04142nas a2200757 4500008004100000022001400041245008700055210006900142260001300211300001100224490000600235520194100241653002202182653002102204653002102225653001902246653002302265653004002288653003202328653001302360653001102373653001402384653001902398653003602417653002002453653001802473100002002491700002202511700001802533700002302551700002602574700002202600700002402622700001602646700002002662700001802682700002102700700001902721700002202740700002402762700002502786700002002811700001802831700002302849700002402872700002902896700002302925700002002948700002802968700002102996700002003017700002103037700001903058700002103077700002203098700002203120700002203142700002703164700002103191700002203212700002403234700002103258700002303279710004603302856003603348 2010 eng d a1942-326800aCandidate gene association resource (CARe): design, methods, and proof of concept.0 aCandidate gene association resource CARe design methods and proo c2010 Jun a267-750 v33 a
BACKGROUND: The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40,000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans.
METHODS AND RESULTS: CARe has assembled DNA samples for >40,000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups.
CONCLUSIONS: The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of approximately 2000 biological candidate loci in all participants and genome-wide association study in approximately 8000 African American participants. CARe will serve as a valuable resource for the scientific community.
10aAfrican Americans10aCholesterol, HDL10aCholesterol, LDL10aCohort Studies10aDatabases, Genetic10aEuropean Continental Ancestry Group10aGenetic Association Studies10aGenotype10aHumans10aPhenotype10aPilot Projects10aPolymorphism, Single Nucleotide10aResearch Design10aTriglycerides1 aMusunuru, Kiran1 aLettre, Guillaume1 aYoung, Taylor1 aFarlow, Deborah, N1 aPirruccello, James, P1 aEjebe, Kenechi, G1 aKeating, Brendan, J1 aYang, Qiong1 aChen, Ming-Huei1 aLapchyk, Nina1 aCrenshaw, Andrew1 aZiaugra, Liuda1 aRachupka, Anthony1 aBenjamin, Emelia, J1 aCupples, Adrienne, L1 aFornage, Myriam1 aFox, Ervin, R1 aHeckbert, Susan, R1 aHirschhorn, Joel, N1 aNewton-Cheh, Christopher1 aNizzari, Marcia, M1 aPaltoo, Dina, N1 aPapanicolaou, George, J1 aPatel, Sanjay, R1 aPsaty, Bruce, M1 aRader, Daniel, J1 aRedline, Susan1 aRich, Stephen, S1 aRotter, Jerome, I1 aTaylor, Herman, A1 aTracy, Russell, P1 aVasan, Ramachandran, S1 aWilson, James, G1 aKathiresan, Sekar1 aFabsitz, Richard, R1 aBoerwinkle, Eric1 aGabriel, Stacey, B1 aNHLBI Candidate Gene Association Resource uhttps://chs-nhlbi.org/node/118804248nas a2200877 4500008004100000022001400041245015200055210006900207260001600276300001200292490000700304520170700311653001002018653002202028653000902050653001902059653001902078653001302097653004002110653001102150653001702161653003402178653001302212653001102225653001702236653000902253653001602262653001402278653003602292653001202328100001802340700002102358700001302379700002502392700002402417700002302441700001502464700002402479700001902503700002102522700002702543700002002570700002402590700002102614700002302635700001902658700002302677700002302700700001602723700002102739700002002760700001902780700002202799700002502821700002102846700002202867700002202889700001902911700001702930700002302947700002302970700002302993700001603016700002003032700002203052700002403074700002203098700002303120700002003143700001803163700002603181700001803207700001703225710009203242856003603334 2011 eng d a1460-208300aAssociation of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study.0 aAssociation of genetic variation with systolic and diastolic blo c2011 Jun 01 a2273-840 v203 aThe prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.
10aAdult10aAfrican Americans10aAged10aBlood Pressure10aCohort Studies10aDiastole10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHumans10aHypertension10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aSystole1 aFox, Ervin, R1 aYoung, Hunter, J1 aLi, Yali1 aDreisbach, Albert, W1 aKeating, Brendan, J1 aMusani, Solomon, K1 aLiu, Kiang1 aMorrison, Alanna, C1 aGanesh, Santhi1 aKutlar, Abdullah1 aRamachandran, Vasan, S1 aPolak, Josef, F1 aFabsitz, Richard, R1 aDries, Daniel, L1 aFarlow, Deborah, N1 aRedline, Susan1 aAdeyemo, Adebowale1 aHirschorn, Joel, N1 aSun, Yan, V1 aWyatt, Sharon, B1 aPenman, Alan, D1 aPalmas, Walter1 aRotter, Jerome, I1 aTownsend, Raymond, R1 aDoumatey, Ayo, P1 aTayo, Bamidele, O1 aMosley, Thomas, H1 aLyon, Helen, N1 aKang, Sun, J1 aRotimi, Charles, N1 aCooper, Richard, S1 aFranceschini, Nora1 aCurb, David1 aMartin, Lisa, W1 aEaton, Charles, B1 aKardia, Sharon, L R1 aTaylor, Herman, A1 aCaulfield, Mark, J1 aEhret, Georg, B1 aJohnson, Toby1 aChakravarti, Aravinda1 aZhu, Xiaofeng1 aLevy, Daniel1 aInternational Consortium for Blood Pressure Genome-wide Association Studies (ICBP-GWAS) uhttps://chs-nhlbi.org/node/127303311nas a2200601 4500008004100000022001400041245020900055210006900264260001600333300001100349490000800360520151200368653001001880653002201890653000901912653002801921653001901949653004001968653001102008653001502019653003802034653001502072653001102087653000902098653001602107653001402123653003602137653001702173100002502190700002102215700002402236700002002260700002302280700002002303700001902323700002302342700002002365700001202385700001602397700002302413700001802436700002102454700001902475700002202494700002102516700002202537700002102559700002102580700001702601700003002618700002502648856003602673 2011 eng d a1528-002000aAssociation of genomic loci from a cardiovascular gene SNP array with fibrinogen levels in European Americans and African-Americans from six cohort studies: the Candidate Gene Association Resource (CARe).0 aAssociation of genomic loci from a cardiovascular gene SNP array c2011 Jan 06 a268-750 v1173 aSeveral common genomic loci, involving various immunity- and metabolism-related genes, have been associated with plasma fibrinogen in European Americans (EAs). The genetic determinants of fibrinogen in African Americans (AAs) are poorly characterized. Using a vascular gene-centric array in 23,634 EA and 6657 AA participants from 6 studies comprising the Candidate Gene Association Resource project, we examined the association of 47,539 common and lower frequency variants with fibrinogen concentration. We identified a rare Pro265Leu variant in FGB (rs6054) associated with lower fibrinogen. Common fibrinogen gene single nucleotide polymorphisms (FGB rs1800787 and FGG rs2066861) significantly associated with fibrinogen in EAs were prevalent in AAs and showed consistent associations. Several fibrinogen locus single nucleotide polymorphism associated with lower fibrinogen were exclusive to AAs; these include a newly reported association with FGA rs10050257. For IL6R, IL1RN, and NLRP3 inflammatory gene loci, associations with fibrinogen were concordant between EAs and AAs, but not at other loci (CPS1, PCCB, and SCL22A5-IRF1). The association of FGG rs2066861 with fibrinogen differed according to assay type used to measure fibrinogen. Further characterization of common and lower-frequency genetic variants that contribute to interpopulation differences in fibrinogen phenotype may help refine our understanding of the contribution of hemostasis and inflammation to atherothrombotic risk.
