05521nas a2201561 4500008004100000022001400041245010000055210006900155260001300224300001200237490000700249520109100256653001201347653002101359653002301380653002601403653002401429653001701453653003401470653002801504653001101532653000901543653002101552653001901573653002201592653004001614653003601654653002001690100002201710700001801732700002501750700001801775700002901793700001901822700001501841700002101856700002201877700001901899700002101918700002501939700002201964700002601986700001902012700002302031700001702054700002202071700002602093700001802119700002002137700002202157700001202179700001902191700002602210700001902236700001902255700001802274700001802292700001902310700001802329700001802347700002702365700001902392700002402411700001902435700001702454700002002471700002702491700001702518700002602535700002202561700001702583700002302600700002202623700002402645700002402669700002002693700001902713700002502732700002002757700002302777700002802800700001902828700002402847700001702871700002102888700002402909700002202933700002002955700001702975700002202992700001903014700003003033700002103063700002003084700002303104700002203127700001903149700002003168700002103188700002803209700002903237700003003266700002603296700002303322700002103345700001903366700001603385700001703401700002603418700002403444700002203468700002203490700002903512700002003541700002003561700001803581700001603599700002003615700002103635700002603656700002403682700002003706700002403726700002303750700002203773700002203795700002003817700002603837700002203863700001903885700001903904856003603923 2010 eng d a1546-171800aCommon variants in 22 loci are associated with QRS duration and cardiac ventricular conduction.0 aCommon variants in 22 loci are associated with QRS duration and c2010 Dec a1068-760 v423 a
The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.
10aAnimals10aAnimals, Newborn10aChromosomes, Human10aComputational Biology10aElectrocardiography10aGenetic Loci10aGenome-Wide Association Study10aHeart Conduction System10aHumans10aMice10aMice, Transgenic10aModels, Animal10aMyocytes, Cardiac10aNAV1.8 Voltage-Gated Sodium Channel10aPolymorphism, Single Nucleotide10aSodium Channels1 aSotoodehnia, Nona1 aIsaacs, Aaron1 ade Bakker, Paul, I W1 aDörr, Marcus1 aNewton-Cheh, Christopher1 aNolte, Ilja, M1 aHarst, Pim1 aMüller, Martina1 aEijgelsheim, Mark1 aAlonso, Alvaro1 aHicks, Andrew, A1 aPadmanabhan, Sandosh1 aHayward, Caroline1 aSmith, Albert, Vernon1 aPolasek, Ozren1 aGiovannone, Steven1 aFu, Jingyuan1 aMagnani, Jared, W1 aMarciante, Kristin, D1 aPfeufer, Arne1 aGharib, Sina, A1 aTeumer, Alexander1 aLi, Man1 aBis, Joshua, C1 aRivadeneira, Fernando1 aAspelund, Thor1 aKöttgen, Anna1 aJohnson, Toby1 aRice, Kenneth1 aSie, Mark, P S1 aWang, Ying, A1 aKlopp, Norman1 aFuchsberger, Christian1 aWild, Sarah, H1 aLeach, Irene, Mateo1 aEstrada, Karol1 aVölker, Uwe1 aWright, Alan, F1 aAsselbergs, Folkert, W1 aQu, Jiaxiang1 aChakravarti, Aravinda1 aSinner, Moritz, F1 aKors, Jan, A1 aPetersmann, Astrid1 aHarris, Tamara, B1 aSoliman, Elsayed, Z1 aMunroe, Patricia, B1 aPsaty, Bruce, M1 aOostra, Ben, A1 aCupples, Adrienne, L1 aPerz, Siegfried1 ade Boer, Rudolf, A1 aUitterlinden, André, G1 aVölzke, Henry1 aSpector, Timothy, D1 aLiu, Fang-Yu1 aBoerwinkle, Eric1 aDominiczak, Anna, F1 aRotter, Jerome, I1 avan Herpen, Gé1 aLevy, Daniel1 aWichmann, H-Erich1 aGilst, Wiek, H1 aWitteman, Jacqueline, C M1 aKroemer, Heyo, K1 aKao, Linda, W H1 aHeckbert, Susan, R1 aMeitinger, Thomas1 aHofman, Albert1 aCampbell, Harry1 aFolsom, Aaron, R1 avan Veldhuisen, Dirk, J1 aSchwienbacher, Christine1 aO'Donnell, Christopher, J1 aVolpato, Claudia, Beu1 aCaulfield, Mark, J1 aConnell, John, M1 aLauner, Lenore1 aLu, Xiaowen1 aFranke, Lude1 aFehrmann, Rudolf, S N1 aMeerman, Gerard, te1 aGroen, Harry, J M1 aWeersma, Rinse, K1 avan den Berg, Leonard, H1 aWijmenga, Cisca1 aOphoff, Roel, A1 aNavis, Gerjan1 aRudan, Igor1 aSnieder, Harold1 aWilson, James, F1 aPramstaller, Peter, P1 aSiscovick, David, S1 aWang, Thomas, J1 aGudnason, Vilmundur1 aDuijn, Cornelia, M1 aFelix, Stephan, B1 aFishman, Glenn, I1 aJamshidi, Yalda1 aStricker, Bruno, H Ch1 aSamani, Nilesh, J1 aKääb, Stefan1 aArking, Dan, E uhttps://chs-nhlbi.org/node/124405042nas a2201093 4500008004100000022001400041245017600055210006900231260001300300300001200313490000700325520188300332653001002215653000902225653001802234653001702252653004002269653001202309653001102321653001702332653003402349653001302383653001102396653001202407653000902419653001602428653003602444100002702480700002302507700002202530700002402552700002502576700001702601700002602618700002102644700002402665700001402689700001702703700002002720700002602740700002002766700001802786700002102804700002902825700002502854700002502879700002502904700002302929700002302952700002102975700002002996700002103016700002703037700002103064700001903085700001903104700002303123700001703146700002403163700002803187700002403215700001903239700001703258700001803275700001903293700002503312700002003337700001803357700001703375700002103392700002203413700002003435700002503455700001703480700001803497700003103515700002803546700002503574700002103599700002103620700002303641700002003664700003003684700001903714700002503733700002103758700002003779700002503799700002403824700002003848700002003868710002403888856003603912 2010 eng d a1935-554800aInteractions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies.0 aInteractions of dietary wholegrain intake with fasting glucose a c2010 Dec a2684-910 v333 aOBJECTIVE: Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin.
RESEARCH DESIGN AND METHODS: Via meta-analysis of data from 14 cohorts comprising ∼ 48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value <0.0028 (0.05 of 18 tests) as statistically significant.
