04741nas a2201021 4500008004100000022001400041245008000055210006900135260001300204300001200217490000700229520186200236653001002098653000902108653001902117653002402136653001102160653003802171653003402209653001102243653002602254653000902280653001602289653002402305653001702329100001702346700002602363700001902389700002102408700002002429700002502449700002302474700002002497700002902517700002102546700001602567700002202583700002202605700001802627700002402645700002302669700002002692700002502712700002002737700002302757700001402780700002402794700002602818700002402844700001902868700001902887700001902906700002102925700002102946700001702967700002102984700001603005700002003021700002603041700001903067700002303086700002103109700002003130700001803150700002003168700002003188700002103208700002403229700002403253700002103277700001503298700002603313700001803339700002303357700002003380700001903400700002303419700002003442700001903462700002203481700002003503700002203523700002003545700002003565700002203585710007603607856003603683 2015 eng d a1524-462800aWhite Matter Lesion Progression: Genome-Wide Search for Genetic Influences.0 aWhite Matter Lesion Progression GenomeWide Search for Genetic In c2015 Nov a3048-570 v463 a
BACKGROUND AND PURPOSE: White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.
METHODS: Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies.
RESULTS: A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10(-8)). Four loci were suggestive (P<1×10(-5)) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10(-6)); 12q13.13 (rs4761974, P=8.71×10(-7)); 20p12.1 (rs6135309, P=3.69×10(-6)); and 4p15.31 (rs7664442, P=2.26×10(-6)). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden.
CONCLUSIONS: Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.
10aAdult10aAged10aCohort Studies10aDisease Progression10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLeukoencephalopathies10aMale10aMiddle Aged10aProspective Studies10aWhite Matter1 aHofer, Edith1 aCavalieri, Margherita1 aBis, Joshua, C1 aDeCarli, Charles1 aFornage, Myriam1 aSigurdsson, Sigurdur1 aSrikanth, Velandai1 aTrompet, Stella1 aVerhaaren, Benjamin, F J1 aWolf, Christiane1 aYang, Qiong1 aAdams, Hieab, H H1 aAmouyel, Philippe1 aBeiser, Alexa1 aBuckley, Brendan, M1 aCallisaya, Michele1 aChauhan, Ganesh1 ade Craen, Anton, J M1 aDufouil, Carole1 aDuijn, Cornelia, M1 aFord, Ian1 aFreudenberger, Paul1 aGottesman, Rebecca, F1 aGudnason, Vilmundur1 aHeiss, Gerardo1 aHofman, Albert1 aLumley, Thomas1 aMartinez, Oliver1 aMazoyer, Bernard1 aMoran, Chris1 aNiessen, Wiro, J1 aPhan, Thanh1 aPsaty, Bruce, M1 aSatizabal, Claudia, L1 aSattar, Naveed1 aSchilling, Sabrina1 aShibata, Dean, K1 aSlagboom, Eline1 aSmith, Albert1 aStott, David, J1 aTaylor, Kent, D1 aThomson, Russell1 aTöglhofer, Anna, M1 aTzourio, Christophe1 avan Buchem, Mark1 aWang, Jing1 aWestendorp, Rudi, G J1 aWindham, Gwen1 aVernooij, Meike, W1 aZijdenbos, Alex1 aBeare, Richard1 aDebette, Stephanie1 aIkram, Arfan, M1 aJukema, Wouter1 aLauner, Lenore, J1 aLongstreth, W T1 aMosley, Thomas, H1 aSeshadri, Sudha1 aSchmidt, Helena1 aSchmidt, Reinhold1 aCohorts for Heart and Aging Research in Genomic Epidemiology Consortium uhttps://chs-nhlbi.org/node/686103298nas a2200793 4500008004100000022001400041245008800055210006900143260001300212300001300225490000700238520090200245100002601147700002501173700001901198700002201217700002201239700002101261700002001282700001401302700002101316700002101337700002401358700002301382700002101405700001601426700001801442700003001460700002101490700002601511700002001537700001801557700002001575700002301595700002201618700002001640700002001660700002001680700002101700700002101721700002401742700002301766700002001789700002401809700002101833700002001854700001701874700002801891700002001919700002201939700001901961700003001980700002802010700002202038700001902060700001802079700002002097700002802117700002102145700002002166700002002186700002302206700002402229700002302253710007602276710004502352710007102397856003602468 2016 eng d a1553-740400aRare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.0 aRare Functional Variant in TM2D3 is Associated with LateOnset Al c2016 Oct ae10063270 v123 aWe performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.
1 aJakobsdottir, Johanna1 avan der Lee, Sven, J1 aBis, Joshua, C1 aChouraki, Vincent1 aLi-Kroeger, David1 aYamamoto, Shinya1 aGrove, Megan, L1 aNaj, Adam1 aVronskaya, Maria1 aSalazar, Jose, L1 aDeStefano, Anita, L1 aBrody, Jennifer, A1 aSmith, Albert, V1 aAmin, Najaf1 aSims, Rebecca1 aIbrahim-Verbaas, Carla, A1 aChoi, Seung-Hoan1 aSatizabal, Claudia, L1 aLopez, Oscar, L1 aBeiser, Alexa1 aIkram, Arfan, M1 aGarcia, Melissa, E1 aHayward, Caroline1 aVarga, Tibor, V1 aRipatti, Samuli1 aFranks, Paul, W1 aHallmans, Göran1 aRolandsson, Olov1 aJansson, Jan-Håkon1 aPorteous, David, J1 aSalomaa, Veikko1 aEiriksdottir, Gudny1 aRice, Kenneth, M1 aBellen, Hugo, J1 aLevy, Daniel1 aUitterlinden, André, G1 aEmilsson, Valur1 aRotter, Jerome, I1 aAspelund, Thor1 aO'Donnell, Christopher, J1 aFitzpatrick, Annette, L1 aLauner, Lenore, J1 aHofman, Albert1 aSan Wang, Li-1 aWilliams, Julie1 aSchellenberg, Gerard, D1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aSeshadri, Sudha1 aShulman, Joshua, M1 aGudnason, Vilmundur1 aDuijn, Cornelia, M1 aCohorts for Heart and Aging Research in Genomic Epidemiology Consortium1 aAlzheimer’s Disease Genetic Consortium1 aGenetic and Environmental Risk in Alzheimer’s Disease consortium uhttps://chs-nhlbi.org/node/726017687nas a2205785 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02010465700002210485700002510507700001910532700001610551700001910567700002010586700002110606700002110627700002610648700002110674700002410695700001610719700002110735700002810756700001810784700002110802700002210823700002210845700001710867700001910884700002010903700002410923700001810947700002710965700002210992700002011014700002011034700002311054700001911077700002411096700001711120700002311137700003011160700002411190700002411214700002211238700002311260700001711283700002311300700002311323700003111346700002011377700001811397700002411415700002411439700002211463700002811485700002011513700002711533700001611560700002211576700003111598700002211629700002311651700002111674700001811695700002611713700002011739700002011759700002811779710002011807710003811827856003611865 2017 eng d a1546-171800aRare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.0 aRare coding variants in PLCG2 ABI3 and TREM2 implicate microglia c2017 Sep a1373-13840 v493 aWe identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
10aAdaptor Proteins, Signal Transducing10aAlzheimer Disease10aAmino Acid Sequence10aCase-Control Studies10aExome10aGene Expression Profiling10aGene Frequency10aGenetic Predisposition to Disease10aGenotype10aHumans10aImmunity, Innate10aLinkage Disequilibrium10aMembrane Glycoproteins10aMicroglia10aOdds Ratio10aPhospholipase C gamma10aPolymorphism, Single Nucleotide10aProtein Interaction Maps10aReceptors, Immunologic10aSequence Homology, Amino Acid1 aSims, Rebecca1 avan der Lee, Sven, J1 aNaj, Adam, C1 aBellenguez, Céline1 aBadarinarayan, Nandini1 aJakobsdottir, Johanna1 aKunkle, Brian, W1 aBoland, Anne1 aRaybould, Rachel1 aBis, Joshua, C1 aMartin, Eden, R1 aGrenier-Boley, Benjamin1 aHeilmann-Heimbach, Stefanie1 aChouraki, Vincent1 aKuzma, Amanda, B1 aSleegers, Kristel1 aVronskaya, Maria1 aRuiz, Agustin1 aGraham, Robert, R1 aOlaso, Robert1 aHoffmann, Per1 aGrove, Megan, L1 aVardarajan, Badri, N1 aHiltunen, Mikko1 aNöthen, Markus, M1 aWhite, Charles, C1 aHamilton-Nelson, Kara, L1 aEpelbaum, Jacques1 aMaier, Wolfgang1 aChoi, Seung-Hoan1 aBeecham, Gary, W1 aDulary, Cécile1 aHerms, Stefan1 aSmith, Albert, V1 aFunk, Cory, C1 aDerbois, Céline1 aForstner, Andreas, J1 aAhmad, Shahzad1 aLi, Hongdong1 aBacq, Delphine1 aHarold, Denise1 aSatizabal, Claudia, L1 aValladares, Otto1 aSquassina, Alessio1 aThomas, Rhodri1 aBrody, Jennifer, A1 aQu, Liming1 aSánchez-Juan, Pascual1 aMorgan, Taniesha1 aWolters, Frank, J1 aZhao, Yi1 aGarcia, Florentino, Sanchez1 aDenning, Nicola1 aFornage, Myriam1 aMalamon, John1 aNaranjo, Maria, Candida De1 aMajounie, Elisa1 aMosley, Thomas, H1 aDombroski, Beth1 aWallon, David1 aLupton, Michelle, K1 aDupuis, Josée1 aWhitehead, Patrice1 aFratiglioni, Laura1 aMedway, Christopher1 aJian, Xueqiu1 aMukherjee, Shubhabrata1 aKeller, Lina1 aBrown, Kristelle1 aLin, Honghuang1 aCantwell, Laura, B1 aPanza, Francesco1 aMcGuinness, Bernadette1 aMoreno-Grau, Sonia1 aBurgess, Jeremy, D1 aSolfrizzi, Vincenzo1 aProitsi, Petra1 aAdams, Hieab, H1 aAllen, Mariet1 aSeripa, Davide1 aPastor, Pau1 aCupples, Adrienne, L1 aPrice, Nathan, D1 aHannequin, Didier1 aFrank-García, Ana1 aLevy, Daniel1 aChakrabarty, Paramita1 aCaffarra, Paolo1 aGiegling, Ina1 aBeiser, Alexa, S1 aGiedraitis, Vilmantas1 aHampel, Harald1 aGarcia, Melissa, E1 aWang, Xue1 aLannfelt, Lars1 aMecocci, Patrizia1 aEiriksdottir, Gudny1 aCrane, Paul, K1 aPasquier, Florence1 aBoccardi, Virginia1 aHenández, Isabel1 aBarber, Robert, C1 aScherer, Martin1 aTarraga, Lluis1 aAdams, Perrie, M1 aLeber, Markus1 aChen, Yuning1 aAlbert, Marilyn, S1 aRiedel-Heller, Steffi1 aEmilsson, Valur1 aBeekly, Duane1 aBraae, Anne1 aSchmidt, Reinhold1 aBlacker, Deborah1 aMasullo, Carlo1 aSchmidt, Helena1 aDoody, Rachelle, S1 aSpalletta, Gianfranco1 aJr, W, T Longstre1 aFairchild, Thomas, J1 aBossù, Paola1 aLopez, Oscar, L1 aFrosch, Matthew, P1 aSacchinelli, Eleonora1 aGhetti, Bernardino1 aYang, Qiong1 aHuebinger, Ryan, M1 aJessen, Frank1 aLi, Shuo1 aKamboh, Ilyas1 aMorris, John1 aSotolongo-Grau, Oscar1 aKatz, Mindy, J1 aCorcoran, Chris1 aDunstan, Melanie1 aBraddel, Amy1 aThomas, Charlene1 aMeggy, Alun1 aMarshall, Rachel1 aGerrish, Amy1 aChapman, Jade1 aAguilar, Miquel1 aTaylor, Sarah1 aHill, Matt1 aFairén, Mònica, Díez1 aHodges, Angela1 aVellas, Bruno1 aSoininen, Hilkka1 aKloszewska, Iwona1 aDaniilidou, Makrina1 aUphill, James1 aPatel, Yogen1 aHughes, Joseph, T1 aLord, Jenny1 aTurton, James1 aHartmann, Annette, M1 aCecchetti, Roberta1 aFenoglio, Chiara1 aSerpente, Maria1 aArcaro, Marina1 aCaltagirone, Carlo1 aOrfei, Maria, Donata1 aCiaramella, Antonio1 aPichler, Sabrina1 aMayhaus, Manuel1 aGu, Wei1 aLleo, Alberto1 aFortea, Juan1 aBlesa, Rafael1 aBarber, Imelda, S1 aBrookes, Keeley1 aCupidi, Chiara1 aMaletta, Raffaele, Giovanni1 aCarrell, David1 aSorbi, Sandro1 aMoebus, Susanne1 aUrbano, Maria1 aPilotto, Alberto1 aKornhuber, Johannes1 aBosco, Paolo1 aTodd, Stephen1 aCraig, David1 aJohnston, Janet1 aGill, Michael1 aLawlor, Brian1 aLynch, Aoibhinn1 aFox, Nick, C1 aHardy, John1 aAlbin, Roger, L1 aApostolova, Liana, G1 aArnold, Steven, E1 aAsthana, Sanjay1 aAtwood, Craig, S1 aBaldwin, Clinton, T1 aBarnes, Lisa, L1 aBarral, Sandra1 aBeach, Thomas, G1 aBecker, James, T1 aBigio, Eileen, H1 aBird, Thomas, D1 aBoeve, Bradley, F1 aBowen, James, D1 aBoxer, Adam1 aBurke, James, R1 aBurns, Jeffrey, M1 aBuxbaum, Joseph, D1 aCairns, Nigel, J1 aCao, Chuanhai1 aCarlson, Chris, S1 aCarlsson, Cynthia, M1 aCarney, Regina, M1 aCarrasquillo, Minerva, M1 aCarroll, Steven, L1 aDiaz, Carolina, Ceballos1 aChui, Helena, C1 aClark, David, G1 aCribbs, David, H1 aCrocco, Elizabeth, A1 aDeCarli, Charles1 aDick, Malcolm1 aDuara, Ranjan1 aEvans, Denis, A1 aFaber, Kelley, M1 aFallon, Kenneth, B1 aFardo, David, W1 aFarlow, Martin, R1 aFerris, Steven1 aForoud, Tatiana, M1 aGalasko, Douglas, R1 aGearing, Marla1 aGeschwind, Daniel, H1 aGilbert, John, R1 aGraff-Radford, Neill, R1 aGreen, Robert, C1 aGrowdon, John, H1 aHamilton, Ronald, L1 aHarrell, Lindy, E1 aHonig, Lawrence, S1 aHuentelman, Matthew, J1 aHulette, Christine, M1 aHyman, Bradley, T1 aJarvik, Gail, P1 aAbner, Erin1 aJin, Lee-Way1 aJun, Gyungah1 aKarydas, Anna1 aKaye, Jeffrey, A1 aKim, Ronald1 aKowall, Neil, W1 aKramer, Joel, H1 aLaFerla, Frank, M1 aLah, James, J1 aLeverenz, James, B1 aLevey, Allan, I1 aLi, Ge1 aLieberman, Andrew, P1 aLunetta, Kathryn, L1 aLyketsos, Constantine, G1 