10aAdult10aAfrican Americans10aAged10aCardiovascular Diseases10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aFibrinogen10aGenetic Predisposition to Disease10aHaplotypes10aHumans10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aRisk Factors1 aWassel, Christina, L1 aLange, Leslie, A1 aKeating, Brendan, J1 aTaylor, Kira, C1 aJohnson, Andrew, D1 aPalmer, Cameron1 aHo, Lindsey, A1 aSmith, Nicholas, L1 aLange, Ethan, M1 aLi, Yun1 aYang, Qiong1 aDelaney, Joseph, A1 aTang, Weihong1 aTofler, Geoffrey1 aRedline, Susan1 aTaylor, Herman, A1 aWilson, James, G1 aTracy, Russell, P1 aJacobs, David, R1 aFolsom, Aaron, R1 aGreen, David1 aO'Donnell, Christopher, J1 aReiner, Alexander, P uhttps://chs-nhlbi.org/node/156203101nas a2200493 4500008004100000022001400041245016400055210006900219260001600288300001200304490000700316520162000323653001001943653002201953653000901975653002801984653004002012653001502052653001102067653003802078653001102116653000902127653001602136653003602152100002002188700002102208700002102229700001702250700002402267700001802291700002302309700002302332700001802355700002102373700001902394700001902413700002202432700003002454700002102484700001702505700002402522700002502546856003602571 2011 eng d a1460-208300aA gene-centric association scan for Coagulation Factor VII levels in European and African Americans: the Candidate Gene Association Resource (CARe) Consortium.0 agenecentric association scan for Coagulation Factor VII levels i c2011 Sep 01 a3525-340 v203 aPolymorphisms in several distinct genomic regions, including the F7 gene, were recently associated with factor VII (FVII) levels in European Americans (EAs). The genetic determinants of FVII in African Americans (AAs) are unknown. We used a 50,000 single nucleotide polymorphism (SNP) gene-centric array having dense coverage of over 2,000 candidate genes for cardiovascular disease (CVD) pathways in a community-based sample of 16,324 EA and 3898 AA participants from the Candidate Gene Association Resource (CARe) consortium. Our aim was the discovery of new genomic loci and more detailed characterization of existing loci associated with FVII levels. In EAs, we identified three new loci associated with FVII, of which APOA5 on chromosome 11q23 and HNF4A on chromosome 20q12-13 were replicated in a sample of 4289 participants from the Whitehall II study. We confirmed four previously reported FVII-associated loci (GCKR, MS4A6A, F7 and PROCR) in CARe EA samples. In AAs, the F7 and PROCR regions were significantly associated with FVII. Several of the FVII-associated regions are known to be associated with lipids and other cardiovascular-related traits. At the F7 locus, there was evidence of at least five independently associated SNPs in EAs and three independent signals in AAs. Though the variance in FVII explained by the existing loci is substantial (20% in EA and 10% in AA), larger sample sizes and investigation of lower frequency variants may be required to identify additional FVII-associated loci in EAs and AAs and further clarify the relationship between FVII and other CVD risk factors.
10aAdult10aAfrican Americans10aAged10aCardiovascular Diseases10aEuropean Continental Ancestry Group10aFactor VII10aFemale10aGenetic Predisposition to Disease10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide1 aTaylor, Kira, C1 aLange, Leslie, A1 aZabaneh, Delilah1 aLange, Ethan1 aKeating, Brendan, J1 aTang, Weihong1 aSmith, Nicholas, L1 aDelaney, Joseph, A1 aKumari, Meena1 aHingorani, Aroon1 aNorth, Kari, E1 aKivimaki, Mika1 aTracy, Russell, P1 aO'Donnell, Christopher, J1 aFolsom, Aaron, R1 aGreen, David1 aHumphries, Steve, E1 aReiner, Alexander, P uhttps://chs-nhlbi.org/node/156804310nas 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/608403691nas a2200649 4500008004100000022001400041245014200055210006900197260001300266300001100279490000800290520184900298653001202147653001202159653001602171653002002187653001002207653002302217653000902240653002502249653001102274653002002285653002202305653001802327653001302345653001102358653002502369653000902394653000902403653001302412653001402425653003602439653000902475653001702484653001602501100002802517700001802545700002202563700002102585700002302606700002402629700002202653700001802675700002302693700002002716700002302736700002102759700002202780700002102802700001902823700002802842700002502870700002402895700002402919710006202943856003603005 2012 eng d a1943-263100aUltraconserved elements in the human genome: association and transmission analyses of highly constrained single-nucleotide polymorphisms.0 aUltraconserved elements in the human genome association and tran c2012 Sep a253-660 v1923 aUltraconserved elements in the human genome likely harbor important biological functions as they are dosage sensitive and are able to direct tissue-specific expression. Because they are under purifying selection, variants in these elements may have a lower frequency in the population but a higher likelihood of association with complex traits. We tested a set of highly constrained SNPs (hcSNPs) distributed genome-wide among ultraconserved and nearly ultraconserved elements for association with seven traits related to reproductive (age at natural menopause, number of children, age at first child, and age at last child) and overall [longevity, body mass index (BMI), and height] fitness. Using up to 24,047 European-American samples from the National Heart, Lung, and Blood Institute Candidate Gene Association Resource (CARe), we observed an excess of associations with BMI and height. In an independent replication panel the most strongly associated SNPs showed an 8.4-fold enrichment of associations at the nominal level, including three variants in previously identified loci and one in a locus (DENND1A) previously shown to be associated with polycystic ovary syndrome. Finally, using 1430 family trios, we showed that the transmissions from heterozygous parents to offspring of the derived alleles of rare (frequency ≤ 0.5%) hcSNPs are not biased, particularly after adjusting for the rates of genotype missingness and error in the data. The lack of transmission bias ruled out an immediately and strongly deleterious effect due to the rare derived alleles, consistent with the observation that mice homozygous for the deletion of ultraconserved elements showed no overt phenotype. Our study also illustrated the importance of carefully modeling potential technical confounders when analyzing genotype data of rare variants.
10aAlleles10aAnimals10aBody Height10aBody Mass Index10aChild10aConserved Sequence10aDogs10aEvolution, Molecular10aFemale10aGenetic Fitness10aGenetic Variation10aGenome, Human10aGenotype10aHumans10aInheritance Patterns10aMale10aMice10aPedigree10aPhenotype10aPolymorphism, Single Nucleotide10aRats10aReproduction10aYoung Adult1 aChiang, Charleston, W K1 aLiu, Ching-Ti1 aLettre, Guillaume1 aLange, Leslie, A1 aJorgensen, Neal, W1 aKeating, Brendan, J1 aVedantam, Sailaja1 aNock, Nora, L1 aFranceschini, Nora1 aReiner, Alex, P1 aDemerath, Ellen, W1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aWilson, James, G1 aNorth, Kari, E1 aPapanicolaou, George, J1 aCupples, Adrienne, L1 aMurabito, Joanne, M1 aHirschhorn, Joel, N1 aGenetic Investigation of ANthropometric Traits Consortium uhttps://chs-nhlbi.org/node/154402926nas a2200277 4500008004100000022001400041245012100055210006900176260001600245300001200261490000700273520206400280653002002344653001902364653001802383653001102401653003602412100001502448700002502463700002002488700002202508700002102530700002402551710003702575856003602612 2013 eng d a1460-208300aGene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals.0 aGenecentric metaanalyses of 108 912 individuals confirm known bo c2013 Jan 01 a184-2010 v223 aRecent genetic association studies have made progress in uncovering components of the genetic architecture of the body mass index (BMI). We used the ITMAT-Broad-Candidate Gene Association Resource (CARe) (IBC) array comprising up to 49 320 single nucleotide polymorphisms (SNPs) across ~2100 metabolic and cardiovascular-related loci to genotype up to 108 912 individuals of European ancestry (EA), African-Americans, Hispanics and East Asians, from 46 studies, to provide additional insight into SNPs underpinning BMI. We used a five-phase study design: Phase I focused on meta-analysis of EA studies providing individual level genotype data; Phase II performed a replication of cohorts providing summary level EA data; Phase III meta-analyzed results from the first two phases; associated SNPs from Phase III were used for replication in Phase IV; finally in Phase V, a multi-ethnic meta-analysis of all samples from four ethnicities was performed. At an array-wide significance (P < 2.40E-06), we identify novel BMI associations in loci translocase of outer mitochondrial membrane 40 homolog (yeast) - apolipoprotein E - apolipoprotein C-I (TOMM40-APOE-APOC1) (rs2075650, P = 2.95E-10), sterol regulatory element binding transcription factor 2 (SREBF2, rs5996074, P = 9.43E-07) and neurotrophic tyrosine kinase, receptor, type 2 [NTRK2, a brain-derived neurotrophic factor (BDNF) receptor gene, rs1211166, P = 1.04E-06] in the Phase IV meta-analysis. Of 10 loci with previous evidence for BMI association represented on the IBC array, eight were replicated, with the remaining two showing nominal significance. Conditional analyses revealed two independent BMI-associated signals in BDNF and melanocortin 4 receptor (MC4R) regions. Of the 11 array-wide significant SNPs, three are associated with gene expression levels in both primary B-cells and monocytes; with rs4788099 in SH2B adaptor protein 1 (SH2B1) notably being associated with the expression of multiple genes in cis. These multi-ethnic meta-analyses expand our knowledge of BMI genetics.
