04323nas a2201033 4500008004100000022001400041245011200055210006900167260001300236300001300249490000600262520134000268653000901608653002001617653001901637653004001656653001101696653003801707653003401745653001101779653000901790653001601799653002601815653001201841653003601853653002401889100002601913700002501939700001901964700001901983700002202002700001202024700002302036700002102059700001902080700002402099700002002123700002202143700002102165700002502186700002402211700002302235700002602258700002102284700001902305700002302324700002102347700002102368700002202389700002202411700002202433700002002455700002202475700001602497700002002513700002002533700002202553700002602575700001602601700002302617700002202640700001602662700001602678700002502694700001902719700002102738700001902759700002402778700002402802700003002826700002702856700002202883700002402905700001902929700001902948700002602967700002802993700003003021700001903051700002203070700002403092700002603116700002303142700002303165700002503188700002103213700001903234856003603253 2009 eng d a1553-740400aNRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium.0 aNRXN3 is a novel locus for waist circumference a genomewide asso c2009 Jun ae10005390 v53 a
Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4x10(-7))]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3x10(-8) for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4x10(-6), 0.024 z-score units (0.10 kg/m(2)) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07-1.19; p = 3.2x10(-5) per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.
10aAged10aBody Mass Index10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aNerve Tissue Proteins10aObesity10aPolymorphism, Single Nucleotide10aWaist Circumference1 aHeard-Costa, Nancy, L1 aZillikens, Carola, M1 aMonda, Keri, L1 aJohansson, Asa1 aHarris, Tamara, B1 aFu, Mao1 aHaritunians, Talin1 aFeitosa, Mary, F1 aAspelund, Thor1 aEiriksdottir, Gudny1 aGarcia, Melissa1 aLauner, Lenore, J1 aSmith, Albert, V1 aMitchell, Braxton, D1 aMcArdle, Patrick, F1 aShuldiner, Alan, R1 aBielinski, Suzette, J1 aBoerwinkle, Eric1 aBrancati, Fred1 aDemerath, Ellen, W1 aPankow, James, S1 aArnold, Alice, M1 aChen, Yii-Der Ida1 aGlazer, Nicole, L1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aAmin, Najaf1 aCampbell, Harry1 aGyllensten, Ulf1 aPattaro, Cristian1 aPramstaller, Peter, P1 aRudan, Igor1 aStruchalin, Maksim1 aVitart, Veronique1 aGao, Xiaoyi1 aKraja, Aldi1 aProvince, Michael, A1 aZhang, Qunyuan1 aAtwood, Larry, D1 aDupuis, Josée1 aHirschhorn, Joel, N1 aJaquish, Cashell, E1 aO'Donnell, Christopher, J1 aVasan, Ramachandran, S1 aWhite, Charles, C1 aAulchenko, Yurii, S1 aEstrada, Karol1 aHofman, Albert1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aWitteman, Jacqueline, C M1 aOostra, Ben, A1 aKaplan, Robert, C1 aGudnason, Vilmundur1 aO'Connell, Jeffrey, R1 aBorecki, Ingrid, B1 aDuijn, Cornelia, M1 aCupples, Adrienne, L1 aFox, Caroline, S1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/110708598nas a2202365 4500008004100000022001400041245007900055210006900134260001600203300001100219490000800230520193500238653005002173653001602223653002002239653002602259653001102285653002202296653003402318653001102352653000902363653002602372653001402398653003602412653001302448653002302461100001502484700002002499700002202519700002202541700002802563700002302591700001902614700002502633700003202658700001802690700001902708700002602727700003102753700001902784700001802803700002002821700001202841700001702853700002202870700002502892700002002917700002002937700001602957700002002973700001902993700001903012700001803031700002103049700001803070700002603088700001903114700002103133700002003154700002103174700001903195700002103214700002003235700001903255700003503274700002403309700002103333700001803354700001503372700002803387700001903415700003403434700001803468700001803486700002003504700002203524700002103546700002103567700002503588700002903613700002303642700001603665700002003681700002203701700001403723700002303737700001603760700001803776700001903794700002203813700001903835700002103854700002203875700002203897700002003919700002103939700002303960700002003983700002004003700001804023700002104041700002304062700002404085700001904109700001804128700002704146700001804173700001704191700002204208700001904230700001904249700002404268700002604292700002104318700001704339700002004356700001904376700002004395700002004415700002004435700002504455700002004480700002404500700002204524700002004546700001604566700001904582700002104601700001904622700002304641700002304664700002504687700002504712700002404737700002304761700002504784700002104809700002104830700002104851700002404872700002104896700002204917700002404939700002804963700001704991700002305008700001905031700001805050700002105068700003005089700002605119700002205145700002405167700002005191700002705211700001905238700002305257700002005280700002105300700002005321700002405341700001505365700002005380700001805400700001905418700002805437700002505465700002805490700002605518700002505544700002705569700002305596700002505619700002405644700001905668700002205687700001805709700002005727700001905747700002205766700002205788700002105810700002105831700002405852700002005876700002505896700002405921700002205945700002305967700002105990700002006011700002006031700002806051700002106079700002506100700002406125700002406149700002306173856003606196 2012 eng d a1476-468700aFTO genotype is associated with phenotypic variability of body mass index.0 aFTO genotype is associated with phenotypic variability of body m c2012 Oct 11 a267-720 v4903 aThere is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
