05943nas a2201657 4500008004100000022001400041245014100055210006900196260001600265300001100281490000700292520126000299653005101559653001001610653003901620653000901659653001201668653001201680653002101692653002101713653001901734653002101753653004001774653001101814653001901825653003201844653001701876653002201893653001101915653001801926653000901944653000901953653002301962653003601985653001602021653001402037653002702051653001602078653001802094100002002112700001802132700001902150700001902169700002402188700002402212700002302236700002502259700002002284700002002304700001802324700002602342700002102368700001702389700002502406700002102431700001702452700001702469700001802486700002102504700002002525700001802545700001902563700002302582700001602605700001902621700002502640700002402665700002202689700002202711700002602733700002402759700002502783700002602808700002102834700001902855700002802874700002202902700002002924700002602944700002502970700002502995700001903020700002103039700002303060700001803083700001803101700002003119700002403139700001903163700002503182700002003207700001803227700002903245700002003274700001503294700002103309700002203330700002303352700001903375700002203394700001603416700002103432700002403453700002003477700001803497700002103515700001903536700001503555700002103570700002203591700001903613700002503632700002103657700001903678700001603697700002403713700002203737700002103759700001703780700001903797700002503816700002203841700001903863700001803882700002303900700001703923700002403940700002103964700002303985700002404008700002104032700002004053700002204073700003004095700001804125700002104143700002204164700002504186710003804211856003604249 2014 eng d a1537-660500aAssociation of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks.0 aAssociation of lowfrequency and rare codingsequence variants wit c2014 Feb 06 a223-320 v943 a
Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.
10a1-Alkyl-2-acetylglycerophosphocholine Esterase10aAdult10aAfrican Continental Ancestry Group10aAged10aAlleles10aAnimals10aCholesterol, HDL10aCholesterol, LDL10aCohort Studies10aCoronary Disease10aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aGenetic Association Studies10aGenetic Code10aGenetic Variation10aHumans10aLinear Models10aMale10aMice10aMice, Inbred C57BL10aMicrotubule-Associated Proteins10aMiddle Aged10aPhenotype10aSequence Analysis, DNA10aSubtilisins10aTriglycerides1 aPeloso, Gina, M1 aAuer, Paul, L1 aBis, Joshua, C1 aVoorman, Arend1 aMorrison, Alanna, C1 aStitziel, Nathan, O1 aBrody, Jennifer, A1 aKhetarpal, Sumeet, A1 aCrosby, Jacy, R1 aFornage, Myriam1 aIsaacs, Aaron1 aJakobsdottir, Johanna1 aFeitosa, Mary, F1 aDavies, Gail1 aHuffman, Jennifer, E1 aManichaikul, Ani1 aDavis, Brian1 aLohman, Kurt1 aJoon, Aron, Y1 aSmith, Albert, V1 aGrove, Megan, L1 aZanoni, Paolo1 aRedon, Valeska1 aDemissie, Serkalem1 aLawson, Kim1 aPeters, Ulrike1 aCarlson, Christopher1 aJackson, Rebecca, D1 aRyckman, Kelli, K1 aMackey, Rachel, H1 aRobinson, Jennifer, G1 aSiscovick, David, S1 aSchreiner, Pamela, J1 aMychaleckyj, Josyf, C1 aPankow, James, S1 aHofman, Albert1 aUitterlinden, André, G1 aHarris, Tamara, B1 aTaylor, Kent, D1 aStafford, Jeanette, M1 aReynolds, Lindsay, M1 aMarioni, Riccardo, E1 aDehghan, Abbas1 aFranco, Oscar, H1 aPatel, Aniruddh, P1 aLu, Yingchang1 aHindy, George1 aGottesman, Omri1 aBottinger, Erwin, P1 aMelander, Olle1 aOrho-Melander, Marju1 aLoos, Ruth, J F1 aDuga, Stefano1 aMerlini, Piera, Angelica1 aFarrall, Martin1 aGoel, Anuj1 aAsselta, Rosanna1 aGirelli, Domenico1 aMartinelli, Nicola1 aShah, Svati, H1 aKraus, William, E1 aLi, Mingyao1 aRader, Daniel, J1 aReilly, Muredach, P1 aMcPherson, Ruth1 aWatkins, Hugh1 aArdissino, Diego1 aZhang, Qunyuan1 aWang, Judy1 aTsai, Michael, Y1 aTaylor, Herman, A1 aCorrea, Adolfo1 aGriswold, Michael, E1 aLange, Leslie, A1 aStarr, John, M1 aRudan, Igor1 aEiriksdottir, Gudny1 aLauner, Lenore, J1 aOrdovas, Jose, M1 aLevy, Daniel1 aChen, Y-D, Ida1 aReiner, Alexander, P1 aHayward, Caroline1 aPolasek, Ozren1 aDeary, Ian, J1 aBorecki, Ingrid, B1 aLiu, Yongmei1 aGudnason, Vilmundur1 aWilson, James, G1 aDuijn, Cornelia, M1 aKooperberg, Charles1 aRich, Stephen, S1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aO'Donnell, Christopher, J1 aRice, Kenneth1 aBoerwinkle, Eric1 aKathiresan, Sekar1 aCupples, Adrienne, L1 aNHLBI GO Exome Sequencing Project uhttps://chs-nhlbi.org/node/659005734nas a2201333 4500008004100000022001400041245007800055210006900133260001500202300001000217490000800227520196900235653003902204653002502243653002102268653004002289653001002329653001302339653001702352653001102369653001002380653001302390653001702403653002702420653001802447110010402465700001702569700002002586700001802606700002302624700002402647700002102671700001802692700002202710700001402732700001802746700002002764700002302784700002202807700001202829700001302841700001402854700002002868700001602888700001502904700002002919700001802939700002802957700002102985700002203006700002303028700002303051700001203074700001903086700002503105700002103130700002003151700002303171700001803194700002303212700002903235700002303264700002303287700001903310700002003329700001903349700001903368700002203387700002403409700002403433700002303457700002203480700001703502700002203519700002003541700001903561700001903580700002003599700001903619700002603638700002003664700002403684700003003708700002003738700002803758700002203786700002103808700001903829700001803848700002503866700002103891700002003912700002003932700002303952700002203975700002203997700002204019700002004041700002404061700002104085700002404106700002104130700002204151700001604173700002104189700002004210700002604230700002004256700002504276700002004301700002104321700002204342856003604364 2014 eng d a1533-440600aLoss-of-function mutations in APOC3, triglycerides, and coronary disease.0 aLossoffunction mutations in APOC3 triglycerides and coronary dis c2014 Jul 3 a22-310 v3713 aBACKGROUND: Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype.
METHODS: We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons.
RESULTS: An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P=8×10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P=4×10(-6)).
CONCLUSIONS: Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.).
10aAfrican Continental Ancestry Group10aApolipoprotein C-III10aCoronary Disease10aEuropean Continental Ancestry Group10aExome10aGenotype10aHeterozygote10aHumans10aLiver10aMutation10aRisk Factors10aSequence Analysis, DNA10aTriglycerides1 aTG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute1 aCrosby, Jacy1 aPeloso, Gina, M1 aAuer, Paul, L1 aCrosslin, David, R1 aStitziel, Nathan, O1 aLange, Leslie, A1 aLu, Yingchang1 aTang, Zheng-Zheng1 aZhang, He1 aHindy, George1 aMasca, Nicholas1 aStirrups, Kathleen1 aKanoni, Stavroula1 aDo, Ron1 aJun, Goo1 aHu, Youna1 aKang, Hyun, Min1 aXue, Chenyi1 aGoel, Anuj1 aFarrall, Martin1 aDuga, Stefano1 aMerlini, Pier, Angelica1 aAsselta, Rosanna1 aGirelli, Domenico1 aOlivieri, Oliviero1 aMartinelli, Nicola1 aYin, Wu1 aReilly, Dermot1 aSpeliotes, Elizabeth1 aFox, Caroline, S1 aHveem, Kristian1 aHolmen, Oddgeir, L1 aNikpay, Majid1 aFarlow, Deborah, N1 aAssimes, Themistocles, L1 aFranceschini, Nora1 aRobinson, Jennifer1 aNorth, Kari, E1 aMartin, Lisa, W1 aDePristo, Mark1 aGupta, Namrata1 aEscher, Stefan, A1 aJansson, Jan-Håkan1 aVan Zuydam, Natalie1 aPalmer, Colin, N A1 aWareham, Nicholas1 aKoch, Werner1 aMeitinger, Thomas1 aPeters, Annette1 aLieb, Wolfgang1 aErbel, Raimund1 aKönig, Inke, R1 aKruppa, Jochen1 aDegenhardt, Franziska1 aGottesman, Omri1 aBottinger, Erwin, P1 aO'Donnell, Christopher, J1 aPsaty, Bruce, M1 aBallantyne, Christie, M1 aAbecasis, Goncalo1 aOrdovas, Jose, M1 aMelander, Olle1 aWatkins, Hugh1 aOrho-Melander, Marju1 aArdissino, Diego1 aLoos, Ruth, J F1 aMcPherson, Ruth1 aWiller, Cristen, J1 aErdmann, Jeanette1 aHall, Alistair, S1 aSamani, Nilesh, J1 aDeloukas, Panos1 aSchunkert, Heribert1 aWilson, James, G1 aKooperberg, Charles1 aRich, Stephen, S1 aTracy, Russell, P1 aLin, Dan-Yu1 aAltshuler, David1 aGabriel, Stacey1 aNickerson, Deborah, A1 aJarvik, Gail, P1 aCupples, Adrienne, L1 aReiner, Alex, P1 aBoerwinkle, Eric1 aKathiresan, Sekar uhttps://chs-nhlbi.org/node/660503227nas a2200505 4500008004100000022001400041245012600055210006900181260001600250300001200266490000700278520166100285653003501946653002301981653004002004653001002044653001102054653003202065653002102097653002602118100002002144700002002164700002302184700002402207700002902231700001802260700002502278700001902303700002602322700002302348700001702371700002202388700002202410700002002432700002402452700002502476700003002501700002502531700002102556700002002577700002402597700002602621710003802647856003602685 2014 eng d a1460-208300aQuantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset.0 aQuantifying rare deleterious variation in 12 human cytochrome P4 c2014 Apr 15 a1957-630 v233 aThe study of genetic influences on drug response and efficacy ('pharmacogenetics') has existed for over 50 years. Yet, we still lack a complete picture of how genetic variation, both common and rare, affects each individual's responses to medications. Exome sequencing is a promising alternative method for pharmacogenetic discovery as it provides information on both common and rare variation in large numbers of individuals. Using exome data from 2203 AA and 4300 Caucasian individuals through the NHLBI Exome Sequencing Project, we conducted a survey of coding variation within 12 Cytochrome P450 (CYP) genes that are collectively responsible for catalyzing nearly 75% of all known Phase I drug oxidation reactions. In addition to identifying many polymorphisms with known pharmacogenetic effects, we discovered over 730 novel nonsynonymous alleles across the 12 CYP genes of interest. These alleles include many with diverse functional effects such as premature stop codons, aberrant splicesites and mutations at conserved active site residues. Our analysis considering both novel, predicted functional alleles as well as known, actionable CYP alleles reveals that rare, deleterious variation contributes markedly to the overall burden of pharmacogenetic alleles within the populations considered, and that the contribution of rare variation to this burden is over three times greater in AA individuals as compared with Caucasians. While most of these impactful alleles are individually rare, 7.6-11.7% of individuals interrogated in the study carry at least one newly described potentially deleterious alleles in a major drug-metabolizing CYP.
10aCytochrome P-450 Enzyme System10aDatabases, Genetic10aEuropean Continental Ancestry Group10aExome10aHumans10aPharmaceutical Preparations10aPharmacogenetics10aPolymorphism, Genetic1 aGordon, Adam, S1 aTabor, Holly, K1 aJohnson, Andrew, D1 aSnively, Beverly, M1 aAssimes, Themistocles, L1 aAuer, Paul, L1 aIoannidis, John, P A1 aPeters, Ulrike1 aRobinson, Jennifer, G1 aSucheston, Lara, E1 aWang, Danxin1 aSotoodehnia, Nona1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aJackson, Rebecca, D1 aHerrington, David, M1 aO'Donnell, Christopher, J1 aReiner, Alexander, P1 aRich, Stephen, S1 aRieder, Mark, J1 aBamshad, Michael, J1 aNickerson, Deborah, A1 aNHLBI GO Exome Sequencing Project uhttps://chs-nhlbi.org/node/656504486nas a2200901 4500008004100000022001400041245009600055210006900151260001600220300001100236490000700247520184700254653001002101653002202111653002302133653002802156653001902184653004002203653001002243653001102253653001902264653003802283653003402321653003802355653001102393653000902404653001102413653003602424653002902460653001702489100002202506700001802528700001902546700001902565700001402584700002102598700002102619700002002640700002402660700001902684700002802703700002002731700002202751700001202773700002402785700002402809700002102833700002002854700002102874700001902895700002102914700001602935700002002951700001502971700001902986700002003005700001803025700002103043700001803064700002203082700002403104700002303128700002303151700001903174700002603193700002203219700001903241700001903260700002103279700002103300700002403321700002403345700002003369700002003389710006503409710007403474856003603548 2015 eng d a1460-208300aAssociation of exome sequences with plasma C-reactive protein levels in >9000 participants.0 aAssociation of exome sequences with plasma Creactive protein lev c2015 Jan 15 a559-710 v243 aC-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in ∼25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 × 10(-6)). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 × 10(-15)). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-ε2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 × 10(-8)), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In gene-based tests, a burden of rare/lower frequency variation in CRP in EAs (P ≤ 6.8 × 10(-4)) and in retinoic acid receptor-related orphan receptor α (RORA) in AAs (P = 1.7 × 10(-3)) were associated with CRP levels at the candidate gene level (P < 2.0 × 10(-3)). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels.
10aAdult10aAfrican Americans10aC-Reactive Protein10aCardiovascular Diseases10aCohort Studies10aEuropean Continental Ancestry Group10aExome10aFemale10aGene Frequency10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHepatocyte Nuclear Factor 1-alpha10aHumans10aMale10aPlasma10aPolymorphism, Single Nucleotide10aReceptors, Interleukin-610aRisk Factors1 aSchick, Ursula, M1 aAuer, Paul, L1 aBis, Joshua, C1 aLin, Honghuang1 aWei, Peng1 aPankratz, Nathan1 aLange, Leslie, A1 aBrody, Jennifer1 aStitziel, Nathan, O1 aKim, Daniel, S1 aCarlson, Christopher, S1 aFornage, Myriam1 aHaessler, Jeffery1 aHsu, Li1 aJackson, Rebecca, D1 aKooperberg, Charles1 aLeal, Suzanne, M1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aTracy, Russell1 aArdissino, Diego1 aShah, Svati1 aWiller, Cristen1 aLoos, Ruth1 aMelander, Olle1 aMcPherson, Ruth1 aHovingh, Kees1 aReilly, Muredach1 aWatkins, Hugh1 aGirelli, Domenico1 aFontanillas, Pierre1 aChasman, Daniel, I1 aGabriel, Stacey, B1 aGibbs, Richard1 aNickerson, Deborah, A1 aKathiresan, Sekar1 aPeters, Ulrike1 aDupuis, Josée1 aWilson, James, G1 aRich, Stephen, S1 aMorrison, Alanna, C1 aBenjamin, Emelia, J1 aGross, Myron, D1 aReiner, Alex, P1 aCohorts for Heart and Aging Research in Genomic Epidemiology1 aNational Heart, Lung, and Blood Institute GO Exome Sequencing Project uhttps://chs-nhlbi.org/node/659706191nas a2201513 4500008004100000022001400041245010300055210006900158260001500227300001000242490000800252520194100260653001602201653001702217653001202234653002202246653002502268653002102293653002802314653001002342653001102352653003802363653002502401653001702426653001102443653000902454653001602463653001302479653002602492653005302518653001902571653001802590653001802608100001202626700002402638700001802662700002902680700001802709700002802727700001702755700002002772700001502792700001202807700002002819700002102839700002102860700002002881700001802901700002202919700002302941700002302964700002202987700002003009700002803029700002103057700001703078700002403095700002803119700001803147700002303165700002203188700002403210700002203234700001903256700002203275700001903297700001803316700002903334700001503363700002203378700002003400700002003420700002203440700001503462700002303477700001603500700001903516700001703535700001703552700002903569700001903598700002003617700002103637700002203658700002303680700002003703700001903723700002203742700001203764700002103776700002003797700002403817700002003841700002503861700002103886700002103907700002403928700002203952700002503974700002103999700002404020700002104044700001904065700002004084700002204104700002204126700002004148700002004168700002804188700002404216700002404240700002104264700002004285700002504305700002404330700002004354700002604374700002504400700001804425700002604443700002104469700002304490700003004513700002104543700002004564700002204584710003504606856003604641 2015 eng d a1476-468700aExome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.0 aExome sequencing identifies rare LDLR and APOA5 alleles conferri c2015 Feb 5 a102-60 v5183 aMyocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.