RESULTS: Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: -0.009 mmol/l glucose [-0.013 to -0.005], P < 0.0001 and -0.011 pmol/l [ln] insulin [-0.015 to -0.007], P = 0.0003). No interactions met our multiple testing-adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele.
CONCLUSIONS: Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.
10aAdult10aAged10aBlood Glucose10aEdible Grain10aEuropean Continental Ancestry Group10aFasting10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHumans10aInsulin10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide1 aNettleton, Jennifer, A1 aMcKeown, Nicola, M1 aKanoni, Stavroula1 aLemaitre, Rozenn, N1 aHivert, Marie-France1 aNgwa, Julius1 avan Rooij, Frank, J A1 aSonestedt, Emily1 aWojczynski, Mary, K1 aYe, Zheng1 aTanaka, Tosh1 aGarcia, Melissa1 aAnderson, Jennifer, S1 aFollis, Jack, L1 aDjoussé, Luc1 aMukamal, Kenneth1 aPapoutsakis, Constantina1 aMozaffarian, Dariush1 aZillikens, Carola, M1 aBandinelli, Stefania1 aBennett, Amanda, J1 aBorecki, Ingrid, B1 aFeitosa, Mary, F1 aFerrucci, Luigi1 aForouhi, Nita, G1 aGroves, Christopher, J1 aHallmans, Göran1 aHarris, Tamara1 aHofman, Albert1 aHouston, Denise, K1 aHu, Frank, B1 aJohansson, Ingegerd1 aKritchevsky, Stephen, B1 aLangenberg, Claudia1 aLauner, Lenore1 aLiu, Yongmei1 aLoos, Ruth, J1 aNalls, Michael1 aOrho-Melander, Marju1 aRenstrom, Frida1 aRice, Kenneth1 aRiserus, Ulf1 aRolandsson, Olov1 aRotter, Jerome, I1 aSaylor, Georgia1 aSijbrands, Eric, J G1 aSjogren, Per1 aSmith, Albert1 aSteingrímsdóttir, Laufey1 aUitterlinden, André, G1 aWareham, Nicholas, J1 aProkopenko, Inga1 aPankow, James, S1 aDuijn, Cornelia, M1 aFlorez, Jose, C1 aWitteman, Jacqueline, C M1 aDupuis, Josée1 aDedoussis, George, V1 aOrdovas, Jose, M1 aIngelsson, Erik1 aCupples, Adrienne, L1 aSiscovick, David, S1 aFranks, Paul, W1 aMeigs, James, B1 aMAGIC investigators uhttps://chs-nhlbi.org/node/122203867nas a2200745 4500008004100000022001400041245012900055210006900184260001300253300001100266490000600277520177500283653002802058653002102086653001102107653001702118653003402135653000902169653001102178653000902189653001702198653001402215100001602229700001902245700001902264700002102283700002202304700002002326700002302346700001902369700002402388700002202412700001902434700001902453700002002472700001902492700002102511700002002532700001202552700002002564700002102584700002302605700001202628700001902640700002002659700002102679700002002700700002202720700003002742700002102772700002302793700001902816700002602835700002002861700002802881700002102909700002002930700002002950700002402970700002402994700002803018700002103046700001803067856003603085 2010 eng d a1942-326800aMultiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors.0 aMultiple genetic loci influence serum urate levels and their rel c2010 Dec a523-300 v33 aBACKGROUND: Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed a genome-wide association study to search for genetic susceptibility loci for serum urate and gout and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD).
METHODS AND RESULTS: Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology consortium for serum urate and gout in 28 283 white participants. The effect of the most significant single-nucleotide polymorphism at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Women's Genome Health Study (n=22 054). Single-nucleotide polymorphisms at 8 genetic loci achieved genome-wide significance with serum urate levels (P=4×10(-8) to 2×10(-242) in SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, and SLC17A1). Only 2 loci (SLC2A9, ABCG2) showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio, 12.4 per 100 μmol/L; P=3×10(-39)) but not with blood pressure, glucose, estimated glomerular filtration rate, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes also was observed in the Women's Genome Health Study.
CONCLUSIONS: The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD.
10aCardiovascular Diseases10aCoronary Disease10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGout10aHumans10aMale10aRisk Factors10aUric Acid1 aYang, Qiong1 aKöttgen, Anna1 aDehghan, Abbas1 aSmith, Albert, V1 aGlazer, Nicole, L1 aChen, Ming-Huei1 aChasman, Daniel, I1 aAspelund, Thor1 aEiriksdottir, Gudny1 aHarris, Tamara, B1 aLauner, Lenore1 aNalls, Michael1 aHernandez, Dena1 aArking, Dan, E1 aBoerwinkle, Eric1 aGrove, Megan, L1 aLi, Man1 aKao, W, H Linda1 aChonchol, Michel1 aHaritunians, Talin1 aLi, Guo1 aLumley, Thomas1 aPsaty, Bruce, M1 aShlipak, Michael1 aHwang, Shih-Jen1 aLarson, Martin, G1 aO'Donnell, Christopher, J1 aUpadhyay, Ashish1 aDuijn, Cornelia, M1 aHofman, Albert1 aRivadeneira, Fernando1 aStricker, Bruno1 aUitterlinden, André, G1 aParé, Guillaume1 aParker, Alex, N1 aRidker, Paul, M1 aSiscovick, David, S1 aGudnason, Vilmundur1 aWitteman, Jacqueline, C1 aFox, Caroline, S1 aCoresh, Josef uhttps://chs-nhlbi.org/node/123513785nas a2204513 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2011 eng d a1476-468700aGenetic variants in novel pathways influence blood pressure and cardiovascular disease risk.0 aGenetic variants in novel pathways influence blood pressure and c2011 Sep 11 a103-90 v4783 aBlood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