10aAlpha-Ketoglutarate-Dependent Dioxygenase FTO10aBody Height10aBody Mass Index10aCo-Repressor Proteins10aFemale10aGenetic Variation10aGenome-Wide Association Study10aHumans10aMale10aNerve Tissue Proteins10aPhenotype10aPolymorphism, Single Nucleotide10aProteins10aRepressor Proteins1 aYang, Jian1 aLoos, Ruth, J F1 aPowell, Joseph, E1 aMedland, Sarah, E1 aSpeliotes, Elizabeth, K1 aChasman, Daniel, I1 aRose, Lynda, M1 aThorleifsson, Gudmar1 aSteinthorsdottir, Valgerdur1 aMägi, Reedik1 aWaite, Lindsay1 aSmith, Albert, Vernon1 aYerges-Armstrong, Laura, M1 aMonda, Keri, L1 aHadley, David1 aMahajan, Anubha1 aLi, Guo1 aKapur, Karen1 aVitart, Veronique1 aHuffman, Jennifer, E1 aWang, Sophie, R1 aPalmer, Cameron1 aEsko, Tõnu1 aFischer, Krista1 aZhao, Jing Hua1 aDemirkan, Ayse1 aIsaacs, Aaron1 aFeitosa, Mary, F1 aLuan, Jian'an1 aHeard-Costa, Nancy, L1 aWhite, Charles1 aJackson, Anne, U1 aPreuss, Michael1 aZiegler, Andreas1 aEriksson, Joel1 aKutalik, Zoltán1 aFrau, Francesca1 aNolte, Ilja, M1 avan Vliet-Ostaptchouk, Jana, V1 aHottenga, Jouke-Jan1 aJacobs, Kevin, B1 aVerweij, Niek1 aGoel, Anuj1 aMedina-Gómez, Carolina1 aEstrada, Karol1 aBragg-Gresham, Jennifer, Lynn1 aSanna, Serena1 aSidore, Carlo1 aTyrer, Jonathan1 aTeumer, Alexander1 aProkopenko, Inga1 aMangino, Massimo1 aLindgren, Cecilia, M1 aAssimes, Themistocles, L1 aShuldiner, Alan, R1 aHui, Jennie1 aBeilby, John, P1 aMcArdle, Wendy, L1 aHall, Per1 aHaritunians, Talin1 aZgaga, Lina1 aKolcic, Ivana1 aPolasek, Ozren1 aZemunik, Tatijana1 aOostra, Ben, A1 aJunttila, Juhani1 aGrönberg, Henrik1 aSchreiber, Stefan1 aPeters, Annette1 aHicks, Andrew, A1 aStephens, Jonathan1 aFoad, Nicola, S1 aLaitinen, Jaana1 aPouta, Anneli1 aKaakinen, Marika1 aWillemsen, Gonneke1 aVink, Jacqueline, M1 aWild, Sarah, H1 aNavis, Gerjan1 aAsselbergs, Folkert, W1 aHomuth, Georg1 aJohn, Ulrich1 aIribarren, Carlos1 aHarris, Tamara1 aLauner, Lenore1 aGudnason, Vilmundur1 aO'Connell, Jeffrey, R1 aBoerwinkle, Eric1 aCadby, Gemma1 aPalmer, Lyle, J1 aJames, Alan, L1 aMusk, Arthur, W1 aIngelsson, Erik1 aPsaty, Bruce, M1 aBeckmann, Jacques, S1 aWaeber, Gérard1 aVollenweider, Peter1 aHayward, Caroline1 aWright, Alan, F1 aRudan, Igor1 aGroop, Leif, C1 aMetspalu, Andres1 aKhaw, Kay, Tee1 aDuijn, Cornelia, M1 aBorecki, Ingrid, B1 aProvince, Michael, A1 aWareham, Nicholas, J1 aTardif, Jean-Claude1 aHuikuri, Heikki, V1 aCupples, Adrienne, L1 aAtwood, Larry, D1 aFox, Caroline, S1 aBoehnke, Michael1 aCollins, Francis, S1 aMohlke, Karen, L1 aErdmann, Jeanette1 aSchunkert, Heribert1 aHengstenberg, Christian1 aStark, Klaus1 aLorentzon, Mattias1 aOhlsson, Claes1 aCusi, Daniele1 aStaessen, Jan, A1 avan der Klauw, Melanie, M1 aPramstaller, Peter, P1 aKathiresan, Sekar1 aJolley, Jennifer, D1 aRipatti, Samuli1 aJarvelin, Marjo-Riitta1 aGeus, Eco, J C1 aBoomsma, Dorret, I1 aPenninx, Brenda1 aWilson, James, F1 aCampbell, Harry1 aChanock, Stephen, J1 aHarst, Pim1 aHamsten, Anders1 aWatkins, Hugh1 aHofman, Albert1 aWitteman, Jacqueline, C1 aZillikens, Carola, M1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aZillikens, Carola, M1 aKiemeney, Lambertus, A1 aVermeulen, Sita, H1 aAbecasis, Goncalo, R1 aSchlessinger, David1 aSchipf, Sabine1 aStumvoll, Michael1 aTönjes, Anke1 aSpector, Tim, D1 aNorth, Kari, E1 aLettre, Guillaume1 aMcCarthy, Mark, I1 aBerndt, Sonja, I1 aHeath, Andrew, C1 aMadden, Pamela, A F1 aNyholt, Dale, R1 aMontgomery, Grant, W1 aMartin, Nicholas, G1 aMcKnight, Barbara1 aStrachan, David, P1 aHill, William, G1 aSnieder, Harold1 aRidker, Paul, M1 aThorsteinsdottir, Unnur1 aStefansson, Kari1 aFrayling, Timothy, M1 aHirschhorn, Joel, N1 aGoddard, Michael, E1 aVisscher, Peter, M uhttps://chs-nhlbi.org/node/617505378nas a2201249 4500008004100000022001400041245010600055210006900161260001600230300001100246490000800257520186000265653000902125653001102134653002902145653003402174653001102208653000902219653001602228653002602244653003602270653004302306653002502349653003202374653001202406653001902418100001902437700002202456700002002478700001902498700002102517700002002538700002602558700002302584700002202607700001602629700001802645700001902663700001602682700002002698700002602718700002102744700002102765700001502786700002002801700002002821700002302841700002202864700002402886700001902910700001802929700002002947700001702967700001902984700002303003700001903026700002103045700002203066700001903088700001903107700001903126700001803145700001903163700002203182700002203204700001703226700002003243700002003263700001903283700002603302700002203328700001903350700002403369700002003393700002203413700001903435700002203454700002003476700002103496700002603517700002003543700002203563700002603585700001903611700002803630700002503658700002003683700001803703700002503721700002403746700001803770700002003788700002503808700002403833700001703857700002003874700002303894700002503917700001903942700002603961700002003987700001704007700002404024700002104048700002304069856003604092 2012 eng d a1535-497000aGenome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction.0 aGenomewide association studies identify CHRNA53 and HTR4 in the c2012 Oct 01 a622-320 v1863 aRATIONALE: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.