10aAge Factors10aAge of Onset10aAlleles10aApolipoproteins A10aCase-Control Studies10aCholesterol, LDL10aCoronary Artery Disease10aExome10aFemale10aGenetic Predisposition to Disease10aGenetics, Population10aHeterozygote10aHumans10aMale10aMiddle Aged10aMutation10aMyocardial Infarction10aNational Heart, Lung, and Blood Institute (U.S.)10aReceptors, LDL10aTriglycerides10aUnited States1 aDo, Ron1 aStitziel, Nathan, O1 aWon, Hong-Hee1 aJørgensen, Anders, Berg1 aDuga, Stefano1 aMerlini, Pier, Angelica1 aKiezun, Adam1 aFarrall, Martin1 aGoel, Anuj1 aZuk, Or1 aGuella, Illaria1 aAsselta, Rosanna1 aLange, Leslie, A1 aPeloso, Gina, M1 aAuer, Paul, L1 aGirelli, Domenico1 aMartinelli, Nicola1 aFarlow, Deborah, N1 aDePristo, Mark, A1 aRoberts, Robert1 aStewart, Alexander, F R1 aSaleheen, Danish1 aDanesh, John1 aEpstein, Stephen, E1 aSivapalaratnam, Suthesh1 aHovingh, Kees1 aKastelein, John, J1 aSamani, Nilesh, J1 aSchunkert, Heribert1 aErdmann, Jeanette1 aShah, Svati, H1 aKraus, William, E1 aDavies, Robert1 aNikpay, Majid1 aJohansen, Christopher, T1 aWang, Jian1 aHegele, Robert, A1 aHechter, Eliana1 aMärz, Winfried1 aKleber, Marcus, E1 aHuang, Jie1 aJohnson, Andrew, D1 aLi, Mingyao1 aBurke, Greg, L1 aGross, Myron1 aLiu, Yongmei1 aAssimes, Themistocles, L1 aHeiss, Gerardo1 aLange, Ethan, M1 aFolsom, Aaron, R1 aTaylor, Herman, A1 aOlivieri, Oliviero1 aHamsten, Anders1 aClarke, Robert1 aReilly, Dermot, F1 aYin, Wu1 aRivas, Manuel, A1 aDonnelly, Peter1 aRossouw, Jacques, E1 aPsaty, Bruce, M1 aHerrington, David, M1 aWilson, James, G1 aRich, Stephen, S1 aBamshad, Michael, J1 aTracy, Russell, P1 aCupples, Adrienne, L1 aRader, Daniel, J1 aReilly, Muredach, P1 aSpertus, John, A1 aCresci, Sharon1 aHartiala, Jaana1 aTang, W, H Wilson1 aHazen, Stanley, L1 aAllayee, Hooman1 aReiner, Alex, P1 aCarlson, Christopher, S1 aKooperberg, Charles1 aJackson, Rebecca, D1 aBoerwinkle, Eric1 aLander, Eric, S1 aSchwartz, Stephen, M1 aSiscovick, David, S1 aMcPherson, Ruth1 aTybjaerg-Hansen, Anne1 aAbecasis, Goncalo, R1 aWatkins, Hugh1 aNickerson, Deborah, A1 aArdissino, Diego1 aSunyaev, Shamil, R1 aO'Donnell, Christopher, J1 aAltshuler, David1 aGabriel, Stacey1 aKathiresan, Sekar1 aNHLBI Exome Sequencing Project uhttps://chs-nhlbi.org/node/669104841nas a2200685 4500008004100000022001400041245011900055210006900174260001300243300001000256490000700266520281800273653000903091653001903100653001003119653001103129653003803140653002203178653003403200653001103234653000903245653001603254653002003270653005303290653002103343653002403364653002803388653001103416653001803427100001803445700001603463700002203479700002503501700002003526700002003546700002403566700002403590700002803614700001903642700001803661700002503679700002403704700002003728700001603748700001203764700002403776700002003800700001903820700002903839700002103868700002103889700002203910700002503932700002503957700002603982700001904008700002104027710007104048856003604119 2015 eng d a2168-615700aRare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project.0 aRare and Coding Region Genetic Variants Associated With Risk of c2015 Jul a781-80 v723 aIMPORTANCE: Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk.
OBJECTIVE: To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome.
DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP's exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013.
MAIN OUTCOMES AND MEASURES: Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis).
RESULTS: We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 × 10(-8)) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 × 10(-7)) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke).
CONCLUSIONS AND RELEVANCE: Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.
10aAged10aBrain Ischemia10aExome10aFemale10aGenetic Predisposition to Disease10aGenetic Variation10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aMuscle Proteins10aNational Heart, Lung, and Blood Institute (U.S.)10aNuclear Proteins10aOpen Reading Frames10aPalmitoyl-CoA Hydrolase10aStroke10aUnited States1 aAuer, Paul, L1 aNalls, Mike1 aMeschia, James, F1 aWorrall, Bradford, B1 aLongstreth, W T1 aSeshadri, Sudha1 aKooperberg, Charles1 aBurger, Kathleen, M1 aCarlson, Christopher, S1 aCarty, Cara, L1 aChen, Wei-Min1 aCupples, Adrienne, L1 aDeStefano, Anita, L1 aFornage, Myriam1 aHardy, John1 aHsu, Li1 aJackson, Rebecca, D1 aJarvik, Gail, P1 aKim, Daniel, S1 aLakshminarayan, Kamakshi1 aLange, Leslie, A1 aManichaikul, Ani1 aQuinlan, Aaron, R1 aSingleton, Andrew, B1 aThornton, Timothy, A1 aNickerson, Deborah, A1 aPeters, Ulrike1 aRich, Stephen, S1 aNational Heart, Lung, and Blood Institute Exome Sequencing Project uhttps://chs-nhlbi.org/node/684904476nas a2201081 4500008004100000022001400041245011400055210006900169260001600238300001100254490000800265520141200273653001901685653001501704653001601719653001501735653001901750653003201769653002201801653001101823653002601834653003601860653002301896653002601919100002501945700002201970700002401992700002502016700002002041700001802061700002302079700002302102700002002125700001702145700001502162700002502177700003002202700001902232700002102251700002002272700002502292700001802317700002202335700001502357700002002372700002102392700001902413700001802432700002602450700001902476700001502495700002002510700002202530700002802552700002202580700001302602700001802615700001702633700002602650700002102676700002102697700002302718700002402741700001902765700002402784700002402808700002102832700001902853700002402872700002502896700002002921700002202941700002102963700001602984700002303000700002003023700002003043700002403063700001703087700001803104700002003122700002003142700001803162700002103180700002103201700002203222700002203244700001903266700002003285700003003305700002303335856003603358 2015 eng d a1528-002000aRare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF.0 aRare and lowfrequency variants and their association with plasma c2015 Sep 10 ae19-290 v1263 aFibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] ≥0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76,000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n = 2) and rare (n = 10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identified new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information for understanding individual variation in hemostasis pathways.
10aCohort Studies10aFactor VII10aFactor VIII10aFibrinogen10aGene Frequency10aGenetic Association Studies10aGenetic Variation10aHumans10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aPotassium Channels10avon Willebrand Factor1 aHuffman, Jennifer, E1 ade Vries, Paul, S1 aMorrison, Alanna, C1 aSabater-Lleal, Maria1 aKacprowski, Tim1 aAuer, Paul, L1 aBrody, Jennifer, A1 aChasman, Daniel, I1 aChen, Ming-Huei1 aGuo, Xiuqing1 aLin, Li-An1 aMarioni, Riccardo, E1 aMüller-Nurasyid, Martina1 aYanek, Lisa, R1 aPankratz, Nathan1 aGrove, Megan, L1 ade Maat, Moniek, P M1 aCushman, Mary1 aWiggins, Kerri, L1 aQi, Lihong1 aSennblad, Bengt1 aHarris, Sarah, E1 aPolasek, Ozren1 aRiess, Helene1 aRivadeneira, Fernando1 aRose, Lynda, M1 aGoel, Anuj1 aTaylor, Kent, D1 aTeumer, Alexander1 aUitterlinden, André, G1 aVaidya, Dhananjay1 aYao, Jie1 aTang, Weihong1 aLevy, Daniel1 aWaldenberger, Melanie1 aBecker, Diane, M1 aFolsom, Aaron, R1 aGiulianini, Franco1 aGreinacher, Andreas1 aHofman, Albert1 aHuang, Chiang-Ching1 aKooperberg, Charles1 aSilveira, Angela1 aStarr, John, M1 aStrauch, Konstantin1 aStrawbridge, Rona, J1 aWright, Alan, F1 aMcKnight, Barbara1 aFranco, Oscar, H1 aZakai, Neil1 aMathias, Rasika, A1 aPsaty, Bruce, M1 aRidker, Paul, M1 aTofler, Geoffrey, H1 aVölker, Uwe1 aWatkins, Hugh1 aFornage, Myriam1 aHamsten, Anders1 aDeary, Ian, J1 aBoerwinkle, Eric1 aKoenig, Wolfgang1 aRotter, Jerome, I1 aHayward, Caroline1 aDehghan, Abbas1 aReiner, Alex, P1 aO'Donnell, Christopher, J1 aSmith, Nicholas, L uhttps://chs-nhlbi.org/node/678806025nas a2201489 4500008004100000022001400041245009200055210006900147260001500216300000900231490000700240520184700247100002002094700002002114700002202134700002002156700002502176700002402201700002602225700002002251700002202271700002002293700001602313700002002329700002302349700002302372700002102395700001902416700002102435700001702456700002102473700001602494700002302510700001602533700002002549700002102569700002102590700002102611700002302632700002402655700002802679700002302707700002002730700002402750700001802774700002202792700002202814700002002836700002002856700001202876700002402888700002402912700001902936700002202955700002202977700002302999700002503022700002403047700001903071700002503090700002003115700001703135700002203152700002203174700001203196700002403208700002103232700001703253700001803270700002803288700001803316700002303334700001903357700002103376700001803397700001903415700002603434700001703460700002403477700002503501700001903526700002303545700001803568700002003586700002303606700002103629700002103650700002103671700002603692700002203718700001903740700002603759700001903785700002003804700002203824700002303846700002403869700002203893700002103915700001903936700002703955700002303982700002604005700001804031700001804049700002804067700002604095700002004121700002404141700002104165700002104186700002304207700002204230700001804252700001604270700002004286700002104306700002004327700002104347700002104368700002204389700001804411700002304429700002504452700002204477856003604499 2016 eng d a1537-660500aExome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits.0 aExome Genotyping Identifies Pleiotropic Variants Associated with c2016 Jul 7 a8-210 v993 aRed blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.
1 aChami, Nathalie1 aChen, Ming-Huei1 aSlater, Andrew, J1 aEicher, John, D1 aEvangelou, Evangelos1 aTajuddin, Salman, M1 aLove-Gregory, Latisha1 aKacprowski, Tim1 aSchick, Ursula, M1 aNomura, Akihiro1 aGiri, Ayush1 aLessard, Samuel1 aBrody, Jennifer, A1 aSchurmann, Claudia1 aPankratz, Nathan1 aYanek, Lisa, R1 aManichaikul, Ani1 aPazoki, Raha1 aMihailov, Evelin1 aHill, David1 aRaffield, Laura, M1 aBurt, Amber1 aBartz, Traci, M1 aBecker, Diane, M1 aBecker, Lewis, C1 aBoerwinkle, Eric1 aBork-Jensen, Jette1 aBottinger, Erwin, P1 aO'Donoghue, Michelle, L1 aCrosslin, David, R1 ade Denus, Simon1 aDubé, Marie-Pierre1 aElliott, Paul1 aEngström, Gunnar1 aEvans, Michele, K1 aFloyd, James, S1 aFornage, Myriam1 aGao, He1 aGreinacher, Andreas1 aGudnason, Vilmundur1 aHansen, Torben1 aHarris, Tamara, B1 aHayward, Caroline1 aHernesniemi, Jussi1 aHighland, Heather, M1 aHirschhorn, Joel, N1 aHofman, Albert1 aIrvin, Marguerite, R1 aKähönen, Mika1 aLange, Ethan1 aLauner, Lenore, J1 aLehtimäki, Terho1 aLi, Jin1 aLiewald, David, C M1 aLinneberg, Allan1 aLiu, Yongmei1 aLu, Yingchang1 aLyytikäinen, Leo-Pekka1 aMägi, Reedik1 aMathias, Rasika, A1 aMelander, Olle1 aMetspalu, Andres1 aMononen, Nina1 aNalls, Mike, A1 aNickerson, Deborah, A1 aNikus, Kjell1 aO'Donnell, Chris, J1 aOrho-Melander, Marju1 aPedersen, Oluf1 aPetersmann, Astrid1 aPolfus, Linda1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRaitoharju, Emma1 aRichard, Melissa1 aRice, Kenneth, M1 aRivadeneira, Fernando1 aRotter, Jerome, I1 aSchmidt, Frank1 aSmith, Albert, Vernon1 aStarr, John, M1 aTaylor, Kent, D1 aTeumer, Alexander1 aThuesen, Betina, H1 aTorstenson, Eric, S1 aTracy, Russell, P1 aTzoulaki, Ioanna1 aZakai, Neil, A1 aVacchi-Suzzi, Caterina1 aDuijn, Cornelia, M1 avan Rooij, Frank, J A1 aCushman, Mary1 aDeary, Ian, J1 aEdwards, Digna, R Velez1 aVergnaud, Anne-Claire1 aWallentin, Lars1 aWaterworth, Dawn, M1 aWhite, Harvey, D1 aWilson, James, G1 aZonderman, Alan, B1 aKathiresan, Sekar1 aGrarup, Niels1 aEsko, Tõnu1 aLoos, Ruth, J F1 aLange, Leslie, A1 aFaraday, Nauder1 aAbumrad, Nada, A1 aEdwards, Todd, L1 aGanesh, Santhi, K1 aAuer, Paul, L1 aJohnson, Andrew, D1 aReiner, Alexander, P1 aLettre, Guillaume uhttps://chs-nhlbi.org/node/713805559nas a2201297 4500008004100000022001400041245013800055210006900193260001500262300001000277490000700287520188700294100002402181700002202205700002002227700002002247700001602267700002302283700001602306700002002322700001202342700002802354700002102382700002102403700002802424700002102452700001702473700002102490700002602511700002302537700002702560700002402587700002502611700001902636700001602655700002002671700002602691700002002717700002402737700002202761700002502783700002102808700001702829700001802846700001902864700002302883700002602906700001702932700001902949700002402968700002102992700002803013700002003041700002003061700002103081700002103102700002303123700001903146700002003165700002003185700001203205700002403217700002403241700002103265700002403286700002103310700002103331700002103352700002003373700002403393700002203417700001903439700001803458700001703476700002203493700002203515700001803537700002103555700002403576700002403600700002103624700002403645700002003669700002603689700002303715700002303738700001803761700001803779700001803797700002203815700002403837700002003861700002003881700002203901700002203923700001903945700002103964700002203985700002004007700001604027700002004043700002104063700001804084700002304102700002104125700001904146700002204165700002004187700001804207856003604225 2016 eng d a1537-660500aLarge-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.0 aLargeScale Exomewide Association Analysis Identifies Loci for Wh c2016 Jul 7 a22-390 v993 aWhite blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.