10aAfrica10aAsia10aBlood Pressure10aCardiovascular Diseases10aCoronary Artery Disease10aEurope10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aHypertension10aKidney Diseases10aPolymorphism, Single Nucleotide10aStroke1 aInternational Consortium for Blood Pressure Genome-Wide Association Studies1 aEhret, Georg, B1 aMunroe, Patricia, B1 aRice, Kenneth, M1 aBochud, Murielle1 aJohnson, Andrew, D1 aChasman, Daniel, I1 aSmith, Albert, V1 aTobin, Martin, D1 aVerwoert, Germaine, C1 aHwang, Shih-Jen1 aPihur, Vasyl1 aVollenweider, Peter1 aO'Reilly, Paul, F1 aAmin, Najaf1 aBragg-Gresham, Jennifer, L1 aTeumer, Alexander1 aGlazer, Nicole, L1 aLauner, Lenore1 aZhao, Jing Hua1 aAulchenko, Yurii1 aHeath, Simon1 aSõber, Siim1 aParsa, Afshin1 aLuan, Jian'an1 aArora, Pankaj1 aDehghan, Abbas1 aZhang, Feng1 aLucas, Gavin1 aHicks, Andrew, A1 aJackson, Anne, U1 aPeden, John, F1 aTanaka, Toshiko1 aWild, Sarah, H1 aRudan, Igor1 aIgl, Wilmar1 aMilaneschi, Yuri1 aParker, Alex, N1 aFava, Cristiano1 aChambers, John, C1 aFox, Ervin, R1 aKumari, Meena1 aGo, Min Jin1 aHarst, Pim1 aKao, Wen Hong Linda1 aSjögren, Marketa1 aVinay, D G1 aAlexander, Myriam1 aTabara, Yasuharu1 aShaw-Hawkins, Sue1 aWhincup, Peter, H1 aLiu, Yongmei1 aShi, Gang1 aKuusisto, Johanna1 aTayo, Bamidele1 aSeielstad, Mark1 aSim, Xueling1 aNguyen, Khanh-Dung Hoang1 aLehtimäki, Terho1 aMatullo, Giuseppe1 aWu, Ying1 aGaunt, Tom, R1 aOnland-Moret, Charlotte, N1 aCooper, Matthew, N1 aPlatou, Carl, G P1 aOrg, Elin1 aHardy, Rebecca1 aDahgam, Santosh1 aPalmen, Jutta1 aVitart, Veronique1 aBraund, Peter, S1 aKuznetsova, Tatiana1 aUiterwaal, Cuno, S P M1 aAdeyemo, Adebowale1 aPalmas, Walter1 aCampbell, Harry1 aLudwig, Barbara1 aTomaszewski, Maciej1 aTzoulaki, Ioanna1 aPalmer, Nicholette, D1 aAspelund, Thor1 aGarcia, Melissa1 aChang, Yen-Pei, C1 aO'Connell, Jeffrey, R1 aSteinle, Nanette, I1 aGrobbee, Diederick, E1 aArking, Dan, E1 aKardia, Sharon, L1 aMorrison, Alanna, C1 aHernandez, Dena1 aNajjar, Samer1 aMcArdle, Wendy, L1 aHadley, David1 aBrown, Morris, J1 aConnell, John, M1 aHingorani, Aroon, D1 aDay, Ian, N M1 aLawlor, Debbie, A1 aBeilby, John, P1 aLawrence, Robert, W1 aClarke, Robert1 aHopewell, Jemma, C1 aOngen, Halit1 aDreisbach, Albert, W1 aLi, Yali1 aYoung, Hunter, J1 aBis, Joshua, C1 aKähönen, Mika1 aViikari, Jorma1 aAdair, Linda, S1 aLee, Nanette, R1 aChen, Ming-Huei1 aOlden, Matthias1 aPattaro, Cristian1 aBolton, Judith Hoffman, A1 aKöttgen, Anna1 aBergmann, Sven1 aMooser, Vincent1 aChaturvedi, Nish1 aFrayling, Timothy, M1 aIslam, Muhammad1 aJafar, Tazeen, H1 aErdmann, Jeanette1 aKulkarni, Smita, R1 aBornstein, Stefan, R1 aGrässler, Jürgen1 aGroop, Leif1 aVoight, Benjamin, F1 aKettunen, Johannes1 aHoward, Philip1 aTaylor, Andrew1 aGuarrera, Simonetta1 aRicceri, Fulvio1 aEmilsson, Valur1 aPlump, Andrew1 aBarroso, Inês1 aKhaw, Kay-Tee1 aWeder, Alan, B1 aHunt, Steven, C1 aSun, Yan, V1 aBergman, Richard, N1 aCollins, Francis, S1 aBonnycastle, Lori, L1 aScott, Laura, J1 aStringham, Heather, M1 aPeltonen, Leena1 aPerola, Markus1 aVartiainen, Erkki1 aBrand, Stefan-Martin1 aStaessen, Jan, A1 aWang, Thomas, J1 aBurton, Paul, R1 aArtigas, Maria, Soler1 aDong, Yanbin1 aSnieder, Harold1 aWang, Xiaoling1 aZhu, Haidong1 aLohman, Kurt, K1 aRudock, Megan, E1 aHeckbert, Susan, R1 aSmith, Nicholas, L1 aWiggins, Kerri, L1 aDoumatey, Ayo1 aShriner, Daniel1 aVeldre, Gudrun1 aViigimaa, Margus1 aKinra, Sanjay1 aPrabhakaran, Dorairaj1 aTripathy, Vikal1 aLangefeld, Carl, D1 aRosengren, Annika1 aThelle, Dag, S1 aCorsi, Anna Maria1 aSingleton, Andrew1 aForrester, Terrence1 aHilton, Gina1 aMcKenzie, Colin, A1 aSalako, Tunde1 aIwai, Naoharu1 aKita, Yoshikuni1 aOgihara, Toshio1 aOhkubo, Takayoshi1 aOkamura, Tomonori1 aUeshima, Hirotsugu1 aUmemura, Satoshi1 aEyheramendy, Susana1 aMeitinger, Thomas1 aWichmann, H-Erich1 aCho, Yoon Shin1 aKim, Hyung-Lae1 aLee, Jong-Young1 aScott, James1 aSehmi, Joban, S1 aZhang, Weihua1 aHedblad, Bo1 aNilsson, Peter1 aSmith, George Davey1 aWong, Andrew1 aNarisu, Narisu1 aStančáková, Alena1 aRaffel, Leslie, J1 aYao, Jie1 aKathiresan, Sekar1 aO'Donnell, Christopher, J1 aSchwartz, Stephen, M1 aIkram, Arfan, M1 aLongstreth, W T1 aMosley, Thomas, H1 aSeshadri, Sudha1 aShrine, Nick, R G1 aWain, Louise, V1 aMorken, Mario, A1 aSwift, Amy, J1 aLaitinen, Jaana1 aProkopenko, Inga1 aZitting, Paavo1 aCooper, Jackie, A1 aHumphries, Steve, E1 aDanesh, John1 aRasheed, Asif1 aGoel, Anuj1 aHamsten, Anders1 