06025nas a2201489 4500008004100000022001400041245009200055210006900147260001500216300000900231490000700240520184700247100002002094700002002114700002202134700002002156700002502176700002402201700002602225700002002251700002202271700002002293700001602313700002002329700002302349700002302372700002102395700001902416700002102435700001702456700002102473700001602494700002302510700001602533700002002549700002102569700002102590700002102611700002302632700002402655700002802679700002302707700002002730700002402750700001802774700002202792700002202814700002002836700002002856700001202876700002402888700002402912700001902936700002202955700002202977700002302999700002503022700002403047700001903071700002503090700002003115700001703135700002203152700002203174700001203196700002403208700002103232700001703253700001803270700002803288700001803316700002303334700001903357700002103376700001803397700001903415700002603434700001703460700002403477700002503501700001903526700002303545700001803568700002003586700002303606700002103629700002103650700002103671700002603692700002203718700001903740700002603759700001903785700002003804700002203824700002303846700002403869700002203893700002103915700001903936700002703955700002303982700002604005700001804031700001804049700002804067700002604095700002004121700002404141700002104165700002104186700002304207700002204230700001804252700001604270700002004286700002104306700002004327700002104347700002104368700002204389700001804411700002304429700002504452700002204477856003604499 2016 eng d a1537-660500aExome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits.0 aExome Genotyping Identifies Pleiotropic Variants Associated with c2016 Jul 7 a8-210 v993 a
Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.
1 aChami, Nathalie1 aChen, Ming-Huei1 aSlater, Andrew, J1 aEicher, John, D1 aEvangelou, Evangelos1 aTajuddin, Salman, M1 aLove-Gregory, Latisha1 aKacprowski, Tim1 aSchick, Ursula, M1 aNomura, Akihiro1 aGiri, Ayush1 aLessard, Samuel1 aBrody, Jennifer, A1 aSchurmann, Claudia1 aPankratz, Nathan1 aYanek, Lisa, R1 aManichaikul, Ani1 aPazoki, Raha1 aMihailov, Evelin1 aHill, David1 aRaffield, Laura, M1 aBurt, Amber1 aBartz, Traci, M1 aBecker, Diane, M1 aBecker, Lewis, C1 aBoerwinkle, Eric1 aBork-Jensen, Jette1 aBottinger, Erwin, P1 aO'Donoghue, Michelle, L1 aCrosslin, David, R1 ade Denus, Simon1 aDubé, Marie-Pierre1 aElliott, Paul1 aEngström, Gunnar1 aEvans, Michele, K1 aFloyd, James, S1 aFornage, Myriam1 aGao, He1 aGreinacher, Andreas1 aGudnason, Vilmundur1 aHansen, Torben1 aHarris, Tamara, B1 aHayward, Caroline1 aHernesniemi, Jussi1 aHighland, Heather, M1 aHirschhorn, Joel, N1 aHofman, Albert1 aIrvin, Marguerite, R1 aKähönen, Mika1 aLange, Ethan1 aLauner, Lenore, J1 aLehtimäki, Terho1 aLi, Jin1 aLiewald, David, C M1 aLinneberg, Allan1 aLiu, Yongmei1 aLu, Yingchang1 aLyytikäinen, Leo-Pekka1 aMägi, Reedik1 aMathias, Rasika, A1 aMelander, Olle1 aMetspalu, Andres1 aMononen, Nina1 aNalls, Mike, A1 aNickerson, Deborah, A1 aNikus, Kjell1 aO'Donnell, Chris, J1 aOrho-Melander, Marju1 aPedersen, Oluf1 aPetersmann, Astrid1 aPolfus, Linda1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRaitoharju, Emma1 aRichard, Melissa1 aRice, Kenneth, M1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSchmidt, Frank1 aSmith, Albert, Vernon1 aStarr, John, M1 aTaylor, Kent, D1 aTeumer, Alexander1 aThuesen, Betina, H1 aTorstenson, Eric, S1 aTracy, Russell, P1 aTzoulaki, Ioanna1 aZakai, Neil, A1 aVacchi-Suzzi, Caterina1 aDuijn, Cornelia, M1 avan Rooij, Frank, J A1 aCushman, Mary1 aDeary, Ian, J1 aEdwards, Digna, R Velez1 aVergnaud, Anne-Claire1 aWallentin, Lars1 aWaterworth, Dawn, M1 aWhite, Harvey, D1 aWilson, James, G1 aZonderman, Alan, B1 aKathiresan, Sekar1 aGrarup, Niels1 aEsko, Tõnu1 aLoos, Ruth, J F1 aLange, Leslie, A1 aFaraday, Nauder1 aAbumrad, Nada, A1 aEdwards, Todd, L1 aGanesh, Santhi, K1 aAuer, Paul, L1 aJohnson, Andrew, D1 aReiner, Alexander, P1 aLettre, Guillaume uhttps://chs-nhlbi.org/node/713805559nas a2201297 4500008004100000022001400041245013800055210006900193260001500262300001000277490000700287520188700294100002402181700002202205700002002227700002002247700001602267700002302283700001602306700002002322700001202342700002802354700002102382700002102403700002802424700002102452700001702473700002102490700002602511700002302537700002702560700002402587700002502611700001902636700001602655700002002671700002602691700002002717700002402737700002202761700002502783700002102808700001702829700001802846700001902864700002302883700002602906700001702932700001902949700002402968700002102992700002803013700002003041700002003061700002103081700002103102700002303123700001903146700002003165700002003185700001203205700002403217700002403241700002103265700002403286700002103310700002103331700002103352700002003373700002403393700002203417700001903439700001803458700001703476700002203493700002203515700001803537700002103555700002403576700002403600700002103624700002403645700002003669700002603689700002303715700002303738700001803761700001803779700001803797700002203815700002403837700002003861700002003881700002203901700002203923700001903945700002103964700002203985700002004007700001604027700002004043700002104063700001804084700002304102700002104125700001904146700002204165700002004187700001804207856003604225 2016 eng d a1537-660500aLarge-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.0 aLargeScale Exomewide Association Analysis Identifies Loci for Wh c2016 Jul 7 a22-390 v993 aWhite blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.
1 aTajuddin, Salman, M1 aSchick, Ursula, M1 aEicher, John, D1 aChami, Nathalie1 aGiri, Ayush1 aBrody, Jennifer, A1 aHill, David1 aKacprowski, Tim1 aLi, Jin1 aLyytikäinen, Leo-Pekka1 aManichaikul, Ani1 aMihailov, Evelin1 aO'Donoghue, Michelle, L1 aPankratz, Nathan1 aPazoki, Raha1 aPolfus, Linda, M1 aSmith, Albert, Vernon1 aSchurmann, Claudia1 aVacchi-Suzzi, Caterina1 aWaterworth, Dawn, M1 aEvangelou, Evangelos1 aYanek, Lisa, R1 aBurt, Amber1 aChen, Ming-Huei1 avan Rooij, Frank, J A1 aFloyd, James, S1 aGreinacher, Andreas1 aHarris, Tamara, B1 aHighland, Heather, M1 aLange, Leslie, A1 aLiu, Yongmei1 aMägi, Reedik1 aNalls, Mike, A1 aMathias, Rasika, A1 aNickerson, Deborah, A1 aNikus, Kjell1 aStarr, John, M1 aTardif, Jean-Claude1 aTzoulaki, Ioanna1 aEdwards, Digna, R Velez1 aWallentin, Lars1 aBartz, Traci, M1 aBecker, Lewis, C1 aDenny, Joshua, C1 aRaffield, Laura, M1 aRioux, John, D1 aFriedrich, Nele1 aFornage, Myriam1 aGao, He1 aHirschhorn, Joel, N1 aLiewald, David, C M1 aRich, Stephen, S1 aUitterlinden, Andre1 aBastarache, Lisa1 aBecker, Diane, M1 aBoerwinkle, Eric1 ade Denus, Simon1 aBottinger, Erwin, P1 aHayward, Caroline1 aHofman, Albert1 aHomuth, Georg1 aLange, Ethan1 aLauner, Lenore, J1 aLehtimäki, Terho1 aLu, Yingchang1 aMetspalu, Andres1 aO'Donnell, Chris, J1 aQuarells, Rakale, C1 aRichard, Melissa1 aTorstenson, Eric, S1 aTaylor, Kent, D1 aVergnaud, Anne-Claire1 aZonderman, Alan, B1 aCrosslin, David, R1 aDeary, Ian, J1 aDörr, Marcus1 aElliott, Paul1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKähönen, Mika1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aSlater, Andrew, J1 aDehghan, Abbas1 aWhite, Harvey, D1 aGanesh, Santhi, K1 aLoos, Ruth, J F1 aEsko, Tõnu1 aFaraday, Nauder1 aWilson, James, G1 aCushman, Mary1 aJohnson, Andrew, D1 aEdwards, Todd, L1 aZakai, Neil, A1 aLettre, Guillaume1 aReiner, Alex, P1 aAuer, Paul, L uhttps://chs-nhlbi.org/node/714606109nas a2201525 4500008004100000022001400041245009200055210006900147260001500216300001000231490000700241520179700248100002002045700002002065700002002085700002002105700002002125700001902145700002402164700002202188700002202210700002102232700001802253700002302271700001602294700002302310700002102333700002102354700001602375700001702391700001702408700002502425700002102450700001202471700002602483700002302509700002102532700002102553700001602574700002302590700002802613700001702641700002302658700002002681700002102701700001802722700002302740700002202763700001802785700001902803700002602822700002302848700002102871700002302892700002002915700002502935700002002960700002002980700002203000700002403022700002203046700002003068700002103088700002403109700001903133700002403152700002003176700001803196700002403214700002003238700002603258700002203284700002203306700002403328700002803352700002403380700001703404700002203421700002203443700002103465700002503486700002103511700001203532700001703544700002103561700002103582700001803603700002103621700002103642700001603663700002703679700001903706700002303725700002203748700002203770700002503792700001903817700002803836700002403864700002003888700002103908700002003929700002003949700002103969700002003990700001604010700002404026700002204050700001804072700002404090700001704114700001904131700001904150700002604169700002804195700002104223700001904244700002104263700002204284700002204306700002004328700001804348700002004366700002204386700002304408710003804431710003204469710004604501856003604547 2016 eng d a1537-660500aPlatelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals.0 aPlateletRelated Variants Identified by Exomechip Metaanalysis in c2016 Jul 7 a40-550 v993 aPlatelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.
1 aEicher, John, D1 aChami, Nathalie1 aKacprowski, Tim1 aNomura, Akihiro1 aChen, Ming-Huei1 aYanek, Lisa, R1 aTajuddin, Salman, M1 aSchick, Ursula, M1 aSlater, Andrew, J1 aPankratz, Nathan1 aPolfus, Linda1 aSchurmann, Claudia1 aGiri, Ayush1 aBrody, Jennifer, A1 aLange, Leslie, A1 aManichaikul, Ani1 aHill, David1 aPazoki, Raha1 aElliot, Paul1 aEvangelou, Evangelos1 aTzoulaki, Ioanna1 aGao, He1 aVergnaud, Anne-Claire1 aMathias, Rasika, A1 aBecker, Diane, M1 aBecker, Lewis, C1 aBurt, Amber1 aCrosslin, David, R1 aLyytikäinen, Leo-Pekka1 aNikus, Kjell1 aHernesniemi, Jussi1 aKähönen, Mika1 aRaitoharju, Emma1 aMononen, Nina1 aRaitakari, Olli, T1 aLehtimäki, Terho1 aCushman, Mary1 aZakai, Neil, A1 aNickerson, Deborah, A1 aRaffield, Laura, M1 aQuarells, Rakale1 aWiller, Cristen, J1 aPeloso, Gina, M1 aAbecasis, Goncalo, R1 aLiu, Dajiang, J1 aDeloukas, Panos1 aSamani, Nilesh, J1 aSchunkert, Heribert1 aErdmann, Jeanette1 aFornage, Myriam1 aRichard, Melissa1 aTardif, Jean-Claude1 aRioux, John, D1 aDubé, Marie-Pierre1 ade Denus, Simon1 aLu, Yingchang1 aBottinger, Erwin, P1 aLoos, Ruth, J F1 aSmith, Albert, Vernon1 aHarris, Tamara, B1 aLauner, Lenore, J1 aGudnason, Vilmundur1 aEdwards, Digna, R Velez1 aTorstenson, Eric, S1 aLiu, Yongmei1 aTracy, Russell, P1 aRotter, Jerome, I1 aRich, Stephen, S1 aHighland, Heather, M1 aBoerwinkle, Eric1 aLi, Jin1 aLange, Ethan1 aWilson, James, G1 aMihailov, Evelin1 aMägi, Reedik1 aHirschhorn, Joel1 aMetspalu, Andres1 aEsko, Tõnu1 aVacchi-Suzzi, Caterina1 aNalls, Mike, A1 aZonderman, Alan, B1 aEvans, Michele, K1 aEngström, Gunnar1 aOrho-Melander, Marju1 aMelander, Olle1 aO'Donoghue, Michelle, L1 aWaterworth, Dawn, M1 aWallentin, Lars1 aWhite, Harvey, D1 aFloyd, James, S1 aBartz, Traci, M1 aRice, Kenneth, M1 aPsaty, Bruce, M1 aStarr, J, M1 aLiewald, David, C M1 aHayward, Caroline1 aDeary, Ian, J1 aGreinacher, Andreas1 aVölker, Uwe1 aThiele, Thomas1 aVölzke, Henry1 avan Rooij, Frank, J A1 aUitterlinden, André, G1 aFranco, Oscar, H1 aDehghan, Abbas1 aEdwards, Todd, L1 aGanesh, Santhi, K1 aKathiresan, Sekar1 aFaraday, Nauder1 aAuer, Paul, L1 aReiner, Alex, P1 aLettre, Guillaume1 aJohnson, Andrew, D1 aGlobal Lipids Genetics Consortium1 aCARDIoGRAM Exome Consortium1 aMyocardial Infarction Genetics Consortium uhttps://chs-nhlbi.org/node/713905835nas a2201585 4500008004100000022001400041245012700055210006900182260001500251300001000266490000700276520141400283100001801697700002401715700001901739700002801758700001901786700001901805700002501824700001801849700001301867700002001880700002001900700002101920700001701941700002401958700002501982700001202007700002202019700002002041700002002061700002202081700002602103700001902129700001802148700001802166700002502184700002102209700002102230700002202251700002102273700001702294700001702311700001702328700001502345700002102360700002402381700003102405700002402436700002402460700002002484700001902504700001402523700002102537700002402558700001902582700002402601700002202625700001802647700001902665700002102684700002202705700001802727700002002745700002002765700002302785700001602808700002202824700002002846700001602866700002202882700002302904700002302927700001702950700002202967700002302989700001703012700002003029700002203049700002303071700001603094700002003110700001503130700002103145700002203166700001903188700002503207700002403232700002103256700002103277700002203298700001603320700002303336700002403359700002203383700001803405700001303423700001803436700002203454700002103476700002303497700002603520700002303546700002103569700002003590700002003610700002403630700001903654700002103673700002303694700002203717700002603739700002103765700002203786700002203808700002503830700002003855700002403875700002003899700002103919700002003940700001903960700002103979700002004000700002204020700002204042700002004064710002004084710002004104710002504124710002204149710002104171710002104192856003604213 2016 eng d a1537-660500aTrans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin.0 aTransethnic Metaanalysis and Functional Annotation Illuminates t c2016 Jul 7 a56-750 v993 aKnowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.