10aBody Mass Index10aCohort Studies10aEthnic Groups10aHumans10aPolymorphism, Single Nucleotide1 aGuo, Yiran1 aLanktree, Matthew, B1 aTaylor, Kira, C1 aHakonarson, Hakon1 aLange, Leslie, A1 aKeating, Brendan, J1 aIBC 50K SNP array BMI Consortium uhttps://chs-nhlbi.org/node/155004091nas a2200793 4500008004100000022001400041245011400055210006900169260001600238300001200254490000700266520179600273653001002069653002202079653000902101653002502110653002402135653002802159653004002187653001102227653004402238653003202282653002202314653003402336653001302370653001102383653000902394653001602403653001502419653003602434653001602470100002502486700002002511700001802531700001902549700001902568700002002587700001802607700002202625700002102647700002002668700002602688700002102714700001802735700002402753700002102777700002102798700003002819700002202849700002002871700001802891700002202909700002402931700002202955700002102977700002202998700002103020700002103041700002103062700002203083700002403105700002003129700002003149700002403169700002203193700002003215710002603235856003603261 2013 eng d a1460-208300aGenome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia.0 aGenomewide and genecentric analyses of circulating myeloperoxida c2013 Aug 15 a3381-930 v223 aIncreased systemic levels of myeloperoxidase (MPO) are associated with the risk of coronary artery disease (CAD). To identify the genetic factors that are associated with circulating MPO levels, we carried out a genome-wide association study (GWAS) and a gene-centric analysis in subjects of European ancestry and African Americans (AAs). A locus on chromosome 1q31.1 containing the complement factor H (CFH) gene was strongly associated with serum MPO levels in 9305 subjects of European ancestry (lead SNP rs800292; P = 4.89 × 10(-41)) and in 1690 AA subjects (rs505102; P = 1.05 × 10(-8)). Gene-centric analyses in 8335 subjects of European ancestry additionally identified two rare MPO coding sequence variants that were associated with serum MPO levels (rs28730837, P = 5.21 × 10(-12); rs35897051, P = 3.32 × 10(-8)). A GWAS for plasma MPO levels in 9260 European ancestry subjects identified a chromosome 17q22 region near MPO that was significantly associated (lead SNP rs6503905; P = 2.94 × 10(-12)), but the CFH locus did not exhibit evidence of association with plasma MPO levels. Functional analyses revealed that rs800292 was associated with levels of complement proteins in serum. Variants at chromosome 17q22 also had pleiotropic cis effects on gene expression. In a case-control analysis of ∼80 000 subjects from CARDIoGRAM, none of the identified single-nucleotide polymorphisms (SNPs) were associated with CAD. These results suggest that distinct genetic factors regulate serum and plasma MPO levels, which may have relevance for various acute and chronic inflammatory disorders. The clinical implications for CAD and a better understanding of the functional basis for the association of CFH and MPO variants with circulating MPO levels require further study.
10aAdult10aAfrican Americans10aAged10aCase-Control Studies10aComplement Factor H10aCoronary Artery Disease10aEuropean Continental Ancestry Group10aFemale10aGene Expression Regulation, Enzymologic10aGenetic Association Studies10aGenetic Variation10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMiddle Aged10aPeroxidase10aPolymorphism, Single Nucleotide10aYoung Adult1 aReiner, Alexander, P1 aHartiala, Jaana1 aZeller, Tanja1 aBis, Joshua, C1 aDupuis, Josée1 aFornage, Myriam1 aBaumert, Jens1 aKleber, Marcus, E1 aWild, Philipp, S1 aBaldus, Stephan1 aBielinski, Suzette, J1 aFontes, João, D1 aIllig, Thomas1 aKeating, Brendan, J1 aLange, Leslie, A1 aOjeda, Francisco1 aMüller-Nurasyid, Martina1 aMunzel, Thomas, F1 aPsaty, Bruce, M1 aRice, Kenneth1 aRotter, Jerome, I1 aSchnabel, Renate, B1 aTang, W, H Wilson1 aThorand, Barbara1 aErdmann, Jeanette1 aJacobs, David, R1 aWilson, James, G1 aKoenig, Wolfgang1 aTracy, Russell, P1 aBlankenberg, Stefan1 aMärz, Winfried1 aGross, Myron, D1 aBenjamin, Emelia, J1 aHazen, Stanley, L1 aAllayee, Hooman1 aCARDIoGRAM consortium uhttps://chs-nhlbi.org/node/628209008nas a2202809 4500008004100000022001400041245010800055210006900163260001300232300001000245490000700255520108900262653002201351653002001373653002501393653001901418653001701437653003801454653003401492653001101526653002701537653001201564653003601576100001901612700001801631700002001649700002001669700002101689700002101710700001901731700002601750700002401776700002401800700001801824700002201842700002501864700001801889700001201907700001701919700001701936700001801953700002201971700001601993700002402009700001902033700002402052700002202076700002502098700002202123700002102145700002002166700002102186700001602207700002202223700002202245700001802267700001802285700001802303700001502321700002102336700002802357700002402385700002002409700003202429700002002461700002202481700002102503700001302524700002302537700002902560700002002589700001702609700002302626700001902649700002202668700002402690700002302714700002202737700002302759700002302782700002402805700002202829700001702851700002402868700001802892700002102910700002102931700002302952700002202975700001702997700001803014700001603032700002103048700002103069700001703090700002403107700002603131700002003157700002603177700001803203700002803221700001503249700002003264700002203284700001603306700002003322700002903342700002203371700001803393700002503411700002203436700002703458700002303485700002903508700002103537700002803558700002603586700002203612700002503634700003103659700002803690700002203718700002003740700002103760700002303781700002103804700001903825700003203844700002803876700002303904700002003927700001903947700002203966700002403988700002704012700002804039700001904067700002104086700002304107700001904130700002204149700001504171700001904186700002104205700002104226700001904247700001804266700002304284700001904307700001404326700001904340700001404359700002304373700002104396700002604417700002204443700002004465700001904485700002004504700002804524700001704552700002104569700001804590700002104608700002104629700002204650700002104672700002304693700002404716700002204740700001904762700002404781700002304805700002004828700001804848700002204866700001804888700002004906700002704926700002204953700002304975700001504998700001405013700002005027700001705047700001905064700002005083700002205103700002505125700002405150700002105174700002405195700001905219700002505238700002305263700001505286700002205301700002405323700002205347700002705369700002005396700002105416700001905437700002405456700002405480700002005504700001905524700002305543700002505566700002205591700002505613700002405638700002505662700002305687700001905710700002105729700001905750700001505769700002005784700002305804700002005827700001805847700002305865700002405888700002805912700002405940700002005964700002405984700002006008700001906028700002706047710002106074710002106095710002606116710002006142856003606162 2013 eng d a1546-171800aA meta-analysis identifies new loci associated with body mass index in individuals of African ancestry.0 ametaanalysis identifies new loci associated with body mass index c2013 Jun a690-60 v453 aGenome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.