aWatkins, Hugh1 aBakker, Stephan, J L1 aGilst, Wiek, H1 aJanipalli, Charles, S1 aMani, Radha, K1 aYajnik, Chittaranjan, S1 aHofman, Albert1 aMattace-Raso, Francesco, U S1 aOostra, Ben, A1 aDemirkan, Ayse1 aIsaacs, Aaron1 aRivadeneira, Fernando1 aLakatta, Edward, G1 aOrrù, Marco1 aScuteri, Angelo1 aAla-Korpela, Mika1 aKangas, Antti, J1 aLyytikäinen, Leo-Pekka1 aSoininen, Pasi1 aTukiainen, Taru1 aWürtz, Peter1 aOng, Rick Twee-Hee1 aDörr, Marcus1 aKroemer, Heyo, K1 aVölker, Uwe1 aVölzke, Henry1 aGalan, Pilar1 aHercberg, Serge1 aLathrop, Mark1 aZelenika, Diana1 aDeloukas, Panos1 aMangino, Massimo1 aSpector, Tim, D1 aZhai, Guangju1 aMeschia, James, F1 aNalls, Michael, A1 aSharma, Pankaj1 aTerzic, Janos1 aKumar, Kranthi, M V1 aDenniff, Matthew1 aZukowska-Szczechowska, Ewa1 aWagenknecht, Lynne, E1 aFowkes, Gerald, F R1 aCharchar, Fadi, J1 aSchwarz, Peter, E H1 aHayward, Caroline1 aGuo, Xiuqing1 aRotimi, Charles1 aBots, Michiel, L1 aBrand, Eva1 aSamani, Nilesh, J1 aPolasek, Ozren1 aTalmud, Philippa, J1 aNyberg, Fredrik1 aKuh, Diana1 aLaan, Maris1 aHveem, Kristian1 aPalmer, Lyle, J1 aSchouw, Yvonne, T1 aCasas, Juan, P1 aMohlke, Karen, L1 aVineis, Paolo1 aRaitakari, Olli1 aGanesh, Santhi, K1 aWong, Tien, Y1 aTai, Shyong, E1 aCooper, Richard, S1 aLaakso, Markku1 aRao, Dabeeru, C1 aHarris, Tamara, B1 aMorris, Richard, W1 aDominiczak, Anna, F1 aKivimaki, Mika1 aMarmot, Michael, G1 aMiki, Tetsuro1 aSaleheen, Danish1 aChandak, Giriraj, R1 aCoresh, Josef1 aNavis, Gerjan1 aSalomaa, Veikko1 aHan, Bok-Ghee1 aZhu, Xiaofeng1 aKooner, Jaspal, S1 aMelander, Olle1 aRidker, Paul, M1 aBandinelli, Stefania1 aGyllensten, Ulf, B1 aWright, Alan, F1 aWilson, James, F1 aFerrucci, Luigi1 aFarrall, Martin1 aTuomilehto, Jaakko1 aPramstaller, Peter, P1 aElosua, Roberto1 aSoranzo, Nicole1 aSijbrands, Eric, J G1 aAltshuler, David1 aLoos, Ruth, J F1 aShuldiner, Alan, R1 aGieger, Christian1 aMeneton, Pierre1 aUitterlinden, André, G1 aWareham, Nicholas, J1 aGudnason, Vilmundur1 aRotter, Jerome, I1 aRettig, Rainer1 aUda, Manuela1 aStrachan, David, P1 aWitteman, Jacqueline, C M1 aHartikainen, Anna-Liisa1 aBeckmann, Jacques, S1 aBoerwinkle, Eric1 aVasan, Ramachandran, S1 aBoehnke, Michael1 aLarson, Martin, G1 aJarvelin, Marjo-Riitta1 aPsaty, Bruce, M1 aAbecasis, Goncalo, R1 aChakravarti, Aravinda1 aElliott, Paul1 aDuijn, Cornelia, M1 aNewton-Cheh, Christopher1 aLevy, Daniel1 aCaulfield, Mark, J1 aJohnson, Toby1 aCARDIoGRAM consortium1 aCKDGen Consortium1 aKidneyGen Consortium1 aEchoGen consortium1 aCHARGE-HF consortium 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2011 eng d a1546-171800aGenome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.0 aGenomewide association study identifies six new loci influencing c2011 Sep 11 a1005-110 v433 aNumerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
10aArteries10aBlood Pressure10aCase-Control Studies10aFollow-Up Studies10aGenetic Loci10aGenome-Wide Association Study10aHumans10aHypertension10aLinkage Disequilibrium10aPolymorphism, Single Nucleotide1 aWain, Louise, V1 aVerwoert, Germaine, C1 aO'Reilly, Paul, F1 aShi, Gang1 aJohnson, Toby1 aJohnson, Andrew, D1 aBochud, Murielle1 aRice, Kenneth, M1 aHenneman, Peter1 aSmith, Albert, V1 aEhret, Georg, B1 aAmin, Najaf1 aLarson, Martin, G1 aMooser, Vincent1 aHadley, David1 aDörr, Marcus1 aBis, Joshua, C1 aAspelund, Thor1 aEsko, Tõnu1 aJanssens, Cecile, J W1 aZhao, Jing Hua1 aHeath, Simon1 aLaan, Maris1 aFu, Jingyuan1 aPistis, Giorgio1 aLuan, Jian'an1 aArora, Pankaj1 aLucas, Gavin1 aPirastu, Nicola1 aPichler, Irene1 aJackson, Anne, U1 aWebster, Rebecca, J1 aZhang, Feng1 aPeden, John, F1 aSchmidt, Helena1 aTanaka, Toshiko1 aCampbell, Harry1 aIgl, Wilmar1 aMilaneschi, Yuri1 aHottenga, Jouke-Jan1 aVitart, Veronique1 aChasman, Daniel, I1 aTrompet, Stella1 aBragg-Gresham, Jennifer, L1 aAlizadeh, Behrooz, Z1 aChambers, John, C1 aGuo, Xiuqing1 aLehtimäki, Terho1 aKuhnel, Brigitte1 aLopez, Lorna, M1 aPolasek, Ozren1 aBoban, Mladen1 aNelson, Christopher, P1 aMorrison, Alanna, C1 aPihur, Vasyl1 aGanesh, Santhi, K1 aHofman, Albert1 aKundu, Suman1 aMattace-Raso, Francesco, U S1 aRivadeneira, Fernando1 aSijbrands, Eric, J G1 aUitterlinden, André, G1 aHwang, Shih-Jen1 aVasan, Ramachandran, S1 aWang, Thomas, J1 aBergmann, Sven1 aVollenweider, Peter1 aWaeber, Gérard1 aLaitinen, Jaana1 aPouta, Anneli1 aZitting, Paavo1 aMcArdle, Wendy, L1 aKroemer, Heyo, K1 aVölker, Uwe1 aVölzke, Henry1 aGlazer, Nicole, L1 aTaylor, Kent, D1 aHarris, Tamara, B1 aAlavere, Helene1 aHaller, Toomas1 aKeis, Aime1 aTammesoo, Mari-Liis1 aAulchenko, Yurii1 aBarroso, Inês1 aKhaw, Kay-Tee1 aGalan, Pilar1 aHercberg, Serge1 aLathrop, Mark1 aEyheramendy, Susana1 aOrg, Elin1 aSõber, Siim1 aLu, Xiaowen1 aNolte, Ilja, M1 aPenninx, Brenda, W1 aCorre, Tanguy1 aMasciullo, Corrado1 aSala, Cinzia1 aGroop, Leif1 aVoight, Benjamin, F1 