aMarson, Daniel, C1 aMartiniuk, Frank1 aMash, Deborah, C1 aMasliah, Eliezer1 aMcCormick, Wayne, C1 aMcCurry, Susan, M1 aMcDavid, Andrew, N1 aMcKee, Ann, C1 aMesulam, Marsel1 aMiller, Bruce, L1 aMiller, Carol, A1 aMiller, Joshua, W1 aMorris, John, C1 aMurrell, Jill, R1 aMyers, Amanda, J1 aO'Bryant, Sid1 aOlichney, John, M1 aPankratz, Vernon, S1 aParisi, Joseph, E1 aPaulson, Henry, L1 aPerry, William1 aPeskind, Elaine1 aPierce, Aimee1 aPoon, Wayne, W1 aPotter, Huntington1 aQuinn, Joseph, F1 aRaj, Ashok1 aRaskind, Murray1 aReisberg, Barry1 aReitz, Christiane1 aRingman, John, M1 aRoberson, Erik, D1 aRogaeva, Ekaterina1 aRosen, Howard, J1 aRosenberg, Roger, N1 aSager, Mark, A1 aSaykin, Andrew, J1 aSchneider, Julie, A1 aSchneider, Lon, S1 aSeeley, William, W1 aSmith, Amanda, G1 aSonnen, Joshua, A1 aSpina, Salvatore1 aStern, Robert, A1 aSwerdlow, Russell, H1 aTanzi, Rudolph, E1 aThornton-Wells, Tricia, A1 aTrojanowski, John, Q1 aTroncoso, Juan, C1 aVan Deerlin, Vivianna, M1 aVan Eldik, Linda, J1 aVinters, Harry, V1 aVonsattel, Jean, Paul1 aWeintraub, Sandra1 aWelsh-Bohmer, Kathleen, A1 aWilhelmsen, Kirk, C1 aWilliamson, Jennifer1 aWingo, Thomas, S1 aWoltjer, Randall, L1 aWright, Clinton, B1 aYu, Chang-En1 aYu, Lei1 aGarzia, Fabienne1 aGolamaully, Feroze1 aSeptier, Gislain1 aEngelborghs, Sebastien1 aVandenberghe, Rik1 aDe Deyn, Peter, P1 aFernadez, Carmen, Muñoz1 aBenito, Yoland, Aladro1 aThonberg, Håkan1 aForsell, Charlotte1 aLilius, Lena1 aKinhult-Ståhlbom, Anne1 aKilander, Lena1 aBrundin, RoseMarie1 aConcari, Letizia1 aHelisalmi, Seppo1 aKoivisto, Anne, Maria1 aHaapasalo, Annakaisa1 aDermecourt, Vincent1 aFiévet, Nathalie1 aHanon, Olivier1 aDufouil, Carole1 aBrice, Alexis1 aRitchie, Karen1 aDubois, Bruno1 aHimali, Jayanadra, J1 aKeene, Dirk1 aTschanz, JoAnn1 aFitzpatrick, Annette, L1 aKukull, Walter, A1 aNorton, Maria1 aAspelund, Thor1 aLarson, Eric, B1 aMunger, Ron1 aRotter, Jerome, I1 aLipton, Richard, B1 aBullido, María, J1 aHofman, Albert1 aMontine, Thomas, J1 aCoto, Eliecer1 aBoerwinkle, Eric1 aPetersen, Ronald, C1 aAlvarez, Victoria1 aRivadeneira, Fernando1 aReiman, Eric, M1 aGallo, Maura1 aO'Donnell, Christopher, J1 aReisch, Joan, S1 aBruni, Amalia, Cecilia1 aRoyall, Donald, R1 aDichgans, Martin1 aSano, Mary1 aGalimberti, Daniela1 aSt George-Hyslop, Peter1 aScarpini, Elio1 aTsuang, Debby, W1 aMancuso, Michelangelo1 aBonuccelli, Ubaldo1 aWinslow, Ashley, R1 aDaniele, Antonio1 aWu, Chuang-Kuo1 aPeters, Oliver1 aNacmias, Benedetta1 aRiemenschneider, Matthias1 aHeun, Reinhard1 aBrayne, Carol1 aRubinsztein, David, C1 aBras, Jose1 aGuerreiro, Rita1 aAl-Chalabi, Ammar1 aShaw, Christopher, E1 aCollinge, John1 aMann, David1 aTsolaki, Magda1 aClarimon, Jordi1 aSussams, Rebecca1 aLovestone, Simon1 aO'Donovan, Michael, C1 aOwen, Michael, J1 aBehrens, Timothy, W1 aMead, Simon1 aGoate, Alison, M1 aUitterlinden, André, G1 aHolmes, Clive1 aCruchaga, Carlos1 aIngelsson, Martin1 aBennett, David, A1 aPowell, John1 aGolde, Todd, E1 aGraff, Caroline1 aDe Jager, Philip, L1 aMorgan, Kevin1 aErtekin-Taner, Nilufer1 aCombarros, Onofre1 aPsaty, Bruce, M1 aPassmore, Peter1 aYounkin, Steven, G1 aBerr, Claudine1 aGudnason, Vilmundur1 aRujescu, Dan1 aDickson, Dennis, W1 aDartigues, Jean-François1 aDeStefano, Anita, L1 aOrtega-Cubero, Sara1 aHakonarson, Hakon1 aCampion, Dominique1 aBoada, Merce1 aKauwe, John, Keoni1 aFarrer, Lindsay, A1 aVan Broeckhoven, Christine1 aIkram, Arfan, M1 aJones, Lesley1 aHaines, Jonathan, L1 aTzourio, Christophe1 aLauner, Lenore, J1 aEscott-Price, Valentina1 aMayeux, Richard1 aDeleuze, Jean-Francois1 aAmin, Najaf1 aHolmans, Peter, A1 aPericak-Vance, Margaret, A1 aAmouyel, Philippe1 aDuijn, Cornelia, M1 aRamirez, Alfredo1 aSan Wang, Li-1 aLambert, Jean-Charles1 aSeshadri, Sudha1 aWilliams, Julie1 aSchellenberg, Gerard, D1 aARUK Consortium1 aGERAD/PERADES, CHARGE, ADGC, EADI uhttps://chs-nhlbi.org/node/758703062nas a2200601 4500008004100000022001400041245009700055210006900152260001300221300001200234490000700246520134100253100002101594700002201615700002501637700001801662700001901680700001901699700002101718700001601739700001801755700003001773700002601803700002301829700002901852700002001881700002001901700002001921700002401941700003501965700002202000700002002022700001802042700001602060700002102076700001902097700002002116700002002136700002202156700001902178700001702197700002002214700002602234700002002260700001802280700002602298700002402324700001702348700001902365700002102384700001902405856003602424 2017 eng d a1573-728400aTrends in the incidence of dementia: design and methods in the Alzheimer Cohorts Consortium.0 aTrends in the incidence of dementia design and methods in the Al c2017 Oct a931-9380 v323 aSeveral studies have reported a decline in incidence of dementia which may have large implications for the projected burden of disease, and provide important guidance to preventive efforts. However, reports are conflicting or inconclusive with regard to the impact of gender and education with underlying causes of a presumed declining trend remaining largely unidentified. The Alzheimer Cohorts Consortium aggregates data from nine international population-based cohorts to determine changes in the incidence of dementia since 1990. We will employ Poisson regression models to calculate incidence rates in each cohort and Cox proportional hazard regression to compare 5-year cumulative hazards across study-specific epochs. Finally, we will meta-analyse changes per decade across cohorts, and repeat all analysis stratified by sex, education and APOE genotype. In all cohorts combined, there are data on almost 69,000 people at risk of dementia with the range of follow-up years between 2 and 27. The average age at baseline is similar across cohorts ranging between 72 and 77. Uniting a wide range of disease-specific and methodological expertise in research teams, the first analyses within the Alzheimer Cohorts Consortium are underway to tackle outstanding challenges in the assessment of time-trends in dementia occurrence.
1 aChibnik, Lori, B1 aWolters, Frank, J1 aBäckman, Kristoffer1 aBeiser, Alexa1 aBerr, Claudine1 aBis, Joshua, C1 aBoerwinkle, Eric1 aBos, Daniel1 aBrayne, Carol1 aDartigues, Jean-François1 aDarweesh, Sirwan, K L1 aDebette, Stephanie1 aDavis-Plourde, Kendra, L1 aDufouil, Carole1 aFornage, Myriam1 aGrasset, Leslie1 aGudnason, Vilmundur1 aHadjichrysanthou, Christoforos1 aHelmer, Catherine1 aIkram, Arfan, M1 aIkram, Kamran1 aKern, Silke1 aKuller, Lewis, H1 aLauner, Lenore1 aLopez, Oscar, L1 aMatthews, Fiona1 aMeirelles, Osorio1 aMosley, Thomas1 aOwer, Alison1 aPsaty, Bruce, M1 aSatizabal, Claudia, L1 aSeshadri, Sudha1 aSkoog, Ingmar1 aStephan, Blossom, C M1 aTzourio, Christophe1 aWaziry, Reem1 aWong, Mei, Mei1 aZettergren, Anna1 aHofman, Albert uhttps://chs-nhlbi.org/node/755405244nas a2201057 4500008004100000022001400041245014200055210006900197260001600266520216400282100001702446700002602463700002102489700002402510700001902534700002302553700001802576700001802594700001702612700002502629700002102654700001902675700002202694700001302716700002202729700001402751700002302765700001802788700001902806700002002825700002402845700001802869700002202887700001602909700002102925700002402946700002402970700001902994700002303013700002603036700001903062700002403081700002203105700002303127700001803150700003703168700001903205700002103224700002003245700002103265700002003286700001603306700002403322700001903346700002003365700002503385700002803410700002703438700002003465700002203485700002503507700002103532700002303553700002103576700002703597700002603624700001703650700002503667700002303692700002303715700002203738700002303760700002003783700002203803700002403825700002203849700002203871700002103893700001803914700002003932700002403952700002003976700002303996700001904019700002004038700002004058700002204078700002004100710003004120856003604150 2018 eng d a1524-462800aExome Chip Analysis Identifies Low-Frequency and Rare Variants in for White Matter Hyperintensities on Brain Magnetic Resonance Imaging.0 aExome Chip Analysis Identifies LowFrequency and Rare Variants in c2018 Jul 123 aBACKGROUND AND PURPOSE: White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored.
METHODS: In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies.
RESULTS: At 17q25, we confirmed the association of multiple common variants in , , and (<6×10). We also identified a novel association with 2 low-frequency nonsynonymous variants in (lead, rs34136221; =4.5×10) partially independent of known common signal (=1.4×10). We further identified a locus at 2q33 containing common variants in , , and (lead, rs2351524; =1.9×10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency variants (=2.8×10).
CONCLUSIONS: Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.
1 aJian, Xueqiu1 aSatizabal, Claudia, L1 aSmith, Albert, V1 aWittfeld, Katharina1 aBis, Joshua, C1 aSmith, Jennifer, A1 aHsu, Fang-Chi1 aNho, Kwangsik1 aHofer, Edith1 aHagenaars, Saskia, P1 aNyquist, Paul, A1 aMishra, Aniket1 aAdams, Hieab, H H1 aLi, Shuo1 aTeumer, Alexander1 aZhao, Wei1 aFreedman, Barry, I1 aSaba, Yasaman1 aYanek, Lisa, R1 aChauhan, Ganesh1 avan Buchem, Mark, A1 aCushman, Mary1 aRoyle, Natalie, A1 aBryan, Nick1 aNiessen, Wiro, J1 aWindham, Beverly, G1 aDeStefano, Anita, L1 aHabes, Mohamad1 aHeckbert, Susan, R1 aPalmer, Nicholette, D1 aLewis, Cora, E1 aEiriksdottir, Gudny1 aMaillard, Pauline1 aMathias, Rasika, A1 aHomuth, Georg1 aValdés-Hernández, Maria, Del C1 aDivers, Jasmin1 aBeiser, Alexa, S1 aLangner, Sönke1 aRice, Kenneth, M1 aBastin, Mark, E1 aYang, Qiong1 aMaldjian, Joseph, A1 aStarr, John, M1 aSidney, Stephen1 aRisacher, Shannon, L1 aUitterlinden, André, G1 aGudnason, Vilmundur, G1 aNauck, Matthias1 aRotter, Jerome, I1 aSchreiner, Pamela, J1 aBoerwinkle, Eric1 aDuijn, Cornelia, M1 aMazoyer, Bernard1 avon Sarnowski, Bettina1 aGottesman, Rebecca, F1 aLevy, Daniel1 aSigurdsson, Sigurdur1 aVernooij, Meike, W1 aTurner, Stephen, T1 aSchmidt, Reinhold1 aWardlaw, Joanna, M1 aPsaty, Bruce, M1 aMosley, Thomas, H1 aDeCarli, Charles, S1 aSaykin, Andrew, J1 aBowden, Donald, W1 aBecker, Diane, M1 aDeary, Ian, J1 aSchmidt, Helena1 aKardia, Sharon, L R1 aIkram, Arfan, M1 aDebette, Stephanie1 aGrabe, Hans, J1 aLongstreth, W T1 aSeshadri, Sudha1 aLauner, Lenore, J1 aFornage, Myriam1 aneuroCHARGE Working Group uhttps://chs-nhlbi.org/node/779604406nas a2201225 4500008004100000022001400041245011600055210006900171260001600240300000900256490000600265520095200271100002001223700002001243700001701263700001601280700002601296700001901322700002201341700001901363700002501382700001701407700001801424700002201442700001901464700002001483700001801503700002501521700002501546700002301571700001901594700002301613700001601636700001601652700002801668700002001696700002101716700002101737700001801758700001901776700001601795700001801811700002001829700002401849700001801873700002101891700002501912700002601937700002601963700002401989700002202013700001802035700002202053700001802075700001902093700001302112700002102125700002002146700002202166700002302188700002102211700002202232700002102254700002002275700002102295700002502316700002002341700002002361700001402381700002202395700001902417700002602436700002202462700002402484700002502508700002002533700002002553700002602573700002802599700003302627700002302660700001302683700001702696700002002713700002402733700002402757700001902781700002202800700002302822700002202845700001902867700001802886700002302904700002002927700002602947700002102973700002502994700002003019700002303039700002203062700002003084700002003104700002003124856003603144 2018 eng d a2041-172300aGenome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume.0 aGenomewide association study of 23500 individuals identifies 7 l c2018 Sep 26 a39450 v93 aThe volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρ = -0.59, p-value = 3.14 × 10), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.
