04841nas 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 a
IMPORTANCE: 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/684906994nas a2202101 4500008004100000022001400041245009900055210006900154260001600223300001000239490000600249520104500255100001901300700001901319700002301338700002201361700001701383700001601400700002801416700002201444700001901466700001801485700002201503700002701525700002201552700002301574700001901597700002001616700001801636700002201654700002301676700002201699700002001721700002801741700002801769700002201797700002001819700002701839700003001866700001901896700001701915700002201932700002201954700001801976700001701994700002102011700002702032700002202059700002302081700002202104700001902126700001702145700001802162700002002180700002202200700002502222700002102247700001802268700002102286700002002307700002302327700002202350700002702372700002102399700002102420700002402441700001902465700002102484700002002505700002102525700001902546700002502565700001902590700002602609700002602635700002102661700001902682700002402701700002002725700002602745700001902771700002102790700002002811700002402831700001702855700001802872700002402890700002102914700002202935700001302957700001202970700001902982700002403001700001803025700002503043700002203068700002003090700002203110700003903132700002103171700001803192700002203210700001903232700001803251700002003269700001703289700001903306700002403325700001703349700002003366700002003386700002003406700002303426700002703449700002203476700002103498700002203519700002303541700002403564700002203588700002103610700002203631700002303653700003203676700002403708700002203732700002003754700002803774700002403802700002003826700002203846700002503868700002203893700002803915700002403943700001803967700002603985700002404011700002304035700001704058700002004075700002304095700001804118700002204136700002304158700001504181700002104196700002004217700002704237700001904264700002004283700001904303700002404322700001504346700002204361700001504383700002804398700002404426700002904450700002004479700002504499700002204524700002204546700001904568700002204587700001704609700002304626700002204649700002604671700002704697700002704724700002304751700002104774700002204795700002004817700001904837856003604856 2017 eng d a2041-172300aGenetic loci associated with heart rate variability and their effects on cardiac disease risk.0 aGenetic loci associated with heart rate variability and their ef c2017 Jun 14 a158050 v83 aReduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.741 aNolte, Ilja, M1 aMunoz, Loretto1 aTragante, Vinicius1 aAmare, Azmeraw, T1 aJansen, Rick1 aVaez, Ahmad1 avon der Heyde, Benedikt1 aAvery, Christy, L1 aBis, Joshua, C1 aDierckx, Bram1 avan Dongen, Jenny1 aGogarten, Stephanie, M1 aGoyette, Philippe1 aHernesniemi, Jussi1 aHuikari, Ville1 aHwang, Shih-Jen1 aJaju, Deepali1 aKerr, Kathleen, F1 aKluttig, Alexander1 aKrijthe, Bouwe, P1 aKumar, Jitender1 avan der Laan, Sander, W1 aLyytikäinen, Leo-Pekka1 aMaihofer, Adam, X1 aMinassian, Arpi1 avan der Most, Peter, J1 aMüller-Nurasyid, Martina1 aNivard, Michel1 aSalvi, Erika1 aStewart, James, D1 aThayer, Julian, F1 aVerweij, Niek1 aWong, Andrew1 aZabaneh, Delilah1 aZafarmand, Mohammad, H1 aAbdellaoui, Abdel1 aAlbarwani, Sulayma1 aAlbert, Christine1 aAlonso, Alvaro1 aAshar, Foram1 aAuvinen, Juha1 aAxelsson, Tomas1 aBaker, Dewleen, G1 ade Bakker, Paul, I W1 aBarcella, Matteo1 aBayoumi, Riad1 aBieringa, Rob, J1 aBoomsma, Dorret1 aBoucher, Gabrielle1 aBritton, Annie, R1 aChristophersen, Ingrid1 aDietrich, Andrea1 aEhret, George, B1 aEllinor, Patrick, T1 aEskola, Markku1 aFelix, Janine, F1 aFloras, John, S1 aFranco, Oscar, H1 aFriberg, Peter1 aGademan, Maaike, G J1 