04494nas a2200925 4500008004100000022001400041245008800055210006900143260001300212300001100225490000600236520191100242653001002153653002202163653000902185653002402194653004002218653001102258653002702269653002202296653001802318653003402336653001102370653000902381653001602390653003602406100001802442700002202460700002102482700002202503700001702525700001902542700002002561700002002581700001702601700002002618700001802638700002202656700002202678700002402700700002402724700001202748700002402760700002202784700001402806700001902820700001602839700001902855700002202874700001702896700002002913700002402933700001902957700002502976700002103001700002403022700002503046700002003071700002403091700002203115700002803137700001903165700002003184700001903204700002003223700001903243700002303262700002203285700002103307700002003328700001903348700002203367700001803389700002203407700002303429700002103452700002903473710003003502856003603532 2012 eng d a1942-326800aImpact of ancestry and common genetic variants on QT interval in African Americans.0 aImpact of ancestry and common genetic variants on QT interval in c2012 Dec a647-550 v53 a
BACKGROUND: Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval.
METHODS AND RESULTS: First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12,097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13,105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5 × 10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2 × 10(-15)) and ATP1B1 (rs1320976, P=2 × 10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values (P<10(-5)) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF, and PLN.
CONCLUSIONS: We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of African ancestry.
10aAdult10aAfrican Americans10aAged10aElectrocardiography10aEuropean Continental Ancestry Group10aFemale10aGenealogy and Heraldry10aGenetic Variation10aGenome, Human10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide1 aSmith, Gustav1 aAvery, Christy, L1 aEvans, Daniel, S1 aNalls, Michael, A1 aMeng, Yan, A1 aSmith, Erin, N1 aPalmer, Cameron1 aTanaka, Toshiko1 aMehra, Reena1 aButler, Anne, M1 aYoung, Taylor1 aBuxbaum, Sarah, G1 aKerr, Kathleen, F1 aBerenson, Gerald, S1 aSchnabel, Renate, B1 aLi, Guo1 aEllinor, Patrick, T1 aMagnani, Jared, W1 aChen, Wei1 aBis, Joshua, C1 aCurb, David1 aHsueh, Wen-Chi1 aRotter, Jerome, I1 aLiu, Yongmei1 aNewman, Anne, B1 aLimacher, Marian, C1 aNorth, Kari, E1 aReiner, Alexander, P1 aQuibrera, Miguel1 aSchork, Nicholas, J1 aSingleton, Andrew, B1 aPsaty, Bruce, M1 aSoliman, Elsayed, Z1 aSolomon, Allen, J1 aSrinivasan, Sathanur, R1 aAlonso, Alvaro1 aWallace, Robert1 aRedline, Susan1 aZhang, Zhu-Ming1 aPost, Wendy, S1 aZonderman, Alan, B1 aTaylor, Herman, A1 aMurray, Sarah, S1 aFerrucci, Luigi1 aArking, Dan, E1 aEvans, Michele, K1 aFox, Ervin, R1 aSotoodehnia, Nona1 aHeckbert, Susan, R1 aWhitsel, Eric, A1 aNewton-Cheh, Christopher1 aCARe and COGENT consortia uhttps://chs-nhlbi.org/node/617904310nas a2200901 4500008004100000022001400041245011000055210006900165260001300234300001100247490000600258520179200264653001002056653002202066653001902088653002402107653001102131653001702142653003402159653001102193653000902204653002702213653001602240653003602256100002002292700001702312700002102329700002202350700001902372700002002391700001202411700002202423700002102445700001902466700001902485700002402504700002402528700001702552700001402569700001502583700002402598700002302622700001902645700001902664700002402683700002202707700001202729700002402741700001702765700002202782700002602804700001702830700001702847700002002864700002902884700001902913700002302932700002002955700002102975700001902996700002003015700002203035700002403057700002403081700002503105700001803130700002403148700002803172700002003200700002303220700002003243700002103263700002203284700002203306700002203328700002203350856003603372 2012 eng d a1942-326800aNovel loci associated with PR interval in a genome-wide association study of 10 African American cohorts.0 aNovel loci associated with PR interval in a genomewide associati c2012 Dec a639-460 v53 aBACKGROUND: The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans.
