and Blood Institute's Exome Sequencing Project (n=607), and the UK10K (n=1275) and by examining Exome Sequencing Project African ancestry participants (n=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African ancestry participants (P=1.3×10(-3)). Three common variants were associated with PR and QRS interval duration among European ancestry participants and one among African ancestry participants. These included 2 well-known missense variants: rs1805124 (H558R) was associated with PR and QRS shortening in European ancestry participants (P=6.25×10(-4) and P=5.2×10(-3), respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82×10(-3)). Among European ancestry participants, 2 novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35×10(-7) and P=2.69×10(-4), respectively) and rs6599230 was associated with PR shortening (P=2.67×10(-5)).
CONCLUSIONS: By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.
10aAdult10aAged10aAged, 80 and over10aAging10aCohort Studies10aFemale10aGenetic Variation10aGenome-Wide Association Study10aGenomics10aHeart Conduction System10aHeart Diseases10aHumans10aMale10aMiddle Aged10aNAV1.5 Voltage-Gated Sodium Channel10aPolymorphism, Single Nucleotide10aSequence Analysis, DNA1 aMagnani, Jared, W1 aBrody, Jennifer, A1 aPrins, Bram, P1 aArking, Dan, E1 aLin, Honghuang1 aYin, Xiaoyan1 aLiu, Ching-Ti1 aMorrison, Alanna, C1 aZhang, Feng1 aSpector, Tim, D1 aAlonso, Alvaro1 aBis, Joshua, C1 aHeckbert, Susan, R1 aLumley, Thomas1 aSitlani, Colleen, M1 aCupples, Adrienne, L1 aLubitz, Steven, A1 aSoliman, Elsayed, Z1 aPulit, Sara, L1 aNewton-Cheh, Christopher1 aO'Donnell, Christopher, J1 aEllinor, Patrick, T1 aBenjamin, Emelia, J1 aMuzny, Donna, M1 aGibbs, Richard, A1 aSantibanez, Jireh1 aTaylor, Herman, A1 aRotter, Jerome, I1 aLange, Leslie, A1 aPsaty, Bruce, M1 aJackson, Rebecca1 aRich, Stephen, S1 aBoerwinkle, Eric1 aJamshidi, Yalda1 aSotoodehnia, Nona1 aCHARGE Consortium1 aNHLBI Exome Sequencing Project (ESP)1 aUK10K uhttps://chs-nhlbi.org/node/658303990nas a2200757 4500008004100000022001400041245017100055210006900226260001300295300001100308490000600319520184400325653001002169653000902179653002202188653001002210653001902220653001102239653002202250653003402272653001302306653001902319653001102338653000902349653001602358653003602374653002002410653002702430100001902457700001402476700002302490700001902513700001902532700001902551700002202570700002102592700002402613700002102637700001802658700001802676700002002694700002302714700003002737700002302767700001602790700001702806700001902823700001402842700001602856700002402872700001902896700002402915700001802939700002202957700001902979700001702998700002403015700002403039700002303063700002003086700002003106700002503126700002403151700002103175856003603196 2014 eng d a1942-326800aStrategies to design and analyze targeted sequencing data: cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.0 aStrategies to design and analyze targeted sequencing data cohort c2014 Jun a335-430 v73 aBACKGROUND: Genome-wide association studies have identified thousands of genetic variants that influence a variety of diseases and health-related quantitative traits. However, the causal variants underlying the majority of genetic associations remain unknown. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study aims to follow up genome-wide association study signals and identify novel associations of the allelic spectrum of identified variants with cardiovascular-related traits.
METHODS AND RESULTS: The study included 4231 participants from 3 CHARGE cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, and the Framingham Heart Study. We used a case-cohort design in which we selected both a random sample of participants and participants with extreme phenotypes for each of 14 traits. We sequenced and analyzed 77 genomic loci, which had previously been associated with ≥1 of 14 phenotypes. A total of 52 736 variants were characterized by sequencing and passed our stringent quality control criteria. For common variants (minor allele frequency ≥1%), we performed unweighted regression analyses to obtain P values for associations and weighted regression analyses to obtain effect estimates that accounted for the sampling design. For rare variants, we applied 2 approaches: collapsed aggregate statistics and joint analysis of variants using the sequence kernel association test.
CONCLUSIONS: We sequenced 77 genomic loci in participants from 3 cohorts. We established a set of filters to identify high-quality variants and implemented statistical and bioinformatics strategies to analyze the sequence data and identify potentially functional variants within genome-wide association study loci.
10aAdult10aAged10aAged, 80 and over10aAging10aCohort Studies10aFemale10aGenetic Variation10aGenome-Wide Association Study10aGenomics10aHeart Diseases10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aResearch Design10aSequence Analysis, DNA1 aLin, Honghuang1 aWang, Min1 aBrody, Jennifer, A1 aBis, Joshua, C1 aDupuis, Josée1 aLumley, Thomas1 aMcKnight, Barbara1 aRice, Kenneth, M1 aSitlani, Colleen, M1 aReid, Jeffrey, G1 aBressler, Jan1 aLiu, Xiaoming1 aDavis, Brian, C1 aJohnson, Andrew, D1 aO'Donnell, Christopher, J1 aKovar, Christie, L1 aDinh, Huyen1 aWu, Yuanqing1 aNewsham, Irene1 aChen, Han1 aBroka, Andi1 aDeStefano, Anita, L1 aGupta, Mayetri1 aLunetta, Kathryn, L1 aLiu, Ching-Ti1 aWhite, Charles, C1 aXing, Chuanhua1 aZhou, Yanhua1 aBenjamin, Emelia, J1 aSchnabel, Renate, B1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aMuzny, Donna, M1 aCupples, Adrienne, L1 aMorrison, Alanna, C1 aBoerwinkle, Eric uhttps://chs-nhlbi.org/node/657803677nas a2200613 4500008004100000022001400041245016900055210006900224260001300293300001000306490000700316520181200323653000902135653002402144653001102168653003802179653002202217653003402239653002502273653001102298653002702309653000902336653001602345653003602361653002902397100001902426700002202445700002302467700001902490700002402509700002202533700002202555700002202577700002202599700002202621700002202643700002102665700002002686700002202706700001902728700002202747700001702769700002302786700002402809700001902833700002102852700001902873700002302892700001902915700002402934700002402958710004502982856003603027 2014 eng d a1556-387100aTargeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study.0 aTargeted sequencing in candidate genes for atrial fibrillation t c2014 Mar a452-70 v113 aBACKGROUND: Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF.
OBJECTIVE: To study the association of genetic variants with AF at GWAS top loci.
METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital.
RESULTS: One common variant (rs11265611; P = 1.70 × 10(-6)) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r(2) = .69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P = .01).
CONCLUSIONS: We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.
10aAged10aAtrial Fibrillation10aFemale10aGenetic Predisposition to Disease10aGenetic Variation10aGenome-Wide Association Study10aHomeodomain Proteins10aHumans10aLinkage Disequilibrium10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aReceptors, Interleukin-61 aLin, Honghuang1 aSinner, Moritz, F1 aBrody, Jennifer, A1 aArking, Dan, E1 aLunetta, Kathryn, L1 aRienstra, Michiel1 aLubitz, Steven, A1 aMagnani, Jared, W1 aSotoodehnia, Nona1 aMcKnight, Barbara1 aMcManus, David, D1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aBis, Joshua, C1 aGibbs, Richard, A1 aMuzny, Donna1 aKovar, Christie, L1 aMorrison, Alanna, C1 aGupta, Mayetri1 aFolsom, Aaron, R1 aKääb, Stefan1 aHeckbert, Susan, R1 aAlonso, Alvaro1 aEllinor, Patrick, T1 aBenjamin, Emelia, J1 aCHARGE Atrial Fibrillation Working Group uhttps://chs-nhlbi.org/node/614904486nas a2200901 4500008004100000022001400041245009600055210006900151260001600220300001100236490000700247520184700254653001002101653002202111653002302133653002802156653001902184653004002203653001002243653001102253653001902264653003802283653003402321653003802355653001102393653000902404653001102413653003602424653002902460653001702489100002202506700001802528700001902546700001902565700001402584700002102598700002102619700002002640700002402660700001902684700002802703700002002731700002202751700001202773700002402785700002402809700002102833700002002854700002102874700001902895700002102914700001602935700002002951700001502971700001902986700002003005700001803025700002103043700001803064700002203082700002403104700002303128700002303151700001903174700002603193700002203219700001903241700001903260700002103279700002103300700002403321700002403345700002003369700002003389710006503409710007403474856003603548 2015 eng d a1460-208300aAssociation of exome sequences with plasma C-reactive protein levels in >9000 participants.0 aAssociation of exome sequences with plasma Creactive protein lev c2015 Jan 15 a559-710 v243 aC-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in ∼25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 × 10(-6)). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 × 10(-15)). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-ε2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 × 10(-8)), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In gene-based tests, a burden of rare/lower frequency variation in CRP in EAs (P ≤ 6.8 × 10(-4)) and in retinoic acid receptor-related orphan receptor α (RORA) in AAs (P = 1.7 × 10(-3)) were associated with CRP levels at the candidate gene level (P < 2.0 × 10(-3)). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels.
10aAdult10aAfrican Americans10aC-Reactive Protein10aCardiovascular Diseases10aCohort Studies10aEuropean Continental Ancestry Group10aExome10aFemale10aGene Frequency10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHepatocyte Nuclear Factor 1-alpha10aHumans10aMale10aPlasma10aPolymorphism, Single Nucleotide10aReceptors, Interleukin-610aRisk Factors1 aSchick, Ursula, M1 aAuer, Paul, L1 aBis, Joshua, C1 aLin, Honghuang1 aWei, Peng1 aPankratz, Nathan1 aLange, Leslie, A1 aBrody, Jennifer1 aStitziel, Nathan, O1 aKim, Daniel, S1 aCarlson, Christopher, S1 aFornage, Myriam1 aHaessler, Jeffery1 aHsu, Li1 aJackson, Rebecca, D1 aKooperberg, Charles1 aLeal, Suzanne, M1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aTracy, Russell1 aArdissino, Diego1 aShah, Svati1 aWiller, Cristen1 aLoos, Ruth1 aMelander, Olle1 aMcPherson, Ruth1 aHovingh, Kees1 aReilly, Muredach1 aWatkins, Hugh1 aGirelli, Domenico1 aFontanillas, Pierre1 aChasman, Daniel, I1 aGabriel, Stacey, B1 aGibbs, Richard1 aNickerson, Deborah, A1 aKathiresan, Sekar1 aPeters, Ulrike1 aDupuis, Josée1 aWilson, James, G1 aRich, Stephen, S1 aMorrison, Alanna, C1 aBenjamin, Emelia, J1 aGross, Myron, D1 aReiner, Alex, P1 aCohorts for Heart and Aging Research in Genomic Epidemiology1 aNational Heart, Lung, and Blood Institute GO Exome Sequencing Project uhttps://chs-nhlbi.org/node/659705220nas a2201201 4500008004100000022001400041245010300055210006900158260001600227300000800243490000700251520181700258100002002075700001802095700002302113700002602136700002302162700002002185700002002205700002202225700001902247700001702266700002302283700001602306700002202322700001702344700001802361700001802379700002802397700001902425700001902444700002002463700002202483700002202505700001702527700002302544700001302567700002302580700001902603700002302622700002202645700002102667700002102688700001802709700001602727700001402743700002402757700002902781700002102810700002502831700001802856700002002874700002002894700002102914700001902935700001902954700002202973700002102995700001403016700001603030700002003046700001903066700001903085700002003104700001903124700002503143700002203168700002403190700001903214700002303233700002403256700002403280700002103304700002503325700002503350700002503375700002003400700002603420700002203446700002203468700002303490700002803513700002603541700002103567700002203588700001703610700002303627700001803650700002203668700001903690700002003709700001603729700002903745700002103774700002103795700002103816700002603837700002403863700001903887710002703906710004903933856003603982 2016 eng d a1474-760X00aDNA methylation signatures of chronic low-grade inflammation are associated with complex diseases.0 aDNA methylation signatures of chronic lowgrade inflammation are c2016 Dec 12 a2550 v173 aBACKGROUND: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.
RESULTS: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10(-7)) in the discovery panel of European ancestry and replicated (P < 2.29 × 10(-4)) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10(-5)), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10(-3)), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10(-5)). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.
CONCLUSION: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.