1 aVojinovic, Dina1 aAdams, Hieab, H1 aJian, Xueqiu1 aYang, Qiong1 aSmith, Albert, Vernon1 aBis, Joshua, C1 aTeumer, Alexander1 aScholz, Markus1 aArmstrong, Nicola, J1 aHofer, Edith1 aSaba, Yasaman1 aLuciano, Michelle1 aBernard, Manon1 aTrompet, Stella1 aYang, Jingyun1 aGillespie, Nathan, A1 avan der Lee, Sven, J1 aNeumann, Alexander1 aAhmad, Shahzad1 aAndreassen, Ole, A1 aAmes, David1 aAmin, Najaf1 aArfanakis, Konstantinos1 aBastin, Mark, E1 aBecker, Diane, M1 aBeiser, Alexa, S1 aBeyer, Frauke1 aBrodaty, Henry1 aBryan, Nick1 aBülow, Robin1 aDale, Anders, M1 aDe Jager, Philip, L1 aDeary, Ian, J1 aDeCarli, Charles1 aFleischman, Debra, A1 aGottesman, Rebecca, F1 avan der Grond, Jeroen1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHomuth, Georg1 aKnopman, David, S1 aKwok, John, B1 aLewis, Cora, E1 aLi, Shuo1 aLoeffler, Markus1 aLopez, Oscar, L1 aMaillard, Pauline1 aMarroun, Hanan, El1 aMather, Karen, A1 aMosley, Thomas, H1 aMuetzel, Ryan, L1 aNauck, Matthias1 aNyquist, Paul, A1 aPanizzon, Matthew, S1 aPausova, Zdenka1 aPsaty, Bruce, M1 aRice, Ken1 aRotter, Jerome, I1 aRoyle, Natalie1 aSatizabal, Claudia, L1 aSchmidt, Reinhold1 aSchofield, Peter, R1 aSchreiner, Pamela, J1 aSidney, Stephen1 aStott, David, J1 aThalamuthu, Anbupalam1 aUitterlinden, André, G1 aHernández, Maria, C Valdés1 aVernooij, Meike, W1 aWen, Wei1 aWhite, Tonya1 aWitte, Veronica1 aWittfeld, Katharina1 aWright, Margaret, J1 aYanek, Lisa, R1 aTiemeier, Henning1 aKremen, William, S1 aBennett, David, A1 aJukema, Wouter1 aPaus, Tomáš1 aWardlaw, Joanna, M1 aSchmidt, Helena1 aSachdev, Perminder, S1 aVillringer, Arno1 aGrabe, Hans, Jörgen1 aLongstreth, W T1 aDuijn, Cornelia, M1 aLauner, Lenore, J1 aSeshadri, Sudha1 aIkram, Arfan, M1 aFornage, Myriam uhttps://chs-nhlbi.org/node/784916401nas a2205425 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2018 eng d a1546-171800aMultiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.0 aMultiancestry genomewide association study of 520000 subjects id c2018 Apr a524-5370 v503 aStroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.
1 aMalik, Rainer1 aChauhan, Ganesh1 aTraylor, Matthew1 aSargurupremraj, Muralidharan1 aOkada, Yukinori1 aMishra, Aniket1 aRutten-Jacobs, Loes1 aGiese, Anne-Katrin1 avan der Laan, Sander, W1 aGretarsdottir, Solveig1 aAnderson, Christopher, D1 aChong, Michael1 aAdams, Hieab, H H1 aAgo, Tetsuro1 aAlmgren, Peter1 aAmouyel, Philippe1 aAy, Hakan1 aBartz, Traci, M1 aBenavente, Oscar, R1 aBevan, Steve1 aBoncoraglio, Giorgio, B1 aBrown, Robert, D1 aButterworth, Adam, S1 aCarrera, Caty1 aCarty, Cara, L1 aChasman, Daniel, I1 aChen, Wei-Min1 aCole, John, W1 aCorrea, Adolfo1 aCotlarciuc, Ioana1 aCruchaga, Carlos1 aDanesh, John1 ade Bakker, Paul, I W1 aDeStefano, Anita, L1 aHoed, Marcel, den1 aDuan, Qing1 aEngelter, Stefan, T1 aFalcone, Guido, J1 aGottesman, Rebecca, F1 aGrewal, Raji, P1 aGudnason, Vilmundur1 aGustafsson, Stefan1 aHaessler, Jeffrey1 aHarris, Tamara, B1 aHassan, Ahamad1 aHavulinna, Aki, S1 aHeckbert, Susan, R1 aHolliday, Elizabeth, G1 aHoward, George1 aHsu, Fang-Chi1 aHyacinth, Hyacinth, I1 aIkram, Arfan, M1 aIngelsson, Erik1 aIrvin, Marguerite, R1 aJian, Xueqiu1 aJimenez-Conde, Jordi1 aJohnson, Julie, A1 aJukema, Wouter1 aKanai, Masahiro1 aKeene, Keith, L1 aKissela, Brett, M1 aKleindorfer, Dawn, O1 aKooperberg, Charles1 aKubo, Michiaki1 aLange, Leslie, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLee, Jin-Moo1 aLemmens, Robin1 aLeys, Didier1 aLewis, Cathryn, M1 aLin, Wei-Yu1 aLindgren, Arne, G1 aLorentzen, Erik1 aMagnusson, Patrik, K1 aMaguire, Jane1 aManichaikul, Ani1 aMcArdle, Patrick, F1 aMeschia, James, F1 aMitchell, Braxton, D1 aMosley, Thomas, H1 aNalls, Michael, A1 aNinomiya, Toshiharu1 aO'Donnell, Martin, J1 aPsaty, Bruce, M1 aPulit, Sara, L1 aRannikmae, Kristiina1 aReiner, Alexander, P1 aRexrode, Kathryn, M1 aRice, Kenneth1 aRich, Stephen, S1 aRidker, Paul, M1 aRost, Natalia, S1 aRothwell, Peter, M1 aRotter, Jerome, I1 aRundek, Tatjana1 aSacco, Ralph, L1 aSakaue, Saori1 aSale, Michèle, M1 aSalomaa, Veikko1 aSapkota, Bishwa, R1 aSchmidt, Reinhold1 aSchmidt, Carsten, O1 aSchminke, Ulf1 aSharma, Pankaj1 aSlowik, Agnieszka1 aSudlow, Cathie, L M1 aTanislav, Christian1 aTatlisumak, Turgut1 aTaylor, Kent, D1 aThijs, Vincent, N S1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTiedt, Steffen1 aTrompet, Stella1 aTzourio, Christophe1 aDuijn, Cornelia, M1 aWalters, Matthew1 aWareham, Nicholas, J1 aWassertheil-Smoller, Sylvia1 aWilson, James, G1 aWiggins, Kerri, L1 aYang, Qiong1 aYusuf, Salim1 aBis, Joshua, C1 aPastinen, Tomi1 aRuusalepp, Arno1 aSchadt, Eric, E1 aKoplev, Simon1 aBjörkegren, Johan, L M1 aCodoni, Veronica1 aCivelek, Mete1 aSmith, Nicholas, L1 aTrégouët, David, A1 aChristophersen, Ingrid, E1 aRoselli, Carolina1 aLubitz, Steven, A1 aEllinor, Patrick, T1 aTai, Shyong, E1 aKooner, Jaspal, S1 aKato, Norihiro1 aHe, Jiang1 aHarst, Pim1 aElliott, Paul1 aChambers, John, C1 aTakeuchi, Fumihiko1 aJohnson, Andrew, D1 aSanghera, Dharambir, K1 aMelander, Olle1 aJern, Christina1 aStrbian, Daniel1 aFernandez-Cadenas, Israel1 aLongstreth, W T1 aRolfs, Arndt1 aHata, Jun1 aWoo, Daniel1 aRosand, Jonathan1 aParé, Guillaume1 aHopewell, Jemma, C1 aSaleheen, Danish1 aStefansson, Kari1 aWorrall, Bradford, B1 aKittner, Steven, J1 aSeshadri, Sudha1 aFornage, Myriam1 aMarkus, Hugh, S1 aHowson, Joanna, M M1 aKamatani, Yoichiro1 aDebette, Stephanie1 aDichgans, Martin1 aMalik, Rainer1 aChauhan, Ganesh1 aTraylor, Matthew1 aSargurupremraj, Muralidharan1 aOkada, Yukinori1 aMishra, Aniket1 aRutten-Jacobs, Loes1 aGiese, Anne-Katrin1 avan der Laan, Sander, W1 aGretarsdottir, Solveig1 aAnderson, Christopher, D1 aChong, Michael1 aAdams, Hieab, H H1 aAgo, Tetsuro1 aAlmgren, Peter1 aAmouyel, Philippe1 aAy, Hakan1 aBartz, Traci, M1 aBenavente, Oscar, R1 aBevan, Steve1 aBoncoraglio, Giorgio, B1 aBrown, Robert, D1 aButterworth, Adam, S1 aCarrera, Caty1 aCarty, Cara, L1 aChasman, Daniel, I1 aChen, Wei-Min1 aCole, John, W1 aCorrea, Adolfo1 aCotlarciuc, Ioana1 aCruchaga, Carlos1 aDanesh, John1 ade Bakker, Paul, I W1 aDeStefano, Anita, L1 aHoed, Marcel, den1 aDuan, Qing1 aEngelter, Stefan, T1 aFalcone, Guido, J1 aGottesman, Rebecca, F1 aGrewal, Raji, P1 aGudnason, Vilmundur1 aGustafsson, Stefan1 aHaessler, Jeffrey1 aHarris, Tamara, B1 aHassan, Ahamad1 aHavulinna, Aki, S1 aHeckbert, Susan, R1 aHolliday, Elizabeth, G1 aHoward, George1 aHsu, Fang-Chi1 aHyacinth, Hyacinth, I1 aIkram, Arfan, M1 aIngelsson, Erik1 aIrvin, Marguerite, R1 aJian, Xueqiu1 aJimenez-Conde, Jordi1 aJohnson, Julie, A1 aJukema, Wouter1 aKanai, Masahiro1 aKeene, Keith, L1 aKissela, Brett, M1 aKleindorfer, Dawn, O1 aKooperberg, Charles1 aKubo, Michiaki1 aLange, Leslie, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLee, Jin-Moo1 aLemmens, Robin1 aLeys, Didier1 aLewis, Cathryn, M1 aLin, Wei-Yu1 aLindgren, Arne, G1 aLorentzen, Erik1 aMagnusson, Patrik, K1 aMaguire, Jane1 aManichaikul, Ani1 aMcArdle, Patrick, F1 aMeschia, James, F1 aMitchell, Braxton, D1 aMosley, Thomas, H1 aNalls, Michael, A1 aNinomiya, Toshiharu1 aO'Donnell, Martin, J1 aPsaty, Bruce, M1 aPulit, Sara, L1 aRannikmae, Kristiina1 aReiner, Alexander, P1 aRexrode, Kathryn, M1 aRice, Kenneth1 aRich, Stephen, S1 aRidker, Paul, M1 aRost, Natalia, S1 aRothwell, Peter, M1 aRotter, Jerome, I1 aRundek, Tatjana1 aSacco, Ralph, L1 aSakaue, Saori1 aSale, Michèle, M1 aSalomaa, Veikko1 aSapkota, Bishwa, R1 aSchmidt, Reinhold1 aSchmidt, Carsten, O1 aSchminke, Ulf1 aSharma, Pankaj1 aSlowik, Agnieszka1 aSudlow, Cathie, L M1 aTanislav, Christian1 aTatlisumak, Turgut1 aTaylor, Kent, D1 aThijs, Vincent, N S1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTiedt, Steffen1 aTrompet, Stella1 aTzourio, Christophe1 aDuijn, Cornelia, M1 aWalters, Matthew1 aWareham, Nicholas, J1 aWassertheil-Smoller, Sylvia1 aWilson, James, G1 aWiggins, Kerri, L1 aYang, Qiong1 aYusuf, Salim1 aAmin, Najaf1 aAparicio, Hugo, S1 aArnett, Donna, K1 aAttia, John1 aBeiser, Alexa, S1 aBerr, Claudine1 aBuring, Julie, E1 aBustamante, Mariana1 aCaso, Valeria1 aCheng, Yu-Ching1 aChoi, Seung, Hoan1 aChowhan, Ayesha1 aCullell, Natalia1 aDartigues, Jean-François1 aDelavaran, Hossein1 aDelgado, Pilar1 aDörr, Marcus1 aEngström, Gunnar1 aFord, Ian1 aGurpreet, Wander, S1 aHamsten, Anders1 aHeitsch, Laura1 aHozawa, Atsushi1 aIbanez, Laura1 aIlinca, Andreea1 aIngelsson, Martin1 aIwasaki, Motoki1 aJackson, Rebecca, D1 aJood, Katarina1 aJousilahti, Pekka1 aKaffashian, Sara1 aKalra, Lalit1 aKamouchi, Masahiro1 aKitazono, Takanari1 aKjartansson, Olafur1 aKloss, Manja1 aKoudstaal, Peter, J1 aKrupinski, Jerzy1 aLabovitz, Daniel, L1 aLaurie, Cathy, C1 aLevi, Christopher, R1 aLi, Linxin1 aLind, Lars1 aLindgren, Cecilia, M1 aLioutas, Vasileios1 aLiu, Yong, Mei1 aLopez, Oscar, L1 aMakoto, Hirata1 aMartinez-Majander, Nicolas1 aMatsuda, Koichi1 aMinegishi, Naoko1 aMontaner, Joan1 aMorris, Andrew, P1 aMuiño, Elena1 aMüller-Nurasyid, Martina1 aNorrving, Bo1 aOgishima, Soichi1 aParati, Eugenio, A1 aPeddareddygari, Leema, Reddy1 aPedersen, Nancy, L1 aPera, Joanna1 aPerola, Markus1 aPezzini, Alessandro1 aPileggi, Silvana1 aRabionet, Raquel1 aRiba-Llena, Iolanda1 aRibasés, Marta1 aRomero, Jose, R1 aRoquer, Jaume1 aRudd, Anthony, G1 aSarin, Antti-Pekka1 aSarju, Ralhan1 aSarnowski, Chloe1 aSasaki, Makoto1 aSatizabal, Claudia, L1 aSatoh, Mamoru1 aSattar, Naveed1 aSawada, Norie1 aSibolt, Gerli1 aSigurdsson, Ásgeir1 aSmith, Albert1 aSobue, Kenji1 aSoriano-Tárraga, Carolina1 aStanne, Tara1 aStine, Colin1 aStott, David, J1 aStrauch, Konstantin1 aTakai, Takako1 aTanaka, Hideo1 aTanno, Kozo1 aTeumer, Alexander1 aTomppo, Liisa1 aTorres-Aguila, Nuria, P1 