10aAfrican Americans10aBody Mass Index10aCase-Control Studies10aGene Frequency10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aObesity10aPolymorphism, Single Nucleotide1 aMonda, Keri, L1 aChen, Gary, K1 aTaylor, Kira, C1 aPalmer, Cameron1 aEdwards, Todd, L1 aLange, Leslie, A1 aC Y Ng, Maggie1 aAdeyemo, Adebowale, A1 aAllison, Matthew, A1 aBielak, Lawrence, F1 aChen, Guanjie1 aGraff, Mariaelisa1 aIrvin, Marguerite, R1 aRhie, Suhn, K1 aLi, Guo1 aLiu, Yongmei1 aLiu, Youfang1 aLu, Yingchang1 aNalls, Michael, A1 aSun, Yan, V1 aWojczynski, Mary, K1 aYanek, Lisa, R1 aAldrich, Melinda, C1 aAdemola, Adeyinka1 aAmos, Christopher, I1 aBandera, Elisa, V1 aBock, Cathryn, H1 aBritton, Angela1 aBroeckel, Ulrich1 aCai, Quiyin1 aCaporaso, Neil, E1 aCarlson, Chris, S1 aCarpten, John1 aCasey, Graham1 aChen, Wei-Min1 aChen, Fang1 aChen, Yii-der, I1 aChiang, Charleston, W K1 aCoetzee, Gerhard, A1 aDemerath, Ellen1 aDeming-Halverson, Sandra, L1 aDriver, Ryan, W1 aDubbert, Patricia1 aFeitosa, Mary, F1 aFeng, Ye1 aFreedman, Barry, I1 aGillanders, Elizabeth, M1 aGottesman, Omri1 aGuo, Xiuqing1 aHaritunians, Talin1 aHarris, Tamara1 aHarris, Curtis, C1 aHennis, Anselm, J M1 aHernandez, Dena, G1 aMcNeill, Lorna, H1 aHoward, Timothy, D1 aHoward, Barbara, V1 aHoward, Virginia, J1 aJohnson, Karen, C1 aKang, Sun, J1 aKeating, Brendan, J1 aKolb, Suzanne1 aKuller, Lewis, H1 aKutlar, Abdullah1 aLangefeld, Carl, D1 aLettre, Guillaume1 aLohman, Kurt1 aLotay, Vaneet1 aLyon, Helen1 aManson, JoAnn, E1 aMaixner, William1 aMeng, Yan, A1 aMonroe, Kristine, R1 aMorhason-Bello, Imran1 aMurphy, Adam, B1 aMychaleckyj, Josyf, C1 aNadukuru, Raj1 aNathanson, Katherine, L1 aNayak, Uma1 aN'diaye, Amidou1 aNemesure, Barbara1 aWu, Suh-Yuh1 aLeske, Cristina1 aNeslund-Dudas, Christine1 aNeuhouser, Marian1 aNyante, Sarah1 aOchs-Balcom, Heather1 aOgunniyi, Adesola1 aOgundiran, Temidayo, O1 aOjengbede, Oladosu1 aOlopade, Olufunmilayo, I1 aPalmer, Julie, R1 aRuiz-Narvaez, Edward, A1 aPalmer, Nicholette, D1 aPress, Michael, F1 aRampersaud, Evandine1 aRasmussen-Torvik, Laura, J1 aRodriguez-Gil, Jorge, L1 aSalako, Babatunde1 aSchadt, Eric, E1 aSchwartz, Ann, G1 aShriner, Daniel, A1 aSiscovick, David1 aSmith, Shad, B1 aWassertheil-Smoller, Sylvia1 aSpeliotes, Elizabeth, K1 aSpitz, Margaret, R1 aSucheston, Lara1 aTaylor, Herman1 aTayo, Bamidele, O1 aTucker, Margaret, A1 aVan Den Berg, David, J1 aEdwards, Digna, R Velez1 aWang, Zhaoming1 aWiencke, John, K1 aWinkler, Thomas, W1 aWitte, John, S1 aWrensch, Margaret1 aWu, Xifeng1 aYang, James, J1 aLevin, Albert, M1 aYoung, Taylor, R1 aZakai, Neil, A1 aCushman, Mary1 aZanetti, Krista, A1 aZhao, Jing Hua1 aZhao, Wei1 aZheng, Yonglan1 aZhou, Jie1 aZiegler, Regina, G1 aZmuda, Joseph, M1 aFernandes, Jyotika, K1 aGilkeson, Gary, S1 aKamen, Diane, L1 aHunt, Kelly, J1 aSpruill, Ida, J1 aAmbrosone, Christine, B1 aAmbs, Stefan1 aArnett, Donna, K1 aAtwood, Larry1 aBecker, Diane, M1 aBerndt, Sonja, I1 aBernstein, Leslie1 aBlot, William, J1 aBorecki, Ingrid, B1 aBottinger, Erwin, P1 aBowden, Donald, W1 aBurke, Gregory1 aChanock, Stephen, J1 aCooper, Richard, S1 aDing, Jingzhong1 aDuggan, David1 aEvans, Michele, K1 aFox, Caroline1 aGarvey, Timothy1 aBradfield, Jonathan, P1 aHakonarson, Hakon1 aGrant, Struan, F A1 aHsing, Ann1 aChu, Lisa1 aHu, Jennifer, J1 aHuo, Dezheng1 aIngles, Sue, A1 aJohn, Esther, M1 aJordan, Joanne, M1 aKabagambe, Edmond, K1 aKardia, Sharon, L R1 aKittles, Rick, A1 aGoodman, Phyllis, J1 aKlein, Eric, A1 aKolonel, Laurence, N1 aLe Marchand, Loïc1 aLiu, Simin1 aMcKnight, Barbara1 aMillikan, Robert, C1 aMosley, Thomas, H1 aPadhukasahasram, Badri1 aWilliams, Keoki1 aPatel, Sanjay, R1 aPeters, Ulrike1 aPettaway, Curtis, A1 aPeyser, Patricia, A1 aPsaty, Bruce, M1 aRedline, Susan1 aRotimi, Charles, N1 aRybicki, Benjamin, A1 aSale, Michèle, M1 aSchreiner, Pamela, J1 aSignorello, Lisa, B1 aSingleton, Andrew, B1 aStanford, Janet, L1 aStrom, Sara, S1 aThun, Michael, J1 aVitolins, Mara1 aZheng, Wei1 aMoore, Jason, H1 aWilliams, Scott, M1 aKetkar, Shamika1 aZhu, Xiaofeng1 aZonderman, Alan, B1 aKooperberg, Charles1 aPapanicolaou, George, J1 aHenderson, Brian, E1 aReiner, Alex, P1 aHirschhorn, Joel, N1 aLoos, Ruth, J F1 aNorth, Kari, E1 aHaiman, Christopher, A1 aNABEC Consortium1 aUKBEC Consortium1 aBioBank Japan Project1 aAGEN Consortium uhttps://chs-nhlbi.org/node/607808212nas a2202197 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2014 eng d a1756-183300aAssociation between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data.0 aAssociation between alcohol and cardiovascular disease Mendelian c2014 Jul 10 ag41640 v3493 aOBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease.
DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies.
PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers.
MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption.
RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)).
CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.