aGeyer, Mark, A1 aGiedraitis, Vilmantas1 aHartman, Catharina, A1 aHemerich, Daiane1 aHofman, Albert1 aHottenga, Jouke-Jan1 aHuikuri, Heikki1 aHutri-Kähönen, Nina1 aJouven, Xavier1 aJunttila, Juhani1 aJuonala, Markus1 aKiviniemi, Antti, M1 aKors, Jan, A1 aKumari, Meena1 aKuznetsova, Tatiana1 aLaurie, Cathy, C1 aLefrandt, Joop, D1 aLi, Yong1 aLi, Yun1 aLiao, Duanping1 aLimacher, Marian, C1 aLin, Henry, J1 aLindgren, Cecilia, M1 aLubitz, Steven, A1 aMahajan, Anubha1 aMcKnight, Barbara1 aSchwabedissen, Henriette, Meyer Zu1 aMilaneschi, Yuri1 aMononen, Nina1 aMorris, Andrew, P1 aNalls, Mike, A1 aNavis, Gerjan1 aNeijts, Melanie1 aNikus, Kjell1 aNorth, Kari, E1 aO'Connor, Daniel, T1 aOrmel, Johan1 aPerz, Siegfried1 aPeters, Annette1 aPsaty, Bruce, M1 aRaitakari, Olli, T1 aRisbrough, Victoria, B1 aSinner, Moritz, F1 aSiscovick, David1 aSmit, Johannes, H1 aSmith, Nicholas, L1 aSoliman, Elsayed, Z1 aSotoodehnia, Nona1 aStaessen, Jan, A1 aStein, Phyllis, K1 aStilp, Adrienne, M1 aStolarz-Skrzypek, Katarzyna1 aStrauch, Konstantin1 aSundström, Johan1 aSwenne, Cees, A1 aSyvänen, Ann-Christine1 aTardif, Jean-Claude1 aTaylor, Kent, D1 aTeumer, Alexander1 aThornton, Timothy, A1 aTinker, Lesley, E1 aUitterlinden, André, G1 avan Setten, Jessica1 aVoss, Andreas1 aWaldenberger, Melanie1 aWilhelmsen, Kirk, C1 aWillemsen, Gonneke1 aWong, Quenna1 aZhang, Zhu-Ming1 aZonderman, Alan, B1 aCusi, Daniele1 aEvans, Michele, K1 aGreiser, Halina, K1 aHarst, Pim1 aHassan, Mohammad1 aIngelsson, Erik1 aJarvelin, Marjo-Riitta1 aKääb, Stefan1 aKähönen, Mika1 aKivimaki, Mika1 aKooperberg, Charles1 aKuh, Diana1 aLehtimäki, Terho1 aLind, Lars1 aNievergelt, Caroline, M1 aO'Donnell, Chris, J1 aOldehinkel, Albertine, J1 aPenninx, Brenda1 aReiner, Alexander, P1 aRiese, Harriëtte1 avan Roon, Arie, M1 aRioux, John, D1 aRotter, Jerome, I1 aSofer, Tamar1 aStricker, Bruno, H1 aTiemeier, Henning1 aVrijkotte, Tanja, G M1 aAsselbergs, Folkert, W1 aBrundel, Bianca, J J M1 aHeckbert, Susan, R1 aWhitsel, Eric, A1 aHoed, Marcel, den1 aSnieder, Harold1 aGeus, Eco, J C uhttps://chs-nhlbi.org/node/757904580nas a2200937 4500008004100000022001400041245022100055210006900276260001300345300001200358490000700370520179400377100002102171700002402192700002202216700002202238700002702260700002202287700002002309700002102329700001602350700002102366700001602387700001202403700002102415700001902436700002302455700001902478700002302497700002102520700002402541700002502565700001502590700002102605700002902626700002202655700002302677700002202700700001902722700002002741700001702761700002202778700001202800700002002812700002102832700001802853700002302871700002302894700002902917700001802946700002502964700002102989700001903010700002503029700002403054700001903078700001703097700002303114700002003137700002403157700002203181700002003203700001803223700002003241700002503261700002803286700002403314700002103338700002403359700001903383700002103402700001703423700002903440700002403469700002203493700002703515700002003542700002303562700002103585856003603606 2017 eng d a1468-624400aA genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.0 agenomewide interaction analysis of tricyclictetracyclic antidepr c2017 May a313-3230 v543 aBACKGROUND: Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals.
METHODS AND RESULTS: We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, pinteraction=3.9e(-9)) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e(-8)). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, pinteraction=2.55e(-8)). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (pinteraction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries.
CONCLUSIONS: Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.