1 aLigthart, Symen1 aMarzi, Carola1 aAslibekyan, Stella1 aMendelson, Michael, M1 aConneely, Karen, N1 aTanaka, Toshiko1 aColicino, Elena1 aWaite, Lindsay, L1 aJoehanes, Roby1 aGuan, Weihua1 aBrody, Jennifer, A1 aElks, Cathy1 aMarioni, Riccardo1 aJhun, Min, A1 aAgha, Golareh1 aBressler, Jan1 aWard-Caviness, Cavin, K1 aChen, Brian, H1 aHuan, Tianxiao1 aBakulski, Kelly1 aSalfati, Elias, L1 aFiorito, Giovanni1 aWahl, Simone1 aSchramm, Katharina1 aSha, Jin1 aHernandez, Dena, G1 aJust, Allan, C1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aPilling, Luke, C1 aPankow, James, S1 aTsao, Phil, S1 aLiu, Chunyu1 aZhao, Wei1 aGuarrera, Simonetta1 aMichopoulos, Vasiliki, J1 aSmith, Alicia, K1 aPeters, Marjolein, J1 aMelzer, David1 aVokonas, Pantel1 aFornage, Myriam1 aProkisch, Holger1 aBis, Joshua, C1 aChu, Audrey, Y1 aHerder, Christian1 aGrallert, Harald1 aYao, Chen1 aShah, Sonia1 aMcRae, Allan, F1 aLin, Honghuang1 aHorvath, Steve1 aFallin, Daniele1 aHofman, Albert1 aWareham, Nicholas, J1 aWiggins, Kerri, L1 aFeinberg, Andrew, P1 aStarr, John, M1 aVisscher, Peter, M1 aMurabito, Joanne, M1 aKardia, Sharon, L R1 aAbsher, Devin, M1 aBinder, Elisabeth, B1 aSingleton, Andrew, B1 aBandinelli, Stefania1 aPeters, Annette1 aWaldenberger, Melanie1 aMatullo, Giuseppe1 aSchwartz, Joel, D1 aDemerath, Ellen, W1 aUitterlinden, André, G1 avan Meurs, Joyce, B J1 aFranco, Oscar, H1 aChen, Yii-Der Ida1 aLevy, Daniel1 aTurner, Stephen, T1 aDeary, Ian, J1 aRessler, Kerry, J1 aDupuis, Josée1 aFerrucci, Luigi1 aOng, Ken, K1 aAssimes, Themistocles, L1 aBoerwinkle, Eric1 aKoenig, Wolfgang1 aArnett, Donna, K1 aBaccarelli, Andrea, A1 aBenjamin, Emelia, J1 aDehghan, Abbas1 aWHI-EMPC Investigators1 aCHARGE epigenetics of Coronary Heart Disease uhttps://chs-nhlbi.org/node/734903189nas a2200433 4500008004100000022001400041245005100055210005000106260001300156300001300169490000700182520196300189100002202152700002302174700002502197700002202222700001802244700003002262700001902292700002102311700002202332700001902354700002502373700002102398700002602419700001702445700002002462700002002482700002402502700002202526700002402548700002402572700002302596700001902619700002402638700001902662710003802681856003602719 2016 eng d a1553-740400aWhole Exome Sequencing in Atrial Fibrillation.0 aWhole Exome Sequencing in Atrial Fibrillation c2016 Sep ae10062840 v123 aAtrial fibrillation (AF) is a morbid and heritable arrhythmia. Over 35 genes have been reported to underlie AF, most of which were described in small candidate gene association studies. Replication remains lacking for most, and therefore the contribution of coding variation to AF susceptibility remains poorly understood. We examined whole exome sequencing data in a large community-based sample of 1,734 individuals with and 9,423 without AF from the Framingham Heart Study, Cardiovascular Health Study, Atherosclerosis Risk in Communities Study, and NHLBI-GO Exome Sequencing Project and meta-analyzed the results. We also examined whether genetic variation was enriched in suspected AF genes (N = 37) in AF cases versus controls. The mean age ranged from 59 to 73 years; 8,656 (78%) were of European ancestry. None of the 99,404 common variants evaluated was significantly associated after adjusting for multiple testing. Among the most significantly associated variants was a common (allele frequency = 86%) missense variant in SYNPO2L (rs3812629, p.Pro707Leu, [odds ratio 1.27, 95% confidence interval 1.13-1.43, P = 6.6x10-5]) which lies at a known AF susceptibility locus and is in linkage disequilibrium with a top marker from prior analyses at the locus. We did not observe significant associations between rare variants and AF in gene-based tests. Individuals with AF did not display any statistically significant enrichment for common or rare coding variation in previously implicated AF genes. In conclusion, we did not observe associations between coding genetic variants and AF, suggesting that large-effect coding variation is not the predominant mechanism underlying AF. A coding variant in SYNPO2L requires further evaluation to determine whether it is causally related to AF. Efforts to identify biologically meaningful coding variation underlying AF may require large sample sizes or populations enriched for large genetic effects.
1 aLubitz, Steven, A1 aBrody, Jennifer, A1 aBihlmeyer, Nathan, A1 aRoselli, Carolina1 aWeng, Lu-Chen1 aChristophersen, Ingrid, E1 aAlonso, Alvaro1 aBoerwinkle, Eric1 aGibbs, Richard, A1 aBis, Joshua, C1 aCupples, Adrienne, L1 aMohler, Peter, J1 aNickerson, Deborah, A1 aMuzny, Donna1 aPerez, Marco, V1 aPsaty, Bruce, M1 aSoliman, Elsayed, Z1 aSotoodehnia, Nona1 aLunetta, Kathryn, L1 aBenjamin, Emelia, J1 aHeckbert, Susan, R1 aArking, Dan, E1 aEllinor, Patrick, T1 aLin, Honghuang1 aNHLBI GO Exome Sequencing Project uhttps://chs-nhlbi.org/node/725006088nas a2201561 4500008004100000022001400041245007200055210006900127260001600196520173100212100002801943700002101971700002401992700001802016700002002034700002202054700002502076700001602101700001802117700001802135700001802153700002002171700002002191700001502211700002302226700003002249700001902279700001302298700002102311700002802332700002002360700002402380700002002404700001902424700001802443700002102461700002102482700002102503700001702524700002202541700001902563700001902582700002002601700002502621700002302646700002202669700002402691700002102715700002402736700002202760700002202782700001702804700002302821700001902844700002202863700002302885700001902908700002002927700002002947700002402967700001802991700002203009700001203031700001303043700002103056700001503077700002503092700002103117700002203138700002103160700002203181700002703203700001703230700002503247700002003272700002303292700001803315700002003333700001503353700002303368700002603391700002203417700001603439700001903455700001703474700002203491700002403513700002403537700002203561700002603583700002003609700002103629700002403650700002103674700001803695700002403713700001703737700002603754700001603780700002803796700001903824700001903843700002103862700002003883700002303903700002403926700001903950700002703969700002203996700002204018700002404040700001804064700002204082700001904104700002204123700002304145700002304168700001804191700002904209700002004238700001904258700002204277700001804299700002404317700002204341700001904363700002404382700001504406700002204421700002304443700002404466856003604490 2017 eng d a1460-208300aDiscovery of novel heart rate-associated loci using the Exome Chip.0 aDiscovery of novel heart rateassociated loci using the Exome Chi c2017 Apr 033 aBackground 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.
1 avan den Berg, Marten, E1 aWarren, Helen, R1 aCabrera, Claudia, P1 aVerweij, Niek1 aMifsud, Borbala1 aHaessler, Jeffrey1 aBihlmeyer, Nathan, A1 aFu, Yi-Ping1 aWeiss, Stefan1 aLin, Henry, J1 aGrarup, Niels1 aLi-Gao, Ruifang1 aPistis, Giorgio1 aShah, Nabi1 aBrody, Jennifer, A1 aMüller-Nurasyid, Martina1 aLin, Honghuang1 aMei, Hao1 aSmith, Albert, V1 aLyytikäinen, Leo-Pekka1 aHall, Leanne, M1 avan Setten, Jessica1 aTrompet, Stella1 aPrins, Bram, P1 aIsaacs, Aaron1 aRadmanesh, Farid1 aMarten, Jonathan1 aEntwistle, Aiman1 aKors, Jan, A1 aSilva, Claudia, T1 aAlonso, Alvaro1 aBis, Joshua, C1 ade Boer, Rudolf1 ade Haan, Hugoline, G1 ade Mutsert, Renée1 aDedoussis, George1 aDominiczak, Anna, F1 aDoney, Alex, S F1 aEllinor, Patrick, T1 aEppinga, Ruben, N1 aFelix, Stephan, B1 aGuo, Xiuqing1 aHagemeijer, Yanick1 aHansen, Torben1 aHarris, Tamara, B1 aHeckbert, Susan, R1 aHuang, Paul, L1 aHwang, Shih-Jen1 aKähönen, Mika1 aKanters, Jørgen, K1 aKolcic, Ivana1 aLauner, Lenore, J1 aLi, Man1 aYao, Jie1 aLinneberg, Allan1 aLiu, Simin1 aMacfarlane, Peter, W1 aMangino, Massimo1 aMorris, Andrew, D1 aMulas, Antonella1 aMurray, Alison, D1 aNelson, Christopher, P1 aOrrù, Marco1 aPadmanabhan, Sandosh1 aPeters, Annette1 aPorteous, David, J1 aPoulter, Neil1 aPsaty, Bruce, M1 aQi, Lihong1 aRaitakari, Olli, T1 aRivadeneira, Fernando1 aRoselli, Carolina1 aRudan, Igor1 aSattar, Naveed1 aSever, Peter1 aSinner, Moritz, F1 aSoliman, Elsayed, Z1 aSpector, Timothy, D1 aStanton, Alice, V1 aStirrups, Kathleen, E1 aTaylor, Kent, D1 aTobin, Martin, D1 aUitterlinden, Andre1 aVaartjes, Ilonca1 aHoes, Arno, W1 avan der Meer, Peter1 aVölker, Uwe1 aWaldenberger, Melanie1 aXie, Zhijun1 aZoledziewska, Magdalena1 aTinker, Andrew1 aPolasek, Ozren1 aRosand, Jonathan1 aJamshidi, Yalda1 aDuijn, Cornelia, M1 aZeggini, Eleftheria1 aJukema, Wouter1 aAsselbergs, Folkert, W1 aSamani, Nilesh, J1 aLehtimäki, Terho1 aGudnason, Vilmundur1 aWilson, James1 aLubitz, Steven, A1 aKääb, Stefan1 aSotoodehnia, Nona1 aCaulfield, Mark, J1 aPalmer, Colin, N A1 aSanna, Serena1 aMook-Kanamori, Dennis, O1 aDeloukas, Panos1 aPedersen, Oluf1 aRotter, Jerome, I1 aDörr, Marcus1 aO'Donnell, Chris, J1 aHayward, Caroline1 aArking, Dan, E1 aKooperberg, Charles1 aHarst, Pim1 aEijgelsheim, Mark1 aStricker, Bruno, H1 aMunroe, Patricia, B uhttps://chs-nhlbi.org/node/736306999nas a2202113 4500008004100000022001400041245011100055210006900166260001300235300001200248490000700260520104100267100003001308700002201338700002201360700001701382700002301399700001801422700001901440700001901459700002101478700002501499700001801524700002201542700001501564700001801579700002501597700001801622700002001640700003001660700001801690700002301708700002601731700001801757700002001775700002201795700002301817700002301840700002201863700002801885700002101913700001801934700002801952700001701980700001901997700002602016700002702042700001302069700002102082700001802103700002202121700002202143700001802165700002202183700001502205700002102220700001902241700001602260700002302276700002302299700002002322700001602342700002502358700002102383700002302404700002602427700001802453700002302471700001902494700002302513700002602536700001902562700002002581700002002601700002002621700002202641700002202663700002202685700002402707700002502731700002202756700002002778700002602798700002002824700001902844700002102863700002002884700001802904700002302922700002002945700002002965700001502985700002103000700001803021700002403039700002303063700002503086700001903111700001503130700001903145700002203164700001403186700002003200700002203220700001703242700002203259700002503281700001203306700002103318700001803339700001903357700001803376700002903394700002003423700002103443700002503464700002003489700002203509700002703531700002303558700001703581700002503598700002003623700001803643700002103661700002203682700001903704700002903723700002303752700002503775700003203800700001903832700001903851700002203870700002403892700002803916700001903944700002103963700001703984700002404001700002204025700001804047700001704065700002104082700002004103700002404123700001904147700002004166700001904186700001704205700002104222700001504243700002304258700002204281700002304303700001904326700002204345700002204367700002004389700002204409700002304431700001904454700002204473700002404495700001904519700001804538700001904556700002304575700002304598700002404621700002204645700002404667700002204691700002404713710003804737710005304775710002104828856003604849 2017 eng d a1546-171800aLarge-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.0 aLargescale analyses of common and rare variants identify 12 new c2017 Jun a946-9520 v493 aAtrial 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.
1 aChristophersen, Ingrid, E1 aRienstra, Michiel1 aRoselli, Carolina1 aYin, Xiaoyan1 aGeelhoed, Bastiaan1 aBarnard, John1 aLin, Honghuang1 aArking, Dan, E1 aSmith, Albert, V1 aAlbert, Christine, M1 aChaffin, Mark1 aTucker, Nathan, R1 aLi, Molong1 aKlarin, Derek1 aBihlmeyer, Nathan, A1 aLow, Siew-Kee1 aWeeke, Peter, E1 aMüller-Nurasyid, Martina1 aSmith, Gustav1 aBrody, Jennifer, A1 aNiemeijer, Maartje, N1 aDörr, Marcus1 aTrompet, Stella1 aHuffman, Jennifer1 aGustafsson, Stefan1 aSchurmann, Claudia1 aKleber, Marcus, E1 aLyytikäinen, Leo-Pekka1 aSeppälä, Ilkka1 aMalik, Rainer1 aHorimoto, Andrea, R V R1 aPerez, Marco1 aSinisalo, Juha1 aAeschbacher, Stefanie1 aThériault, Sébastien1 aYao, Jie1 aRadmanesh, Farid1 aWeiss, Stefan1 aTeumer, Alexander1 aChoi, Seung, Hoan1 aWeng, Lu-Chen1 aClauss, Sebastian1 aDeo, Rajat1 aRader, Daniel, J1 aShah, Svati, H1 aSun, Albert1 aHopewell, Jemma, C1 aDebette, Stephanie1 aChauhan, Ganesh1 aYang, Qiong1 aWorrall, Bradford, B1 aParé, Guillaume1 aKamatani, Yoichiro1 aHagemeijer, Yanick, P1 aVerweij, Niek1 aSiland, Joylene, E1 aKubo, Michiaki1 aSmith, Jonathan, D1 aVan Wagoner, David, R1 aBis, Joshua, C1 aPerz, Siegfried1 aPsaty, Bruce, M1 aRidker, Paul, M1 aMagnani, Jared, W1 aHarris, Tamara, B1 aLauner, Lenore, J1 aShoemaker, Benjamin1 aPadmanabhan, Sandosh1 aHaessler, Jeffrey1 aBartz, Traci, M1 aWaldenberger, Melanie1 aLichtner, Peter1 aArendt, Marina1 aKrieger, Jose, E1 aKähönen, Mika1 aRisch, Lorenz1 aMansur, Alfredo, J1 aPeters, Annette1 aSmith, Blair, H1 aLind, Lars1 aScott, Stuart, A1 aLu, Yingchang1 aBottinger, Erwin, B1 aHernesniemi, Jussi1 aLindgren, Cecilia, M1 aWong, Jorge, A1 aHuang, Jie1 aEskola, Markku1 aMorris, Andrew, P1 aFord, Ian1 aReiner, Alex, P1 aDelgado, Graciela1 aChen, Lin, Y1 aChen, Yii-Der Ida1 aSandhu, Roopinder, K1 aLi, Man1 aBoerwinkle, Eric1 aEisele, Lewin1 aLannfelt, Lars1 aRost, Natalia1 aAnderson, Christopher, D1 aTaylor, Kent, D1 aCampbell, Archie1 aMagnusson, Patrik, K1 aPorteous, David1 aHocking, Lynne, J1 aVlachopoulou, Efthymia1 aPedersen, Nancy, L1 aNikus, Kjell1 aOrho-Melander, Marju1 aHamsten, Anders1 aHeeringa, Jan1 aDenny, Joshua, C1 aKriebel, Jennifer1 aDarbar, Dawood1 aNewton-Cheh, Christopher1 aShaffer, Christian1 aMacfarlane, Peter, W1 aHeilmann-Heimbach, Stefanie1 aAlmgren, Peter1 aHuang, Paul, L1 aSotoodehnia, Nona1 aSoliman, Elsayed, Z1 aUitterlinden, André, G1 aHofman, Albert1 aFranco, Oscar, H1 aVölker, Uwe1 aJöckel, Karl-Heinz1 aSinner, Moritz, F1 aLin, Henry, J1 aGuo, Xiuqing1 aDichgans, Martin1 aIngelsson, Erik1 aKooperberg, Charles1 aMelander, Olle1 aLoos, Ruth, J F1 aLaurikka, Jari1 aConen, David1 aRosand, Jonathan1 aHarst, Pim1 aLokki, Marja-Liisa1 aKathiresan, Sekar1 aPereira, Alexandre1 aJukema, Wouter1 aHayward, Caroline1 aRotter, Jerome, I1 aMärz, Winfried1 aLehtimäki, Terho1 aStricker, Bruno, H1 aChung, Mina, K1 aFelix, Stephan, B1 aGudnason, Vilmundur1 aAlonso, Alvaro1 aRoden, Dan, M1 aKääb, Stefan1 aChasman, Daniel, I1 aHeckbert, Susan, R1 aBenjamin, Emelia, J1 aTanaka, Toshihiro1 aLunetta, Kathryn, L1 aLubitz, Steven, A1 aEllinor, Patrick, T1 aMETASTROKE Consortium of the ISGC1 aNeurology Working Group of the CHARGE Consortium1 aAFGen Consortium uhttps://chs-nhlbi.org/node/739606419nas a2201621 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2017 eng d a1558-823800aLarge-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function.0 aLargescale genomewide analysis identifies genetic variants assoc c2017 May 01 a1798-18120 v1273 aBACKGROUND: 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.