METHODS AND RESULTS: We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 × 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 × 10(-8)).
CONCLUSIONS: This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.
10aAdult10aAfrican Americans10aCohort Studies10aElectrocardiography10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aMiddle Aged10aPolymorphism, Single Nucleotide1 aButler, Anne, M1 aYin, Xiaoyan1 aEvans, Daniel, S1 aNalls, Michael, A1 aSmith, Erin, N1 aTanaka, Toshiko1 aLi, Guo1 aBuxbaum, Sarah, G1 aWhitsel, Eric, A1 aAlonso, Alvaro1 aArking, Dan, E1 aBenjamin, Emelia, J1 aBerenson, Gerald, S1 aBis, Josh, C1 aChen, Wei1 aDeo, Rajat1 aEllinor, Patrick, T1 aHeckbert, Susan, R1 aHeiss, Gerardo1 aHsueh, Wen-Chi1 aKeating, Brendan, J1 aKerr, Kathleen, F1 aLi, Yun1 aLimacher, Marian, C1 aLiu, Yongmei1 aLubitz, Steven, A1 aMarciante, Kristin, D1 aMehra, Reena1 aMeng, Yan, A1 aNewman, Anne, B1 aNewton-Cheh, Christopher1 aNorth, Kari, E1 aPalmer, Cameron, D1 aPsaty, Bruce, M1 aQuibrera, Miguel1 aRedline, Susan1 aReiner, Alex, P1 aRotter, Jerome, I1 aSchnabel, Renate, B1 aSchork, Nicholas, J1 aSingleton, Andrew, B1 aSmith, Gustav1 aSoliman, Elsayed, Z1 aSrinivasan, Sathanur, R1 aZhang, Zhu-Ming1 aZonderman, Alan, B1 aFerrucci, Luigi1 aMurray, Sarah, S1 aEvans, Michele, K1 aSotoodehnia, Nona1 aMagnani, Jared, W1 aAvery, Christy, L uhttps://chs-nhlbi.org/node/608404382nas a2200853 4500008004100000022001400041245015400055210006900209260001600278520191500294100002102209700002202230700001902252700001202271700001802283700001902301700002002320700002002340700002202360700001902382700001902401700002402420700001902444700001902463700001902482700001402501700001902515700002402534700001502558700002202573700001802595700002302613700001902636700002302655700001902678700001802697700002002715700002202735700001502757700001702772700002002789700002202809700002102831700001702852700001702869700002302886700002902909700001902938700002002957700001902977700002202996700002403018700002403042700002103066700002503087700002303112700002403135700002803159700002203187700002603209700002103235700001803256700002003274700002303294700002203317700002003339700002103359700002303380700002103403700002003424700002203444710002603466856003603492 2016 eng d a1460-208300aFine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans.0 aFinemapping novel loci identification and SNP association transf c2016 Aug 293 aThe electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 × 10(-14)) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 × 10(-4)). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 × 10(-8)) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10(-9)). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 × 10(-7)), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.