OBJECTIVES: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases.
METHODS: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV(1) and its ratio to FVC (FEV(1)/FVC) both less than their respective lower limits of normal as determined by published reference equations.
MEASUREMENTS AND MAIN RESULTS: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis.
CONCLUSIONS: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.
10aAged10aFemale10aForced Expiratory Volume10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aPulmonary Disease, Chronic Obstructive10aReceptors, Nicotinic10aReceptors, Serotonin, 5-HT410aSmoking10aVital Capacity1 aWilk, Jemma, B1 aShrine, Nick, R G1 aLoehr, Laura, R1 aZhao, Jing Hua1 aManichaikul, Ani1 aLopez, Lorna, M1 aSmith, Albert, Vernon1 aHeckbert, Susan, R1 aSmolonska, Joanna1 aTang, Wenbo1 aLoth, Daan, W1 aCurjuric, Ivan1 aHui, Jennie1 aCho, Michael, H1 aLatourelle, Jeanne, C1 aHenry, Amanda, P1 aAldrich, Melinda1 aBakke, Per1 aBeaty, Terri, H1 aBentley, Amy, R1 aBorecki, Ingrid, B1 aBrusselle, Guy, G1 aBurkart, Kristin, M1 aChen, Ting-Hsu1 aCouper, David1 aCrapo, James, D1 aDavies, Gail1 aDupuis, Josée1 aFranceschini, Nora1 aGulsvik, Amund1 aHancock, Dana, B1 aHarris, Tamara, B1 aHofman, Albert1 aImboden, Medea1 aJames, Alan, L1 aKhaw, Kay-Tee1 aLahousse, Lies1 aLauner, Lenore, J1 aLitonjua, Augusto1 aLiu, Yongmei1 aLohman, Kurt, K1 aLomas, David, A1 aLumley, Thomas1 aMarciante, Kristin, D1 aMcArdle, Wendy, L1 aMeibohm, Bernd1 aMorrison, Alanna, C1 aMusk, Arthur, W1 aMyers, Richard, H1 aNorth, Kari, E1 aPostma, Dirkje, S1 aPsaty, Bruce, M1 aRich, Stephen, S1 aRivadeneira, Fernando1 aRochat, Thierry1 aRotter, Jerome, I1 aArtigas, Maria, Soler1 aStarr, John, M1 aUitterlinden, André, G1 aWareham, Nicholas, J1 aWijmenga, Cisca1 aZanen, Pieter1 aProvince, Michael, A1 aSilverman, Edwin, K1 aDeary, Ian, J1 aPalmer, Lyle, J1 aCassano, Patricia, A1 aGudnason, Vilmundur1 aBarr, Graham1 aLoos, Ruth, J F1 aStrachan, David, P1 aLondon, Stephanie, J1 aBoezen, Marike1 aProbst-Hensch, Nicole1 aGharib, Sina, A1 aHall, Ian, P1 aO'Connor, George, T1 aTobin, Martin, D1 aStricker, Bruno, H uhttps://chs-nhlbi.org/node/609205536nas a2201405 4500008004100000022001400041245012000055210006900175260000900244300001300253490000600266520151700272653002901789653002001818653001801838653003401856653002001890653002301910653001101933653000901944653002601953653003601979653004402015653004302059653002802102653001202130653003002142653001902172100002102191700002602212700002002238700001802258700002102276700002602297700001802323700001902341700001602360700002202376700002102398700002202419700001702441700001602458700001902474700001802493700001902511700002002530700002402550700001902574700002202593700001802615700001702633700002202650700002102672700001802693700001902711700001802730700002002748700001702768700002002785700002202805700002602827700001902853700002202872700002402894700002202918700001902940700002402959700002302983700002203006700002203028700002003050700001903070700002003089700001903109700002103128700001903149700002403168700002303192700002603215700002103241700002803262700001703290700001903307700002003326700002003346700002803366700002003394700002103414700002003435700002403455700001903479700002103498700001903519700002203538700001803560700002803578700002803606700001803634700002303652700001703675700002503692700001903717700002503736700002403761700002903785700002003814700002703834700002303861700002403884700001903908700001703927700002503944700002303969700002003992700001704012700001904029700002104048700002504069856003604094 2012 eng d a1553-740400aGenome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function.0 aGenomewide joint metaanalysis of SNP and SNPbysmoking interactio c2012 ae10030980 v83 aGenome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.