10aAdult10aAged10aAlcohol Dehydrogenase10aAlcohol Drinking10aBiomarkers10aCoronary Disease10aFemale10aGenetic Markers10aGenotype10aHumans10aMale10aMendelian Randomization Analysis10aMiddle Aged10aModels, Statistical10aPolymorphism, Single Nucleotide10aStroke1 aHolmes, Michael, V1 aDale, Caroline, E1 aZuccolo, Luisa1 aSilverwood, Richard, J1 aGuo, Yiran1 aYe, Zheng1 aPrieto-Merino, David1 aDehghan, Abbas1 aTrompet, Stella1 aWong, Andrew1 aCavadino, Alana1 aDrogan, Dagmar1 aPadmanabhan, Sandosh1 aLi, Shanshan1 aYesupriya, Ajay1 aLeusink, Maarten1 aSundström, Johan1 aHubacek, Jaroslav, A1 aPikhart, Hynek1 aSwerdlow, Daniel, I1 aPanayiotou, Andrie, G1 aBorinskaya, Svetlana, A1 aFinan, Chris1 aShah, Sonia1 aKuchenbaecker, Karoline, B1 aShah, Tina1 aEngmann, Jorgen1 aFolkersen, Lasse1 aEriksson, Per1 aRicceri, Fulvio1 aMelander, Olle1 aSacerdote, Carlotta1 aGamble, Dale, M1 aRayaprolu, Sruti1 aRoss, Owen, A1 aMcLachlan, Stela1 aVikhireva, Olga1 aSluijs, Ivonne1 aScott, Robert, A1 aAdamkova, Vera1 aFlicker, Leon1 avan Bockxmeer, Frank, M1 aPower, Christine1 aMarques-Vidal, Pedro1 aMeade, Tom1 aMarmot, Michael, G1 aFerro, Jose, M1 aPaulos-Pinheiro, Sofia1 aHumphries, Steve, E1 aTalmud, Philippa, J1 aLeach, Irene, Mateo1 aVerweij, Niek1 aLinneberg, Allan1 aSkaaby, Tea1 aDoevendans, Pieter, A1 aCramer, Maarten, J1 aHarst, Pim1 aKlungel, Olaf, H1 aDowling, Nicole, F1 aDominiczak, Anna, F1 aKumari, Meena1 aNicolaides, Andrew, N1 aWeikert, Cornelia1 aBoeing, Heiner1 aEbrahim, Shah1 aGaunt, Tom, R1 aPrice, Jackie, F1 aLannfelt, Lars1 aPeasey, Anne1 aKubinova, Ruzena1 aPajak, Andrzej1 aMalyutina, Sofia1 aVoevoda, Mikhail, I1 aTamosiunas, Abdonas1 avan der Zee, Anke, H Maitland1 aNorman, Paul, E1 aHankey, Graeme, J1 aBergmann, Manuela, M1 aHofman, Albert1 aFranco, Oscar, H1 aCooper, Jackie1 aPalmen, Jutta1 aSpiering, Wilko1 ade Jong, Pim, A1 aKuh, Diana1 aHardy, Rebecca1 aUitterlinden, André, G1 aIkram, Arfan, M1 aFord, Ian1 aHyppönen, Elina1 aAlmeida, Osvaldo, P1 aWareham, Nicholas, J1 aKhaw, Kay-Tee1 aHamsten, Anders1 aHusemoen, Lise, Lotte N1 aTjønneland, Anne1 aTolstrup, Janne, S1 aRimm, Eric1 aBeulens, Joline, W J1 aVerschuren, W, M Monique1 aOnland-Moret, Charlotte, N1 aHofker, Marten, H1 aWannamethee, Goya1 aWhincup, Peter, H1 aMorris, Richard1 aVicente, Astrid, M1 aWatkins, Hugh1 aFarrall, Martin1 aJukema, Wouter1 aMeschia, James1 aCupples, Adrienne, L1 aSharp, Stephen, J1 aFornage, Myriam1 aKooperberg, Charles1 aLaCroix, Andrea, Z1 aDai, James, Y1 aLanktree, Matthew, B1 aSiscovick, David, S1 aJorgenson, Eric1 aSpring, Bonnie1 aCoresh, Josef1 aLi, Yun, R1 aBuxbaum, Sarah, G1 aSchreiner, Pamela, J1 aEllison, Curtis1 aTsai, Michael, Y1 aPatel, Sanjay, R1 aRedline, Susan1 aJohnson, Andrew, D1 aHoogeveen, Ron, C1 aHakonarson, Hakon1 aRotter, Jerome, I1 aBoerwinkle, Eric1 ade Bakker, Paul, I W1 aKivimaki, Mika1 aAsselbergs, Folkert, W1 aSattar, Naveed1 aLawlor, Debbie, A1 aWhittaker, John1 aSmith, George, Davey1 aMukamal, Kenneth1 aPsaty, Bruce, M1 aWilson, James, G1 aLange, Leslie, A1 aHamidovic, Ajna1 aHingorani, Aroon, D1 aNordestgaard, Børge, G1 aBobak, Martin1 aLeon, David, A1 aLangenberg, Claudia1 aPalmer, Tom, M1 aReiner, Alex, P1 aKeating, Brendan, J1 aDudbridge, Frank1 aCasas, Juan, P1 aInterAct Consortium uhttps://chs-nhlbi.org/node/656904043nas a2200769 4500008004100000022001400041245014200055210006900197260001300266300001100279490000800290520183700298653001002135653002202145653000902167653001502176653002302191653002802214653001802242653001102260653001702271653003802288653002502326653003402351653001102385653002702396653001602423653003602439653001702475100001802492700002002510700001202530700001902542700001802561700002302579700002402602700001702626700001802643700002302661700001702684700001802701700002302719700002402742700002102766700001702787700002002804700001902824700001502843700002702858700002302885700002102908700002102929700002802950700002202978700002803000700002003028700002203048700002103070700001903091700002103110700002203131700001903153700002003172700002403192700002103216856003603237 2014 eng d a1432-120300aLarge multiethnic Candidate Gene Study for C-reactive protein levels: identification of a novel association at CD36 in African Americans.0 aLarge multiethnic Candidate Gene Study for Creactive protein lev c2014 Aug a985-950 v1333 aC-reactive protein (CRP) is a heritable biomarker of systemic inflammation and a predictor of cardiovascular disease (CVD). Large-scale genetic association studies for CRP have largely focused on individuals of European descent. We sought to uncover novel genetic variants for CRP in a multiethnic sample using the ITMAT Broad-CARe (IBC) array, a custom 50,000 SNP gene-centric array having dense coverage of over 2,000 candidate CVD genes. We performed analyses on 7,570 African Americans (AA) from the Candidate gene Association Resource (CARe) study and race-combined meta-analyses that included 29,939 additional individuals of European descent from CARe, the Women's Health Initiative (WHI) and KORA studies. We observed array-wide significance (p < 2.2 × 10(-6)) for four loci in AA, three of which have been reported previously in individuals of European descent (IL6R, p = 2.0 × 10(-6); CRP, p = 4.2 × 10(-71); APOE, p = 1.6 × 10(-6)). The fourth significant locus, CD36 (p = 1.6 × 10(-6)), was observed at a functional variant (rs3211938) that is extremely rare in individuals of European descent. We replicated the CD36 finding (p = 1.8 × 10(-5)) in an independent sample of 8,041 AA women from WHI; a meta-analysis combining the CARe and WHI AA results at rs3211938 reached genome-wide significance (p = 1.5 × 10(-10)). In the race-combined meta-analyses, 13 loci reached significance, including ten (CRP, TOMM40/APOE/APOC1, HNF1A, LEPR, GCKR, IL6R, IL1RN, NLRP3, HNF4A and BAZ1B/BCL7B) previously associated with CRP, and one (ARNTL) previously reported to be nominally associated with CRP. Two novel loci were also detected (RPS6KB1, p = 2.0 × 10(-6); CD36, p = 1.4 × 10(-6)). These results highlight both shared and unique genetic risk factors for CRP in AA compared to populations of European descent.
10aAdult10aAfrican Americans10aAged10aBiomarkers10aC-Reactive Protein10aCardiovascular Diseases10aCD36 Antigens10aFemale10aGenetic Loci10aGenetic Predisposition to Disease10aGenetics, Population10aGenome-Wide Association Study10aHumans10aMeta-Analysis as Topic10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors1 aEllis, Jaclyn1 aLange, Ethan, M1 aLi, Jin1 aDupuis, Josée1 aBaumert, Jens1 aWalston, Jeremy, D1 aKeating, Brendan, J1 aDurda, Peter1 aFox, Ervin, R1 aPalmer, Cameron, D1 aMeng, Yan, A1 aYoung, Taylor1 aFarlow, Deborah, N1 aSchnabel, Renate, B1 aMarzi, Carola, S1 aLarkin, Emma1 aMartin, Lisa, W1 aBis, Joshua, C1 aAuer, Paul1 aRamachandran, Vasan, S1 aGabriel, Stacey, B1 aWillis, Monte, S1 aPankow, James, S1 aPapanicolaou, George, J1 aRotter, Jerome, I1 aBallantyne, Christie, M1 aGross, Myron, D1 aLettre, Guillaume1 aWilson, James, G1 aPeters, Ulrike1 aKoenig, Wolfgang1 aTracy, Russell, P1 aRedline, Susan1 aReiner, Alex, P1 aBenjamin, Emelia, J1 aLange, Leslie, A uhttps://chs-nhlbi.org/node/655803195nas a2200577 4500008004100000022001400041245014300055210006900198260001300267300001100280490000700291520150000298653001001798653002201808653000901830653004001839653001601879653001101895653001701906653003401923653001101957653000901968653003501977653001602012653003602028653002702064653002602091100001802117700001802135700001702153700002102170700002102191700001602212700002202228700002402250700001702274700002102291700002402312700001802336700002202354700002102376700002302397700002302420700001802443700002102461700003002482700002302512700002502535700002102560856003602581 2015 eng d a1096-865200aGene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans.0 aGenecentric approach identifies new and known loci for FVIII act c2015 Jun a534-400 v903 aCoagulation factor VIII and von Willebrand factor (VWF) are key proteins in procoagulant activation. Higher FVIII coagulant activity (FVIII :C) and VWF antigen (VWF :Ag) are risk factors for cardiovascular disease and venous thromboembolism. Beyond associations with ABO blood group, genetic determinants of FVIII and VWF are not well understood, especially in non European-American populations. We performed a genetic association study of FVIII :C and VWF:Ag that assessed 50,000 gene-centric single nucleotide polymorphisms (SNPs) in 18,556 European Americans (EAs) and 5,047 African Americans (AAs) from five population-based cohorts. Previously unreported associations for FVIII :C were identified in both AAs and EAs with KNG1 (most significantly associated SNP rs710446, Ile581Thr, Ile581Thr, P = 5.10 × 10(-7) in EAs and P = 3.88 × 10(-3) in AAs) and VWF rs7962217 (Gly2705Arg,P = 6.30 × 10(-9) in EAs and P = 2.98 × 10(-2) in AAs. Significant associations for FVIII :C were also observed with F8/TMLHE region SNP rs12557310 in EAs (P = 8.02 × 10(-10) ), with VWF rs1800380 in AAs (P = 5.62 × 10(-11) ), and with MAT1A rs2236568 in AAs (P51.69 × 10(-6) ). We replicated previously reported associations of FVIII :C and VWF :Ag with the ABO blood group, VWF rs1063856(Thr789Ala), rs216321 (Ala852Gln), and VWF rs2229446 (Arg2185Gln). Findings from this study expand our understanding of genetic influences for FVIII :C and VWF :Ag in both EAs and AAs.