1 aNoordam, Raymond1 aSitlani, Colleen, M1 aAvery, Christy, L1 aStewart, James, D1 aGogarten, Stephanie, M1 aWiggins, Kerri, L1 aTrompet, Stella1 aWarren, Helen, R1 aSun, Fangui1 aEvans, Daniel, S1 aLi, Xiaohui1 aLi, Jin1 aSmith, Albert, V1 aBis, Joshua, C1 aBrody, Jennifer, A1 aBusch, Evan, L1 aCaulfield, Mark, J1 aChen, Yii-der, I1 aCummings, Steven, R1 aCupples, Adrienne, L1 aDuan, Qing1 aFranco, Oscar, H1 aMéndez-Giráldez, Rául1 aHarris, Tamara, B1 aHeckbert, Susan, R1 avan Heemst, Diana1 aHofman, Albert1 aFloyd, James, S1 aKors, Jan, A1 aLauner, Lenore, J1 aLi, Yun1 aLi-Gao, Ruifang1 aLange, Leslie, A1 aLin, Henry, J1 ade Mutsert, Renée1 aNapier, Melanie, D1 aNewton-Cheh, Christopher1 aPoulter, Neil1 aReiner, Alexander, P1 aRice, Kenneth, M1 aRoach, Jeffrey1 aRodriguez, Carlos, J1 aRosendaal, Frits, R1 aSattar, Naveed1 aSever, Peter1 aSeyerle, Amanda, A1 aSlagboom, Eline1 aSoliman, Elsayed, Z1 aSotoodehnia, Nona1 aStott, David, J1 aStürmer, Til1 aTaylor, Kent, D1 aThornton, Timothy, A1 aUitterlinden, André, G1 aWilhelmsen, Kirk, C1 aWilson, James, G1 aGudnason, Vilmundur1 aJukema, Wouter1 aLaurie, Cathy, C1 aLiu, Yongmei1 aMook-Kanamori, Dennis, O1 aMunroe, Patricia, B1 aRotter, Jerome, I1 aVasan, Ramachandran, S1 aPsaty, Bruce, M1 aStricker, Bruno, H1 aWhitsel, Eric, A uhttps://chs-nhlbi.org/node/735303317nas a2200649 4500008004100000022001400041245014700055210006900202260000900271300000900280490000700289520140100296100002301697700001901720700002601739700002101765700002201786700001801808700002301826700002101849700002401870700002101894700002101915700002301936700001801959700002101977700001801998700001702016700001802033700001802051700001802069700002402087700001302111700001702124700001402141700002302155700001902178700001702197700002202214700001702236700002102253700002802274700002002302700001902322700002502341700002002366700002002386700002502406700001802431700002102449700001902470700003102489700002002520700002202540710006902562856003602631 2018 eng d a1421-982400aGenetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project.0 aGenetic Variation in Genes Underlying Diverse Dementias May Expl c2018 a1-170 v453 aBACKGROUND/AIMS: The Alzheimer's Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimer's disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP.
METHODS: We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as "pathogenic" in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study. The participants were clinically evaluated for AD, and they represent European, Caribbean Hispanic, and isolate Dutch populations.
RESULTS/CONCLUSIONS: Pathogenic variants in dementia genes were predominantly rare and conserved coding changes. Pathogenic variants within ARSA, CSF1R, and GRN were observed, and candidate variants in GRN and CHMP2B were nominated in ADSP families. An independent case-control study provided evidence of an association between variants in TREM2, APOE, ARSA, CSF1R, PSEN1, and MAPT and risk of AD. Variants in genes which cause dementing disorders may influence the clinical diagnosis of AD in a small proportion of cases within the ADSP.
1 aBlue, Elizabeth, E1 aBis, Joshua, C1 aDorschner, Michael, O1 aTsuang, Debby, W1 aBarral, Sandra, M1 aBeecham, Gary1 aBelow, Jennifer, E1 aBush, William, S1 aButkiewicz, Mariusz1 aCruchaga, Carlos1 aDeStefano, Anita1 aFarrer, Lindsay, A1 aGoate, Alison1 aHaines, Jonathan1 aJaworski, Jim1 aJun, Gyungah1 aKunkle, Brian1 aKuzma, Amanda1 aLee, Jenny, J1 aLunetta, Kathryn, L1 aMa, Yiyi1 aMartin, Eden1 aNaj, Adam1 aNato, Alejandro, Q1 aNavas, Patrick1 aNguyen, Hiep1 aReitz, Christiane1 aReyes, Dolly1 aSalerno, William1 aSchellenberg, Gerard, D1 aSeshadri, Sudha1 aSohi, Harkirat1 aThornton, Timothy, A1 aValadares, Otto1 aDuijn, Cornelia1 aVardarajan, Badri, N1 aSan Wang, Li-1 aBoerwinkle, Eric1 aDupuis, Josée1 aPericak-Vance, Margaret, A1 aMayeux, Richard1 aWijsman, Ellen, M1 aon behalf of the Alzheimer’s Disease Sequencing Project uhttps://chs-nhlbi.org/node/778604205nas a2200877 4500008004100000022001400041245012500055210006900180260001300249300001200262490000700274520175300281100001402034700001902048700002202067700002302089700002302112700001702135700002402152700002502176700001802201700002002219700002002239700002302259700001502282700002102297700001602318700002802334700002002362700002202382700002002404700002102424700002202445700001902467700002102486700002402507700002002531700001902551700002002570700002002590700002202610700002002632700002802652700001902680700002102699700001902720700002202739700001402761700002202775700002002797700001902817700001502836700002002851700001802871700001902889700001702908700002002925700002202945700002502967700002302992700001903015700001703034700002003051700002003071700002003091700002003111700002103131700002403152700002103176700001803197700002303215700001803238700001603256700001903272856003603291 