1 aLiu, Ching-Ti1 aRaghavan, Sridharan1 aMaruthur, Nisa1 aKabagambe, Edmond, Kato1 aHong, Jaeyoung1 aC Y Ng, Maggie1 aHivert, Marie-France1 aLu, Yingchang1 aAn, Ping1 aBentley, Amy, R1 aDrolet, Anne, M1 aGaulton, Kyle, J1 aGuo, Xiuqing1 aArmstrong, Loren, L1 aIrvin, Marguerite, R1 aLi, Man1 aLipovich, Leonard1 aRybin, Denis, V1 aTaylor, Kent, D1 aAgyemang, Charles1 aPalmer, Nicholette, D1 aCade, Brian, E1 aChen, Wei-Min1 aDauriz, Marco1 aDelaney, Joseph, A C1 aEdwards, Todd, L1 aEvans, Daniel, S1 aEvans, Michele, K1 aLange, Leslie, A1 aLeong, Aaron1 aLiu, Jingmin1 aLiu, Yongmei1 aNayak, Uma1 aPatel, Sanjay, R1 aPorneala, Bianca, C1 aRasmussen-Torvik, Laura, J1 aSnijder, Marieke, B1 aStallings, Sarah, C1 aTanaka, Toshiko1 aYanek, Lisa, R1 aZhao, Wei1 aBecker, Diane, M1 aBielak, Lawrence, F1 aBiggs, Mary, L1 aBottinger, Erwin, P1 aBowden, Donald, W1 aChen, Guanjie1 aCorrea, Adolfo1 aCouper, David, J1 aCrawford, Dana, C1 aCushman, Mary1 aEicher, John, D1 aFornage, Myriam1 aFranceschini, Nora1 aFu, Yi-Ping1 aGoodarzi, Mark, O1 aGottesman, Omri1 aHara, Kazuo1 aHarris, Tamara, B1 aJensen, Richard, A1 aJohnson, Andrew, D1 aJhun, Min, A1 aKarter, Andrew, J1 aKeller, Margaux, F1 aKho, Abel, N1 aKizer, Jorge, R1 aKrauss, Ronald, M1 aLangefeld, Carl, D1 aLi, Xiaohui1 aLiang, Jingling1 aLiu, Simin1 aLowe, William, L1 aMosley, Thomas, H1 aNorth, Kari, E1 aPacheco, Jennifer, A1 aPeyser, Patricia, A1 aPatrick, Alan, L1 aRice, Kenneth, M1 aSelvin, Elizabeth1 aSims, Mario1 aSmith, Jennifer, A1 aTajuddin, Salman, M1 aVaidya, Dhananjay1 aWren, Mary, P1 aYao, Jie1 aZhu, Xiaofeng1 aZiegler, Julie, T1 aZmuda, Joseph, M1 aZonderman, Alan, B1 aZwinderman, Aeilko, H1 aAdeyemo, Adebowale1 aBoerwinkle, Eric1 aFerrucci, Luigi1 aHayes, Geoffrey1 aKardia, Sharon, L R1 aMiljkovic, Iva1 aPankow, James, S1 aRotimi, Charles, N1 aSale, Michèle, M1 aWagenknecht, Lynne, E1 aArnett, Donna, K1 aChen, Yii-Der Ida1 aNalls, Michael, A1 aProvince, Michael, A1 aKao, Linda, W H1 aSiscovick, David, S1 aPsaty, Bruce, M1 aWilson, James, G1 aLoos, Ruth, J F1 aDupuis, Josée1 aRich, Stephen, S1 aFlorez, Jose, C1 aRotter, Jerome, I1 aMorris, Andrew, P1 aMeigs, James, B1 aAAAG Consortium1 aCARe Consortium1 aCOGENT-BP Consortium1 aeMERGE Consortium1 aMEDIA Consortium1 aMAGIC Consortium uhttps://chs-nhlbi.org/node/714106485nas a2201489 4500008004100000022001400041245020200055210006900257260001600326300001300342490000700355520221400362100001902576700002202595700001802617700002102635700001902656700001802675700001902693700001902712700002102731700002402752700001802776700002302794700001902817700002402836700001502860700001702875700002102892700002202913700002002935700002402955700002202979700002203001700002703023700001803050700001803068700002203086700002503108700002703133700002303160700001503183700002403198700002803222700002203250700002003272700002103292700002203313700002103335700002403356700001803380700002403398700002203422700002003444700002303464700002003487700002303507700002003530700002403550700001903574700001703593700001803610700001903628700002003647700001803667700001603685700001203701700002203713700001503735700002203750700002203772700001903794700002203813700001903835700002503854700002203879700002303901700001703924700002403941700002303965700002503988700001604013700001904029700002204048700001904070700001304089700001804102700002304120700002304143700002304166700001704189700001804206700002104224700002204245700002104267700002804288700001804316700001904334700001404353700001504367700002104382700002304403700002404426700002904450700001404479700002304493700002204516700002004538700002204558700002104580700002304601700002204624700002204646700002404668700001204692700002104704700002004725700002204745700002104767700002204788700002504810700002704835700002004862700001904882710005804901856003604959 2017 eng d a1553-740400aDiscovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African ancestry anthropometry genetics consortium.0 aDiscovery and finemapping of adiposity loci using high density i c2017 Apr 21 ae10067190 v133 aGenome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.
1 aC Y Ng, Maggie1 aGraff, Mariaelisa1 aLu, Yingchang1 aJustice, Anne, E1 aMudgal, Poorva1 aLiu, Ching-Ti1 aYoung, Kristin1 aYanek, Lisa, R1 aFeitosa, Mary, F1 aWojczynski, Mary, K1 aRand, Kristin1 aBrody, Jennifer, A1 aCade, Brian, E1 aDimitrov, Latchezar1 aDuan, Qing1 aGuo, Xiuqing1 aLange, Leslie, A1 aNalls, Michael, A1 aOkut, Hayrettin1 aTajuddin, Salman, M1 aTayo, Bamidele, O1 aVedantam, Sailaja1 aBradfield, Jonathan, P1 aChen, Guanjie1 aChen, Wei-Min1 aChesi, Alessandra1 aIrvin, Marguerite, R1 aPadhukasahasram, Badri1 aSmith, Jennifer, A1 aZheng, Wei1 aAllison, Matthew, A1 aAmbrosone, Christine, B1 aBandera, Elisa, V1 aBartz, Traci, M1 aBerndt, Sonja, I1 aBernstein, Leslie1 aBlot, William, J1 aBottinger, Erwin, P1 aCarpten, John1 aChanock, Stephen, J1 aChen, Yii-Der Ida1 aConti, David, V1 aCooper, Richard, S1 aFornage, Myriam1 aFreedman, Barry, I1 aGarcia, Melissa1 aGoodman, Phyllis, J1 aHsu, Yu-Han, H1 aHu, Jennifer1 aHuff, Chad, D1 aIngles, Sue, A1 aJohn, Esther, M1 aKittles, Rick1 aKlein, Eric1 aLi, Jin1 aMcKnight, Barbara1 aNayak, Uma1 aNemesure, Barbara1 aOgunniyi, Adesola1 aOlshan, Andrew1 aPress, Michael, F1 aRohde, Rebecca1 aRybicki, Benjamin, A1 aSalako, Babatunde1 aSanderson, Maureen1 aShao, Yaming1 aSiscovick, David, S1 aStanford, Janet, L1 aStevens, Victoria, L1 aStram, Alex1 aStrom, Sara, S1 aVaidya, Dhananjay1 aWitte, John, S1 aYao, Jie1 aZhu, Xiaofeng1 aZiegler, Regina, G1 aZonderman, Alan, B1 aAdeyemo, Adebowale1 aAmbs, Stefan1 aCushman, Mary1 aFaul, Jessica, D1 aHakonarson, Hakon1 aLevin, Albert, M1 aNathanson, Katherine, L1 aWare, Erin, B1 aWeir, David, R1 aZhao, Wei1 aZhi, Degui1 aArnett, Donna, K1 aGrant, Struan, F A1 aKardia, Sharon, L R1 aOloapde, Olufunmilayo, I1 aRao, D, C1 aRotimi, Charles, N1 aSale, Michèle, M1 aWilliams, Keoki1 aZemel, Babette, S1 aBecker, Diane, M1 aBorecki, Ingrid, B1 aEvans, Michele, K1 aHarris, Tamara, B1 aHirschhorn, Joel, N1 aLi, Yun1 aPatel, Sanjay, R1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aWilson, James, G1 aBowden, Donald, W1 aCupples, Adrienne, L1 aHaiman, Christopher, A1 aLoos, Ruth, J F1 aNorth, Kari, E1 aBone Mineral Density in Childhood Study (BMDCS) Group uhttps://chs-nhlbi.org/node/735205566nas a2201489 4500008004100000022001400041245010700055210006900162260001600231300000800247490000600255520135700261100002001618700002001638700002801658700002001686700001701706700002601723700002001749700001901769700002601788700002501814700001401839700001901853700002101872700002901893700002101922700002301943700002301966700002201989700001402011700002802025700002002053700002002073700002102093700002002114700002502134700002502159700002202184700001902206700002402225700001902249700002102268700002402289700001902313700002402332700002102356700001602377700002102393700002402414700002102438700002302459700001702482700002102499700001402520700002602534700002002560700002202580700002102602700002402623700002302647700002002670700002002690700001802710700001502728700002102743700002302764700002402787700001902811700001802830700002502848700002202873700001702895700001502912700002502927700002402952700002602976700002003002700002603022700002203048700001803070700002203088700002003110700002003130700002003150700002303170700002203193700003503215700002603250700002303276700002303299700002403322700001803346700001803364700002303382700002303405700002203428700002203450700001903472700002703491700001803518700002003536700002403556700001903580700002103599700001703620700002003637700002303657700002103680700001903701700002403720700002803744700002303772700001903795700001903814700002103833700002303854700002203877700002003899700002403919700001903943700002003962700001603982700002103998700002104019856003604040 2017 eng d a2041-172300aGenome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.0 aGenomewide metaanalysis associates HLADQA1DRB1 and LPA and lifes c2017 Oct 13 a9100 v83 aGenomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Variability in human longevity is genetically influenced. Using genetic data of parental lifespan, the authors identify associations at HLA-DQA/DRB1 and LPA and find that genetic variants that increase educational attainment have a positive effect on lifespan whereas increasing BMI negatively affects lifespan.