aMelander, Olle1 aO'Donnell, Christopher, J1 aSalomaa, Veikko1 ad'Adamo, Adamo, Pio1 aFabretto, Antonella1 aFaletra, Flavio1 aUlivi, Sheila1 aDel Greco, Fabiola, M1 aFacheris, Maurizio1 aCollins, Francis, S1 aBergman, Richard, N1 aBeilby, John, P1 aHung, Joseph1 aMusk, William1 aMangino, Massimo1 aShin, So-Youn1 aSoranzo, Nicole1 aWatkins, Hugh1 aGoel, Anuj1 aHamsten, Anders1 aGider, Pierre1 aLoitfelder, Marisa1 aZeginigg, Marion1 aHernandez, Dena1 aNajjar, Samer, S1 aNavarro, Pau1 aWild, Sarah, H1 aCorsi, Anna Maria1 aSingleton, Andrew1 aGeus, Eco, J C1 aWillemsen, Gonneke1 aParker, Alex, N1 aRose, Lynda, M1 aBuckley, Brendan1 aStott, David1 aOrrù, Marco1 aUda, Manuela1 avan der Klauw, Melanie, M1 aZhang, Weihua1 aLi, Xinzhong1 aScott, James1 aChen, Yii-Der Ida1 aBurke, Gregory, L1 aKähönen, Mika1 aViikari, Jorma1 aDöring, Angela1 aMeitinger, Thomas1 aDavies, Gail1 aStarr, John, M1 aEmilsson, Valur1 aPlump, Andrew1 aLindeman, Jan, H1 aHoen, Peter, A C 't1 aKönig, Inke, R1 aFelix, Janine, F1 aClarke, Robert1 aHopewell, Jemma, C1 aOngen, Halit1 aBreteler, Monique1 aDebette, Stephanie1 aDeStefano, Anita, L1 aFornage, Myriam1 aMitchell, Gary, F1 aSmith, Nicholas, L1 aHolm, Hilma1 aStefansson, Kari1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aSamani, Nilesh, J1 aPreuss, Michael1 aRudan, Igor1 aHayward, Caroline1 aDeary, Ian, J1 aWichmann, H-Erich1 aRaitakari, Olli, T1 aPalmas, Walter1 aKooner, Jaspal, S1 aStolk, Ronald, P1 aJukema, Wouter1 aWright, Alan, F1 aBoomsma, Dorret, I1 aBandinelli, Stefania1 aGyllensten, Ulf, B1 aWilson, James, F1 aFerrucci, Luigi1 aSchmidt, Reinhold1 aFarrall, Martin1 aSpector, Tim, D1 aPalmer, Lyle, J1 aTuomilehto, Jaakko1 aPfeufer, Arne1 aGasparini, Paolo1 aSiscovick, David1 aAltshuler, David1 aLoos, Ruth, J F1 aToniolo, Daniela1 aSnieder, Harold1 aGieger, Christian1 aMeneton, Pierre1 aWareham, Nicholas, J1 aOostra, Ben, A1 aMetspalu, Andres1 aLauner, Lenore1 aRettig, Rainer1 aStrachan, David, P1 aBeckmann, Jacques, S1 aWitteman, Jacqueline, C M1 aErdmann, Jeanette1 aDijk, Ko Willems1 aBoerwinkle, Eric1 aBoehnke, Michael1 aRidker, Paul, M1 aJarvelin, Marjo-Riitta1 aChakravarti, Aravinda1 aAbecasis, Goncalo, R1 aGudnason, Vilmundur1 aNewton-Cheh, Christopher1 aLevy, Daniel1 aMunroe, Patricia, B1 aPsaty, Bruce, M1 aCaulfield, Mark, J1 aRao, Dabeeru, C1 aTobin, Martin, D1 aElliott, Paul1 aDuijn, Cornelia, M1 aLifeLines Cohort Study1 aEchoGen consortium1 aAortaGen Consortium1 aCHARGE Consortium Heart Failure Working Group1 aKidneyGen Consortium1 aCKDGen Consortium1 aCardiogenics consortium1 aCardioGram uhttps://chs-nhlbi.org/node/132408598nas a2202365 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2012 eng d a1476-468700aFTO genotype is associated with phenotypic variability of body mass index.0 aFTO genotype is associated with phenotypic variability of body m c2012 Oct 11 a267-720 v4903 aThere is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
10aAlpha-Ketoglutarate-Dependent Dioxygenase FTO10aBody Height10aBody Mass Index10aCo-Repressor Proteins10aFemale10aGenetic Variation10aGenome-Wide Association Study10aHumans10aMale10aNerve Tissue Proteins10aPhenotype10aPolymorphism, Single Nucleotide10aProteins10aRepressor Proteins1 aYang, Jian1 aLoos, Ruth, J F1 aPowell, Joseph, E1 aMedland, Sarah, E1 aSpeliotes, Elizabeth, K1 aChasman, Daniel, I1 aRose, Lynda, M1 aThorleifsson, Gudmar1 aSteinthorsdottir, Valgerdur1 aMägi, Reedik1 aWaite, Lindsay1 aSmith, Albert, Vernon1 aYerges-Armstrong, Laura, M1 aMonda, Keri, L1 aHadley, David1 aMahajan, Anubha1 aLi, Guo1 aKapur, Karen1 aVitart, Veronique1 aHuffman, Jennifer, E1 aWang, Sophie, R1 aPalmer, Cameron1 aEsko, Tõnu1 aFischer, Krista1 aZhao, Jing Hua1 aDemirkan, Ayse1 aIsaacs, Aaron1 aFeitosa, Mary, F1 aLuan, Jian'an1 aHeard-Costa, Nancy, L1 aWhite, Charles1 aJackson, Anne, U1 aPreuss, Michael1 aZiegler, Andreas1 aEriksson, Joel1 aKutalik, Zoltán1 aFrau, Francesca1 aNolte, Ilja, M1 avan Vliet-Ostaptchouk, Jana, V1 aHottenga, Jouke-Jan1 aJacobs, Kevin, B1 aVerweij, Niek1 aGoel, Anuj1 aMedina-Gómez, Carolina1 aEstrada, Karol1 aBragg-Gresham, Jennifer, Lynn1 aSanna, Serena1 aSidore, Carlo1 aTyrer, Jonathan1 aTeumer, Alexander1 aProkopenko, Inga1 aMangino, Massimo1 aLindgren, Cecilia, M1 aAssimes, Themistocles, L1 aShuldiner, Alan, R1 aHui, Jennie1 aBeilby, John, P1 aMcArdle, Wendy, L1 aHall, Per1 aHaritunians, Talin1 aZgaga, Lina1 aKolcic, Ivana1 aPolasek, Ozren1 aZemunik, Tatijana1 aOostra, Ben, A1 aJunttila, Juhani1 aGrönberg, Henrik1 aSchreiber, Stefan1 aPeters, Annette1 aHicks, Andrew, A1 aStephens, Jonathan1 aFoad, Nicola, S1 aLaitinen, Jaana1 aPouta, Anneli1 aKaakinen, Marika1 aWillemsen, Gonneke1 aVink, Jacqueline, M1 aWild, Sarah, H1 aNavis, Gerjan1 aAsselbergs, Folkert, W1 aHomuth, Georg1 aJohn, Ulrich1 aIribarren, Carlos1 aHarris, Tamara1 aLauner, Lenore1 