2018 eng d a1535-498900aMultiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men.0 aMultiethnic MetaAnalysis Identifies RAI1 as a Possible Obstructi c2018 Mar a391-4010 v583 aObstructive sleep apnea (OSA) is a common heritable disorder displaying marked sexual dimorphism in disease prevalence and progression. Previous genetic association studies have identified a few genetic loci associated with OSA and related quantitative traits, but they have only focused on single ethnic groups, and a large proportion of the heritability remains unexplained. The apnea-hypopnea index (AHI) is a commonly used quantitative measure characterizing OSA severity. Because OSA differs by sex, and the pathophysiology of obstructive events differ in rapid eye movement (REM) and non-REM (NREM) sleep, we hypothesized that additional genetic association signals would be identified by analyzing the NREM/REM-specific AHI and by conducting sex-specific analyses in multiethnic samples. We performed genome-wide association tests for up to 19,733 participants of African, Asian, European, and Hispanic/Latino American ancestry in 7 studies. We identified rs12936587 on chromosome 17 as a possible quantitative trait locus for NREM AHI in men (N = 6,737; P = 1.7 × 10) but not in women (P = 0.77). The association with NREM AHI was replicated in a physiological research study (N = 67; P = 0.047). This locus overlapping the RAI1 gene and encompassing genes PEMT1, SREBF1, and RASD1 was previously reported to be associated with coronary artery disease, lipid metabolism, and implicated in Potocki-Lupski syndrome and Smith-Magenis syndrome, which are characterized by abnormal sleep phenotypes. We also identified gene-by-sex interactions in suggestive association regions, suggesting that genetic variants for AHI appear to vary by sex, consistent with the clinical observations of strong sexual dimorphism.
1 aChen, Han1 aCade, Brian, E1 aGleason, Kevin, J1 aBjonnes, Andrew, C1 aStilp, Adrienne, M1 aSofer, Tamar1 aConomos, Matthew, P1 aAncoli-Israel, Sonia1 aArens, Raanan1 aAzarbarzin, Ali1 aBell, Graeme, I1 aBelow, Jennifer, E1 aChun, Sung1 aEvans, Daniel, S1 aEwert, Ralf1 aFrazier-Wood, Alexis, C1 aGharib, Sina, A1 aHaba-Rubio, José1 aHagen, Erika, W1 aHeinzer, Raphael1 aHillman, David, R1 aJohnson, Craig1 aKutalik, Zoltán1 aLane, Jacqueline, M1 aLarkin, Emma, K1 aLee, Seung, Ku1 aLiang, Jingjing1 aLoredo, Jose, S1 aMukherjee, Sutapa1 aPalmer, Lyle, J1 aPapanicolaou, George, J1 aPenzel, Thomas1 aPeppard, Paul, E1 aPost, Wendy, S1 aRamos, Alberto, R1 aRice, Ken1 aRotter, Jerome, I1 aSands, Scott, A1 aShah, Neomi, A1 aShin, Chol1 aStone, Katie, L1 aStubbe, Beate1 aSul, Jae, Hoon1 aTafti, Mehdi1 aTaylor, Kent, D1 aTeumer, Alexander1 aThornton, Timothy, A1 aTranah, Gregory, J1 aWang, Chaolong1 aWang, Heming1 aWarby, Simon, C1 aWellman, Andrew1 aZee, Phyllis, C1 aHanis, Craig, L1 aLaurie, Cathy, C1 aGottlieb, Daniel, J1 aPatel, Sanjay, R1 aZhu, Xiaofeng1 aSunyaev, Shamil, R1 aSaxena, Richa1 aLin, Xihong1 aRedline, Susan uhttps://chs-nhlbi.org/node/767505481nas a2201285 4500008004100000022001400041245015800055210006900213260001600282520179200298100001902090700001702109700002102126700001702147700002902164700002102193700002402214700002002238700001302258700002002271700002102291700002102312700001302333700001502346700001902361700001602380700002202396700002102418700002302439700002302462700002502485700001902510700001902529700002102548700002502569700003002594700002302624700002702647700002002674700002302694700002202717700002202739700001802761700002802779700001902807700002402826700002202850700002102872700002002893700002402913700002002937700001902957700001602976700001802992700002003010700001803030700002203048700001903070700001803089700002003107700002003127700001903147700002003166700001803186700001903204700002003223700003103243700001903274700002003293700002003313700001903333700001903352700002203371700001903393700002003412700002103432700002003453700002103473700002203494700002103516700002503537700002003562700002403582700002503606700002303631700002203654700001703676700001903693700002303712700002003735700001903755700002003774700002403794700002603818700002003844700001903864700001503883700002103898700002403919700002403943700001903967700002003986700002804006700002004034700001704054700002004071700002304091710004504114856003604159 2018 eng d a1476-557800aWhole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.0 aWhole exome sequencing study identifies novel rare and common Al c2018 Aug 143 aThe Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.