1 aJoshi, Peter, K1 aPirastu, Nicola1 aKentistou, Katherine, A1 aFischer, Krista1 aHofer, Edith1 aSchraut, Katharina, E1 aClark, David, W1 aNutile, Teresa1 aBarnes, Catriona, L K1 aTimmers, Paul, R H J1 aShen, Xia1 aGandin, Ilaria1 aMcDaid, Aaron, F1 aHansen, Thomas, Folkmann1 aGordon, Scott, D1 aGiulianini, Franco1 aBoutin, Thibaud, S1 aAbdellaoui, Abdel1 aZhao, Wei1 aMedina-Gómez, Carolina1 aBartz, Traci, M1 aTrompet, Stella1 aLange, Leslie, A1 aRaffield, Laura1 avan der Spek, Ashley1 aGalesloot, Tessel, E1 aProitsi, Petroula1 aYanek, Lisa, R1 aBielak, Lawrence, F1 aPayton, Antony1 aMurgia, Federico1 aConcas, Maria, Pina1 aBiino, Ginevra1 aTajuddin, Salman, M1 aSeppälä, Ilkka1 aAmin, Najaf1 aBoerwinkle, Eric1 aBørglum, Anders, D1 aCampbell, Archie1 aDemerath, Ellen, W1 aDemuth, Ilja1 aFaul, Jessica, D1 aFord, Ian1 aGialluisi, Alessandro1 aGögele, Martin1 aGraff, Mariaelisa1 aHingorani, Aroon1 aHottenga, Jouke-Jan1 aHougaard, David, M1 aHurme, Mikko, A1 aIkram, Arfan, M1 aJylhä, Marja1 aKuh, Diana1 aLigthart, Lannie1 aLill, Christina, M1 aLindenberger, Ulman1 aLumley, Thomas1 aMägi, Reedik1 aMarques-Vidal, Pedro1 aMedland, Sarah, E1 aMilani, Lili1 aNagy, Reka1 aOllier, William, E R1 aPeyser, Patricia, A1 aPramstaller, Peter, P1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRuggiero, Daniela1 aSaba, Yasaman1 aSchmidt, Reinhold1 aSchmidt, Helena1 aSlagboom, Eline1 aSmith, Blair, H1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aSteinhagen-Thiessen, Elisabeth1 avan Rooij, Frank, J A1 aVerbeek, André, L1 aVermeulen, Sita, H1 aVollenweider, Peter1 aWang, Yunpeng1 aWerge, Thomas1 aWhitfield, John, B1 aZonderman, Alan, B1 aLehtimäki, Terho1 aEvans, Michele, K1 aPirastu, Mario1 aFuchsberger, Christian1 aBertram, Lars1 aPendleton, Neil1 aKardia, Sharon, L R1 aCiullo, Marina1 aBecker, Diane, M1 aWong, Andrew1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aWilson, James, G1 aJukema, Wouter1 aKiemeney, Lambertus1 aUitterlinden, André, G1 aFranceschini, Nora1 aNorth, Kari, E1 aWeir, David, R1 aMetspalu, Andres1 aBoomsma, Dorret, I1 aHayward, Caroline1 aChasman, Daniel1 aMartin, Nicholas, G1 aSattar, Naveed1 aCampbell, Harry1 aEsko, Tõnu1 aKutalik, Zoltán1 aWilson, James, F uhttps://chs-nhlbi.org/node/756811080nas a2202833 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2017 eng d a1549-167600aImpact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.0 aImpact of common genetic determinants of Hemoglobin A1c on type c2017 Sep ae10023830 v143 aBACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.
METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.
CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.
10aDiabetes Mellitus, Type 210aGenetic Variation10aGenome-Wide Association Study10aGlycated Hemoglobin A10aHumans10aPhenotype10aRisk1 aWheeler, Eleanor1 aLeong, Aaron1 aLiu, Ching-Ti1 aHivert, Marie-France1 aStrawbridge, Rona, J1 aPodmore, Clara1 aLi, Man1 aYao, Jie1 aSim, Xueling1 aHong, Jaeyoung1 aChu, Audrey, Y1 aZhang, Weihua1 aWang, Xu1 aChen, Peng1 aMaruthur, Nisa, M1 aPorneala, Bianca, C1 aSharp, Stephen, J1 aJia, Yucheng1 aKabagambe, Edmond, K1 aChang, Li-Ching1 aChen, Wei-Min1 aElks, Cathy, E1 aEvans, Daniel, S1 aFan, Qiao1 aGiulianini, Franco1 aGo, Min Jin1 aHottenga, Jouke-Jan1 aHu, Yao1 aJackson, Anne, U1 aKanoni, Stavroula1 aKim, Young, Jin1 aKleber, Marcus, E1 aLadenvall, Claes1 aLecoeur, Cécile1 aLim, Sing-Hui1 aLu, Yingchang1 aMahajan, Anubha1 aMarzi, Carola1 aNalls, Mike, A1 aNavarro, Pau1 aNolte, Ilja, M1 aRose, Lynda, M1 aRybin, Denis, V1 aSanna, Serena1 aShi, Yuan1 aStram, Daniel, O1 aTakeuchi, Fumihiko1 aTan, Shu, Pei1 avan der Most, Peter, J1 avan Vliet-Ostaptchouk, Jana, V1 aWong, Andrew1 aYengo, Loic1 aZhao, Wanting1 aGoel, Anuj1 aLarrad, Maria, Teresa Mar1 aRadke, Dörte1 aSalo, Perttu1 aTanaka, Toshiko1 avan Iperen, Erik, P A1 aAbecasis, Goncalo1 aAfaq, Saima1 aAlizadeh, Behrooz, Z1 aBertoni, Alain, G1 aBonnefond, Amélie1 aBöttcher, Yvonne1 aBottinger, Erwin, P1 aCampbell, Harry1 aCarlson, Olga, D1 aChen, Chien-Hsiun1 aCho, Yoon Shin1 aGarvey, Timothy1 aGieger, Christian1 aGoodarzi, Mark, O1 aGrallert, Harald1 aHamsten, Anders1 aHartman, Catharina, A1 aHerder, Christian1 aHsiung, Chao, Agnes1 aHuang, Jie1 aIgase, Michiya1 aIsono, Masato1 aKatsuya, Tomohiro1 aKhor, Chiea-Chuen1 aKiess, Wieland1 aKohara, Katsuhiko1 aKovacs, Peter1 aLee, Juyoung1 aLee, Wen-Jane1 aLehne, Benjamin1 aLi, Huaixing1 aLiu, Jianjun1 aLobbens, Stephane1 aLuan, Jian'an1 aLyssenko, Valeriya1 aMeitinger, Thomas1 aMiki, Tetsuro1 aMiljkovic, Iva1 aMoon, Sanghoon1 aMulas, Antonella1 aMüller, Gabriele1 aMüller-Nurasyid, Martina1 aNagaraja, Ramaiah1 aNauck, Matthias1 aPankow, James, S1 aPolasek, Ozren1 aProkopenko, Inga1 aRamos, Paula, S1 aRasmussen-Torvik, Laura1 aRathmann, Wolfgang1 aRich, Stephen, S1 aRobertson, Neil, R1 aRoden, Michael1 aRoussel, Ronan1 aRudan, Igor1 aScott, Robert, A1 aScott, William, R1 aSennblad, Bengt1 aSiscovick, David, S1 aStrauch, Konstantin1 aSun, Liang1 aSwertz, Morris1 aTajuddin, Salman, M1 aTaylor, Kent, D1 aTeo, Yik-Ying1 aTham, Yih, Chung1 aTönjes, Anke1 aWareham, Nicholas, J1 aWillemsen, Gonneke1 aWilsgaard, Tom1 aHingorani, Aroon, D1 aEgan, Josephine1 aFerrucci, Luigi1 aHovingh, Kees1 aJula, Antti1 aKivimaki, Mika1 aKumari, Meena1 aNjølstad, Inger1 aPalmer, Colin, N A1 aRíos, Manuel, Serrano1 aStumvoll, Michael1 aWatkins, Hugh1 aAung, Tin1 aBlüher, Matthias1 aBoehnke, Michael1 aBoomsma, Dorret, I1 aBornstein, Stefan, R1 aChambers, John, C1 aChasman, Daniel, I1 aChen, Yii-Der Ida1 aChen, Yduan-Tsong1 aCheng, Ching-Yu1 aCucca, Francesco1 aGeus, Eco, J C1 aDeloukas, Panos1 aEvans, Michele, K1 aFornage, Myriam1 aFriedlander, Yechiel1 aFroguel, Philippe1 aGroop, Leif1 aGross, Myron, D1 aHarris, Tamara, B1 aHayward, Caroline1 aHeng, Chew-Kiat1 aIngelsson, Erik1 aKato, Norihiro1 aKim, Bong-Jo1 aKoh, Woon-Puay1 aKooner, Jaspal, S1 aKörner, Antje1 aKuh, Diana1 aKuusisto, Johanna1 aLaakso, Markku1 aLin, Xu1 aLiu, Yongmei1 aLoos, Ruth, J F1 aMagnusson, Patrik, K E1 aMärz, Winfried1 aMcCarthy, Mark, I1 aOldehinkel, Albertine, J1 aOng, Ken, K1 aPedersen, Nancy, L1 aPereira, Mark, A1 aPeters, Annette1 aRidker, Paul, M1 aSabanayagam, Charumathi1 aSale, Michele1 aSaleheen, Danish1 aSaltevo, Juha1 aSchwarz, Peter, Eh1 aSheu, Wayne, H H1 aSnieder, Harold1 aSpector, Timothy, D1 aTabara, Yasuharu1 aTuomilehto, Jaakko1 avan Dam, Rob, M1 aWilson, James, G1 aWilson, James, F1 aWolffenbuttel, Bruce, H R1 aWong, Tien, Yin1 aWu, Jer-Yuarn1 aYuan, Jian-Min1 aZonderman, Alan, B1 aSoranzo, Nicole1 aGuo, Xiuqing1 aRoberts, David, J1 aFlorez, Jose, C1 aSladek, Robert1 aDupuis, Josée1 aMorris, Andrew, P1 aTai, E-Shyong1 aSelvin, Elizabeth1 aRotter, Jerome, I1 aLangenberg, Claudia1 aBarroso, Inês1 aMeigs, James, B1 aEPIC-CVD Consortium1 aEPIC-InterAct Consortium1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/759605167nas a2201273 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2017 eng d a1553-740400aSingle-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.0 aSingletrait and multitrait genomewide association analyses ident c2017 May ae10067280 v133 aHypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.
10aAfrican Americans10aAnimals10aBasic Helix-Loop-Helix Transcription Factors10aBlood Pressure10aCadherins10aCase-Control Studies10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aHypertension10aMale10aMembrane Proteins10aMice10aMultifactorial Inheritance10aPolymorphism, Single Nucleotide1 aLiang, Jingjing1 aLe, Thu, H1 aEdwards, Digna, R Velez1 aTayo, Bamidele, O1 aGaulton, Kyle, J1 aSmith, Jennifer, A1 aLu, Yingchang1 aJensen, Richard, A1 aChen, Guanjie1 aYanek, Lisa, R1 aSchwander, Karen1 aTajuddin, Salman, M1 aSofer, Tamar1 aKim, Wonji1 aKayima, James1 aMcKenzie, Colin, A1 aFox, Ervin1 aNalls, Michael, A1 aYoung, Hunter, J1 aSun, Yan, V1 aLane, Jacqueline, M1 aCechova, Sylvia1 aZhou, Jie1 aTang, Hua1 aFornage, Myriam1 aMusani, Solomon, K1 aWang, Heming1 aLee, Juyoung1 aAdeyemo, Adebowale1 aDreisbach, Albert, W1 aForrester, Terrence1 aChu, Pei-Lun1 aCappola, Anne1 aEvans, Michele, K1 aMorrison, Alanna, C1 aMartin, Lisa, W1 aWiggins, Kerri, L1 aHui, Qin1 aZhao, Wei1 aJackson, Rebecca, D1 aWare, Erin, B1 aFaul, Jessica, D1 aReiner, Alex, P1 aBray, Michael1 aDenny, Joshua, C1 aMosley, Thomas, H1 aPalmas, Walter1 aGuo, Xiuqing1 aPapanicolaou, George, J1 aPenman, Alan, D1 aPolak, Joseph, F1 aRice, Kenneth1 aTaylor, Ken, D1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aLiu, Kiang1 aRisch, Neil1 aHunt, Steven, C1 aKooperberg, Charles1 aZonderman, Alan, B1 aLaurie, Cathy, C1 aBecker, Diane, M1 aCai, Jianwen1 aLoos, Ruth, J F1 aPsaty, Bruce, M1 aWeir, David, R1 aKardia, Sharon, L R1 aArnett, Donna, K1 aWon, Sungho1 aEdwards, Todd, L1 aRedline, Susan1 aCooper, Richard, S1 aRao, D, C1 aRotter, Jerome, I1 aRotimi, Charles1 aLevy, Daniel1 aChakravarti, Aravinda1 aZhu, Xiaofeng1 aFranceschini, Nora uhttps://chs-nhlbi.org/node/757207247nas a2202185 4500008004100000022001400041245013000055210006900185260001500254300000900269490000600278520110800284653002001392653003101412653003501443653002101478653003801499653003401537653001101571653001401582653002801596653003601624653002801660653001701688100002301705700002801728700002201756700001701778700001901795700002401814700002201838700002401860700002301884700001601907700002001923700001901943700002101962700001701983700003002000700001902030700001502049700001902064700003302083700002102116700002002137700002002157700002102177700002502198700002002223700002302243700001802266700001902284700001802303700001902321700002302340700001902363700002202382700001902404700002802423700001702451700002102468700002002489700001902509700002002528700002002548700001602568700002102584700002302605700002302628700002502651700002402676700002002700700002502720700002302745700002002768700001502788700001902803700002002822700001702842700002102859700002002880700002002900700002102920700002602941700001902967700002002986700001903006700002003025700002003045700001903065700002003084700001803104700001903122700002503141700002203166700001603188700002303204700002003227700002003247700002003267700001703287700001803304700002003322700001903342700003103361700001503392700002303407700002203430700002003452700001803472700002103490700002103511700002103532700001803553700001903571700001903590700001903609700002003628700002103648700002603669700001903695700002203714700002203736700002003758700001803778700001703796700001803813700002103831700002103852700001903873700002203892700002303914700002303937700002503960700002203985700001604007700001604023700002104039700002004060700002004080700001704100700002304117700001604140700002204156700002204178700002504200700001504225700001804240700002104258700002304279700001604302700001804318700002004336700001704356700001804373700001904391700002204410700002404432700002004456700002004476700002304496700002304519700002904542700002204571700002004593700002104613700002104634700002204655700002304677700002004700700001904720700002804739700002104767700002204788700002304810700002404833700001704857700002404874700002404898700002804922700001904950700003004969710002604999856003605025 2018 eng d a2041-172300aGWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.0 aGWAS and colocalization analyses implicate carotid intimamedia t c2018 12 03 a51410 v93 aCarotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