1 aWild, Philipp, S1 aFelix, Janine, F1 aSchillert, Arne1 aTeumer, Alexander1 aChen, Ming-Huei1 aLeening, Maarten, J G1 aVölker, Uwe1 aGroßmann, Vera1 aBrody, Jennifer, A1 aIrvin, Marguerite, R1 aShah, Sanjiv, J1 aPramana, Setia1 aLieb, Wolfgang1 aSchmidt, Reinhold1 aStanton, Alice, V1 aMalzahn, Dörthe1 aSmith, Albert, Vernon1 aSundström, Johan1 aMinelli, Cosetta1 aRuggiero, Daniela1 aLyytikäinen, Leo-Pekka1 aTiller, Daniel1 aSmith, Gustav1 aMonnereau, Claire1 aDi Tullio, Marco, R1 aMusani, Solomon, K1 aMorrison, Alanna, C1 aPers, Tune, H1 aMorley, Michael1 aKleber, Marcus, E1 aAragam, Jayashri1 aBenjamin, Emelia, J1 aBis, Joshua, C1 aBisping, Egbert1 aBroeckel, Ulrich1 aCheng, Susan1 aDeckers, Jaap, W1 aM, Fabiola, del Greco1 aEdelmann, Frank1 aFornage, Myriam1 aFranke, Lude1 aFriedrich, Nele1 aHarris, Tamara, B1 aHofer, Edith1 aHofman, Albert1 aHuang, Jie1 aHughes, Alun, D1 aKähönen, Mika1 aInvestigators, Knhi1 aKruppa, Jochen1 aLackner, Karl, J1 aLannfelt, Lars1 aLaskowski, Rafael1 aLauner, Lenore, J1 aLeosdottir, Margrét1 aLin, Honghuang1 aLindgren, Cecilia, M1 aLoley, Christina1 aMacRae, Calum, A1 aMascalzoni, Deborah1 aMayet, Jamil1 aMedenwald, Daniel1 aMorris, Andrew, P1 aMüller, Christian1 aMüller-Nurasyid, Martina1 aNappo, Stefania1 aNilsson, Peter, M1 aNuding, Sebastian1 aNutile, Teresa1 aPeters, Annette1 aPfeufer, Arne1 aPietzner, Diana1 aPramstaller, Peter, P1 aRaitakari, Olli, T1 aRice, Kenneth, M1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aRuohonen, Saku, T1 aSacco, Ralph, L1 aSamdarshi, Tandaw, E1 aSchmidt, Helena1 aSharp, Andrew, S P1 aShields, Denis, C1 aSorice, Rossella1 aSotoodehnia, Nona1 aStricker, Bruno, H1 aSurendran, Praveen1 aThom, Simon1 aTöglhofer, Anna, M1 aUitterlinden, André, G1 aWachter, Rolf1 aVölzke, Henry1 aZiegler, Andreas1 aMünzel, Thomas1 aMärz, Winfried1 aCappola, Thomas, P1 aHirschhorn, Joel, N1 aMitchell, Gary, F1 aSmith, Nicholas, L1 aFox, Ervin, R1 aDueker, Nicole, D1 aJaddoe, Vincent, W V1 aMelander, Olle1 aRuss, Martin1 aLehtimäki, Terho1 aCiullo, Marina1 aHicks, Andrew, A1 aLind, Lars1 aGudnason, Vilmundur1 aPieske, Burkert1 aBarron, Anthony, J1 aZweiker, Robert1 aSchunkert, Heribert1 aIngelsson, Erik1 aLiu, Kiang1 aArnett, Donna, K1 aPsaty, Bruce, M1 aBlankenberg, Stefan1 aLarson, Martin, G1 aFelix, Stephan, B1 aFranco, Oscar, H1 aZeller, Tanja1 aVasan, Ramachandran, S1 aDörr, Marcus uhttps://chs-nhlbi.org/node/737317687nas a2205785 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2017 eng d a1546-171800aRare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.0 aRare coding variants in PLCG2 ABI3 and TREM2 implicate microglia c2017 Sep a1373-13840 v493 aWe identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
10aAdaptor Proteins, Signal Transducing10aAlzheimer Disease10aAmino Acid Sequence10aCase-Control Studies10aExome10aGene Expression Profiling10aGene Frequency10aGenetic Predisposition to Disease10aGenotype10aHumans10aImmunity, Innate10aLinkage Disequilibrium10aMembrane Glycoproteins10aMicroglia10aOdds Ratio10aPhospholipase C gamma10aPolymorphism, Single Nucleotide10aProtein Interaction Maps10aReceptors, Immunologic10aSequence Homology, Amino Acid1 aSims, Rebecca1 avan der Lee, Sven, J1 aNaj, Adam, C1 aBellenguez, Céline1 aBadarinarayan, Nandini1 aJakobsdottir, Johanna1 aKunkle, Brian, W1 aBoland, Anne1 aRaybould, Rachel1 aBis, Joshua, C1 aMartin, Eden, R1 aGrenier-Boley, Benjamin1 aHeilmann-Heimbach, Stefanie1 aChouraki, Vincent1 aKuzma, Amanda, B1 aSleegers, Kristel1 aVronskaya, Maria1 aRuiz, Agustin1 aGraham, Robert, R1 aOlaso, Robert1 aHoffmann, Per1 aGrove, Megan, L1 aVardarajan, Badri, N1 aHiltunen, Mikko1 aNöthen, Markus, M1 aWhite, Charles, C1 aHamilton-Nelson, Kara, L1 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Roger, N1 aSager, Mark, A1 aSaykin, Andrew, J1 aSchneider, Julie, A1 aSchneider, Lon, S1 aSeeley, William, W1 aSmith, Amanda, G1 aSonnen, Joshua, A1 aSpina, Salvatore1 aStern, Robert, A1 aSwerdlow, Russell, H1 aTanzi, Rudolph, E1 aThornton-Wells, Tricia, A1 aTrojanowski, John, Q1 aTroncoso, Juan, C1 aVan Deerlin, Vivianna, M1 aVan Eldik, Linda, J1 aVinters, Harry, V1 aVonsattel, Jean, Paul1 aWeintraub, Sandra1 aWelsh-Bohmer, Kathleen, A1 aWilhelmsen, Kirk, C1 aWilliamson, Jennifer1 aWingo, Thomas, S1 aWoltjer, Randall, L1 aWright, Clinton, B1 aYu, Chang-En1 aYu, Lei1 aGarzia, Fabienne1 aGolamaully, Feroze1 aSeptier, Gislain1 aEngelborghs, Sebastien1 aVandenberghe, Rik1 aDe Deyn, Peter, P1 aFernadez, Carmen, Muñoz1 aBenito, Yoland, Aladro1 aThonberg, Håkan1 aForsell, Charlotte1 aLilius, Lena1 aKinhult-Ståhlbom, Anne1 aKilander, Lena1 aBrundin, RoseMarie1 aConcari, Letizia1 aHelisalmi, Seppo1 aKoivisto, Anne, Maria1 aHaapasalo, Annakaisa1 aDermecourt, Vincent1 aFiévet, Nathalie1 aHanon, Olivier1 aDufouil, Carole1 aBrice, Alexis1 aRitchie, Karen1 aDubois, Bruno1 aHimali, Jayanadra, J1 aKeene, Dirk1 aTschanz, JoAnn1 aFitzpatrick, Annette, L1 aKukull, Walter, A1 aNorton, Maria1 aAspelund, Thor1 aLarson, Eric, B1 aMunger, Ron1 aRotter, Jerome, I1 aLipton, Richard, B1 aBullido, María, J1 aHofman, Albert1 aMontine, Thomas, J1 aCoto, Eliecer1 aBoerwinkle, Eric1 aPetersen, Ronald, C1 aAlvarez, Victoria1 aRivadeneira, Fernando1 aReiman, Eric, M1 aGallo, Maura1 aO'Donnell, Christopher, J1 aReisch, Joan, S1 aBruni, Amalia, Cecilia1 aRoyall, Donald, R1 aDichgans, Martin1 aSano, Mary1 aGalimberti, Daniela1 aSt George-Hyslop, Peter1 aScarpini, Elio1 aTsuang, Debby, W1 aMancuso, Michelangelo1 aBonuccelli, Ubaldo1 aWinslow, Ashley, R1 aDaniele, Antonio1 aWu, Chuang-Kuo1 aPeters, Oliver1 aNacmias, Benedetta1 aRiemenschneider, Matthias1 aHeun, Reinhard1 aBrayne, Carol1 aRubinsztein, David, C1 aBras, Jose1 aGuerreiro, Rita1 aAl-Chalabi, Ammar1 aShaw, Christopher, E1 aCollinge, John1 aMann, David1 aTsolaki, Magda1 aClarimon, Jordi1 aSussams, Rebecca1 aLovestone, Simon1 aO'Donovan, Michael, C1 aOwen, Michael, J1 aBehrens, Timothy, W1 aMead, Simon1 aGoate, Alison, M1 aUitterlinden, André, G1 aHolmes, Clive1 aCruchaga, Carlos1 aIngelsson, Martin1 aBennett, David, A1 aPowell, John1 aGolde, Todd, E1 aGraff, Caroline1 aDe Jager, Philip, L1 aMorgan, Kevin1 aErtekin-Taner, Nilufer1 aCombarros, Onofre1 aPsaty, Bruce, M1 aPassmore, Peter1 aYounkin, Steven, G1 aBerr, Claudine1 aGudnason, Vilmundur1 aRujescu, Dan1 aDickson, Dennis, W1 aDartigues, Jean-François1 aDeStefano, Anita, L1 aOrtega-Cubero, Sara1 aHakonarson, Hakon1 aCampion, Dominique1 aBoada, Merce1 aKauwe, John, Keoni1 aFarrer, Lindsay, A1 aVan Broeckhoven, Christine1 aIkram, Arfan, M1 aJones, Lesley1 aHaines, Jonathan, L1 aTzourio, Christophe1 aLauner, Lenore, J1 aEscott-Price, Valentina1 aMayeux, Richard1 aDeleuze, Jean-Francois1 aAmin, Najaf1 aHolmans, Peter, A1 aPericak-Vance, Margaret, A1 aAmouyel, Philippe1 aDuijn, Cornelia, M1 aRamirez, Alfredo1 aSan Wang, Li-1 aLambert, Jean-Charles1 aSeshadri, Sudha1 aWilliams, Julie1 aSchellenberg, Gerard, D1 aARUK Consortium1 aGERAD/PERADES, CHARGE, ADGC, EADI uhttps://chs-nhlbi.org/node/758705196nas a2201345 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2018 eng d a2574-830000aCommon and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval.0 aCommon and Rare Coding Genetic Variation Underlying the Electroc c2018 May ae0020370 v113 aBACKGROUND: 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.
1 aLin, Honghuang1 avan Setten, Jessica1 aSmith, Albert, V1 aBihlmeyer, Nathan, A1 aWarren, Helen, R1 aBrody, Jennifer, A1 aRadmanesh, Farid1 aHall, Leanne1 aGrarup, Niels1 aMüller-Nurasyid, Martina1 aBoutin, Thibaud1 aVerweij, Niek1 aLin, Henry, J1 aLi-Gao, Ruifang1 avan den Berg, Marten, E1 aMarten, Jonathan1 aWeiss, Stefan1 aPrins, Bram, P1 aHaessler, Jeffrey1 aLyytikäinen, Leo-Pekka1 aMei, Hao1 aHarris, Tamara, B1 aLauner, Lenore, J1 aLi, Man1 aAlonso, Alvaro1 aSoliman, Elsayed, Z1 aConnell, John, M1 aHuang, Paul, L1 aWeng, Lu-Chen1 aJameson, Heather, S1 aHucker, William1 aHanley, Alan1 aTucker, Nathan, R1 aChen, Yii-Der Ida1 aBis, Joshua, C1 aRice, Kenneth, M1 aSitlani, Colleen, M1 aKors, Jan, A1 aXie, Zhijun1 aWen, Chengping1 aMagnani, Jared, W1 aNelson, Christopher, P1 aKanters, Jørgen, K1 aSinner, Moritz, F1 aStrauch, Konstantin1 aPeters, Annette1 aWaldenberger, Melanie1 aMeitinger, Thomas1 aBork-Jensen, Jette1 aPedersen, Oluf1 aLinneberg, Allan1 aRudan, Igor1 ade Boer, Rudolf, A1 avan der Meer, Peter1 aYao, Jie1 aGuo, Xiuqing1 aTaylor, Kent, D1 aSotoodehnia, Nona1 aRotter, Jerome, I1 aMook-Kanamori, Dennis, O1 aTrompet, Stella1 aRivadeneira, Fernando1 aUitterlinden, Andre1 aEijgelsheim, Mark1 aPadmanabhan, Sandosh1 aSmith, Blair, H1 aVölzke, Henry1 aFelix, Stephan, B1 aHomuth, Georg1 aVölker, Uwe1 aMangino, Massimo1 aSpector, Timothy, D1 aBots, Michiel, L1 aPerez, Marco1 aKähönen, Mika1 aRaitakari, Olli, T1 aGudnason, Vilmundur1 aArking, Dan, E1 aMunroe, Patricia, B1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aBenjamin, Emelia, J1 aRosand, Jonathan1 aSamani, Nilesh, J1 aHansen, Torben1 aKääb, Stefan1 aPolasek, Ozren1 aHarst, Pim1 aHeckbert, Susan, R1 aJukema, Wouter1 aStricker, Bruno, H1 aHayward, Caroline1 aDörr, Marcus1 aJamshidi, Yalda1 aAsselbergs, Folkert, W1 aKooperberg, Charles1 aLehtimäki, Terho1 aWilson, James, G1 aEllinor, Patrick, T1 aLubitz, Steven, A1 aIsaacs, Aaron uhttps://chs-nhlbi.org/node/780103950nas a2200685 4500008004100000022001400041245009900055210006900154260001300223300001200236490000700248520197400255100002002229700002302249700001902272700002302291700001702314700001902331700002102350700002202371700002202393700001802415700002402433700001902457700001302476700002202489700002102511700001902532700002302551700002402574700001902598700002402617700002502641700001902666700002902685700001802714700002302732700002602755700001902781700002102800700003002821700002202851700002602873700002302899700002302922700002402945700001702969700002202986700002403008700002203032700002503054700002103079700002003100700002003120700002103140700002103161700002203182700002403204856003603228 2018 eng d a2574-830000aCommon Coding Variants in Are Associated With the Nav1.8 Late Current and Cardiac Conduction.0 aCommon Coding Variants in Are Associated With the Nav18 Late Cur c2018 May ae0016630 v113 aBACKGROUND: Genetic variants at the / locus are strongly associated with electrocardiographic PR and QRS intervals. While is the canonical cardiac sodium channel gene, the role of in cardiac conduction is less well characterized.
