03424nas a2200589 4500008004100000022001400041245010200055210006900157260001600226300001100242490000800253520173500261653001901996653003402015653001302049653001102062653001502073653003602088653002102124653001302145653003002158100001702188700002402205700002002229700002102249700002002270700001402290700001902304700002802323700001602351700002302367700002402390700002802414700002102442700002202463700001602485700002002501700002402521700002102545700002702566700002502593700002202618700001602640700001802656700002102674700002102695700002002716700002002736700002402756700001802780856003602798 2010 eng d a1091-649000aGenome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology.0 aGenomewide association identifies OBFC1 as a locus involved in h c2010 May 18 a9293-80 v1073 a
Telomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies (n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/oligosaccharide-binding folds containing one gene (OBFC1; rs4387287; P = 3.9 x 10(-9)) and chemokine (C-X-C motif) receptor 4 gene (CXCR4; rs4452212; P = 2.9 x 10(-8)) were associated with LTL at a genome-wide significance level (P < 5 x 10(-8)). We attempted replication of the top SNPs at these loci through de novo genotyping of 1,893 additional individuals and in silico lookup in another observational study (n = 2,876), and we confirmed the association findings for OBFC1 but not CXCR4. In addition, we confirmed the telomerase RNA component (TERC) as a gene associated with LTL (P = 1.1 x 10(-5)). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into aging-related disorders linked to altered LTL dynamics.
10aCohort Studies10aGenome-Wide Association Study10aGenotype10aHumans10aLeukocytes10aPolymorphism, Single Nucleotide10aReceptors, CXCR410aTelomere10aTelomere-Binding Proteins1 aLevy, Daniel1 aNeuhausen, Susan, L1 aHunt, Steven, C1 aKimura, Masayuki1 aHwang, Shih-Jen1 aChen, Wei1 aBis, Joshua, C1 aFitzpatrick, Annette, L1 aSmith, Erin1 aJohnson, Andrew, D1 aGardner, Jeffrey, P1 aSrinivasan, Sathanur, R1 aSchork, Nicholas1 aRotter, Jerome, I1 aHerbig, Utz1 aPsaty, Bruce, M1 aSastrasinh, Malinee1 aMurray, Sarah, S1 aVasan, Ramachandran, S1 aProvince, Michael, A1 aGlazer, Nicole, L1 aLu, Xiaobin1 aCao, Xiaojian1 aKronmal, Richard1 aMangino, Massimo1 aSoranzo, Nicole1 aSpector, Tim, D1 aBerenson, Gerald, S1 aAviv, Abraham uhttps://chs-nhlbi.org/node/119203248nas a2200673 4500008004100000022001400041245010800055210006900163260001600232300001200248490000700260520130900267653003401576653001101610653003901621653001301660653002501673653003001698100002101728700002001749700002401769700002001793700002101813700002801834700002301862700001901885700002101904700001901925700001401944700002801958700002001986700002202006700002202028700002702050700002302077700002402100700001902124700001802143700002002161700002102181700002102202700002502223700002102248700002202269700001702291700001902308700002002327700002102347700001402368700002002382700001902402700002202421700002002443700001602463700002402479700001702503700001802520856003602538 2012 eng d a1460-208300aGenome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans.0 aGenomewide metaanalysis points to CTC1 and ZNF676 as genes regul c2012 Dec 15 a5385-940 v213 aLeukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 × 10(-11)) and with the telomerase RNA component TERC (rs1317082, P = 1.1 × 10(-8)). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 × 10(-8)) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 × 10(-8)) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.