10aADAMTS9 Protein10aAmino Acid Oxidoreductases10aCarotid Intima-Media Thickness10aCoronary Disease10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLod Score10aPlaque, Atherosclerotic10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aRisk Factors1 aFranceschini, Nora1 aGiambartolomei, Claudia1 ade Vries, Paul, S1 aFinan, Chris1 aBis, Joshua, C1 aHuntley, Rachael, P1 aLovering, Ruth, C1 aTajuddin, Salman, M1 aWinkler, Thomas, W1 aGraff, Misa1 aKavousi, Maryam1 aDale, Caroline1 aSmith, Albert, V1 aHofer, Edith1 avan Leeuwen, Elisabeth, M1 aNolte, Ilja, M1 aLu, Lingyi1 aScholz, Markus1 aSargurupremraj, Muralidharan1 aPitkänen, Niina1 aFranzén, Oscar1 aJoshi, Peter, K1 aNoordam, Raymond1 aMarioni, Riccardo, E1 aHwang, Shih-Jen1 aMusani, Solomon, K1 aSchminke, Ulf1 aPalmas, Walter1 aIsaacs, Aaron1 aCorrea, Adolfo1 aZonderman, Alan, B1 aHofman, Albert1 aTeumer, Alexander1 aCox, Amanda, J1 aUitterlinden, André, G1 aWong, Andrew1 aSmit, Andries, J1 aNewman, Anne, B1 aBritton, Annie1 aRuusalepp, Arno1 aSennblad, Bengt1 aHedblad, Bo1 aPasaniuc, Bogdan1 aPenninx, Brenda, W1 aLangefeld, Carl, D1 aWassel, Christina, L1 aTzourio, Christophe1 aFava, Cristiano1 aBaldassarre, Damiano1 aO'Leary, Daniel, H1 aTeupser, Daniel1 aKuh, Diana1 aTremoli, Elena1 aMannarino, Elmo1 aGrossi, Enzo1 aBoerwinkle, Eric1 aSchadt, Eric, E1 aIngelsson, Erik1 aVeglia, Fabrizio1 aRivadeneira, Fernando1 aBeutner, Frank1 aChauhan, Ganesh1 aHeiss, Gerardo1 aSnieder, Harold1 aCampbell, Harry1 aVölzke, Henry1 aMarkus, Hugh, S1 aDeary, Ian, J1 aJukema, Wouter1 ade Graaf, Jacqueline1 aPrice, Jacqueline1 aPott, Janne1 aHopewell, Jemma, C1 aLiang, Jingjing1 aThiery, Joachim1 aEngmann, Jorgen1 aGertow, Karl1 aRice, Kenneth1 aTaylor, Kent, D1 aDhana, Klodian1 aKiemeney, Lambertus, A L M1 aLind, Lars1 aRaffield, Laura, M1 aLauner, Lenore, J1 aHoldt, Lesca, M1 aDörr, Marcus1 aDichgans, Martin1 aTraylor, Matthew1 aSitzer, Matthias1 aKumari, Meena1 aKivimaki, Mika1 aNalls, Mike, A1 aMelander, Olle1 aRaitakari, Olli1 aFranco, Oscar, H1 aRueda-Ochoa, Oscar, L1 aRoussos, Panos1 aWhincup, Peter, H1 aAmouyel, Philippe1 aGiral, Philippe1 aAnugu, Pramod1 aWong, Quenna1 aMalik, Rainer1 aRauramaa, Rainer1 aBurkhardt, Ralph1 aHardy, Rebecca1 aSchmidt, Reinhold1 ade Mutsert, Renée1 aMorris, Richard, W1 aStrawbridge, Rona, J1 aWannamethee, Goya1 aHägg, Sara1 aShah, Sonia1 aMcLachlan, Stela1 aTrompet, Stella1 aSeshadri, Sudha1 aKurl, Sudhir1 aHeckbert, Susan, R1 aRing, Susan1 aHarris, Tamara, B1 aLehtimäki, Terho1 aGalesloot, Tessel, E1 aShah, Tina1 ade Faire, Ulf1 aPlagnol, Vincent1 aRosamond, Wayne, D1 aPost, Wendy1 aZhu, Xiaofeng1 aZhang, Xiaoling1 aGuo, Xiuqing1 aSaba, Yasaman1 aDehghan, Abbas1 aSeldenrijk, Adrie1 aMorrison, Alanna, C1 aHamsten, Anders1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aLawlor, Deborah, A1 aMook-Kanamori, Dennis, O1 aBowden, Donald, W1 aSchmidt, Helena1 aWilson, James, F1 aWilson, James, G1 aRotter, Jerome, I1 aWardlaw, Joanna, M1 aDeanfield, John1 aHalcox, Julian1 aLyytikäinen, Leo-Pekka1 aLoeffler, Markus1 aEvans, Michele, K1 aDebette, Stephanie1 aHumphries, Steve, E1 aVölker, Uwe1 aGudnason, Vilmundur1 aHingorani, Aroon, D1 aBjörkegren, Johan, L M1 aCasas, Juan, P1 aO'Donnell, Christopher, J1 aMEGASTROKE Consortium uhttps://chs-nhlbi.org/node/791312060nas a2203745 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2018 eng d a1537-660500aA Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.0 aLargeScale Multiancestry Genomewide Study Accounting for Smoking c2018 Mar 01 a375-4000 v1023 aGenome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).
1 aSung, Yun, J1 aWinkler, Thomas, W1 aFuentes, Lisa, de Las1 aBentley, Amy, R1 aBrown, Michael, R1 aKraja, Aldi, T1 aSchwander, Karen1 aNtalla, Ioanna1 aGuo, Xiuqing1 aFranceschini, Nora1 aLu, Yingchang1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aMarten, Jonathan1 aMusani, Solomon, K1 aLi, Changwei1 aFeitosa, Mary, F1 aKilpeläinen, Tuomas, O1 aRichard, Melissa, A1 aNoordam, Raymond1 aAslibekyan, Stella1 aAschard, Hugues1 aBartz, Traci, M1 aDorajoo, Rajkumar1 aLiu, Yongmei1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, Vernon1 aTajuddin, Salman, M1 aTayo, Bamidele, O1 aWarren, Helen, R1 aZhao, Wei1 aZhou, Yanhua1 aMatoba, Nana1 aSofer, Tamar1 aAlver, Maris1 aAmini, Marzyeh1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aGandin, Ilaria1 aGao, Chuan1 aGiulianini, Franco1 aGoel, Anuj1 aHarris, Sarah, E1 aHartwig, Fernando, Pires1 aHorimoto, Andrea, R V R1 aHsu, Fang-Chi1 aJackson, Anne, U1 aKähönen, Mika1 aKasturiratne, Anuradhani1 aKuhnel, Brigitte1 aLeander, Karin1 aLee, Wen-Jane1 aLin, Keng-Hung1 aLuan, Jian, 'an1 aMcKenzie, Colin, A1 aMeian, He1 aNelson, Christopher, P1 aRauramaa, Rainer1 aSchupf, Nicole1 aScott, Robert, A1 aSheu, Wayne, H H1 aStančáková, Alena1 aTakeuchi, Fumihiko1 avan der Most, Peter, J1 aVarga, Tibor, V1 aWang, Heming1 aWang, Yajuan1 aWare, Erin, B1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAfaq, Saima1 aAlfred, Tamuno1 aAmin, Najaf1 aArking, Dan1 aAung, Tin1 aBarr, Graham1 aBielak, Lawrence, F1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aBraund, Peter, S1 aBrody, Jennifer, A1 aBroeckel, Ulrich1 aCabrera, Claudia, P1 aCade, Brian1 aCaizheng, Yu1 aCampbell, Archie1 aCanouil, Mickaël1 aChakravarti, Aravinda1 aChauhan, Ganesh1 aChristensen, Kaare1 aCocca, Massimiliano1 aCollins, Francis, S1 aConnell, John, M1 ade Mutsert, Renée1 ade Silva, Janaka1 aDebette, Stephanie1 aDörr, Marcus1 aDuan, Qing1 aEaton, Charles, B1 aEhret, Georg1 aEvangelou, Evangelos1 aFaul, Jessica, D1 aFisher, Virginia, A1 aForouhi, Nita, G1 aFranco, Oscar, H1 aFriedlander, Yechiel1 aGao, He1 aGigante, Bruna1 aGraff, Misa1 aGu, Charles1 aGu, Dongfeng1 aGupta, Preeti1 aHagenaars, Saskia, P1 aHarris, Tamara, B1 aHe, Jiang1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHofman, Albert1 aHoward, Barbara, V1 aHunt, Steven1 aIrvin, Marguerite, R1 aJia, Yucheng1 aJoehanes, Roby1 aJustice, Anne, E1 aKatsuya, Tomohiro1 aKaufman, Joel1 aKerrison, Nicola, D1 aKhor, Chiea, Chuen1 aKoh, Woon-Puay1 aKoistinen, Heikki, A1 aKomulainen, Pirjo1 aKooperberg, Charles1 aKrieger, Jose, E1 aKubo, Michiaki1 aKuusisto, Johanna1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLewis, Cora, E1 aLi, Yize1 aLim, Sing, Hui1 aLin, Shiow1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLiu, Jingmin1 aLiu, Kiang1 aLiu, Yeheng1 aLoh, Marie1 aLohman, Kurt, K1 aLong, Jirong1 aLouie, Tin1 aMägi, Reedik1 aMahajan, Anubha1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilani, Lili1 aMomozawa, Yukihide1 aMorris, Andrew, P1 aMosley, Thomas, H1 aMunson, Peter1 aMurray, Alison, D1 aNalls, Mike, A1 aNasri, Ubaydah1 aNorris, Jill, M1 aNorth, Kari1 aOgunniyi, Adesola1 aPadmanabhan, Sandosh1 aPalmas, Walter, R1 aPalmer, Nicholette, D1 aPankow, James, S1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aRaitakari, Olli, T1 aRenstrom, Frida1 aRice, Treva, K1 aRidker, Paul, M1 aRobino, Antonietta1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRudan, Igor1 aSabanayagam, Charumathi1 aSalako, Babatunde, L1 aSandow, Kevin1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aScott, William, R1 aSeshadri, Sudha1 aSever, Peter1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aTang, Hua1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aUitterlinden, André, G1 aWaldenberger, Melanie1 aWang, Lihua1 aWang, Ya, X1 aBin Wei, Wen1 aWilliams, Christine1 aWilson, Gregory1 aWojczynski, Mary, K1 aYao, Jie1 aYuan, Jian-Min1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aChen, Yii-Der Ida1 ade Faire, Ulf1 aDeary, Ian, J1 aEsko, Tõnu1 aFarrall, Martin1 aForrester, Terrence1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aHorta, Bernardo, Lessa1 aHung, Yi-Jen1 aJonas, Jost, B1 aKato, Norihiro1 aKooner, Jaspal, S1 aLaakso, Markku1 aLehtimäki, Terho1 aLiang, Kae-Woei1 aMagnusson, Patrik, K E1 aNewman, Anne, B1 aOldehinkel, Albertine, J1 aPereira, Alexandre, C1 aRedline, Susan1 aRettig, Rainer1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aWu, Tangchun1 aZheng, Wei1 aKamatani, Yoichiro1 aLaurie, Cathy, C1 aBouchard, Claude1 aCooper, Richard, S1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKardia, Sharon, L R1 aKritchevsky, Stephen, B1 aLevy, Daniel1 aO'Connell, Jeff, R1 aPsaty, Bruce, M1 avan Dam, Rob, M1 aSims, Mario1 aArnett, Donna, K1 aMook-Kanamori, Dennis, O1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aFornage, Myriam1 aRotimi, Charles, N1 aProvince, Michael, A1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aLoos, Ruth, J F1 aReiner, Alex, P1 aRotter, Jerome, I1 aZhu, Xiaofeng1 aBierut, Laura, J1 aGauderman, James1 aCaulfield, Mark, J1 aElliott, Paul1 aRice, Kenneth1 aMunroe, Patricia, B1 aMorrison, Alanna, C1 aCupples, Adrienne, L1 aRao, Dabeeru, C1 aChasman, Daniel, I1 aCHARGE Neurology Working Group1 aCOGENT-Kidney Consortium1 aGIANT Consortium1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/768611027nas a2203421 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2018 eng d a1932-620300aNovel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.0 aNovel genetic associations for blood pressure identified via gen c2018 ae01981660 v133 aHeavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
1 aFeitosa, Mary, F1 aKraja, Aldi, T1 aChasman, Daniel, I1 aSung, Yun, J1 aWinkler, Thomas, W1 aNtalla, Ioanna1 aGuo, Xiuqing1 aFranceschini, Nora1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aMarten, Jonathan1 aMusani, Solomon, K1 aLi, Changwei1 aBentley, Amy, R1 aBrown, Michael, R1 aSchwander, Karen1 aRichard, Melissa, A1 aNoordam, Raymond1 aAschard, Hugues1 aBartz, Traci, M1 aBielak, Lawrence, F1 aDorajoo, Rajkumar1 aFisher, Virginia1 aHartwig, Fernando, P1 aHorimoto, Andrea, R V R1 aLohman, Kurt, K1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, V1 aTajuddin, Salman, M1 aWojczynski, Mary, K1 aAlver, Maris1 aBoissel, Mathilde1 aCai, Qiuyin1 aCampbell, Archie1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aGao, Chuan1 aGoel, Anuj1 aHagemeijer, Yanick1 aHarris, Sarah, E1 aHe, Meian1 aHsu, Fang-Chi1 aJackson, Anne, U1 aKähönen, Mika1 aKasturiratne, Anuradhani1 aKomulainen, Pirjo1 aKuhnel, Brigitte1 aLaguzzi, Federica1 aLuan, Jian'an1 aMatoba, Nana1 aNolte, Ilja, M1 aPadmanabhan, Sandosh1 aRiaz, Muhammad1 aRueedi, Rico1 aRobino, Antonietta1 aSaid, Abdullah1 aScott, Robert, A1 aSofer, Tamar1 aStančáková, Alena1 aTakeuchi, Fumihiko1 aTayo, Bamidele, O1 avan der Most, Peter, J1 aVarga, Tibor, V1 aVitart, Veronique1 aWang, Yajuan1 aWare, Erin, B1 aWarren, Helen, R1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAfaq, Saima1 aAmin, Najaf1 aAmini, Marzyeh1 aArking, Dan, E1 aAung, Tin1 aBoerwinkle, Eric1 aBorecki, Ingrid1 aBroeckel, Ulrich1 aBrown, Morris1 aBrumat, Marco1 aBurke, Gregory, L1 aCanouil, Mickaël1 aChakravarti, Aravinda1 aCharumathi, Sabanayagam1 aChen, Yii-Der, Ida1 aConnell, John, M1 aCorrea, Adolfo1 aFuentes, Lisa, de Las1 ade Mutsert, Renée1 ade Silva, Janaka1 aDeng, Xuan1 aDing, Jingzhong1 aDuan, Qing1 aEaton, Charles, B1 aEhret, Georg1 aEppinga, Ruben, N1 aEvangelou, Evangelos1 aFaul, Jessica, D1 