aTouze, Emmanuel1 aTsugane, Shoichiro1 aUitterlinden, André, G1 aValdimarsson, Einar, M1 avan der Lee, Sven, J1 aVölzke, Henry1 aWakai, Kenji1 aWeir, David1 aWilliams, Stephen, R1 aWolfe, Charles, D A1 aWong, Quenna1 aXu, Huichun1 aYamaji, Taiki1 aSanghera, Dharambir, K1 aMelander, Olle1 aJern, Christina1 aStrbian, Daniel1 aFernandez-Cadenas, Israel1 aLongstreth, W T1 aRolfs, Arndt1 aHata, Jun1 aWoo, Daniel1 aRosand, Jonathan1 aParé, Guillaume1 aHopewell, Jemma, C1 aSaleheen, Danish1 aStefansson, Kari1 aWorrall, Bradford, B1 aKittner, Steven, J1 aSeshadri, Sudha1 aFornage, Myriam1 aMarkus, Hugh, S1 aHowson, Joanna, M M1 aKamatani, Yoichiro1 aDebette, Stephanie1 aDichgans, Martin1 aAFGen Consortium1 aCohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium1 aInternational Genomics of Blood Pressure (iGEN-BP) Consortium1 aINVENT Consortium1 aSTARNET1 aBioBank Japan Cooperative Hospital Group1 aCOMPASS Consortium1 aEPIC-CVD Consortium1 aEPIC-InterAct Consortium1 aInternational Stroke Genetics Consortium (ISGC)1 aMETASTROKE Consortium1 aNeurology Working Group of the CHARGE Consortium1 aNINDS Stroke Genetics Network (SiGN)1 aUK Young Lacunar DNA Study1 aMEGASTROKE Consortium1 aMEGASTROKE Consortium: uhttps://chs-nhlbi.org/node/768308823nas a2202773 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2018 eng d a2041-172300aStudy of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.0 aStudy of 300486 individuals identifies 148 independent genetic l c2018 May 29 a20980 v93 aGeneral cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
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Veronique1 aVoineskos, Aristotle, N1 aKaprio, Jaakko1 aWagner, Michael1 aWagner, Holger1 aWeinhold, Leonie1 aWen, Hoyan1 aWiden, Elisabeth1 aYang, Qiong1 aZhao, Wei1 aAdams, Hieab, H H1 aArking, Dan, E1 aBilder, Robert, M1 aBitsios, Panos1 aBoerwinkle, Eric1 aChiba-Falek, Ornit1 aCorvin, Aiden1 aDe Jager, Philip, L1 aDebette, Stephanie1 aDonohoe, Gary1 aElliott, Paul1 aFitzpatrick, Annette, L1 aGill, Michael1 aGlahn, David, C1 aHägg, Sara1 aHansell, Narelle, K1 aHariri, Ahmad, R1 aIkram, Kamran1 aJukema, Wouter1 aVuoksimaa, Eero1 aKeller, Matthew, C1 aKremen, William, S1 aLauner, Lenore1 aLindenberger, Ulman1 aPalotie, Aarno1 aPedersen, Nancy, L1 aPendleton, Neil1 aPorteous, David, J1 aRäikkönen, Katri1 aRaitakari, Olli, T1 aRamirez, Alfredo1 aReinvang, Ivar1 aRudan, Igor1 aSchmidt, Reinhold1 aSchmidt, Helena1 aSchofield, Peter, W1 aSchofield, Peter, R1 aStarr, John, M1 aSteen, Vidar, M1 aTrollor, Julian, N1 aTurner, Steven, T1 aDuijn, Cornelia, M1 aVillringer, Arno1 aWeinberger, Daniel, R1 aWeir, David, R1 aWilson, James, F1 aMalhotra, Anil1 aMcIntosh, Andrew, M1 aGale, Catharine, R1 aSeshadri, Sudha1 aMosley, Thomas, H1 aBressler, Jan1 aLencz, Todd1 aDeary, Ian, J uhttps://chs-nhlbi.org/node/778811242nas a2203601 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2019 eng d a1546-171800aGenetic architecture of subcortical brain structures in 38,851 individuals.0 aGenetic architecture of subcortical brain structures in 38851 in c2019 Nov a1624-16360 v513 aSubcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
1 aSatizabal, Claudia, L1 aAdams, Hieab, H H1 aHibar, Derrek, P1 aWhite, Charles, C1 aKnol, Maria, J1 aStein, Jason, L1 aScholz, Markus1 aSargurupremraj, Muralidharan1 aJahanshad, Neda1 aRoshchupkin, Gennady, V1 aSmith, Albert, V1 aBis, Joshua, C1 aJian, Xueqiu1 aLuciano, Michelle1 aHofer, Edith1 aTeumer, Alexander1 avan der Lee, Sven, J1 aYang, Jingyun1 aYanek, Lisa, R1 aLee, Tom, V1 aLi, Shuo1 aHu, Yanhui1 aKoh, Jia, Yu1 aEicher, John, D1 aDesrivières, Sylvane1 aArias-Vasquez, Alejandro1 aChauhan, Ganesh1 aAthanasiu, Lavinia1 aRentería, Miguel, E1 aKim, Sungeun1 aHoehn, David1 aArmstrong, Nicola, J1 aChen, Qiang1 aHolmes, Avram, J1 aBraber, Anouk, den1 aKloszewska, Iwona1 aAndersson, Micael1 aEspeseth, Thomas1 aGrimm, Oliver1 aAbramovic, Lucija1 aAlhusaini, Saud1 aMilaneschi, Yuri1 aPapmeyer, Martina1 aAxelsson, Tomas1 aEhrlich, Stefan1 aRoiz-Santiañez, Roberto1 aKraemer, Bernd1 aHåberg, Asta, K1 aJones, Hannah, J1 aPike, Bruce1 aStein, Dan, J1 aStevens, Allison1 aBralten, Janita1 aVernooij, Meike, W1 aHarris, Tamara, B1 aFilippi, Irina1 aWitte, Veronica1 aGuadalupe, Tulio1 aWittfeld, Katharina1 aMosley, Thomas, H1 aBecker, James, T1 aDoan, Nhat, Trung1 aHagenaars, Saskia, P1 aSaba, Yasaman1 aCuellar-Partida, Gabriel1 aAmin, Najaf1 aHilal, Saima1 aNho, Kwangsik1 aMirza-Schreiber, Nazanin1 aArfanakis, Konstantinos1 aBecker, Diane, M1 aAmes, David1 aGoldman, Aaron, L1 aLee, Phil, H1 aBoomsma, Dorret, I1 aLovestone, Simon1 aGiddaluru, Sudheer1 aLe Hellard, Stephanie1 aMattheisen, Manuel1 aBohlken, Marc, M1 aKasperaviciute, Dalia1 aSchmaal, Lianne1 aLawrie, Stephen, M1 aAgartz, Ingrid1 aWalton, Esther1 aTordesillas-Gutierrez, Diana1 aDavies, Gareth, E1 aShin, Jean1 aIpser, Jonathan, C1 aVinke, Louis, N1 aHoogman, Martine1 aJia, Tianye1 aBurkhardt, Ralph1 aKlein, Marieke1 aCrivello, Fabrice1 aJanowitz, Deborah1 aCarmichael, Owen1 aHaukvik, Unn, K1 aAribisala, Benjamin, S1 aSchmidt, Helena1 aStrike, Lachlan, T1 aCheng, Ching-Yu1 aRisacher, Shannon, L1 aPütz, Benno1 aFleischman, Debra, A1 aAssareh, Amelia, A1 aMattay, Venkata, S1 aBuckner, Randy, L1 aMecocci, Patrizia1 aDale, Anders, M1 aCichon, Sven1 aBoks, Marco, P1 aMatarin, Mar1 aPenninx, Brenda, W J H1 aCalhoun, Vince, D1 aChakravarty, Mallar1 aMarquand, Andre, F1 aMacare, Christine1 aMasouleh, Shahrzad, Kharabian1 aOosterlaan, Jaap1 aAmouyel, Philippe1 aHegenscheid, Katrin1 aRotter, Jerome, I1 aSchork, Andrew, J1 aLiewald, David, C M1 ade Zubicaray, Greig, I1 aWong, Tien, Yin1 aShen, Li1 aSämann, Philipp, G1 aBrodaty, Henry1 aRoffman, Joshua, L1 aGeus, Eco, J C1 aTsolaki, Magda1 aErk, Susanne1 avan Eijk, Kristel, R1 aCavalleri, Gianpiero, L1 avan der Wee, Nic, J A1 aMcIntosh, Andrew, M1 aGollub, Randy, L1 aBulayeva, Kazima, B1 aBernard, Manon1 aRichards, Jennifer, S1 aHimali, Jayandra, J1 aLoeffler, Markus1 aRommelse, Nanda1 aHoffmann, Wolfgang1 aWestlye, Lars, T1 aHernández, Maria, C Valdés1 aHansell, Narelle, K1 avan Erp, Theo, G M1 aWolf, Christiane1 aKwok, John, B J1 aVellas, Bruno1 aHeinz, Andreas1 aLoohuis, Loes, M Olde1 aDelanty, Norman1 aHo, Beng-Choon1 aChing, Christopher, R K1 aShumskaya, Elena1 aSingh, Baljeet1 aHofman, Albert1 avan der Meer, Dennis1 aHomuth, Georg1 aPsaty, Bruce, M1 aBastin, Mark, E1 aMontgomery, Grant, W1 aForoud, Tatiana, M1 aReppermund, Simone1 aHottenga, Jouke-Jan1 aSimmons, Andrew1 aMeyer-Lindenberg, Andreas1 aCahn, Wiepke1 aWhelan, Christopher, D1 avan Donkelaar, Marjolein, M J1 aYang, Qiong1 aHosten, Norbert1 aGreen, Robert, C1 aThalamuthu, Anbupalam1 aMohnke, Sebastian1 aPol, Hilleke, E Hulshoff1 aLin, Honghuang1 aJack, Clifford, R1 aSchofield, Peter, R1 aMühleisen, Thomas, W1 aMaillard, Pauline1 aPotkin, Steven, G1 aWen, Wei1 aFletcher, Evan1 aToga, Arthur, W1 aGruber, Oliver1 aHuentelman, Matthew1 aSmith, George, Davey1 aLauner, Lenore, J1 aNyberg, Lars1 aJönsson, Erik, G1 aCrespo-Facorro, Benedicto1 aKoen, Nastassja1 aGreve, Douglas, N1 aUitterlinden, André, G1 aWeinberger, Daniel, R1 aSteen, Vidar, M1 aFedko, Iryna, O1 aGroenewold, Nynke, A1 aNiessen, Wiro, J1 aToro, Roberto1 aTzourio, Christophe1 aLongstreth, William, T1 aIkram, Kamran1 aSmoller, Jordan, W1 avan Tol, Marie-Jose1 aSussmann, Jessika, E1 aPaus, Tomáš1 aLemaître, Hervé1 aSchroeter, Matthias, L1 aMazoyer, Bernard1 aAndreassen, Ole, A1 aHolsboer, Florian1 aDepondt, Chantal1 aVeltman, Dick, J1 aTurner, Jessica, A1 aPausova, Zdenka1 aSchumann, Gunter1 avan Rooij, Daan1 aDjurovic, Srdjan1 aDeary, Ian, J1 aMcMahon, Katie, L1 aMüller-Myhsok, Bertram1 aBrouwer, Rachel, M1 aSoininen, Hilkka1 aPandolfo, Massimo1 aWassink, Thomas, H1 aCheung, Joshua, W1 aWolfers, Thomas1 aMartinot, Jean-Luc1 aZwiers, Marcel, P1 aNauck, Matthias1 aMelle, Ingrid1 aMartin, Nicholas, G1 aKanai, Ryota1 aWestman, Eric1 aKahn, René, S1 aSisodiya, Sanjay, M1 aWhite, Tonya1 aSaremi, Arvin1 avan Bokhoven, Hans1 aBrunner, Han, G1 aVölzke, Henry1 aWright, Margaret, J1 aEnt, Dennis, van 't1 aNöthen, Markus, M1 aOphoff, Roel, A1 aBuitelaar, Jan, K1 aFernández, Guillén1 aSachdev, Perminder, S1 aRietschel, Marcella1 avan Haren, Neeltje, E M1 aFisher, Simon, E1 aBeiser, Alexa, S1 aFrancks, Clyde1 aSaykin, Andrew, J1 aMather, Karen, A1 aRomanczuk-Seiferth, Nina1 aHartman, Catharina, A1 aDeStefano, Anita, L1 aHeslenfeld, Dirk, J1 aWeiner, Michael, W1 aWalter, Henrik1 aHoekstra, Pieter, J1 aNyquist, Paul, A1 aFranke, Barbara1 aBennett, David, A1 aGrabe, Hans, J1 aJohnson, Andrew, D1 aChen, Christopher1 aDuijn, Cornelia, M1 aLopez, Oscar, L1 aFornage, Myriam1 aWardlaw, Joanna, M1 aSchmidt, Reinhold1 aDeCarli, Charles1 aDe Jager, Philip, L1 aVillringer, Arno1 aDebette, Stephanie1 aGudnason, Vilmundur1 aMedland, Sarah, E1 aShulman, Joshua, M1 aThompson, Paul, M1 aSeshadri, Sudha1 aIkram, Arfan, M uhttps://chs-nhlbi.org/node/820602443nas a2200337 4500008004100000022001400041245008600055210006900141260001500210300001400225490000700239520146500246100002101711700002401732700002101756700002101777700002101798700002601819700002201845700002201867700002501889700002001914700002001934700002201954700001701976700002001993700001702013700002002030700001902050856003602069 2020 eng d a1526-632X00aAssociation of CD14 with incident dementia and markers of brain aging and injury.0 aAssociation of CD14 with incident dementia and markers of brain c2020 01 21 ae254-e2660 v943 aOBJECTIVE: To test the hypothesis that the inflammatory marker plasma soluble CD14 (sCD14) associates with incident dementia and related endophenotypes in 2 community-based cohorts.