aGudnason, Vilmundur1 aO'Connell, Jeffrey, R1 aBoerwinkle, Eric1 aCadby, Gemma1 aPalmer, Lyle, J1 aJames, Alan, L1 aMusk, Arthur, W1 aIngelsson, Erik1 aPsaty, Bruce, M1 aBeckmann, Jacques, S1 aWaeber, Gérard1 aVollenweider, Peter1 aHayward, Caroline1 aWright, Alan, F1 aRudan, Igor1 aGroop, Leif, C1 aMetspalu, Andres1 aKhaw, Kay, Tee1 aDuijn, Cornelia, M1 aBorecki, Ingrid, B1 aProvince, Michael, A1 aWareham, Nicholas, J1 aTardif, Jean-Claude1 aHuikuri, Heikki, V1 aCupples, Adrienne, L1 aAtwood, Larry, D1 aFox, Caroline, S1 aBoehnke, Michael1 aCollins, Francis, S1 aMohlke, Karen, L1 aErdmann, Jeanette1 aSchunkert, Heribert1 aHengstenberg, Christian1 aStark, Klaus1 aLorentzon, Mattias1 aOhlsson, Claes1 aCusi, Daniele1 aStaessen, Jan, A1 avan der Klauw, Melanie, M1 aPramstaller, Peter, P1 aKathiresan, Sekar1 aJolley, Jennifer, D1 aRipatti, Samuli1 aJarvelin, Marjo-Riitta1 aGeus, Eco, J C1 aBoomsma, Dorret, I1 aPenninx, Brenda1 aWilson, James, F1 aCampbell, Harry1 aChanock, Stephen, J1 aHarst, Pim1 aHamsten, Anders1 aWatkins, Hugh1 aHofman, Albert1 aWitteman, Jacqueline, C1 aZillikens, Carola, M1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aZillikens, Carola, M1 aKiemeney, Lambertus, A1 aVermeulen, Sita, H1 aAbecasis, Goncalo, R1 aSchlessinger, David1 aSchipf, Sabine1 aStumvoll, Michael1 aTönjes, Anke1 aSpector, Tim, D1 aNorth, Kari, E1 aLettre, Guillaume1 aMcCarthy, Mark, I1 aBerndt, Sonja, I1 aHeath, Andrew, C1 aMadden, Pamela, A F1 aNyholt, Dale, R1 aMontgomery, Grant, W1 aMartin, Nicholas, G1 aMcKnight, Barbara1 aStrachan, David, P1 aHill, William, G1 aSnieder, Harold1 aRidker, Paul, M1 aThorsteinsdottir, Unnur1 aStefansson, Kari1 aFrayling, Timothy, M1 aHirschhorn, Joel, N1 aGoddard, Michael, E1 aVisscher, Peter, M uhttps://chs-nhlbi.org/node/617504181nas a2201057 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2013 eng d a1460-208300aA genome-wide association study of early menopause and the combined impact of identified variants.0 agenomewide association study of early menopause and the combined c2013 Apr 01 a1465-720 v223 aEarly menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.
10aCase-Control Studies10aFemale10aGene Frequency10aGenome-Wide Association Study10aHumans10aMenopause, Premature10aPolymorphism, Single Nucleotide10aPrimary Ovarian Insufficiency10aQuantitative Trait Loci10aRisk1 aPerry, John, R B1 aCorre, Tanguy1 aEsko, Tõnu1 aChasman, Daniel, I1 aFischer, Krista1 aFranceschini, Nora1 aHe, Chunyan1 aKutalik, Zoltán1 aMangino, Massimo1 aRose, Lynda, M1 aSmith, Albert, Vernon1 aStolk, Lisette1 aSulem, Patrick1 aWeedon, Michael, N1 aZhuang, Wei, V1 aArnold, Alice1 aAshworth, Alan1 aBergmann, Sven1 aBuring, Julie, E1 aBurri, Andrea1 aChen, Constance1 aCornelis, Marilyn, C1 aCouper, David, J1 aGoodarzi, Mark, O1 aGudnason, Vilmundur1 aHarris, Tamara1 aHofman, Albert1 aJones, Michael1 aKraft, Peter1 aLauner, Lenore1 aLaven, Joop, S E1 aLi, Guo1 aMcKnight, Barbara1 aMasciullo, Corrado1 aMilani, Lili1 aOrr, Nicholas1 aPsaty, Bruce, M1 aRidker, Paul, M1 aRivadeneira, Fernando1 aSala, Cinzia1 aSalumets, Andres1 aSchoemaker, Minouk1 aTraglia, Michela1 aWaeber, Gérard1 aChanock, Stephen, J1 aDemerath, Ellen, W1 aGarcia, Melissa1 aHankinson, Susan, E1 aHu, Frank, B1 aHunter, David, J1 aLunetta, Kathryn, L1 aMetspalu, Andres1 aMontgomery, Grant, W1 aMurabito, Joanne, M1 aNewman, Anne, B1 aOng, Ken, K1 aSpector, Tim, D1 aStefansson, Kari1 aSwerdlow, Anthony, J1 aThorsteinsdottir, Unnur1 avan Dam, Rob, M1 aUitterlinden, André, G1 aVisser, Jenny, A1 aVollenweider, Peter1 aToniolo, Daniela1 aMurray, Anna1 aReproGen Consortium uhttps://chs-nhlbi.org/node/615304392nas a2200841 4500008004100000022001400041245013900055210006900194260000900263300001100272490000600283520190900289653002202198653002402220653003802244653003402282653001302316653001102329653003902340653002502379653002602404653003602430653001302466653001702479653002902496100002702525700002102552700002302573700003202596700002302628700001702651700001902668700001402687700001902701700002102720700002102741700002302762700002402785700002402809700001902833700002002852700002002872700002302892700002402915700001902939700001602958700001702974700001902991700002203010700002203032700001903054700002003073700002203093700002203115700002103137700001703158700001703175700001903192700002803211700002403239700001603263700002803279700002603307700001903333700002103352700001803373700002503391700001803416700001603434700001903450710004503469856003603514 2013 eng d a1932-620300aInsights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis.0 aInsights into the genetic architecture of early stage agerelated c2013 ae538300 v83 aGenetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10(-6)) and upstream of GLI2 (rs6721654; P = 6.5×10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.