1 aTajuddin, Salman, M1 aSchick, Ursula, M1 aEicher, John, D1 aChami, Nathalie1 aGiri, Ayush1 aBrody, Jennifer, A1 aHill, David1 aKacprowski, Tim1 aLi, Jin1 aLyytikäinen, Leo-Pekka1 aManichaikul, Ani1 aMihailov, Evelin1 aO'Donoghue, Michelle, L1 aPankratz, Nathan1 aPazoki, Raha1 aPolfus, Linda, M1 aSmith, Albert, Vernon1 aSchurmann, Claudia1 aVacchi-Suzzi, Caterina1 aWaterworth, Dawn, M1 aEvangelou, Evangelos1 aYanek, Lisa, R1 aBurt, Amber1 aChen, Ming-Huei1 avan Rooij, Frank, J A1 aFloyd, James, S1 aGreinacher, Andreas1 aHarris, Tamara, B1 aHighland, Heather, M1 aLange, Leslie, A1 aLiu, Yongmei1 aMägi, Reedik1 aNalls, Mike, A1 aMathias, Rasika, A1 aNickerson, Deborah, A1 aNikus, Kjell1 aStarr, John, M1 aTardif, Jean-Claude1 aTzoulaki, Ioanna1 aEdwards, Digna, R Velez1 aWallentin, Lars1 aBartz, Traci, M1 aBecker, Lewis, C1 aDenny, Joshua, C1 aRaffield, Laura, M1 aRioux, John, D1 aFriedrich, Nele1 aFornage, Myriam1 aGao, He1 aHirschhorn, Joel, N1 aLiewald, David, C M1 aRich, Stephen, S1 aUitterlinden, Andre1 aBastarache, Lisa1 aBecker, Diane, M1 aBoerwinkle, Eric1 ade Denus, Simon1 aBottinger, Erwin, P1 aHayward, Caroline1 aHofman, Albert1 aHomuth, Georg1 aLange, Ethan1 aLauner, Lenore, J1 aLehtimäki, Terho1 aLu, Yingchang1 aMetspalu, Andres1 aO'Donnell, Chris, J1 aQuarells, Rakale, C1 aRichard, Melissa1 aTorstenson, Eric, S1 aTaylor, Kent, D1 aVergnaud, Anne-Claire1 aZonderman, Alan, B1 aCrosslin, David, R1 aDeary, Ian, J1 aDörr, Marcus1 aElliott, Paul1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKähönen, Mika1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aSlater, Andrew, J1 aDehghan, Abbas1 aWhite, Harvey, D1 aGanesh, Santhi, K1 aLoos, Ruth, J F1 aEsko, Tõnu1 aFaraday, Nauder1 aWilson, James, G1 aCushman, Mary1 aJohnson, Andrew, D1 aEdwards, Todd, L1 aZakai, Neil, A1 aLettre, Guillaume1 aReiner, Alex, P1 aAuer, Paul, L uhttps://chs-nhlbi.org/node/714604937nas a2201345 4500008004100000022001400041245012400055210006900179260001300248300001200261490000700273520113500280100001601415700001901431700002301450700002301473700002301496700001901519700001801538700002401556700001801580700001801598700001701616700001901633700002001652700002201672700002301694700001901717700001901736700001801755700001901773700001601792700001401808700002601822700001501848700002601863700001601889700001301905700001301918700001901931700002201950700002001972700002101992700002002013700001402033700001902047700001802066700002402084700002202108700001902130700002402149700002002173700001202193700002702205700002202232700002002254700002402274700002802298700002402326700002102350700002402371700002102395700002202416700002802438700002102466700002702487700003002514700002002544700001502564700002402579700002002603700001702623700002302640700001902663700001902682700002202701700002202723700001802745700002202763700001902785700001902804700001402823700001802837700001402855700002102869700002302890700002802913700001702941700001902958700001902977700001702996700002003013700002103033700002403054700002503078700002303103700002303126700002103149700002603170700002203196700002003218700002003238700002003258700002003278700002903298700001703327700002303344710002603367710002303393710002603416710002503442710006603467710002203533856003603555 2016 eng d a1546-171800aMeta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci.0 aMetaanalysis identifies common and rare variants influencing blo c2016 Oct a1162-700 v483 aMeta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.
1 aLiu, Chunyu1 aKraja, Aldi, T1 aSmith, Jennifer, A1 aBrody, Jennifer, A1 aFranceschini, Nora1 aBis, Joshua, C1 aRice, Kenneth1 aMorrison, Alanna, C1 aLu, Yingchang1 aWeiss, Stefan1 aGuo, Xiuqing1 aPalmas, Walter1 aMartin, Lisa, W1 aChen, Yii-Der Ida1 aSurendran, Praveen1 aDrenos, Fotios1 aCook, James, P1 aAuer, Paul, L1 aChu, Audrey, Y1 aGiri, Ayush1 aZhao, Wei1 aJakobsdottir, Johanna1 aLin, Li-An1 aStafford, Jeanette, M1 aAmin, Najaf1 aMei, Hao1 aYao, Jie1 aVoorman, Arend1 aLarson, Martin, G1 aGrove, Megan, L1 aSmith, Albert, V1 aHwang, Shih-Jen1 aChen, Han1 aHuan, Tianxiao1 aKosova, Gulum1 aStitziel, Nathan, O1 aKathiresan, Sekar1 aSamani, Nilesh1 aSchunkert, Heribert1 aDeloukas, Panos1 aLi, Man1 aFuchsberger, Christian1 aPattaro, Cristian1 aGorski, Mathias1 aKooperberg, Charles1 aPapanicolaou, George, J1 aRossouw, Jacques, E1 aFaul, Jessica, D1 aKardia, Sharon, L R1 aBouchard, Claude1 aRaffel, Leslie, J1 aUitterlinden, André, G1 aFranco, Oscar, H1 aVasan, Ramachandran, S1 aO'Donnell, Christopher, J1 aTaylor, Kent, D1 aLiu, Kiang1 aBottinger, Erwin, P1 aGottesman, Omri1 aDaw, Warwick1 aGiulianini, Franco1 aGanesh, Santhi1 aSalfati, Elias1 aHarris, Tamara, B1 aLauner, Lenore, J1 aDörr, Marcus1 aFelix, Stephan, B1 aRettig, Rainer1 aVölzke, Henry1 aKim, Eric1 aLee, Wen-Jane1 aLee, I-Te1 aSheu, Wayne, H-H1 aTsosie, Krystal, S1 aEdwards, Digna, R Velez1 aLiu, Yongmei1 aCorrea, Adolfo1 aWeir, David, R1 aVölker, Uwe1 aRidker, Paul, M1 aBoerwinkle, Eric1 aGudnason, Vilmundur1 aReiner, Alexander, P1 aDuijn, Cornelia, M1 aBorecki, Ingrid, B1 aEdwards, Todd, L1 aChakravarti, Aravinda1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aLoos, Ruth, J F1 aFornage, Myriam1 aEhret, Georg, B1 aNewton-Cheh, Christopher1 aLevy, Daniel1 aChasman, Daniel, I1 aCHD Exome+ Consortium1 aExomeBP Consortium1 aGoT2DGenes Consortium1 aT2D-GENES Consortium1 aMyocardial Infarction Genetics and CARDIoGRAM Exome Consortia1 aCKDGen Consortium uhttps://chs-nhlbi.org/node/726405818nas a2201705 4500008004100000022001400041245009600055210006900151260001600220300001100236490000700247520107200254100002201326700002301348700002501371700002001396700002501416700002201441700001801463700002201481700002501503700002001528700002301548700002001571700003001591700001901621700002301640700002201663700001701685700001901702700001801721700001901739700001901758700002801777700001601805700002401821700002001845700002401865700002001889700002301909700001801932700001701950700001901967700002701986700001802013700001902031700001702050700001502067700001602082700002102098700002302119700001602142700002202158700002502180700002102205700001802226700002002244700002502264700001302289700002002302700002402322700001802346700002002364700002302384700002302407700002102430700002502451700002402476700001602500700003202516700002002548700002102568700002202589700002402611700002002635700002102655700002502676700001902701700002002720700002802740700001902768700001902787700001702806700002602823700001802849700002202867700001502889700002002904700002702924700001502951700002002966700002102986700001903007700002303026700001903049700002303068700001703091700002003108700002003128700002603148700002203174700002003196700001803216700002103234700002003255700002303275700001703298700001903315700002803334700002003362700001903382700002103401700001903422700001603441700002903457700002103486700002403507700002003531700002003551700002303571700001903594700001803613700002103631700002103652700001903673700002003692700002103712700002003733700002403753700002103777700001903798700002303817700002203840700002103862700001903883700001803902700002003920700002103940700002003961700003003981700002304011700002304034700001904057856003604076 2016 eng d a1460-208300aA meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration.0 ametaanalysis of 120 246 individuals identifies 18 new loci for f c2016 Jan 15 a358-700 v253 aGenome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.
1 ade Vries, Paul, S1 aChasman, Daniel, I1 aSabater-Lleal, Maria1 aChen, Ming-Huei1 aHuffman, Jennifer, E1 aSteri, Maristella1 aTang, Weihong1 aTeumer, Alexander1 aMarioni, Riccardo, E1 aGrossmann, Vera1 aHottenga, Jouke, J1 aTrompet, Stella1 aMüller-Nurasyid, Martina1 aZhao, Jing Hua1 aBrody, Jennifer, A1 aKleber, Marcus, E1 aGuo, Xiuqing1 aWang, Jie, Jin1 aAuer, Paul, L1 aAttia, John, R1 aYanek, Lisa, R1 aAhluwalia, Tarunveer, S1 aLahti, Jari1 aVenturini, Cristina1 aTanaka, Toshiko1 aBielak, Lawrence, F1 aJoshi, Peter, K1 aRocanin-Arjo, Ares1 aKolcic, Ivana1 aNavarro, Pau1 aRose, Lynda, M1 aOldmeadow, Christopher1 aRiess, Helene1 aMazur, Johanna1 aBasu, Saonli1 aGoel, Anuj1 aYang, Qiong1 aGhanbari, Mohsen1 aWillemsen, Gonneke1 aRumley, Ann1 aFiorillo, Edoardo1 ade Craen, Anton, J M1 aGrotevendt, Anne1 aScott, Robert1 aTaylor, Kent, D1 aDelgado, Graciela, E1 aYao, Jie1 aKifley, Annette1 aKooperberg, Charles1 aQayyum, Rehan1 aLopez, Lorna, M1 aBerentzen, Tina, L1 aRäikkönen, Katri1 aMangino, Massimo1 aBandinelli, Stefania1 aPeyser, Patricia, A1 aWild, Sarah1 aTrégouët, David-Alexandre1 aWright, Alan, F1 aMarten, Jonathan1 aZemunik, Tatijana1 aMorrison, Alanna, C1 aSennblad, Bengt1 aTofler, Geoffrey1 ade Maat, Moniek, P M1 aGeus, Eco, J C1 aLowe, Gordon, D1 aZoledziewska, Magdalena1 aSattar, Naveed1 aBinder, Harald1 aVölker, Uwe1 aWaldenberger, Melanie1 aKhaw, Kay-Tee1 aMcKnight, Barbara1 aHuang, Jie1 aJenny, Nancy, S1 aHolliday, Elizabeth, G1 aQi, Lihong1 aMcevoy, Mark, G1 aBecker, Diane, M1 aStarr, John, M1 aSarin, Antti-Pekka1 aHysi, Pirro, G1 aHernandez, Dena, G1 aJhun, Min, A1 aCampbell, Harry1 aHamsten, Anders1 aRivadeneira, Fernando1 aMcArdle, Wendy, L1 aSlagboom, Eline1 aZeller, Tanja1 aKoenig, Wolfgang1 aPsaty, Bruce, M1 aHaritunians, Talin1 aLiu, Jingmin1 aPalotie, Aarno1 aUitterlinden, André, G1 aStott, David, J1 aHofman, Albert1 aFranco, Oscar, H1 aPolasek, Ozren1 aRudan, Igor1 aMorange, Pierre-Emmanuel1 aWilson, James, F1 aKardia, Sharon, L R1 aFerrucci, Luigi1 aSpector, Tim, D1 aEriksson, Johan, G1 aHansen, Torben1 aDeary, Ian, J1 aBecker, Lewis, C1 aScott, Rodney, J1 aMitchell, Paul1 aMärz, Winfried1 aWareham, Nick, J1 aPeters, Annette1 aGreinacher, Andreas1 aWild, Philipp, S1 aJukema, Wouter1 aBoomsma, Dorret, I1 aHayward, Caroline1 aCucca, Francesco1 aTracy, Russell1 aWatkins, Hugh1 aReiner, Alex, P1 aFolsom, Aaron, R1 aRidker, Paul, M1 aO'Donnell, Christopher, J1 aSmith, Nicholas, L1 aStrachan, David, P1 aDehghan, Abbas uhttps://chs-nhlbi.org/node/693606109nas a2201525 4500008004100000022001400041245009200055210006900147260001500216300001000231490000700241520179700248100002002045700002002065700002002085700002002105700002002125700001902145700002402164700002202188700002202210700002102232700001802253700002302271700001602294700002302310700002102333700002102354700001602375700001702391700001702408700002502425700002102450700001202471700002602483700002302509700002102532700002102553700001602574700002302590700002802613700001702641700002302658700002002681700002102701700001802722700002302740700002202763700001802785700001902803700002602822700002302848700002102871700002302892700002002915700002502935700002002960700002002980700002203000700002403022700002203046700002003068700002103088700002403109700001903133700002403152700002003176700001803196700002403214700002003238700002603258700002203284700002203306700002403328700002803352700002403380700001703404700002203421700002203443700002103465700002503486700002103511700001203532700001703544700002103561700002103582700001803603700002103621700002103642700001603663700002703679700001903706700002303725700002203748700002203770700002503792700001903817700002803836700002403864700002003888700002103908700002003929700002003949700002103969700002003990700001604010700002404026700002204050700001804072700002404090700001704114700001904131700001904150700002604169700002804195700002104223700001904244700002104263700002204284700002204306700002004328700001804348700002004366700002204386700002304408710003804431710003204469710004604501856003604547 2016 eng d a1537-660500aPlatelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals.0 aPlateletRelated Variants Identified by Exomechip Metaanalysis in c2016 Jul 7 a40-550 v993 aPlatelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.
