06994nas 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 a
Reduced 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/757904205nas 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/767503584nas 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/804405153nas a2201369 4500008004100000022001400041245011700055210006900172260001500241300000900256490000700265520124400272100002301516700001901539700002101558700002701579700002001606700002201626700001901648700002601667700002601693700002001719700002001739700002301759700003001782700001901812700002301831700002901854700002801883700002401911700001901935700001901954700001201973700002401985700002102009700001702030700002502047700001902072700001802091700001502109700002402124700002002148700002002168700002202188700002002210700001702230700002602247700002602273700002102299700002402320700002302344700001802367700001902385700002102404700001902425700002102444700002202465700002102487700002102508700001902529700002102548700002202569700002002591700002102611700002002632700001902652700002202671700001802693700002202711700002402733700002002757700002302777700002002800700001802820700002202838700001402860700002002874700002002894700002202914700002402936700001802960700001702978700002402995700002103019700001803040700002403058700002003082700002203102700002303124700003003147700002503177700002503202700002603227700001903253700001903272700002103291700002003312700001403332700001903346700002503365700001703390700001903407700002103426700002203447700002703469700002203496700002503518700002203543700002403565700002103589700002003610700002003630700002003650710006503670710001203735856003603747 2021 eng d a2041-172300aChromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.0 aChromosome Xq23 is associated with lower atherogenic lipid conce c2021 04 12 a21820 v123 aAutosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.
1 aNatarajan, Pradeep1 aPampana, Akhil1 aGraham, Sarah, E1 aRuotsalainen, Sanni, E1 aPerry, James, A1 ade Vries, Paul, S1 aBroome, Jai, G1 aPirruccello, James, P1 aHonigberg, Michael, C1 aAragam, Krishna1 aWolford, Brooke1 aBrody, Jennifer, A1 aAntonacci-Fulton, Lucinda1 aArden, Moscati1 aAslibekyan, Stella1 aAssimes, Themistocles, L1 aBallantyne, Christie, M1 aBielak, Lawrence, F1 aBis, Joshua, C1 aCade, Brian, E1 aDo, Ron1 aDoddapaneni, Harsha1 aEmery, Leslie, S1 aHung, Yi-Jen1 aIrvin, Marguerite, R1 aKhan, Alyna, T1 aLange, Leslie1 aLee, Jiwon1 aLemaitre, Rozenn, N1 aMartin, Lisa, W1 aMetcalf, Ginger1 aMontasser, May, E1 aMoon, Jee-Young1 aMuzny, Donna1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPeralta, Juan, M1 aPeyser, Patricia, A1 aStilp, Adrienne, M1 aTsai, Michael1 aWang, Fei, Fei1 aWeeks, Daniel, E1 aYanek, Lisa, R1 aWilson, James, G1 aAbecasis, Goncalo1 aArnett, Donna, K1 aBecker, Lewis, C1 aBlangero, John1 aBoerwinkle, Eric1 aBowden, Donald, W1 aChang, Yi-Cheng1 aChen, Yii-der, I1 aChoi, Won, Jung1 aCorrea, Adolfo1 aCurran, Joanne, E1 aDaly, Mark, J1 aDutcher, Susan, K1 aEllinor, Patrick, T1 aFornage, Myriam1 aFreedman, Barry, I1 aGabriel, Stacey1 aGermer, Soren1 aGibbs, Richard, A1 aHe, Jiang1 aHveem, Kristian1 aJarvik, Gail, P1 aKaplan, Robert, C1 aKardia, Sharon, L R1 aKenny, Eimear1 aKim, Ryan, W1 aKooperberg, Charles1 aLaurie, Cathy, C1 aLee, Seonwook1 aLloyd-Jones, Don, M1 aLoos, Ruth, J F1 aLubitz, Steven, A1 aMathias, Rasika, A1 aMartinez, Karine, A Viaud1 aMcGarvey, Stephen, T1 aMitchell, Braxton, D1 aNickerson, Deborah, A1 aNorth, Kari, E1 aPalotie, Aarno1 aPark, Cheol, Joo1 aPsaty, Bruce, M1 aRao, D, C1 aRedline, Susan1 aReiner, Alexander, P1 aSeo, Daekwan1 aSeo, Jeong-Sun1 aSmith, Albert, V1 aTracy, Russell, P1 aVasan, Ramachandran, S1 aKathiresan, Sekar1 aCupples, Adrienne, L1 aRotter, Jerome, I1 aMorrison, Alanna, C1 aRich, Stephen, S1 aRipatti, Samuli1 aWiller, Cristen1 aPeloso, Gina, M1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aFinnGen uhttps://chs-nhlbi.org/node/871108483nas 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/866604296nas a2200973 4500008004100000022001400041245010700055210006900162260001600231520147300247100002301720700002101743700001901764700001801783700001901801700002301820700001901843700001701862700001901879700003001898700002601928700002801954700002801982700002102010700001702031700002202048700002302070700002202093700002202115700002102137700002402158700002302182700002002205700002402225700002002249700002102269700002302290700002402313700002402337700001902361700001902380700002002399700001902419700002502438700002302463700002402486700002002510700002302530700001602553700002202569700002002591700002002611700001702631700002202648700001802670700002402688700002402712700002302736700002402759700001902783700001502802700002302817700002502840700002502865700002202890700002402912700001902936700002602955700002602981700002103007700002103028700002203049700002303071700002003094700002703114700002103141700002003162700002103182700001903203700002003222700002303242700002103265856003603286 2021 eng d a1476-625600aA System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program.0 aSystem for Phenotype Harmonization in the NHLBI TransOmics for P c2021 Apr 163 aGenotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.
1 aStilp, Adrienne, M1 aEmery, Leslie, S1 aBroome, Jai, G1 aButh, Erin, J1 aKhan, Alyna, T1 aLaurie, Cecelia, A1 aWang, Fei, Fei1 aWong, Quenna1 aChen, Dongquan1 aD'Augustine, Catherine, M1 aHeard-Costa, Nancy, L1 aHohensee, Chancellor, R1 aJohnson, William, Craig1 aJuarez, Lucia, D1 aLiu, Jingmin1 aMutalik, Karen, M1 aRaffield, Laura, M1 aWiggins, Kerri, L1 ade Vries, Paul, S1 aKelly, Tanika, N1 aKooperberg, Charles1 aNatarajan, Pradeep1 aPeloso, Gina, M1 aPeyser, Patricia, A1 aReiner, Alex, P1 aArnett, Donna, K1 aAslibekyan, Stella1 aBarnes, Kathleen, C1 aBielak, Lawrence, F1 aBis, Joshua, C1 aCade, Brian, E1 aChen, Ming-Huei1 aCorrea, Adolfo1 aCupples, Adrienne, L1 ade Andrade, Mariza1 aEllinor, Patrick, T1 aFornage, Myriam1 aFranceschini, Nora1 aGan, Weiniu1 aGanesh, Santhi, K1 aGraffelman, Jan1 aGrove, Megan, L1 aGuo, Xiuqing1 aHawley, Nicola, L1 aHsu, Wan-Ling1 aJackson, Rebecca, D1 aJaquish, Cashell, E1 aJohnson, Andrew, D1 aKardia, Sharon, L R1 aKelly, Shannon1 aLee, Jiwon1 aMathias, Rasika, A1 aMcGarvey, Stephen, T1 aMitchell, Braxton, D1 aMontasser, May, E1 aMorrison, Alanna, C1 aNorth, Kari, E1 aNouraie, Seyed, Mehdi1 aOelsner, Elizabeth, C1 aPankratz, Nathan1 aRich, Stephen, S1 aRotter, Jerome, I1 aSmith, Jennifer, A1 aTaylor, Kent, D1 aVasan, Ramachandran, S1 aWeeks, Daniel, E1 aWeiss, Scott, T1 aWilson, Carla, G1 aYanek, Lisa, R1 aPsaty, Bruce, M1 aHeckbert, Susan, R1 aLaurie, Cathy, C uhttps://chs-nhlbi.org/node/871305743nas 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/877905976nas a2201393 4500008004100000022001400041245013400055210006900189260001600258300003400274520189200308100002102200700001402221700001702235700002202252700003002274700002502304700002502329700001502354700002302369700002302392700001702415700002002432700002202452700001302474700001902487700002402506700001902530700001802549700002302567700001902590700002602609700001602635700002302651700002402674700002102698700002902719700002202748700001602770700001902786700001802805700002102823700001802844700002602862700002202888700002102910700001802931700001602949700002002965700001902985700001803004700002403022700002503046700002203071700002103093700002203114700001703136700001703153700002003170700002103190700003303211700002403244700001703268700002203285700003403307700002503341700002203366700002103388700002103409700001903430700002203449700002003471700001903491700001403510700002503524700002103549700002503570700001703595700001403612700002303626700001803649700001703667700002203684700002103706700002203727700002403749700002103773700001903794700002203813700002103835700001903856700002603875700002103901700002003922700001903942700001903961700002503980700002004005700002304025700002404048700002204072700002304094700001404117700002004131700002004151700002004171700001904191700002104210700002204231700002404253700002104277700002504298700001804323700001704341700002104358700002404379710014304403856003604546 2022 eng d a1524-456300aInsights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension.0 aInsights From a LargeScale WholeGenome Sequencing Study of Systo c2022 Jun 02 a101161HYPERTENSIONAHA122193243 aBACKGROUND: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.