10aGenome-Wide Association Study10aHumans10aKruppel-Like Transcription Factors10aTelomere10aTelomere Homeostasis10aTelomere-Binding Proteins1 aMangino, Massimo1 aHwang, Shih-Jen1 aSpector, Timothy, D1 aHunt, Steven, C1 aKimura, Masayuki1 aFitzpatrick, Annette, L1 aChristiansen, Lene1 aPetersen, Inge1 aElbers, Clara, C1 aHarris, Tamara1 aChen, Wei1 aSrinivasan, Sathanur, R1 aKark, Jeremy, D1 aBenetos, Athanase1 aShamieh, Said, El1 aVisvikis-Siest, Sophie1 aChristensen, Kaare1 aBerenson, Gerald, S1 aValdes, Ana, M1 aViñuela, Ana1 aGarcia, Melissa1 aArnett, Donna, K1 aBroeckel, Ulrich1 aProvince, Michael, A1 aPankow, James, S1 aKammerer, Candace1 aLiu, Yongmei1 aNalls, Michael1 aTishkoff, Sarah1 aThomas, Fridtjof1 aZiv, Elad1 aPsaty, Bruce, M1 aBis, Joshua, C1 aRotter, Jerome, I1 aTaylor, Kent, D1 aSmith, Erin1 aSchork, Nicholas, J1 aLevy, Daniel1 aAviv, Abraham uhttps://chs-nhlbi.org/node/609004494nas a2200925 4500008004100000022001400041245008800055210006900143260001300212300001100225490000600236520191100242653001002153653002202163653000902185653002402194653004002218653001102258653002702269653002202296653001802318653003402336653001102370653000902381653001602390653003602406100001802442700002202460700002102482700002202503700001702525700001902542700002002561700002002581700001702601700002002618700001802638700002202656700002202678700002402700700002402724700001202748700002402760700002202784700001402806700001902820700001602839700001902855700002202874700001702896700002002913700002402933700001902957700002502976700002103001700002403022700002503046700002003071700002403091700002203115700002803137700001903165700002003184700001903204700002003223700001903243700002303262700002203285700002103307700002003328700001903348700002203367700001803389700002203407700002303429700002103452700002903473710003003502856003603532 2012 eng d a1942-326800aImpact of ancestry and common genetic variants on QT interval in African Americans.0 aImpact of ancestry and common genetic variants on QT interval in c2012 Dec a647-550 v53 aBACKGROUND: Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval.
METHODS AND RESULTS: First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12,097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13,105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5 × 10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2 × 10(-15)) and ATP1B1 (rs1320976, P=2 × 10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values (P<10(-5)) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF, and PLN.
CONCLUSIONS: We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of African ancestry.
10aAdult10aAfrican Americans10aAged10aElectrocardiography10aEuropean Continental Ancestry Group10aFemale10aGenealogy and Heraldry10aGenetic Variation10aGenome, Human10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide1 aSmith, Gustav1 aAvery, Christy, L1 aEvans, Daniel, S1 aNalls, Michael, A1 aMeng, Yan, A1 aSmith, Erin, N1 aPalmer, Cameron1 aTanaka, Toshiko1 aMehra, Reena1 aButler, Anne, M1 aYoung, Taylor1 aBuxbaum, Sarah, G1 aKerr, Kathleen, F1 aBerenson, Gerald, S1 aSchnabel, Renate, B1 aLi, Guo1 aEllinor, Patrick, T1 aMagnani, Jared, W1 aChen, Wei1 aBis, Joshua, C1 aCurb, David1 aHsueh, Wen-Chi1 aRotter, Jerome, I1 aLiu, Yongmei1 aNewman, Anne, B1 aLimacher, Marian, C1 aNorth, Kari, E1 aReiner, Alexander, P1 aQuibrera, Miguel1 aSchork, Nicholas, J1 aSingleton, Andrew, B1 aPsaty, Bruce, M1 aSoliman, Elsayed, Z1 aSolomon, Allen, J1 aSrinivasan, Sathanur, R1 aAlonso, Alvaro1 aWallace, Robert1 aRedline, Susan1 aZhang, Zhu-Ming1 aPost, Wendy, S1 aZonderman, Alan, B1 aTaylor, Herman, A1 aMurray, Sarah, S1 aFerrucci, Luigi1 aArking, Dan, E1 aEvans, Michele, K1 aFox, Ervin, R1 aSotoodehnia, Nona1 aHeckbert, Susan, R1 aWhitsel, Eric, A1 aNewton-Cheh, Christopher1 aCARe and COGENT consortia uhttps://chs-nhlbi.org/node/617904310nas a2200901 4500008004100000022001400041245011000055210006900165260001300234300001100247490000600258520179200264653001002056653002202066653001902088653002402107653001102131653001702142653003402159653001102193653000902204653002702213653001602240653003602256100002002292700001702312700002102329700002202350700001902372700002002391700001202411700002202423700002102445700001902466700001902485700002402504700002402528700001702552700001402569700001502583700002402598700002302622700001902645700001902664700002402683700002202707700001202729700002402741700001702765700002202782700002602804700001702830700001702847700002002864700002902884700001902913700002302932700002002955700002102975700001902996700002003015700002203035700002403057700002403081700002503105700001803130700002403148700002803172700002003200700002303220700002003243700002103263700002203284700002203306700002203328700002203350856003603372 2012 eng d a1942-326800aNovel loci associated with PR interval in a genome-wide association study of 10 African American cohorts.0 aNovel loci associated with PR interval in a genomewide associati c2012 Dec a639-460 v53 aBACKGROUND: The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans.