1 aEicher, John, D1 aChami, Nathalie1 aKacprowski, Tim1 aNomura, Akihiro1 aChen, Ming-Huei1 aYanek, Lisa, R1 aTajuddin, Salman, M1 aSchick, Ursula, M1 aSlater, Andrew, J1 aPankratz, Nathan1 aPolfus, Linda1 aSchurmann, Claudia1 aGiri, Ayush1 aBrody, Jennifer, A1 aLange, Leslie, A1 aManichaikul, Ani1 aHill, David1 aPazoki, Raha1 aElliot, Paul1 aEvangelou, Evangelos1 aTzoulaki, Ioanna1 aGao, He1 aVergnaud, Anne-Claire1 aMathias, Rasika, A1 aBecker, Diane, M1 aBecker, Lewis, C1 aBurt, Amber1 aCrosslin, David, R1 aLyytikäinen, Leo-Pekka1 aNikus, Kjell1 aHernesniemi, Jussi1 aKähönen, Mika1 aRaitoharju, Emma1 aMononen, Nina1 aRaitakari, Olli, T1 aLehtimäki, Terho1 aCushman, Mary1 aZakai, Neil, A1 aNickerson, Deborah, A1 aRaffield, Laura, M1 aQuarells, Rakale1 aWiller, Cristen, J1 aPeloso, Gina, M1 aAbecasis, Goncalo, R1 aLiu, Dajiang, J1 aDeloukas, Panos1 aSamani, Nilesh, J1 aSchunkert, Heribert1 aErdmann, Jeanette1 aFornage, Myriam1 aRichard, Melissa1 aTardif, Jean-Claude1 aRioux, John, D1 aDubé, Marie-Pierre1 ade Denus, Simon1 aLu, Yingchang1 aBottinger, Erwin, P1 aLoos, Ruth, J F1 aSmith, Albert, Vernon1 aHarris, Tamara, B1 aLauner, Lenore, J1 aGudnason, Vilmundur1 aEdwards, Digna, R Velez1 aTorstenson, Eric, S1 aLiu, Yongmei1 aTracy, Russell, P1 aRotter, Jerome, I1 aRich, Stephen, S1 aHighland, Heather, M1 aBoerwinkle, Eric1 aLi, Jin1 aLange, Ethan1 aWilson, James, G1 aMihailov, Evelin1 aMägi, Reedik1 aHirschhorn, Joel1 aMetspalu, Andres1 aEsko, Tõnu1 aVacchi-Suzzi, Caterina1 aNalls, Mike, A1 aZonderman, Alan, B1 aEvans, Michele, K1 aEngström, Gunnar1 aOrho-Melander, Marju1 aMelander, Olle1 aO'Donoghue, Michelle, L1 aWaterworth, Dawn, M1 aWallentin, Lars1 aWhite, Harvey, D1 aFloyd, James, S1 aBartz, Traci, M1 aRice, Kenneth, M1 aPsaty, Bruce, M1 aStarr, J, M1 aLiewald, David, C M1 aHayward, Caroline1 aDeary, Ian, J1 aGreinacher, Andreas1 aVölker, Uwe1 aThiele, Thomas1 aVölzke, Henry1 avan Rooij, Frank, J A1 aUitterlinden, André, G1 aFranco, Oscar, H1 aDehghan, Abbas1 aEdwards, Todd, L1 aGanesh, Santhi, K1 aKathiresan, Sekar1 aFaraday, Nauder1 aAuer, Paul, L1 aReiner, Alex, P1 aLettre, Guillaume1 aJohnson, Andrew, D1 aGlobal Lipids Genetics Consortium1 aCARDIoGRAM Exome Consortium1 aMyocardial Infarction Genetics Consortium uhttps://chs-nhlbi.org/node/713903283nas a2200565 4500008004100000022001400041245009400055210006900149260001300218300001000231490000600241520164500247100001301892700001901905700002001924700002301944700001601967700001801983700001902001700002102020700002202041700002602063700001902089700002502108700002102133700002002154700002302174700001902197700001602216700002302232700002302255700001702278700001902295700001902314700001702333700001402350700002202364700002902386700001502415700001702430700001902447700002202466700002302488700002002511700001702531700002902548700002402577710008002601856003602681 2016 eng d a1942-326800aRare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk.0 aRare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Leve c2016 Feb a64-700 v93 aBACKGROUND: Rare genetic variants influence blood pressure (BP).
METHODS AND RESULTS: Whole-exome sequencing was performed on DNA samples from 17 956 individuals of European ancestry and African ancestry (14 497, first-stage discovery and 3459, second-stage discovery) to examine the effect of rare variants on hypertension and 4 BP traits: systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. Tests of ≈170 000 common variants (minor allele frequency, ≥1%; statistical significance, P≤2.9×10(-7)) and gene-based tests of rare variants (minor allele frequency, <1%; ≈17 000 genes; statistical significance, P≤1.5×10(-6)) were evaluated for each trait and ancestry, followed by multiethnic meta-analyses. In the first-stage discovery, rare coding variants (splicing, stop-gain, stop-loss, nonsynonymous variants, or indels) in CLCN6 were associated with lower diastolic BP (cumulative minor allele frequency, 1.3%; β=-3.20; P=4.1×10(-6)) and were independent of a nearby common variant (rs17367504) previously associated with BP. CLCN6 rare variants were also associated with lower systolic BP (β=-4.11; P=2.8×10(-4)), mean arterial pressure (β=-3.50; P=8.9×10(-6)), and reduced hypertension risk (odds ratio, 0.72; P=0.017). Meta-analysis of the 2-stage discovery samples showed that CLCN6 was associated with lower diastolic BP at exome-wide significance (cumulative minor allele frequency, 1.1%; β=-3.30; P=5.0×10(-7)).
CONCLUSIONS: These findings implicate the effect of rare coding variants in CLCN6 in BP variation and offer new insights into BP regulation.
1 aYu, Bing1 aPulit, Sara, L1 aHwang, Shih-Jen1 aBrody, Jennifer, A1 aAmin, Najaf1 aAuer, Paul, L1 aBis, Joshua, C1 aBoerwinkle, Eric1 aBurke, Gregory, L1 aChakravarti, Aravinda1 aCorrea, Adolfo1 aDreisbach, Albert, W1 aFranco, Oscar, H1 aEhret, Georg, B1 aFranceschini, Nora1 aHofman, Albert1 aLin, Dan-Yu1 aMetcalf, Ginger, A1 aMusani, Solomon, K1 aMuzny, Donna1 aPalmas, Walter1 aRaffel, Leslie1 aReiner, Alex1 aRice, Ken1 aRotter, Jerome, I1 aVeeraraghavan, Narayanan1 aFox, Ervin1 aGuo, Xiuqing1 aNorth, Kari, E1 aGibbs, Richard, A1 aDuijn, Cornelia, M1 aPsaty, Bruce, M1 aLevy, Daniel1 aNewton-Cheh, Christopher1 aMorrison, Alanna, C1 aCHARGE Consortium and the National Heart, Lung, and Blood Institute GO ESP* uhttps://chs-nhlbi.org/node/693702324nas a2200793 4500008004100000022001400041245015800055210006900213260001600282300000800298490000700306100002100313700002300334700002200357700002100379700001700400700002300417700002000440700001800460700002000478700001500498700001800513700002600531700002200557700002000579700001700599700002900616700002000645700001300665700001600678700002100694700002000715700002100735700001500756700002100771700001600792700001500808700002000823700002300843700002000866700002100886700002000907700002800927700002000955700002200975700002300997700002001020700002901040700002201069700002301091700002101114700002101135700002601156700001901182700002801201700002101229700002001250700002001270700001901290700002101309700002001330700002301350700003001373700002101403700002501424700002201449700002301471856003601494 2016 eng d a1537-660500aWhole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis.0 aWholeExome Sequencing Identifies Loci Associated with Blood Cell c2016 Sep 01 a7850 v991 aPolfus, Linda, M1 aKhajuria, Rajiv, K1 aSchick, Ursula, M1 aPankratz, Nathan1 aPazoki, Raha1 aBrody, Jennifer, A1 aChen, Ming-Huei1 aAuer, Paul, L1 aFloyd, James, S1 aHuang, Jie1 aLange, Leslie1 avan Rooij, Frank, J A1 aGibbs, Richard, A1 aMetcalf, Ginger1 aMuzny, Donna1 aVeeraraghavan, Narayanan1 aWalter, Klaudia1 aChen, Lu1 aYanek, Lisa1 aBecker, Lewis, C1 aPeloso, Gina, M1 aWakabayashi, Aoi1 aKals, Mart1 aMetspalu, Andres1 aEsko, Tõnu1 aFox, Keolu1 aWallace, Robert1 aFranceschini, Nora1 aMatijevic, Nena1 aRice, Kenneth, M1 aBartz, Traci, M1 aLyytikäinen, Leo-Pekka1 aKähönen, Mika1 aLehtimäki, Terho1 aRaitakari, Olli, T1 aLi-Gao, Ruifang1 aMook-Kanamori, Dennis, O1 aLettre, Guillaume1 aDuijn, Cornelia, M1 aFranco, Oscar, H1 aRich, Stephen, S1 aRivadeneira, Fernando1 aHofman, Albert1 aUitterlinden, André, G1 aWilson, James, G1 aPsaty, Bruce, M1 aSoranzo, Nicole1 aDehghan, Abbas1 aBoerwinkle, Eric1 aZhang, Xiaoling1 aJohnson, Andrew, D1 aO'Donnell, Christopher, J1 aJohnsen, Jill, M1 aReiner, Alexander, P1 aGanesh, Santhi, K1 aSankaran, Vijay, G uhttps://chs-nhlbi.org/node/726309668nas a2203061 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2017 eng d a1546-171800aExome-wide association study of plasma lipids in >300,000 individuals.0 aExomewide association study of plasma lipids in 300000 individua c2017 Dec a1758-17660 v493 aWe screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
10aCoronary Artery Disease10aDiabetes Mellitus, Type 210aExome10aGenetic Association Studies10aGenetic Predisposition to Disease10aGenetic Variation10aGenotype10aHumans10aLipids10aMacular Degeneration10aPhenotype10aRisk Factors1 aLiu, Dajiang, J1 aPeloso, Gina, M1 aYu, Haojie1 aButterworth, Adam, S1 aWang, Xiao1 aMahajan, Anubha1 aSaleheen, Danish1 aEmdin, Connor1 aAlam, Dewan1 aAlves, Alexessander, Couto1 aAmouyel, Philippe1 aDi Angelantonio, Emanuele1 aArveiler, Dominique1 aAssimes, Themistocles, L1 aAuer, Paul, L1 aBaber, Usman1 aBallantyne, Christie, M1 aBang, Lia, E1 aBenn, Marianne1 aBis, Joshua, C1 aBoehnke, Michael1 aBoerwinkle, Eric1 aBork-Jensen, Jette1 aBottinger, Erwin, P1 aBrandslund, Ivan1 aBrown, Morris1 aBusonero, Fabio1 aCaulfield, Mark, J1 aChambers, John, C1 aChasman, Daniel, I1 aChen, Eugene1 aChen, Yii-Der Ida1 aChowdhury, Raj1 aChristensen, Cramer1 aChu, Audrey, Y1 aConnell, John, M1 aCucca, Francesco1 aCupples, Adrienne, L1 aDamrauer, Scott, M1 aDavies, Gail1 aDeary, Ian, J1 aDedoussis, George1 aDenny, Joshua, C1 aDominiczak, Anna1 aDubé, Marie-Pierre1 aEbeling, Tapani1 aEiriksdottir, Gudny1 aEsko, Tõnu1 aFarmaki, Aliki-Eleni1 aFeitosa, Mary, F1 aFerrario, Marco1 aFerrieres, Jean1 aFord, Ian1 aFornage, Myriam1 aFranks, Paul, W1 aFrayling, Timothy, M1 aFrikke-Schmidt, Ruth1 aFritsche, Lars, G1 aFrossard, Philippe1 aFuster, Valentin1 aGanesh, Santhi, K1 aGao, Wei1 aGarcia, Melissa, E1 aGieger, Christian1 aGiulianini, Franco1 aGoodarzi, Mark, O1 aGrallert, Harald1 aGrarup, Niels1 aGroop, Leif1 aGrove, Megan, L1 aGudnason, Vilmundur1 aHansen, Torben1 aHarris, Tamara, B1 aHayward, Caroline1 aHirschhorn, Joel, N1 aHolmen, Oddgeir, L1 aHuffman, Jennifer1 aHuo, Yong1 aHveem, Kristian1 aJabeen, Sehrish1 aJackson, Anne, U1 aJakobsdottir, Johanna1 aJarvelin, Marjo-Riitta1 aJensen, Gorm, B1 aJørgensen, Marit, E1 aJukema, Wouter1 aJustesen, Johanne, M1 aKamstrup, Pia, R1 aKanoni, Stavroula1 aKarpe, Fredrik1 aKee, Frank1 aKhera, Amit, V1 aKlarin, Derek1 aKoistinen, Heikki, A1 aKooner, Jaspal, S1 aKooperberg, Charles1 aKuulasmaa, Kari1 aKuusisto, Johanna1 aLaakso, Markku1 aLakka, Timo1 aLangenberg, Claudia1 aLangsted, Anne1 aLauner, Lenore, J1 aLauritzen, Torsten1 aLiewald, David, C M1 aLin, Li, An1 aLinneberg, Allan1 aLoos, Ruth, J F1 aLu, Yingchang1 aLu, Xiangfeng1 aMägi, Reedik1 aMälarstig, Anders1 aManichaikul, Ani1 aManning, Alisa, K1 aMäntyselkä, Pekka1 aMarouli, Eirini1 aMasca, Nicholas, G D1 aMaschio, Andrea1 aMeigs, James, B1 aMelander, Olle1 aMetspalu, Andres1 aMorris, Andrew, P1 aMorrison, Alanna, C1 aMulas, Antonella1 aMüller-Nurasyid, Martina1 aMunroe, Patricia, B1 aNeville, Matt, J1 aNielsen, Jonas, B1 aNielsen, Sune, F1 aNordestgaard, Børge, G1 aOrdovas, Jose, M1 aMehran, Roxana1 aO'Donnell, Christoper, J1 aOrho-Melander, Marju1 aMolony, Cliona, M1 aMuntendam, Pieter1 aPadmanabhan, Sandosh1 aPalmer, Colin, N A1 aPasko, Dorota1 aPatel, Aniruddh, P1 aPedersen, Oluf1 aPerola, Markus1 aPeters, Annette1 aPisinger, Charlotta1 aPistis, Giorgio1 aPolasek, Ozren1 aPoulter, Neil1 aPsaty, Bruce, M1 aRader, Daniel, J1 aRasheed, Asif1 aRauramaa, Rainer1 aReilly, Dermot, F1 aReiner, Alex, P1 aRenstrom, Frida1 aRich, Stephen, S1 aRidker, Paul, M1 aRioux, John, D1 aRobertson, Neil, R1 aRoden, Dan, M1 aRotter, Jerome, I1 aRudan, Igor1 aSalomaa, Veikko1 aSamani, Nilesh, J1 aSanna, Serena1 aSattar, Naveed1 aSchmidt, Ellen, M1 aScott, Robert, A1 aSever, Peter1 aSevilla, Raquel, S1 aShaffer, Christian, M1 aSim, Xueling1 aSivapalaratnam, Suthesh1 aSmall, Kerrin, S1 aSmith, Albert, V1 aSmith, Blair, H1 aSomayajula, Sangeetha1 aSoutham, Lorraine1 aSpector, Timothy, D1 aSpeliotes, Elizabeth, K1 aStarr, John, M1 aStirrups, Kathleen, E1 aStitziel, Nathan1 aStrauch, Konstantin1 aStringham, Heather, M1 aSurendran, Praveen1 aTada, Hayato1 aTall, Alan, R1 aTang, Hua1 aTardif, Jean-Claude1 aTaylor, Kent, D1 aTrompet, Stella1 aTsao, Philip, S1 aTuomilehto, Jaakko1 aTybjaerg-Hansen, Anne1 avan Zuydam, Natalie, R1 aVarbo, Anette1 aVarga, Tibor, V1 aVirtamo, Jarmo1 aWaldenberger, Melanie1 aWang, Nan1 aWareham, Nick, J1 aWarren, Helen, R1 aWeeke, Peter, E1 aWeinstock, Joshua1 aWessel, Jennifer1 aWilson, James, G1 aWilson, Peter, W F1 aXu, Ming1 aYaghootkar, Hanieh1 aYoung, Robin1 aZeggini, Eleftheria1 aZhang, He1 aZheng, Neil, S1 aZhang, Weihua1 aZhang, Yan1 aZhou, Wei1 aZhou, Yanhua1 aZoledziewska, Magdalena1 aHowson, Joanna, M M1 aDanesh, John1 aMcCarthy, Mark, I1 aCowan, Chad, A1 aAbecasis, Goncalo1 aDeloukas, Panos1 aMusunuru, Kiran1 aWiller, Cristen, J1 aKathiresan, Sekar1 aCharge Diabetes Working Group1 aEPIC-InterAct Consortium1 aEPIC-CVD Consortium1 aGOLD Consortium1 aVA Million Veteran Program uhttps://chs-nhlbi.org/node/757303066nas a2200577 4500008004100000022001400041245008100055210006900136260001300205300001300218490000700231520143400238653001101672653002301683653001801706653001101724653004301735653001901778653001701797653001801814653003401832653001101866653001901877653001801896653002001914653000901934653002301943653001401966653001601980653001901996653003602015653003302051653002102084653002302105653002702128100001802155700002302173700002002196700001302216700002502229700002102254700001802275700002002293700001802313700002302331700002502354700002202379700002502401710002602426856003602452 2017 eng d a1553-740400aRare coding variants pinpoint genes that control human hematological traits.0 aRare coding variants pinpoint genes that control human hematolog c2017 Aug ae10069250 v133 aThe identification of rare coding or splice site variants remains the most straightforward strategy to link genes with human phenotypes. Here, we analyzed the association between 137,086 rare (minor allele frequency (MAF) <1%) coding or splice site variants and 15 hematological traits in up to 308,572 participants. We found 56 such rare coding or splice site variants at P<5x10-8, including 31 that are associated with a blood-cell phenotype for the first time. All but one of these 31 new independent variants map to loci previously implicated in hematopoiesis by genome-wide association studies (GWAS). This includes a rare splice acceptor variant (rs146597587, MAF = 0.5%) in interleukin 33 (IL33) associated with reduced eosinophil count (P = 2.4x10-23), and lower risk of asthma (P = 2.6x10-7, odds ratio [95% confidence interval] = 0.56 [0.45-0.70]) and allergic rhinitis (P = 4.2x10-4, odds ratio = 0.55 [0.39-0.76]). The single new locus identified in our study is defined by a rare p.Arg172Gly missense variant (rs145535174, MAF = 0.05%) in plasminogen (PLG) associated with increased platelet count (P = 6.8x10-9), and decreased D-dimer concentration (P = 0.018) and platelet reactivity (P<0.03). Finally, our results indicate that searching for rare coding or splice site variants in very large sample sizes can help prioritize causal genes at many GWAS loci associated with complex human diseases and traits.