10aForced Expiratory Volume10aGene Expression10aGenome, Human10aGenome-Wide Association Study10aHLA-DQ Antigens10aHLA-DQ beta-Chains10aHumans10aLung10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aPotassium Channels, Inwardly Rectifying10aPulmonary Disease, Chronic Obstructive10aReceptors, Cell Surface10aSmoking10aSOX9 Transcription Factor10aVital Capacity1 aHancock, Dana, B1 aArtigas, Maria, Soler1 aGharib, Sina, A1 aHenry, Amanda1 aManichaikul, Ani1 aRamasamy, Adaikalavan1 aLoth, Daan, W1 aImboden, Medea1 aKoch, Beate1 aMcArdle, Wendy, L1 aSmith, Albert, V1 aSmolonska, Joanna1 aSood, Akshay1 aTang, Wenbo1 aWilk, Jemma, B1 aZhai, Guangju1 aZhao, Jing Hua1 aAschard, Hugues1 aBurkart, Kristin, M1 aCurjuric, Ivan1 aEijgelsheim, Mark1 aElliott, Paul1 aGu, Xiangjun1 aHarris, Tamara, B1 aJanson, Christer1 aHomuth, Georg1 aHysi, Pirro, G1 aLiu, Jason, Z1 aLoehr, Laura, R1 aLohman, Kurt1 aLoos, Ruth, J F1 aManning, Alisa, K1 aMarciante, Kristin, D1 aObeidat, Ma'en1 aPostma, Dirkje, S1 aAldrich, Melinda, C1 aBrusselle, Guy, G1 aChen, Ting-Hsu1 aEiriksdottir, Gudny1 aFranceschini, Nora1 aHeinrich, Joachim1 aRotter, Jerome, I1 aWijmenga, Cisca1 aWilliams, Dale1 aBentley, Amy, R1 aHofman, Albert1 aLaurie, Cathy, C1 aLumley, Thomas1 aMorrison, Alanna, C1 aJoubert, Bonnie, R1 aRivadeneira, Fernando1 aCouper, David, J1 aKritchevsky, Stephen, B1 aLiu, Yongmei1 aWjst, Matthias1 aWain, Louise, V1 aVonk, Judith, M1 aUitterlinden, André, G1 aRochat, Thierry1 aRich, Stephen, S1 aPsaty, Bruce, M1 aO'Connor, George, T1 aNorth, Kari, E1 aMirel, Daniel, B1 aMeibohm, Bernd1 aLauner, Lenore, J1 aKhaw, Kay-Tee1 aHartikainen, Anna-Liisa1 aHammond, Christopher, J1 aGläser, Sven1 aMarchini, Jonathan1 aKraft, Peter1 aWareham, Nicholas, J1 aVölzke, Henry1 aStricker, Bruno, H C1 aSpector, Timothy, D1 aProbst-Hensch, Nicole, M1 aJarvis, Deborah1 aJarvelin, Marjo-Riitta1 aHeckbert, Susan, R1 aGudnason, Vilmundur1 aBoezen, Marike1 aBarr, Graham1 aCassano, Patricia, A1 aStrachan, David, P1 aFornage, Myriam1 aHall, Ian, P1 aDupuis, Josée1 aTobin, Martin, D1 aLondon, Stephanie, J uhttps://chs-nhlbi.org/node/608805038nas a2201333 4500008004100000022001400041245007300055210006900128260000900197300000900206490000600215520172900221653001001950653002201960653000901982653003201991653003202023653001102055653001702066653003802083653002202121653003402143653001302177653001102190653000902201653001602210653002602226653001402252653003602266653001802302653002502320653001202345653002402357100001602381700001702397700001502414700001702429700001402446700002002460700001602480700001802496700001802514700001102532700001602543700001702559700001502576700002002591700001402611700001802625700001702643700001402660700001702674700001702691700001502708700001602723700001802739700001602757700001302773700001802786700001702804700001602821700001602837700001602853700001602869700001502885700002002900700001602920700002002936700002002956700001502976700001302991700001503004700001703019700001503036700001503051700001203066700001803078700001903096700001103115700001703126700001603143700001903159700001403178700002103192700001403213700001303227700001503240700001403255700001503269700002403284700001803308700002103326700002003347700001503367700001503382700001403397700001903411700001603430700001503446700001703461700001503478700001703493700001603510700001603526700001603542700001003558700001303568700001803581700002003599700001703619700001703636700001503653856003603668 2012 eng d a2158-318800aGenome-wide meta-analyses of smoking behaviors in African Americans.0 aGenomewide metaanalyses of smoking behaviors in African American c2012 ae1190 v23 aThe identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.