10aApolipoproteins E10aComplement Factor H10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aKruppel-Like Transcription Factors10aMacular Degeneration10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aProteins10aRisk Factors10aZinc Finger Protein Gli31 aHolliday, Elizabeth, G1 aSmith, Albert, V1 aCornes, Belinda, K1 aBuitendijk, Gabriëlle, H S1 aJensen, Richard, A1 aSim, Xueling1 aAspelund, Thor1 aAung, Tin1 aBaird, Paul, N1 aBoerwinkle, Eric1 aCheng, Ching, Yu1 aDuijn, Cornelia, M1 aEiriksdottir, Gudny1 aGudnason, Vilmundur1 aHarris, Tamara1 aHewitt, Alex, W1 aInouye, Michael1 aJonasson, Fridbert1 aKlein, Barbara, E K1 aLauner, Lenore1 aLi, Xiaohui1 aLiew, Gerald1 aLumley, Thomas1 aMcElduff, Patrick1 aMcKnight, Barbara1 aMitchell, Paul1 aPsaty, Bruce, M1 aRochtchina, Elena1 aRotter, Jerome, I1 aScott, Rodney, J1 aTay, Wanting1 aTaylor, Kent1 aTeo, Yik, Ying1 aUitterlinden, André, G1 aViswanathan, Ananth1 aXie, Sophia1 aVingerling, Johannes, R1 aKlaver, Caroline, C W1 aTai, Shyong, E1 aSiscovick, David1 aKlein, Ronald1 aCotch, Mary, Frances1 aWong, Tien, Y1 aAttia, John1 aWang, Jie, Jin1 aWellcome Trust Case Control Consortium 2 uhttps://chs-nhlbi.org/node/587503582nas a2200829 4500008004100000022001400041245006100055210006000116260000900176300000800185490000700193520130000200653003401500653001701534653001101551653001401562653003601576653003201612100002501644700002301669700002601692700002401718700001601742700002301758700002001781700001701801700001201818700002401830700002201854700001801876700002101894700002301915700001801938700001801956700002001974700002401994700002402018700002202042700001502064700001902079700002102098700002002119700001702139700002102156700002302177700001402200700002002214700002302234700002202257700001802279700001902297700002402316700002002340700001602360700002702376700002402403700001802427700002102445700001902466700001902485700002402504700002502528700001902553700002502572700001802597700002202615700002202637700001902659700001902678700001902697856003602716 2014 eng d a1471-215600aGenetic diversity is a predictor of mortality in humans.0 aGenetic diversity is a predictor of mortality in humans c2014 a1590 v153 aBACKGROUND: It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease.
RESULTS: We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person's risk of death by 1.57%.
CONCLUSIONS: This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.
10aGenome-Wide Association Study10aHeterozygote10aHumans10aMortality10aPolymorphism, Single Nucleotide10aProportional Hazards Models1 aBihlmeyer, Nathan, A1 aBrody, Jennifer, A1 aSmith, Albert, Vernon1 aLunetta, Kathryn, L1 aNalls, Mike1 aSmith, Jennifer, A1 aTanaka, Toshiko1 aDavies, Gail1 aYu, Lei1 aMirza, Saira, Saeed1 aTeumer, Alexander1 aCoresh, Josef1 aPankow, James, S1 aFranceschini, Nora1 aScaria, Anish1 aOshima, Junko1 aPsaty, Bruce, M1 aGudnason, Vilmundur1 aEiriksdottir, Gudny1 aHarris, Tamara, B1 aLi, Hanyue1 aKarasik, David1 aKiel, Douglas, P1 aGarcia, Melissa1 aLiu, Yongmei1 aFaul, Jessica, D1 aKardia, Sharon, Lr1 aZhao, Wei1 aFerrucci, Luigi1 aAllerhand, Michael1 aLiewald, David, C1 aRedmond, Paul1 aStarr, John, M1 aDe Jager, Philip, L1 aEvans, Denis, A1 aDirek, Nese1 aIkram, Mohammed, Arfan1 aUitterlinden, Andre1 aHomuth, Georg1 aLorbeer, Roberto1 aGrabe, Hans, J1 aLauner, Lenore1 aMurabito, Joanne, M1 aSingleton, Andrew, B1 aWeir, David, R1 aBandinelli, Stefania1 aDeary, Ian, J1 aBennett, David, A1 aTiemeier, Henning1 aKocher, Thomas1 aLumley, Thomas1 aArking, Dan, E uhttps://chs-nhlbi.org/node/669003799nas a2200637 4500008004100000022001400041245010600055210006900161260001300230300001000243490000700253520205800260653000902318653002202327653001202349653001002361653001402371653001302385653001102398653003402409653001102443653002602454653000902480653003602489653000902525653002102534653001702555653001702572653003502589653001702624100002002641700001602661700002102677700002902698700002702727700002002754700001702774700001702791700002002808700001802828700001902846700002102865700001602886700002002902700002002922700002302942700001902965700001902984700002203003700002003025700002303045700001603068700001803084700002303102856003603125 2015 eng d a1524-462800aGenes from a translational analysis support a multifactorial nature of white matter hyperintensities.0 aGenes from a translational analysis support a multifactorial nat c2015 Feb a341-70 v463 aBACKGROUND AND PURPOSE: White matter hyperintensities (WMH) of presumed vascular origin increase the risk of stroke and dementia. Despite strong WMH heritability, few gene associations have been identified. Relevant experimental models may be informative.
METHODS: We tested the associations between genes that were differentially expressed in brains of young spontaneously hypertensive stroke-prone rats and human WMH (using volume and visual score) in 621 subjects from the Lothian Birth Cohort 1936 (LBC1936). We then attempted replication in 9361 subjects from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE). We also tested the subjects from LBC1936 for previous genome-wide WMH associations found in subjects from CHARGE.