10aAdult10aAfrican Americans10aAged10aEuropean Continental Ancestry Group10aFactor VIII10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMethionine Adenosyltransferase10aMiddle Aged10aPolymorphism, Single Nucleotide10aVenous Thromboembolism10avon Willebrand Factor1 aTang, Weihong1 aCushman, Mary1 aGreen, David1 aRich, Stephen, S1 aLange, Leslie, A1 aYang, Qiong1 aTracy, Russell, P1 aTofler, Geoffrey, H1 aBasu, Saonli1 aWilson, James, G1 aKeating, Brendan, J1 aWeng, Lu-Chen1 aTaylor, Herman, A1 aJacobs, David, R1 aDelaney, Joseph, A1 aPalmer, Cameron, D1 aYoung, Taylor1 aPankow, James, S1 aO'Donnell, Christopher, J1 aSmith, Nicholas, L1 aReiner, Alexander, P1 aFolsom, Aaron, R uhttps://chs-nhlbi.org/node/737608133nas a2201957 4500008004100000022001400041245012800055210006900183260001600252300001100268490000800279520256000287653000902847653002002856653001602876653002102892653002102913653003002934653001102964653002002975653001102995653004103006653005103047653000903098653001603107653003603123653004203159653001703201100002403218700001803242700003103260700002303291700002503314700001503339700001803354700002003372700002303392700002103415700002103436700001803457700002203475700001503497700002803512700002103540700001703561700002203578700001403600700001803614700001903632700002203651700001903673700001503692700001703707700002003724700002603744700002103770700002203791700002503813700002103838700003103859700002203890700002403912700002503936700002103961700002303982700002404005700001904029700002304048700002304071700002104094700002504115700002004140700001904160700001804179700002104197700001404218700001904232700002604251700002404277700002004301700001504321700002004336700003404356700002104390700002304411700002604434700002204460700002604482700001804508700001904526700001904545700002204564700002204586700002304608700002004631700002004651700002104671700002104692700002304713700002104736700002004757700002404777700002104801700002304822700002004845700002204865700001904887700001904906700003704925700002104962700002104983700002205004700002305026700002205049700002405071700002105095700002505116700002005141700002405161700001805185700001805203700002105221700002905242700001905271700002105290700002305311700002005334700002305354700001905377700001805396700001705414700001505431700001905446700002205465700002305487700001505510700002105525700002605546700002305572700002205595700001805617700001805635700002505653700002005678700002105698700002205719700002105741700002405762700002405786700001905810700002505829700002405854700002705878700002105905700001805926700001905944700002105963700002005984700002406004700002406028700001906052710002306071710002106094710002406115856003606139 2015 eng d a1474-547X00aHMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.0 aHMGcoenzyme A reductase inhibition type 2 diabetes and bodyweigh c2015 Jan 24 a351-610 v3853 aBACKGROUND: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.
METHODS: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.
FINDINGS: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials).
INTERPRETATION: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.
FUNDING: The funding sources are cited at the end of the paper.
10aAged10aBody Mass Index10aBody Weight10aCholesterol, HDL10aCholesterol, LDL10aDiabetes Mellitus, Type 210aFemale10aGenetic Testing10aHumans10aHydroxymethylglutaryl CoA Reductases10aHydroxymethylglutaryl-CoA Reductase Inhibitors10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRandomized Controlled Trials as Topic10aRisk Factors1 aSwerdlow, Daniel, I1 aPreiss, David1 aKuchenbaecker, Karoline, B1 aHolmes, Michael, V1 aEngmann, Jorgen, E L1 aShah, Tina1 aSofat, Reecha1 aStender, Stefan1 aJohnson, Paul, C D1 aScott, Robert, A1 aLeusink, Maarten1 aVerweij, Niek1 aSharp, Stephen, J1 aGuo, Yiran1 aGiambartolomei, Claudia1 aChung, Christina1 aPeasey, Anne1 aAmuzu, Antoinette1 aLi, KaWah1 aPalmen, Jutta1 aHoward, Philip1 aCooper, Jackie, A1 aDrenos, Fotios1 aLi, Yun, R1 aLowe, Gordon1 aGallacher, John1 aStewart, Marlene, C W1 aTzoulaki, Ioanna1 aBuxbaum, Sarah, G1 avan der A, Daphne, L1 aForouhi, Nita, G1 aOnland-Moret, Charlotte, N1 aSchouw, Yvonne, T1 aSchnabel, Renate, B1 aHubacek, Jaroslav, A1 aKubinova, Ruzena1 aBaceviciene, Migle1 aTamosiunas, Abdonas1 aPajak, Andrzej1 aTopor-Madry, Roman1 aStepaniak, Urszula1 aMalyutina, Sofia1 aBaldassarre, Damiano1 aSennblad, Bengt1 aTremoli, Elena1 ade Faire, Ulf1 aVeglia, Fabrizio1 aFord, Ian1 aJukema, Wouter1 aWestendorp, Rudi, G J1 ade Borst, Gert, Jan1 ade Jong, Pim, A1 aAlgra, Ale1 aSpiering, Wilko1 avan der Zee, Anke, H Maitland1 aKlungel, Olaf, H1 ade Boer, Anthonius1 aDoevendans, Pieter, A1 aEaton, Charles, B1 aRobinson, Jennifer, G1 aDuggan, David1 aKjekshus, John1 aDowns, John, R1 aGotto, Antonio, M1 aKeech, Anthony, C1 aMarchioli, Roberto1 aTognoni, Gianni1 aSever, Peter, S1 aPoulter, Neil, R1 aWaters, David, D1 aPedersen, Terje, R1 aAmarenco, Pierre1 aNakamura, Haruo1 aMcMurray, John, J V1 aLewsey, James, D1 aChasman, Daniel, I1 aRidker, Paul, M1 aMaggioni, Aldo, P1 aTavazzi, Luigi1 aRay, Kausik, K1 aSeshasai, Sreenivasa, Rao Kondap1 aManson, JoAnn, E1 aPrice, Jackie, F1 aWhincup, Peter, H1 aMorris, Richard, W1 aLawlor, Debbie, A1 aSmith, George Davey1 aBen-Shlomo, Yoav1 aSchreiner, Pamela, J1 aFornage, Myriam1 aSiscovick, David, S1 aCushman, Mary1 aKumari, Meena1 aWareham, Nick, J1 aVerschuren, W, M Monique1 aRedline, Susan1 aPatel, Sanjay, R1 aWhittaker, John, C1 aHamsten, Anders1 aDelaney, Joseph, A1 aDale, Caroline1 aGaunt, Tom, R1 aWong, Andrew1 aKuh, Diana1 aHardy, Rebecca1 aKathiresan, Sekar1 aCastillo, Berta, A1 aHarst, Pim1 aBrunner, Eric, J1 aTybjaerg-Hansen, Anne1 aMarmot, Michael, G1 aKrauss, Ronald, M1 aTsai, Michael1 aCoresh, Josef1 aHoogeveen, Ronald, C1 aPsaty, Bruce, M1 aLange, Leslie, A1 aHakonarson, Hakon1 aDudbridge, Frank1 aHumphries, Steve, E1 aTalmud, Philippa, J1 aKivimaki, Mika1 aTimpson, Nicholas, J1 aLangenberg, Claudia1 aAsselbergs, Folkert, W1 aVoevoda, Mikhail1 aBobak, Martin1 aPikhart, Hynek1 aWilson, James, G1 aReiner, Alex, P1 aKeating, Brendan, J1 aHingorani, Aroon, D1 aSattar, Naveed1 aDIAGRAM Consortium1 aMAGIC Consortium1 aInterAct Consortium uhttps://chs-nhlbi.org/node/686305080nas a2201129 4500008004100000022001400041245007200055210006900127260001600196300001100212490000700223520191200230653002502142653002102167653002802188653001102216653001902227653001302246653002602259653001102285653000902296653003702305653001602342653003602358653002002394653001802414100002302432700002702455700001902482700001902501700002502520700002702545700002202572700002502594700001702619700002402636700002302660700002602683700002802709700001602737700002102753700001502774700002002789700002802809700001502837700002102852700001802873700002102891700002602912700002602938700002202964700001902986700002103005700002203026700001803048700002003066700002103086700001903107700002403126700002103150700002603171700002203197700002403219700002103243700002203264700001903286700002403305700002003329700002103349700001803370700001803388700001803406700002003424700002103444700002103465700001803486700002403504700001903528700001803547700002003565700002103585700002103606700002503627700002103652700002503673700002003698700002403718700001903742700002203761700002103783700002203804700002403826700002403850700001903874710002103893856003603914 2015 eng d a1522-964500aMendelian randomization of blood lipids for coronary heart disease.0 aMendelian randomization of blood lipids for coronary heart disea c2015 Mar 01 a539-500 v363 aAIMS: To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization.