METHODS: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.
RESULTS: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (<5×10). Among them, a rare intergenic variant at novel locus, , was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; =4.99×10) but not stage-2 analysis (=0.11). Furthermore, a novel common variant at the known locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; =4.18×10) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; =7.28×10). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (<1×10 and <1×10, respectively).
DISCUSSION: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.
1 aKelly, Tanika, N1 aSun, Xiao1 aHe, Karen, Y1 aBrown, Michael, R1 aTaliun, Sarah, A Gagliano1 aHellwege, Jacklyn, N1 aIrvin, Marguerite, R1 aMi, Xuenan1 aBrody, Jennifer, A1 aFranceschini, Nora1 aGuo, Xiuqing1 aHwang, Shih-Jen1 ade Vries, Paul, S1 aGao, Yan1 aMoscati, Arden1 aNadkarni, Girish, N1 aYanek, Lisa, R1 aElfassy, Tali1 aSmith, Jennifer, A1 aChung, Ren-Hua1 aBeitelshees, Amber, L1 aPatki, Amit1 aAslibekyan, Stella1 aBlobner, Brandon, M1 aPeralta, Juan, M1 aAssimes, Themistocles, L1 aPalmas, Walter, R1 aLiu, Chunyu1 aBress, Adam, P1 aHuang, Zhijie1 aBecker, Lewis, C1 aHwa, Chii-Min1 aO'Connell, Jeffrey, R1 aCarlson, Jenna, C1 aWarren, Helen, R1 aDas, Sayantan1 aGiri, Ayush1 aMartin, Lisa, W1 aJohnson, Craig1 aFox, Ervin, R1 aBottinger, Erwin, P1 aRazavi, Alexander, C1 aVaidya, Dhananjay1 aChuang, Lee-Ming1 aChang, Yen-Pei, C1 aNaseri, Take1 aJain, Deepti1 aKang, Hyun, Min1 aHung, Adriana, M1 aSrinivasasainagendra, Vinodh1 aSnively, Beverly, M1 aGu, Dongfeng1 aMontasser, May, E1 aReupena, Muagututi'a, Sefuiva1 aHeavner, Benjamin, D1 aLeFaive, Jonathon1 aHixson, James, E1 aRice, Kenneth, M1 aWang, Fei, Fei1 aNielsen, Jonas, B1 aHuang, Jianfeng1 aKhan, Alyna, T1 aZhou, Wei1 aNierenberg, Jovia, L1 aLaurie, Cathy, C1 aArmstrong, Nicole, D1 aShi, Mengyao1 aPan, Yang1 aStilp, Adrienne, M1 aEmery, Leslie1 aWong, Quenna1 aHawley, Nicola, L1 aMinster, Ryan, L1 aCurran, Joanne, E1 aMunroe, Patricia, B1 aWeeks, Daniel, E1 aNorth, Kari, E1 aTracy, Russell, P1 aKenny, Eimear, E1 aShimbo, Daichi1 aChakravarti, Aravinda1 aRich, Stephen, S1 aReiner, Alex, P1 aBlangero, John1 aRedline, Susan1 aMitchell, Braxton, D1 aRao, Dabeeru, C1 aChen, Yii-Der, Ida1 aKardia, Sharon, L R1 aKaplan, Robert, C1 aMathias, Rasika, A1 aHe, Jiang1 aPsaty, Bruce, M1 aFornage, Myriam1 aLoos, Ruth, J F1 aCorrea, Adolfo1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aKooperberg, Charles1 aEdwards, Todd, L1 aAbecasis, Goncalo, R1 aZhu, Xiaofeng1 aLevy, Daniel1 aArnett, Donna, K1 aMorrison, Alanna, C1 aNHLBI Trans-Omics for Precision Medicine TOPMed) Consortium, The Samoan Obesity, Lifestyle, and Genetic Adaptations Study (OLaGA) Group† uhttps://chs-nhlbi.org/node/909913363nas a2204429 4500008004100000022001400041245012700055210006900182260001300251300001200264490000700276520118600283653003001469653001401499653003801513653003401551653001101585653003601596653001701632100002001649700002801669700001801697700001901715700002101734700002401755700001701779700001801796700001701814700002001831700002201851700002301873700001901896700001901915700001901934700002301953700002101976700001501997700001702012700001802029700002702047700003102074700001502105700001702120700002302137700002302160700001502183700001702198700001602215700002402231700002102255700001802276700002702294700002202321700001902343700002202362700001302384700002402397700002102421700001402442700003202456700001902488700001502507700001802522700002202540700001302562700001702575700002102592700002102613700002202634700002002656700002002676700001702696700001402713700001402727700001802741700001702759700002102776700002002797700002202817700002602839700002202865700002302887700002102910700002302931700001802954700001902972700001802991700002303009700002103032700002503053700001303078700001903091700002103110700001903131700001603150700001903166700002203185700002003207700002303227700003103250700002003281700002003301700001903321700001603340700002303356700002103379700002303400700002203423700002403445700002203469700002303491700002003514700001803534700001303552700002003565700002103585700002003606700002103626700001803647700001903665700002103684700002203705700002403727700002103751700001403772700001503786700002103801700002103822700002103843700002203864700002003886700002003906700001403926700002003940700002103960700002503981700002304006700002704029700002004056700002504076700002604101700003604127700003904163700002204202700002504224700001804249700001704267700001204284700002204296700001504318700002604333700002204359700002404381700001704405700001804422700001504440700001704455700002104472700001804493700002104511700002704532700002204559700002304581700001804604700001704622700002104639700001804660700001904678700002504697700002304722700002304745700002204768700002904790700002204819700002204841700002404863700002104887700001704908700002204925700002504947700001804972700002204990700002205012700002405034700002205058700001805080700002105098700002005119700002005139700001705159700001505176700001205191700002005203700002005223700002505243700002105268700001805289700001705307700001905324700001505343700001805358700001905376700001205395700001205407700002305419700002205442700001905464700002205483700002105505700002205526700002405548700002105572700002205593700001505615700002605630700001905656700002005675700001905695700002105714700002105735700002005756700002105776700002105797700001805818700002305836700003105859700002505890700001905915700001905934700001805953700002805971700001805999700001806017700001906035700002606054700002306080700002306103700001606126700002006142700002006162700002306182700001806205700002506223700002306248700002406271700001606295700002306311700002006334700002106354700002506375700002806400700002106428700002106449700001806470700002306488700002406511700002106535700002906556700002006585700002406605700001706629700002306646700002606669700002106695700002106716700003006737700002106767700002106788700002806809700001806837700002406855700001606879700002006895700001606915700001906931700001706950700001706967700001506984700002206999700001907021700001307040700001907053700001907072700001507091700002507106700002007131700002407151700002007175700002307195700002007218700001807238700002307256700002107279700002207300700001707322700002407339700002207363700002107385700002407406700002107430700002107451700002207472700002207494700002107516700002107537700002407558700001807582700002007600700002007620700001907640700001607659700002907675700002407704700002407728700002507752700002107777700002207798700001907820700002207839700001707861700002007878700001907898700001707917700002707934700002107961700002007982700002408002700001908026700001808045700001908063700001908082700001908101700001908120700001908139700002308158700001508181700002208196700002208218700002008240700001908260700002708279700002008306700002108326700001908347700001908366700001808385700002408403700002508427700001708452700002208469700001708491700002208508700002208530700002108552700002008573700001808593700002108611700002008632700002108652700001908673700002208692700002308714700002208737700001708759700002108776700002208797700002208819700002208841710001208863710002208875856003608897 2022 eng d a1546-171800aMulti-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation.0 aMultiancestry genetic study of type 2 diabetes highlights the po c2022 May a560-5720 v543 aWe assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.