10aAdult10aAfrican Americans10aAged10aChromosomes, Human, Pair 1010aChromosomes, Human, Pair 1510aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenetic Variation10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMiddle Aged10aNerve Tissue Proteins10aPhenotype10aPolymorphism, Single Nucleotide10aProteoglycans10aReceptors, Nicotinic10aSmoking10aStatistics as Topic1 aDavid, S, P1 aHamidovic, A1 aChen, G, K1 aBergen, A, W1 aWessel, J1 aKasberger, J, L1 aBrown, W, M1 aPetruzella, S1 aThacker, E, L1 aKim, Y1 aNalls, M, A1 aTranah, G, J1 aSung, Y, J1 aAmbrosone, C, B1 aArnett, D1 aBandera, E, V1 aBecker, D, M1 aBecker, L1 aBerndt, S, I1 aBernstein, L1 aBlot, W, J1 aBroeckel, U1 aBuxbaum, S, G1 aCaporaso, N1 aCasey, G1 aChanock, S, J1 aDeming, S, L1 aDiver, W, R1 aEaton, C, B1 aEvans, D, S1 aEvans, M, K1 aFornage, M1 aFranceschini, N1 aHarris, T B1 aHenderson, B, E1 aHernandez, D, G1 aHitsman, B1 aHu, J, J1 aHunt, S, C1 aIngles, S, A1 aJohn, E, M1 aKittles, R1 aKolb, S1 aKolonel, L, N1 aLe Marchand, L1 aLiu, Y1 aLohman, K, K1 aMcKnight, B1 aMillikan, R, C1 aMurphy, A1 aNeslund-Dudas, C1 aNyante, S1 aPress, M1 aPsaty, B M1 aRao, D, C1 aRedline, S1 aRodriguez-Gil, J, L1 aRybicki, B, A1 aSignorello, L, B1 aSingleton, A, B1 aSmoller, J1 aSnively, B1 aSpring, B1 aStanford, J, L1 aStrom, S, S1 aSwan, G, E1 aTaylor, K, D1 aThun, M, J1 aWilson, A, F1 aWitte, J, S1 aYamamura, Y1 aYanek, L, R1 aYu, K1 aZheng, W1 aZiegler, R, G1 aZonderman, A, B1 aJorgenson, E1 aHaiman, C, A1 aFurberg, H uhttps://chs-nhlbi.org/node/680404392nas a2200841 4500008004100000022001400041245013900055210006900194260000900263300001100272490000600283520190900289653002202198653002402220653003802244653003402282653001302316653001102329653003902340653002502379653002602404653003602430653001302466653001702479653002902496100002702525700002102552700002302573700003202596700002302628700001702651700001902668700001402687700001902701700002102720700002102741700002302762700002402785700002402809700001902833700002002852700002002872700002302892700002402915700001902939700001602958700001702974700001902991700002203010700002203032700001903054700002003073700002203093700002203115700002103137700001703158700001703175700001903192700002803211700002403239700001603263700002803279700002603307700001903333700002103352700001803373700002503391700001803416700001603434700001903450710004503469856003603514 2013 eng d a1932-620300aInsights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis.0 aInsights into the genetic architecture of early stage agerelated c2013 ae538300 v83 aGenetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10(-6)) and upstream of GLI2 (rs6721654; P = 6.5×10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.
10aApolipoproteins E10aComplement Factor H10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aKruppel-Like Transcription Factors10aMacular Degeneration10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aProteins10aRisk Factors10aZinc Finger Protein Gli31 aHolliday, Elizabeth, G1 aSmith, Albert, V1 aCornes, Belinda, K1 aBuitendijk, Gabriëlle, H S1 aJensen, Richard, A1 aSim, Xueling1 aAspelund, Thor1 aAung, Tin1 aBaird, Paul, N1 aBoerwinkle, Eric1 aCheng, Ching, Yu1 aDuijn, Cornelia, M1 aEiriksdottir, Gudny1 aGudnason, Vilmundur1 aHarris, Tamara1 aHewitt, Alex, W1 aInouye, Michael1 aJonasson, Fridbert1 aKlein, Barbara, E K1 aLauner, Lenore1 aLi, Xiaohui1 aLiew, Gerald1 aLumley, Thomas1 aMcElduff, Patrick1 aMcKnight, Barbara1 aMitchell, Paul1 aPsaty, Bruce, M1 aRochtchina, Elena1 aRotter, Jerome, I1 aScott, Rodney, J1 aTay, Wanting1 aTaylor, Kent1 aTeo, Yik, Ying1 aUitterlinden, André, G1 aViswanathan, Ananth1 aXie, Sophia1 aVingerling, Johannes, R1 aKlaver, Caroline, C W1 aTai, Shyong, E1 aSiscovick, David1 aKlein, Ronald1 aCotch, Mary, Frances1 aWong, Tien, Y1 aAttia, John1 aWang, Jie, Jin1 aWellcome Trust Case Control Consortium 2 uhttps://chs-nhlbi.org/node/587506414nas a2201585 4500008004100000022001400041245015100055210006900206260001300275300001300288490000700301520179000308653000902098653002002107653002802127653002202155653001102177653001102188653003102199653001902230653001702249653003802266653003402304653001102338653000902349653001602358653002602374653001402400653003602414653002102450653001702471653001102488653001502499653003302514653001702547653001802564653001802582100001502600700002502615700002402640700002402664700002002688700002702708700002502735700003202760700001802792700002302810700002202833700001802855700002102873700001802894700001902912700002302931700001702954700002102971700001602992700002803008700002403036700002003060700002703080700002003107700002603127700002203153700001603175700002403191700002103215700002103236700002003257700002003277700002503297700002503322700002403347700001603371700002203387700002003409700001503429700002003444700002103464700002303485700002803508700002203536700001903558700001903577700001903596700002303615700002203638700002203660700002003682700001403702700001703716700002003733700002203753700001803775700002803793700002303821700001903844700002003863700001803883700001903901700003003920700002103950700001703971700002003988700001904008700002104027700002604048700002204074700002404096700002204120700001904142700002804161700002004189700002104209700002204230700002004252700002004272700002404292700002004316700002004336700001804356700002104374700002904395700002004424700002304444700002204467700001504489700002004504700002704524700002304551700003004574710010804604710002604712710005404738856003604792 2014 eng d a1524-463600aGenome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2.0 aGenomewide association study for circulating tissue plasminogen c2014 May a1093-1010 v343 aOBJECTIVE: Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases. We conducted a meta-analysis of genome-wide association studies to identify novel correlates of circulating levels of tPA.
APPROACH AND RESULTS: Fourteen cohort studies with tPA measures (N=26 929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P<5.0×10(-8)). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9×10(-14)) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3×10(-9)) is intronic to POLB and <200 kb away from the tPA encoding the gene PLAT. We identified a nonsynonymous SNP (rs2020921) in modest linkage disequilibrium with rs3136739 (r(2)=0.50) within exon 5 of PLAT (P=2.0×10(-8)). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0×10(-9)) within intron 7 of STX2. We further found evidence for the association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased the release of tPA from vascular endothelial cells, whereas silencing STX2 increased the tPA release. Through an in silico lookup, we found no associations of the 3 lead SNPs with coronary artery disease or stroke.
CONCLUSIONS: We identified 3 loci associated with circulating tPA levels, the PLAT region, STXBP5, and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.