10aAsthma10aDatabases, Genetic10aEndometriosis10aFemale10aFibrin Fibrinogen Degradation Products10aGene Frequency10aGenetic Loci10aGenome, Human10aGenome-Wide Association Study10aHumans10aInterleukin-3310aLinear Models10aLogistic Models10aMale10aMutation, Missense10aPhenotype10aPlasminogen10aPlatelet Count10aPolymorphism, Single Nucleotide10aPrincipal Component Analysis10aProtein Splicing10aRhinitis, Allergic10aSequence Analysis, DNA1 aMousas, Abdou1 aNtritsos, Georgios1 aChen, Ming-Huei1 aSong, Ci1 aHuffman, Jennifer, E1 aTzoulaki, Ioanna1 aElliott, Paul1 aPsaty, Bruce, M1 aAuer, Paul, L1 aJohnson, Andrew, D1 aEvangelou, Evangelos1 aLettre, Guillaume1 aReiner, Alexander, P1 aBlood-Cell Consortium uhttps://chs-nhlbi.org/node/757705314nas a2201501 4500008004100000022001400041245010000055210006900155260001600224520106300240100002301303700001801326700002801344700002001372700002101392700002401413700002301437700002101460700002301481700002101504700002501525700001801550700001701568700002101585700002001606700001801626700001601644700001901660700003401679700001901713700002101732700002101753700001701774700002801791700002101819700002401840700002401864700002001888700002001908700001901928700002301947700001601970700001701986700002002003700002202023700002102045700001802066700002202084700002102106700002302127700002902150700002802179700001902207700002202226700002302248700002202271700001702293700002202310700001902332700002302351700002102374700002402395700002202419700002102441700002002462700002002482700002202502700002202524700001202546700001502558700001802573700001802591700002102609700002102630700002702651700002802678700002902706700002202735700002302757700002002780700002302800700002202823700002202845700002002867700002302887700002102910700001602931700002402947700002002971700002202991700002803013700001303041700001303054700001703067700001903084700001803103700002003121700002303141700002003164700001703184700001803201700002003219700002003239700002203259700002503281700002203306700002003328700002203348700002503370700002103395700002203416700002003438700002103458700002003479700002003499700001903519700002603538700002503564700002203589700002403611700002503635700002503660700002103685700002303706700001903729700002803748856003603776 2020 eng d a1939-327X00aGenetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.0 aGenetic Studies of Leptin Concentrations Implicate Leptin in the c2020 Sep 113 aLeptin influences food intake by informing the brain about the status of body fat stores. Rare mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in , and , and one intergenic variant near The missense variant Val94Met (rs17151919) in was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10, n=3,901). Using analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.
1 aYaghootkar, Hanieh1 aZhang, Yiying1 aSpracklen, Cassandra, N1 aKaraderi, Tugce1 aHuang, Lam, Opal1 aBradfield, Jonathan1 aSchurmann, Claudia1 aFine, Rebecca, S1 aPreuss, Michael, H1 aKutalik, Zoltán1 aWittemans, Laura, Bl1 aLu, Yingchang1 aMetz, Sophia1 aWillems, Sara, M1 aLi-Gao, Ruifang1 aGrarup, Niels1 aWang, Shuai1 aMolnos, Sophie1 aSandoval-Zárate, América, A1 aNalls, Mike, A1 aLange, Leslie, A1 aHaesser, Jeffrey1 aGuo, Xiuqing1 aLyytikäinen, Leo-Pekka1 aFeitosa, Mary, F1 aSitlani, Colleen, M1 aVenturini, Cristina1 aMahajan, Anubha1 aKacprowski, Tim1 aWang, Carol, A1 aChasman, Daniel, I1 aAmin, Najaf1 aBroer, Linda1 aRobertson, Neil1 aYoung, Kristin, L1 aAllison, Matthew1 aAuer, Paul, L1 aBlüher, Matthias1 aBorja, Judith, B1 aBork-Jensen, Jette1 aCarrasquilla, Germán, D1 aChristofidou, Paraskevi1 aDemirkan, Ayse1 aDoege, Claudia, A1 aGarcia, Melissa, E1 aGraff, Mariaelisa1 aGuo, Kaiying1 aHakonarson, Hakon1 aHong, Jaeyoung1 aChen, Yii-Der, Ida1 aJackson, Rebecca1 aJakupović, Hermina1 aJousilahti, Pekka1 aJustice, Anne, E1 aKähönen, Mika1 aKizer, Jorge, R1 aKriebel, Jennifer1 aLeDuc, Charles, A1 aLi, Jin1 aLind, Lars1 aLuan, Jian'an1 aMackey, David1 aMangino, Massimo1 aMännistö, Satu1 aCarli, Jayne, F Martin1 aMedina-Gómez, Carolina1 aMook-Kanamori, Dennis, O1 aMorris, Andrew, P1 ade Mutsert, Renée1 aNauck, Matthias1 aNedeljkovic, Ivana1 aPennell, Craig, E1 aPradhan, Arund, D1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aScott, Robert, A1 aSkaaby, Tea1 aStrauch, Konstantin1 aTaylor, Kent, D1 aTeumer, Alexander1 aUitterlinden, André, G1 aWu, Ying1 aYao, Jie1 aWalker, Mark1 aNorth, Kari, E1 aKovacs, Peter1 aIkram, Arfan, M1 aDuijn, Cornelia, M1 aRidker, Paul, M1 aLye, Stephen1 aHomuth, Georg1 aIngelsson, Erik1 aSpector, Tim, D1 aMcKnight, Barbara1 aProvince, Michael, A1 aLehtimäki, Terho1 aAdair, Linda, S1 aRotter, Jerome, I1 aReiner, Alexander, P1 aWilson, James, G1 aHarris, Tamara, B1 aRipatti, Samuli1 aGrallert, Harald1 aMeigs, James, B1 aSalomaa, Veikko1 aHansen, Torben1 avan Dijk, Ko, Willems1 aWareham, Nicholas, J1 aGrant, Struan, Fa1 aLangenberg, Claudia1 aFrayling, Timothy, M1 aLindgren, Cecilia, M1 aMohlke, Karen, L1 aLeibel, Rudolph, L1 aLoos, Ruth, Jf1 aKilpeläinen, Tuomas, O uhttps://chs-nhlbi.org/node/849106570nas a2201753 4500008004100000022001400041245007100055210006900126260001200195300001200207490000800219520164100227100002301868700002501891700002601916700002201942700001701964700002401981700002002005700001902025700002602044700001902070700001602089700002002105700002902125700002702154700001602181700002202197700002002219700002002239700002502259700002402284700001902308700002002327700001902347700002002366700002402386700002002410700002602430700002702456700002502483700002402508700001402532700002202546700002302568700002102591700002302612700001902635700002302654700001702677700002302694700001802717700002102735700001902756700002302775700002502798700002202823700002402845700002402869700001902893700002702912700001902939700001702958700002202975700001902997700002103016700001903037700002203056700001903078700001903097700002003116700002203136700002203158700002503180700001903205700002103224700002303245700002103268700002303289700002303312700002203335700001903357700001803376700002203394700002103416700002203437700002103459700002103480700002003501700001903521700002003540700002203560700001803582700002203600700002003622700001703642700001703659700001603676700001503692700002703707700002303734700001703757700002403774700002103798700002003819700002103839700002403860700002503884700002403909700002303933700002503956700002303981700002104004700001904025700002004044700001904064700002804083700001804111700002104129700002104150700002304171700001804194700002004212700002304232700001804255700002404273700002104297700002504318700002104343700001704364700001704381700001804398700002104416700002204437700002104459700001704480700002204497700002004519700002304539700002304562700002504585700002404610700002204634700002304656700002204679700002304701710005604724856003604780 2020 eng d a1476-468700aInherited causes of clonal haematopoiesis in 97,691 whole genomes.0 aInherited causes of clonal haematopoiesis in 97691 whole genomes c2020 10 a763-7680 v5863 aAge is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
1 aBick, Alexander, G1 aWeinstock, Joshua, S1 aNandakumar, Satish, K1 aFulco, Charles, P1 aBao, Erik, L1 aZekavat, Seyedeh, M1 aSzeto, Mindy, D1 aLiao, Xiaotian1 aLeventhal, Matthew, J1 aNasser, Joseph1 aChang, Kyle1 aLaurie, Cecelia1 aBurugula, Bala, Bharathi1 aGibson, Christopher, J1 aLin, Amy, E1 aTaub, Margaret, A1 aAguet, Francois1 aArdlie, Kristin1 aMitchell, Braxton, D1 aBarnes, Kathleen, C1 aMoscati, Arden1 aFornage, Myriam1 aRedline, Susan1 aPsaty, Bruce, M1 aSilverman, Edwin, K1 aWeiss, Scott, T1 aPalmer, Nicholette, D1 aVasan, Ramachandran, S1 aBurchard, Esteban, G1 aKardia, Sharon, L R1 aHe, Jiang1 aKaplan, Robert, C1 aSmith, Nicholas, L1 aArnett, Donna, K1 aSchwartz, David, A1 aCorrea, Adolfo1 ade Andrade, Mariza1 aGuo, Xiuqing1 aKonkle, Barbara, A1 aCuster, Brian1 aPeralta, Juan, M1 aGui, Hongsheng1 aMeyers, Deborah, A1 aMcGarvey, Stephen, T1 aChen, Ida Yii-Der1 aShoemaker, Benjamin1 aPeyser, Patricia, A1 aBroome, Jai, G1 aGogarten, Stephanie, M1 aWang, Fei, Fei1 aWong, Quenna1 aMontasser, May, E1 aDaya, Michelle1 aKenny, Eimear, E1 aNorth, Kari, E1 aLauner, Lenore, J1 aCade, Brian, E1 aBis, Joshua, C1 aCho, Michael, H1 aLasky-Su, Jessica1 aBowden, Donald, W1 aCupples, Adrienne, L1 aC Y Mak, Angel1 aBecker, Lewis, C1 aSmith, Jennifer, A1 aKelly, Tanika, N1 aAslibekyan, Stella1 aHeckbert, Susan, R1 aTiwari, Hemant, K1 aYang, Ivana, V1 aHeit, John, A1 aLubitz, Steven, A1 aJohnsen, Jill, M1 aCurran, Joanne, E1 aWenzel, Sally, E1 aWeeks, Daniel, E1 aRao, Dabeeru, C1 aDarbar, Dawood1 aMoon, Jee-Young1 aTracy, Russell, P1 aButh, Erin, J1 aRafaels, Nicholas1 aLoos, Ruth, J F1 aDurda, Peter1 aLiu, Yongmei1 aHou, Lifang1 aLee, Jiwon1 aKachroo, Priyadarshini1 aFreedman, Barry, I1 aLevy, Daniel1 aBielak, Lawrence, F1 aHixson, James, E1 aFloyd, James, S1 aWhitsel, Eric, A1 aEllinor, Patrick, T1 aIrvin, Marguerite, R1 aFingerlin, Tasha, E1 aRaffield, Laura, M1 aArmasu, Sebastian, M1 aWheeler, Marsha, M1 aSabino, Ester, C1 aBlangero, John1 aWilliams, Keoki1 aLevy, Bruce, D1 aSheu, Wayne, Huey-Herng1 aRoden, Dan, M1 aBoerwinkle, Eric1 aManson, JoAnn, E1 aMathias, Rasika, A1 aDesai, Pinkal1 aTaylor, Kent, D1 aJohnson, Andrew, D1 aAuer, Paul, L1 aKooperberg, Charles1 aLaurie, Cathy, C1 aBlackwell, Thomas, W1 aSmith, Albert, V1 aZhao, Hongyu1 aLange, Ethan1 aLange, Leslie1 aRich, Stephen, S1 aRotter, Jerome, I1 aWilson, James, G1 aScheet, Paul1 aKitzman, Jacob, O1 aLander, Eric, S1 aEngreitz, Jesse, M1 aEbert, Benjamin, L1 aReiner, Alexander, P1 aJaiswal, Siddhartha1 aAbecasis, Goncalo1 aSankaran, Vijay, G1 aKathiresan, Sekar1 aNatarajan, Pradeep1 aNHLBI Trans-Omics for Precision Medicine Consortium uhttps://chs-nhlbi.org/node/862105243nas a2201489 4500008004100000022001400041245006800055210006300123260001600186300001800202490000800220520113000228100002201358700001701380700001801397700002101415700001801436700001501454700002001469700002301489700002301512700002501535700002201560700001601582700002201598700002801620700002301648700002201671700001801693700001901711700002201730700001701752700001701769700002001786700002001806700002101826700002001847700002301867700002401890700002301914700002601937700002901963700002301992700002002015700001702035700003002052700001602082700002002098700001802118700001602136700002202152700002202174700002002196700001702216700001802233700002002251700001202271700002402283700001902307700001902326700002402345700001502369700002002384700002002404700002002424700002302444700002002467700002402487700002302511700002102534700002202555700002102577700001702598700002802615700002102643700002002664700002102684700001802705700002402723700002402747700001702771700002102788700001902809700002002828700002002848700002302868700002102891700002902912700002302941700002202964700002002986700002803006700002303034700001403057700002403071700002103095700001703116700001903133700002503152700001803177700001203195700001803207700002103225700002003246700002303266700001503289700001203304700002003316700002203336700002003358700001903378700002503397700002003422700002203442700002003464700002303484700001803507700002203525700002503547700002503572700002403597700002203621700002303643700002003666710003103686856003603717 2020 eng d a1097-417200aThe Polygenic and Monogenic Basis of Blood Traits and Diseases.0 aPolygenic and Monogenic Basis of Blood Traits and Diseases c2020 Sep 03 a1214-1231.e110 v1823 aBlood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.