METHODS: We sequenced the locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology.
RESULTS: We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium ( =0.86) with each other to be the strongest signals for PR (rs10428132, β=-4.74, =1.52×10) and QRS intervals (rs6599251, QRS β=-0.73; =1.2×10), respectively. Although these variants were not associated with or expression in human atrial tissue (n=490), they were in high linkage disequilibrium ( ≥0.72) with a common missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2±3.3%, =0.03, and I962V+V1073A, 22.4±0.8%, =0.0004 versus wild-type 11.7±1.6%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4±1.2%, =0.03).
CONCLUSIONS: Our findings suggest an association between genetic variation in , the late sodium current, and alterations in cardiac conduction.
1 aMacri, Vincenzo1 aBrody, Jennifer, A1 aArking, Dan, E1 aHucker, William, J1 aYin, Xiaoyan1 aLin, Honghuang1 aMills, Robert, W1 aSinner, Moritz, F1 aLubitz, Steven, A1 aLiu, Ching-Ti1 aMorrison, Alanna, C1 aAlonso, Alvaro1 aLi, Ning1 aFedorov, Vadim, V1 aJanssen, Paul, M1 aBis, Joshua, C1 aHeckbert, Susan, R1 aDolmatova, Elena, V1 aLumley, Thomas1 aSitlani, Colleen, M1 aCupples, Adrienne, L1 aPulit, Sara, L1 aNewton-Cheh, Christopher1 aBarnard, John1 aSmith, Jonathan, D1 aVan Wagoner, David, R1 aChung, Mina, K1 aVlahakes, Gus, J1 aO'Donnell, Christopher, J1 aRotter, Jerome, I1 aMargulies, Kenneth, B1 aMorley, Michael, P1 aCappola, Thomas, P1 aBenjamin, Emelia, J1 aMuzny, Donna1 aGibbs, Richard, A1 aJackson, Rebecca, D1 aMagnani, Jared, W1 aHerndon, Caroline, N1 aRich, Stephen, S1 aPsaty, Bruce, M1 aMilan, David, J1 aBoerwinkle, Eric1 aMohler, Peter, J1 aSotoodehnia, Nona1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/780205658nas a2201489 4500008004100000022001400041245010600055210006900161260001500230300000700245490000700252520146500259100001901724700002101743700002301764700002701787700001901814700002501833700002501858700002301883700002501906700002901931700002201960700002301982700001702005700001702022700001802039700002202057700002002079700002102099700001802120700002002138700001902158700001802177700002802195700002102223700001302244700003002257700001902287700002502306700002102331700001902352700002302371700002002394700002402414700002102438700001802459700002102477700001802498700001902516700002002535700002102555700002302576700002402599700002202623700002402645700001702669700002202686700002202708700002202730700002302752700001902775700001702794700002002811700001702831700002202848700002202870700001202892700002102904700002702925700001902952700001702971700002002988700001903008700002003027700002303047700002103070700002203091700002203113700002403135700002003159700002403179700002803203700001903231700002003250700002403270700002103294700002403315700001703339700001903356700002603375700002103401700001603422700002703438700001803465700002303483700002103506700002803527700002403555700001903579700001903598700002403617700002403641700002203665700001803687700002203705700002903727700002403756700003203780700002103812700001603833700002203849700002403871700002003895700001603915700002303931700001803954700002203972700002003994700001504014700002104029700002404050700001904074700001904093700002004112856003604132 2018 eng d a1474-760X00aExome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.0 aExomechip metaanalysis identifies novel loci associated with car c2018 07 17 a870 v193 aBACKGROUND: 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.
1 aPrins, Bram, P1 aMead, Timothy, J1 aBrody, Jennifer, A1 aSveinbjornsson, Gardar1 aNtalla, Ioanna1 aBihlmeyer, Nathan, A1 avan den Berg, Marten1 aBork-Jensen, Jette1 aCappellani, Stefania1 aVan Duijvenboden, Stefan1 aKlena, Nikolai, T1 aGabriel, George, C1 aLiu, Xiaoqin1 aGulec, Cagri1 aGrarup, Niels1 aHaessler, Jeffrey1 aHall, Leanne, M1 aIorio, Annamaria1 aIsaacs, Aaron1 aLi-Gao, Ruifang1 aLin, Honghuang1 aLiu, Ching-Ti1 aLyytikäinen, Leo-Pekka1 aMarten, Jonathan1 aMei, Hao1 aMüller-Nurasyid, Martina1 aOrini, Michele1 aPadmanabhan, Sandosh1 aRadmanesh, Farid1 aRamirez, Julia1 aRobino, Antonietta1 aSchwartz, Molly1 avan Setten, Jessica1 aSmith, Albert, V1 aVerweij, Niek1 aWarren, Helen, R1 aWeiss, Stefan1 aAlonso, Alvaro1 aArnar, David, O1 aBots, Michiel, L1 ade Boer, Rudolf, A1 aDominiczak, Anna, F1 aEijgelsheim, Mark1 aEllinor, Patrick, T1 aGuo, Xiuqing1 aFelix, Stephan, B1 aHarris, Tamara, B1 aHayward, Caroline1 aHeckbert, Susan, R1 aHuang, Paul, L1 aJukema, J, W1 aKähönen, Mika1 aKors, Jan, A1 aLambiase, Pier, D1 aLauner, Lenore, J1 aLi, Man1 aLinneberg, Allan1 aNelson, Christopher, P1 aPedersen, Oluf1 aPerez, Marco1 aPeters, Annette1 aPolasek, Ozren1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRice, Kenneth, M1 aRotter, Jerome, I1 aSinner, Moritz, F1 aSoliman, Elsayed, Z1 aSpector, Tim, D1 aStrauch, Konstantin1 aThorsteinsdottir, Unnur1 aTinker, Andrew1 aTrompet, Stella1 aUitterlinden, Andre1 aVaartjes, Ilonca1 avan der Meer, Peter1 aVölker, Uwe1 aVölzke, Henry1 aWaldenberger, Melanie1 aWilson, James, G1 aXie, Zhijun1 aAsselbergs, Folkert, W1 aDörr, Marcus1 aDuijn, Cornelia, M1 aGasparini, Paolo1 aGudbjartsson, Daniel, F1 aGudnason, Vilmundur1 aHansen, Torben1 aKääb, Stefan1 aKanters, Jørgen, K1 aKooperberg, Charles1 aLehtimäki, Terho1 aLin, Henry, J1 aLubitz, Steven, A1 aMook-Kanamori, Dennis, O1 aConti, Francesco, J1 aNewton-Cheh, Christopher, H1 aRosand, Jonathan1 aRudan, Igor1 aSamani, Nilesh, J1 aSinagra, Gianfranco1 aSmith, Blair, H1 aHolm, Hilma1 aStricker, Bruno, H1 aUlivi, Sheila1 aSotoodehnia, Nona1 aApte, Suneel, S1 aHarst, Pim1 aStefansson, Kari1 aMunroe, Patricia, B1 aArking, Dan, E1 aLo, Cecilia, W1 aJamshidi, Yalda uhttps://chs-nhlbi.org/node/780905298nas a2201333 4500008004100000022001400041245011200055210006900167260001300236300001200249490000700261520154600268100002501814700002301839700002601862700002101888700001901909700001801928700001801946700002101964700002101985700002002006700001802026700001302044700003002057700002502087700001802112700001702130700001302147700002002160700002502180700001802205700001902223700002402242700002202266700002802288700001202316700001902328700002402347700001902371700001602390700002202406700002002428700002302448700002202471700002502493700002102518700001902539700001602558700002402574700001702598700002102615700002202636700002702658700002102685700002302706700001902729700001902748700002102767700002202788700002002810700002602830700002202856700002002878700001802898700001602916700002302932700002402955700001802979700002002997700002303017700002003040700001903060700001803079700002503097700002603122700002403148700001703172700001803189700001903207700002203226700002103248700002403269700002103293700001703314700002303331700002003354700001803374700002403392700002403416700002203440700002303462700003203485700002203517700002103539700002203560700002403582700002103606700001903627700001903646700001503665700002303680700002203703700002903725700002203754700001803776700002003794700002703814700002403841700002203865700001903887700002203906856003603928 2018 eng d a2574-830000aExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals.0 aExomeChipWide Analysis of 95 626 Individuals Identifies 10 Novel c2018 Jan ae0017580 v113 aBACKGROUND: 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.
1 aBihlmeyer, Nathan, A1 aBrody, Jennifer, A1 aSmith, Albert, Vernon1 aWarren, Helen, R1 aLin, Honghuang1 aIsaacs, Aaron1 aLiu, Ching-Ti1 aMarten, Jonathan1 aRadmanesh, Farid1 aHall, Leanne, M1 aGrarup, Niels1 aMei, Hao1 aMüller-Nurasyid, Martina1 aHuffman, Jennifer, E1 aVerweij, Niek1 aGuo, Xiuqing1 aYao, Jie1 aLi-Gao, Ruifang1 avan den Berg, Marten1 aWeiss, Stefan1 aPrins, Bram, P1 avan Setten, Jessica1 aHaessler, Jeffrey1 aLyytikäinen, Leo-Pekka1 aLi, Man1 aAlonso, Alvaro1 aSoliman, Elsayed, Z1 aBis, Joshua, C1 aAustin, Tom1 aChen, Yii-Der Ida1 aPsaty, Bruce, M1 aHarrris, Tamara, B1 aLauner, Lenore, J1 aPadmanabhan, Sandosh1 aDominiczak, Anna1 aHuang, Paul, L1 aXie, Zhijun1 aEllinor, Patrick, T1 aKors, Jan, A1 aCampbell, Archie1 aMurray, Alison, D1 aNelson, Christopher, P1 aTobin, Martin, D1 aBork-Jensen, Jette1 aHansen, Torben1 aPedersen, Oluf1 aLinneberg, Allan1 aSinner, Moritz, F1 aPeters, Annette1 aWaldenberger, Melanie1 aMeitinger, Thomas1 aPerz, Siegfried1 aKolcic, Ivana1 aRudan, Igor1 ade Boer, Rudolf, A1 avan der Meer, Peter1 aLin, Henry, J1 aTaylor, Kent, D1 ade Mutsert, Renée1 aTrompet, Stella1 aJukema, Wouter1 aMaan, Arie, C1 aStricker, Bruno, H C1 aRivadeneira, Fernando1 aUitterlinden, Andre1 aVölker, Uwe1 aHomuth, Georg1 aVölzke, Henry1 aFelix, Stephan, B1 aMangino, Massimo1 aSpector, Timothy, D1 aBots, Michiel, L1 aPerez, Marco1 aRaitakari, Olli, T1 aKähönen, Mika1 aMononen, Nina1 aGudnason, Vilmundur1 aMunroe, Patricia, B1 aLubitz, Steven, A1 aDuijn, Cornelia, M1 aNewton-Cheh, Christopher, H1 aHayward, Caroline1 aRosand, Jonathan1 aSamani, Nilesh, J1 aKanters, Jørgen, K1 aWilson, James, G1 aKääb, Stefan1 aPolasek, Ozren1 aHarst, Pim1 aHeckbert, Susan, R1 aRotter, Jerome, I1 aMook-Kanamori, Dennis, O1 aEijgelsheim, Mark1 aDörr, Marcus1 aJamshidi, Yalda1 aAsselbergs, Folkert, W1 aKooperberg, Charles1 aLehtimäki, Terho1 aArking, Dan, E1 aSotoodehnia, Nona uhttps://chs-nhlbi.org/node/778411426nas a2203589 4500008004100000022001400041245015500055210006900210260001600279300001200295490000800307520141100315100002001726700001601746700001601762700002701778700002201805700001901827700002701846700002001873700001801893700001901911700001301930700002101943700001901964700001901983700001502002700001202017700001902029700001802048700002002066700002102086700002502107700001802132700001602150700002002166700001802186700002102204700001502225700001802240700002102258700002002279700002202299700002102321700002302342700001802365700002702383700002802410700002702438700001802465700001902483700001902502700002102521700001902542700001602561700002602577700002002603700002202623700001802645700001602663700001902679700002202698700001802720700001302738700002102751700002602772700002402798700002002822700002502842700002102867700001902888700002202907700001802929700002102947700002002968700002302988700001303011700001903024700001603043700001803059700002403077700001703101700002003118700002303138700002703161700002803188700001503216700002503231700001403256700002203270700002203292700001903314700001703333700001703350700001503367700001603382700001803398700002003416700001903436700002503455700002003480700001703500700002003517700001903537700001803556700002303574700002303597700001903620700002303639700002703662700002803689700002403717700002503741700002603766700001703792700002203809700002303831700002003854700002003874700002303894700002303917700002203940700001803962700002503980700001704005700002004022700002204042700002204064700002204086700002004108700001904128700002104147700002504168700002704193700001904220700002404239700002304263700002004286700002004306700002204326700002104348700001904369700002204388700002004410700002604430700001904456700002404475700002704499700002004526700002404546700002604570700001904596700002004615700002004635700002004655700001704675700002204692700002404714700001704738700002204755700002204777700002204799700002004821700002404841700002204865700003004887700002404917700002604941700002504967700002104992700001505013700002305028700002005051700002405071700002005095700002105115700002805136700002005164700002805184700001905212700002405231700001905255700002205274700002305296700001905319700002205338700001905360700002105379700002205400700002105422700002105443700002005464700001805484700002505502700001905527700002105546700001505567700001505582700002205597700002005619700002405639700002105663700002405684700001805708700002405726700002505750700002605775700002405801700002205825700002105847700001705868700002005885700002305905700002005928700002105948700002305969700002405992700002306016700002306039700002306062700001906085700002406104700002106128700002706149700001906176700002006195700002006215700001806235700002806253700002006281700002406301700001106325700002106336700002306357700002206380700002006402700002106422700002306443700001906466700002006485700001706505700002306522700002106545700002706566700002106593700002506614700001706639700002206656700001906678700002006697700002506717700002906742700002006771700002106791700002606812700002506838700002206863700002006885700001806905700001806923700002406941700001506965700001906980700002206999700001907021700002207040700002207062700002307084700002107107700002407128700002307152700002207175700001907197700001507216700002107231700002007252700002007272700002007292700002407312700002007336700002407356700002207380700002007402700002207422700001907444700002107463700002707484700002007511700001707531700001907548700001707567700002107584700002407605700002307629700001907652700002007671700001907691700002507710710002707735710003807762856003607800 2018 eng d a1537-660500aGenome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.0 aGenome Analyses of 200000 Individuals Identify 58 Loci for Chron c2018 Nov 01 a691-7060 v1033 aC-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.