1 aBis, Joshua, C1 aJian, Xueqiu1 aKunkle, Brian, W1 aChen, Yuning1 aHamilton-Nelson, Kara, L1 aBush, William, S1 aSalerno, William, J1 aLancour, Daniel1 aMa, Yiyi1 aRenton, Alan, E1 aMarcora, Edoardo1 aFarrell, John, J1 aZhao, Yi1 aQu, Liming1 aAhmad, Shahzad1 aAmin, Najaf1 aAmouyel, Philippe1 aBeecham, Gary, W1 aBelow, Jennifer, E1 aCampion, Dominique1 aCharbonnier, Camille1 aChung, Jaeyoon1 aCrane, Paul, K1 aCruchaga, Carlos1 aCupples, Adrienne, L1 aDartigues, Jean-François1 aDebette, Stephanie1 aDeleuze, Jean-Francois1 aFulton, Lucinda1 aGabriel, Stacey, B1 aGenin, Emmanuelle1 aGibbs, Richard, A1 aGoate, Alison1 aGrenier-Boley, Benjamin1 aGupta, Namrata1 aHaines, Jonathan, L1 aHavulinna, Aki, S1 aHelisalmi, Seppo1 aHiltunen, Mikko1 aHowrigan, Daniel, P1 aIkram, Arfan, M1 aKaprio, Jaakko1 aKonrad, Jan1 aKuzma, Amanda1 aLander, Eric, S1 aLathrop, Mark1 aLehtimäki, Terho1 aLin, Honghuang1 aMattila, Kari1 aMayeux, Richard1 aMuzny, Donna, M1 aNasser, Waleed1 aNeale, Benjamin1 aNho, Kwangsik1 aNicolas, Gaël1 aPatel, Devanshi1 aPericak-Vance, Margaret, A1 aPerola, Markus1 aPsaty, Bruce, M1 aQuenez, Olivier1 aRajabli, Farid1 aRedon, Richard1 aReitz, Christiane1 aRemes, Anne, M1 aSalomaa, Veikko1 aSarnowski, Chloe1 aSchmidt, Helena1 aSchmidt, Michael1 aSchmidt, Reinhold1 aSoininen, Hilkka1 aThornton, Timothy, A1 aTosto, Giuseppe1 aTzourio, Christophe1 avan der Lee, Sven, J1 aDuijn, Cornelia, M1 aVardarajan, Badri1 aWang, Weixin1 aWijsman, Ellen1 aWilson, Richard, K1 aWitten, Daniela1 aWorley, Kim, C1 aZhang, Xiaoling1 aBellenguez, Céline1 aLambert, Jean-Charles1 aKurki, Mitja, I1 aPalotie, Aarno1 aDaly, Mark1 aBoerwinkle, Eric1 aLunetta, Kathryn, L1 aDeStefano, Anita, L1 aDupuis, Josée1 aMartin, Eden, R1 aSchellenberg, Gerard, D1 aSeshadri, Sudha1 aNaj, Adam, C1 aFornage, Myriam1 aFarrer, Lindsay, A1 aAlzheimer’s Disease Sequencing Project uhttps://chs-nhlbi.org/node/778503584nas a2200649 4500008004100000022001400041245010200055210006900157260001500226300001200241490000700253520177200260100001702032700001902049700001702068700002002085700001402105700002402119700002302143700001802166700002502184700001902209700002302228700002402251700002102275700002002296700001702316700002002333700001302353700002002366700002002386700002202406700003002428700002502458700002002483700001802503700001902521700002002540700002302560700002002583700002002603700002102623700002402644700002102668700001402689700001902703700002202722700002302744700001702767700001602784700002202800700002102822700001802843700001902861700001802880856003602898 2019 eng d a1460-208300aAdmixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans.0 aAdmixture mapping identifies novel loci for obstructive sleep ap c2019 02 15 a675-6870 v283 aObstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Its prevalence and severity vary across ancestral background. Although OSA traits are heritable, few genetic associations have been identified. To identify genetic regions associated with OSA and improve statistical power, we applied admixture mapping on three primary OSA traits [the apnea hypopnea index (AHI), overnight average oxyhemoglobin saturation (SaO2) and percentage time SaO2 < 90%] and a secondary trait (respiratory event duration) in a Hispanic/Latino American population study of 11 575 individuals with significant variation in ancestral background. Linear mixed models were performed using previously inferred African, European and Amerindian local genetic ancestry markers. Global African ancestry was associated with a lower