METHODS: Our samples included the prospective community-based Framingham Heart Study (FHS) and Cardiovascular Health Study (CHS) cohorts. Plasma sCD14 was measured at baseline and related to the incidence of dementia, domains of cognitive function, and MRI-defined brain volumes. Follow-up for dementia occurred over a mean of 10 years (SD 4) in the FHS and a mean of 6 years (SD 3) in the CHS.
RESULTS: We studied 1,588 participants from the FHS (mean age 69 ± 6 years, 47% male, 131 incident events) and 3,129 participants from the CHS (mean age 72 ± 5 years, 41% male, 724 incident events) for the risk of incident dementia. Meta-analysis across the 2 cohorts showed that each SD unit increase in sCD14 was associated with a 12% increase in the risk of incident dementia (95% confidence interval 1.03-1.23; = 0.01) following adjustments for age, sex, ε4 status, and vascular risk factors. Higher levels of sCD14 were associated with various cognitive and MRI markers of accelerated brain aging in both cohorts and with a greater progression of brain atrophy and a decline in executive function in the FHS.
CONCLUSION: sCD14 is an inflammatory marker related to brain atrophy, cognitive decline, and incident dementia.
1 aPase, Matthew, P1 aHimali, Jayandra, J1 aBeiser, Alexa, S1 aDeCarli, Charles1 aMcGrath, Emer, R1 aSatizabal, Claudia, L1 aAparicio, Hugo, J1 aAdams, Hieab, H H1 aReiner, Alexander, P1 aLongstreth, W T1 aFornage, Myriam1 aTracy, Russell, P1 aLopez, Oscar1 aPsaty, Bruce, M1 aLevy, Daniel1 aSeshadri, Sudha1 aBis, Joshua, C uhttps://chs-nhlbi.org/node/828704156nas a2200889 4500008004100000022001400041245009300055210006900148260001500217300000800232490000700240520170200247653001001949653001001959653001401969653003401983653001602017653001102033653003602044653003002080100001802110700001702128700002102145700001802166700001902184700001702203700002202220700001602242700002302258700002002281700001602301700002202317700001802339700002102357700002102378700001802399700002402417700002502441700002602466700002002492700001702512700001702529700002402546700001902570700001802589700002002607700002502627700001802652700001902670700001902689700002302708700001602731700002602747700002002773700002202793700002002815700002202835700002002857700002302877700002502900700001802925700002302943700002002966700001602986700001403002700002403016700002203040700002803062700002003090700002003110700001703130700002303147700002003170700002203190700001803212856003603230 2021 eng d a2158-318800aAssociation of low-frequency and rare coding variants with information processing speed.0 aAssociation of lowfrequency and rare coding variants with inform c2021 12 04 a6130 v113 aMeasures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.
10aAdult10aAging10aCognition10aGenome-Wide Association Study10aGeroscience10aHumans10aPolymorphism, Single Nucleotide10aUbiquitin-Protein Ligases1 aBressler, Jan1 aDavies, Gail1 aSmith, Albert, V1 aSaba, Yasaman1 aBis, Joshua, C1 aJian, Xueqiu1 aHayward, Caroline1 aYanek, Lisa1 aSmith, Jennifer, A1 aMirza, Saira, S1 aWang, Ruiqi1 aAdams, Hieab, H H1 aBecker, Diane1 aBoerwinkle, Eric1 aCampbell, Archie1 aCox, Simon, R1 aEiriksdottir, Gudny1 aFawns-Ritchie, Chloe1 aGottesman, Rebecca, F1 aGrove, Megan, L1 aGuo, Xiuqing1 aHofer, Edith1 aKardia, Sharon, L R1 aKnol, Maria, J1 aKoini, Marisa1 aLopez, Oscar, L1 aMarioni, Riccardo, E1 aNyquist, Paul1 aPattie, Alison1 aPolasek, Ozren1 aPorteous, David, J1 aRudan, Igor1 aSatizabal, Claudia, L1 aSchmidt, Helena1 aSchmidt, Reinhold1 aSidney, Stephen1 aSimino, Jeannette1 aSmith, Blair, H1 aTurner, Stephen, T1 avan der Lee, Sven, J1 aWare, Erin, B1 aWhitmer, Rachel, A1 aYaffe, Kristine1 aYang, Qiong1 aZhao, Wei1 aGudnason, Vilmundur1 aLauner, Lenore, J1 aFitzpatrick, Annette, L1 aPsaty, Bruce, M1 aFornage, Myriam1 aIkram, Arfan1 aDuijn, Cornelia, M1 aSeshadri, Sudha1 aMosley, Thomas, H1 aDeary, Ian, J uhttps://chs-nhlbi.org/node/898802650nas a2200589 4500008004100000022001400041245008000055210006900135260001600204490000600220520090300226100001301129700002401142700002201166700002301188700002401211700001401235700002701249700002501276700001301301700001701314700002501331700002401356700002101380700002101401700002001422700002401442700002301466700002001489700002501509700002101534700002001555700002401575700002301599700002701622700001701649700002801666700002001694700001401714700001901728700002201747700002001769700002101789700001701810700002201827700001901849700002601868700001901894700001601913710009501929856003602024 2021 eng d a2666-979X00aAssociation of mitochondrial DNA copy number with cardiometabolic diseases.0 aAssociation of mitochondrial DNA copy number with cardiometaboli c2021 Oct 130 v13 aMitochondrial DNA (mtDNA) is present in multiple copies in human cells. We evaluated cross-sectional associations of whole blood mtDNA copy number (CN) with several cardiometabolic disease traits in 408,361 participants of multiple ancestries in TOPMed and UK Biobank. Age showed a threshold association with mtDNA CN: among younger participants (<65 years of age), each additional 10 years of age was associated with 0.03 standard deviation (s.d.) higher level of mtDNA CN ( = 0.0014) versus a 0.14 s.d. lower level of mtDNA CN ( = 1.82 × 10) among older participants (≥65 years). At lower mtDNA CN levels, we found age-independent associations with increased odds of obesity ( = 5.6 × 10), hypertension ( = 2.8 × 10), diabetes ( = 3.6 × 10), and hyperlipidemia ( = 6.3 × 10). The observed decline in mtDNA CN after 65 years of age may be a key to understanding age-related diseases.
1 aLiu, Xue1 aLongchamps, Ryan, J1 aWiggins, Kerri, L1 aRaffield, Laura, M1 aBielak, Lawrence, F1 aZhao, Wei1 aPitsillides, Achilleas1 aBlackwell, Thomas, W1 aYao, Jie1 aGuo, Xiuqing1 aKurniansyah, Nuzulul1 aThyagarajan, Bharat1 aPankratz, Nathan1 aRich, Stephen, S1 aTaylor, Kent, D1 aPeyser, Patricia, A1 aHeckbert, Susan, R1 aSeshadri, Sudha1 aCupples, Adrienne, L1 aBoerwinkle, Eric1 aGrove, Megan, L1 aLarson, Nicholas, B1 aSmith, Jennifer, A1 aVasan, Ramachandran, S1 aSofer, Tamar1 aFitzpatrick, Annette, L1 aFornage, Myriam1 aDing, Jun1 aCorrea, Adolfo1 aAbecasis, Goncalo1 aPsaty, Bruce, M1 aWilson, James, G1 aLevy, Daniel1 aRotter, Jerome, I1 aBis, Joshua, C1 aSatizabal, Claudia, L1 aArking, Dan, E1 aLiu, Chunyu1 aTOPMed mtDNA Working Group in NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/899702923nas a2200289 4500008004100000022001400041245013200055210006900187260001600256300001400272490000700286520203000293100002202323700002002345700002202365700002202387700001902409700001802428700002602446700002002472700002002492700002402512700002102536700002002557700002002577856003602597 2022 eng d a1526-632X00aAssociation of Serum Neurofilament Light Chain Concentration and MRI Findings in Older Adults: The Cardiovascular Health Study.0 aAssociation of Serum Neurofilament Light Chain Concentration and c2022 Mar 01 ae903-e9110 v983 aBACKGROUND AND OBJECTIVES: Neurofilament light chain (NfL) in blood is a sensitive but nonspecific marker of brain injury. This study sought to evaluate associations between NfL concentration and MRI findings of vascular brain injury in older adults.
METHODS: A longitudinal cohort study included 2 cranial MRI scans performed about 5 years apart and assessed for white matter hyperintensities (WMH) and infarcts. About 1 year before their second MRI, 1,362 participants (median age 77 years, 61.4% women) without a history of TIA or stroke had measurement of 4 biomarkers: NfL, total tau, glial fibrillary acidic protein (GFAP), and ubiquitin carboxyl-terminal hydrolase L1. Most (n = 1,279) also had the first MRI scan, and some (n = 633) had quantitative measurements of hippocampal and WMH. In primary analyses, we assessed associations of NfL with a 10-point white matter grade (WMG) and prevalent infarcts on second MRI and with worsening WMG and incident infarct comparing the 2 scans. A value <0.0125 (0.05/4) was considered significant for these analyses. We also assessed associations with hippocampal and WMH volume.
RESULTS: In fully adjusted models, log(NfL) concentration was associated with WMG (β = 0.27; = 2.3 × 10) and worsening WMG (relative risk [RR] 1.24; = 0.0022), but less strongly with prevalent brain infarcts (RR 1.18; = 0.013) and not with incident brain infarcts (RR 1.18; = 0.18). Associations were also present with WMH volume (β = 2,242.9, = 0.0036). For the other 3 biomarkers, the associations for log (GFAP) concentration with WMG and worsening WMG were significant.
DISCUSSION: Among older adults without a history of stroke, higher serum NfL concentration was associated with covert MRI findings of vascular brain injury, especially the burden of WMH and its worsening. Whether these results offer opportunities for the use of NfL as a noninvasive biomarker of WMH or to control vascular risk factors remains to be determined.
1 aFohner, Alison, E1 aBartz, Traci, M1 aTracy, Russell, P1 aAdams, Hieab, H H1 aBis, Joshua, C1 aDjoussé, Luc1 aSatizabal, Claudia, L1 aLopez, Oscar, L1 aSeshadri, Sudha1 aMukamal, Kenneth, J1 aKuller, Lewis, H1 aPsaty, Bruce, M1 aLongstreth, W T uhttps://chs-nhlbi.org/node/899003642nas a2200589 4500008004100000022001400041245009900055210006900154260001600223520192000239100002002159700001702179700002602196700002402222700002202246700001702268700002002285700002402305700001802329700002402347700001602371700002002387700002202407700002402429700002602453700002002479700002202499700002202521700002502543700002002568700002002588700002702608700002102635700002602656700002202682700002502704700001802729700002002747700002702767700002302794700001902817700002202836700001302858700002102871700002402892700001902916700002002935700002202955700001902977700002002996856003603016 2022 eng d a1875-890800aAssociations of Pulmonary Function with MRI Brain Volumes: A Coordinated Multi-Study Analysis.0 aAssociations of Pulmonary Function with MRI Brain Volumes A Coor c2022 Oct 033 aBACKGROUND: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent.
OBJECTIVE: To study the cross-sectional associations of pulmonary function with structural brain variables.
METHODS: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses.
RESULTS: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume.
CONCLUSION: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.
1 aFrenzel, Stefan1 aBis, Josh, C1 aGudmundsson, Elias, F1 aO'Donnell, Adrienne1 aSimino, Jeannette1 aYaqub, Amber1 aBartz, Traci, M1 aBrusselle, Guy, G O1 aBülow, Robin1 aDeCarli, Charles, S1 aEwert, Ralf1 aGharib, Sina, A1 aGhosh, Saptaparni1 aGireud-Goss, Monica1 aGottesman, Rebecca, F1 aIkram, Arfan, M1 aKnopman, David, S1 aLauner, Lenore, J1 aLondon, Stephanie, J1 aLongstreth, W T1 aLopez, Oscar, L1 avan Lent, Debora, Melo1 aO'Connor, George1 aSatizabal, Claudia, L1 aShrestha, Srishti1 aSigurdsson, Sigurdur1 aStubbe, Beate1 aTalluri, Rajesh1 aVasan, Ramachandran, S1 aVernooij, Meike, W1 aVölzke, Henry1 aWiggins, Kerri, L1 aYu, Bing1 aBeiser, Alexa, S1 aGudnason, Vilmundur1 aMosley, Thomas1 aPsaty, Bruce, M1 aWolters, Frank, J1 aGrabe, Hans, J1 aSeshadri, Sudha uhttps://chs-nhlbi.org/node/916304975nas a2200733 4500008004100000022001400041245010200055210006900157260001600226520287800242100001603120700001903136700001603155700001903171700001303190700002203203700002203225700002203247700001903269700001703288700001303305700002203318700002303340700002003363700002103383700002303404700002003427700002603447700002003473700001603493700002403509700002003533700002103553700002803574700002603602700002403628700003303652700002303685700002303708700002403731700001603755700001403771700002103785700001703806700001803823700001803841700002103859700002203880700002003902700002603922700002303948700002203971700002403993700002704017700001704044700001904061700002004080700002004100700002204120700002004142700002304162700002004185856003604205 2022 eng d a1460-215600aEpigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI.0 aEpigenetic and integrative crossomics analyses of cerebral white c2022 Aug 093 aCerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at approximately 450,000 CpG sites in 9,732 middle-aged to older adults from 14 community-based studies. Single-CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single-CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5), and colocalized with FOLH1 expression in brain (posterior probability =0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single-CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis, and multi-omics colocalization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug repositioning analysis indicated antihyperlipidemic agents, more specifically peroxisome proliferator-activated receptor alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood brain barrier disruption.