1 aLigthart, Symen1 aVaez, Ahmad1 aVõsa, Urmo1 aStathopoulou, Maria, G1 ade Vries, Paul, S1 aPrins, Bram, P1 avan der Most, Peter, J1 aTanaka, Toshiko1 aNaderi, Elnaz1 aRose, Lynda, M1 aWu, Ying1 aKarlsson, Robert1 aBarbalic, Maja1 aLin, Honghuang1 aPool, Rene1 aZhu, Gu1 aMace, Aurelien1 aSidore, Carlo1 aTrompet, Stella1 aMangino, Massimo1 aSabater-Lleal, Maria1 aKemp, John, P1 aAbbasi, Ali1 aKacprowski, Tim1 aVerweij, Niek1 aSmith, Albert, V1 aHuang, Tao1 aMarzi, Carola1 aFeitosa, Mary, F1 aLohman, Kurt, K1 aKleber, Marcus, E1 aMilaneschi, Yuri1 aMueller, Christian1 aHuq, Mahmudul1 aVlachopoulou, Efthymia1 aLyytikäinen, Leo-Pekka1 aOldmeadow, Christopher1 aDeelen, Joris1 aPerola, Markus1 aZhao, Jing Hua1 aFeenstra, Bjarke1 aAmini, Marzyeh1 aLahti, Jari1 aSchraut, Katharina, E1 aFornage, Myriam1 aSuktitipat, Bhoom1 aChen, Wei-Min1 aLi, Xiaohui1 aNutile, Teresa1 aMalerba, Giovanni1 aLuan, Jian'an1 aBak, Tom1 aSchork, Nicholas1 aM, Fabiola, del Greco1 aThiering, Elisabeth1 aMahajan, Anubha1 aMarioni, Riccardo, E1 aMihailov, Evelin1 aEriksson, Joel1 aOzel, Ayse, Bilge1 aZhang, Weihua1 aNethander, Maria1 aCheng, Yu-Ching1 aAslibekyan, Stella1 aAng, Wei1 aGandin, Ilaria1 aYengo, Loic1 aPortas, Laura1 aKooperberg, Charles1 aHofer, Edith1 aRajan, Kumar, B1 aSchurmann, Claudia1 aHollander, Wouter, den1 aAhluwalia, Tarunveer, S1 aZhao, Jing1 aDraisma, Harmen, H M1 aFord, Ian1 aTimpson, Nicholas1 aTeumer, Alexander1 aHuang, Hongyan1 aWahl, Simone1 aLiu, Yongmei1 aHuang, Jie1 aUh, Hae-Won1 aGeller, Frank1 aJoshi, Peter, K1 aYanek, Lisa, R1 aTrabetti, Elisabetta1 aLehne, Benjamin1 aVozzi, Diego1 aVerbanck, Marie1 aBiino, Ginevra1 aSaba, Yasaman1 aMeulenbelt, Ingrid1 aO'Connell, Jeff, R1 aLaakso, Markku1 aGiulianini, Franco1 aMagnusson, Patrik, K E1 aBallantyne, Christie, M1 aHottenga, Jouke Jan1 aMontgomery, Grant, W1 aRivadineira, Fernando1 aRueedi, Rico1 aSteri, Maristella1 aHerzig, Karl-Heinz1 aStott, David, J1 aMenni, Cristina1 aFrånberg, Mattias1 aSt Pourcain, Beate1 aFelix, Stephan, B1 aPers, Tune, H1 aBakker, Stephan, J L1 aKraft, Peter1 aPeters, Annette1 aVaidya, Dhananjay1 aDelgado, Graciela1 aSmit, Johannes, H1 aGroßmann, Vera1 aSinisalo, Juha1 aSeppälä, Ilkka1 aWilliams, Stephen, R1 aHolliday, Elizabeth, G1 aMoed, Matthijs1 aLangenberg, Claudia1 aRäikkönen, Katri1 aDing, Jingzhong1 aCampbell, Harry1 aSale, Michèle, M1 aChen, Yii-der, I1 aJames, Alan, L1 aRuggiero, Daniela1 aSoranzo, Nicole1 aHartman, Catharina, A1 aSmith, Erin, N1 aBerenson, Gerald, S1 aFuchsberger, Christian1 aHernandez, Dena1 aTiesler, Carla, M T1 aGiedraitis, Vilmantas1 aLiewald, David1 aFischer, Krista1 aMellström, Dan1 aLarsson, Anders1 aWang, Yunmei1 aScott, William, R1 aLorentzon, Matthias1 aBeilby, John1 aRyan, Kathleen, A1 aPennell, Craig, E1 aVuckovic, Dragana1 aBalkau, Beverly1 aConcas, Maria, Pina1 aSchmidt, Reinhold1 ade Leon, Carlos, F Mendes1 aBottinger, Erwin, P1 aKloppenburg, Margreet1 aPaternoster, Lavinia1 aBoehnke, Michael1 aMusk, A, W1 aWillemsen, Gonneke1 aEvans, David, M1 aMadden, Pamela, A F1 aKähönen, Mika1 aKutalik, Zoltán1 aZoledziewska, Magdalena1 aKarhunen, Ville1 aKritchevsky, Stephen, B1 aSattar, Naveed1 aLachance, Genevieve1 aClarke, Robert1 aHarris, Tamara, B1 aRaitakari, Olli, T1 aAttia, John, R1 avan Heemst, Diana1 aKajantie, Eero1 aSorice, Rossella1 aGambaro, Giovanni1 aScott, Robert, A1 aHicks, Andrew, A1 aFerrucci, Luigi1 aStandl, Marie1 aLindgren, Cecilia, M1 aStarr, John, M1 aKarlsson, Magnus1 aLind, Lars1 aLi, Jun, Z1 aChambers, John, C1 aMori, Trevor, A1 ade Geus, Eco, J C N1 aHeath, Andrew, C1 aMartin, Nicholas, G1 aAuvinen, Juha1 aBuckley, Brendan, M1 ade Craen, Anton, J M1 aWaldenberger, Melanie1 aStrauch, Konstantin1 aMeitinger, Thomas1 aScott, Rodney, J1 aMcEvoy, Mark1 aBeekman, Marian1 aBombieri, Cristina1 aRidker, Paul, M1 aMohlke, Karen, L1 aPedersen, Nancy, L1 aMorrison, Alanna, C1 aBoomsma, Dorret, I1 aWhitfield, John, B1 aStrachan, David, P1 aHofman, Albert1 aVollenweider, Peter1 aCucca, Francesco1 aJarvelin, Marjo-Riitta1 aJukema, Wouter1 aSpector, Tim, D1 aHamsten, Anders1 aZeller, Tanja1 aUitterlinden, André, G1 aNauck, Matthias1 aGudnason, Vilmundur1 aQi, Lu1 aGrallert, Harald1 aBorecki, Ingrid, B1 aRotter, Jerome, I1 aMärz, Winfried1 aWild, Philipp, S1 aLokki, Marja-Liisa1 aBoyle, Michael1 aSalomaa, Veikko1 aMelbye, Mads1 aEriksson, Johan, G1 aWilson, James, F1 aPenninx, Brenda, W J H1 aBecker, Diane, M1 aWorrall, Bradford, B1 aGibson, Greg1 aKrauss, Ronald, M1 aCiullo, Marina1 aZaza, Gianluigi1 aWareham, Nicholas, J1 aOldehinkel, Albertine, J1 aPalmer, Lyle, J1 aMurray, Sarah, S1 aPramstaller, Peter, P1 aBandinelli, Stefania1 aHeinrich, Joachim1 aIngelsson, Erik1 aDeary, Ian, J1 aMägi, Reedik1 aVandenput, Liesbeth1 aHarst, Pim1 aDesch, Karl, C1 aKooner, Jaspal, S1 aOhlsson, Claes1 aHayward, Caroline1 aLehtimäki, Terho1 aShuldiner, Alan, R1 aArnett, Donna, K1 aBeilin, Lawrence, J1 aRobino, Antonietta1 aFroguel, Philippe1 aPirastu, Mario1 aJess, Tine1 aKoenig, Wolfgang1 aLoos, Ruth, J F1 aEvans, Denis, A1 aSchmidt, Helena1 aSmith, George Davey1 aSlagboom, Eline1 aEiriksdottir, Gudny1 aMorris, Andrew, P1 aPsaty, Bruce, M1 aTracy, Russell, P1 aNolte, Ilja, M1 aBoerwinkle, Eric1 aVisvikis-Siest, Sophie1 aReiner, Alex, P1 aGross, Myron1 aBis, Joshua, C1 aFranke, Lude1 aFranco, Oscar, H1 aBenjamin, Emelia, J1 aChasman, Daniel, I1 aDupuis, Josée1 aSnieder, Harold1 aDehghan, Abbas1 aAlizadeh, Behrooz, Z1 aLifeLines Cohort Study1 aCHARGE Inflammation Working Group uhttps://chs-nhlbi.org/node/792008664nas a2202749 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2018 eng d a1546-171800aMulti-ethnic genome-wide association study for atrial fibrillation.0 aMultiethnic genomewide association study for atrial fibrillation c2018 Sep a1225-12330 v503 aAtrial 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.
1 aRoselli, Carolina1 aChaffin, Mark, D1 aWeng, Lu-Chen1 aAeschbacher, Stefanie1 aAhlberg, Gustav1 aAlbert, Christine, M1 aAlmgren, Peter1 aAlonso, Alvaro1 aAnderson, Christopher, D1 aAragam, Krishna, G1 aArking, Dan, E1 aBarnard, John1 aBartz, Traci, M1 aBenjamin, Emelia, J1 aBihlmeyer, Nathan, A1 aBis, Joshua, C1 aBloom, Heather, L1 aBoerwinkle, Eric1 aBottinger, Erwin, B1 aBrody, Jennifer, A1 aCalkins, Hugh1 aCampbell, Archie1 aCappola, Thomas, P1 aCarlquist, John1 aChasman, Daniel, I1 aChen, Lin, Y1 aChen, Yii-Der Ida1 aChoi, Eue-Keun1 aChoi, Seung, Hoan1 aChristophersen, Ingrid, E1 aChung, Mina, K1 aCole, John, W1 aConen, David1 aCook, James1 aCrijns, Harry, J1 aCutler, Michael, J1 aDamrauer, Scott, M1 aDaniels, Brian, R1 aDarbar, Dawood1 aDelgado, Graciela1 aDenny, Joshua, C1 aDichgans, Martin1 aDörr, Marcus1 aDudink, Elton, A1 aDudley, Samuel, C1 aEsa, Nada1 aEsko, Tõnu1 aEskola, Markku1 aFatkin, Diane1 aFelix, Stephan, B1 aFord, Ian1 aFranco, Oscar, H1 aGeelhoed, Bastiaan1 aGrewal, Raji, P1 aGudnason, Vilmundur1 aGuo, Xiuqing1 aGupta, Namrata1 aGustafsson, Stefan1 aGutmann, Rebecca1 aHamsten, Anders1 aHarris, Tamara, B1 aHayward, Caroline1 aHeckbert, Susan, R1 aHernesniemi, Jussi1 aHocking, Lynne, J1 aHofman, Albert1 aHorimoto, Andrea, R V R1 aHuang, Jie1 aHuang, Paul, L1 aHuffman, Jennifer1 aIngelsson, Erik1 aIpek, Esra, Gucuk1 aIto, Kaoru1 aJimenez-Conde, Jordi1 aJohnson, Renee1 aJukema, Wouter1 aKääb, Stefan1 aKähönen, Mika1 aKamatani, Yoichiro1 aKane, John, P1 aKastrati, Adnan1 aKathiresan, Sekar1 aKatschnig-Winter, Petra1 aKavousi, Maryam1 aKessler, Thorsten1 aKietselaer, Bas, L1 aKirchhof, Paulus1 aKleber, Marcus, E1 aKnight, Stacey1 aKrieger, Jose, E1 aKubo, Michiaki1 aLauner, Lenore, J1 aLaurikka, Jari1 aLehtimäki, Terho1 aLeineweber, Kirsten1 aLemaitre, Rozenn, N1 aLi, Man1 aLim, Hong, Euy1 aLin, Henry, J1 aLin, Honghuang1 aLind, Lars1 aLindgren, Cecilia, M1 aLokki, Marja-Liisa1 aLondon, Barry1 aLoos, Ruth, J F1 aLow, Siew-Kee1 aLu, Yingchang1 aLyytikäinen, Leo-Pekka1 aMacfarlane, Peter, W1 aMagnusson, Patrik, K1 aMahajan, Anubha1 aMalik, Rainer1 aMansur, Alfredo, J1 aMarcus, Gregory, M1 aMargolin, Lauren1 aMargulies, Kenneth, B1 aMärz, Winfried1 aMcManus, David, D1 aMelander, Olle1 aMohanty, Sanghamitra1 aMontgomery, Jay, A1 aMorley, Michael, P1 aMorris, Andrew, P1 aMüller-Nurasyid, Martina1 aNatale, Andrea1 aNazarian, Saman1 aNeumann, Benjamin1 aNewton-Cheh, Christopher1 aNiemeijer, Maartje, N1 aNikus, Kjell1 aNilsson, Peter1 aNoordam, Raymond1 aOellers, Heidi1 aOlesen, Morten, S1 aOrho-Melander, Marju1 aPadmanabhan, Sandosh1 aPak, Hui-Nam1 aParé, Guillaume1 aPedersen, Nancy, L1 aPera, Joanna1 aPereira, Alexandre1 aPorteous, David1 aPsaty, Bruce, M1 aPulit, Sara, L1 aPullinger, Clive, R1 aRader, Daniel, J1 aRefsgaard, Lena1 aRibasés, Marta1 aRidker, Paul, M1 aRienstra, Michiel1 aRisch, Lorenz1 aRoden, Dan, M1 aRosand, Jonathan1 aRosenberg, Michael, A1 aRost, Natalia1 aRotter, Jerome, I1 aSaba, Samir1 aSandhu, Roopinder, K1 aSchnabel, Renate, B1 aSchramm, Katharina1 aSchunkert, Heribert1 aSchurman, Claudia1 aScott, Stuart, A1 aSeppälä, Ilkka1 aShaffer, Christian1 aShah, Svati1 aShalaby, Alaa, A1 aShim, Jaemin1 aShoemaker, Benjamin1 aSiland, Joylene, E1 aSinisalo, Juha1 aSinner, Moritz, F1 aSlowik, Agnieszka1 aSmith, Albert, V1 aSmith, Blair, H1 aSmith, Gustav1 aSmith, Jonathan, D1 aSmith, Nicholas, L1 aSoliman, Elsayed, Z1 aSotoodehnia, Nona1 aStricker, Bruno, H1 aSun, Albert1 aSun, Han1 aSvendsen, Jesper, H1 aTanaka, Toshihiro1 aTanriverdi, Kahraman1 aTaylor, Kent, D1 aTeder-Laving, Maris1 aTeumer, Alexander1 aThériault, Sébastien1 aTrompet, Stella1 aTucker, Nathan, R1 aTveit, Arnljot1 aUitterlinden, André, G1 aHarst, Pim1 aVan Gelder, Isabelle, C1 aVan Wagoner, David, R1 aVerweij, Niek1 aVlachopoulou, Efthymia1 aVölker, Uwe1 aWang, Biqi1 aWeeke, Peter, E1 aWeijs, Bob1 aWeiss, Raul1 aWeiss, Stefan1 aWells, Quinn, S1 aWiggins, Kerri, L1 aWong, Jorge, A1 aWoo, Daniel1 aWorrall, Bradford, B1 aYang, Pil-Sung1 aYao, Jie1 aYoneda, Zachary, T1 aZeller, Tanja1 aZeng, Lingyao1 aLubitz, Steven, A1 aLunetta, Kathryn, L1 aEllinor, Patrick, T uhttps://chs-nhlbi.org/node/781105872nas a2201645 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2018 eng d a2041-172300aPR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity.0 aPR interval genomewide association metaanalysis identifies 50 lo c2018 Jul 25 a29040 v93 aElectrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.