10aDiabetes Mellitus, Type 210aEthnicity10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aPolymorphism, Single Nucleotide10aRisk Factors1 aMahajan, Anubha1 aSpracklen, Cassandra, N1 aZhang, Weihua1 aC Y Ng, Maggie1 aPetty, Lauren, E1 aKitajima, Hidetoshi1 aYu, Grace, Z1 aRüeger, Sina1 aSpeidel, Leo1 aKim, Young, Jin1 aHorikoshi, Momoko1 aMercader, Josep, M1 aTaliun, Daniel1 aMoon, Sanghoon1 aKwak, Soo-Heon1 aRobertson, Neil, R1 aRayner, Nigel, W1 aLoh, Marie1 aKim, Bong-Jo1 aChiou, Joshua1 aMiguel-Escalada, Irene1 aParolo, Pietro, Della Brio1 aLin, Kuang1 aBragg, Fiona1 aPreuss, Michael, H1 aTakeuchi, Fumihiko1 aNano, Jana1 aGuo, Xiuqing1 aLamri, Amel1 aNakatochi, Masahiro1 aScott, Robert, A1 aLee, Jung-Jin1 aHuerta-Chagoya, Alicia1 aGraff, Mariaelisa1 aChai, Jin-Fang1 aParra, Esteban, J1 aYao, Jie1 aBielak, Lawrence, F1 aTabara, Yasuharu1 aHai, Yang1 aSteinthorsdottir, Valgerdur1 aCook, James, P1 aKals, Mart1 aGrarup, Niels1 aSchmidt, Ellen, M1 aPan, Ian1 aSofer, Tamar1 aWuttke, Matthias1 aSarnowski, Chloe1 aGieger, Christian1 aNousome, Darryl1 aTrompet, Stella1 aLong, Jirong1 aSun, Meng1 aTong, Lin1 aChen, Wei-Min1 aAhmad, Meraj1 aNoordam, Raymond1 aJ Y Lim, Victor1 aTam, Claudia, H T1 aJoo, Yoonjung, Yoonie1 aChen, Chien-Hsiun1 aRaffield, Laura, M1 aLecoeur, Cécile1 aPrins, Bram, Peter1 aNicolas, Aude1 aYanek, Lisa, R1 aChen, Guanjie1 aJensen, Richard, A1 aTajuddin, Salman1 aKabagambe, Edmond, K1 aAn, Ping1 aXiang, Anny, H1 aChoi, Hyeok, Sun1 aCade, Brian, E1 aTan, Jingyi1 aFlanagan, Jack1 aAbaitua, Fernando1 aAdair, Linda, S1 aAdeyemo, Adebowale1 aAguilar-Salinas, Carlos, A1 aAkiyama, Masato1 aAnand, Sonia, S1 aBertoni, Alain1 aBian, Zheng1 aBork-Jensen, Jette1 aBrandslund, Ivan1 aBrody, Jennifer, A1 aBrummett, Chad, M1 aBuchanan, Thomas, A1 aCanouil, Mickaël1 aChan, Juliana, C N1 aChang, Li-Ching1 aChee, Miao-Li1 aChen, Ji1 aChen, Shyh-Huei1 aChen, Yuan-Tsong1 aChen, Zhengming1 aChuang, Lee-Ming1 aCushman, Mary1 aDas, Swapan, K1 ade Silva, Janaka1 aDedoussis, George1 aDimitrov, Latchezar1 aDoumatey, Ayo, P1 aDu, Shufa1 aDuan, Qing1 aEckardt, Kai-Uwe1 aEmery, Leslie, S1 aEvans, Daniel, S1 aEvans, Michele, K1 aFischer, Krista1 aFloyd, James, S1 aFord, Ian1 aFornage, Myriam1 aFranco, Oscar, H1 aFrayling, Timothy, M1 aFreedman, Barry, I1 aFuchsberger, Christian1 aGenter, Pauline1 aGerstein, Hertzel, C1 aGiedraitis, Vilmantas1 aGonzález-Villalpando, Clicerio1 aGonzalez-Villalpando, Maria, Elena1 aGoodarzi, Mark, O1 aGordon-Larsen, Penny1 aGorkin, David1 aGross, Myron1 aGuo, Yu1 aHackinger, Sophie1 aHan, Sohee1 aHattersley, Andrew, T1 aHerder, Christian1 aHoward, Annie-Green1 aHsueh, Willa1 aHuang, Mengna1 aHuang, Wei1 aHung, Yi-Jen1 aHwang, Mi, Yeong1 aHwu, Chii-Min1 aIchihara, Sahoko1 aIkram, Mohammad, Arfan1 aIngelsson, Martin1 aIslam, Md, Tariqul1 aIsono, Masato1 aJang, Hye-Mi1 aJasmine, Farzana1 aJiang, Guozhi1 aJonas, Jost, B1 aJørgensen, Marit, E1 aJørgensen, Torben1 aKamatani, Yoichiro1 aKandeel, Fouad, R1 aKasturiratne, Anuradhani1 aKatsuya, Tomohiro1 aKaur, Varinderpal1 aKawaguchi, Takahisa1 aKeaton, Jacob, M1 aKho, Abel, N1 aKhor, Chiea-Chuen1 aKibriya, Muhammad, G1 aKim, Duk-Hwan1 aKohara, Katsuhiko1 aKriebel, Jennifer1 aKronenberg, Florian1 aKuusisto, Johanna1 aLäll, Kristi1 aLange, Leslie, A1 aLee, Myung-Shik1 aLee, Nanette, R1 aLeong, Aaron1 aLi, Liming1 aLi, Yun1 aLi-Gao, Ruifang1 aLigthart, Symen1 aLindgren, Cecilia, M1 aLinneberg, Allan1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLocke, Adam, E1 aLouie, Tin1 aLuan, Jian'an1 aLuk, Andrea, O1 aLuo, Xi1 aLv, Jun1 aLyssenko, Valeriya1 aMamakou, Vasiliki1 aMani, Radha, K1 aMeitinger, Thomas1 aMetspalu, Andres1 aMorris, Andrew, D1 aNadkarni, Girish, N1 aNadler, Jerry, L1 aNalls, Michael, A1 aNayak, Uma1 aNongmaithem, Suraj, S1 aNtalla, Ioanna1 aOkada, Yukinori1 aOrozco, Lorena1 aPatel, Sanjay, R1 aPereira, Mark, A1 aPeters, Annette1 aPirie, Fraser, J1 aPorneala, Bianca1 aPrasad, Gauri1 aPreissl, Sebastian1 aRasmussen-Torvik, Laura, J1 aReiner, Alexander, P1 aRoden, Michael1 aRohde, Rebecca1 aRoll, Kathryn1 aSabanayagam, Charumathi1 aSander, Maike1 aSandow, Kevin1 aSattar, Naveed1 aSchönherr, Sebastian1 aSchurmann, Claudia1 aShahriar, Mohammad1 aShi, Jinxiu1 aShin, Dong, Mun1 aShriner, Daniel1 aSmith, Jennifer, A1 aSo, Wing, Yee1 aStančáková, Alena1 aStilp, Adrienne, M1 aStrauch, Konstantin1 aSuzuki, Ken1 aTakahashi, Atsushi1 aTaylor, Kent, D1 aThorand, Barbara1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTomlinson, Brian1 aTorres, Jason, M1 aTsai, Fuu-Jen1 aTuomilehto, Jaakko1 aTusié-Luna, Teresa1 aUdler, Miriam, S1 aValladares-Salgado, Adan1 avan Dam, Rob, M1 avan Klinken, Jan, B1 aVarma, Rohit1 aVujkovic, Marijana1 aWacher-Rodarte, Niels1 aWheeler, Eleanor1 aWhitsel, Eric, A1 aWickremasinghe, Ananda, R1 aDijk, Ko Willems1 aWitte, Daniel, R1 aYajnik, Chittaranjan, S1 aYamamoto, Ken1 aYamauchi, Toshimasa1 aYengo, Loic1 aYoon, Kyungheon1 aYu, Canqing1 aYuan, Jian-Min1 aYusuf, Salim1 aZhang, Liang1 aZheng, Wei1 aRaffel, Leslie, J1 aIgase, Michiya1 aIpp, Eli1 aRedline, Susan1 aCho, Yoon Shin1 aLind, Lars1 aProvince, Michael, A1 aHanis, Craig, L1 aPeyser, Patricia, A1 aIngelsson, Erik1 aZonderman, Alan, B1 aPsaty, Bruce, M1 aWang, Ya-Xing1 aRotimi, Charles, N1 aBecker, Diane, M1 aMatsuda, Fumihiko1 aLiu, Yongmei1 aZeggini, Eleftheria1 aYokota, Mitsuhiro1 aRich, Stephen, S1 aKooperberg, Charles1 aPankow, James, S1 aEngert, James, C1 aChen, Yii-Der Ida1 aFroguel, Philippe1 aWilson, James, G1 aSheu, Wayne, H H1 aKardia, Sharon, L R1 aWu, Jer-Yuarn1 aHayes, Geoffrey1 aMa, Ronald, C W1 aWong, Tien-Yin1 aGroop, Leif1 aMook-Kanamori, Dennis, O1 aChandak, Giriraj, R1 aCollins, Francis, S1 aBharadwaj, Dwaipayan1 aParé, Guillaume1 aSale, Michèle, M1 aAhsan, Habibul1 aMotala, Ayesha, A1 aShu, Xiao-Ou1 aPark, Kyong-Soo1 aJukema, Wouter1 aCruz, Miguel1 aMcKean-Cowdin, Roberta1 aGrallert, Harald1 aCheng, Ching-Yu1 aBottinger, Erwin, P1 aDehghan, Abbas1 aTai, E-Shyong1 aDupuis, Josée1 aKato, Norihiro1 aLaakso, Markku1 aKöttgen, Anna1 aKoh, Woon-Puay1 aPalmer, Colin, N A1 aLiu, Simin1 aAbecasis, Goncalo1 aKooner, Jaspal, S1 aLoos, Ruth, J F1 aNorth, Kari, E1 aHaiman, Christopher, A1 