1 aEvans, Daniel, S1 aAvery, Christy, L1 aNalls, Mike, A1 aLi, Guo1 aBarnard, John1 aSmith, Erin, N1 aTanaka, Toshiko1 aButler, Anne, M1 aBuxbaum, Sarah, G1 aAlonso, Alvaro1 aArking, Dan, E1 aBerenson, Gerald, S1 aBis, Joshua, C1 aBuyske, Steven1 aCarty, Cara, L1 aChen, Wei1 aChung, Mina, K1 aCummings, Steven, R1 aDeo, Rajat1 aEaton, Charles, B1 aFox, Ervin, R1 aHeckbert, Susan, R1 aHeiss, Gerardo1 aHindorff, Lucia, A1 aHsueh, Wen-Chi1 aIsaacs, Aaron1 aJamshidi, Yalda1 aKerr, Kathleen, F1 aLiu, Felix1 aLiu, Yongmei1 aLohman, Kurt, K1 aMagnani, Jared, W1 aMaher, Joseph, F1 aMehra, Reena1 aMeng, Yan, A1 aMusani, Solomon, K1 aNewton-Cheh, Christopher1 aNorth, Kari, E1 aPsaty, Bruce, M1 aRedline, Susan1 aRotter, Jerome, I1 aSchnabel, Renate, B1 aSchork, Nicholas, J1 aShohet, Ralph, V1 aSingleton, Andrew, B1 aSmith, Jonathan, D1 aSoliman, Elsayed, Z1 aSrinivasan, Sathanur, R1 aTaylor, Herman, A1 aVan Wagoner, David, R1 aWilson, James, G1 aYoung, Taylor1 aZhang, Zhu-Ming1 aZonderman, Alan, B1 aEvans, Michele, K1 aFerrucci, Luigi1 aMurray, Sarah, S1 aTranah, Gregory, J1 aWhitsel, Eric, A1 aReiner, Alex, P1 aSotoodehnia, Nona1 aCHARGE QRS Consortium uhttps://chs-nhlbi.org/node/725902737nas a2200541 4500008004100000022001400041245012200055210006900177260001200246300001200258490000800270520112500278653001001403653002001413653002501433653004001458653001101498653003401509653001101543653001401554653002001568653000901588653003701597653001201634653003601646653003201682653002701714100002101741700002001762700002101782700001901803700002901822700003001851700002501881700002001906700001701926700002001943700002301963700001801986700001802004700002302022700002402045700002302069700002002092700002502112710002202137856003602159 2017 eng d a1432-120300aAssessing the causal relationship between obesity and venous thromboembolism through a Mendelian Randomization study.0 aAssessing the causal relationship between obesity and venous thr c2017 07 a897-9020 v1363 aObservational studies have shown an association between obesity and venous thromboembolism (VTE) but it is not known if observed associations are causal, due to reverse causation or confounding bias. We conducted a Mendelian Randomization study of body mass index (BMI) and VTE. We identified 95 single nucleotide polymorphisms (SNPs) that have been previously associated with BMI and assessed the association between genetically predicted high BMI and VTE leveraging data from a previously conducted GWAS within the INVENT consortium comprising a total of 7507 VTE cases and 52,632 controls of European ancestry. Five BMI SNPs were associated with VTE at P < 0.05, with the strongest association seen for the FTO SNP rs1558902 (OR 1.07, 95% CI 1.02-1.12, P = 0.005). In addition, we observed a significant association between genetically predicted BMI and VTE (OR = 1.59, 95% CI 1.30-1.93 per standard deviation increase in BMI, P = 5.8 × 10). Our study provides evidence for a causal relationship between high BMI and risk of VTE. Reducing obesity levels will likely result in lower incidence in VTE.
10aAdult10aBody Mass Index10aCase-Control Studies10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aIncidence10aLogistic Models10aMale10aMendelian Randomization Analysis10aObesity10aPolymorphism, Single Nucleotide10aProportional Hazards Models10aVenous Thromboembolism1 aLindström, Sara1 aGermain, Marine1 aCrous-Bou, Marta1 aSmith, Erin, N1 aMorange, Pierre-Emmanuel1 aVlieg, Astrid, van Hylcka1 ade Haan, Hugoline, G1 aChasman, Daniel1 aRidker, Paul1 aBrody, Jennifer1 ade Andrade, Mariza1 aHeit, John, A1 aTang, Weihong1 aDeVivo, Immaculata1 aGrodstein, Francine1 aSmith, Nicholas, L1 aTregouet, David1 aKabrhel, Christopher1 aINVENT Consortium uhttps://chs-nhlbi.org/node/777711426nas 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/792004216nas a2200841 4500008004100000022001400041245011700055210006900172260001600241300001400257490000800271520173700279100002102016700001302037700001902050700002002069700003002089700002302119700002302142700002002165700002202185700002102207700002302228700001902251700002002270700002202290700002002312700002202332700002102354700002402375700002502399700002102424700002402445700002202469700002302491700002302514700001902537700002302556700002302579700002302602700001802625700002202643700002502665700002502690700002102715700002102736700002302757700001702780700002102797700002502818700002602843700002702869700002402896700001502920700002202935700001702957700002402974700002402998700001803022700002003040700001803060700002403078700002003102700002003122700002903142700002303171700002503194700003203219700002303251710002803274710003603302856003603338 2019 eng d a1528-002000aGenomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.0 aGenomic and transcriptomic association studies identify 16 novel c2019 Nov 07 a1645-16570 v1343 aVenous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.