1 avan Setten, Jessica1 aBrody, Jennifer, A1 aJamshidi, Yalda1 aSwenson, Brenton, R1 aButler, Anne, M1 aCampbell, Harry1 aDel Greco, Fabiola, M1 aEvans, Daniel, S1 aGibson, Quince1 aGudbjartsson, Daniel, F1 aKerr, Kathleen, F1 aKrijthe, Bouwe, P1 aLyytikäinen, Leo-Pekka1 aMüller, Christian1 aMüller-Nurasyid, Martina1 aNolte, Ilja, M1 aPadmanabhan, Sandosh1 aRitchie, Marylyn, D1 aRobino, Antonietta1 aSmith, Albert, V1 aSteri, Maristella1 aTanaka, Toshiko1 aTeumer, Alexander1 aTrompet, Stella1 aUlivi, Sheila1 aVerweij, Niek1 aYin, Xiaoyan1 aArnar, David, O1 aAsselbergs, Folkert, W1 aBader, Joel, S1 aBarnard, John1 aBis, Josh1 aBlankenberg, Stefan1 aBoerwinkle, Eric1 aBradford, Yuki1 aBuckley, Brendan, M1 aChung, Mina, K1 aCrawford, Dana1 aHoed, Marcel, den1 aDenny, Josh, C1 aDominiczak, Anna, F1 aEhret, Georg, B1 aEijgelsheim, Mark1 aEllinor, Patrick, T1 aFelix, Stephan, B1 aFranco, Oscar, H1 aFranke, Lude1 aHarris, Tamara, B1 aHolm, Hilma1 aIlaria, Gandin1 aIorio, Annamaria1 aKähönen, Mika1 aKolcic, Ivana1 aKors, Jan, A1 aLakatta, Edward, G1 aLauner, Lenore, J1 aLin, Honghuang1 aLin, Henry, J1 aLoos, Ruth, J F1 aLubitz, Steven, A1 aMacfarlane, Peter, W1 aMagnani, Jared, W1 aLeach, Irene, Mateo1 aMeitinger, Thomas1 aMitchell, Braxton, D1 aMünzel, Thomas1 aPapanicolaou, George, J1 aPeters, Annette1 aPfeufer, Arne1 aPramstaller, Peter, P1 aRaitakari, Olli, T1 aRotter, Jerome, I1 aRudan, Igor1 aSamani, Nilesh, J1 aSchlessinger, David1 aAldana, Claudia, T Silva1 aSinner, Moritz, F1 aSmith, Jonathan, D1 aSnieder, Harold1 aSoliman, Elsayed, Z1 aSpector, Timothy, D1 aStott, David, J1 aStrauch, Konstantin1 aTarasov, Kirill, V1 aThorsteinsdottir, Unnur1 aUitterlinden, André, G1 aVan Wagoner, David, R1 aVölker, Uwe1 aVölzke, Henry1 aWaldenberger, Melanie1 aWestra, Harm, Jan1 aWild, Philipp, S1 aZeller, Tanja1 aAlonso, Alvaro1 aAvery, Christy, L1 aBandinelli, Stefania1 aBenjamin, Emelia, J1 aCucca, Francesco1 aDörr, Marcus1 aFerrucci, Luigi1 aGasparini, Paolo1 aGudnason, Vilmundur1 aHayward, Caroline1 aHeckbert, Susan, R1 aHicks, Andrew, A1 aJukema, Wouter1 aKääb, Stefan1 aLehtimäki, Terho1 aLiu, Yongmei1 aMunroe, Patricia, B1 aParsa, Afshin1 aPolasek, Ozren1 aPsaty, Bruce, M1 aRoden, Dan, M1 aSchnabel, Renate, B1 aSinagra, Gianfranco1 aStefansson, Kari1 aStricker, Bruno, H1 aHarst, Pim1 aDuijn, Cornelia, M1 aWilson, James, F1 aGharib, Sina, A1 ade Bakker, Paul, I W1 aIsaacs, Aaron1 aArking, Dan, E1 aSotoodehnia, Nona uhttps://chs-nhlbi.org/node/781505481nas a2201285 4500008004100000022001400041245015800055210006900213260001600282520179200298100001902090700001702109700002102126700001702147700002902164700002102193700002402214700002002238700001302258700002002271700002102291700002102312700001302333700001502346700001902361700001602380700002202396700002102418700002302439700002302462700002502485700001902510700001902529700002102548700002502569700003002594700002302624700002702647700002002674700002302694700002202717700002202739700001802761700002802779700001902807700002402826700002202850700002102872700002002893700002402913700002002937700001902957700001602976700001802992700002003010700001803030700002203048700001903070700001803089700002003107700002003127700001903147700002003166700001803186700001903204700002003223700003103243700001903274700002003293700002003313700001903333700001903352700002203371700001903393700002003412700002103432700002003453700002103473700002203494700002103516700002503537700002003562700002403582700002503606700002303631700002203654700001703676700001903693700002303712700002003735700001903755700002003774700002403794700002603818700002003844700001903864700001503883700002103898700002403919700002403943700001903967700002003986700002804006700002004034700001704054700002004071700002304091710004504114856003604159 2018 eng d a1476-557800aWhole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.0 aWhole exome sequencing study identifies novel rare and common Al c2018 Aug 143 aThe Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.
1 aBis, Joshua, C1 aJian, Xueqiu1 aKunkle, Brian, W1 aChen, Yuning1 aHamilton-Nelson, Kara, L1 aBush, William, S1 aSalerno, William, J1 aLancour, Daniel1 aMa, Yiyi1 aRenton, Alan, E1 aMarcora, Edoardo1 aFarrell, John, J1 aZhao, Yi1 aQu, Liming1 aAhmad, Shahzad1 aAmin, Najaf1 aAmouyel, Philippe1 aBeecham, Gary, W1 aBelow, Jennifer, E1 aCampion, Dominique1 aCharbonnier, Camille1 aChung, Jaeyoon1 aCrane, Paul, K1 aCruchaga, Carlos1 aCupples, Adrienne, L1 aDartigues, Jean-François1 aDebette, Stephanie1 aDeleuze, Jean-Francois1 aFulton, Lucinda1 aGabriel, Stacey, B1 aGenin, Emmanuelle1 aGibbs, Richard, A1 aGoate, Alison1 aGrenier-Boley, Benjamin1 aGupta, Namrata1 aHaines, Jonathan, L1 aHavulinna, Aki, S1 aHelisalmi, Seppo1 aHiltunen, Mikko1 aHowrigan, Daniel, P1 aIkram, Arfan, M1 aKaprio, Jaakko1 aKonrad, Jan1 aKuzma, Amanda1 aLander, Eric, S1 aLathrop, Mark1 aLehtimäki, Terho1 aLin, Honghuang1 aMattila, Kari1 aMayeux, Richard1 aMuzny, Donna, M1 aNasser, Waleed1 aNeale, Benjamin1 aNho, Kwangsik1 aNicolas, Gaël1 aPatel, Devanshi1 aPericak-Vance, Margaret, A1 aPerola, Markus1 aPsaty, Bruce, M1 aQuenez, Olivier1 aRajabli, Farid1 aRedon, Richard1 aReitz, Christiane1 aRemes, Anne, M1 aSalomaa, Veikko1 aSarnowski, Chloe1 aSchmidt, Helena1 aSchmidt, Michael1 aSchmidt, Reinhold1 aSoininen, Hilkka1 aThornton, Timothy, A1 aTosto, Giuseppe1 aTzourio, Christophe1 avan der Lee, Sven, J1 aDuijn, Cornelia, M1 aVardarajan, Badri1 aWang, Weixin1 aWijsman, Ellen1 aWilson, Richard, K1 aWitten, Daniela1 aWorley, Kim, C1 aZhang, Xiaoling1 aBellenguez, Céline1 aLambert, Jean-Charles1 aKurki, Mitja, I1 aPalotie, Aarno1 aDaly, Mark1 aBoerwinkle, Eric1 aLunetta, Kathryn, L1 aDeStefano, Anita, L1 aDupuis, Josée1 aMartin, Eden, R1 aSchellenberg, Gerard, D1 aSeshadri, Sudha1 aNaj, Adam, C1 aFornage, Myriam1 aFarrer, Lindsay, A1 aAlzheimer’s Disease Sequencing Project uhttps://chs-nhlbi.org/node/778504940nas a2200661 4500008004100000022001400041245014200055210006900197260001600266520300700282100002403289700002203313700003003335700001903365700001903384700002303403700002003426700001903446700002303465700001703488700002203505700001803527700001903545700002203564700002203586700002303608700002103631700001803652700001803670700002103688700001803709700002403727700002003751700002103771700002003792700002003812700002003832700001503852700002003867700001903887700002403906700002203930700002103952700001803973700001903991700002104010700002204031700001604053700002204069700002204091700002404113700002204137700002004159700001504179700002504194700002304219856003604242 2019 eng d a2380-659100aAssessment of the Relationship Between Genetic Determinants of Thyroid Function and Atrial Fibrillation: A Mendelian Randomization Study.0 aAssessment of the Relationship Between Genetic Determinants of T c2019 Jan 233 aImportance: 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.