aFlorez, Jose, C1 aSaleheen, Danish1 aHansen, Torben1 aPedersen, Oluf1 aMägi, Reedik1 aLangenberg, Claudia1 aWareham, Nicholas, J1 aMaeda, Shiro1 aKadowaki, Takashi1 aLee, Juyoung1 aMillwood, Iona, Y1 aWalters, Robin, G1 aStefansson, Kari1 aMyers, Simon, R1 aFerrer, Jorge1 aGaulton, Kyle, J1 aMeigs, James, B1 aMohlke, Karen, L1 aGloyn, Anna, L1 aBowden, Donald, W1 aBelow, Jennifer, E1 aChambers, John, C1 aSim, Xueling1 aBoehnke, Michael1 aRotter, Jerome, I1 aMcCarthy, Mark, I1 aMorris, Andrew, P1 aFinnGen1 aeMERGE Consortium uhttps://chs-nhlbi.org/node/910408881nas a2202605 4500008004100000022001400041245012200055210006900177260001500246300001000261490000800271520141300279653001201692653001801704653002501722653002601747653002301773653003001796653001001826653003801836653002201874653002501896653003401921653001101955653002101966653001101987653001001998653003402008653003102042653002402073653001402097653003602111100001802147700001902165700002102184700002002205700001802225700003202243700001702275700001702292700003102309700003002340700002102370700002102391700002302412700001602435700002802451700002902479700001802508700002102526700002402547700001902571700001902590700002102609700002502630700002102655700002202676700002102698700002302719700001902742700001902761700001902780700002702799700001702826700002002843700002102863700002002884700002002904700001902924700002902943700002402972700001902996700002503015700002203040700001703062700002203079700002303101700002403124700002803148700002203176700002403198700002103222700002003243700002003263700002303283700002103306700003103327700002803358700001803386700002203404700002203426700002103448700002303469700003903492700002203531700002103553700001803574700001903592700001703611700001903628700001503647700002003662700001903682700001403701700002603715700001703741700002103758700002503779700002603804700002003830700002003850700002403870700001803894700002103912700001903933700001703952700001703969700002003986700002504006700002404031700002204055700002004077700001904097700002104116700001504137700001704152700001804169700002104187700002404208700002104232700001704253700002004270700002204290700002304312700002004335700002804355700003604383700002304419700002504442700002004467700002004487700002204507700001904529700002604548700002304574700001504597700002104612700002204633700002004655700002904675700002404704700002004728700002104748700002204769700002604791700002504817700001904842700002304861700002604884700002104910700002104931700001904952700002104971700002404992700001905016700002005035700002005055700001405075700001405089700001905103700002505122700003105147700002105178700001905199700002405218700002305242700001705265700001905282700001705301700001605318700002105334700001805355700002305373700001905396700002205415700002005437700001905457700002005476700002105496700002105517700002205538700002305560700002405583700002105607700002005628700002705648700003005675700001905705700001605724700001805740700002105758700002105779700002105800700001905821700001905840700002205859700002105881700002205902700002105924700002205945700002305967700002305990700002306013700001906036700002006055710006106075710006506136710003806201856003606239 2022 eng d a1537-660500aRare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes.0 aRare coding variants in 35 genes associate with circulating lipi c2022 01 06 a81-960 v1093 aLarge-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.
10aAlleles10aBlood Glucose10aCase-Control Studies10aComputational Biology10aDatabases, Genetic10aDiabetes Mellitus, Type 210aExome10aGenetic Predisposition to Disease10aGenetic Variation10aGenetics, Population10aGenome-Wide Association Study10aHumans10aLipid Metabolism10aLipids10aLiver10aMolecular Sequence Annotation10aMultifactorial Inheritance10aOpen Reading Frames10aPhenotype10aPolymorphism, Single Nucleotide1 aHindy, George1 aDornbos, Peter1 aChaffin, Mark, D1 aLiu, Dajiang, J1 aWang, Minxian1 aSelvaraj, Margaret, Sunitha1 aZhang, David1 aPark, Joseph1 aAguilar-Salinas, Carlos, A1 aAntonacci-Fulton, Lucinda1 aArdissino, Diego1 aArnett, Donna, K1 aAslibekyan, Stella1 aAtzmon, Gil1 aBallantyne, Christie, M1 aBarajas-Olmos, Francisco1 aBarzilai, Nir1 aBecker, Lewis, C1 aBielak, Lawrence, F1 aBis, Joshua, C1 aBlangero, John1 aBoerwinkle, Eric1 aBonnycastle, Lori, L1 aBottinger, Erwin1 aBowden, Donald, W1 aBown, Matthew, J1 aBrody, Jennifer, A1 aBroome, Jai, G1 aBurtt, Noel, P1 aCade, Brian, E1 aCenteno-Cruz, Federico1 aChan, Edmund1 aChang, Yi-Cheng1 aChen, Yii-der, I1 aCheng, Ching-Yu1 aChoi, Won, Jung1 aChowdhury, Raj1 aContreras-Cubas, Cecilia1 aCórdova, Emilio, J1 aCorrea, Adolfo1 aCupples, Adrienne, L1 aCurran, Joanne, E1 aDanesh, John1 ade Vries, Paul, S1 aDeFronzo, Ralph, A1 aDoddapaneni, Harsha1 aDuggirala, Ravindranath1 aDutcher, Susan, K1 aEllinor, Patrick, T1 aEmery, Leslie, S1 aFlorez, Jose, C1 aFornage, Myriam1 aFreedman, Barry, I1 aFuster, Valentin1 aGaray-Sevilla, Ma, Eugenia1 aGarcía-Ortiz, Humberto1 aGermer, Soren1 aGibbs, Richard, A1 aGieger, Christian1 aGlaser, Benjamin1 aGonzalez, Clicerio1 aGonzalez-Villalpando, Maria, Elena1 aGraff, Mariaelisa1 aGraham, Sarah, E1 aGrarup, Niels1 aGroop, Leif, C1 aGuo, Xiuqing1 aGupta, Namrata1 aHan, Sohee1 aHanis, Craig, L1 aHansen, Torben1 aHe, Jiang1 aHeard-Costa, Nancy, L1 aHung, Yi-Jen1 aHwang, Mi, Yeong1 aIrvin, Marguerite, R1 aIslas-Andrade, Sergio1 aJarvik, Gail, P1 aKang, Hyun, Min1 aKardia, Sharon, L R1 aKelly, Tanika1 aKenny, Eimear, E1 aKhan, Alyna, T1 aKim, Bong-Jo1 aKim, Ryan, W1 aKim, Young, Jin1 aKoistinen, Heikki, A1 aKooperberg, Charles1 aKuusisto, Johanna1 aKwak, Soo, Heon1 aLaakso, Markku1 aLange, Leslie, A1 aLee, Jiwon1 aLee, Juyoung1 aLee, Seonwook1 aLehman, Donna, M1 aLemaitre, Rozenn, N1 aLinneberg, Allan1 aLiu, Jianjun1 aLoos, Ruth, J F1 aLubitz, Steven, A1 aLyssenko, Valeriya1 aMa, Ronald, C W1 aMartin, Lisa, Warsinger1 aMartínez-Hernández, Angélica1 aMathias, Rasika, A1 aMcGarvey, Stephen, T1 aMcPherson, Ruth1 aMeigs, James, B1 aMeitinger, Thomas1 aMelander, Olle1 aMendoza-Caamal, Elvia1 aMetcalf, Ginger, A1 aMi, Xuenan1 aMohlke, Karen, L1 aMontasser, May, E1 aMoon, Jee-Young1 aMoreno-Macias, Hortensia1 aMorrison, Alanna, C1 