10aAged10aCells, Cultured10aCoronary Artery Disease10aEndothelial Cells10aEurope10aFemale10aGene Expression Regulation10aGene Silencing10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aNerve Tissue Proteins10aPhenotype10aPolymorphism, Single Nucleotide10aR-SNARE Proteins10aRisk Factors10aStroke10aSyntaxin 110aTissue Plasminogen Activator10aTransfection10aUnited States10aUp-Regulation1 aHuang, Jie1 aHuffman, Jennifer, E1 aYamakuchi, Munekazu1 aYamkauchi, Munekazu1 aTrompet, Stella1 aAsselbergs, Folkert, W1 aSabater-Lleal, Maria1 aTrégouët, David-Alexandre1 aChen, Wei-Min1 aSmith, Nicholas, L1 aKleber, Marcus, E1 aShin, So-Youn1 aBecker, Diane, M1 aTang, Weihong1 aDehghan, Abbas1 aJohnson, Andrew, D1 aTruong, Vinh1 aFolkersen, Lasse1 aYang, Qiong1 aOudot-Mellkah, Tiphaine1 aBuckley, Brendan, M1 aMoore, Jason, H1 aWilliams, Frances, M K1 aCampbell, Harry1 aSilbernagel, Günther1 aVitart, Veronique1 aRudan, Igor1 aTofler, Geoffrey, H1 aNavis, Gerjan, J1 aDeStefano, Anita1 aWright, Alan, F1 aChen, Ming-Huei1 ade Craen, Anton, J M1 aWorrall, Bradford, B1 aRudnicka, Alicja, R1 aRumley, Ann1 aBookman, Ebony, B1 aPsaty, Bruce, M1 aChen, Fang1 aKeene, Keith, L1 aFranco, Oscar, H1 aBöhm, Bernhard, O1 aUitterlinden, André, G1 aCarter, Angela, M1 aJukema, Wouter1 aSattar, Naveed1 aBis, Joshua, C1 aIkram, Mohammad, A1 aSale, Michèle, M1 aMcKnight, Barbara1 aFornage, Myriam1 aFord, Ian1 aTaylor, Kent1 aSlagboom, Eline1 aMcArdle, Wendy, L1 aHsu, Fang-Chi1 aFranco-Cereceda, Anders1 aGoodall, Alison, H1 aYanek, Lisa, R1 aFurie, Karen, L1 aCushman, Mary1 aHofman, Albert1 aWitteman, Jacqueline, C M1 aFolsom, Aaron, R1 aBasu, Saonli1 aMatijevic, Nena1 aGilst, Wiek, H1 aWilson, James, F1 aWestendorp, Rudi, G J1 aKathiresan, Sekar1 aReilly, Muredach, P1 aTracy, Russell, P1 aPolasek, Ozren1 aWinkelmann, Bernhard, R1 aGrant, Peter, J1 aHillege, Hans, L1 aCambien, Francois1 aStott, David, J1 aLowe, Gordon, D1 aSpector, Timothy, D1 aMeigs, James, B1 aMärz, Winfried1 aEriksson, Per1 aBecker, Lewis, C1 aMorange, Pierre-Emmanuel1 aSoranzo, Nicole1 aWilliams, Scott, M1 aHayward, Caroline1 aHarst, Pim1 aHamsten, Anders1 aLowenstein, Charles, J1 aStrachan, David, P1 aO'Donnell, Christopher, J1 aCohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium Neurology Working Group1 aCARDIoGRAM consortium1 aCHARGE Consortium Hemostatic Factor Working Group uhttps://chs-nhlbi.org/node/636704476nas a2201081 4500008004100000022001400041245011400055210006900169260001600238300001100254490000800265520141200273653001901685653001501704653001601719653001501735653001901750653003201769653002201801653001101823653002601834653003601860653002301896653002601919100002501945700002201970700002401992700002502016700002002041700001802061700002302079700002302102700002002125700001702145700001502162700002502177700003002202700001902232700002102251700002002272700002502292700001802317700002202335700001502357700002002372700002102392700001902413700001802432700002602450700001902476700001502495700002002510700002202530700002802552700002202580700001302602700001802615700001702633700002602650700002102676700002102697700002302718700002402741700001902765700002402784700002402808700002102832700001902853700002402872700002502896700002002921700002202941700002102963700001602984700002303000700002003023700002003043700002403063700001703087700001803104700002003122700002003142700001803162700002103180700002103201700002203222700002203244700001903266700002003285700003003305700002303335856003603358 2015 eng d a1528-002000aRare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF.0 aRare and lowfrequency variants and their association with plasma c2015 Sep 10 ae19-290 v1263 aFibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] ≥0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76,000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n = 2) and rare (n = 10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identified new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information for understanding individual variation in hemostasis pathways.