1 aVuckovic, Dragana1 aBao, Erik, L1 aAkbari, Parsa1 aLareau, Caleb, A1 aMousas, Abdou1 aJiang, Tao1 aChen, Ming-Huei1 aRaffield, Laura, M1 aTardaguila, Manuel1 aHuffman, Jennifer, E1 aRitchie, Scott, C1 aMegy, Karyn1 aPonstingl, Hannes1 aPenkett, Christopher, J1 aAlbers, Patrick, K1 aWigdor, Emilie, M1 aSakaue, Saori1 aMoscati, Arden1 aManansala, Regina1 aLo, Ken, Sin1 aQian, Huijun1 aAkiyama, Masato1 aBartz, Traci, M1 aBen-Shlomo, Yoav1 aBeswick, Andrew1 aBork-Jensen, Jette1 aBottinger, Erwin, P1 aBrody, Jennifer, A1 avan Rooij, Frank, J A1 aChitrala, Kumaraswamy, N1 aWilson, Peter, W F1 aChoquet, Helene1 aDanesh, John1 aDi Angelantonio, Emanuele1 aDimou, Niki1 aDing, Jingzhong1 aElliott, Paul1 aEsko, Tõnu1 aEvans, Michele, K1 aFelix, Stephan, B1 aFloyd, James, S1 aBroer, Linda1 aGrarup, Niels1 aGuo, Michael, H1 aGuo, Qi1 aGreinacher, Andreas1 aHaessler, Jeff1 aHansen, Torben1 aHowson, Joanna, M M1 aHuang, Wei1 aJorgenson, Eric1 aKacprowski, Tim1 aKähönen, Mika1 aKamatani, Yoichiro1 aKanai, Masahiro1 aKarthikeyan, Savita1 aKoskeridis, Fotios1 aLange, Leslie, A1 aLehtimäki, Terho1 aLinneberg, Allan1 aLiu, Yongmei1 aLyytikäinen, Leo-Pekka1 aManichaikul, Ani1 aMatsuda, Koichi1 aMohlke, Karen, L1 aMononen, Nina1 aMurakami, Yoshinori1 aNadkarni, Girish, N1 aNikus, Kjell1 aPankratz, Nathan1 aPedersen, Oluf1 aPreuss, Michael1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRich, Stephen, S1 aRodriguez, Benjamin, A T1 aRosen, Jonathan, D1 aRotter, Jerome, I1 aSchubert, Petra1 aSpracklen, Cassandra, N1 aSurendran, Praveen1 aTang, Hua1 aTardif, Jean-Claude1 aGhanbari, Mohsen1 aVölker, Uwe1 aVölzke, Henry1 aWatkins, Nicholas, A1 aWeiss, Stefan1 aCai, Na1 aKundu, Kousik1 aWatt, Stephen, B1 aWalter, Klaudia1 aZonderman, Alan, B1 aCho, Kelly1 aLi, Yun1 aLoos, Ruth, J F1 aKnight, Julian, C1 aGeorges, Michel1 aStegle, Oliver1 aEvangelou, Evangelos1 aOkada, Yukinori1 aRoberts, David, J1 aInouye, Michael1 aJohnson, Andrew, D1 aAuer, Paul, L1 aAstle, William, J1 aReiner, Alexander, P1 aButterworth, Adam, S1 aOuwehand, Willem, H1 aLettre, Guillaume1 aSankaran, Vijay, G1 aSoranzo, Nicole1 aVA Million Veteran Program uhttps://chs-nhlbi.org/node/849005226nas a2201465 4500008004100000022001400041245010900055210006900164260001600233300001800249490000800267520110800275100002001383700002301403700001801426700001801444700002501462700001901487700001901506700001501525700001801540700002201558700001701580700001501597700002201612700002501634700001701659700001701676700001701693700002101710700002301731700001901754700002001773700002001793700002101813700002001834700002301854700002401877700002301901700002601924700003101950700001501981700002001996700001902016700001702035700003002052700001602082700002002098700001802118700001602136700002202152700002002174700001702194700001802211700002002229700002402249700001902273700001902292700002402311700002002335700001502355700002002370700002002390700002002410700002302430700002002453700002402473700002202497700002102519700002202540700002102562700002102583700001702604700002802621700002102649700002202670700002002692700002102712700001802733700002402751700002402775700002002799700001702819700002402836700002102860700001902881700002002900700002002920700002302940700002202963700002102985700002903006700002303035700002203058700002003080700002803100700002303128700001403151700002403165700002503189700002103214700001703235700001903252700002503271700002303296700002303319700001203342700002503354700002803379700002803407700001703435700002003452700002203472700002503494700002303519700002303542700002003565700002003585700002303605700002503628700001803653700002203671710003103693856003603724 2020 eng d a1097-417200aTrans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.0 aTransethnic and AncestrySpecific BloodCell Genetics in 746667 In c2020 Sep 03 a1198-1213.e140 v1823 aMost loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.
1 aChen, Ming-Huei1 aRaffield, Laura, M1 aMousas, Abdou1 aSakaue, Saori1 aHuffman, Jennifer, E1 aMoscati, Arden1 aTrivedi, Bhavi1 aJiang, Tao1 aAkbari, Parsa1 aVuckovic, Dragana1 aBao, Erik, L1 aZhong, Xue1 aManansala, Regina1 aLaplante, Véronique1 aChen, Minhui1 aLo, Ken, Sin1 aQian, Huijun1 aLareau, Caleb, A1 aBeaudoin, Mélissa1 aHunt, Karen, A1 aAkiyama, Masato1 aBartz, Traci, M1 aBen-Shlomo, Yoav1 aBeswick, Andrew1 aBork-Jensen, Jette1 aBottinger, Erwin, P1 aBrody, Jennifer, A1 avan Rooij, Frank, J A1 aChitrala, Kumaraswamynaidu1 aCho, Kelly1 aChoquet, Helene1 aCorrea, Adolfo1 aDanesh, John1 aDi Angelantonio, Emanuele1 aDimou, Niki1 aDing, Jingzhong1 aElliott, Paul1 aEsko, Tõnu1 aEvans, Michele, K1 aFloyd, James, S1 aBroer, Linda1 aGrarup, Niels1 aGuo, Michael, H1 aGreinacher, Andreas1 aHaessler, Jeff1 aHansen, Torben1 aHowson, Joanna, M M1 aHuang, Qin, Qin1 aHuang, Wei1 aJorgenson, Eric1 aKacprowski, Tim1 aKähönen, Mika1 aKamatani, Yoichiro1 aKanai, Masahiro1 aKarthikeyan, Savita1 aKoskeridis, Fotis1 aLange, Leslie, A1 aLehtimäki, Terho1 aLerch, Markus, M1 aLinneberg, Allan1 aLiu, Yongmei1 aLyytikäinen, Leo-Pekka1 aManichaikul, Ani1 aMartin, Hilary, C1 aMatsuda, Koichi1 aMohlke, Karen, L1 aMononen, Nina1 aMurakami, Yoshinori1 aNadkarni, Girish, N1 aNauck, Matthias1 aNikus, Kjell1 aOuwehand, Willem, H1 aPankratz, Nathan1 aPedersen, Oluf1 aPreuss, Michael1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRoberts, David, J1 aRich, Stephen, S1 aRodriguez, Benjamin, A T1 aRosen, Jonathan, D1 aRotter, Jerome, I1 aSchubert, Petra1 aSpracklen, Cassandra, N1 aSurendran, Praveen1 aTang, Hua1 aTardif, Jean-Claude1 aTrembath, Richard, C1 aGhanbari, Mohsen1 aVölker, Uwe1 aVölzke, Henry1 aWatkins, Nicholas, A1 aZonderman, Alan, B1 aWilson, Peter, W F1 aLi, Yun1 aButterworth, Adam, S1 aGauchat, Jean-François1 aChiang, Charleston, W K1 aLi, Bingshan1 aLoos, Ruth, J F1 aAstle, William, J1 aEvangelou, Evangelos1 avan Heel, David, A1 aSankaran, Vijay, G1 aOkada, Yukinori1 aSoranzo, Nicole1 aJohnson, Andrew, D1 aReiner, Alexander, P1 aAuer, Paul, L1 aLettre, Guillaume1 aVA Million Veteran Program uhttps://chs-nhlbi.org/node/848108483nas a2202413 4500008004100000022001400041245007200055210006900127260001200196300001200208490000800220520169100228100001901919700002201938700002401960700002201984700002402006700001702030700003002047700002002077700002702097700002002124700003002144700002202174700002002196700001802216700002302234700001802257700002202275700002102297700002302318700002002341700002502361700002102386700001702407700001802424700002402442700001802466700002002484700002202504700001902526700002302545700001902568700002302587700001802610700001802628700001702646700001902663700002102682700002102703700002402724700002402748700001902772700002102791700002202812700002302834700002502857700001902882700002202901700002202923700002302945700002202968700002002990700002203010700001903032700002003051700001903071700002203090700001803112700001903130700001903149700002303168700001903191700002203210700002403232700002103256700001703277700001803294700002103312700001703333700002003350700002303370700002703393700002803420700001803448700002103466700002403487700001703511700002103528700001403549700002603563700002303589700002503612700002103637700002303658700001903681700002403700700001803724700001903742700002103761700002103782700002003803700002303823700002403846700001903870700002103889700002203910700001703932700001603949700001803965700001603983700002003999700001704019700002104036700002204057700002404079700001904103700002104122700002204143700002304165700002204188700002504210700002004235700002304255700002204278700002204300700002504322700002504347700002204372700002504394700002404419700002404443700001904467700002304486700002104509700001904530700002604549700002604575700002104601700002004622700002404642700002004666700001904686700002004705700001404725700001904739700002504758700001504783700002204798700002004820700002104840700002604861700002304887700001904910700002004929700002304949700001904972700002404991700002305015700002305038700002205061700002305083700001805106700002005124700001905144700002505163700002205188700002705210700002705237700003005264700001805294700002105312700001905333700002005352700001805372700002305390700001805413700001705431700002105448700002805469700002405497700002105521700002005542700001905562700002105581700002105602700002405623700001805647700001605665700002805681700002605709700002405735700002105759700002405780700002105804700002505825700002105850700002405871700002305895700002505918700002505943710006505968856003606033 2021 eng d a1476-468700aSequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.0 aSequencing of 53831 diverse genomes from the NHLBI TOPMed Progra c2021 02 a290-2990 v5903 aThe Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
1 aTaliun, Daniel1 aHarris, Daniel, N1 aKessler, Michael, D1 aCarlson, Jedidiah1 aSzpiech, Zachary, A1 aTorres, Raul1 aTaliun, Sarah, A Gagliano1 aCorvelo, André1 aGogarten, Stephanie, M1 aKang, Hyun, Min1 aPitsillides, Achilleas, N1 aLeFaive, Jonathon1 aLee, Seung-Been1 aTian, Xiaowen1 aBrowning, Brian, L1 aDas, Sayantan1 aEmde, Anne-Katrin1 aClarke, Wayne, E1 aLoesch, Douglas, P1 aShetty, Amol, C1 aBlackwell, Thomas, W1 aSmith, Albert, V1 aWong, Quenna1 aLiu, Xiaoming1 aConomos, Matthew, P1 aBobo, Dean, M1 aAguet, Francois1 aAlbert, Christine1 aAlonso, Alvaro1 aArdlie, Kristin, G1 aArking, Dan, E1 aAslibekyan, Stella1 aAuer, Paul, L1 aBarnard, John1 aBarr, Graham1 aBarwick, Lucas1 aBecker, Lewis, C1 aBeer, Rebecca, L1 aBenjamin, Emelia, J1 aBielak, Lawrence, F1 aBlangero, John1 aBoehnke, Michael1 aBowden, Donald, W1 aBrody, Jennifer, A1 aBurchard, Esteban, G1 aCade, Brian, E1 aCasella, James, F1 aChalazan, Brandon1 aChasman, Daniel, I1 aChen, Yii-Der Ida1 aCho, Michael, H1 aChoi, Seung, Hoan1 aChung, Mina, K1 aClish, Clary, B1 aCorrea, Adolfo1 aCurran, Joanne, E1 aCuster, Brian1 aDarbar, Dawood1 aDaya, Michelle1 ade Andrade, Mariza1 aDeMeo, Dawn, L1 aDutcher, Susan, K1 aEllinor, Patrick, T1 aEmery, Leslie, S1 aEng, Celeste1 aFatkin, Diane1 aFingerlin, Tasha1 aForer, Lukas1 aFornage, Myriam1 aFranceschini, Nora1 aFuchsberger, Christian1 aFullerton, Stephanie, M1 aGermer, Soren1 aGladwin, Mark, T1 aGottlieb, Daniel, J1 aGuo, Xiuqing1 aHall, Michael, E1 aHe, Jiang1 aHeard-Costa, Nancy, L1 aHeckbert, Susan, R1 aIrvin, Marguerite, R1 aJohnsen, Jill, M1 aJohnson, Andrew, D1 aKaplan, Robert1 aKardia, Sharon, L R1 aKelly, Tanika1 aKelly, Shannon1 aKenny, Eimear, E1 aKiel, Douglas, P1 aKlemmer, Robert1 aKonkle, Barbara, A1 aKooperberg, Charles1 aKöttgen, Anna1 aLange, Leslie, A1 aLasky-Su, Jessica1 aLevy, Daniel1 aLin, Xihong1 aLin, Keng-Han1 aLiu, Chunyu1 aLoos, Ruth, J F1 aGarman, Lori1 aGerszten, Robert1 aLubitz, Steven, A1 aLunetta, Kathryn, L1 aC Y Mak, Angel1 aManichaikul, Ani1 aManning, Alisa, K1 aMathias, Rasika, A1 aMcManus, David, D1 aMcGarvey, Stephen, T1 aMeigs, James, B1 aMeyers, Deborah, A1 aMikulla, Julie, L1 aMinear, Mollie, A1 aMitchell, Braxton, D1 aMohanty, Sanghamitra1 aMontasser, May, E1 aMontgomery, Courtney1 aMorrison, Alanna, C1 aMurabito, Joanne, M1 aNatale, Andrea1 aNatarajan, Pradeep1 aNelson, Sarah, C1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPankratz, Nathan1 aPeloso, Gina, M1 aPeyser, Patricia, A1 aPleiness, Jacob1 aPost, Wendy, S1 aPsaty, Bruce, M1 aRao, D, C1 aRedline, Susan1 aReiner, Alexander, P1 aRoden, Dan1 aRotter, Jerome, I1 aRuczinski, Ingo1 aSarnowski, Chloe1 aSchoenherr, Sebastian1 aSchwartz, David, A1 aSeo, Jeong-Sun1 aSeshadri, Sudha1 aSheehan, Vivien, A1 aSheu, Wayne, H1 aShoemaker, Benjamin1 aSmith, Nicholas, L1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aStilp, Adrienne, M1 aTang, Weihong1 aTaylor, Kent, D1 aTelen, Marilyn1 aThornton, Timothy, A1 aTracy, Russell, P1 aVan Den Berg, David, J1 aVasan, Ramachandran, S1 aViaud-Martinez, Karine, A1 aVrieze, Scott1 aWeeks, Daniel, E1 aWeir, Bruce, S1 aWeiss, Scott, T1 aWeng, Lu-Chen1 aWiller, Cristen, J1 aZhang, Yingze1 aZhao, Xutong1 aArnett, Donna, K1 aAshley-Koch, Allison, E1 aBarnes, Kathleen, C1 aBoerwinkle, Eric1 aGabriel, Stacey1 aGibbs, Richard1 aRice, Kenneth, M1 aRich, Stephen, S1 aSilverman, Edwin, K1 aQasba, Pankaj1 aGan, Weiniu1 aPapanicolaou, George, J1 aNickerson, Deborah, A1 aBrowning, Sharon, R1 aZody, Michael, C1 aZöllner, Sebastian1 aWilson, James, G1 aCupples, Adrienne, L1 aLaurie, Cathy, C1 aJaquish, Cashell, E1 aHernandez, Ryan, D1 aO'Connor, Timothy, D1 aAbecasis, Goncalo, R1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/866604419nas a2200925 4500008004100000022001400041245011400055210006900169260001600238520175700254100002002011700001202031700001402043700001702057700001602074700002002090700002102110700002002131700002302151700002502174700002302199700001902222700002002241700001902261700002002280700002302300700002002323700002102343700002002364700002302384700001902407700001402426700002002440700001902460700002502479700001802504700002002522700002102542700001902563700002102582700002502603700002002628700001902648700002202667700002002689700002002709700002002729700001602749700002002765700002402785700002102809700002702830700002002857700001502877700002502892700002402917700002202941700001902963700002602982700002103008700002003029700002703049700002103076700002203097700002103119700002303140700001403163700002203177700002403199700002303223700002303246700001203269700001803281700002203299700002503321700002303346700002303369710006503392856003603457 2021 eng d a1460-208300aWhole genome sequence analysis of platelet traits in the NHLBI trans-omics for precision medicine initiative.0 aWhole genome sequence analysis of platelet traits in the NHLBI t c2021 Sep 063 aPlatelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing from NHLBI's Trans-Omics for Precision Medicine Initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several GWAS identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of whole genome sequencing in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.