aMuzny, Donna, M1 aNelson, Sarah, C1 aNilsson, Peter, M1 aO'Connell, Jeffrey, R1 aOrho-Melander, Marju1 aOrozco, Lorena1 aPalmer, Colin, N A1 aPalmer, Nicholette, D1 aPark, Cheol, Joo1 aPark, Kyong, Soo1 aPedersen, Oluf1 aPeralta, Juan, M1 aPeyser, Patricia, A1 aPost, Wendy, S1 aPreuss, Michael1 aPsaty, Bruce, M1 aQi, Qibin1 aRao, D, C1 aRedline, Susan1 aReiner, Alexander, P1 aRevilla-Monsalve, Cristina1 aRich, Stephen, S1 aSamani, Nilesh1 aSchunkert, Heribert1 aSchurmann, Claudia1 aSeo, Daekwan1 aSeo, Jeong-Sun1 aSim, Xueling1 aSladek, Rob1 aSmall, Kerrin, S1 aSo, Wing, Yee1 aStilp, Adrienne, M1 aTai, Shyong, E1 aTam, Claudia, H T1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aThameem, Farook1 aTomlinson, Brian1 aTsai, Michael, Y1 aTuomi, Tiinamaija1 aTuomilehto, Jaakko1 aTusié-Luna, Teresa1 aUdler, Miriam, S1 avan Dam, Rob, M1 aVasan, Ramachandran, S1 aMartinez, Karine, A Viaud1 aWang, Fei, Fei1 aWang, Xuzhi1 aWatkins, Hugh1 aWeeks, Daniel, E1 aWilson, James, G1 aWitte, Daniel, R1 aWong, Tien-Yin1 aYanek, Lisa, R1 aKathiresan, Sekar1 aRader, Daniel, J1 aRotter, Jerome, I1 aBoehnke, Michael1 aMcCarthy, Mark, I1 aWiller, Cristen, J1 aNatarajan, Pradeep1 aFlannick, Jason, A1 aKhera, Amit, V1 aPeloso, Gina, M1 aAMP-T2D-GENES, Myocardial Infarction Genetics Consortium1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aNHLBI TOPMed Lipids Working Group uhttps://chs-nhlbi.org/node/897503611nas 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/958813865nas a2204393 4500008004100000245014900041210006900190260001600259520157500275100001601850700003201866700002201898700002101920700001801941700001901959700001701978700002701995700002102022700001802043700002202061700002002083700002002103700002002123700002302143700002102166700002202187700002302209700001502232700001702247700001502264700001702279700001802296700001302314700002002327700002202347700002302369700001502392700001602407700002402423700001902447700002102466700001902487700001802506700001302524700001902537700002202556700001902578700002402597700002102621700001402642700002502656700001802681700001702699700002102716700002102737700002202758700002002780700002002800700001902820700001702839700001402856700001402870700001802884700002602902700002102928700002002949700002202969700002602991700002203017700002303039700002303062700001803085700001903103700001803122700002303140700002203163700001303185700001903198700002103217700001903238700001603257700002203273700002203295700001703317700001603334700002003350700002303370700003103393700002803424700002003452700001903472700002303491700002103514700002403535700002303559700002503582700002203607700002303629700002003652700001803672700001303690700002003703700002103723700002003744700002103764700001803785700001703803700001903820700002103839700002203860700002403882700002103906700001403927700001503941700002103956700002103977700002103998700002204019700002004041700002004061700001404081700002104095700002504116700002304141700002004164700002504184700002604209700003604235700003904271700002504310700001704335700002204352700002204374700001504396700002604411700002204437700002204459700002404481700001704505700001804522700001504540700001704555700002104572700001804593700002104611700002704632700002204659700002304681700001804704700001704722700002104739700001804760700001904778700002304797700002204820700002904842700002204871700002204893700002404915700002104939700001704960700002204977700002504999700001805024700002405042700002205066700001805088700002105106700002005127700002005147700002005167700001705187700001505204700001205219700002005231700002005251700002505271700002105296700001805317700001705335700001905352700001505371700001805386700001905404700001205423700001205435700002005447700002305467700001705490700002205507700002705529700002005556700002205576700002105598700001305619700002205632700002105654700002205675700001505697700001905712700002005731700001905751700002105770700001805791700001305809700002105822700002005843700002105863700002605884700002105910700001805931700003105949700002505980700001906005700001906024700001906043700002806062700001806090700002506108700001906133700002606152700002306178700001706201700001606218700002006234700002206254700002306276700001806299700002506317700003206342700002306374700002406397700002006421700002106441700002806462700002106490700001706511700001806528700002306546700002406569700002106593700002906614700002006643700002406663700001706687700002606704700002106730700003006751700002106781700002106802700002806823700001806851700002206869700002006891700001606911700001906927700001706946700002506963700001706988700001507005700002807020700002807048700003207076700002307108700002207131700001907153700001307172700001907185700001907204700001507223700002507238700002007263700002007283700002007303700002307323700002007346700001807366700002307384700002107407700002207428700001707450700002207467700002407489700002407513700002107537700002107558700002307579700002207602700002107624700002107645700001807666700002007684700002007704700001907724700002907743700002207772700002407794700002407818700002507842700002107867700002207888700001907910700002207929700001707951700002007968700001907988700001708007700002208024700002108046700002708067700002108094700002008115700002108135700001808156700001908174700001908193700001908212700001908231700001908250700002208269700002308291700002208314700002408336700001508360700001908375700002108394700001908415700001908434700002508453700001708478700001708495700002208512700002208534700002108556700002208577700002108599700002408620700002708644700002008671700002008691700002108711700002408732700002408756700001808780700002108798700002408819700002208843700002208865700001908887700001708906700002308923700002008946700002008966700002208986700002009008700002009028700002809048700002309076700002109099700002209120700002309142700002409165700002209189700002409211710007009235710005509305710007509360856003609435 2023 eng d00aMulti-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.0 aMultiancestry genomewide study in 25 million individuals reveals c2023 Mar 313 aType 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5×10 ) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.