10aCohort Studies10aFactor VII10aFactor VIII10aFibrinogen10aGene Frequency10aGenetic Association Studies10aGenetic Variation10aHumans10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aPotassium Channels10avon Willebrand Factor1 aHuffman, Jennifer, E1 ade Vries, Paul, S1 aMorrison, Alanna, C1 aSabater-Lleal, Maria1 aKacprowski, Tim1 aAuer, Paul, L1 aBrody, Jennifer, A1 aChasman, Daniel, I1 aChen, Ming-Huei1 aGuo, Xiuqing1 aLin, Li-An1 aMarioni, Riccardo, E1 aMüller-Nurasyid, Martina1 aYanek, Lisa, R1 aPankratz, Nathan1 aGrove, Megan, L1 ade Maat, Moniek, P M1 aCushman, Mary1 aWiggins, Kerri, L1 aQi, Lihong1 aSennblad, Bengt1 aHarris, Sarah, E1 aPolasek, Ozren1 aRiess, Helene1 aRivadeneira, Fernando1 aRose, Lynda, M1 aGoel, Anuj1 aTaylor, Kent, D1 aTeumer, Alexander1 aUitterlinden, André, G1 aVaidya, Dhananjay1 aYao, Jie1 aTang, Weihong1 aLevy, Daniel1 aWaldenberger, Melanie1 aBecker, Diane, M1 aFolsom, Aaron, R1 aGiulianini, Franco1 aGreinacher, Andreas1 aHofman, Albert1 aHuang, Chiang-Ching1 aKooperberg, Charles1 aSilveira, Angela1 aStarr, John, M1 aStrauch, Konstantin1 aStrawbridge, Rona, J1 aWright, Alan, F1 aMcKnight, Barbara1 aFranco, Oscar, H1 aZakai, Neil1 aMathias, Rasika, A1 aPsaty, Bruce, M1 aRidker, Paul, M1 aTofler, Geoffrey, H1 aVölker, Uwe1 aWatkins, Hugh1 aFornage, Myriam1 aHamsten, Anders1 aDeary, Ian, J1 aBoerwinkle, Eric1 aKoenig, Wolfgang1 aRotter, Jerome, I1 aHayward, Caroline1 aDehghan, Abbas1 aReiner, Alex, P1 aO'Donnell, Christopher, J1 aSmith, Nicholas, L uhttps://chs-nhlbi.org/node/678804860nas a2201081 4500008004100000022001400041245007600055210006900131260001600200300001200216490000800228520186200236653000902098653001902107653001602126653002802142653002002170653002402190653002202214653003402236653001102270653003702281653001602318653002602334653002802360653001702388100002402405700001902429700002002448700002002468700001702488700002302505700002502528700002202553700001902575700002002594700002202614700001702636700001902653700002202672700002102694700001702715700002202732700001802754700002402772700001602796700002602812700002802838700002402866700002102890700002002911700001202931700002202943700001902965700002002984700002203004700002403026700001403050700002303064700001803087700002303105700001903128700002003147700001603167700001903183700002203202700002303224700002003247700002003267700002003287700002303307700002203330700001903352700001703371700001803388700001903406700002603425700001703451700002003468700002903488700002203517700002303539700002103562700001803583700002603601700002103627700001803648700001903666700001703685700002003702710002003722856003603742 2017 eng d a1537-660500aDNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.0 aDNA Methylation Analysis Identifies Loci for Blood Pressure Regu c2017 Dec 07 a888-9020 v1013 aGenome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.
10aAged10aBlood Pressure10aCpG Islands10aCross-Sectional Studies10aDNA Methylation10aEpigenesis, Genetic10aGenetic Variation10aGenome-Wide Association Study10aHumans10aMendelian Randomization Analysis10aMiddle Aged10aNerve Tissue Proteins10aQuantitative Trait Loci10aTetraspanins1 aRichard, Melissa, A1 aHuan, Tianxiao1 aLigthart, Symen1 aGondalia, Rahul1 aJhun, Min, A1 aBrody, Jennifer, A1 aIrvin, Marguerite, R1 aMarioni, Riccardo1 aShen, Jincheng1 aTsai, Pei-Chien1 aMontasser, May, E1 aJia, Yucheng1 aSyme, Catriona1 aSalfati, Elias, L1 aBoerwinkle, Eric1 aGuan, Weihua1 aMosley, Thomas, H1 aBressler, Jan1 aMorrison, Alanna, C1 aLiu, Chunyu1 aMendelson, Michael, M1 aUitterlinden, André, G1 avan Meurs, Joyce, B1 aFranco, Oscar, H1 aZhang, Guosheng1 aLi, Yun1 aStewart, James, D1 aBis, Joshua, C1 aPsaty, Bruce, M1 aChen, Yii-Der Ida1 aKardia, Sharon, L R1 aZhao, Wei1 aTurner, Stephen, T1 aAbsher, Devin1 aAslibekyan, Stella1 aStarr, John, M1 aMcRae, Allan, F1 aHou, Lifang1 aJust, Allan, C1 aSchwartz, Joel, D1 aVokonas, Pantel, S1 aMenni, Cristina1 aSpector, Tim, D1 aShuldiner, Alan1 aDamcott, Coleen, M1 aRotter, Jerome, I1 aPalmas, Walter1 aLiu, Yongmei1 aPaus, Tomáš1 aHorvath, Steve1 aO'Connell, Jeffrey, R1 aGuo, Xiuqing1 aPausova, Zdenka1 aAssimes, Themistocles, L1 aSotoodehnia, Nona1 aSmith, Jennifer, A1 aArnett, Donna, K1 aDeary, Ian, J1 aBaccarelli, Andrea, A1 aBell, Jordana, T1 aWhitsel, Eric1 aDehghan, Abbas1 aLevy, Daniel1 aFornage, Myriam1 aBIOS Consortium uhttps://chs-nhlbi.org/node/758304619nas a2201021 