1 aLittle, Amarise1 aHu, Yao1 aSun, Quan1 aJain, Deepti1 aBroome, Jai1 aChen, Ming-Huei1 aThibord, Florian1 aMcHugh, Caitlin1 aSurendran, Praveen1 aBlackwell, Thomas, W1 aBrody, Jennifer, A1 aBhan, Arunoday1 aChami, Nathalie1 aVries, Paul, S1 aEkunwe, Lynette1 aHeard-Costa, Nancy1 aHobbs, Brian, D1 aManichaikul, Ani1 aMoon, Jee-Young1 aPreuss, Michael, H1 aRyan, Kathleen1 aWang, Zhe1 aWheeler, Marsha1 aYanek, Lisa, R1 aAbecasis, Goncalo, R1 aAlmasy, Laura1 aBeaty, Terri, H1 aBecker, Lewis, C1 aBlangero, John1 aBoerwinkle, Eric1 aButterworth, Adam, S1 aChoquet, Helene1 aCorrea, Adolfo1 aCurran, Joanne, E1 aFaraday, Nauder1 aFornage, Myriam1 aGlahn, David, C1 aHou, Lifang1 aJorgenson, Eric1 aKooperberg, Charles1 aLewis, Joshua, P1 aLloyd-Jones, Donald, M1 aLoos, Ruth, J F1 aMin, Nancy1 aMitchell, Braxton, D1 aMorrison, Alanna, C1 aNickerson, Debbie1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aPankratz, Nathan1 aPsaty, Bruce, M1 aVasan, Ramachandran, S1 aRich, Stephen, S1 aRotter, Jerome, I1 aSmith, Albert, V1 aSmith, Nicholas, L1 aTang, Hua1 aTracy, Russell, P1 aConomos, Matthew, P1 aLaurie, Cecelia, A1 aMathias, Rasika, A1 aLi, Yun1 aAuer, Paul, L1 aThornton, Timothy1 aReiner, Alexander, P1 aJohnson, Andrew, D1 aRaffield, Laura, M1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/891305743nas a2201309 4500008004100000022001400041245011800055210006900173260001500242300001200257490000800269520205100277653001002328653000902338653003202347653002202379653001702401653001102418653001702429653002202446653003402468653001702502653001102519653000902530653001602539653005302555653001402608653002002622653003102642653001802673100001202691700002302703700002302726700001702749700001702766700001802783700001502801700003602816700002302852700002002875700001902895700002002914700001302934700001702947700001602964700002002980700002203000700002003022700001403042700002303056700002303079700002503102700002003127700001903147700002803166700002303194700001403217700002003231700002303251700001503274700002003289700002103309700001803330700002003348700002203368700001803390700001803408700002103426700002003447700002203467700002003489700002703509700002703536700002303563700001903586700002103605700002103626700002103647700002503668700001603693700002603709700002403735700002003759700001903779700001903798700001903817700002003836700002003856700002403876700002303900700002903923700001403952700002003966700002003986700002504006700002204031700002104053700002504074700002304099700001804122700001204140700002304152700002204175700002104197700002104218700002304239700002104262700002404283700002504307710006504332856003604397 2021 eng d a1537-660500aWhole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program.0 aWholegenome sequencing association analysis of quantitative red c2021 05 06 a874-8930 v1083 aWhole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.
10aAdult10aAged10aChromosomes, Human, Pair 1610aDatasets as Topic10aErythrocytes10aFemale10aGene Editing10aGenetic Variation10aGenome-Wide Association Study10aHEK293 Cells10aHumans10aMale10aMiddle Aged10aNational Heart, Lung, and Blood Institute (U.S.)10aPhenotype10aQuality Control10aReproducibility of Results10aUnited States1 aHu, Yao1 aStilp, Adrienne, M1 aMcHugh, Caitlin, P1 aRao, Shuquan1 aJain, Deepti1 aZheng, Xiuwen1 aLane, John1 ade Bellefon, Sébastian, Méric1 aRaffield, Laura, M1 aChen, Ming-Huei1 aYanek, Lisa, R1 aWheeler, Marsha1 aYao, Yao1 aRen, Chunyan1 aBroome, Jai1 aMoon, Jee-Young1 ade Vries, Paul, S1 aHobbs, Brian, D1 aSun, Quan1 aSurendran, Praveen1 aBrody, Jennifer, A1 aBlackwell, Thomas, W1 aChoquet, Helene1 aRyan, Kathleen1 aDuggirala, Ravindranath1 aHeard-Costa, Nancy1 aWang, Zhe1 aChami, Nathalie1 aPreuss, Michael, H1 aMin, Nancy1 aEkunwe, Lynette1 aLange, Leslie, A1 aCushman, Mary1 aFaraday, Nauder1 aCurran, Joanne, E1 aAlmasy, Laura1 aKundu, Kousik1 aSmith, Albert, V1 aGabriel, Stacey1 aRotter, Jerome, I1 aFornage, Myriam1 aLloyd-Jones, Donald, M1 aVasan, Ramachandran, S1 aSmith, Nicholas, L1 aNorth, Kari, E1 aBoerwinkle, Eric1 aBecker, Lewis, C1 aLewis, Joshua, P1 aAbecasis, Goncalo, R1 aHou, Lifang1 aO'Connell, Jeffrey, R1 aMorrison, Alanna, C1 aBeaty, Terri, H1 aKaplan, Robert1 aCorrea, Adolfo1 aBlangero, John1 aJorgenson, Eric1 aPsaty, Bruce, M1 aKooperberg, Charles1 aWalton, Russell, T1 aKleinstiver, Benjamin, P1 aTang, Hua1 aLoos, Ruth, J F1 aSoranzo, Nicole1 aButterworth, Adam, S1 aNickerson, Debbie1 aRich, Stephen, S1 aMitchell, Braxton, D1 aJohnson, Andrew, D1 aAuer, Paul, L1 aLi, Yun1 aMathias, Rasika, A1 aLettre, Guillaume1 aPankratz, Nathan1 aLaurie, Cathy, C1 aLaurie, Cecelia, A1 aBauer, Daniel, E1 aConomos, Matthew, P1 aReiner, Alexander, P1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/877905763nas a2201477 4500008004100000022001400041245012500055210006900180260001500249300001400264490000800278520153200286653001101818653001501829653002301844653003801867653001801905653003401923653001101957653001501968653005301983653001402036653003602050653001402086653001302100653004302113653002802156653001902184653001802203653002802221100002402249700002302273700002102296700002302317700002902340700002502369700002302394700001602417700002002433700002002453700002402473700001502497700002202512700001902534700002002553700002002573700002302593700002502616700002002641700001802661700001702679700002102696700002802717700001502745700002002760700002302780700002002803700001902823700002102842700001402863700002302877700002202900700002002922700001402942700002002956700001902976700001502995700002503010700001803035700002403053700002003077700002103097700001903118700002103137700002503158700001903183700002003202700002003222700001903242700001503261700001903276700002003295700002003315700002403335700001603359700002303375700002003398700001903418700002403437700001803461700002303479700002203502700002103524700001703545700001203562700002703574700002003601700002103621700002303642700002503665700002403690700001503714700002603729700002303755700001903778700002603797700002203823700002103845700002003866700002003886700002103906700002003927700002203947700002403969700002303993700001404016700002204030700002504052700002704077700001404104700002304118700002504141700001804166710006504184856003604249 2021 eng d a1537-660500aWhole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program.0 aWholegenome sequencing in diverse subjects identifies genetic co c2021 10 07 a1836-18510 v1083 aMany common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.
10aAsthma10aBiomarkers10aDermatitis, Atopic10aGenetic Predisposition to Disease10aGenome, Human10aGenome-Wide Association Study10aHumans10aLeukocytes10aNational Heart, Lung, and Blood Institute (U.S.)10aPhenotype10aPolymorphism, Single Nucleotide10aPrognosis10aProteome10aPulmonary Disease, Chronic Obstructive10aQuantitative Trait Loci10aUnited Kingdom10aUnited States10aWhole Genome Sequencing1 aMikhaylova, Anna, V1 aMcHugh, Caitlin, P1 aPolfus, Linda, M1 aRaffield, Laura, M1 aBoorgula, Meher, Preethi1 aBlackwell, Thomas, W1 aBrody, Jennifer, A1 aBroome, Jai1 aChami, Nathalie1 aChen, Ming-Huei1 aConomos, Matthew, P1 aCox, Corey1 aCurran, Joanne, E1 aDaya, Michelle1 aEkunwe, Lynette1 aGlahn, David, C1 aHeard-Costa, Nancy1 aHighland, Heather, M1 aHobbs, Brian, D1 aIlboudo, Yann1 aJain, Deepti1 aLange, Leslie, A1 aMiller-Fleming, Tyne, W1 aMin, Nancy1 aMoon, Jee-Young1 aPreuss, Michael, H1 aRosen, Jonathon1 aRyan, Kathleen1 aSmith, Albert, V1 aSun, Quan1 aSurendran, Praveen1 ade Vries, Paul, S1 aWalter, Klaudia1 aWang, Zhe1 aWheeler, Marsha1 aYanek, Lisa, R1 aZhong, Xue1 aAbecasis, Goncalo, R1 aAlmasy, Laura1 aBarnes, Kathleen, C1 aBeaty, Terri, H1 aBecker, Lewis, C1 aBlangero, John1 aBoerwinkle, Eric1 aButterworth, Adam, S1 aChavan, Sameer1 aCho, Michael, H1 aChoquet, Helene1 aCorrea, Adolfo1 aCox, Nancy1 aDeMeo, Dawn, L1 aFaraday, Nauder1 aFornage, Myriam1 aGerszten, Robert, E1 aHou, Lifang1 aJohnson, Andrew, D1 aJorgenson, Eric1 aKaplan, Robert1 aKooperberg, Charles1 aKundu, Kousik1 aLaurie, Cecelia, A1 aLettre, Guillaume1 aLewis, Joshua, P1 aLi, Bingshan1 aLi, Yun1 aLloyd-Jones, Donald, M1 aLoos, Ruth, J F1 aManichaikul, Ani1 aMeyers, Deborah, A1 aMitchell, Braxton, D1 aMorrison, Alanna, C1 aNgo, Debby1 aNickerson, Deborah, A1 aNongmaithem, Suraj1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aOrtega, Victor, E1 aPankratz, Nathan1 aPerry, James, A1 aPsaty, Bruce, M1 aRich, Stephen, S1 aSoranzo, Nicole1 aRotter, Jerome, I1 aSilverman, Edwin, K1 aSmith, Nicholas, L1 aTang, Hua1 aTracy, Russell, P1 aThornton, Timothy, A1 aVasan, Ramachandran, S1 aZein, Joe1 aMathias, Rasika, A1 aReiner, Alexander, P1 aAuer, Paul, L1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/891404304nas a2201045 4500008004100000022001400041245011400055210006900169260001300238300001400251490000700265520128500272653002201557653001101579653003401590653001101624653001401635653002801649100001401677700001401691700001701705700002201722700003201744700002401776700001801800700001501818700001401833700001401847700001601861700002101877700001801898700002401916700001901940700002501959700001901984700002102003700002202024700002302046700001902069700002402088700001902112700002502131700002202156700002202178700002802200700002302228700002302251700002502274700001702299700002102316700002402337700001902361700002102380700002002401700002102421700002202442700002002464700002302484700002002507700002502527700002202552700002402574700001702598700002602615700002602641700002402667700002002691700002302711700001902734700002502753700003402778700002102812700002102833700002302854700002002877700002202897700002702919700002102946700002102967700001902988700001403007700002203021700002303043700002303066700002003089700001603109710006503125710003203190856003603222 2022 eng d a1548-710500aA framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies.0 aframework for detecting noncoding rarevariant associations of la c2022 Dec a1599-16110 v193 aLarge-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 TOPMed samples. We also analyze five non-lipid TOPMed traits.