1 aEllervik, Christina1 aRoselli, Carolina1 aChristophersen, Ingrid, E1 aAlonso, Alvaro1 aPietzner, Maik1 aSitlani, Collen, M1 aTrompet, Stella1 aArking, Dan, E1 aGeelhoed, Bastiaan1 aGuo, Xiuqing1 aKleber, Marcus, E1 aLin, Henry, J1 aLin, Honghuang1 aMacfarlane, Peter1 aSelvin, Elizabeth1 aShaffer, Christian1 aSmith, Albert, V1 aVerweij, Niek1 aWeiss, Stefan1 aCappola, Anne, R1 aDörr, Marcus1 aGudnason, Vilmundur1 aHeckbert, Susan1 aMooijaart, Simon1 aMärz, Winfried1 aPsaty, Bruce, M1 aRidker, Paul, M1 aRoden, Dan1 aStott, David, J1 aVölzke, Henry1 aBenjamin, Emelia, J1 aDelgado, Graciela1 aEllinor, Patrick1 aHomuth, Georg1 aKöttgen, Anna1 aJukema, Johan, W1 aLubitz, Steven, A1 aMora, Samia1 aRienstra, Michiel1 aRotter, Jerome, I1 aShoemaker, Benjamin1 aSotoodehnia, Nona1 aTaylor, Kent, D1 aHarst, Pim1 aAlbert, Christine, M1 aChasman, Daniel, I uhttps://chs-nhlbi.org/node/797311242nas a2203601 4500008004100000022001400041245008000055210006900135260001300204300001400217490000700231520105900238100002601297700002201323700002101345700002201366700001901388700002001407700001901427700003301446700002001479700002801499700002101527700001901548700001701567700002201584700001701606700002201623700002501645700001801670700001901688700001601707700001301723700001501736700001701751700002001768700002601788700002901814700002001843700002301863700002501886700001701911700001701928700002501945700001601970700002101986700002302007700002202030700002202052700002102074700001802095700002202113700002002135700002102155700002202176700002002198700002002218700002902238700001902267700002102286700002102307700001602328700001802344700002102362700002002383700002302403700002202426700001902448700002002467700002102487700002402508700002202532700002102554700002202575700002502597700001802622700002902640700001602669700001702685700001802702700002902720700002802749700002102777700001602798700002202814700001702836700002302853700002102876700002302897700002602920700002302946700002102969700002602990700002003016700002303036700001903059700001903078700003303097700002203130700001503152700002303167700002003190700002103210700001603231700002103247700001903268700002203287700002203309700002103331700002003352700002703372700002003399700002303419700002003442700002503462700001703487700002503504700002303529700002303552700002203575700002203597700002003619700001703639700001903656700001703675700002703692700002203719700002403741700002303765700002203788700003403810700002103844700002203865700002403887700002203911700002203933700002403955700002703979700002004006700001304026700002404039700001904063700002304082700001904105700001904124700001704143700002504160700002804185700002604213700002404239700002104263700002404284700001904308700002604327700002404353700002104377700002004398700002304418700002104441700003304462700002404495700002304519700002104542700002004563700001804583700001904601700002604620700002004646700001904666700002804685700002104713700001904734700001904753700002504772700001804797700002004815700002004835700002504855700002304880700002304903700002404926700002004950700003004970700001705000700002705017700003405044700001605078700002005094700002105114700002605135700002205161700002905183700001905212700002205231700002405253700002605277700002205303700002205325700001305347700001905360700002005379700001905399700002405418700002505442700002205467700001705489700002205506700003005528700002005558700002205578700002805600700002605628700002005654700002005674700002505694700002105719700001805740700002405758700002705782700001805809700002305827700002405850700002505874700001805899700002205917700002705939700002105966700002305987700002206010700002106032700002106053700002306074700002006097700002106117700002006138700002106158700001806179700002206197700002806219700002306247700002106270700002206291700002306313700002206336700002006358700002306378700002206401700002006423700001806443700002406461700001706485700001806502700001906520700002406539700001706563700001806580700002306598700002006621700001906641700002406660700002406684700002306708700002006731700002206751700002506773700002606798700002406824700002806848700002106876700002106897700001906918700002206937700002106959700002906980700002607009700002407035700002407059700002307083700001907106700002407125700002107149700002007170700002207190700001907212700002307231700002207254700002307276700002007299700002007319700002307339700002207362700002107384700002407405700002107429700002307450700002407473700002207497700002307519700002207542700002007564700002007584856003607604 2019 eng d a1546-171800aGenetic architecture of subcortical brain structures in 38,851 individuals.0 aGenetic architecture of subcortical brain structures in 38851 in c2019 Nov a1624-16360 v513 aSubcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
1 aSatizabal, Claudia, L1 aAdams, Hieab, H H1 aHibar, Derrek, P1 aWhite, Charles, C1 aKnol, Maria, J1 aStein, Jason, L1 aScholz, Markus1 aSargurupremraj, Muralidharan1 aJahanshad, Neda1 aRoshchupkin, Gennady, V1 aSmith, Albert, V1 aBis, Joshua, C1 aJian, Xueqiu1 aLuciano, Michelle1 aHofer, Edith1 aTeumer, Alexander1 avan der Lee, Sven, J1 aYang, Jingyun1 aYanek, Lisa, R1 aLee, Tom, V1 aLi, Shuo1 aHu, Yanhui1 aKoh, Jia, Yu1 aEicher, John, D1 aDesrivières, Sylvane1 aArias-Vasquez, Alejandro1 aChauhan, Ganesh1 aAthanasiu, Lavinia1 aRentería, Miguel, E1 aKim, Sungeun1 aHoehn, David1 aArmstrong, Nicola, J1 aChen, Qiang1 aHolmes, Avram, J1 aBraber, Anouk, den1 aKloszewska, Iwona1 aAndersson, Micael1 aEspeseth, Thomas1 aGrimm, Oliver1 aAbramovic, Lucija1 aAlhusaini, Saud1 aMilaneschi, Yuri1 aPapmeyer, Martina1 aAxelsson, Tomas1 aEhrlich, Stefan1 aRoiz-Santiañez, Roberto1 aKraemer, Bernd1 aHåberg, Asta, K1 aJones, Hannah, J1 aPike, Bruce1 aStein, Dan, J1 aStevens, Allison1 aBralten, Janita1 aVernooij, Meike, W1 aHarris, Tamara, B1 aFilippi, Irina1 aWitte, Veronica1 aGuadalupe, Tulio1 aWittfeld, Katharina1 aMosley, Thomas, H1 aBecker, James, T1 aDoan, Nhat, Trung1 aHagenaars, Saskia, P1 aSaba, Yasaman1 aCuellar-Partida, Gabriel1 aAmin, Najaf1 aHilal, Saima1 aNho, Kwangsik1 aMirza-Schreiber, Nazanin1 aArfanakis, Konstantinos1 aBecker, Diane, M1 aAmes, David1 aGoldman, Aaron, L1 aLee, Phil, H1 aBoomsma, Dorret, I1 aLovestone, Simon1 aGiddaluru, Sudheer1 aLe Hellard, Stephanie1 aMattheisen, Manuel1 aBohlken, Marc, M1 aKasperaviciute, Dalia1 aSchmaal, Lianne1 aLawrie, Stephen, M1 aAgartz, Ingrid1 aWalton, Esther1 aTordesillas-Gutierrez, Diana1 aDavies, Gareth, E1 aShin, Jean1 aIpser, Jonathan, C1 aVinke, Louis, N1 aHoogman, Martine1 aJia, Tianye1 aBurkhardt, Ralph1 aKlein, Marieke1 aCrivello, Fabrice1 aJanowitz, Deborah1 aCarmichael, Owen1 aHaukvik, Unn, K1 aAribisala, Benjamin, S1 aSchmidt, Helena1 aStrike, Lachlan, T1 aCheng, Ching-Yu1 aRisacher, Shannon, L1 aPütz, Benno1 aFleischman, Debra, A1 aAssareh, Amelia, A1 aMattay, Venkata, S1 aBuckner, Randy, L1 aMecocci, Patrizia1 aDale, Anders, M1 aCichon, Sven1 aBoks, Marco, P1 aMatarin, Mar1 aPenninx, Brenda, W J H1 aCalhoun, Vince, D1 aChakravarty, Mallar1 aMarquand, Andre, F1 aMacare, Christine1 aMasouleh, Shahrzad, Kharabian1 aOosterlaan, Jaap1 aAmouyel, Philippe1 aHegenscheid, Katrin1 aRotter, Jerome, I1 aSchork, Andrew, J1 aLiewald, David, C M1 ade Zubicaray, Greig, I1 aWong, Tien, Yin1 aShen, Li1 aSämann, Philipp, G1 aBrodaty, Henry1 aRoffman, Joshua, L1 aGeus, Eco, J C1 aTsolaki, Magda1 aErk, Susanne1 avan Eijk, Kristel, R1 aCavalleri, Gianpiero, L1 avan der Wee, Nic, J A1 aMcIntosh, Andrew, M1 aGollub, Randy, L1 aBulayeva, Kazima, B1 aBernard, Manon1 aRichards, Jennifer, S1 aHimali, Jayandra, J1 aLoeffler, Markus1 aRommelse, Nanda1 aHoffmann, Wolfgang1 aWestlye, Lars, T1 aHernández, Maria, C Valdés1 aHansell, Narelle, K1 avan Erp, Theo, G M1 aWolf, Christiane1 aKwok, John, B J1 aVellas, Bruno1 aHeinz, Andreas1 aLoohuis, Loes, M Olde1 aDelanty, Norman1 aHo, Beng-Choon1 aChing, Christopher, R K1 aShumskaya, Elena1 aSingh, Baljeet1 aHofman, Albert1 avan der Meer, Dennis1 aHomuth, Georg1 aPsaty, Bruce, M1 aBastin, Mark, E1 aMontgomery, Grant, W1 aForoud, Tatiana, M1 aReppermund, Simone1 aHottenga, Jouke-Jan1 aSimmons, Andrew1 aMeyer-Lindenberg, Andreas1 aCahn, Wiepke1 aWhelan, Christopher, D1 avan Donkelaar, Marjolein, M J1 aYang, Qiong1 aHosten, Norbert1 aGreen, Robert, C1 aThalamuthu, Anbupalam1 aMohnke, Sebastian1 aPol, Hilleke, E Hulshoff1 aLin, Honghuang1 aJack, Clifford, R1 aSchofield, Peter, R1 aMühleisen, Thomas, W1 aMaillard, Pauline1 aPotkin, Steven, G1 aWen, Wei1 aFletcher, Evan1 aToga, Arthur, W1 aGruber, Oliver1 aHuentelman, Matthew1 aSmith, George, Davey1 aLauner, Lenore, J1 aNyberg, Lars1 aJönsson, Erik, G1 aCrespo-Facorro, Benedicto1 aKoen, Nastassja1 aGreve, Douglas, N1 aUitterlinden, André, G1 aWeinberger, Daniel, R1 aSteen, Vidar, M1 aFedko, Iryna, O1 aGroenewold, Nynke, A1 aNiessen, Wiro, J1 aToro, Roberto1 aTzourio, Christophe1 aLongstreth, William, T1 aIkram, Kamran1 aSmoller, Jordan, W1 avan Tol, Marie-Jose1 aSussmann, Jessika, E1 aPaus, Tomáš1 aLemaître, Hervé1 aSchroeter, Matthias, L1 aMazoyer, Bernard1 aAndreassen, Ole, A1 aHolsboer, Florian1 aDepondt, Chantal1 aVeltman, Dick, J1 aTurner, Jessica, A1 aPausova, Zdenka1 aSchumann, Gunter1 avan Rooij, Daan1 aDjurovic, Srdjan1 aDeary, Ian, J1 aMcMahon, Katie, L1 aMüller-Myhsok, Bertram1 aBrouwer, Rachel, M1 aSoininen, Hilkka1 aPandolfo, Massimo1 aWassink, Thomas, H1 aCheung, Joshua, W1 aWolfers, Thomas1 aMartinot, Jean-Luc1 aZwiers, Marcel, P1 aNauck, Matthias1 aMelle, Ingrid1 aMartin, Nicholas, G1 aKanai, Ryota1 aWestman, Eric1 aKahn, René, S1 aSisodiya, Sanjay, M1 aWhite, Tonya1 aSaremi, Arvin1 avan Bokhoven, Hans1 aBrunner, Han, G1 aVölzke, Henry1 aWright, Margaret, J1 aEnt, Dennis, van 't1 aNöthen, Markus, M1 aOphoff, Roel, A1 aBuitelaar, Jan, K1 aFernández, Guillén1 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2019 eng d a1546-171800aGenetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.0 aGenetic metaanalysis of diagnosed Alzheimers disease identifies c2019 Mar a414-4300 v513 aRisk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
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Nick1 aLopez, Oscar, L1 aIngelsson, Martin1 aDeloukas, Panagiotis1 aCruchaga, Carlos1 aGraff, Caroline1 aGwilliam, Rhian1 aFornage, Myriam1 aGoate, Alison, M1 aSánchez-Juan, Pascual1 aKehoe, Patrick, G1 aAmin, Najaf1 aErtekin-Taner, Nilifur1 aBerr, Claudine1 aDebette, Stephanie1 aLove, Seth1 aLauner, Lenore, J1 aYounkin, Steven, G1 aDartigues, Jean-François1 aCorcoran, Chris1 aIkram, Arfan, M1 aDickson, Dennis, W1 aNicolas, Gaël1 aCampion, Dominique1 aTschanz, JoAnn1 aSchmidt, Helena1 aHakonarson, Hakon1 aClarimon, Jordi1 aMunger, Ron1 aSchmidt, Reinhold1 aFarrer, Lindsay, A1 aVan Broeckhoven, Christine1 aO'Donovan, Michael, C1 aDeStefano, Anita, L1 aJones, Lesley1 aHaines, Jonathan, L1 aDeleuze, Jean-Francois1 aOwen, Michael, J1 aGudnason, Vilmundur1 aMayeux, Richard1 aEscott-Price, Valentina1 aPsaty, Bruce, M1 aRamirez, Alfredo1 aSan Wang, Li-1 aRuiz, Agustin1 aDuijn, Cornelia, M1 aHolmans, Peter, A1 aSeshadri, Sudha1 aWilliams, Julie1 aAmouyel, Phillippe1 aSchellenberg, Gerard, D1 aLambert, Jean-Charles1 aPericak-Vance, Margaret, A1 aAlzheimer Disease Genetics Consortium (ADGC),1 aEuropean Alzheimer’s Disease Initiative (EADI),1 aCohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE),1 aGenetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD/PERADES), uhttps://chs-nhlbi.org/node/797707958nas a2202377 4500008004100000022001400041245011500055210006900170260001600239300000900255490000700264520122900271100001901500700001801519700002501537700002401562700002701586700002201613700002201635700002101657700002201678700002301700700002001723700002101743700002201764700002101786700002201807700002401829700002101853700002001874700001801894700001901912700001601931700002401947700003201971700002902003700002002032700002902052700002602081700002002107700002002127700002202147700002602169700001602195700002002211700002102231700001902252700001502271700002502286700002202311700002702333700002202360700002202382700002402404700001802428700002002446700002502466700001802491700001702509700002302526700002102549700002502570700002202595700002302617700001902640700002302659700002602682700001702708700001802725700002702743700002602770700002202796700002802818700002302846700002602869700002002895700002002915700002102935700001802956700001702974700002302991700001903014700002403033700002203057700002203079700002103101700002403122700002003146700002403166700002303190700001903213700001303232700001803245700002203263700003003285700002003315700002603335700002103361700002403382700002203406700002703428700001503455700001803470700001903488700002303507700002203530700002403552700002303576700001803599700001803617700001903635700001803654700002403672700001803696700001903714700001903733700002303752700002003775700001803795700002203813700002603835700002703861700002203888700002603910700001403936700001903950700002503969700002003994700001804014700002204032700001704054700001804071700002204089700001604111700002504127700002004152700001704172700002304189700001804212700002204230700002004252700001304272700002304285700001804308700002904326700002104355700002104376700001404397700002304411700001504434700002304449700001704472700001904489700003204508700002404540700002204564700002304586700002004609700002304629700002404652700002804676700002204704700002404726700002404750700001904774700002504793700002104818700001904839700001904858700002104877700002004898700002404918700002204942700002704964700002204991700002105013700002305034700002005057700001705077700001905094700002405113700002205137700001905159700001905178700002905197700002005226700002805246700001605274700001905290700002505309700002805334700002805362700002405390700001905414700002105433700002405454700002005478700002205498700002405520856003605544 2020 eng d a2041-172300aMulti-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.0 aMultiancestry GWAS of the electrocardiographic PR interval ident c2020 May 21 a25420 v113 aThe 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.