4500008004100000022001400041245012900055210006900184260001200253300001300265490000700278520172700285653001502012653001002027653000902037653002202046653003802068653002602106653003402132653001102166653002902177653002202206653003402228653001502262653001102277653001202288653004202300653000902342653001602351653002602367653005002393653001102443653001902454653003602473653002802509653002602537653001002563653002602573653001602599100001902615700001402634700002302648700001502671700002502686700001802711700002202729700002302751700001702774700002402791700002102815700002802836700002002864700002202884700002402906700002202930700001902952700002202971700001502993700002003008700001303028700002203041700002103063700001903084700002203103700002203125700002103147700001403168700001903182700001703201700002003218700002503238700001703263700002003280700002003300700002003320700002003340700002203360700002003382700002303402700002103425700002303446700002103469700001803490700001803508700001603526700001903542856003603561 2019 eng d a1553-740400aAssociations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep.0 aAssociations of variants In the hexokinase 1 and interleukin 18 c2019 04 ae10077390 v153 aSleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10(-6) were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10(-8)). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aCell Adhesion Molecules, Neuronal10aComputational Biology10aExtracellular Matrix Proteins10aFemale10aGene Regulatory Networks10aGenetic Variation10aGenome-Wide Association Study10aHexokinase10aHumans10aHypoxia10aInterleukin-18 Receptor alpha Subunit10aMale10aMiddle Aged10aNerve Tissue Proteins10aNLR Family, Pyrin Domain-Containing 3 Protein10aOxygen10aOxyhemoglobins10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aSerine Endopeptidases10aSleep10aSleep Apnea Syndromes10aYoung Adult1 aCade, Brian, E1 aChen, Han1 aStilp, Adrienne, M1 aLouie, Tin1 aAncoli-Israel, Sonia1 aArens, Raanan1 aBarfield, Richard1 aBelow, Jennifer, E1 aCai, Jianwen1 aConomos, Matthew, P1 aEvans, Daniel, S1 aFrazier-Wood, Alexis, C1 aGharib, Sina, A1 aGleason, Kevin, J1 aGottlieb, Daniel, J1 aHillman, David, R1 aJohnson, Craig1 aLederer, David, J1 aLee, Jiwon1 aLoredo, Jose, S1 aMei, Hao1 aMukherjee, Sutapa1 aPatel, Sanjay, R1 aPost, Wendy, S1 aPurcell, Shaun, M1 aRamos, Alberto, R1 aReid, Kathryn, J1 aRice, Ken1 aShah, Neomi, A1 aSofer, Tamar1 aTaylor, Kent, D1 aThornton, Timothy, A1 aWang, Heming1 aYaffe, Kristine1 aZee, Phyllis, C1 aHanis, Craig, L1 aPalmer, Lyle, J1 aRotter, Jerome, I1 aStone, Katie, L1 aTranah, Gregory, J1 aWilson, James, G1 aSunyaev, Shamil, R1 aLaurie, Cathy, C1 aZhu, Xiaofeng1 aSaxena, Richa1 aLin, Xihong1 aRedline, Susan uhttps://chs-nhlbi.org/node/804410097nas 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/797605141nas 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2022 eng d a2399-364200aWhole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program.0 aWhole genome sequence association analysis of fasting glucose an c2022 07 28 a7560 v53 aThe genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.
10aDiabetes Mellitus, Type 210aFasting10aGlucose10aHumans10aInsulin10aNational Heart, Lung, and Blood Institute (U.S.)10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aPrecision Medicine10aReceptors, Immunologic10aUnited States1 aDiCorpo, Daniel1 aGaynor, Sheila, M1 aRussell, Emily, M1 aWesterman, Kenneth, E1 aRaffield, Laura, M1 aMajarian, Timothy, D1 aWu, Peitao1 aSarnowski, Chloe1 aHighland, Heather, M1 aJackson, Anne1 aHasbani, Natalie, R1 ade Vries, Paul, S1 aBrody, Jennifer, A1 aHidalgo, Bertha1 aGuo, Xiuqing1 aPerry, James, A1 aO'Connell, Jeffrey, R1 aLent, Samantha1 aMontasser, May, E1 aCade, Brian, E1 aJain, Deepti1 aWang, Heming1 aAlbanus, Ricardo, D'Oliveira1 aVarshney, Arushi1 aYanek, Lisa, R1 aLange, Leslie1 aPalmer, Nicholette, D1 aAlmeida, Marcio1 aPeralta, Juan, M1 aAslibekyan, Stella1 aBaldridge, Abigail, S1 aBertoni, Alain, G1 aBielak, Lawrence, F1 aChen, Chung-Shiuan1 aChen, Yii-Der Ida1 aChoi, Won, Jung1 aGoodarzi, Mark, O1 aFloyd, James, S1 aIrvin, Marguerite, R1 aKalyani, Rita, R1 aKelly, Tanika, N1 aLee, Seonwook1 aLiu, Ching-Ti1 aLoesch, Douglas1 aManson, JoAnn, E1 aMinster, Ryan, L1 aNaseri, Take1 aPankow, James, S1 aRasmussen-Torvik, Laura, J1 aReiner, Alexander, P1 aReupena, Muagututi'a, Sefuiva1 aSelvin, Elizabeth1 aSmith, Jennifer, A1 aWeeks, Daniel, E1 aXu, Huichun1 aYao, Jie1 aZhao, Wei1 aParker, Stephen1 aAlonso, Alvaro1 aArnett, Donna, K1 aBlangero, John1 aBoerwinkle, Eric1 aCorrea, Adolfo1 aCupples, Adrienne, L1 aCurran, Joanne, E1 aDuggirala, Ravindranath1 aHe, Jiang1 aHeckbert, Susan, R1 aKardia, Sharon, L R1 aKim, Ryan, W1 aKooperberg, Charles1 aLiu, Simin1 aMathias, Rasika, A1 aMcGarvey, Stephen, T1 aMitchell, Braxton, D1 aMorrison, Alanna, C1 aPeyser, Patricia, A1 aPsaty, Bruce, M1 aRedline, Susan1 aShuldiner, Alan, R1 aTaylor, Kent, D1 aVasan, Ramachandran, S1 aViaud-Martinez, Karine, A1 aFlorez, Jose, C1 aWilson, James, G1 aSladek, Robert1 aRich, Stephen, S1 aRotter, Jerome, I1 aLin, Xihong1 aDupuis, Josée1 aMeigs, James, B1 aWessel, Jennifer1 aManning, Alisa, K uhttps://chs-nhlbi.org/node/9158