1 aSuzuki, Ken1 aHatzikotoulas, Konstantinos1 aSoutham, Lorraine1 aTaylor, Henry, J1 aYin, Xianyong1 aLorenz, Kim, M1 aMandla, Ravi1 aHuerta-Chagoya, Alicia1 aRayner, Nigel, W1 aBocher, Ozvan1 ade, S, V Arruda A1 aSonehara, Kyuto1 aNamba, Shinichi1 aLee, Simon, S K1 aPreuss, Michael, H1 aPetty, Lauren, E1 aSchroeder, Philip1 aVanderwerff, Brett1 aKals, Mart1 aBragg, Fiona1 aLin, Kuang1 aGuo, Xiuqing1 aZhang, Weihua1 aYao, Jie1 aKim, Young, Jin1 aGraff, Mariaelisa1 aTakeuchi, Fumihiko1 aNano, Jana1 aLamri, Amel1 aNakatochi, Masahiro1 aMoon, Sanghoon1 aScott, Robert, A1 aCook, James, P1 aLee, Jung-Jin1 aPan, Ian1 aTaliun, Daniel1 aParra, Esteban, J1 aChai, Jin-Fang1 aBielak, Lawrence, F1 aTabara, Yasuharu1 aHai, Yang1 aThorleifsson, Gudmar1 aGrarup, Niels1 aSofer, Tamar1 aWuttke, Matthias1 aSarnowski, Chloe1 aGieger, Christian1 aNousome, Darryl1 aTrompet, Stella1 aKwak, Soo-Heon1 aLong, Jirong1 aSun, Meng1 aTong, Lin1 aChen, Wei-Min1 aNongmaithem, Suraj, S1 aNoordam, Raymond1 aJ Y Lim, Victor1 aTam, Claudia, H T1 aJoo, Yoonjung, Yoonie1 aChen, Chien-Hsiun1 aRaffield, Laura, M1 aPrins, Bram, Peter1 aNicolas, Aude1 aYanek, Lisa, R1 aChen, Guanjie1 aBrody, Jennifer, A1 aKabagambe, Edmond1 aAn, Ping1 aXiang, Anny, H1 aChoi, Hyeok, Sun1 aCade, Brian, E1 aTan, Jingyi1 aBroadaway, Alaine1 aWilliamson, Alice1 aKamali, Zoha1 aCui, Jinrui1 aAdair, Linda, S1 aAdeyemo, Adebowale1 aAguilar-Salinas, Carlos, A1 aAhluwalia, Tarunveer, S1 aAnand, Sonia, S1 aBertoni, Alain1 aBork-Jensen, Jette1 aBrandslund, Ivan1 aBuchanan, Thomas, A1 aBurant, Charles, F1 aButterworth, Adam, S1 aCanouil, Mickaël1 aChan, Juliana, C N1 aChang, Li-Ching1 aChee, Miao-Li1 aChen, Ji1 aChen, Shyh-Huei1 aChen, Yuan-Tsong1 aChen, Zhengming1 aChuang, Lee-Ming1 aCushman, Mary1 aDanesh, John1 aDas, Swapan, K1 ade Silva, Janaka1 aDedoussis, George1 aDimitrov, Latchezar1 aDoumatey, Ayo, P1 aDu, Shufa1 aDuan, Qing1 aEckardt, Kai-Uwe1 aEmery, Leslie, S1 aEvans, Daniel, S1 aEvans, Michele, K1 aFischer, Krista1 aFloyd, James, S1 aFord, Ian1 aFranco, Oscar, H1 aFrayling, Timothy, M1 aFreedman, Barry, I1 aGenter, Pauline1 aGerstein, Hertzel, C1 aGiedraitis, Vilmantas1 aGonzález-Villalpando, Clicerio1 aGonzalez-Villalpando, Maria, Elena1 aGordon-Larsen, Penny1 aGross, Myron1 aGuare, Lindsay, A1 aHackinger, Sophie1 aHan, Sohee1 aHattersley, Andrew, T1 aHerder, Christian1 aHorikoshi, Momoko1 aHoward, Annie-Green1 aHsueh, Willa1 aHuang, Mengna1 aHuang, Wei1 aHung, Yi-Jen1 aHwang, Mi, Yeong1 aHwu, Chii-Min1 aIchihara, Sahoko1 aIkram, Mohammad, Arfan1 aIngelsson, Martin1 aIslam, Md, Tariqul1 aIsono, Masato1 aJang, Hye-Mi1 aJasmine, Farzana1 aJiang, Guozhi1 aJonas, Jost, B1 aJørgensen, Torben1 aKandeel, Fouad, R1 aKasturiratne, Anuradhani1 aKatsuya, Tomohiro1 aKaur, Varinderpal1 aKawaguchi, Takahisa1 aKeaton, Jacob, M1 aKho, Abel, N1 aKhor, Chiea-Chuen1 aKibriya, Muhammad, G1 aKim, Duk-Hwan1 aKronenberg, Florian1 aKuusisto, Johanna1 aLäll, Kristi1 aLange, Leslie, A1 aLee, Kyung, Min1 aLee, Myung-Shik1 aLee, Nanette, R1 aLeong, Aaron1 aLi, Liming1 aLi, Yun1 aLi-Gao, Ruifang1 aLithgart, Symen1 aLindgren, Cecilia, M1 aLinneberg, Allan1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLocke, Adam, E1 aLouie, Tin1 aLuan, Jian'an1 aLuk, Andrea, O1 aLuo, Xi1 aLv, Jun1 aLynch, Julie, A1 aLyssenko, Valeriya1 aMaeda, Shiro1 aMamakou, Vasiliki1 aMansuri, Sohail, Rafik1 aMatsuda, Koichi1 aMeitinger, Thomas1 aMetspalu, Andres1 aMo, Huan1 aMorris, Andrew, D1 aNadler, Jerry, L1 aNalls, Michael, A1 aNayak, Uma1 aNtalla, Ioanna1 aOkada, Yukinori1 aOrozco, Lorena1 aPatel, Sanjay, R1 aPatil, Snehal1 aPei, Pei1 aPereira, Mark, A1 aPeters, Annette1 aPirie, Fraser, J1 aPolikowsky, Hannah, G1 aPorneala, Bianca1 aPrasad, Gauri1 aRasmussen-Torvik, Laura, J1 aReiner, Alexander, P1 aRoden, Michael1 aRohde, Rebecca1 aRoll, Katheryn1 aSabanayagam, Charumathi1 aSandow, Kevin1 aSankareswaran, Alagu1 aSattar, Naveed1 aSchönherr, Sebastian1 aShahriar, Mohammad1 aShen, Botong1 aShi, Jinxiu1 aShin, Dong, Mun1 aShojima, Nobuhiro1 aSmith, Jennifer, A1 aSo, Wing, Yee1 aStančáková, Alena1 aSteinthorsdottir, Valgerdur1 aStilp, Adrienne, M1 aStrauch, Konstantin1 aTaylor, Kent, D1 aThorand, Barbara1 aThorsteinsdottir, Unnur1 aTomlinson, Brian1 aTran, Tam, C1 aTsai, Fuu-Jen1 aTuomilehto, Jaakko1 aTusié-Luna, Teresa1 aUdler, Miriam, S1 aValladares-Salgado, Adan1 avan Dam, Rob, M1 avan Klinken, Jan, B1 aVarma, Rohit1 aWacher-Rodarte, Niels1 aWheeler, Eleanor1 aWickremasinghe, Ananda, R1 aDijk, Ko Willems1 aWitte, Daniel, R1 aYajnik, Chittaranjan, S1 aYamamoto, Ken1 aYamamoto, Kenichi1 aYoon, Kyungheon1 aYu, Canqing1 aYuan, Jian-Min1 aYusuf, Salim1 aZawistowski, Matthew1 aZhang, Liang1 aZheng, Wei1 aProject, Biobank, Japan1 aBioBank, Penn, Medicine1 aCenter, Regeneron, Genetics1 aConsortium, eMERGE1 aRaffel, Leslie, J1 aIgase, Michiya1 aIpp, Eli1 aRedline, Susan1 aCho, Yoon Shin1 aLind, Lars1 aProvince, Michael, A1 aFornage, Myriam1 aHanis, Craig, L1 aIngelsson, Erik1 aZonderman, Alan, B1 aPsaty, Bruce, M1 aWang, Ya-Xing1 aRotimi, Charles, N1 aBecker, Diane, M1 aMatsuda, Fumihiko1 aLiu, Yongmei1 aYokota, Mitsuhiro1 aKardia, Sharon, L R1 aPeyser, Patricia, A1 aPankow, James, S1 aEngert, James, C1 aBonnefond, Amélie1 aFroguel, Philippe1 aWilson, James, G1 aSheu, Wayne, H H1 aWu, Jer-Yuarn1 aHayes, Geoffrey1 aMa, Ronald, C W1 aWong, Tien-Yin1 aMook-Kanamori, Dennis, O1 aTuomi, Tiinamaija1 aChandak, Giriraj, R1 aCollins, Francis, S1 aBharadwaj, Dwaipayan1 aParé, Guillaume1 aSale, Michèle, M1 aAhsan, Habibul1 aMotala, Ayesha, A1 aShu, Xiao-Ou1 aPark, Kyong-Soo1 aJukema, Wouter1 aCruz, Miguel1 aChen, Yii-Der Ida1 aRich, Stephen, S1 aMcKean-Cowdin, Roberta1 aGrallert, Harald1 aCheng, Ching-Yu1 aGhanbari, Mohsen1 aTai, E-Shyong1 aDupuis, Josée1 aKato, Norihiro1 aLaakso, Markku1 aKöttgen, Anna1 aKoh, Woon-Puay1 aBowden, Donald, W1 aPalmer, Colin, N A1 aKooner, Jaspal, S1 aKooperberg, Charles1 aLiu, Simin1 aNorth, Kari, E1 aSaleheen, Danish1 aHansen, Torben1 aPedersen, Oluf1 aWareham, Nicholas, J1 aLee, Juyoung1 aKim, Bong-Jo1 aMillwood, Iona, Y1 aWalters, Robin, G1 aStefansson, Kari1 aGoodarzi, Mark, O1 aMohlke, Karen, L1 aLangenberg, Claudia1 aHaiman, Christopher, A1 aLoos, Ruth, J