aFelix, Stephan, B1 aForouhi, Nita, G1 aForrester, Terrence1 aFranco, Oscar, H1 aFriedlander, Yechiel1 aGandin, Ilaria1 aGao, He1 aGhanbari, Mohsen1 aGigante, Bruna1 aGu, Charles1 aGu, Dongfeng1 aHagenaars, Saskia, P1 aHallmans, Göran1 aHarris, Tamara, B1 aHe, Jiang1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHoward, Barbara, V1 aIkram, Arfan, M1 aJohn, Ulrich1 aKatsuya, Tomohiro1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKrieger, Jose, E1 aKritchevsky, Stephen, B1 aKubo, Michiaki1 aKuusisto, Johanna1 aLakka, Timo, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLewis, Cora, E1 aLi, Yize1 aLin, Shiow1 aLiu, Jianjun1 aLiu, Jingmin1 aLoh, Marie1 aLouie, Tin1 aMägi, Reedik1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMilani, Lili1 aMohlke, Karen, L1 aMomozawa, Yukihide1 aNalls, Mike, A1 aNelson, Christopher, P1 aSotoodehnia, Nona1 aNorris, Jill, M1 aO'Connell, Jeff, R1 aPalmer, Nicholette, D1 aPerls, Thomas1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPoulter, Neil1 aRaffel, Leslie, J1 aRaitakari, Olli, T1 aRoll, Kathryn1 aRose, Lynda, M1 aRosendaal, Frits, R1 aRotter, Jerome, I1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aSchupf, Nicole1 aScott, William, R1 aSever, Peter, S1 aShi, Yuan1 aSidney, Stephen1 aSims, Mario1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aStringham, Heather, M1 aTan, Nicholas, Y Q1 aTang, Hua1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aTurner, Stephen, T1 aUitterlinden, André, G1 aVollenweider, Peter1 aWaldenberger, Melanie1 aWang, Lihua1 aWang, Ya, Xing1 aBin Wei, Wen1 aWilliams, Christine1 aYao, Jie1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aDeary, Ian, J1 aEsko, Tõnu1 aFarrall, Martin1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aJonas, Jost, Bruno1 aKamatani, Yoichiro1 aKato, Norihiro1 aKooner, Jaspal, S1 aKutalik, Zoltán1 aLaakso, Markku1 aLaurie, Cathy, C1 aLeander, Karin1 aLehtimäki, Terho1 aStudy, Lifelines, Cohort1 aMagnusson, Patrik, K E1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aPolasek, Ozren1 aPorteous, David, J1 aRauramaa, Rainer1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aWu, Tangchun1 aZheng, Wei1 aBouchard, Claude1 aChristensen, Kaare1 aEvans, Michele, K1 aGudnason, Vilmundur1 aHorta, Bernardo, L1 aKardia, Sharon, L R1 aLiu, Yongmei1 aPereira, Alexandre, C1 aPsaty, Bruce, M1 aRidker, Paul, M1 avan Dam, Rob, M1 aGauderman, James1 aZhu, Xiaofeng1 aMook-Kanamori, Dennis, O1 aFornage, Myriam1 aRotimi, Charles, N1 aCupples, Adrienne, L1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aKooperberg, Charles1 aPalmas, Walter1 aRice, Kenneth1 aMorrison, Alanna, C1 aElliott, Paul1 aCaulfield, Mark, J1 aMunroe, Patricia, B1 aRao, Dabeeru, C1 aProvince, Michael, A1 aLevy, Daniel1 aInterAct Consortium uhttps://chs-nhlbi.org/node/779215950nas a2205365 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2019 eng d a2041-172300aAssociations of autozygosity with a broad range of human phenotypes.0 aAssociations of autozygosity with a broad range of human phenoty c2019 Oct 31 a49570 v103 aIn many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
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aNutile, Teresa1 aPalviainen, Teemu1 aPrasad, Gauri1 aPrasad, Rashmi, B1 aPriyanka, Tallapragada, Divya Sri1 aRizzi, Federica1 aSalvi, Erika1 aSapkota, Bishwa, R1 aShriner, Daniel1 aSkotte, Line1 aSmart, Melissa, C1 aSmith, Albert, Vernon1 avan der Spek, Ashley1 aSpracklen, Cassandra, N1 aStrawbridge, Rona, J1 aTajuddin, Salman, M1 aTrompet, Stella1 aTurman, Constance1 aVerweij, Niek1 aViberti, Clara1 aWang, Lihua1 aWarren, Helen, R1 aWootton, Robyn, E1 aYanek, Lisa, R1 aYao, Jie1 aYousri, Noha, A1 aZhao, Wei1 aAdeyemo, Adebowale, A1 aAfaq, Saima1 aAguilar-Salinas, Carlos, Alberto1 aAkiyama, Masato1 aAlbert, Matthew, L1 aAllison, Matthew, A1 aAlver, Maris1 aAung, Tin1 aAzizi, Fereidoun1 aBentley, Amy, R1 aBoeing, Heiner1 aBoerwinkle, Eric1 aBorja, Judith, B1 ade Borst, Gert, J1 aBottinger, Erwin, P1 aBroer, Linda1 aCampbell, Harry1 aChanock, Stephen1 aChee, Miao-Li1 aChen, Guanjie1 aChen, Yii-der, I1 aChen, Zhengming1 aChiu, Yen-Feng1 aCocca, Massimiliano1 aCollins, Francis, S1 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2019 eng d a1546-171800aA catalog of genetic loci associated with kidney function from analyses of a million individuals.0 acatalog of genetic loci associated with kidney function from ana c2019 06 a957-9720 v513 aChronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
10aChromosome Mapping10aEuropean Continental Ancestry Group10aGenetic Association Studies10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aInheritance Patterns10aKidney Function Tests10aPhenotype10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aQuantitative Trait, Heritable10aRenal Insufficiency, Chronic10aUromodulin1 aWuttke, Matthias1 aLi, Yong1 aLi, Man1 aSieber, Karsten, B1 aFeitosa, Mary, F1 aGorski, Mathias1 aTin, Adrienne1 aWang, Lihua1 aChu, Audrey, Y1 aHoppmann, Anselm1 aKirsten, Holger1 aGiri, Ayush1 aChai, Jin-Fang1 aSveinbjornsson, Gardar1 aTayo, Bamidele, O1 aNutile, Teresa1 aFuchsberger, Christian1 aMarten, Jonathan1 aCocca, Massimiliano1 aGhasemi, Sahar1 aXu, Yizhe1 aHorn, Katrin1 aNoce, Damia1 avan der Most, Peter, J1 aSedaghat, Sanaz1 aYu, Zhi1 aAkiyama, Masato1 aAfaq, Saima1 aAhluwalia, Tarunveer, S1 aAlmgren, Peter1 aAmin, Najaf1 aArnlöv, Johan1 aBakker, Stephan, J L1 aBansal, Nisha1 aBaptista, Daniela1 aBergmann, Sven1 aBiggs, Mary, L1 aBiino, Ginevra1 aBoehnke, Michael1 aBoerwinkle, Eric1 aBoissel, Mathilde1 aBottinger, Erwin, P1 aBoutin, Thibaud, S1 aBrenner, Hermann1 aBrumat, Marco1 aBurkhardt, Ralph1 aButterworth, Adam, S1 aCampana, Eric1 aCampbell, Archie1 aCampbell, Harry1 aCanouil, Mickaël1 aCarroll, Robert, J1 aCatamo, Eulalia1 aChambers, John, C1 aChee, Miao-Ling1 aChee, Miao-Li1 aChen, Xu1 aCheng, Ching-Yu1 aCheng, Yurong1 aChristensen, Kaare1 aCifkova, Renata1 aCiullo, Marina1 aConcas, Maria, Pina1 aCook, James, P1 aCoresh, Josef1 aCorre, Tanguy1 aSala, Cinzia, Felicita1 aCusi, Daniele1 aDanesh, John1 aDaw, Warwick1 ade Borst, Martin, H1 aDe Grandi, Alessandro1 ade Mutsert, Renée1 ade Vries, Aiko, P J1 aDegenhardt, Frauke1 aDelgado, Graciela1 aDemirkan, Ayse1 aDi Angelantonio, Emanuele1 aDittrich, Katalin1 aDivers, Jasmin1 aDorajoo, Rajkumar1 aEckardt, Kai-Uwe1 aEhret, Georg1 aElliott, Paul1 aEndlich, Karlhans1 aEvans, Michele, K1 aFelix, Janine, F1 aFoo, Valencia, Hui Xian1 aFranco, Oscar, H1 aFranke, Andre1 aFreedman, Barry, I1 aFreitag-Wolf, Sandra1 aFriedlander, Yechiel1 aFroguel, Philippe1 aGansevoort, Ron, T1 aGao, He1 aGasparini, Paolo1 aGaziano, Michael1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGirotto, Giorgia1 aGiulianini, Franco1 aGögele, Martin1 aGordon, Scott, D1 aGudbjartsson, Daniel, F1 aGudnason, Vilmundur1 aHaller, Toomas1 aHamet, Pavel1 aHarris, Tamara, B1 aHartman, Catharina, A1 aHayward, Caroline1 aHellwege, Jacklyn, N1 aHeng, Chew-Kiat1 aHicks, Andrew, A1 aHofer, Edith1 aHuang, Wei1 aHutri-Kähönen, Nina1 aHwang, Shih-Jen1 aIkram, Arfan, M1 aIndridason, Olafur, S1 aIngelsson, Erik1 aIsing, Marcus1 aJaddoe, Vincent, W V1 aJakobsdottir, Johanna1 aJonas, Jost, B1 aJoshi, Peter, K1 aJosyula, Navya, Shilpa1 aJung, Bettina1 aKähönen, Mika1 aKamatani, Yoichiro1 aKammerer, Candace, M1 aKanai, Masahiro1 aKastarinen, Mika1 aKerr, Shona, M1 aKhor, Chiea-Chuen1 aKiess, Wieland1 aKleber, Marcus, E1 aKoenig, Wolfgang1 aKooner, Jaspal, S1 aKörner, Antje1 aKovacs, Peter1 aKraja, Aldi, T1 aKrajcoviechova, Alena1 aKramer, Holly1 aKrämer, Bernhard, K1 aKronenberg, Florian1 aKubo, Michiaki1 aKuhnel, Brigitte1 aKuokkanen, Mikko1 aKuusisto, Johanna1 aLa Bianca, Martina1 aLaakso, Markku1 aLange, Leslie, A1 aLangefeld, Carl, D1 aLee, Jeannette, Jen-Mai1 aLehne, Benjamin1 aLehtimäki, Terho1 aLieb, Wolfgang1 aLim, Su-Chi1 aLind, Lars1 aLindgren, Cecilia, M1 aLiu, Jun1 aLiu, Jianjun1 aLoeffler, Markus1 aLoos, Ruth, J F1 aLucae, Susanne1 aLukas, Mary, Ann1 aLyytikäinen, Leo-Pekka1 aMägi, Reedik1 aMagnusson, Patrik, K E1 aMahajan, Anubha1 aMartin, Nicholas, G1 aMartins, Jade1 aMärz, Winfried1 aMascalzoni, Deborah1 aMatsuda, Koichi1 aMeisinger, Christa1 aMeitinger, Thomas1 aMelander, Olle1 aMetspalu, Andres1 aMikaelsdottir, Evgenia, K1 aMilaneschi, Yuri1 aMiliku, Kozeta1 aMishra, Pashupati, P1 aMohlke, Karen, L1 aMononen, Nina1 aMontgomery, Grant, W1 aMook-Kanamori, Dennis, O1 aMychaleckyj, Josyf, C1 aNadkarni, Girish, N1 aNalls, Mike, A1 aNauck, Matthias1 aNikus, Kjell1 aNing, Boting1 aNolte, Ilja, M1 aNoordam, Raymond1 aO'Connell, Jeffrey1 aO'Donoghue, Michelle, L1 aOlafsson, Isleifur1 aOldehinkel, Albertine, J1 aOrho-Melander, Marju1 aOuwehand, Willem, H1 aPadmanabhan, Sandosh1 aPalmer, Nicholette, D1 aPalsson, Runolfur1 aPenninx, Brenda, W J H1 aPerls, Thomas1 aPerola, Markus1 aPirastu, Mario1 aPirastu, Nicola1 aPistis, Giorgio1 aPodgornaia, Anna, I1 aPolasek, Ozren1 aPonte, Belen1 aPorteous, David, J1 aPoulain, Tanja1 aPramstaller, Peter, P1 aPreuss, Michael, H1 aPrins, Bram, P1 aProvince, Michael, A1 aRabelink, Ton, J1 aRaffield, Laura, M1 aRaitakari, Olli, T1 aReilly, Dermot, F1 aRettig, Rainer1 aRheinberger, Myriam1 aRice, Kenneth, M1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRizzi, Federica1 aRoberts, David, J1 aRobino, Antonietta1 aRossing, Peter1 aRudan, Igor1 aRueedi, Rico1 aRuggiero, Daniela1 aRyan, Kathleen, A1 aSaba, Yasaman1 aSabanayagam, Charumathi1 aSalomaa, Veikko1 aSalvi, Erika1 aSaum, Kai-Uwe1 aSchmidt, Helena1 aSchmidt, Reinhold1 aSchöttker, Ben1 aSchulz, Christina-Alexandra1 aSchupf, Nicole1 aShaffer, Christian, M1 aShi, Yuan1 aSmith, Albert, V1 aSmith, Blair, H1 aSoranzo, Nicole1 aSpracklen, Cassandra, N1 aStrauch, Konstantin1 aStringham, Heather, M1 aStumvoll, Michael1 aSvensson, Per, O1 aSzymczak, Silke1 aTai, E-Shyong1 aTajuddin, Salman, M1 aTan, Nicholas, Y Q1 aTaylor, Kent, D1 aTeren, Andrej1 aTham, Yih-Chung1 aThiery, Joachim1 aThio, Chris, H L1 aThomsen, Hauke1 aThorleifsson, Gudmar1 aToniolo, Daniela1 aTönjes, Anke1 aTremblay, Johanne1 aTzoulaki, Ioanna1 aUitterlinden, André, G1 aVaccargiu, Simona1 avan Dam, Rob, M1 aHarst, Pim1 aDuijn, Cornelia, M1 aEdward, Digna, R Velez1 aVerweij, Niek1 aVogelezang, Suzanne1 aVölker, Uwe1 aVollenweider, Peter1 aWaeber, Gérard1 aWaldenberger, Melanie1 aWallentin, Lars1 aWang, Ya, Xing1 aWang, Chaolong1 aWaterworth, Dawn, M1 aBin Wei, Wen1 aWhite, Harvey1 aWhitfield, John, B1 aWild, Sarah, H1 aWilson, James, F1 aWojczynski, Mary, K1 aWong, Charlene1 aWong, Tien-Yin1 aXu, Liang1 aYang, Qiong1 aYasuda, Masayuki1 aYerges-Armstrong, Laura, M1 aZhang, Weihua1 aZonderman, Alan, B1 aRotter, Jerome, I1 aBochud, Murielle1 aPsaty, Bruce, M1 aVitart, Veronique1 aWilson, James, G1 aDehghan, Abbas1 aParsa, Afshin1 aChasman, Daniel, I1 aHo, Kevin1 aMorris, Andrew, P1 aDevuyst, Olivier1 aAkilesh, Shreeram1 aPendergrass, Sarah, A1 aSim, Xueling1 aBöger, Carsten, A1 aOkada, Yukinori1 aEdwards, Todd, L1 aSnieder, Harold1 aStefansson, Kari1 aHung, Adriana, M1 aHeid, Iris, M1 aScholz, Markus1 aTeumer, Alexander1 aKöttgen, Anna1 aPattaro, Cristian1 aLifeLines Cohort Study1 aV. A. 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We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.