1 aNtalla, Ioanna1 aWeng, Lu-Chen1 aCartwright, James, H1 aHall, Amelia, Weber1 aSveinbjornsson, Gardar1 aTucker, Nathan, R1 aChoi, Seung, Hoan1 aChaffin, Mark, D1 aRoselli, Carolina1 aBarnes, Michael, R1 aMifsud, Borbala1 aWarren, Helen, R1 aHayward, Caroline1 aMarten, Jonathan1 aCranley, James, J1 aConcas, Maria, Pina1 aGasparini, Paolo1 aBoutin, Thibaud1 aKolcic, Ivana1 aPolasek, Ozren1 aRudan, Igor1 aAraujo, Nathalia, M1 aLima-Costa, Maria, Fernanda1 aRibeiro, Antonio, Luiz P1 aSouza, Renan, P1 aTarazona-Santos, Eduardo1 aGiedraitis, Vilmantas1 aIngelsson, Erik1 aMahajan, Anubha1 aMorris, Andrew, P1 aM, Fabiola, del Greco1 aFoco, Luisa1 aGögele, Martin1 aHicks, Andrew, A1 aCook, James, P1 aLind, Lars1 aLindgren, Cecilia, M1 aSundström, Johan1 aNelson, Christopher, P1 aRiaz, Muhammad, B1 aSamani, Nilesh, J1 aSinagra, Gianfranco1 aUlivi, Sheila1 aKähönen, Mika1 aMishra, Pashupati, P1 aMononen, Nina1 aNikus, Kjell1 aCaulfield, Mark, J1 aDominiczak, Anna1 aPadmanabhan, Sandosh1 aMontasser, May, E1 aO'Connell, Jeff, R1 aRyan, Kathleen1 aShuldiner, Alan, R1 aAeschbacher, Stefanie1 aConen, David1 aRisch, Lorenz1 aThériault, Sébastien1 aHutri-Kähönen, Nina1 aLehtimäki, Terho1 aLyytikäinen, Leo-Pekka1 aRaitakari, Olli, T1 aBarnes, Catriona, L K1 aCampbell, Harry1 aJoshi, Peter, K1 aWilson, James, F1 aIsaacs, Aaron1 aKors, Jan, A1 aDuijn, Cornelia, M1 aHuang, Paul, L1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aLauner, Lenore, J1 aSmith, Albert, V1 aBottinger, Erwin, P1 aLoos, Ruth, J F1 aNadkarni, Girish, N1 aPreuss, Michael, H1 aCorrea, Adolfo1 aMei, Hao1 aWilson, James1 aMeitinger, Thomas1 aMüller-Nurasyid, Martina1 aPeters, Annette1 aWaldenberger, Melanie1 aMangino, Massimo1 aSpector, Timothy, D1 aRienstra, Michiel1 avan de Vegte, Yordi, J1 aHarst, Pim1 aVerweij, Niek1 aKääb, Stefan1 aSchramm, Katharina1 aSinner, Moritz, F1 aStrauch, Konstantin1 aCutler, Michael, J1 aFatkin, Diane1 aLondon, Barry1 aOlesen, Morten1 aRoden, Dan, M1 aShoemaker, Benjamin1 aSmith, Gustav1 aBiggs, Mary, L1 aBis, Joshua, C1 aBrody, Jennifer, A1 aPsaty, Bruce, M1 aRice, Kenneth1 aSotoodehnia, Nona1 aDe Grandi, Alessandro1 aFuchsberger, Christian1 aPattaro, Cristian1 aPramstaller, Peter, P1 aFord, Ian1 aJukema, Wouter1 aMacfarlane, Peter, W1 aTrompet, Stella1 aDörr, Marcus1 aFelix, Stephan, B1 aVölker, Uwe1 aWeiss, Stefan1 aHavulinna, Aki, S1 aJula, Antti1 aSääksjärvi, Katri1 aSalomaa, Veikko1 aGuo, Xiuqing1 aHeckbert, Susan, R1 aLin, Henry, J1 aRotter, Jerome, I1 aTaylor, Kent, D1 aYao, Jie1 ade Mutsert, Renée1 aMaan, Arie, C1 aMook-Kanamori, Dennis, O1 aNoordam, Raymond1 aCucca, Francesco1 aDing, Jun1 aLakatta, Edward, G1 aQian, Yong1 aTarasov, Kirill, V1 aLevy, Daniel1 aLin, Honghuang1 aNewton-Cheh, Christopher, H1 aLunetta, Kathryn, L1 aMurray, Alison, D1 aPorteous, David, J1 aSmith, Blair, H1 aStricker, Bruno, H1 aUitterlinden, Andre1 avan den Berg, Marten, E1 aHaessler, Jeffrey1 aJackson, Rebecca, D1 aKooperberg, Charles1 aPeters, Ulrike1 aReiner, Alexander, P1 aWhitsel, Eric, A1 aAlonso, Alvaro1 aArking, Dan, E1 aBoerwinkle, Eric1 aEhret, Georg, B1 aSoliman, Elsayed, Z1 aAvery, Christy, L1 aGogarten, Stephanie, M1 aKerr, Kathleen, F1 aLaurie, Cathy, C1 aSeyerle, Amanda, A1 aStilp, Adrienne1 aAssa, Solmaz1 aSaid, Abdullah1 avan der Ende, Yldau1 aLambiase, Pier, D1 aOrini, Michele1 aRamirez, Julia1 aVan Duijvenboden, Stefan1 aArnar, David, O1 aGudbjartsson, Daniel, F1 aHolm, Hilma1 aSulem, Patrick1 aThorleifsson, Gudmar1 aThorolfsdottir, Rosa, B1 aThorsteinsdottir, Unnur1 aBenjamin, Emelia, J1 aTinker, Andrew1 aStefansson, Kari1 aEllinor, Patrick, T1 aJamshidi, Yalda1 aLubitz, Steven, A1 aMunroe, Patricia, B uhttps://chs-nhlbi.org/node/836804417nas a2200649 4500008004100000022001400041245006500055210006400120260001500184300001400199490000800213520264800221653000902869653001002878653002402888653002002912653002402932653001602956653001102972653002202983653001103005653001403016653000903030653003703039653001603076653002703092653002003119100002203139700002203161700001503183700001903198700001503217700002403232700003203256700002003288700001903308700002303327700001903350700001903369700002303388700001803411700002103429700002103450700002003471700002003491700002003511700002203531700002403553700002403577700002103601700002103622700002203643700002403665700001903689700002303708856003603731 2021 eng d a1524-453900aEpigenetic Age and the Risk of Incident Atrial Fibrillation.0 aEpigenetic Age and the Risk of Incident Atrial Fibrillation c2021 12 14 a1899-19110 v1443 aBACKGROUND: The most prominent risk factor for atrial fibrillation (AF) is chronological age; however, underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge in a phenomenon referred to as epigenetic age acceleration (EAA), which may reflect accelerated biological aging. We sought to evaluate for associations between epigenetic age measures and incident AF.
METHODS: Measures for 4 epigenetic clocks (Horvath, Hannum, DNA methylation [DNAm] PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 (plasminogen activator inhibitor-1) levels (ie, DNAm PAI-1) were determined for study participants from 3 population-based cohort studies. Cox models evaluated for associations with incident AF and results were combined via random-effects meta-analyses. Two-sample summary-level Mendelian randomization analyses evaluated for associations between genetic instruments of the EAA measures and AF.
RESULTS: Among 5600 participants (mean age, 65.5 years; female, 60.1%; Black, 50.7%), there were 905 incident AF cases during a mean follow-up of 12.9 years. Unadjusted analyses revealed all 4 epigenetic clocks and the DNAm PAI-1 predictor were associated with statistically significant higher hazards of incident AF, though the magnitudes of their point estimates were smaller relative to the associations observed for chronological age. The pooled EAA estimates for each epigenetic measure, with the exception of Horvath EAA, were associated with incident AF in models adjusted for chronological age, race, sex, and smoking variables. After multivariable adjustment for additional known AF risk factors that could also potentially function as mediators, pooled EAA measures for 2 clocks remained statistically significant. Five-year increases in EAA measures for DNAm GrimAge and DNAm PhenoAge were associated with 19% (adjusted hazard ratio [HR], 1.19 [95% CI, 1.09-1.31]; <0.01) and 15% (adjusted HR, 1.15 [95% CI, 1.05-1.25]; <0.01) higher hazards of incident AF, respectively. Mendelian randomization analyses for the 5 EAA measures did not reveal statistically significant associations with AF.
CONCLUSIONS: Our study identified adjusted associations between EAA measures and incident AF, suggesting that biological aging plays an important role independent of chronological age, though a potential underlying causal relationship remains unclear. These aging processes may be modifiable and not constrained by the immutable factor of time.
10aAged10aAging10aAtrial Fibrillation10aDNA Methylation10aEpigenesis, Genetic10aEpigenomics10aFemale10aFollow-Up Studies10aHumans10aIncidence10aMale10aMendelian Randomization Analysis10aMiddle Aged10aModels, Cardiovascular10aModels, Genetic1 aRoberts, Jason, D1 aVittinghoff, Eric1 aLu, Ake, T1 aAlonso, Alvaro1 aWang, Biqi1 aSitlani, Colleen, M1 aMohammadi-Shemirani, Pedrum1 aFornage, Myriam1 aKornej, Jelena1 aBrody, Jennifer, A1 aArking, Dan, E1 aLin, Honghuang1 aHeckbert, Susan, R1 aProkic, Ivana1 aGhanbari, Mohsen1 aSkanes, Allan, C1 aBartz, Traci, M1 aPerez, Marco, V1 aTaylor, Kent, D1 aLubitz, Steven, A1 aEllinor, Patrick, T1 aLunetta, Kathryn, L1 aPankow, James, S1 aParé, Guillaume1 aSotoodehnia, Nona1 aBenjamin, Emelia, J1 aHorvath, Steve1 aMarcus, Gregory, M uhttps://chs-nhlbi.org/node/900103779nas a2200673 4500008004100000245013300041210006900174260001600243520177100259100001902030700002202049700001402071700002002085700002002105700001502125700001902140700002202159700002702181700001402208700002102222700002002243700001902263700002102282700001902303700001702322700002202339700002102361700002202382700002502404700002102429700002002450700002502470700002402495700002202519700001902541700001602560700002302576700002002599700001902619700001502638700002102653700002302674700002202697700002402719700002002743700001902763700001902782700001602801700002002817700002402837700002502861700002302886700001602909700001802925700002302943710006502966710003803031856003603069 2023 eng d00aWhole Genome Sequencing Based Analysis of Inflammation Biomarkers in the Trans-Omics for Precision Medicine (TOPMed) Consortium.0 aWhole Genome Sequencing Based Analysis of Inflammation Biomarker c2023 Sep 123 aInflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38,465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program. We identified 22 distinct single-variant associations across 6 traits - E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin - that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.
1 aJiang, Min-Zhi1 aGaynor, Sheila, M1 aLi, Xihao1 aVan Buren, Eric1 aStilp, Adrienne1 aButh, Erin1 aWang, Fei, Fei1 aManansala, Regina1 aGogarten, Stephanie, M1 aLi, Zilin1 aPolfus, Linda, M1 aSalimi, Shabnam1 aBis, Joshua, C1 aPankratz, Nathan1 aYanek, Lisa, R1 aDurda, Peter1 aTracy, Russell, P1 aRich, Stephen, S1 aRotter, Jerome, I1 aMitchell, Braxton, D1 aLewis, Joshua, P1 aPsaty, Bruce, M1 aPratte, Katherine, A1 aSilverman, Edwin, K1 aKaplan, Robert, C1 aAvery, Christy1 aNorth, Kari1 aMathias, Rasika, A1 aFaraday, Nauder1 aLin, Honghuang1 aWang, Biqi1 aCarson, April, P1 aNorwood, Arnita, F1 aGibbs, Richard, A1 aKooperberg, Charles1 aLundin, Jessica1 aPeters, Ulrike1 aDupuis, Josée1 aHou, Lifang1 aFornage, Myriam1 aBenjamin, Emelia, J1 aReiner, Alexander, P1 aBowler, Russell, P1 aLin, Xihong1 aAuer, Paul, L1 aRaffield, Laura, M1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aTOPMed Inflammation Working Group uhttps://chs-nhlbi.org/node/950002608nas a2200541 4500008004100000022001400041245006100055210005800116260001600174300000800190490000700198520111600205653002201321653002601343653001801369653001001387653001301397653001101410100002001421700001701441700001701458700002101475700002101496700002601517700002201543700001901565700002901584700001501613700001801628700002101646700001801667700002001685700002301705700002101728700002001749700002001769700001901789700002101808700002801829700002301857700002101880700002101901700001701922700002801939700001801967710004501985856003602030 2024 eng d a2041-172300aHuman whole-exome genotype data for Alzheimer's disease.0 aHuman wholeexome genotype data for Alzheimers disease c2024 Jan 23 a6840 v153 aThe heterogeneity of the whole-exome sequencing (WES) data generation methods present a challenge to a joint analysis. Here we present a bioinformatics strategy for joint-calling 20,504 WES samples collected across nine studies and sequenced using ten capture kits in fourteen sequencing centers in the Alzheimer's Disease Sequencing Project. The joint-genotype called variant-called format (VCF) file contains only positions within the union of capture kits. The VCF was then processed specifically to account for the batch effects arising from the use of different capture kits from different studies. We identified 8.2 million autosomal variants. 96.82% of the variants are high-quality, and are located in 28,579 Ensembl transcripts. 41% of the variants are intronic and 1.8% of the variants are with CADD > 30, indicating they are of high predicted pathogenicity. Here we show our new strategy can generate high-quality data from processing these diversely generated WES samples. The improved ability to combine data sequenced in different batches benefits the whole genomics research community.
10aAlzheimer Disease10aComputational Biology10aData Accuracy10aExome10aGenotype10aHumans1 aLeung, Yuk, Yee1 aNaj, Adam, C1 aChou, Yi-Fan1 aValladares, Otto1 aSchmidt, Michael1 aHamilton-Nelson, Kara1 aWheeler, Nicholas1 aLin, Honghuang1 aGangadharan, Prabhakaran1 aQu, Liming1 aClark, Kaylyn1 aKuzma, Amanda, B1 aLee, Wan-Ping1 aCantwell, Laura1 aNicaretta, Heather1 aHaines, Jonathan1 aFarrer, Lindsay1 aSeshadri, Sudha1 aBrkanac, Zoran1 aCruchaga, Carlos1 aPericak-Vance, Margaret1 aMayeux, Richard, P1 aBush, William, S1 aDeStefano, Anita1 aMartin, Eden1 aSchellenberg, Gerard, D1 aSan Wang, Li-1 aAlzheimer’s Disease Sequencing Project uhttps://chs-nhlbi.org/node/9577