METHODS AND RESULTS: We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 × 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 × 10(-8)).
CONCLUSIONS: This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.
10aAdult10aAfrican Americans10aCohort Studies10aElectrocardiography10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aMiddle Aged10aPolymorphism, Single Nucleotide1 aButler, Anne, M1 aYin, Xiaoyan1 aEvans, Daniel, S1 aNalls, Michael, A1 aSmith, Erin, N1 aTanaka, Toshiko1 aLi, Guo1 aBuxbaum, Sarah, G1 aWhitsel, Eric, A1 aAlonso, Alvaro1 aArking, Dan, E1 aBenjamin, Emelia, J1 aBerenson, Gerald, S1 aBis, Josh, C1 aChen, Wei1 aDeo, Rajat1 aEllinor, Patrick, T1 aHeckbert, Susan, R1 aHeiss, Gerardo1 aHsueh, Wen-Chi1 aKeating, Brendan, J1 aKerr, Kathleen, F1 aLi, Yun1 aLimacher, Marian, C1 aLiu, Yongmei1 aLubitz, Steven, A1 aMarciante, Kristin, D1 aMehra, Reena1 aMeng, Yan, A1 aNewman, Anne, B1 aNewton-Cheh, Christopher1 aNorth, Kari, E1 aPalmer, Cameron, D1 aPsaty, Bruce, M1 aQuibrera, Miguel1 aRedline, Susan1 aReiner, Alex, P1 aRotter, Jerome, I1 aSchnabel, Renate, B1 aSchork, Nicholas, J1 aSingleton, Andrew, B1 aSmith, Gustav1 aSoliman, Elsayed, Z1 aSrinivasan, Sathanur, R1 aZhang, Zhu-Ming1 aZonderman, Alan, B1 aFerrucci, Luigi1 aMurray, Sarah, S1 aEvans, Michele, K1 aSotoodehnia, Nona1 aMagnani, Jared, W1 aAvery, Christy, L uhttps://chs-nhlbi.org/node/608404052nas a2200913 4500008004100000022001400041245006900055210006600124260001300190300001000203490000700213520168500220653001001905653000901915653002201924653001001946653001101956653001101967653000901978653001601987653001602003653001302019100002102032700001602053700001702069700001902086700001902105700002102124700002402145700001702169700002202186700002702208700001902235700002002254700002602274700001402300700001802314700002302332700001802355700001502373700001502388700002002403700002502423700001702448700002902465700001802494700002002512700001802532700001902550700001902569700002102588700002002609700001802629700001802647700002102665700001902686700001902705700002402724700002302748700001202771700001902783700002002802700001602822700002102838700001702859700001702876700001602893700001502909700001402924700001502938700002802953700002002981700001603001700001503017700002603032700002103058710002303079856003603102 2014 eng d a1873-681500aGender and telomere length: systematic review and meta-analysis.0 aGender and telomere length systematic review and metaanalysis c2014 Mar a15-270 v513 aBACKGROUND: It is widely believed that females have longer telomeres than males, although results from studies have been contradictory.
METHODS: We carried out a systematic review and meta-analyses to test the hypothesis that in humans, females have longer telomeres than males and that this association becomes stronger with increasing age. Searches were conducted in EMBASE and MEDLINE (by November 2009) and additional datasets were obtained from study investigators. Eligible observational studies measured telomeres for both females and males of any age, had a minimum sample size of 100 and included participants not part of a diseased group. We calculated summary estimates using random-effects meta-analyses. Heterogeneity between studies was investigated using sub-group analysis and meta-regression.
RESULTS: Meta-analyses from 36 cohorts (36,230 participants) showed that on average females had longer telomeres than males (standardised difference in telomere length between females and males 0.090, 95% CI 0.015, 0.166; age-adjusted). There was little evidence that these associations varied by age group (p=1.00) or cell type (p=0.29). However, the size of this difference did vary by measurement methods, with only Southern blot but neither real-time PCR nor Flow-FISH showing a significant difference. This difference was not associated with random measurement error.