10aGenetic Variation10aGenome10aGenome-Wide Association Study10aHumans10aPhenotype10aWhole Genome Sequencing1 aLi, Zilin1 aLi, Xihao1 aZhou, Hufeng1 aGaynor, Sheila, M1 aSelvaraj, Margaret, Sunitha1 aArapoglou, Theodore1 aQuick, Corbin1 aLiu, Yaowu1 aChen, Han1 aSun, Ryan1 aDey, Rounak1 aArnett, Donna, K1 aAuer, Paul, L1 aBielak, Lawrence, F1 aBis, Joshua, C1 aBlackwell, Thomas, W1 aBlangero, John1 aBoerwinkle, Eric1 aBowden, Donald, W1 aBrody, Jennifer, A1 aCade, Brian, E1 aConomos, Matthew, P1 aCorrea, Adolfo1 aCupples, Adrienne, L1 aCurran, Joanne, E1 ade Vries, Paul, S1 aDuggirala, Ravindranath1 aFranceschini, Nora1 aFreedman, Barry, I1 aGöring, Harald, H H1 aGuo, Xiuqing1 aKalyani, Rita, R1 aKooperberg, Charles1 aKral, Brian, G1 aLange, Leslie, A1 aLin, Bridget, M1 aManichaikul, Ani1 aManning, Alisa, K1 aMartin, Lisa, W1 aMathias, Rasika, A1 aMeigs, James, B1 aMitchell, Braxton, D1 aMontasser, May, E1 aMorrison, Alanna, C1 aNaseri, Take1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPeyser, Patricia, A1 aPsaty, Bruce, M1 aRaffield, Laura, M1 aRedline, Susan1 aReiner, Alexander, P1 aReupena, Muagututi'a, Sefuiva1 aRice, Kenneth, M1 aRich, Stephen, S1 aSmith, Jennifer, A1 aTaylor, Kent, D1 aTaub, Margaret, A1 aVasan, Ramachandran, S1 aWeeks, Daniel, E1 aWilson, James, G1 aYanek, Lisa, R1 aZhao, Wei1 aRotter, Jerome, I1 aWiller, Cristen, J1 aNatarajan, Pradeep1 aPeloso, Gina, M1 aLin, Xihong1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aTOPMed Lipids Working Group uhttps://chs-nhlbi.org/node/925303215nas a2200481 4500008004100000022001400041245015300055210006900208260001600277520174000293100002102033700001402054700002302068700002002091700001902111700002502130700002602155700001802181700002102199700001802220700002202238700002102260700002102281700002202302700002402324700001902348700002102367700002302388700001902411700002202430700002302452700001702475700002002492700001802512700002802530700002302558700001902581700003002600700002002630700002402650700002302674856003602697 2022 eng d a1460-208300aWhole exome sequencing of 14 389 individuals from the ESP and CHARGE consortia identifies novel rare variation associated with hemostatic factors.0 aWhole exome sequencing of 14 389 individuals from the ESP and CH c2022 May 123 aPlasma levels of fibrinogen, coagulation factors VII and VIII, and von Willebrand factor (vWF) are four intermediate phenotypes that are heritable and have been associated with the risk of clinical thrombotic events. To identify rare and low-frequency variants associated with these hemostatic factors, we conducted whole exome sequencing in 10 860 individuals of European ancestry (EA) and 3529 African Americans (AAs) from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium and the National Heart, Lung, and Blood Institute's Exome Sequencing Project (ESP). Gene-based tests demonstrated significant associations with rare variation (minor allele frequency < 5%) in FGG (with fibrinogen, p = 9.1x10-13), F7 (with factor VII, p = 1.3x10-72; seven novel variants), and VWF (with factor VIII and vWF; p = 3.2x10-14; one novel variant). These eight novel rare variant associations were independent of the known common variants at these loci and tended to have much larger effect sizes. In addition, one of the rare novel variants in F7 was significantly associated with an increased risk of venous thromboembolism in AAs (Ile200Ser; rs141219108; p = 4.2x10-5). After restricting gene-based analyses to only loss-of-function variants, a novel significant association was detected and replicated between factor VIII levels and a stop-gain mutation exclusive to African Americans (rs3211938) in CD36. This variant has previously been linked to dyslipidemia but not with levels of a hemostatic factor. These efforts represent the largest integration of whole exome sequence data from two national projects to identify genetic variation associated with plasma hemostatic factors.
1 aPankratz, Nathan1 aWei, Peng1 aBrody, Jennifer, A1 aChen, Ming-Huei1 aVries, Paul, S1 aHuffman, Jennifer, E1 aStimson, Mary, Rachel1 aAuer, Paul, L1 aBoerwinkle, Eric1 aCushman, Mary1 aMaat, Moniek, P M1 aFolsom, Aaron, R1 aFranco, Oscar, H1 aGibbs, Richard, A1 aHaagenson, Kelly, K1 aHofman, Albert1 aJohnsen, Jill, M1 aKovar, Christie, L1 aKraaij, Robert1 aMcKnight, Barbara1 aMetcalf, Ginger, A1 aMuzny, Donna1 aPsaty, Bruce, M1 aTang, Weihong1 aUitterlinden, André, G1 aRooij, Jeroen, G J1 aDehghan, Abbas1 aO'Donnell, Christopher, J1 aReiner, Alex, P1 aMorrison, Alanna, C1 aSmith, Nicholas, L uhttps://chs-nhlbi.org/node/910703611nas a2200889 4500008004100000022001400041245012300055210006900178260001600247300000900263490000700272520111000279653001601389653003401405653001101439653002801450100002301478700002301501700001701524700002701541700001801568700001301586700002401599700002301623700001501646700001901661700002301680700001301703700002401716700002001740700001301760700001901773700002001792700002201812700001801834700002001852700001301872700001701885700001501902700002001917700001901937700001901956700001801975700002101993700001902014700002002033700002202053700002002075700002202095700002102117700002002138700002502158700002402183700002002207700002002227700002102247700002202268700001402290700002202304700002102326700002502347700002502372700002102397700002302418700002302441700002602464700002402490700001202514700002802526700002702554700002102581700002402602700002102626700001802647700002002665856003602685 2022 eng d a2041-172300aWhole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program.0 aWhole genome sequencing identifies structural variants contribut c2022 Dec 08 a75920 v133 aGenome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.
10aBlood Cells10aGenome-Wide Association Study10aHumans10aWhole Genome Sequencing1 aWheeler, Marsha, M1 aStilp, Adrienne, M1 aRao, Shuquan1 aHalldorsson, Bjarni, V1 aBeyter, Doruk1 aWen, Jia1 aMihkaylova, Anna, V1 aMcHugh, Caitlin, P1 aLane, John1 aJiang, Min-Zhi1 aRaffield, Laura, M1 aJun, Goo1 aSedlazeck, Fritz, J1 aMetcalf, Ginger1 aYao, Yao1 aBis, Joshua, B1 aChami, Nathalie1 ade Vries, Paul, S1 aDesai, Pinkal1 aFloyd, James, S1 aGao, Yan1 aKammers, Kai1 aKim, Wonji1 aMoon, Jee-Young1 aRatan, Aakrosh1 aYanek, Lisa, R1 aAlmasy, Laura1 aBecker, Lewis, C1 aBlangero, John1 aCho, Michael, H1 aCurran, Joanne, E1 aFornage, Myriam1 aKaplan, Robert, C1 aLewis, Joshua, P1 aLoos, Ruth, J F1 aMitchell, Braxton, D1 aMorrison, Alanna, C1 aPreuss, Michael1 aPsaty, Bruce, M1 aRich, Stephen, S1 aRotter, Jerome, I1 aTang, Hua1 aTracy, Russell, P1 aBoerwinkle, Eric1 aAbecasis, Goncalo, R1 aBlackwell, Thomas, W1 aSmith, Albert, V1 aJohnson, Andrew, D1 aMathias, Rasika, A1 aNickerson, Deborah, A1 aConomos, Matthew, P1 aLi, Yun1 aÞorsteinsdottir, Unnur1 aMagnússon, Magnús, K1 aStefansson, Kari1 aPankratz, Nathan, D1 aBauer, Daniel, E1 aAuer, Paul, L1 aReiner, Alex, P uhttps://chs-nhlbi.org/node/926102868nas a2200625 4500008004100000245005900041210005800100260001600158520116400174100001801338700001901356700002001375700002501395700002301420700002501443700002101468700002101489700001801510700002001528700001401548700002101562700002101583700002001604700001901624700002001643700001901663700001701682700002401699700002001723700001501743700001601758700001701774700002001791700002001811700001901831700001801850700001601868700002301884700001801907700002301925700002101948700002201969700001701991700001502008700001802023700002302041700001802064700001702082700001802099700001702117700002402134700002502158700002302183856003602206 2023 eng d00aDeterminants of mosaic chromosomal alteration fitness.0 aDeterminants of mosaic chromosomal alteration fitness c2023 Oct 213 aClonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well-understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our estimates of mCA fitness were correlated (R = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using a theoretical probability distribution. Individuals with lymphoid-associated mCAs had a significantly higher white blood cell count and faster clonal expansion rate. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified , , and locus variants as modulators of mCA clonal expansion rate.
1 aPershad, Yash1 aMack, Taralynn1 aPoisner, Hannah1 aJakubek, Yasminka, A1 aStilp, Adrienne, M1 aMitchell, Braxton, D1 aLewis, Joshua, P1 aBoerwinkle, Eric1 aLoos, Ruth, J1 aChami, Nathalie1 aWang, Zhe1 aBarnes, Kathleen1 aPankratz, Nathan1 aFornage, Myriam1 aRedline, Susan1 aPsaty, Bruce, M1 aBis, Joshua, C1 aShojaie, Ali1 aSilverman, Edwin, K1 aCho, Michael, H1 aYun, Jeong1 aDeMeo, Dawn1 aLevy, Daniel1 aJohnson, Andrew1 aMathias, Rasika1 aTaub, Margaret1 aArnett, Donna1 aNorth, Kari1 aRaffield, Laura, M1 aCarson, April1 aDoyle, Margaret, F1 aRich, Stephen, S1 aRotter, Jerome, I1 aGuo, Xiuqing1 aCox, Nancy1 aRoden, Dan, M1 aFranceschini, Nora1 aDesai, Pinkal1 aReiner, Alex1 aAuer, Paul, L1 aScheet, Paul1 aJaiswal, Siddhartha1 aWeinstock, Joshua, S1 aBick, Alexander, G uhttps://chs-nhlbi.org/node/958803311nas a2200829 4500008004100000022001400041245009300055210006900148260001300217300001400230490000700244520101000251653001701261653001801278653003401296653002301330653001101353653001401364653002301378100002501401700001501426700002001441700001701461700002001478700001701498700001801515700002101533700001901554700002101573700002301594700002101617700002301638700001701661700001701678700002401695700001501719700002301734700002001757700001701777700002401794700002101818700002001839700001701859700002601876700002201902700002301924700002501947700002601972700001601998700002102014700002402035700002302059700001702082700002302099700002702122700001902149700002102168700002202189700002402211700002302235700002002258700001902278700002002297700001502317700001202332700001802344700002302362700002502385700001702410700001802427856003602445 2023 eng d a1546-171800aMosaic chromosomal alterations in blood across ancestries using whole-genome sequencing.0 aMosaic chromosomal alterations in blood across ancestries using c2023 Nov a1912-19190 v553 aMegabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis.
10aBlack People10aGenome, Human10aGenome-Wide Association Study10aHispanic or Latino10aHumans10aMosaicism10aPrecision Medicine1 aJakubek, Yasminka, A1 aZhou, Ying1 aStilp, Adrienne1 aBacon, Jason1 aWong, Justin, W1 aOzcan, Zuhal1 aArnett, Donna1 aBarnes, Kathleen1 aBis, Joshua, C1 aBoerwinkle, Eric1 aBrody, Jennifer, A1 aCarson, April, P1 aChasman, Daniel, I1 aChen, Jiawen1 aCho, Michael1 aConomos, Matthew, P1 aCox, Nancy1 aDoyle, Margaret, F1 aFornage, Myriam1 aGuo, Xiuqing1 aKardia, Sharon, L R1 aLewis, Joshua, P1 aLoos, Ruth, J F1 aMa, Xiaolong1 aMachiela, Mitchell, J1 aMack, Taralynn, M1 aMathias, Rasika, A1 aMitchell, Braxton, D1 aMychaleckyj, Josyf, C1 aNorth, Kari1 aPankratz, Nathan1 aPeyser, Patricia, A1 aPreuss, Michael, H1 aPsaty, Bruce1 aRaffield, Laura, M1 aVasan, Ramachandran, S1 aRedline, Susan1 aRich, Stephen, S1 aRotter, Jerome, I1 aSilverman, Edwin, K1 aSmith, Jennifer, A1 aSmith, Aaron, P1 aTaub, Margaret1 aTaylor, Kent, D1 aYun, Jeong1 aLi, Yun1 aDesai, Pinkal1 aBick, Alexander, G1 aReiner, Alexander, P1 aScheet, Paul1 aAuer, Paul, L uhttps://chs-nhlbi.org/node/953803779nas a2200673 4500008004100000245013300041210006900174260001600243520177100259100001902030700002202049700001402071700002002085700002002105700001502125700001902140700002202159700002702181700001402208700002102222700002002243700001902263700002102282700001902303700001702322700002202339700002102361700002202382700002502404700002102429700002002450700002502470700002402495700002202519700001902541700001602560700002302576700002002599700001902619700001502638700002102653700002302674700002202697700002402719700002002743700001902763700001902782700001602801700002002817700002402837700002502861700002302886700001602909700001802925700002302943710006502966710003803031856003603069 2023 eng d00aWhole Genome Sequencing Based Analysis of Inflammation Biomarkers in the Trans-Omics for Precision Medicine (TOPMed) Consortium.0 aWhole Genome Sequencing Based Analysis of Inflammation Biomarker c2023 Sep 123 aInflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38,465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program. We identified 22 distinct single-variant associations across 6 traits - E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin - that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.
1 aJiang, Min-Zhi1 aGaynor, Sheila, M1 aLi, Xihao1 aVan Buren, Eric1 aStilp, Adrienne1 aButh, Erin1 aWang, Fei, Fei1 aManansala, Regina1 aGogarten, Stephanie, M1 aLi, Zilin1 aPolfus, Linda, M1 aSalimi, Shabnam1 aBis, Joshua, C1 aPankratz, Nathan1 aYanek, Lisa, R1 aDurda, Peter1 aTracy, Russell, P1 aRich, Stephen, S1 aRotter, Jerome, I1 aMitchell, Braxton, D1 aLewis, Joshua, P1 aPsaty, Bruce, M1 aPratte, Katherine, A1 aSilverman, Edwin, K1 aKaplan, Robert, C1 aAvery, Christy1 aNorth, Kari1 aMathias, Rasika, A1 aFaraday, Nauder1 aLin, Honghuang1 aWang, Biqi1 aCarson, April, P1 aNorwood, Arnita, F1 aGibbs, Richard, A1 aKooperberg, Charles1 aLundin, Jessica1 aPeters, Ulrike1 aDupuis, Josée1 aHou, Lifang1 aFornage, Myriam1 aBenjamin, Emelia, J1 aReiner, Alexander, P1 aBowler, Russell, P1 aLin, Xihong1 aAuer, Paul, L1 aRaffield, Laura, M1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aTOPMed Inflammation Working Group uhttps://chs-nhlbi.org/node/9500