METHODS AND RESULTS: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75).
CONCLUSION: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.
10aCase-Control Studies10aCholesterol, HDL10aCoronary Artery Disease10aFemale10aGene Frequency10aGenotype10aGenotyping Techniques10aHumans10aMale10aMendelian Randomization Analysis10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Assessment10aTriglycerides1 aHolmes, Michael, V1 aAsselbergs, Folkert, W1 aPalmer, Tom, M1 aDrenos, Fotios1 aLanktree, Matthew, B1 aNelson, Christopher, P1 aDale, Caroline, E1 aPadmanabhan, Sandosh1 aFinan, Chris1 aSwerdlow, Daniel, I1 aTragante, Vinicius1 avan Iperen, Erik, P A1 aSivapalaratnam, Suthesh1 aShah, Sonia1 aElbers, Clara, C1 aShah, Tina1 aEngmann, Jorgen1 aGiambartolomei, Claudia1 aWhite, Jon1 aZabaneh, Delilah1 aSofat, Reecha1 aMcLachlan, Stela1 aDoevendans, Pieter, A1 aBalmforth, Anthony, J1 aHall, Alistair, S1 aNorth, Kari, E1 aAlmoguera, Berta1 aHoogeveen, Ron, C1 aCushman, Mary1 aFornage, Myriam1 aPatel, Sanjay, R1 aRedline, Susan1 aSiscovick, David, S1 aTsai, Michael, Y1 aKarczewski, Konrad, J1 aHofker, Marten, H1 aVerschuren, Monique1 aBots, Michiel, L1 aSchouw, Yvonne, T1 aMelander, Olle1 aDominiczak, Anna, F1 aMorris, Richard1 aBen-Shlomo, Yoav1 aPrice, Jackie1 aKumari, Meena1 aBaumert, Jens1 aPeters, Annette1 aThorand, Barbara1 aKoenig, Wolfgang1 aGaunt, Tom, R1 aHumphries, Steve, E1 aClarke, Robert1 aWatkins, Hugh1 aFarrall, Martin1 aWilson, James, G1 aRich, Stephen, S1 ade Bakker, Paul, I W1 aLange, Leslie, A1 aSmith, George, Davey1 aReiner, Alex, P1 aTalmud, Philippa, J1 aKivimaki, Mika1 aLawlor, Debbie, A1 aDudbridge, Frank1 aSamani, Nilesh, J1 aKeating, Brendan, J1 aHingorani, Aroon, D1 aCasas, Juan, P1 aUCLEB consortium uhttps://chs-nhlbi.org/node/656803683nas a2200757 4500008004100000022001400041245011200055210006900167260000900236300000700245490000700252520150800259100002401767700002201791700002101813700001601834700001601850700002701866700002501893700002101918700002201939700001601961700001901977700001701996700002402013700001802037700002302055700001802078700002802096700002302124700002602147700002002173700002202193700002302215700002002238700002302258700002302281700002002304700003102324700001802355700001802373700002702391700002002418700002402438700001802462700002202480700002202502700001802524700002102542700002102563700002002584700001902604700002802623700002002651700002402671700002202695700002102717700001902738700001802757700002002775700001902795700002702814700002402841700002402865856003602889 2017 eng d a1756-038100aDiscovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals.0 aDiscovery and replication of SNPSNP interactions for quantitativ c2017 a250 v103 aBACKGROUND: The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG).
RESULTS: Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n = 12,853 to n = 16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p < 0.001 in a previous association study. 2. A filter that only tested interactions identified by Biofilter 2.0. Pairwise models that reached an interaction significance level of p < 0.001 in the discovery dataset were tested for replication. We identified thirteen SNP-SNP models that were significant in more than one replication cohort after accounting for multiple testing.
CONCLUSIONS: These results may reveal novel insights into the genetic etiology of lipid levels. Furthermore, we developed a pipeline to perform a computationally efficient interaction analysis with multi-cohort replication.
1 aHolzinger, Emily, R1 aVerma, Shefali, S1 aMoore, Carrie, B1 aHall, Molly1 aDe, Rishika1 aGilbert-Diamond, Diane1 aLanktree, Matthew, B1 aPankratz, Nathan1 aAmuzu, Antoinette1 aBurt, Amber1 aDale, Caroline1 aDudek, Scott1 aFurlong, Clement, E1 aGaunt, Tom, R1 aKim, Daniel, Seung1 aRiess, Helene1 aSivapalaratnam, Suthesh1 aTragante, Vinicius1 avan Iperen, Erik, P A1 aBrautbar, Ariel1 aCarrell, David, S1 aCrosslin, David, R1 aJarvik, Gail, P1 aKuivaniemi, Helena1 aKullo, Iftikhar, J1 aLarson, Eric, B1 aRasmussen-Torvik, Laura, J1 aTromp, Gerard1 aBaumert, Jens1 aCruickshanks, Karen, J1 aFarrall, Martin1 aHingorani, Aroon, D1 aHovingh, G, K1 aKleber, Marcus, E1 aKlein, Barbara, E1 aKlein, Ronald1 aKoenig, Wolfgang1 aLange, Leslie, A1 aMӓrz, Winfried1 aNorth, Kari, E1 aOnland-Moret, Charlotte1 aReiner, Alex, P1 aTalmud, Philippa, J1 aSchouw, Yvonne, T1 aWilson, James, G1 aKivimaki, Mika1 aKumari, Meena1 aMoore, Jason, H1 aDrenos, Fotios1 aAsselbergs, Folkert, W1 aKeating, Brendan, J1 aRitchie, Marylyn, D uhttps://chs-nhlbi.org/node/756609591nas a2202833 4500008004100000022001400041245011900055210006900174260001600243300001200259490000800271520174700279100002202026700002102048700002202069700002002091700001802111700002102129700001502150700002302165700001802188700002102206700002402227700001902251700001702270700001902287700002602306700002402332700002402356700002802380700001702408700002202425700002102447700001802468700002202486700001702508700002102525700002102546700002202567700002402589700002102613700002402634700002202658700002702680700002302707700002102730700001902751700001902770700001602789700001902805700001902824700001802843700001802861700002402879700001802903700001702921700002102938700001802959700002202977700002802999700001403027700002203041700002003063700002303083700001803106700002003124700002203144700002403166700002003190700001603210700001503226700002203241700002403263700002103287700002003308700001803328700002303346700002003369700002903389700002103418700002003439700002303459700001703482700002203499700002303521700002203544700002203566700002403588700001903612700002303631700002403654700002903678700002303707700002003730700001803750700001903768700002003787700001803807700001703825700001903842700002503861700002003886700002203906700002203928700002503950700001703975700002203992700002404014700002104038700001904059700001804078700002504096700002404121700001804145700002104163700001804184700002304202700002304225700002