CONCLUSIONS: Telomere length is longer in females than males, although this difference was not universally found in studies that did not use Southern blot methods. Further research on explanations for the methodological differences is required.
10aAdult10aAged10aAged, 80 and over10aAging10aFemale10aHumans10aMale10aMiddle Aged10aSex Factors10aTelomere1 aGardner, Michael1 aBann, David1 aWiley, Laura1 aCooper, Rachel1 aHardy, Rebecca1 aNitsch, Dorothea1 aMartin-Ruiz, Carmen1 aShiels, Paul1 aSayer, Avan Aihie1 aBarbieri, Michelangela1 aBekaert, Sofie1 aBischoff, Claus1 aBrooks-Wilson, Angela1 aChen, Wei1 aCooper, Cyrus1 aChristensen, Kaare1 aDe Meyer, Tim1 aDeary, Ian1 aDer, Geoff1 aRoux, Ana, Diez1 aFitzpatrick, Annette1 aHajat, Anjum1 aHalaschek-Wiener, Julius1 aHarris, Sarah1 aHunt, Steven, C1 aJagger, Carol1 aJeon, Hyo-Sung1 aKaplan, Robert1 aKimura, Masayuki1 aLansdorp, Peter1 aLi, Changyong1 aMaeda, Toyoki1 aMangino, Massimo1 aNawrot, Tim, S1 aNilsson, Peter1 aNordfjall, Katarina1 aPaolisso, Giuseppe1 aRen, Fu1 aRiabowol, Karl1 aRobertson, Tony1 aRoos, Goran1 aStaessen, Jan, A1 aSpector, Tim1 aTang, Nelson1 aUnryn, Brad1 aHarst, Pim1 aWoo, Jean1 aXing, Chao1 aYadegarfar, Mohammad, E1 aPark, Jae, Yong1 aYoung, Neal1 aKuh, Diana1 avon Zglinicki, Thomas1 aBen-Shlomo, Yoav1 aHalcyon study team uhttps://chs-nhlbi.org/node/624605300nas a2201225 4500008004100000022001400041245016600055210006900221260001600290300001300306490000700319520181200326653001402138653001002152653000902162653002202171653002002193653004002213653001102253653003402264653001102298653000902309653001602318653002402334653002002358653001602378100002202394700001502416700002502431700002302456700002102479700002602500700002502526700002102551700001802572700002302590700002402613700002302637700001902660700001602679700001402695700002902709700001802738700002202756700001402778700002002792700002302812700001802835700002402853700002302877700001902900700003102919700002702950700002602977700001803003700001603021700002003037700002203057700001803079700001603097700001903113700002103132700002103153700002903174700002003203700002103223700002403244700002203268700001503290700002203305700002303327700001803350700002203368700002003390700002103410700002403431700002203455700001903477700002503496700002103521700002103542700002503563700001903588700002103607700002203628700002403650700002203674700001903696700002303715700002103738700002003759700001703779700002203796700002103818700002303839700002103862700001903883700002003902700002103922700002003943710003003963710002103993710002404014856003604038 2014 eng d a1460-208300aGene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations.0 aGenecentric metaanalyses for central adiposity traits in up to 5 c2014 May 01 a2498-5100 v233 aWaist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.