1 ade Vries, Paul, S1 aBrown, Michael, R1 aBentley, Amy, R1 aSung, Yun, J1 aWinkler, Thomas, W1 aNtalla, Ioanna1 aSchwander, Karen1 aKraja, Aldi, T1 aGuo, Xiuqing1 aFranceschini, Nora1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aHuffman, Jennifer, E1 aMusani, Solomon, K1 aLi, Changwei1 aFeitosa, Mary, F1 aRichard, Melissa, A1 aNoordam, Raymond1 aAschard, Hugues1 aBartz, Traci, M1 aBielak, Lawrence, F1 aDeng, Xuan1 aDorajoo, Rajkumar1 aLohman, Kurt, K1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, V1 aTajuddin, Salman, M1 aEvangelou, Evangelos1 aGraff, Mariaelisa1 aAlver, Maris1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aGandin, Ilaria1 aGao, Chuan1 aGoel, Anuj1 aHagemeijer, Yanick1 aHarris, Sarah, E1 aHartwig, Fernando, P1 aHe, Meian1 aHorimoto, Andrea, R V R1 aHsu, Fang-Chi1 aJackson, Anne, U1 aKasturiratne, Anuradhani1 aKomulainen, Pirjo1 aKuhnel, Brigitte1 aLaguzzi, Federica1 aLee, Joseph, H1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMatoba, Nana1 aNolte, Ilja, M1 aPietzner, Maik1 aRiaz, Muhammad1 aSaid, Abdullah1 aScott, Robert, A1 aSofer, Tamar1 aStančáková, Alena1 aTakeuchi, Fumihiko1 aTayo, Bamidele, O1 avan der Most, Peter, J1 aVarga, Tibor, V1 aWang, Yajuan1 aWare, Erin, B1 aWen, Wanqing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAfaq, Saima1 aAmin, Najaf1 aAmini, Marzyeh1 aArking, Dan, E1 aAung, Tin1 aBallantyne, Christie1 aBoerwinkle, Eric1 aBroeckel, Ulrich1 aCampbell, Archie1 aCanouil, Mickaël1 aCharumathi, Sabanayagam1 aChen, Yii-Der Ida1 aConnell, John, M1 ade Faire, Ulf1 aFuentes, Lisa, de Las1 ade Mutsert, Renée1 ade Silva, Janaka1 aDing, Jingzhong1 aDominiczak, Anna, F1 aDuan, Qing1 aEaton, Charles, B1 aEppinga, Ruben, N1 aFaul, Jessica, D1 aFisher, Virginia1 aForrester, Terrence1 aFranco, Oscar, H1 aFriedlander, Yechiel1 aGhanbari, Mohsen1 aGiulianini, Franco1 aGrabe, Hans, J1 aGrove, Megan, L1 aGu, Charles1 aHarris, Tamara, B1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHixson, James, E1 aHoward, Barbara, V1 aIkram, Arfan, M1 aJacobs, David, R1 aJohnson, Craig1 aJonas, Jost, Bruno1 aKammerer, Candace, M1 aKatsuya, Tomohiro1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKoistinen, Heikki, A1 aKolcic, Ivana1 aKooperberg, Charles1 aKrieger, Jose, E1 aKritchevsky, Steve, B1 aKubo, Michiaki1 aKuusisto, Johanna1 aLakka, Timo, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLemaitre, Rozenn, N1 aLi, Yize1 aLiang, Jingjing1 aLiu, Jianjun1 aLiu, Kiang1 aLoh, Marie1 aLouie, Tin1 aMägi, Reedik1 aManichaikul, Ani, W1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMilani, Lili1 aMohlke, Karen, L1 aMosley, Thomas, H1 aMukamal, Kenneth, J1 aNalls, Mike, A1 aNauck, Matthias1 aNelson, Christopher, P1 aSotoodehnia, Nona1 aO'Connell, Jeff, R1 aPalmer, Nicholette, D1 aPazoki, Raha1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aPoulter, Neil1 aRaffel, Leslie, J1 aRaitakari, Olli, T1 aReiner, Alex, P1 aRice, Treva, K1 aRich, Stephen, S1 aRobino, Antonietta1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRudan, Igor1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aScott, William, R1 aSever, Peter1 aShi, Yuan1 aSidney, Stephen1 aSims, Mario1 aSmith, Blair, H1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aTan, Nicholas1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aUitterlinden, André, G1 avan Heemst, Diana1 aVuckovic, Dragana1 aWaldenberger, Melanie1 aWang, Lihua1 aWang, Yujie1 aWang, Zhe1 aBin Wei, Wen1 aWilliams, Christine1 aWilson, Gregory1 aWojczynski, Mary, K1 aYao, Jie1 aYu, Bing1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aDeary, Ian, J1 aEsko, Tõnu1 aFarrall, Martin1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aHorta, Bernardo, L1 aKamatani, Yoichiro1 aKato, Norihiro1 aKooner, Jaspal, S1 aLaakso, Markku1 aLeander, Karin1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aPenninx, Brenda1 aPereira, Alexandre, C1 aRauramaa, Rainer1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWang, Ya, Xing1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aZheng, Wei1 aElliott, Paul1 aNorth, Kari, E1 aBouchard, Claude1 aEvans, Michele, K1 aGudnason, Vilmundur1 aLiu, Ching-Ti1 aLiu, Yongmei1 aPsaty, Bruce, M1 aRidker, Paul, M1 avan Dam, Rob, M1 aKardia, Sharon, L R1 aZhu, Xiaofeng1 aRotimi, Charles, N1 aMook-Kanamori, Dennis, O1 aFornage, Myriam1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aLiu, Jingmin1 aRotter, Jerome, I1 aGauderman, James1 aProvince, Michael, A1 aMunroe, Patricia, B1 aRice, Kenneth1 aChasman, Daniel, I1 aCupples, Adrienne, L1 aRao, Dabeeru, C1 aMorrison, Alanna, C1 aInterAct Consortium1 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2019 eng d a1546-171800aMulti-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids.0 aMultiancestry genomewide genesmoking interaction study of 387272 c2019 Apr a636-6480 v513 aThe concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.
1 aBentley, Amy, R1 aSung, Yun, J1 aBrown, Michael, R1 aWinkler, Thomas, W1 aKraja, Aldi, T1 aNtalla, Ioanna1 aSchwander, Karen1 aChasman, Daniel, I1 aLim, Elise1 aDeng, Xuan1 aGuo, Xiuqing1 aLiu, Jingmin1 aLu, Yingchang1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aHuffman, Jennifer, E1 aMusani, Solomon, K1 aLi, Changwei1 aFeitosa, Mary, F1 aRichard, Melissa, A1 aNoordam, Raymond1 aBaker, Jenna1 aChen, Guanjie1 aAschard, Hugues1 aBartz, Traci, M1 aDing, Jingzhong1 aDorajoo, Rajkumar1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, V1 aTajuddin, Salman, M1 aZhao, Wei1 aGraff, Mariaelisa1 aAlver, Maris1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aEvangelou, Evangelos1 aGao, Chuan1 aGoel, Anuj1 aHagemeijer, Yanick1 aHarris, Sarah, E1 aHartwig, Fernando, P1 aHe, Meian1 aHorimoto, Andrea, R V R1 aHsu, Fang-Chi1 aHung, Yi-Jen1 aJackson, Anne, U1 aKasturiratne, Anuradhani1 aKomulainen, Pirjo1 aKuhnel, Brigitte1 aLeander, Karin1 aLin, Keng-Hung1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMatoba, Nana1 aNolte, Ilja, M1 aPietzner, Maik1 aPrins, Bram1 aRiaz, Muhammad1 aRobino, Antonietta1 aSaid, Abdullah1 aSchupf, Nicole1 aScott, Robert, A1 aSofer, Tamar1 aStančáková, Alena1 aTakeuchi, Fumihiko1 aTayo, Bamidele, O1 avan der Most, Peter, J1 aVarga, Tibor, V1 aWang, Tzung-Dau1 aWang, Yajuan1 aWare, Erin, B1 aWen, Wanqing1 aXiang, Yong-Bing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAdeyemo, Adebowale1 aAfaq, Saima1 aAmin, Najaf1 aAmini, Marzyeh1 aArking, Dan, E1 aArzumanyan, Zorayr1 aAung, Tin1 aBallantyne, Christie1 aBarr, Graham1 aBielak, Lawrence, F1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aBroeckel, Ulrich1 aBrown, Morris1 aCade, Brian, E1 aCampbell, Archie1 aCanouil, Mickaël1 aCharumathi, Sabanayagam1 aChen, Yii-Der Ida1 aChristensen, Kaare1 aConcas, Maria, Pina1 aConnell, John, M1 aFuentes, Lisa, de Las1 ade Silva, Janaka1 ade Vries, Paul, S1 aDoumatey, Ayo1 aDuan, Qing1 aEaton, Charles, B1 aEppinga, Ruben, N1 aFaul, Jessica, D1 aFloyd, James, S1 aForouhi, Nita, G1 aForrester, Terrence1 aFriedlander, Yechiel1 aGandin, Ilaria1 aGao, He1 aGhanbari, Mohsen1 aGharib, Sina, A1 aGigante, Bruna1 aGiulianini, Franco1 aGrabe, Hans, J1 aGu, Charles1 aHarris, Tamara, B1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHixson, James, E1 aIkram, Arfan, M1 aJia, Yucheng1 aJoehanes, Roby1 aJohnson, Craig1 aJonas, Jost, Bruno1 aJustice, Anne, E1 aKatsuya, Tomohiro1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKolcic, Ivana1 aKooperberg, Charles1 aKrieger, Jose, E1 aKritchevsky, Stephen, B1 aKubo, Michiaki1 aKuusisto, Johanna1 aLakka, Timo, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLewis, Cora, E1 aLi, Yize1 aLiang, Jingjing1 aLin, Shiow1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLiu, Kiang1 aLoh, Marie1 aLohman, Kurt, K1 aLouie, Tin1 aLuzzi, Anna1 aMägi, Reedik1 aMahajan, Anubha1 aManichaikul, Ani, W1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMilani, Lili1 aMohlke, Karen, L1 aMomozawa, Yukihide1 aMorris, Andrew, P1 aMurray, Alison, D1 aNalls, Mike, A1 aNauck, Matthias1 aNelson, Christopher, P1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPapanicolau, George, J1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aPoulter, Neil1 aRaitakari, Olli, T1 aReiner, Alex, P1 aRenstrom, Frida1 aRice, Treva, K1 aRich, Stephen, S1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRosendaal, Frits, R1 aRudan, Igor1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aScott, William, R1 aSever, Peter1 aShi, Yuan1 aSidney, Stephen1 aSims, Mario1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aStringham, Heather, M1 aTan, Nicholas, Y Q1 aTang, Hua1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aTiemeier, Henning1 aTurner, Stephen, T1 aUitterlinden, André, G1 avan Heemst, Diana1 aWaldenberger, Melanie1 aWang, Heming1 aWang, Lan1 aWang, Lihua1 aBin Wei, Wen1 aWilliams, Christine, A1 aWilson, Gregory1 aWojczynski, Mary, K1 aYao, Jie1 aYoung, Kristin1 aYu, Caizheng1 aYuan, Jian-Min1 aZhou, Jie1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aCooper, Richard, S1 ade Faire, Ulf1 aDeary, Ian, J1 aElliott, Paul1 aEsko, Tõnu1 aFarrall, Martin1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aHorta, Bernardo, L1 aJuang, Jyh-Ming, Jimmy1 aKamatani, Yoichiro1 aKammerer, Candace, M1 aKato, Norihiro1 aKooner, Jaspal, S1 aLaakso, Markku1 aLaurie, Cathy, C1 aLee, I-Te1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aPereira, Alexandre, C1 aRauramaa, Rainer1 aRedline, Susan1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWang, Jun-Sing1 aWang, Ya, Xing1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aWu, Tangchun1 aZeggini, Eleftheria1 aZheng, Wei1 aBouchard, Claude1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKardia, Sharon, L R1 aLiu, Yongmei1 aPsaty, Bruce, M1 aRidker, Paul, M1 avan Dam, Rob, M1 aMook-Kanamori, Dennis, O1 aFornage, Myriam1 aProvince, Michael, A1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aLoos, Ruth, J F1 aFranceschini, Nora1 aRotter, Jerome, I1 aZhu, Xiaofeng1 aBierut, Laura, J1 aGauderman, James1 aRice, Kenneth1 aMunroe, Patricia, B1 aMorrison, Alanna, C1 aRao, Dabeeru, C1 aRotimi, Charles, N1 aCupples, Adrienne, L1 aCOGENT-Kidney Consortium1 aEPIC-InterAct Consortium1 aUnderstanding Society Scientific Group1 aLifelines Cohort uhttps://chs-nhlbi.org/node/800506391nas a2201909 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2019 eng d a2041-172300aMulti-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.0 aMultiancestry sleepbySNP interaction analysis in 126926 individu c2019 Nov 12 a51210 v103 aBoth short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.