1 aYang, Yunju1 aKnol, Maria, J1 aWang, Ruiqi1 aMishra, Aniket1 aLiu, Dan1 aLuciano, Michelle1 aTeumer, Alexander1 aArmstrong, Nicola1 aBis, Joshua, C1 aJhun, Min, A1 aLi, Shuo1 aAdams, Hieab, H H1 aAziz, Nasir, Ahmad1 aBastin, Mark, E1 aBourgey, Mathieu1 aBrody, Jennifer, A1 aFrenzel, Stefan1 aGottesman, Rebecca, F1 aHosten, Norbert1 aHou, Lifang1 aKardia, Sharon, L R1 aLohner, Valerie1 aMarquis, Pascale1 aManiega, Susana, Muñoz1 aSatizabal, Claudia, L1 aSorond, Farzaneh, A1 aHernández, Maria, C Valdés1 aDuijn, Cornelia, M1 aVernooij, Meike, W1 aWittfeld, Katharina1 aYang, Qiong1 aZhao, Wei1 aBoerwinkle, Eric1 aLevy, Daniel1 aDeary, Ian, J1 aJiang, Jiyang1 aMather, Karen, A1 aMosley, Thomas, H1 aPsaty, Bruce, M1 aSachdev, Perminder, S1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aDeCarli, Charles, S1 aBreteler, Monique, M B1 aIkram, Arfan1 aGrabe, Hans, J1 aWardlaw, Joanna1 aLongstreth, W T1 aLauner, Lenore, J1 aSeshadri, Sudha1 aDebette, Stephanie1 aFornage, Myriam uhttps://chs-nhlbi.org/node/918405288nas a2201585 4500008004100000022001400041245009100055210006900146260001600215520091300231100001601144700002101160700001601181700002001197700001901217700001601236700002501252700001801277700001901295700001901314700002101333700001801354700002101372700002001393700001601413700001801429700001801447700001701465700002401482700001901506700002101525700002801546700002201574700001401596700002001610700002101630700001901651700002401670700002401694700002301718700002701741700002001768700001901788700001901807700002101826700002101847700001901868700002201887700001801909700001801927700001301945700001601958700001301974700001701987700001702004700002502021700002102046700001902067700002002086700001902106700001802125700002402143700002702167700001902194700001902213700002302232700002502255700002102280700002402301700001902325700002602344700002402370700002602394700002102420700002202441700002102463700002302484700002002507700001702527700002202544700002602566700002002592700002302612700002502635700002102660700001702681700002202698700002402720700002002744700001302764700002002777700001202797700001602809700001402825700001602839700001602855700002202871700001902893700002302912700002202935700002202957700002002979700001902999700002403018700001603042700002103058700002303079700001903102700002003121700002103141700002003162700002903182700002603211700002203237700002003259700002403279700002003303700001903323700002003342700002003362700002003382700001903402700002103421700002403442700002603466700002303492700002303515700002203538700002203560700002303582700001803605700002003623700002303643856003603666 2022 eng d a1476-557800aGenome-wide meta-analyses reveal novel loci for verbal short-term memory and learning.0 aGenomewide metaanalyses reveal novel loci for verbal shortterm m c2022 Aug 163 aUnderstanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.
1 aLahti, Jari1 aTuominen, Samuli1 aYang, Qiong1 aPergola, Giulio1 aAhmad, Shahzad1 aAmin, Najaf1 aArmstrong, Nicola, J1 aBeiser, Alexa1 aBey, Katharina1 aBis, Joshua, C1 aBoerwinkle, Eric1 aBressler, Jan1 aCampbell, Archie1 aCampbell, Harry1 aChen, Qiang1 aCorley, Janie1 aCox, Simon, R1 aDavies, Gail1 aDe Jager, Philip, L1 aDerks, Eske, M1 aFaul, Jessica, D1 aFitzpatrick, Annette, L1 aFohner, Alison, E1 aFord, Ian1 aFornage, Myriam1 aGerring, Zachary1 aGrabe, Hans, J1 aGrodstein, Francine1 aGudnason, Vilmundur1 aSimonsick, Eleanor1 aHolliday, Elizabeth, G1 aJoshi, Peter, K1 aKajantie, Eero1 aKaprio, Jaakko1 aKarell, Pauliina1 aKleineidam, Luca1 aKnol, Maria, J1 aKochan, Nicole, A1 aKwok, John, B1 aLeber, Markus1 aLam, Max1 aLee, Teresa1 aLi, Shuo1 aLoukola, Anu1 aLuck, Tobias1 aMarioni, Riccardo, E1 aMather, Karen, A1 aMedland, Sarah1 aMirza, Saira, S1 aNalls, Mike, A1 aNho, Kwangsik1 aO'Donnell, Adrienne1 aOldmeadow, Christopher1 aPainter, Jodie1 aPattie, Alison1 aReppermund, Simone1 aRisacher, Shannon, L1 aRose, Richard, J1 aSadashivaiah, Vijay1 aScholz, Markus1 aSatizabal, Claudia, L1 aSchofield, Peter, W1 aSchraut, Katharina, E1 aScott, Rodney, J1 aSimino, Jeannette1 aSmith, Albert, V1 aSmith, Jennifer, A1 aStott, David, J1 aSurakka, Ida1 aTeumer, Alexander1 aThalamuthu, Anbupalam1 aTrompet, Stella1 aTurner, Stephen, T1 avan der Lee, Sven, J1 aVillringer, Arno1 aVölker, Uwe1 aWilson, Robert, S1 aWittfeld, Katharina1 aVuoksimaa, Eero1 aXia, Rui1 aYaffe, Kristine1 aYu, Lei1 aZare, Habil1 aZhao, Wei1 aAmes, David1 aAttia, John1 aBennett, David, A1 aBrodaty, Henry1 aChasman, Daniel, I1 aGoldman, Aaron, L1 aHayward, Caroline1 aIkram, Arfan, M1 aJukema, Wouter1 aKardia, Sharon, L R1 aLencz, Todd1 aLoeffler, Markus1 aMattay, Venkata, S1 aPalotie, Aarno1 aPsaty, Bruce, M1 aRamirez, Alfredo1 aRidker, Paul, M1 aRiedel-Heller, Steffi, G1 aSachdev, Perminder, S1 aSaykin, Andrew, J1 aScherer, Martin1 aSchofield, Peter, R1 aSidney, Stephen1 aStarr, John, M1 aTrollor, Julian1 aUlrich, William1 aWagner, Michael1 aWeir, David, R1 aWilson, James, F1 aWright, Margaret, J1 aWeinberger, Daniel, R1 aDebette, Stephanie1 aEriksson, Johan, G1 aMosley, Thomas, H1 aLauner, Lenore, J1 aDuijn, Cornelia, M1 aDeary, Ian, J1 aSeshadri, Sudha1 aRäikkönen, Katri uhttps://chs-nhlbi.org/node/916915436nas a2205137 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2022 eng d a1546-171800aNew insights into the genetic etiology of Alzheimer's disease and related dementias.0 aNew insights into the genetic etiology of Alzheimers disease and c2022 Apr a412-4360 v543 aCharacterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
10aAlzheimer Disease10aCognitive Dysfunction10aGenome-Wide Association Study10aHumans10atau Proteins1 aBellenguez, Céline1 aKüçükali, Fahri1 aJansen, Iris, E1 aKleineidam, Luca1 aMoreno-Grau, Sonia1 aAmin, Najaf1 aNaj, Adam, C1 aCampos-Martin, Rafael1 aGrenier-Boley, Benjamin1 aAndrade, Victor1 aHolmans, Peter, A1 aBoland, Anne1 aDamotte, Vincent1 avan der Lee, Sven, J1 aCosta, Marcos, R1 aKuulasmaa, Teemu1 aYang, Qiong1 ade Rojas, Itziar1 aBis, Joshua, C1 aYaqub, Amber1 aProkic, Ivana1 aChapuis, Julien1 aAhmad, Shahzad1 aGiedraitis, Vilmantas1 aAarsland, Dag1 aGarcia-Gonzalez, Pablo1 aAbdelnour, Carla1 aAlarcón-Martín, Emilio1 aAlcolea, Daniel1 aAlegret, Montserrat1 aAlvarez, Ignacio1 aAlvarez, Victoria1 aArmstrong, Nicola, J1 aTsolaki, Anthoula1 aAntunez, Carmen1 aAppollonio, Ildebrando1 aArcaro, Marina1 aArchetti, Silvana1 aPastor, Alfonso, Arias1 aArosio, Beatrice1 aAthanasiu, Lavinia1 aBailly, Henri1 aBanaj, Nerisa1 aBaquero, Miquel1 aBarral, Sandra1 aBeiser, Alexa1 aPastor, Ana, Belén1 aBelow, Jennifer, E1 aBenchek, Penelope1 aBenussi, Luisa1 aBerr, Claudine1 aBesse, Céline1 aBessi, Valentina1 aBinetti, Giuliano1 aBizarro, Alessandra1 aBlesa, Rafael1 aBoada, Merce1 aBoerwinkle, Eric1 aBorroni, Barbara1 aBoschi, Silvia1 aBossù, Paola1 aBråthen, Geir1 aBressler, Jan1 aBresner, Catherine1 aBrodaty, Henry1 aBrookes, Keeley, J1 aBrusco, Luis, Ignacio1 aBuiza-Rueda, Dolores1 aBûrger, Katharina1 aBurholt, Vanessa1 aBush, William, S1 aCalero, Miguel1 aCantwell, Laura, B1 aChene, Geneviève1 aChung, Jaeyoon1 aCuccaro, Michael, L1 aCarracedo, Angel1 aCecchetti, Roberta1 aCervera-Carles, Laura1 aCharbonnier, Camille1 aChen, Hung-Hsin1 aChillotti, Caterina1 aCiccone, Simona1 aClaassen, Jurgen, A H R1 aClark, Christopher1 aConti, Elisa1 aCorma-Gómez, Anaïs1 aCostantini, Emanuele1 aCustodero, Carlo1 aDaian, Delphine1 aDalmasso, Maria, Carolina1 aDaniele, Antonio1 aDardiotis, Efthimios1 aDartigues, Jean-François1 ade Deyn, Peter, Paul1 aLopes, Katia, de Paiva1 ade Witte, Lot, D1 aDebette, Stephanie1 aDeckert, Jürgen1 aDel Ser, Teodoro1 aDenning, Nicola1 aDeStefano, Anita1 aDichgans, Martin1 aDiehl-Schmid, Janine1 aDiez-Fairen, Monica1 aRossi, Paolo, Dionigi1 aDjurovic, Srdjan1 aDuron, Emmanuelle1 aDüzel, Emrah1 aDufouil, Carole1 aEiriksdottir, Gudny1 aEngelborghs, Sebastiaan1 aEscott-Price, Valentina1 aEspinosa, Ana1 aEwers, Michael1 aFaber, Kelley, M1 aFabrizio, Tagliavini1 aNielsen, Sune, Fallgaard1 aFardo, David, W1 aFarotti, Lucia1 aFenoglio, Chiara1 aFernández-Fuertes, Marta1 aFerrari, Raffaele1 aFerreira, Catarina, B1 aFerri, Evelyn1 aFin, Bertrand1 aFischer, Peter1 aFladby, Tormod1 aFließbach, Klaus1 aFongang, Bernard1 aFornage, Myriam1 aFortea, Juan1 aForoud, Tatiana, M1 aFostinelli, Silvia1 aFox, Nick, C1 aFranco-Macías, Emlio1 aBullido, María, J1 aFrank-García, Ana1 aFroelich, Lutz1 aFulton-Howard, Brian1 aGalimberti, Daniela1 aGarcía-Alberca, Jose, Maria1 aGarcia-Gonzalez, Pablo1 aGarcia-Madrona, Sebastian1 aGarcia-Ribas, Guillermo1 aGhidoni, Roberta1 aGiegling, Ina1 aGiorgio, Giaccone1 aGoate, Alison, M1 aGoldhardt, Oliver1 aGomez-Fonseca, Duber1 aGonzález-Perez, Antonio1 aGraff, Caroline1 aGrande, Giulia1 aGreen, Emma1 aGrimmer, Timo1 aGrünblatt, Edna1 aGrunin, Michelle1 aGudnason, Vilmundur1 aGuetta-Baranes, Tamar1 aHaapasalo, Annakaisa1 aHadjigeorgiou, Georgios1 aHaines, Jonathan, L1 aHamilton-Nelson, Kara, L1 aHampel, Harald1 aHanon, Olivier1 aHardy, John1 aHartmann, Annette, M1 aHausner, Lucrezia1 aHarwood, Janet1 aHeilmann-Heimbach, Stefanie1 aHelisalmi, Seppo1 aHeneka, Michael, T1 aHernandez, Isabel1 aHerrmann, Martin, J1 aHoffmann, Per1 aHolmes, Clive1 aHolstege, Henne1 aVilas, Raquel, Huerto1 aHulsman, Marc1 aHumphrey, Jack1 aBiessels, Geert, Jan1 aJian, Xueqiu1 aJohansson, Charlotte1 aJun, Gyungah, R1 aKastumata, Yuriko1 aKauwe, John1 aKehoe, Patrick, G1 aKilander, Lena1 aStåhlbom, Anne, Kinhult1 aKivipelto, Miia1 aKoivisto, Anne1 aKornhuber, Johannes1 aKosmidis, Mary, H1 aKukull, Walter, A1 aKuksa, Pavel, P1 aKunkle, Brian, W1 aKuzma, Amanda, B1 aLage, Carmen1 aLaukka, Erika, J1 aLauner, Lenore1 aLauria, Alessandra1 aLee, Chien-Yueh1 aLehtisalo, Jenni1 aLerch, Ondrej1 aLleo, Alberto1 aLongstreth, William1 aLopez, Oscar1 ade Munain, Adolfo, Lopez1 aLove, Seth1 aLöwemark, Malin1 aLuckcuck, Lauren1 aLunetta, Kathryn, L1 aMa, Yiyi1 aMacías, Juan1 aMacLeod, Catherine, A1 aMaier, Wolfgang1 aMangialasche, Francesca1 aSpallazzi, Marco1 aMarquié, Marta1 aMarshall, Rachel1 aMartin, Eden, R1 aMontes, Angel, Martín1 aRodríguez, Carmen, Martínez1 aMasullo, Carlo1 aMayeux, Richard1 aMead, Simon1 aMecocci, Patrizia1 aMedina, Miguel1 aMeggy, Alun1 aMehrabian, Shima1 aMendoza, Silvia1 aMenéndez-González, Manuel1 aMir, Pablo1 aMoebus, Susanne1 aMol, Merel1 aMolina-Porcel, Laura1 aMontrreal, Laura1 aMorelli, Laura1 aMoreno, Fermin1 aMorgan, Kevin1 aMosley, Thomas1 aNöthen, Markus, M1 aMuchnik, Carolina1 aMukherjee, Shubhabrata1 aNacmias, Benedetta1 aNgandu, Tiia1 aNicolas, Gaël1 aNordestgaard, Børge, G1 aOlaso, Robert1 aOrellana, Adelina1 aOrsini, Michela1 aOrtega, Gemma1 aPadovani, Alessandro1 aPaolo, Caffarra1 aPapenberg, Goran1 aParnetti, Lucilla1 aPasquier, Florence1 aPastor, Pau1 aPeloso, Gina1 aPérez-Cordón, Alba1 aPérez-Tur, Jordi1 aPericard, Pierre1 aPeters, Oliver1 aPijnenburg, Yolande, A L1 aPineda, Juan, A1 aPiñol-Ripoll, Gerard1 aPisanu, Claudia1 aPolak, Thomas1 aPopp, Julius1 aPosthuma, Danielle1 aPriller, Josef1 aPuerta, Raquel1 aQuenez, Olivier1 aQuintela, Inés1 aThomassen, Jesper, Qvist1 aRábano, Alberto1 aRainero, Innocenzo1 