10aAdiposity10aAdult10aAged10aAged, 80 and over10aBody Mass Index10aEuropean Continental Ancestry Group10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aWaist Circumference10aWaist-Hip Ratio10aYoung Adult1 aYoneyama, Sachiko1 aGuo, Yiran1 aLanktree, Matthew, B1 aBarnes, Michael, R1 aElbers, Clara, C1 aKarczewski, Konrad, J1 aPadmanabhan, Sandosh1 aBauer, Florianne1 aBaumert, Jens1 aBeitelshees, Amber1 aBerenson, Gerald, S1 aBoer, Jolanda, M A1 aBurke, Gregory1 aCade, Brian1 aChen, Wei1 aCooper-Dehoff, Rhonda, M1 aGaunt, Tom, R1 aGieger, Christian1 aGong, Yan1 aGorski, Mathias1 aHeard-Costa, Nancy1 aJohnson, Toby1 aLamonte, Michael, J1 aMcDonough, Caitrin1 aMonda, Keri, L1 aOnland-Moret, Charlotte, N1 aNelson, Christopher, P1 aO'Connell, Jeffrey, R1 aOrdovas, Jose1 aPeter, Inga1 aPeters, Annette1 aShaffer, Jonathan1 aShen, Haiqinq1 aSmith, Erin1 aSpeilotes, Liz1 aThomas, Fridtjof1 aThorand, Barbara1 aVerschuren, W, M Monique1 aAnand, Sonia, S1 aDominiczak, Anna1 aDavidson, Karina, W1 aHegele, Robert, A1 aHeid, Iris1 aHofker, Marten, H1 aHuggins, Gordon, S1 aIllig, Thomas1 aJohnson, Julie, A1 aKirkland, Susan1 aKönig, Wolfgang1 aLangaee, Taimour, Y1 aMcCaffery, Jeanne1 aMelander, Olle1 aMitchell, Braxton, D1 aMunroe, Patricia1 aMurray, Sarah, S1 aPapanicolaou, George1 aRedline, Susan1 aReilly, Muredach1 aSamani, Nilesh, J1 aSchork, Nicholas, J1 aSchouw, Yvonne, T1 aShimbo, Daichi1 aShuldiner, Alan, R1 aTobin, Martin, D1 aWijmenga, Cisca1 aYusuf, Salim1 aHakonarson, Hakon1 aLange, Leslie, A1 aDemerath, Ellen, W1 aFox, Caroline, S1 aNorth, Kari, E1 aReiner, Alex, P1 aKeating, Brendan1 aTaylor, Kira, C1 aLook AHEAD Research Group1 aGIANT Consortium1 aCARe IBC Consortium uhttps://chs-nhlbi.org/node/636803409nas a2200625 4500008004100000022001400041245006700055210006500122260001300187300001100200490000700211520169000218653001201908653002101920653003101941653003401972653001102006653001502017653001302032653001702045653001302062653002502075100002102100700002302121700001702144700002002161700001802181700002402199700002102223700001902244700002002263700001602283700002002299700002202319700001702341700002002358700002102378700002302399700001902422700002002441700001702461700002402478700002802502700001402530700002402544700002202568700002402590700002002614700002402634700002302658700002402681700002402705700001802729856003602747 2015 eng d a1468-624400aDCAF4, a novel gene associated with leucocyte telomere length.0 aDCAF4 a novel gene associated with leucocyte telomere length c2015 Mar a157-620 v523 aBACKGROUND: Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR).
RESULTS: Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4×10(-10)) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1×10(-3) and 2×10(-3), respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97×10(-169) to 3.42×10(-24).
CONCLUSIONS: We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.
10aAlleles10aCarrier Proteins10aGene Expression Regulation10aGenome-Wide Association Study10aHumans10aLeukocytes10aMelanoma10aRisk Factors10aTelomere10aTelomere Homeostasis1 aMangino, Massimo1 aChristiansen, Lene1 aStone, Rivka1 aHunt, Steven, C1 aHorvath, Kent1 aEisenberg, Dan, T A1 aKimura, Masayuki1 aPetersen, Inge1 aKark, Jeremy, D1 aHerbig, Utz1 aReiner, Alex, P1 aBenetos, Athanase1 aCodd, Veryan1 aNyholt, Dale, R1 aSinnreich, Ronit1 aChristensen, Kaare1 aNassar, Hisham1 aHwang, Shih-Jen1 aLevy, Daniel1 aBataille, Veronique1 aFitzpatrick, Annette, L1 aChen, Wei1 aBerenson, Gerald, S1 aSamani, Nilesh, J1 aMartin, Nicholas, G1 aTishkoff, Sarah1 aSchork, Nicholas, J1 aKyvik, Kirsten Ohm1 aDalgård, Christine1 aSpector, Timothy, D1 aAviv, Abraham uhttps://chs-nhlbi.org/node/681704382nas a2200853 4500008004100000022001400041245015400055210006900209260001600278520191500294100002102209700002202230700001902252700001202271700001802283700001902301700002002320700002002340700002202360700001902382700001902401700002402420700001902444700001902463700001902482700001402501700001902515700002402534700001502558700002202573700001802595700002302613700001902636700002302655700001902678700001802697700002002715700002202735700001502757700001702772700002002789700002202809700002102831700001702852700001702869700002302886700002902909700001902938700002002957700001902977700002202996700002403018700002403042700002103066700002503087700002303112700002403135700002803159700002203187700002603209700002103235700001803256700002003274700002303294700002203317700002003339700002103359700002303380700002103403700002003424700002203444710002603466856003603492 2016 eng d a1460-208300aFine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans.0 aFinemapping novel loci identification and SNP association transf c2016 Aug 293 aThe electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 × 10(-14)) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 × 10(-4)). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 × 10(-8)) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10(-9)). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 × 10(-7)), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.