AHI, higher SaO2 and shorter event duration. Admixture mapping analysis of the primary OSA traits identified local African ancestry at the chromosomal region 2q37 as genome-wide significantly associated with AHI (P < 5.7 × 10-5), and European and Amerindian ancestries at 18q21 suggestively associated with both AHI and percentage time SaO2 < 90% (P < 10-3). Follow-up joint ancestry-SNP association analyses identified novel variants in ferrochelatase (FECH), significantly associated with AHI and percentage time SaO2 < 90% after adjusting for multiple tests (P < 8 × 10-6). These signals contributed to the admixture mapping associations and were replicated in independent cohorts. In this first admixture mapping study of OSA, novel associations with variants in the iron/heme metabolism pathway suggest a role for iron in influencing respiratory traits underlying OSA.
1 aWang, Heming1 aCade, Brian, E1 aSofer, Tamar1 aSands, Scott, A1 aChen, Han1 aBrowning, Sharon, R1 aStilp, Adrienne, M1 aLouie, Tin, L1 aThornton, Timothy, A1 aJohnson, Craig1 aBelow, Jennifer, E1 aConomos, Matthew, P1 aEvans, Daniel, S1 aGharib, Sina, A1 aGuo, Xiuqing1 aWood, Alexis, C1 aMei, Hao1 aYaffe, Kristine1 aLoredo, Jose, S1 aRamos, Alberto, R1 aBarrett-Connor, Elizabeth1 aAncoli-Israel, Sonia1 aZee, Phyllis, C1 aArens, Raanan1 aShah, Neomi, A1 aTaylor, Kent, D1 aTranah, Gregory, J1 aStone, Katie, L1 aHanis, Craig, L1 aWilson, James, G1 aGottlieb, Daniel, J1 aPatel, Sanjay, R1 aRice, Ken1 aPost, Wendy, S1 aRotter, Jerome, I1 aSunyaev, Shamil, R1 aCai, Jianwen1 aLin, Xihong1 aPurcell, Shaun, M1 aLaurie, Cathy, C1 aSaxena, Richa1 aRedline, Susan1 aZhu, Xiaofeng uhttps://chs-nhlbi.org/node/804904619nas a2201021 4500008004100000022001400041245012900055210006900184260001200253300001300265490000700278520172700285653001502012653001002027653000902037653002202046653003802068653002602106653003402132653001102166653002902177653002202206653003402228653001502262653001102277653001202288653004202300653000902342653001602351653002602367653005002393653001102443653001902454653003602473653002802509653002602537653001002563653002602573653001602599100001902615700001402634700002302648700001502671700002502686700001802711700002202729700002302751700001702774700002402791700002102815700002802836700002002864700002202884700002402906700002202930700001902952700002202971700001502993700002003008700001303028700002203041700002103063700001903084700002203103700002203125700002103147700001403168700001903182700001703201700002003218700002503238700001703263700002003280700002003300700002003320700002003340700002203360700002003382700002303402700002103425700002303446700002103469700001803490700001803508700001603526700001903542856003603561 2019 eng d a1553-740400aAssociations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep.0 aAssociations of variants In the hexokinase 1 and interleukin 18 c2019 04 ae10077390 v153 aSleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10(-6) were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10(-8)). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aCell Adhesion Molecules, Neuronal10aComputational Biology10aExtracellular Matrix Proteins10aFemale10aGene Regulatory Networks10aGenetic Variation10aGenome-Wide Association Study10aHexokinase10aHumans10aHypoxia10aInterleukin-18 Receptor alpha Subunit10aMale10aMiddle Aged10aNerve Tissue Proteins10aNLR Family, Pyrin Domain-Containing 3 Protein10aOxygen10aOxyhemoglobins10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aSerine Endopeptidases10aSleep10aSleep Apnea Syndromes10aYoung Adult1 aCade, Brian, E1 aChen, Han1 aStilp, Adrienne, M1 aLouie, Tin1 aAncoli-Israel, Sonia1 aArens, Raanan1 aBarfield, Richard1 aBelow, Jennifer, E1 aCai, Jianwen1 aConomos, Matthew, P1 aEvans, Daniel, S1 aFrazier-Wood, Alexis, C1 aGharib, Sina, A1 aGleason, Kevin, J1 aGottlieb, Daniel, J1 aHillman, David, R1 aJohnson, Craig1 aLederer, David, J1 aLee, Jiwon1 aLoredo, Jose, S1 aMei, Hao1 aMukherjee, Sutapa1 aPatel, Sanjay, R1 aPost, Wendy, S1 aPurcell, Shaun, M1 aRamos, Alberto, R1 aReid, Kathryn, J1 aRice, Ken1 aShah, Neomi, A1 aSofer, Tamar1 aTaylor, Kent, D1 aThornton, Timothy, A1 aWang, Heming1 aYaffe, Kristine1 aZee, Phyllis, C1 aHanis, Craig, L1 aPalmer, Lyle, J1 aRotter, Jerome, I1 aStone, Katie, L1 aTranah, Gregory, J1 aWilson, James, G1 aSunyaev, Shamil, R1 aLaurie, Cathy, C1 aZhu, Xiaofeng1 aSaxena, Richa1 aLin, Xihong1 aRedline, Susan uhttps://chs-nhlbi.org/node/804408483nas 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/866604364nas a2200997 4500008004100000022001400041245016200055210006900217260001300286300001100299490000700310520151100317100002001828700002201848700002301870700002301893700002301916700002601939700002501965700002001990700002102010700002602031700001702057700002502074700002202099700001702121700001702138700002002155700002002175700002302195700001702218700002102235700001802256700001802274700001902292700001202311700001802323700001502341700002302356700002802379700001802407700002002425700002002445700002102465700002302486700002002509700002102529700002302550700001802573700002202591700002302613700002202636700001802658700002002676700002302696700002302719700001902742700002002761700001402781700002002795700002202815700002002837700002102857700002102878700001702899700002402916700001902940700002502959700001402984700002302998700002403021700002303045700002503068700002603093700002103119700002703140700002203167700001703189700002103206700001903227700002103246700001603267700002403283700002303307856003603330 2021 eng d a2352-396400aWhole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium.0 aWhole genome sequence analyses of eGFR in 23732 people represent c2021 Jan a1031570 v633 aBACKGROUND: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants.
METHODS: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity.
FINDINGS: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants.
INTERPRETATION: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.
1 aLin, Bridget, M1 aGrinde, Kelsey, E1 aBrody, Jennifer, A1 aBreeze, Charles, E1 aRaffield, Laura, M1 aMychaleckyj, Josyf, C1 aThornton, Timothy, A1 aPerry, James, A1 aBaier, Leslie, J1 aFuentes, Lisa, de Las1 aGuo, Xiuqing1 aHeavner, Benjamin, D1 aHanson, Robert, L1 aHung, Yi-Jen1 aQian, Huijun1 aHsiung, Chao, A1 aHwang, Shih-Jen1 aIrvin, Margaret, R1 aJain, Deepti1 aKelly, Tanika, N1 aKobes, Sayuko1 aLange, Leslie1 aLash, James, P1 aLi, Yun1 aLiu, Xiaoming1 aMi, Xuenan1 aMusani, Solomon, K1 aPapanicolaou, George, J1 aParsa, Afshin1 aReiner, Alex, P1 aSalimi, Shabnam1 aSheu, Wayne, H-H1 aShuldiner, Alan, R1 aTaylor, Kent, D1 aSmith, Albert, V1 aSmith, Jennifer, A1 aTin, Adrienne1 aVaidya, Dhananjay1 aWallace, Robert, B1 aYamamoto, Kenichi1 aSakaue, Saori1 aMatsuda, Koichi1 aKamatani, Yoichiro1 aMomozawa, Yukihide1 aYanek, Lisa, R1 aYoung, Betsi, A1 aZhao, Wei1 aOkada, Yukinori1 aAbecasis, Gonzalo1 aPsaty, Bruce, M1 aArnett, Donna, K1 aBoerwinkle, Eric1 aCai, Jianwen1 aDer Chen, Ida, Yii-1 aCorrea, Adolfo1 aCupples, Adrienne, L1 aHe, Jiang1 aKardia, Sharon, Lr1 aKooperberg, Charles1 