F1 aFlorez, Jose, C1 aRader, Daniel, J1 aRitchie, Marylyn, D1 aZöllner, Sebastian1 aMägi, Reedik1 aDenny, Joshua, C1 aYamauchi, Toshimasa1 aKadowaki, Takashi1 aChambers, John, C1 aC Y Ng, Maggie1 aSim, Xueling1 aBelow, Jennifer, E1 aTsao, Philip, S1 aChang, Kyong-Mi1 aMcCarthy, Mark, I1 aMeigs, James, B1 aMahajan, Anubha1 aSpracklen, Cassandra, N1 aMercader, Josep, M1 aBoehnke, Michael1 aRotter, Jerome, I1 aVujkovic, Marijana1 aVoight, Benjamin, F1 aMorris, Andrew, P1 aZeggini, Eleftheria1 aVA Million Veteran Program, AMED GRIFIN Diabetes Initiative Japan1 aInternational Consortium for Blood Pressure (ICBP)1 aMeta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) uhttps://chs-nhlbi.org/node/938514002nas a2204477 4500008004100000022001400041245007300055210006900128260001600197520170400213100001601917700003201933700002201965700002101987700001802008700001902026700001702045700002702062700002602089700002202115700002102137700001802158700002302176700002002199700002002219700002002239700002302259700002102282700002202303700002302325700001502348700001702363700001502380700001702395700001802412700001302430700002002443700002202463700002302485700001502508700001602523700002402539700001902563700002102582700001902603700001802622700001302640700001902653700002202672700001902694700002402713700002102737700001402758700002502772700001802797700001702815700002102832700002102853700002202874700002002896700002002916700001902936700001702955700001402972700001402986700001803000700002603018700002103044700002003065700002203085700002603107700002203133700002303155700002303178700001803201700001903219700001803238700002303256700002203279700001303301700001903314700002103333700001903354700001603373700002203389700002203411700001703433700001603450700002603466700002003492700002303512700003103535700002803566700002003594700001903614700002303633700002103656700002403677700002303701700002503724700002203749700002303771700002003794700001803814700001303832700002003845700002103865700002003886700002103906700001803927700001703945700001903962700002103981700002204002700002404024700002104048700001404069700001504083700002104098700002104119700002104140700002204161700002004183700002004203700001404223700002104237700002504258700002304283700002004306700002504326700002604351700003604377700003904413700002504452700001704477700002204494700002204516700001904538700001504557700002604572700002204598700002204620700002404642700001704666700001804683700001504701700001704716700002104733700001804754700002104772700002704793700002204820700002304842700001804865700001704883700002104900700001804921700001904939700002304958700002504981700002205006700002905028700002205057700002205079700002405101700002105125700001705146700002205163700002505185700001805210700002405228700002205252700001805274700002105292700002005313700002005333700002005353700001705373700001505390700001205405700002005417700002005437700002505457700002105482700001805503700001705521700001905538700001505557700001805572700001905590700001205609700001205621700002005633700002305653700001705676700002205693700002705715700002005742700002205762700001905784700002105803700001305824700002205837700002105859700002105880700002205901700001505923700001905938700002005957700001905977700002105996700001806017700001306035700002106048700002006069700002106089700002606110700002106136700001806157700003106175700002506206700001906231700001906250700001906269700002806288700001806316700002506334700001906359700002606378700002306404700001706427700001606444700002006460700002206480700002306502700001806525700002506543700003206568700002306600700002406623700002006647700002106667700002806688700002106716700001706737700001806754700002306772700002406795700002106819700002906840700002006869700002406889700001706913700002606930700002106956700003006977700002107007700002107028700002807049700001807077700002207095700002007117700001607137700001907153700001707172700002507189700001707214700001507231700002207246700001907268700001307287700001907300700001907319700001507338700002507353700002007378700002007398700002007418700002307438700002007461700001807481700002307499700002107522700002207543700001707565700002207582700002407604700002407628700002107652700002107673700002307694700002207717700002107739700002107760700001807781700002007799700002007819700001907839700002907858700002207887700002407909700002407933700002507957700002107982700002208003700001908025700002208044700001708066700002008083700001908103700001708122700002208139700002108161700002708182700002108209700002008230700002108250700001808271700001908289700001908308700001908327700001908346700001908365700002208384700002308406700002208429700002408451700001508475700001908490700002108509700001908530700001908549700002508568700001708593700001708610700002208627700002208649700002108671700001908692700002208711700002108733700002408754700002708778700002008805700002008825700002108845700002408866700002408890700001808914700002508932700002308957700002308980700001709003700002109020700002409041700002209065700002209087700001909109700001709128700002309145700002009168700002009188700002209208700002009230700002009250700002809270700002309298700002109321700002209342700002309364700002409387700002209411700002409433710003109457856003609488 2024 eng d a1476-468700aGenetic drivers of heterogeneity in type 2 diabetes pathophysiology.0 aGenetic drivers of heterogeneity in type 2 diabetes pathophysiol c2024 Feb 193 aType 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell type. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.