1 aNoordam, Raymond1 aBos, Maxime, M1 aWang, Heming1 aWinkler, Thomas, W1 aBentley, Amy, R1 aKilpeläinen, Tuomas, O1 ade Vries, Paul, S1 aSung, Yun, Ju1 aSchwander, Karen1 aCade, Brian, E1 aManning, Alisa1 aAschard, Hugues1 aBrown, Michael, R1 aChen, Han1 aFranceschini, Nora1 aMusani, Solomon, K1 aRichard, Melissa1 aVojinovic, Dina1 aAslibekyan, Stella1 aBartz, Traci, M1 aFuentes, Lisa, de Las1 aFeitosa, Mary1 aHorimoto, Andrea, R1 aIlkov, Marjan1 aKho, Minjung1 aKraja, Aldi1 aLi, Changwei1 aLim, Elise1 aLiu, Yongmei1 aMook-Kanamori, Dennis, O1 aRankinen, Tuomo1 aTajuddin, Salman, M1 avan der Spek, Ashley1 aWang, Zhe1 aMarten, Jonathan1 aLaville, Vincent1 aAlver, Maris1 aEvangelou, Evangelos1 aGraff, Maria, E1 aHe, Meian1 aKuhnel, Brigitte1 aLyytikäinen, Leo-Pekka1 aMarques-Vidal, Pedro1 aNolte, Ilja, M1 aPalmer, Nicholette, D1 aRauramaa, Rainer1 aShu, Xiao-Ou1 aSnieder, Harold1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aAdolfo, Correa1 aBallantyne, Christie1 aBielak, Larry1 aBiermasz, Nienke, R1 aBoerwinkle, Eric1 aDimou, Niki1 aEiriksdottir, Gudny1 aGao, Chuan1 aGharib, Sina, A1 aGottlieb, Daniel, J1 aHaba-Rubio, José1 aHarris, Tamara, B1 aHeikkinen, Sami1 aHeinzer, Raphael1 aHixson, James, E1 aHomuth, Georg1 aIkram, Arfan, M1 aKomulainen, Pirjo1 aKrieger, Jose, E1 aLee, Jiwon1 aLiu, Jingmin1 aLohman, Kurt, K1 aLuik, Annemarie, I1 aMägi, Reedik1 aMartin, Lisa, W1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aNalls, Mike, A1 aO'Connell, Jeff1 aPeters, Annette1 aPeyser, Patricia1 aRaitakari, Olli, T1 aReiner, Alex, P1 aRensen, Patrick, C N1 aRice, Treva, K1 aRich, Stephen, S1 aRoenneberg, Till1 aRotter, Jerome, I1 aSchreiner, Pamela, J1 aShikany, James1 aSidney, Stephen, S1 aSims, Mario1 aSitlani, Colleen, M1 aSofer, Tamar1 aStrauch, Konstantin1 aSwertz, Morris, A1 aTaylor, Kent, D1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aVölzke, Henry1 aWaldenberger, Melanie1 aWallance, Robert, B1 aDijk, Ko Willems1 aYu, Caizheng1 aZonderman, Alan, B1 aBecker, Diane, M1 aElliott, Paul1 aEsko, Tõnu1 aGieger, Christian1 aGrabe, Hans, J1 aLakka, Timo, A1 aLehtimäki, Terho1 aNorth, Kari, E1 aPenninx, Brenda, W J H1 aVollenweider, Peter1 aWagenknecht, Lynne, E1 aWu, Tangchun1 aXiang, Yong-Bing1 aZheng, Wei1 aArnett, Donna, K1 aBouchard, Claude1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKardia, Sharon1 aKelly, Tanika, N1 aKritchevsky, Stephen, B1 aLoos, Ruth, J F1 aPereira, Alexandre, C1 aProvince, Mike1 aPsaty, Bruce, M1 aRotimi, Charles1 aZhu, Xiaofeng1 aAmin, Najaf1 aCupples, Adrienne, L1 aFornage, Myriam1 aFox, Ervin, F1 aGuo, Xiuqing1 aGauderman, James1 aRice, Kenneth1 aKooperberg, Charles1 aMunroe, Patricia, B1 aLiu, Ching-Ti1 aMorrison, Alanna, C1 aRao, Dabeeru, C1 avan Heemst, Diana1 aRedline, Susan uhttps://chs-nhlbi.org/node/820210097nas a2203265 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2019 eng d a2041-172300aMulti-ancestry study of blood lipid levels identifies four loci interacting with physical activity.0 aMultiancestry study of blood lipid levels identifies four loci i c2019 01 22 a3760 v103 aMany genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.
10aAdolescent10aAdult10aAfrican Continental Ancestry Group10aAged10aAged, 80 and over10aAsian Continental Ancestry Group10aBrazil10aCalcium-Binding Proteins10aCholesterol10aCholesterol, HDL10aCholesterol, LDL10aEuropean Continental Ancestry Group10aExercise10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHispanic Americans10aHumans10aLIM-Homeodomain Proteins10aLipid Metabolism10aLipids10aMale10aMembrane Proteins10aMicrotubule-Associated Proteins10aMiddle Aged10aMuscle Proteins10aNerve Tissue Proteins10aTranscription Factors10aTriglycerides10aYoung Adult1 aKilpeläinen, Tuomas, O1 aBentley, Amy, R1 aNoordam, Raymond1 aSung, Yun, Ju1 aSchwander, Karen1 aWinkler, Thomas, W1 aJakupović, Hermina1 aChasman, Daniel, I1 aManning, Alisa1 aNtalla, Ioanna1 aAschard, Hugues1 aBrown, Michael, R1 aFuentes, Lisa, de Las1 aFranceschini, Nora1 aGuo, Xiuqing1 aVojinovic, Dina1 aAslibekyan, Stella1 aFeitosa, Mary, F1 aKho, Minjung1 aMusani, Solomon, K1 aRichard, Melissa1 aWang, Heming1 aWang, Zhe1 aBartz, Traci, M1 aBielak, Lawrence, F1 aCampbell, Archie1 aDorajoo, Rajkumar1 aFisher, Virginia1 aHartwig, Fernando, P1 aHorimoto, Andrea, R V R1 aLi, Changwei1 aLohman, Kurt, K1 aMarten, Jonathan1 aSim, Xueling1 aSmith, Albert, V1 aTajuddin, Salman, M1 aAlver, Maris1 aAmini, Marzyeh1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aEvangelou, Evangelos1 aGao, Chuan1 aGraff, Mariaelisa1 aHarris, Sarah, E1 aHe, Meian1 aHsu, Fang-Chi1 aJackson, Anne, U1 aZhao, Jing Hua1 aKraja, Aldi, T1 aKuhnel, Brigitte1 aLaguzzi, Federica1 aLyytikäinen, Leo-Pekka1 aNolte, Ilja, M1 aRauramaa, Rainer1 aRiaz, Muhammad1 aRobino, Antonietta1 aRueedi, Rico1 aStringham, Heather, M1 aTakeuchi, Fumihiko1 avan der Most, Peter, J1 aVarga, Tibor, V1 aVerweij, Niek1 aWare, Erin, B1 aWen, Wanqing1 aLi, Xiaoyin1 aYanek, Lisa, R1 aAmin, Najaf1 aArnett, Donna, K1 aBoerwinkle, Eric1 aBrumat, Marco1 aCade, Brian1 aCanouil, Mickaël1 aChen, Yii-Der Ida1 aConcas, Maria, Pina1 aConnell, John1 ade Mutsert, Renée1 ade Silva, Janaka1 ade Vries, Paul, S1 aDemirkan, Ayse1 aDing, Jingzhong1 aEaton, Charles, B1 aFaul, Jessica, D1 aFriedlander, Yechiel1 aGabriel, Kelley, P1 aGhanbari, Mohsen1 aGiulianini, Franco1 aGu, Chi, Charles1 aGu, Dongfeng1 aHarris, Tamara, B1 aHe, Jiang1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHunt, Steven, C1 aIkram, Arfan, M1 aJonas, Jost, B1 aKoh, Woon-Puay1 aKomulainen, Pirjo1 aKrieger, Jose, E1 aKritchevsky, Stephen, B1 aKutalik, Zoltán1 aKuusisto, Johanna1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLeander, Karin1 aLemaitre, Rozenn, N1 aLewis, Cora, E1 aLiang, Jingjing1 aLiu, Jianjun1 aMägi, Reedik1 aManichaikul, Ani1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMohlke, Karen, L1 aMosley, Thomas, H1 aMurray, Alison, D1 aNalls, Mike, A1 aNang, Ei-Ei, Khaing1 aNelson, Christopher, P1 aNona, Sotoodehnia1 aNorris, Jill, M1 aNwuba, Chiamaka, Vivian1 aO'Connell, Jeff1 aPalmer, Nicholette, D1 aPapanicolau, George, J1 aPazoki, Raha1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aPorteous, David, J1 aPoveda, Alaitz1 aRaitakari, Olli, T1 aRich, Stephen, S1 aRisch, Neil1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRudan, Igor1 aSchreiner, Pamela, J1 aScott, Robert, A1 aSidney, Stephen, S1 aSims, Mario1 aSmith, Jennifer, A1 aSnieder, Harold1 aSofer, Tamar1 aStarr, John, M1 aSternfeld, Barbara1 aStrauch, Konstantin1 aTang, Hua1 aTaylor, Kent, D1 aTsai, Michael, Y1 aTuomilehto, Jaakko1 aUitterlinden, André, G1 avan der Ende, Yldau1 avan Heemst, Diana1 aVoortman, Trudy1 aWaldenberger, Melanie1 aWennberg, Patrik1 aWilson, Gregory1 aXiang, Yong-Bing1 aYao, Jie1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 ade Faire, Ulf1 aDeary, Ian, J1 aElliott, Paul1 aEsko, Tõnu1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aKato, Norihiro1 aLaakso, Markku1 aLakka, Timo, A1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aSamani, Nilesh, J1 aShu, Xiao-Ou1 aHarst, Pim1 avan Vliet-Ostaptchouk, Jana, V1 aVollenweider, Peter1 aWagenknecht, Lynne, E1 aWang, Ya, X1 aWareham, Nicholas, J1 aWeir, David, R1 aWu, Tangchun1 aZheng, Wei1 aZhu, Xiaofeng1 aEvans, Michele, K1 aFranks, Paul, W1 aGudnason, Vilmundur1 aHayward, Caroline1 aHorta, Bernardo, L1 aKelly, Tanika, N1 aLiu, Yongmei1 aNorth, Kari, E1 aPereira, Alexandre, C1 aRidker, Paul, M1 aTai, Shyong, E1 avan Dam, Rob, M1 aFox, Ervin, R1 aKardia, Sharon, L R1 aLiu, Ching-Ti1 aMook-Kanamori, Dennis, O1 aProvince, Michael, A1 aRedline, Susan1 aDuijn, Cornelia, M1 aRotter, Jerome, I1 aKooperberg, Charles, B1 aGauderman, James1 aPsaty, Bruce, M1 aRice, Kenneth1 aMunroe, Patricia, B1 aFornage, Myriam1 aCupples, Adrienne, L1 aRotimi, Charles, N1 aMorrison, Alanna, C1 aRao, Dabeeru, C1 aLoos, Ruth, J F1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/797609183nas 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2019 eng d a1546-171800aTarget genes, variants, tissues and transcriptional pathways influencing human serum urate levels.0 aTarget genes variants tissues and transcriptional pathways influ c2019 Oct a1459-14740 v513 aElevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