104248700002204269700002104291700001204312700001204324700001704336700001704353700001504370700001704385700001804402700001804420700002104438700002104459700002204480700001404502700001904516700001704535700002004552700002204572700001904594700002004613700001804633700001904651700002804670700001504698700002004713700002204733700002904755700002504784700001804809700002504827700002704852700002204879700002304901700002004924700002904944700001904973700002704992700001805019700002305037700002605060700002505086700002105111700002405132700002405156700002205180700001405202700003105216700001905247700002005266700001805286700002805304700002305332700002205355700002805377700002505405700002205430700002205452700002305474700001705497700002505514700002305539700002105562700002305583700002405606700002505630700002405655700002305679700001605702700002505718700002005743700002305763700002505786700001605811700001905827700002005846700001605866700002405882700001905906700001705925700002205942700002105964700002405985700002206009700002706031700002206058700001906080700001906099700001806118700003206136700001906168700002106187700002306208700002006231700002106251700001906272700002206291700001506313700001306328700001606341700002006357700002206377700001406399700001906413700001506432700001506447700001406462700001806476700002306494700001506517700002306532700002006555700002306575700002506598700001806623700002706641700001506668700001906683700001906702856003606721 2021 eng d a1537-660500aDiscovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.0 aDiscovery and finemapping of height loci via highdensity imputat c2021 Apr 01 a564-5820 v1083 aAlthough many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
1 aGraff, Mariaelisa1 aJustice, Anne, E1 aYoung, Kristin, L1 aMarouli, Eirini1 aZhang, Xinruo1 aFine, Rebecca, S1 aLim, Elise1 aBuchanan, Victoria1 aRand, Kristin1 aFeitosa, Mary, F1 aWojczynski, Mary, K1 aYanek, Lisa, R1 aShao, Yaming1 aRohde, Rebecca1 aAdeyemo, Adebowale, A1 aAldrich, Melinda, C1 aAllison, Matthew, A1 aAmbrosone, Christine, B1 aAmbs, Stefan1 aAmos, Christopher1 aArnett, Donna, K1 aAtwood, Larry1 aBandera, Elisa, V1 aBartz, Traci1 aBecker, Diane, M1 aBerndt, Sonja, I1 aBernstein, Leslie1 aBielak, Lawrence, F1 aBlot, William, J1 aBottinger, Erwin, P1 aBowden, Donald, W1 aBradfield, Jonathan, P1 aBrody, Jennifer, A1 aBroeckel, Ulrich1 aBurke, Gregory1 aCade, Brian, E1 aCai, Qiuyin1 aCaporaso, Neil1 aCarlson, Chris1 aCarpten, John1 aCasey, Graham1 aChanock, Stephen, J1 aChen, Guanjie1 aChen, Minhui1 aChen, Yii-der, I1 aChen, Wei-Min1 aChesi, Alessandra1 aChiang, Charleston, W K1 aChu, Lisa1 aCoetzee, Gerry, A1 aConti, David, V1 aCooper, Richard, S1 aCushman, Mary1 aDemerath, Ellen1 aDeming, Sandra, L1 aDimitrov, Latchezar1 aDing, Jingzhong1 aDiver, Ryan1 aDuan, Qing1 aEvans, Michele, K1 aFalusi, Adeyinka, G1 aFaul, Jessica, D1 aFornage, Myriam1 aFox, Caroline1 aFreedman, Barry, I1 aGarcia, Melissa1 aGillanders, Elizabeth, M1 aGoodman, Phyllis1 aGottesman, Omri1 aGrant, Struan, F A1 aGuo, Xiuqing1 aHakonarson, Hakon1 aHaritunians, Talin1 aHarris, Tamara, B1 aHarris, Curtis, C1 aHenderson, Brian, E1 aHennis, Anselm1 aHernandez, Dena, G1 aHirschhorn, Joel, N1 aMcNeill, Lorna, Haughton1 aHoward, Timothy, D1 aHoward, Barbara1 aHsing, Ann, W1 aHsu, Yu-Han, H1 aHu, Jennifer, J1 aHuff, Chad, D1 aHuo, Dezheng1 aIngles, Sue, A1 aIrvin, Marguerite, R1 aJohn, Esther, M1 aJohnson, Karen, C1 aJordan, Joanne, M1 aKabagambe, Edmond, K1 aKang, Sun, J1 aKardia, Sharon, L1 aKeating, Brendan, J1 aKittles, Rick, A1 aKlein, Eric, A1 aKolb, Suzanne1 aKolonel, Laurence, N1 aKooperberg, Charles1 aKuller, Lewis1 aKutlar, Abdullah1 aLange, Leslie1 aLangefeld, Carl, D1 aLe Marchand, Loïc1 aLeonard, Hampton1 aLettre, Guillaume1 aLevin, Albert, M1 aLi, Yun1 aLi, Jin1 aLiu, Yongmei1 aLiu, Youfang1 aLiu, Simin1 aLohman, Kurt1 aLotay, Vaneet1 aLu, Yingchang1 aMaixner, William1 aManson, JoAnn, E1 aMcKnight, Barbara1 aMeng, Yan1 aMonda, Keri, L1 aMonroe, Kris1 aMoore, Jason, H1 aMosley, Thomas, H1 aMudgal, Poorva1 aMurphy, Adam, B1 aNadukuru, Raj1 aNalls, Mike, A1 aNathanson, Katherine, L1 aNayak, Uma1 aN'diaye, Amidou1 aNemesure, Barbara1 aNeslund-Dudas, Christine1 aNeuhouser, Marian, L1 aNyante, Sarah1 aOchs-Balcom, Heather1 aOgundiran, Temidayo, O1 aOgunniyi, Adesola1 aOjengbede, Oladosu1 aOkut, Hayrettin1 aOlopade, Olufunmilayo, I1 aOlshan, Andrew1 aPadhukasahasram, Badri1 aPalmer, Julie1 aPalmer, Cameron, D1 aPalmer, Nicholette, D1 aPapanicolaou, George1 aPatel, Sanjay, R1 aPettaway, Curtis, A1 aPeyser, Patricia, A1 aPress, Michael, F1 aRao, D, C1 aRasmussen-Torvik, Laura, J1 aRedline, Susan1 aReiner, Alex, P1 aRhie, Suhn, K1 aRodriguez-Gil, Jorge, L1 aRotimi, Charles, N1 aRotter, Jerome, I1 aRuiz-Narvaez, Edward, A1 aRybicki, Benjamin, A1 aSalako, Babatunde1 aSale, Michèle, M1 aSanderson, Maureen1 aSchadt, Eric1 aSchreiner, Pamela, J1 aSchurmann, Claudia1 aSchwartz, Ann, G1 aShriner, Daniel, A1 aSignorello, Lisa, B1 aSingleton, Andrew, B1 aSiscovick, David, S1 aSmith, Jennifer, A1 aSmith, Shad1 aSpeliotes, Elizabeth1 aSpitz, Margaret1 aStanford, Janet, L1 aStevens, Victoria, L1 aStram, Alex1 aStrom, Sara, S1 aSucheston, Lara1 aSun, Yan, V1 aTajuddin, Salman, M1 aTaylor, Herman1 aTaylor, Kira1 aTayo, Bamidele, O1 aThun, Michael, J1 aTucker, Margaret, A1 aVaidya, Dhananjay1 aVan Den Berg, David, J1 aVedantam, Sailaja1 aVitolins, Mara1 aWang, Zhaoming1 aWare, Erin, B1 aWassertheil-Smoller, Sylvia1 aWeir, David, R1 aWiencke, John, K1 aWilliams, Scott, M1 aWilliams, Keoki1 aWilson, James, G1 aWitte, John, S1 aWrensch, Margaret1 aWu, Xifeng1 aYao, Jie1 aZakai, Neil1 aZanetti, Krista1 aZemel, Babette, S1 aZhao, Wei1 aZhao, Jing Hua1 aZheng, Wei1 aZhi, Degui1 aZhou, Jie1 aZhu, Xiaofeng1 aZiegler, Regina, G1 aZmuda, Joe1 aZonderman, Alan, B1 aPsaty, Bruce, M1 aBorecki, Ingrid, B1 aCupples, Adrienne, L1 aLiu, Ching-Ti1 aHaiman, Christopher, A1 aLoos, Ruth1 aC Y Ng, Maggie1 aNorth, Kari, E uhttps://chs-nhlbi.org/node/8705