1 aEvans, Daniel, S1 aAvery, Christy, L1 aNalls, Mike, A1 aLi, Guo1 aBarnard, John1 aSmith, Erin, N1 aTanaka, Toshiko1 aButler, Anne, M1 aBuxbaum, Sarah, G1 aAlonso, Alvaro1 aArking, Dan, E1 aBerenson, Gerald, S1 aBis, Joshua, C1 aBuyske, Steven1 aCarty, Cara, L1 aChen, Wei1 aChung, Mina, K1 aCummings, Steven, R1 aDeo, Rajat1 aEaton, Charles, B1 aFox, Ervin, R1 aHeckbert, Susan, R1 aHeiss, Gerardo1 aHindorff, Lucia, A1 aHsueh, Wen-Chi1 aIsaacs, Aaron1 aJamshidi, Yalda1 aKerr, Kathleen, F1 aLiu, Felix1 aLiu, Yongmei1 aLohman, Kurt, K1 aMagnani, Jared, W1 aMaher, Joseph, F1 aMehra, Reena1 aMeng, Yan, A1 aMusani, Solomon, K1 aNewton-Cheh, Christopher1 aNorth, Kari, E1 aPsaty, Bruce, M1 aRedline, Susan1 aRotter, Jerome, I1 aSchnabel, Renate, B1 aSchork, Nicholas, J1 aShohet, Ralph, V1 aSingleton, Andrew, B1 aSmith, Jonathan, D1 aSoliman, Elsayed, Z1 aSrinivasan, Sathanur, R1 aTaylor, Herman, A1 aVan Wagoner, David, R1 aWilson, James, G1 aYoung, Taylor1 aZhang, Zhu-Ming1 aZonderman, Alan, B1 aEvans, Michele, K1 aFerrucci, Luigi1 aMurray, Sarah, S1 aTranah, Gregory, J1 aWhitsel, Eric, A1 aReiner, Alex, P1 aSotoodehnia, Nona1 aCHARGE QRS Consortium uhttps://chs-nhlbi.org/node/725902054nas a2200481 4500008004100000022001400041245005600055210005500111260001300166300001400179490000600193520069800199100002300897700002000920700002000940700002300960700002600983700002401009700002301033700002301056700002101079700002401100700001901124700002101143700002201164700001801186700002101204700002001225700001701245700002001262700002801282700001401310700002401324700002701348700002301375700002501398700002201423700002301445700002401468700002601492700001801518856003601536 2017 eng d a1945-458900aTelomeres and the natural lifespan limit in humans.0 aTelomeres and the natural lifespan limit in humans c2017 Apr a1130-11420 v93 aAn ongoing debate in demography has focused on whether the human lifespan has a maximal natural limit. Taking a mechanistic perspective, and knowing that short telomeres are associated with diminished longevity, we examined whether telomere length dynamics during adult life could set a maximal natural lifespan limit. We define leukocyte telomere length of 5 kb as the 'telomeric brink', which denotes a high risk of imminent death. We show that a subset of adults may reach the telomeric brink within the current life expectancy and more so for a 100-year life expectancy. Thus, secular trends in life expectancy should confront a biological limit due to crossing the telomeric brink.
1 aSteenstrup, Troels1 aKark, Jeremy, D1 aVerhulst, Simon1 aThinggaard, Mikael1 aHjelmborg, Jacob, V B1 aDalgård, Christine1 aKyvik, Kirsten Ohm1 aChristiansen, Lene1 aMangino, Massimo1 aSpector, Timothy, D1 aPetersen, Inge1 aKimura, Masayuki1 aBenetos, Athanase1 aLabat, Carlos1 aSinnreich, Ronit1 aHwang, Shih-Jen1 aLevy, Daniel1 aHunt, Steven, C1 aFitzpatrick, Annette, L1 aChen, Wei1 aBerenson, Gerald, S1 aBarbieri, Michelangela1 aPaolisso, Giuseppe1 aGadalla, Shahinaz, M1 aSavage, Sharon, A1 aChristensen, Kaare1 aYashin, Anatoliy, I1 aArbeev, Konstantin, G1 aAviv, Abraham uhttps://chs-nhlbi.org/node/7591