aRajabli, Farid1 aRamakers, Inez1 aReal, Luis, M1 aReinders, Marcel, J T1 aReitz, Christiane1 aReyes-Dumeyer, Dolly1 aRidge, Perry1 aRiedel-Heller, Steffi1 aRiederer, Peter1 aRoberto, Natalia1 aRodriguez-Rodriguez, Eloy1 aRongve, Arvid1 aAllende, Irene, Rosas1 aRosende-Roca, Maitée1 aRoyo, Jose, Luis1 aRubino, Elisa1 aRujescu, Dan1 aSáez, María, Eugenia1 aSakka, Paraskevi1 aSaltvedt, Ingvild1 aSanabria, Ángela1 aSánchez-Arjona, María, Bernal1 aSanchez-Garcia, Florentino1 aJuan, Pascual, Sánchez1 aSánchez-Valle, Raquel1 aSando, Sigrid, B1 aSarnowski, Chloe1 aSatizabal, Claudia, L1 aScamosci, Michela1 aScarmeas, Nikolaos1 aScarpini, Elio1 aScheltens, Philip1 aScherbaum, Norbert1 aScherer, Martin1 aSchmid, Matthias1 aSchneider, Anja1 aSchott, Jonathan, M1 aSelbæk, Geir1 aSeripa, Davide1 aSerrano, Manuel1 aSha, Jin1 aShadrin, Alexey, A1 aSkrobot, Olivia1 aSlifer, Susan1 aSnijders, Gijsje, J L1 aSoininen, Hilkka1 aSolfrizzi, Vincenzo1 aSolomon, Alina1 aSong, Yeunjoo1 aSorbi, Sandro1 aSotolongo-Grau, Oscar1 aSpalletta, Gianfranco1 aSpottke, Annika1 aSquassina, Alessio1 aStordal, Eystein1 aTartan, Juan, Pablo1 aTarraga, Lluis1 aTesí, Niccolo1 aThalamuthu, Anbupalam1 aThomas, Tegos1 aTosto, Giuseppe1 aTraykov, Latchezar1 aTremolizzo, Lucio1 aTybjærg-Hansen, Anne1 aUitterlinden, Andre1 aUllgren, Abbe1 aUlstein, Ingun1 aValero, Sergi1 aValladares, Otto1 aVan Broeckhoven, Christine1 aVance, Jeffery1 aVardarajan, Badri, N1 avan der Lugt, Aad1 aVan Dongen, Jasper1 avan Rooij, Jeroen1 avan Swieten, John1 aVandenberghe, Rik1 aVerhey, Frans1 aVidal, Jean-Sébastien1 aVogelgsang, Jonathan1 aVyhnalek, Martin1 aWagner, Michael1 aWallon, David1 aSan Wang, Li-1 aWang, Ruiqi1 aWeinhold, Leonie1 aWiltfang, Jens1 aWindle, Gill1 aWoods, Bob1 aYannakoulia, Mary1 aZare, Habil1 aZhao, Yi1 aZhang, Xiaoling1 aZhu, Congcong1 aZulaica, Miren1 aFarrer, Lindsay, A1 aPsaty, Bruce, M1 aGhanbari, Mohsen1 aRaj, Towfique1 aSachdev, Perminder1 aMather, Karen1 aJessen, Frank1 aIkram, Arfan, M1 ade Mendonça, Alexandre1 aHort, Jakub1 aTsolaki, Magda1 aPericak-Vance, Margaret, A1 aAmouyel, Philippe1 aWilliams, Julie1 aFrikke-Schmidt, Ruth1 aClarimon, Jordi1 aDeleuze, Jean-Francois1 aRossi, Giacomina1 aSeshadri, Sudha1 aAndreassen, Ole, A1 aIngelsson, Martin1 aHiltunen, Mikko1 aSleegers, Kristel1 aSchellenberg, Gerard, D1 aDuijn, Cornelia, M1 aSims, Rebecca1 avan der Flier, Wiesje, M1 aRuiz, Agustin1 aRamirez, Alfredo1 aLambert, Jean-Charles1 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2022 eng d a1476-468700aStroke genetics informs drug discovery and risk prediction across ancestries.0 aStroke genetics informs drug discovery and risk prediction acros c2022 Sep 303 aPrevious genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
1 aMishra, Aniket1 aMalik, Rainer1 aHachiya, Tsuyoshi1 aJürgenson, Tuuli1 aNamba, Shinichi1 aPosner, Daniel, C1 aKamanu, Frederick, K1 aKoido, Masaru1 aLe Grand, Quentin1 aShi, Mingyang1 aHe, Yunye1 aGeorgakis, Marios, K1 aCaro, Ilana1 aKrebs, Kristi1 aLiaw, Yi-Ching1 aVaura, Felix, C1 aLin, Kuang1 aWinsvold, Bendik, Slagsvold1 aSrinivasasainagendra, Vinodh1 aParodi, Livia1 aBae, Hee-Joon1 aChauhan, Ganesh1 aChong, Michael, R1 aTomppo, Liisa1 aAkinyemi, Rufus1 aRoshchupkin, Gennady, V1 aHabib, Naomi1 aJee, Yon, Ho1 aThomassen, Jesper, Qvist1 aAbedi, Vida1 aCárcel-Márquez, Jara1 aNygaard, Marianne1 aLeonard, Hampton, L1 aYang, Chaojie1 aYonova-Doing, Ekaterina1 aKnol, Maria, J1 aLewis, Adam, J1 aJudy, Renae, L1 aAgo, Tetsuro1 aAmouyel, Philippe1 aArmstrong, Nicole, D1 aBakker, Mark, K1 aBartz, Traci, M1 aBennett, David, A1 aBis, Joshua, C1 aBordes, Constance1 aBørte, Sigrid1 aCain, Anael1 aRidker, Paul, M1 aCho, Kelly1 aChen, Zhengming1 aCruchaga, Carlos1 aCole, John, W1 aDe Jager, Phil, L1 ade Cid, Rafael1 aEndres, Matthias1 aFerreira, Leslie, E1 aGeerlings, Mirjam, I1 aGasca, Natalie, C1 aGudnason, Vilmundur1 aHata, Jun1 aHe, Jing1 aHeath, Alicia, K1 aHo, Yuk-Lam1 aHavulinna, Aki, S1 aHopewell, Jemma, C1 aHyacinth, Hyacinth, I1 aInouye, Michael1 aJacob, Mina, A1 aJeon, Christina, E1 aJern, Christina1 aKamouchi, Masahiro1 aKeene, Keith, L1 aKitazono, Takanari1 aKittner, Steven, J1 aKonuma, Takahiro1 aKumar, Amit1 aLacaze, Paul1 aLauner, Lenore, J1 aLee, Keon-Joo1 aLepik, Kaido1 aLi, Jiang1 aLi, Liming1 aManichaikul, Ani1 aMarkus, Hugh, S1 aMarston, Nicholas, A1 aMeitinger, Thomas1 aMitchell, Braxton, D1 aMontellano, Felipe, A1 aMorisaki, Takayuki1 aMosley, Thomas, H1 aNalls, Mike, A1 aNordestgaard, Børge, G1 aO'Donnell, Martin, J1 aOkada, Yukinori1 aOnland-Moret, Charlotte, N1 aOvbiagele, Bruce1 aPeters, Annette1 aPsaty, Bruce, M1 aRich, Stephen, S1 aRosand, Jonathan1 aSabatine, Marc, S1 aSacco, Ralph, L1 aSaleheen, Danish1 aSandset, Else, Charlotte1 aSalomaa, Veikko1 aSargurupremraj, Muralidharan1 aSasaki, Makoto1 aSatizabal, Claudia, L1 aSchmidt, Carsten, O1 aShimizu, Atsushi1 aSmith, Nicholas, L1 aSloane, Kelly, L1 aSutoh, Yoichi1 aSun, Yan, V1 aTanno, Kozo1 aTiedt, Steffen1 aTatlisumak, Turgut1 aTorres-Aguila, Nuria, P1 aTiwari, Hemant, K1 aTrégouët, David-Alexandre1 aTrompet, Stella1 aTuladhar, Anil, Man1 aTybjærg-Hansen, Anne1 avan Vugt, Marion1 aVibo, Riina1 aVerma, Shefali, S1 aWiggins, Kerri, L1 aWennberg, Patrik1 aWoo, Daniel1 aWilson, Peter, W F1 aXu, Huichun1 aYang, Qiong1 aYoon, Kyungheon1 aMillwood, Iona, Y1 aGieger, Christian1 aNinomiya, Toshiharu1 aGrabe, Hans, J1 aJukema, Wouter1 aRissanen, Ina, L1 aStrbian, Daniel1 aKim, Young, Jin1 aChen, Pei-Hsin1 aMayerhofer, Ernst1 aHowson, Joanna, M M1 aIrvin, Marguerite, R1 aAdams, Hieab1 aWassertheil-Smoller, Sylvia1 aChristensen, Kaare1 aIkram, Mohammad, A1 aRundek, Tatjana1 aWorrall, Bradford, B1 aLathrop, Mark, G1 aRiaz, Moeen1 aSimonsick, Eleanor, M1 aKõrv, Janika1 aFrança, Paulo, H C1 aZand, Ramin1 aPrasad, Kameshwar1 aFrikke-Schmidt, Ruth1 ade Leeuw, Frank-Erik1 aLiman, Thomas1 aHaeusler, Karl, Georg1 aRuigrok, Ynte, M1 aHeuschmann, Peter, Ulrich1 aLongstreth, W T1 aJung, Keum, Ji1 aBastarache, Lisa1 aParé, Guillaume1 aDamrauer, Scott, M1 aChasman, Daniel, I1 aRotter, Jerome, I1 aAnderson, Christopher, D1 aZwart, John-Anker1 aNiiranen, Teemu, J1 aFornage, Myriam1 aLiaw, Yung-Po1 aSeshadri, Sudha1 aFernandez-Cadenas, Israel1 aWalters, Robin, G1 aRuff, Christian, T1 aOwolabi, Mayowa, O1 aHuffman, Jennifer, E1 aMilani, Lili1 aKamatani, Yoichiro1 aDichgans, Martin1 aDebette, Stephanie1 aCOMPASS Consortium1 aINVENT Consortium1 aDutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study Group1 aEstonian Biobank1 aPRECISEQ Consortium1 aFinnGen Consortium1 aNINDS Stroke Genetics Network (SiGN)1 aMEGASTROKE Consortium1 aSIREN Consortium1 aChina Kadoorie Biobank Collaborative Group1 aVA Million Veteran Program1 aInternational Stroke Genetics Consortium (ISGC)1 aBiobank Japan1 aCHARGE Consortium1 aGIGASTROKE Consortium uhttps://chs-nhlbi.org/node/917203922nas a2200673 4500008004100000022001400041245014500055210006900200260001600269300001200285520190200297100001302199700001802212700001902230700001902249700001402268700002202282700002302304700002402327700001402351700002702365700002202392700001702414700002502431700001302456700001702469700001502486700002402501700002102525700002102546700002002567700002402587700002302611700002002634700002102654700002002675700002402695700002302719700002702742700002802769700002002797700001402817700002102831700002202852700001902874700002202893700002402915700001602939700002002955700002102975700001702996700002203013700001903035700002603054700001903080700001603099710009703115856003603212 2023 eng d a2047-998000aAssociation Between Whole Blood-Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk.0 aAssociation Between Whole BloodDerived Mitochondrial DNA Copy Nu c2023 Oct 07 ae0290903 aBackground The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1-SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04-1.12; <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; =0.11) or in the reverse direction (β=-0.012; =0.076). Additional bidirectional Mendelian randomization analyses revealed that low-density lipoprotein cholesterol had a causal effect on mtDNA CN (β=-0.084; <0.001), but the reverse direction was not significant (=0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low-density lipoprotein cholesterol level (=0.52), whereas there was a strong direct causal effect of higher low-density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=-0.092; <0.001). Conclusions Our findings indicate that high low-density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.
1 aLiu, Xue1 aSun, Xianbang1 aZhang, Yuankai1 aJiang, Wenqing1 aLai, Meng1 aWiggins, Kerri, L1 aRaffield, Laura, M1 aBielak, Lawrence, F1 aZhao, Wei1 aPitsillides, Achilleas1 aHaessler, Jeffrey1 aZheng, Yinan1 aBlackwell, Thomas, W1 aYao, Jie1 aGuo, Xiuqing1 aQian, Yong1 aThyagarajan, Bharat1 aPankratz, Nathan1 aRich, Stephen, S1 aTaylor, Kent, D1 aPeyser, Patricia, A1 aHeckbert, Susan, R1 aSeshadri, Sudha1 aBoerwinkle, Eric1 aGrove, Megan, L1 aLarson, Nicholas, B1 aSmith, Jennifer, A1 aVasan, Ramachandran, S1 aFitzpatrick, Annette, L1 aFornage, Myriam1 aDing, Jun1 aCarson, April, P1 aAbecasis, Goncalo1 aDupuis, Josée1 aReiner, Alexander1 aKooperberg, Charles1 aHou, Lifang1 aPsaty, Bruce, M1 aWilson, James, G1 aLevy, Daniel1 aRotter, Jerome, I1 aBis, Joshua, C1 aSatizabal, Claudia, L1 aArking, Dan, E1 aLiu, Chunyu1 aTOPMed mtDNA Working Group in NHLBI Trans‐Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/950204492nas a2200649 4500008004100000022001400041245014000055210006900195260001600264520258200280100001902862700001302881700002202894700002502916700001702941700002402958700001402982700001902996700002203015700002703037700002903064700001703093700001903110700002203129700002103151700001903172700002103191700001803212700002203230700001603252700002303268700002203291700001903313700001703332700001903349700002303368700002103391700002203412700002003434700001903454700002403473700002403497700002003521700002103541700002003562700002403582700002303606700002003629700002503649700001903674700002003693700002303713700002803736700001603764700002603780856003603806 2023 eng d a1526-632X00aAssociation of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts.0 aAssociation of Mitochondrial DNA Copy Number With Brain MRI Mark c2023 Mar 163 aBACKGROUND AND OBJECTIVES: Previous studies suggest lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer's disease (AD) and AD related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.
METHODS: We included dementia-free participants from nine diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5 to 20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs. ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed Mendelian randomization (MR) analyses to assess causality.
RESULTS: We included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (Beta=0.04; 95% CI 0.02, 0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition.
DISCUSSION: Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the US. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.