1 aLindström, Sara1 aWang, Lu1 aSmith, Erin, N1 aGordon, William1 aVlieg, Astrid, van Hylcka1 ade Andrade, Mariza1 aBrody, Jennifer, A1 aPattee, Jack, W1 aHaessler, Jeffrey1 aBrumpton, Ben, M1 aChasman, Daniel, I1 aSuchon, Pierre1 aChen, Ming-Huei1 aTurman, Constance1 aGermain, Marine1 aWiggins, Kerri, L1 aMacDonald, James1 aBraekkan, Sigrid, K1 aArmasu, Sebastian, M1 aPankratz, Nathan1 aJackson, Rebecca, D1 aNielsen, Jonas, B1 aGiulianini, Franco1 aPuurunen, Marja, K1 aIbrahim, Manal1 aHeckbert, Susan, R1 aDamrauer, Scott, M1 aNatarajan, Pradeep1 aKlarin, Derek1 ade Vries, Paul, S1 aSabater-Lleal, Maria1 aHuffman, Jennifer, E1 aBammler, Theo, K1 aFrazer, Kelly, A1 aMcCauley, Bryan, M1 aTaylor, Kent1 aPankow, James, S1 aReiner, Alexander, P1 aGabrielsen, Maiken, E1 aDeleuze, Jean-Francois1 aO'Donnell, Chris, J1 aKim, Jihye1 aMcKnight, Barbara1 aKraft, Peter1 aHansen, John-Bjarne1 aRosendaal, Frits, R1 aHeit, John, A1 aPsaty, Bruce, M1 aTang, Weihong1 aKooperberg, Charles1 aHveem, Kristian1 aRidker, Paul, M1 aMorange, Pierre-Emmanuel1 aJohnson, Andrew, D1 aKabrhel, Christopher1 aTrégouët, David-Alexandre1 aSmith, Nicholas, L1 aMillion Veteran Program1 aCHARGE Hemostasis Working Group uhttps://chs-nhlbi.org/node/820002918nas a2200589 4500008004100000022001400041245006600055210006200121260001600183520123400199100002101433700002301454700002201477700002001499700002001519700001901539700002001558700002001578700002001598700002101618700002101639700001701660700001701677700001801694700001901712700002601731700001801757700002101775700002401796700002201820700002701842700002901869700001901898700002101917700002001938700002201958700001701980700002501997700002302022700002402045700001702069700002402086700001802110700002302128700002902151700002502180700001702205700002302222700002502245710002202270856003602292 2019 eng d a1098-227200aA large-scale exome array analysis of venous thromboembolism.0 alargescale exome array analysis of venous thromboembolism c2019 Jan 193 aAlthough recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.
1 aLindström, Sara1 aBrody, Jennifer, A1 aTurman, Constance1 aGermain, Marine1 aBartz, Traci, M1 aSmith, Erin, N1 aChen, Ming-Huei1 aPuurunen, Marja1 aChasman, Daniel1 aHassler, Jeffrey1 aPankratz, Nathan1 aBasu, Saonli1 aGuan, Weihua1 aGyorgy, Beata1 aIbrahim, Manal1 aEmpana, Jean-Philippe1 aOlaso, Robert1 aJackson, Rebecca1 aBraekkan, Sigrid, K1 aMcKnight, Barbara1 aDeleuze, Jean-Francois1 aO'Donnell, Cristopher, J1 aJouven, Xavier1 aFrazer, Kelly, A1 aPsaty, Bruce, M1 aWiggins, Kerri, L1 aTaylor, Kent1 aReiner, Alexander, P1 aHeckbert, Susan, R1 aKooperberg, Charles1 aRidker, Paul1 aHansen, John-Bjarne1 aTang, Weihong1 aJohnson, Andrew, D1 aMorange, Pierre-Emmanuel1 aTrégouët, David, A1 aKraft, Peter1 aSmith, Nicholas, L1 aKabrhel, Christopher1 aINVENT Consortium uhttps://chs-nhlbi.org/node/7979