aMathias, Rasika, A1 aMitchell, Braxton, D1 aNickerson, Deborah, A1 aTurner, Steve, T1 aVasan, Ramachandran, S1 aRotter, Jerome, I1 aLevy, Daniel1 aKramer, Holly, J1 aKöttgen, Anna1 aRich, Stephen, S1 aLin, Dan-Yu1 aBrowning, Sharon, R1 aFranceschini, Nora uhttps://chs-nhlbi.org/node/866405763nas 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/891403962nas a2200733 4500008004100000022001400041245014300055210006900198260001600267520182100283100001602104700001602120700001502136700001802151700002202169700002102191700002002212700001802232700001602250700001302266700001902279700002302298700001702321700002002338700002602358700002002384700002302404700003102427700001902458700001902477700002502496700002502521700002002546700001702566700002202583700002102605700002002626700002002646700002402666700002702690700001902717700002102736700002402757700002102781700002202802700001702824700001902841700002002860700002002880700001902900700001902919700002502938700002302963700002602986700002403012700001703036700002503053700002403078700002003102700001903122700002103141710003003162856003603192 2022 eng d a1537-660500aPolygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program.0 aPolygenic transcriptome risk scores for COPD and lung function i c2022 Mar 313 aWhile polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1 s [FEV] and its ratio to forced vital capacity [FEV/FVC]) in the UK Biobank. We examined prediction performance and cross-ethnic portability of PTRS through smoking-stratified analyses both on 29,381 multi-ethnic participants from TOPMed population/family-based cohorts and on 11,771 multi-ethnic participants from TOPMed COPD-enriched studies. Analyses were carried out for two dichotomous COPD traits (moderate-to-severe and severe COPD) and two quantitative lung function traits (FEV and FEV/FVC). While the proposed PTRS showed weaker associations with disease than PRS for European ancestry, the PTRS showed stronger association with COPD than PRS for African Americans (e.g., odds ratio [OR] = 1.24 [95% confidence interval [CI]: 1.08-1.43] for PTRS versus 1.10 [0.96-1.26] for PRS among heavy smokers with ≥ 40 pack-years of smoking) for moderate-to-severe COPD. Cross-ethnic portability of the PTRS was significantly higher than the PRS (paired t test p < 2.2 × 10 with portability gains ranging from 5% to 28%) for both dichotomous COPD traits and across all smoking strata. Our study demonstrates the value of PTRS for improved cross-ethnic portability compared to PRS in predicting COPD risk.
1 aHu, Xiaowei1 aQiao, Dandi1 aKim, Wonji1 aMoll, Matthew1 aBalte, Pallavi, P1 aLange, Leslie, A1 aBartz, Traci, M1 aKumar, Rajesh1 aLi, Xingnan1 aYu, Bing1 aCade, Brian, E1 aLaurie, Cecelia, A1 aSofer, Tamar1 aRuczinski, Ingo1 aNickerson, Deborah, A1 aMuzny, Donna, M1 aMetcalf, Ginger, A1 aDoddapaneni, Harshavardhan1 aGabriel, Stacy1 aGupta, Namrata1 aDugan-Perez, Shannon1 aCupples, Adrienne, L1 aLoehr, Laura, R1 aJain, Deepti1 aRotter, Jerome, I1 aWilson, James, G1 aPsaty, Bruce, M1 aFornage, Myriam1 aMorrison, Alanna, C1 aVasan, Ramachandran, S1 aWashko, George1 aRich, Stephen, S1 aO'Connor, George, T1 aBleecker, Eugene1 aKaplan, Robert, C1 aKalhan, Ravi1 aRedline, Susan1 aGharib, Sina, A1 aMeyers, Deborah1 aOrtega, Victor1 aDupuis, Josée1 aLondon, Stephanie, J1 aLappalainen, Tuuli1 aOelsner, Elizabeth, C1 aSilverman, Edwin, K1 aBarr, Graham1 aThornton, Timothy, A1 aWheeler, Heather, E1 aCho, Michael, H1 aIm, Hae, Kyung1 aManichaikul, Ani1 aTOPMed Lung Working Group uhttps://chs-nhlbi.org/node/9037