1 aTin, Adrienne1 aMarten, Jonathan1 aKuhns, Victoria, L Halperin1 aLi, Yong1 aWuttke, Matthias1 aKirsten, Holger1 aSieber, Karsten, B1 aQiu, Chengxiang1 aGorski, Mathias1 aYu, Zhi1 aGiri, Ayush1 aSveinbjornsson, Gardar1 aLi, Man1 aChu, Audrey, Y1 aHoppmann, Anselm1 aO'Connor, Luke, J1 aPrins, Bram1 aNutile, Teresa1 aNoce, Damia1 aAkiyama, Masato1 aCocca, Massimiliano1 aGhasemi, Sahar1 avan der Most, Peter, J1 aHorn, Katrin1 aXu, Yizhe1 aFuchsberger, Christian1 aSedaghat, Sanaz1 aAfaq, Saima1 aAmin, Najaf1 aArnlöv, Johan1 aBakker, Stephan, J L1 aBansal, Nisha1 aBaptista, Daniela1 aBergmann, Sven1 aBiggs, Mary, L1 aBiino, Ginevra1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aBoutin, Thibaud, S1 aBrumat, Marco1 aBurkhardt, Ralph1 aCampana, Eric1 aCampbell, Archie1 aCampbell, Harry1 aCarroll, Robert, J1 aCatamo, Eulalia1 aChambers, John, C1 aCiullo, Marina1 aConcas, Maria, Pina1 aCoresh, Josef1 aCorre, Tanguy1 aCusi, Daniele1 aFelicita, Sala, Cinzia1 ade Borst, Martin, H1 aDe Grandi, Alessandro1 ade Mutsert, Renée1 ade Vries, Aiko, P J1 aDelgado, Graciela1 aDemirkan, Ayse1 aDevuyst, Olivier1 aDittrich, Katalin1 aEckardt, Kai-Uwe1 aEhret, Georg1 aEndlich, Karlhans1 aEvans, Michele, K1 aGansevoort, Ron, T1 aGasparini, Paolo1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGirotto, Giorgia1 aGögele, Martin1 aGordon, Scott, D1 aGudbjartsson, Daniel, F1 aGudnason, Vilmundur1 aHaller, Toomas1 aHamet, Pavel1 aHarris, Tamara, B1 aHayward, Caroline1 aHicks, Andrew, A1 aHofer, Edith1 aHolm, Hilma1 aHuang, Wei1 aHutri-Kähönen, Nina1 aHwang, Shih-Jen1 aIkram, Arfan, M1 aLewis, Raychel, M1 aIngelsson, Erik1 aJakobsdottir, Johanna1 aJonsdottir, Ingileif1 aJonsson, Helgi1 aJoshi, Peter, K1 aJosyula, Navya, Shilpa1 aJung, Bettina1 aKähönen, Mika1 aKamatani, Yoichiro1 aKanai, Masahiro1 aKerr, Shona, M1 aKiess, Wieland1 aKleber, Marcus, E1 aKoenig, Wolfgang1 aKooner, Jaspal, S1 aKörner, Antje1 aKovacs, Peter1 aKrämer, Bernhard, K1 aKronenberg, Florian1 aKubo, Michiaki1 aKuhnel, Brigitte1 aLa Bianca, Martina1 aLange, Leslie, A1 aLehne, Benjamin1 aLehtimäki, Terho1 aLiu, Jun1 aLoeffler, Markus1 aLoos, Ruth, J F1 aLyytikäinen, Leo-Pekka1 aMägi, Reedik1 aMahajan, Anubha1 aMartin, Nicholas, G1 aMärz, Winfried1 aMascalzoni, Deborah1 aMatsuda, Koichi1 aMeisinger, Christa1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aO'Donnell, Christopher, J1 aWilson, Otis, D1 aGaziano, Michael1 aMishra, Pashupati, P1 aMohlke, Karen, L1 aMononen, Nina1 aMontgomery, Grant, W1 aMook-Kanamori, Dennis, O1 aMüller-Nurasyid, Martina1 aNadkarni, Girish, N1 aNalls, Mike, A1 aNauck, Matthias1 aNikus, Kjell1 aNing, Boting1 aNolte, Ilja, M1 aNoordam, Raymond1 aO'Connell, Jeffrey, R1 aOlafsson, Isleifur1 aPadmanabhan, Sandosh1 aPenninx, Brenda, W J H1 aPerls, Thomas1 aPeters, Annette1 aPirastu, Mario1 aPirastu, Nicola1 aPistis, Giorgio1 aPolasek, Ozren1 aPonte, Belen1 aPorteous, David, J1 aPoulain, Tanja1 aPreuss, Michael, H1 aRabelink, Ton, J1 aRaffield, Laura, M1 aRaitakari, Olli, T1 aRettig, Rainer1 aRheinberger, Myriam1 aRice, Kenneth, M1 aRizzi, Federica1 aRobino, Antonietta1 aRudan, Igor1 aKrajcoviechova, Alena1 aCifkova, Renata1 aRueedi, Rico1 aRuggiero, Daniela1 aRyan, Kathleen, A1 aSaba, Yasaman1 aSalvi, Erika1 aSchmidt, Helena1 aSchmidt, Reinhold1 aShaffer, Christian, M1 aSmith, Albert, V1 aSmith, Blair, H1 aSpracklen, Cassandra, N1 aStrauch, Konstantin1 aStumvoll, Michael1 aSulem, Patrick1 aTajuddin, Salman, M1 aTeren, Andrej1 aThiery, Joachim1 aThio, Chris, H L1 aThorsteinsdottir, Unnur1 aToniolo, Daniela1 aTönjes, Anke1 aTremblay, Johanne1 aUitterlinden, André, G1 aVaccargiu, Simona1 aHarst, Pim1 aDuijn, Cornelia, M1 aVerweij, Niek1 aVölker, Uwe1 aVollenweider, Peter1 aWaeber, Gérard1 aWaldenberger, Melanie1 aWhitfield, John, B1 aWild, Sarah, H1 aWilson, James, F1 aYang, Qiong1 aZhang, Weihua1 aZonderman, Alan, B1 aBochud, Murielle1 aWilson, James, G1 aPendergrass, Sarah, A1 aHo, Kevin1 aParsa, Afshin1 aPramstaller, Peter, P1 aPsaty, Bruce, M1 aBöger, Carsten, A1 aSnieder, Harold1 aButterworth, Adam, S1 aOkada, Yukinori1 aEdwards, Todd, L1 aStefansson, Kari1 aSusztak, Katalin1 aScholz, Markus1 aHeid, Iris, M1 aHung, Adriana, M1 aTeumer, Alexander1 aPattaro, Cristian1 aWoodward, Owen, M1 aVitart, Veronique1 aKöttgen, Anna1 aGerman Chronic Kidney Disease Study1 aLifeLines Cohort Study1 aV. A. Million Veteran Program uhttps://chs-nhlbi.org/node/820709368nas a2202785 4500008004100000022001400041245012700055210006900182260001600251520166300267100002601930700001801956700002101974700002001995700002102015700002102036700002002057700002202077700001702099700001902116700002302135700002002158700002002178700002402198700002102222700002002243700002202263700002502285700002302310700001702333700002002350700001702370700002102387700002302408700001902431700002002450700002102470700001702491700002102508700002402529700002202553700002002575700002102595700001502616700001702631700002202648700001902670700001302689700002302702700001902725700002502744700001502769700002102784700002102805700001402826700001802840700002102858700002202879700001602901700002802917700001902945700001902964700002102983700001903004700001703023700001703040700002003057700001703077700002303094700001803117700001803135700001803153700001903171700001603190700001903206700002103225700001903246700002103265700002303286700002103309700001803330700001903348700002403367700002203391700001903413700002203432700002403454700001803478700002103496700002203517700002403539700002103563700002103584700002403605700001803629700002503647700001203672700001903684700002303703700002103726700001703747700002203764700001403786700002003800700002003820700001703840700002003857700002503877700002003902700002003922700002303942700002803965700001903993700002204012700001904034700001804053700002304071700001304094700002004107700002404127700001804151700001704169700002004186700001804206700002304224700002204247700002104269700002104290700001704311700002904328700001904357700002704376700002004403700002004423700002204443700002504465700002604490700002304516700001804539700002004557700002304577700002404600700001904624700002304643700002204666700001904688700002204707700001604729700003004745700002804775700002504803700002504828700002204853700002304875700001604898700002404914700002304938700001904961700002404980700002205004700002205026700002105048700002805069700002205097700002405119700002605143700001605169700001805185700001805203700001905221700001705240700001305257700001305270700001705283700001905300700001405319700002305333700002105356700002205377700001805399700001805417700001605435700002305451700002205474700002105496700002205517700002305539700002505562700001905587700001905606700001905625700002205644700002705666700002505693700002705718700002205745700001505767700002605782700001705808700001505825700001805840700002105858700002305879700001905902700002205921700002405943700002205967700002305989700002106012700002806033700001706061700002206078700001806100700002506118700002006143700002006163700002306183700001906206700002006225700002306245700002006268700001806288700002106306700002406327700001906351700002406370700002306394700001806417700002406435700002006459700002006479700002006499710002706519856003606546 2020 eng d a1476-557800aGene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.0 aGeneeducational attainment interactions in a multiancestry genom c2020 May 053 aEducational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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aShu, Xiao-Ou1 aSnieder, Harold1 aSofer, Tamar1 aTakeuchi, Fumihiko1 aVerweij, Niek1 aWare, Erin, B1 aWeiss, Stefan1 aYanek, Lisa, R1 aAmin, Najaf1 aArking, Dan, E1 aArnett, Donna, K1 aBergmann, Sven1 aBoerwinkle, Eric1 aBrody, Jennifer, A1 aBroeckel, Ulrich1 aBrumat, Marco1 aBurke, Gregory1 aCabrera, Claudia, P1 aCanouil, Mickaël1 aChee, Miao, Li1 aChen, Yii-Der Ida1 aCocca, Massimiliano1 aConnell, John1 ade Silva, Janaka1 ade Vries, Paul, S1 aEiriksdottir, Gudny1 aFaul, Jessica, D1 aFisher, Virginia1 aForrester, Terrence1 aFox, Ervin, F1 aFriedlander, Yechiel1 aGao, He1 aGigante, Bruna1 aGiulianini, Franco1 aGu, Chi, Charles1 aGu, Dongfeng1 aHarris, Tamara, B1 aHe, Jiang1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHunt, Steven1 aIkram, Arfan, M1 aIrvin, Marguerite, R1 aKähönen, Mika1 aKavousi, Maryam1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKomulainen, Pirjo1 aKraja, Aldi, T1 aKrieger, J, E1 aLangefeld, Carl, D1 aLi, Yize1 aLiang, Jingjing1 aLiewald, David, C M1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLohman, Kurt, K1 aMägi, Reedik1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMilani, Lili1 aMook-Kanamori, Dennis, O1 aNalls, Mike, A1 aNelson, Christopher, P1 aNorris, Jill, M1 aO'Connell, Jeff1 aOgunniyi, Adesola1 aPadmanabhan, Sandosh1 aPalmer, Nicholette, D1 aPedersen, Nancy, L1 aPerls, Thomas1 aPeters, Annette1 aPetersmann, Astrid1 aPeyser, Patricia, A1 aPolasek, Ozren1 aPorteous, David, J1 aRaffel, Leslie, J1 aRice, Treva, K1 aRotter, Jerome, I1 aRudan, Igor1 aRueda-Ochoa, Oscar-Leonel1 aSabanayagam, Charumathi1 aSalako, Babatunde, L1 aSchreiner, Pamela, J1 aShikany, James, M1 aSidney, Stephen, S1 aSims, Mario1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aStarr, John, M1 aStrauch, Konstantin1 aSwertz, Morris, A1 aTeumer, Alexander1 aTham, Yih, Chung1 aUitterlinden, André, G1 aVaidya, Dhananjay1 avan der Ende, Yldau1 aWaldenberger, Melanie1 aWang, Lihua1 aWang, Ya-Xing1 aBin Wei, Wen-1 aWeir, David, R1 aWen, Wanqing1 aYao, Jie1 aYu, Bing1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aZonderman, Alan, B1 aBecker, Diane, M1 aBowden, Donald, W1 aDeary, Ian, J1 aDörr, Marcus1 aEsko, Tõnu1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aJonas, Jost, Bruno1 aKammerer, Candace, M1 aKato, Norihiro1 aLakka, Timo, A1 aLeander, Karin1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aMarques-Vidal, Pedro1 aPenninx, Brenda, W J H1 aSamani, Nilesh, J1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWu, Tangchun1 aZheng, Wei1 aZhu, Xiaofeng1 aBouchard, Claude1 aCooper, Richard, S1 aCorrea, Adolfo1 aEvans, Michele, K1 aGudnason, Vilmundur1 aHayward, Caroline1 aHorta, Bernardo, L1 aKelly, Tanika, N1 aKritchevsky, Stephen, B1 aLevy, Daniel1 aPalmas, Walter, R1 aPereira, A, C1 aProvince, Michael, M1 aPsaty, Bruce, M1 aRidker, Paul, M1 aRotimi, Charles, N1 aTai, Shyong, E1 avan Dam, Rob, M1 aDuijn, Cornelia, M1 aWong, Tien, Yin1 aRice, Kenneth1 aGauderman, James1 aMorrison, Alanna, C1 aNorth, Kari, E1 aKardia, Sharon, L R1 aCaulfield, Mark, J1 aElliott, Paul1 aMunroe, Patricia, B1 aFranks, Paul, W1 aRao, Dabeeru, C1 aFornage, Myriam1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/838109591nas a2202833 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2021 eng d a1537-660500aDiscovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.0 aDiscovery and finemapping of height loci via highdensity imputat c2021 Apr 01 a564-5820 v1083 aAlthough many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
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