1 aSuzuki, Ken1 aHatzikotoulas, Konstantinos1 aSoutham, Lorraine1 aTaylor, Henry, J1 aYin, Xianyong1 aLorenz, Kim, M1 aMandla, Ravi1 aHuerta-Chagoya, Alicia1 aMelloni, Giorgio, E M1 aKanoni, Stavroula1 aRayner, Nigel, W1 aBocher, Ozvan1 aArruda, Ana, Luiza1 aSonehara, Kyuto1 aNamba, Shinichi1 aLee, Simon, S K1 aPreuss, Michael, H1 aPetty, Lauren, E1 aSchroeder, Philip1 aVanderwerff, Brett1 aKals, Mart1 aBragg, Fiona1 aLin, Kuang1 aGuo, Xiuqing1 aZhang, Weihua1 aYao, Jie1 aKim, Young, Jin1 aGraff, Mariaelisa1 aTakeuchi, Fumihiko1 aNano, Jana1 aLamri, Amel1 aNakatochi, Masahiro1 aMoon, Sanghoon1 aScott, Robert, A1 aCook, James, P1 aLee, Jung-Jin1 aPan, Ian1 aTaliun, Daniel1 aParra, Esteban, J1 aChai, Jin-Fang1 aBielak, Lawrence, F1 aTabara, Yasuharu1 aHai, Yang1 aThorleifsson, Gudmar1 aGrarup, Niels1 aSofer, Tamar1 aWuttke, Matthias1 aSarnowski, Chloe1 aGieger, Christian1 aNousome, Darryl1 aTrompet, Stella1 aKwak, Soo-Heon1 aLong, Jirong1 aSun, Meng1 aTong, Lin1 aChen, Wei-Min1 aNongmaithem, Suraj, S1 aNoordam, Raymond1 aJ Y Lim, Victor1 aTam, Claudia, H T1 aJoo, Yoonjung, Yoonie1 aChen, Chien-Hsiun1 aRaffield, Laura, M1 aPrins, Bram, Peter1 aNicolas, Aude1 aYanek, Lisa, R1 aChen, Guanjie1 aBrody, Jennifer, A1 aKabagambe, Edmond1 aAn, Ping1 aXiang, Anny, H1 aChoi, Hyeok, Sun1 aCade, Brian, E1 aTan, Jingyi1 aBroadaway, Alaine1 aWilliamson, Alice1 aKamali, Zoha1 aCui, Jinrui1 aThangam, Manonanthini1 aAdair, Linda, S1 aAdeyemo, Adebowale1 aAguilar-Salinas, Carlos, A1 aAhluwalia, Tarunveer, S1 aAnand, Sonia, S1 aBertoni, Alain1 aBork-Jensen, Jette1 aBrandslund, Ivan1 aBuchanan, Thomas, A1 aBurant, Charles, F1 aButterworth, Adam, S1 aCanouil, Mickaël1 aChan, Juliana, C N1 aChang, Li-Ching1 aChee, Miao-Li1 aChen, Ji1 aChen, Shyh-Huei1 aChen, Yuan-Tsong1 aChen, Zhengming1 aChuang, Lee-Ming1 aCushman, Mary1 aDanesh, John1 aDas, Swapan, K1 ade Silva, Janaka1 aDedoussis, George1 aDimitrov, Latchezar1 aDoumatey, Ayo, P1 aDu, Shufa1 aDuan, Qing1 aEckardt, Kai-Uwe1 aEmery, Leslie, S1 aEvans, Daniel, S1 aEvans, Michele, K1 aFischer, Krista1 aFloyd, James, S1 aFord, Ian1 aFranco, Oscar, H1 aFrayling, Timothy, M1 aFreedman, Barry, I1 aGenter, Pauline1 aGerstein, Hertzel, C1 aGiedraitis, Vilmantas1 aGonzález-Villalpando, Clicerio1 aGonzalez-Villalpando, Maria, Elena1 aGordon-Larsen, Penny1 aGross, Myron1 aGuare, Lindsay, A1 aHackinger, Sophie1 aHakaste, Liisa1 aHan, Sohee1 aHattersley, Andrew, T1 aHerder, Christian1 aHorikoshi, Momoko1 aHoward, Annie-Green1 aHsueh, Willa1 aHuang, Mengna1 aHuang, Wei1 aHung, Yi-Jen1 aHwang, Mi, Yeong1 aHwu, Chii-Min1 aIchihara, Sahoko1 aIkram, Mohammad, Arfan1 aIngelsson, Martin1 aIslam, Md, Tariqul1 aIsono, Masato1 aJang, Hye-Mi1 aJasmine, Farzana1 aJiang, Guozhi1 aJonas, Jost, B1 aJørgensen, Torben1 aKamanu, Frederick, K1 aKandeel, Fouad, R1 aKasturiratne, Anuradhani1 aKatsuya, Tomohiro1 aKaur, Varinderpal1 aKawaguchi, Takahisa1 aKeaton, Jacob, M1 aKho, Abel, N1 aKhor, Chiea-Chuen1 aKibriya, Muhammad, G1 aKim, Duk-Hwan1 aKronenberg, Florian1 aKuusisto, Johanna1 aLäll, Kristi1 aLange, Leslie, A1 aLee, Kyung, Min1 aLee, Myung-Shik1 aLee, Nanette, R1 aLeong, Aaron1 aLi, Liming1 aLi, Yun1 aLi-Gao, Ruifang1 aLigthart, Symen1 aLindgren, Cecilia, M1 aLinneberg, Allan1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLocke, Adam, E1 aLouie, Tin1 aLuan, Jian'an1 aLuk, Andrea, O1 aLuo, Xi1 aLv, Jun1 aLynch, Julie, A1 aLyssenko, Valeriya1 aMaeda, Shiro1 aMamakou, Vasiliki1 aMansuri, Sohail, Rafik1 aMatsuda, Koichi1 aMeitinger, Thomas1 aMelander, Olle1 aMetspalu, Andres1 aMo, Huan1 aMorris, Andrew, D1 aMoura, Filipe, A1 aNadler, Jerry, L1 aNalls, Michael, A1 aNayak, Uma1 aNtalla, Ioanna1 aOkada, Yukinori1 aOrozco, Lorena1 aPatel, Sanjay, R1 aPatil, Snehal1 aPei, Pei1 aPereira, Mark, A1 aPeters, Annette1 aPirie, Fraser, J1 aPolikowsky, Hannah, G1 aPorneala, Bianca1 aPrasad, Gauri1 aRasmussen-Torvik, Laura, J1 aReiner, Alexander, P1 aRoden, Michael1 aRohde, Rebecca1 aRoll, Katheryn1 aSabanayagam, Charumathi1 aSandow, Kevin1 aSankareswaran, Alagu1 aSattar, Naveed1 aSchönherr, Sebastian1 aShahriar, Mohammad1 aShen, Botong1 aShi, Jinxiu1 aShin, Dong, Mun1 aShojima, Nobuhiro1 aSmith, Jennifer, A1 aSo, Wing, Yee1 aStančáková, Alena1 aSteinthorsdottir, Valgerdur1 aStilp, Adrienne, M1 aStrauch, Konstantin1 aTaylor, Kent, D1 aThorand, Barbara1 aThorsteinsdottir, Unnur1 aTomlinson, Brian1 aTran, Tam, C1 aTsai, Fuu-Jen1 aTuomilehto, Jaakko1 aTusié-Luna, Teresa1 aUdler, Miriam, S1 aValladares-Salgado, Adan1 avan Dam, Rob, M1 avan Klinken, Jan, B1 aVarma, Rohit1 aWacher-Rodarte, Niels1 aWheeler, Eleanor1 aWickremasinghe, Ananda, R1 aDijk, Ko Willems1 aWitte, Daniel, R1 aYajnik, Chittaranjan, S1 aYamamoto, Ken1 aYamamoto, Kenichi1 aYoon, Kyungheon1 aYu, Canqing1 aYuan, Jian-Min1 aYusuf, Salim1 aZawistowski, Matthew1 aZhang, Liang1 aZheng, Wei1 aRaffel, Leslie, J1 aIgase, Michiya1 aIpp, Eli1 aRedline, Susan1 aCho, Yoon Shin1 aLind, Lars1 aProvince, Michael, A1 aFornage, Myriam1 aHanis, Craig, L1 aIngelsson, Erik1 aZonderman, Alan, B1 aPsaty, Bruce, M1 aWang, Ya-Xing1 aRotimi, Charles, N1 aBecker, Diane, M1 aMatsuda, Fumihiko1 aLiu, Yongmei1 aYokota, Mitsuhiro1 aKardia, Sharon, L R1 aPeyser, Patricia, A1 aPankow, James, S1 aEngert, James, C1 aBonnefond, Amélie1 aFroguel, Philippe1 aWilson, James, G1 aSheu, Wayne, H H1 aWu, Jer-Yuarn1 aHayes, Geoffrey1 aMa, Ronald, C W1 aWong, Tien-Yin1 aMook-Kanamori, Dennis, O1 aTuomi, Tiinamaija1 aChandak, Giriraj, R1 aCollins, Francis, S1 aBharadwaj, Dwaipayan1 aParé, Guillaume1 aSale, Michèle, M1 aAhsan, Habibul1 aMotala, Ayesha, A1 aShu, Xiao-Ou1 aPark, Kyong-Soo1 aJukema, Wouter1 aCruz, Miguel1 aChen, Yii-Der Ida1 aRich, Stephen, S1 aMcKean-Cowdin, Roberta1 aGrallert, Harald1 aCheng, Ching-Yu1 aGhanbari, Mohsen1 aTai, E-Shyong1 aDupuis, Josée1 aKato, Norihiro1 aLaakso, Markku1 aKöttgen, Anna1 aKoh, Woon-Puay1 aBowden, Donald, W1 aPalmer, Colin, N A1 aKooner, Jaspal, S1 aKooperberg, Charles1 aLiu, Simin1 aNorth, Kari, E1 aSaleheen, Danish1 aHansen, Torben1 aPedersen, Oluf1 aWareham, Nicholas, J1 aLee, Juyoung1 aKim, Bong-Jo1 aMillwood, Iona, Y1 aWalters, Robin, G1 aStefansson, Kari1 aAhlqvist, Emma1 aGoodarzi, Mark, O1 aMohlke, Karen, L1 aLangenberg, Claudia1 aHaiman, Christopher, A1 aLoos, Ruth, J F1 aFlorez, Jose, C1 aRader, Daniel, J1 aRitchie, Marylyn, D1 aZöllner, Sebastian1 aMägi, Reedik1 aMarston, Nicholas, A1 aRuff, Christian, T1 avan Heel, David, A1 aFiner, Sarah1 aDenny, Joshua, C1 aYamauchi, Toshimasa1 aKadowaki, Takashi1 aChambers, John, C1 aC Y Ng, Maggie1 aSim, Xueling1 aBelow, Jennifer, E1 aTsao, Philip, S1 aChang, Kyong-Mi1 aMcCarthy, Mark, I1 aMeigs, James, B1 aMahajan, Anubha1 aSpracklen, Cassandra, N1 aMercader, Josep, M1 aBoehnke, Michael1 aRotter, Jerome, I1 aVujkovic, Marijana1 aVoight, Benjamin, F1 aMorris, Andrew, P1 aZeggini, Eleftheria1 aVA Million Veteran Program uhttps://chs-nhlbi.org/node/9619