1 aZhang, Yuankai1 aLiu, Xue1 aWiggins, Kerri, L1 aKurniansyah, Nuzulul1 aGuo, Xiuqing1 aRodrigue, Amanda, L1 aZhao, Wei1 aYanek, Lisa, R1 aRatliff, Scott, M1 aPitsillides, Achilleas1 aPatiño, Juan, Sebastian1 aSofer, Tamar1 aArking, Dan, E1 aAustin, Thomas, R1 aBeiser, Alexa, S1 aBlangero, John1 aBoerwinkle, Eric1 aBressler, Jan1 aCurran, Joanne, E1 aHou, Lifang1 aHughes, Timothy, M1 aKardia, Sharon, L1 aLauner, Lenore1 aLevy, Daniel1 aMosley, Tom, H1 aNasrallah, Ilya, M1 aRich, Stephen, S1 aRotter, Jerome, I1 aSeshadri, Sudha1 aTarraf, Wassim1 aGonzález, Kevin, A1 aRamachandran, Vasan1 aYaffe, Kristine1 aNyquist, Paul, A1 aPsaty, Bruce, M1 aDeCarli, Charles, S1 aSmith, Jennifer, A1 aGlahn, David, C1 aGonzález, Hector, M1 aBis, Joshua, C1 aFornage, Myriam1 aHeckbert, Susan, R1 aFitzpatrick, Annette, L1 aLiu, Chunyu1 aSatizabal, Claudia, L uhttps://chs-nhlbi.org/node/932302645nas a2200481 4500008004100000022001400041245008100055210006900136260001300205300001400218490000700232520126700239100001701506700001901523700001301542700001501555700002101570700001601591700001301607700002501620700001701645700001901662700001601681700001801697700002301715700001901738700002001757700002701777700002001804700002301824700002001847700002601867700002201893700002001915700001901935700001601954700002001970700002501990700002302015700002402038710006502062856003602127 2023 eng d a1546-170X00aClonal hematopoiesis is associated with protection from Alzheimer's disease.0 aClonal hematopoiesis is associated with protection from Alzheime c2023 Jul a1662-16700 v293 aClonal hematopoiesis of indeterminate potential (CHIP) is a premalignant expansion of mutated hematopoietic stem cells. As CHIP-associated mutations are known to alter the development and function of myeloid cells, we hypothesized that CHIP may also be associated with the risk of Alzheimer's disease (AD), a disease in which brain-resident myeloid cells are thought to have a major role. To perform association tests between CHIP and AD dementia, we analyzed blood DNA sequencing data from 1,362 individuals with AD and 4,368 individuals without AD. Individuals with CHIP had a lower risk of AD dementia (meta-analysis odds ratio (OR) = 0.64, P = 3.8 × 10), and Mendelian randomization analyses supported a potential causal association. We observed that the same mutations found in blood were also detected in microglia-enriched fraction of the brain in seven of eight CHIP carriers. Single-nucleus chromatin accessibility profiling of brain-derived nuclei in six CHIP carriers revealed that the mutated cells comprised a large proportion of the microglial pool in the samples examined. While additional studies are required to validate the mechanistic findings, these results suggest that CHIP may have a role in attenuating the risk of AD.
1 aBouzid, Hind1 aBelk, Julia, A1 aJan, Max1 aQi, Yanyan1 aSarnowski, Chloe1 aWirth, Sara1 aMa, Lisa1 aChrostek, Matthew, R1 aAhmad, Herra1 aNachun, Daniel1 aYao, Winnie1 aBeiser, Alexa1 aBick, Alexander, G1 aBis, Joshua, C1 aFornage, Myriam1 aLongstreth, William, T1 aLopez, Oscar, L1 aNatarajan, Pradeep1 aPsaty, Bruce, M1 aSatizabal, Claudia, L1 aWeinstock, Joshua1 aLarson, Eric, B1 aCrane, Paul, K1 aKeene, Dirk1 aSeshadri, Sudha1 aSatpathy, Ansuman, T1 aMontine, Thomas, J1 aJaiswal, Siddhartha1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/941106165nas a2200505 4500008004100000245012200041210006900163260001600232520464400248100003304892700002104925700001904946700001704965700002204982700001705004700001905021700001605040700001605056700002605072700002605098700001905124700002305143700002105166700002305187700002105210700002005231700002205251700001705273700002005290700002405310700002205334700002005356700002805376700002705404700002405431700001705455700002405472700002005496700002205516700002005538700002005558700002205578700002305600856003605623 2023 eng d00aComplexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics.0 aComplexities of cerebral small vessel disease blood pressure and c2023 Aug 133 aIMPORTANCE: There is increasing recognition that vascular disease, which can be treated, is a key contributor to dementia risk. However, the contribution of specific markers of vascular disease is unclear and, as a consequence, optimal prevention strategies remain unclear.
OBJECTIVE: To disentangle the causal relation of several key vascular traits to dementia risk: (i) white matter hyperintensity (WMH) burden, a highly prevalent imaging marker of covert cerebral small vessel disease (cSVD); (ii) clinical stroke; and (iii) blood pressure (BP), the leading risk factor for cSVD and stroke, for which efficient therapies exist. To account for potential epidemiological biases inherent to late-onset conditions like dementia.
DESIGN SETTING AND PARTICIPANTS: This study first explored the association of genetically determined WMH, BP levels and stroke risk with AD using summary-level data from large genome-wide association studies (GWASs) in a two-sample Mendelian randomization (MR) framework. Second, leveraging individual-level data from large longitudinal population-based cohorts and biobanks with prospective dementia surveillance, the association of weighted genetic risk scores (wGRSs) for WMH, BP, and stroke with incident all-cause-dementia was explored using Cox-proportional hazard and multi-state models. The data analysis was performed from July 26, 2020, through July 24, 2022.
EXPOSURES: Genetically determined levels of WMH volume and BP (systolic, diastolic and pulse blood pressures) and genetic liability to stroke.
MAIN OUTCOMES AND MEASURES: The summary-level MR analyses focused on the outcomes from GWAS of clinically diagnosed AD (n-cases=21,982) and GWAS additionally including self-reported parental history of dementia as a proxy for AD diagnosis (AD , n-cases=53,042). For the longitudinal analyses, individual-level data of 157,698 participants with 10,699 incident all-cause-dementia were studied, exploring AD, vascular or mixed dementia in secondary analyses.
RESULTS: In the two-sample MR analyses, WMH showed strong evidence for a causal association with increased risk of AD (OR, 1.16; 95%CI:1.05-1.28; P=.003) and AD (OR, 1.28; 95%CI:1.07-1.53; P=.008), after accounting for genetically determined pulse pressure for the latter. Genetically predicted BP traits showed evidence for a protective association with both clinically defined AD and AD , with evidence for confounding by shared genetic instruments. In longitudinal analyses the wGRSs for WMH, but not BP or stroke, showed suggestive association with incident all-cause-dementia (HR, 1.02; 95%CI:1.00-1.04; P=.06). BP and stroke wGRSs were strongly associated with mortality but there was no evidence for selective survival bias during follow-up. In secondary analyses, polygenic scores with more liberal instrument definition showed association of both WMH and stroke with all-cause-dementia, AD, and vascular or mixed dementia; associations of stroke, but not WMH, with dementia outcomes were markedly attenuated after adjusting for interim stroke.
CONCLUSION: These findings provide converging evidence that WMH is a leading vascular contributor to dementia risk, which may better capture the brain damage caused by BP (and other etiologies) than BP itself and should be targeted in priority for dementia prevention in the population.
KEY POINTS: Do instrumental variable analyses leveraging genetic information provide evidence for a causal association of various vascular traits with Alzheimer's disease (AD) and all-cause-dementia? How do these associations compare for white matter hyperintensity (WMH) burden, a highly prevalent marker of covert cerebral small vessel disease (cSVD), stroke, and blood pressure traits, the strongest known risk factor for cSVD and stroke? Using Mendelian randomization (MR) leveraging large, published genome-wide association studies, this study showed a putative causal association of larger WMH burden with increased AD risk after accounting for pulse pressure effects, and some evidence for association of lower BP with AD risk with possible confounding by shared genetic instruments. Longitudinal analyses on individual-level data also supported association of genetically determined WMH with incident all-cause-dementia and AD, independently of interim stroke. This study using complementary genetic epidemiology approaches, identified increasing WMH burden to be associated with dementia and AD risk, suggesting the association as specific for cSVD and independent of BP and stroke.
1 aSargurupremraj, Muralidharan1 aSoumaré, Aïcha1 aBis, Joshua, C1 aSurakka, Ida1 aJürgenson, Tuuli1 aJoly, Pierre1 aKnol, Maria, J1 aWang, Ruiqi1 aYang, Qiong1 aSatizabal, Claudia, L1 aGudjonsson, Alexander1 aMishra, Aniket1 aBouteloup, Vincent1 aPhuah, Chia-Ling1 aDuijn, Cornelia, M1 aCruchaga, Carlos1 aDufouil, Carole1 aChene, Geneviève1 aLopez, Oscar1 aPsaty, Bruce, M1 aTzourio, Christophe1 aAmouyel, Philippe1 aAdams, Hieab, H1 aJacqmin-Gadda, Hélène1 aIkram, Mohammad, Arfan1 aGudnason, Vilmundur1 aMilani, Lili1 aWinsvold, Bendik, S1 aHveem, Kristian1 aMatthews, Paul, M1 aLongstreth, W T1 aSeshadri, Sudha1 aLauner, Lenore, J1 aDebette, Stephanie uhttps://chs-nhlbi.org/node/950502945nas a2200397 4500008004100000245009500041210006900136260001600205520178200221100001802003700002002021700001502041700001402056700003002070700001302100700001902113700001702132700001502149700002302164700002202187700002102209700002202230700002102252700002702273700001902300700002002319700002102339700002802360700002602388700001902414700001402433700001702447700001602464710003102480856003602511 2024 eng d00aAssociation analysis of mitochondrial DNA heteroplasmic variants: methods and application.0 aAssociation analysis of mitochondrial DNA heteroplasmic variants c2024 Jan 133 aWe rigorously assessed a comprehensive association testing framework for heteroplasmy, employing both simulated and real-world data. This framework employed a variant allele fraction (VAF) threshold and harnessed multiple gene-based tests for robust identification and association testing of heteroplasmy. Our simulation studies demonstrated that gene-based tests maintained an appropriate type I error rate at α=0.001. Notably, when 5% or more heteroplasmic variants within a target region were linked to an outcome, burden-extension tests (including the adaptive burden test, variable threshold burden test, and z-score weighting burden test) outperformed the sequence kernel association test (SKAT) and the original burden test. Applying this framework, we conducted association analyses on whole-blood derived heteroplasmy in 17,507 individuals of African and European ancestries (31% of African Ancestry, mean age of 62, with 58% women) with whole genome sequencing data. We performed both cohort- and ancestry-specific association analyses, followed by meta-analysis on bothpooled samples and within each ancestry group. Our results suggest that mtDNA-Enco ded genes/regions are likely to exhibit varying rates in somatic aging, with the notably strong associations observed between heteroplasmy in the and genes ( <0.001) and advance aging by the Original Burden test. In contrast, SKAT identified significant associations ( <0.001) between diabetes and the aggregated effects of heteroplasmy in several protein-coding genes. Further research is warranted to validate these findings. In summary, our proposed statistical framework represents a valuable tool for facilitating association testing of heteroplasmy with disease traits in large human populations.
1 aSun, Xianbang1 aBulekova, Katia1 aYang, Jian1 aLai, Meng1 aPitsillides, Achilleas, N1 aLiu, Xue1 aZhang, Yuankai1 aGuo, Xiuqing1 aYong, Qian1 aRaffield, Laura, M1 aRotter, Jerome, I1 aRich, Stephen, S1 aAbecasis, Goncalo1 aCarson, April, P1 aVasan, Ramachandran, S1 aBis, Joshua, C1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aFitzpatrick, Annette, L1 aSatizabal, Claudia, L1 aArking, Dan, E1 aDing, Jun1 aLevy, Daniel1 aLiu, Chunyu1 aTOPMed mtDNA working group uhttps://chs-nhlbi.org/node/958004874nas a2201033 4500008004100000022001400041245014100055210006900196260001600265300000700281490000700288520197200295653000902267653001402276653003402290653001102324653001102335653001402346653001502360653003602375100001302411700002202424700001502446700001502461700001902476700001702495700001602512700001702528700002402545700001602569700001602585700002302601700001702624700002102641700002502662700002102687700001802708700002302726700002202749700002702771700002002798700002002818700001402838700002602852700001902878700002302897700002202920700001802942700002302960700002102983700001803004700002203022700001903044700001903063700002703082700002603109700002203135700001603157700001903173700002403192700002203216700002503238700002203263700001903285700002303304700001803327700002003345700002103365700002303386700002403409700002603433700002303459700002203482700002103504700002303525700002403548700001903572700002203591700002003613700001803633700002303651700001903674700002803693700002003721700001803741700002303759700002203782856003603804 2024 eng d a1758-919300aMulti-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance.0 aMultiomics and pathway analyses of genomewide associations impli c2024 Jan 20 a140 v163 aBACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia.
METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes.
RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues.
CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.
10aAged10aCognition10aGenome-Wide Association Study10aHumans10aMemory10aMicroRNAs10aMultiomics10aPolymorphism, Single Nucleotide1 aMei, Hao1 aSimino, Jeannette1 aLi, Lianna1 aJiang, Fan1 aBis, Joshua, C1 aDavies, Gail1 aHill, David1 aXia, Charley1 aGudnason, Vilmundur1 aYang, Qiong1 aLahti, Jari1 aSmith, Jennifer, A1 aKirin, Mirna1 aDe Jager, Philip1 aArmstrong, Nicola, J1 aGhanbari, Mohsen1 aKolcic, Ivana1 aMoran, Christopher1 aTeumer, Alexander1 aSargurupremraj, Murali1 aMahmud, Shamsed1 aFornage, Myriam1 aZhao, Wei1 aSatizabal, Claudia, L1 aPolasek, Ozren1 aRäikkönen, Katri1 aLiewald, David, C1 aHomuth, Georg1 aCallisaya, Michele1 aMather, Karen, A1 aWindham, Gwen1 aZemunik, Tatijana1 aPalotie, Aarno1 aPattie, Alison1 avan der Auwera, Sandra1 aThalamuthu, Anbupalam1 aKnopman, David, S1 aRudan, Igor1 aStarr, John, M1 aWittfeld, Katharina1 aKochan, Nicole, A1 aGriswold, Michael, E1 aVitart, Veronique1 aBrodaty, Henry1 aGottesman, Rebecca1 aCox, Simon, R1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aChasman, Daniel, I1 aGrodstein, Francine1 aSachdev, Perminder, S1 aSrikanth, Velandai1 aHayward, Caroline1 aWilson, James, F1 aEriksson, Johan, G1 aKardia, Sharon, L R1 aGrabe, Hans, J1 aBennett, David, A1 aIkram, Arfan, M1 aDeary, Ian, J1 aDuijn, Cornelia, M1 aLauner, Lenore1 aFitzpatrick, Annette, L1 aSeshadri, Sudha1 aBressler, Jan1 aDebette, Stephanie1 aMosley, Thomas, H uhttps://chs-nhlbi.org/node/9578