RESULTS: Of 126 spontaneously hypertensive stroke-prone rat genes, 10 were nominally associated with WMH volume or score in subjects from LBC1936, of which 5 (AFP, ALB, GNAI1, RBM8a, and MRPL18) were associated with both WMH volume and score (P<0.05); 2 of the 10 (XPNPEP1, P=6.7×10(-5); FARP1, P=0.024) plus another spontaneously hypertensive stroke-prone rat gene (USMG5, P=0.00014), on chromosomes 10, 13, and 10 respectively, were associated with WMH in subjects from CHARGE. Gene set enrichment showed significant associations for downregulated spontaneously hypertensive stroke-prone rat genes with WMH in humans. In subjects from LBC1936, we replicated CHARGE's genome-wide WMH associations on chromosomes 17 (TRIM65 and TRIM47) and, for the first time, 1 (PMF1).
CONCLUSIONS: Despite not passing multiple testing thresholds individually, these genes collectively are relevant to known WMH associations, proposed WMH mechanisms, or dementia: associations with Alzheimer's disease, late-life depression, ATP production, osmotic regulation, neurodevelopmental abnormalities, and cognitive impairment. If replicated further, they suggest a multifactorial nature for WMH and argue for more consideration of vascular contributions to dementia.
10aAged10aAlzheimer Disease10aAnimals10aBrain10aCausality10aDementia10aFemale10aGenome-Wide Association Study10aHumans10aLeukoencephalopathies10aMale10aPolymorphism, Single Nucleotide10aRats10aRats, Inbred SHR10aRats, Wistar10aRisk Factors10aTranslational Medical Research10aWhite Matter1 aLopez, Lorna, M1 aHill, David1 aHarris, Sarah, E1 aHernandez, Maria, Valdes1 aManiega, Susana, Munoz1 aBastin, Mark, E1 aBailey, Emma1 aSmith, Colin1 aMcBride, Martin1 aMcClure, John1 aGraham, Delyth1 aDominiczak, Anna1 aYang, Qiong1 aFornage, Myriam1 aIkram, Arfan, M1 aDebette, Stephanie1 aLauner, Lenore1 aBis, Joshua, C1 aSchmidt, Reinhold1 aSeshadri, Sudha1 aPorteous, David, J1 aStarr, John1 aDeary, Ian, J1 aWardlaw, Joanna, M uhttps://chs-nhlbi.org/node/681807065nas a2201873 4500008004100000022001400041245015900055210006900214260001600283300001100299490000700310520180500317653000902122653002202131653001002153653002202163653001402185653001902199653001102218653003402229653001302263653001102276653000902287653002102296653001602317653003602333653001302369653001802382653002402400653002202424653002002446100002302466700003002489700001802519700001902537700001802556700001902574700001702593700002102610700002402631700002102655700001602676700002402692700003202716700002302748700001602771700001902787700002302806700001702829700001202846700002202858700002202880700002102902700002002923700002002943700002002963700002002983700001503003700001703018700001803035700001903053700002103072700002203093700001203115700001903127700001903146700002703165700001703192700002003209700002503229700001403254700001903268700001603287700001903303700002303322700002403345700001603369700001803385700002003403700001403423700002203437700001903459700002503478700002603503700002203529700002403551700001603575700001603591700001903607700002703626700002103653700002203674700002003696700001303716700002103729700002403750700002203774700001503796700002403811700002203835700002003857700001703877700001903894700001903913700002003932700001403952700002103966700002503987700002404012700002304036700002204059700002104081700001904102700001904121700002304140700002204163700002504185700002304210700001804233700001904251700002404270700002304294700002304317700002004340700001604360700002804376700002204404700003004426700002104456700002304477700002004500700002004520700001904540700002004559700002004579700002104599700002304620700002604643700002204669700002704691700002204718700002004740700001704760700002304777700002404800700002804824700002404852700003104876700002204907700002004929700001804949700002304967700001904990700002805009700002005037700002205057710007605079856003605155 2015 eng d a1873-240200aGenome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.0 aGenomewide studies of verbal declarative memory in nondemented o c2015 Apr 15 a749-630 v773 aBACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.
METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.
RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.
CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.
10aAged10aAged, 80 and over10aAging10aApolipoproteins E10aClaudin-510aCohort Studies10aFemale10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMemory Disorders10aMiddle Aged10aPolymorphism, Single Nucleotide10aProteins10aProteoglycans10aRegression Analysis10aSulfotransferases10aVerbal Learning1 aDebette, Stephanie1 aVerbaas, Carla, A Ibrahim1 aBressler, Jan1 aSchuur, Maaike1 aSmith, Albert1 aBis, Joshua, C1 aDavies, Gail1 aWolf, Christiane1 aGudnason, Vilmundur1 aChibnik, Lori, B1 aYang, Qiong1 aDeStefano, Anita, L1 ade Quervain, Dominique, J F1 aSrikanth, Velandai1 aLahti, Jari1 aGrabe, Hans, J1 aSmith, Jennifer, A1 aPriebe, Lutz1 aYu, Lei1 aKarbalai, Nazanin1 aHayward, Caroline1 aWilson, James, F1 aCampbell, Harry1 aPetrovic, Katja1 aFornage, Myriam1 aChauhan, Ganesh1 aYeo, Robin1 aBoxall, Ruth1 aBecker, James1 aStegle, Oliver1 aMather, Karen, A1 aChouraki, Vincent1 aSun, Qi1 aRose, Lynda, M1 aResnick, Susan1 aOldmeadow, Christopher1 aKirin, Mirna1 aWright, Alan, F1 aJonsdottir, Maria, K1 aAu, Rhoda1 aBecker, Albert1 aAmin, Najaf1 aNalls, Mike, A1 aTurner, Stephen, T1 aKardia, Sharon, L R1 aOostra, Ben1 aWindham, Gwen1 aCoker, Laura, H1 aZhao, Wei1 aKnopman, David, S1 aHeiss, Gerardo1 aGriswold, Michael, E1 aGottesman, Rebecca, F1 aVitart, Veronique1 aHastie, Nicholas, D1 aZgaga, Lina1 aRudan, Igor1 aPolasek, Ozren1 aHolliday, Elizabeth, G1 aSchofield, Peter1 aChoi, Seung, Hoan1 aTanaka, Toshiko1 aAn, Yang1 aPerry, Rodney, T1 aKennedy, Richard, E1 aSale, Michèle, M1 aWang, Jing1 aWadley, Virginia, G1 aLiewald, David, C1 aRidker, Paul, M1 aGow, Alan, J1 aPattie, Alison1 aStarr, John, M1 aPorteous, David1 aLiu, Xuan1 aThomson, Russell1 aArmstrong, Nicola, J1 aEiriksdottir, Gudny1 aAssareh, Arezoo, A1 aKochan, Nicole, A1 aWiden, Elisabeth1 aPalotie, Aarno1 aHsieh, Yi-Chen1 aEriksson, Johan, G1 aVogler, Christian1 avan Swieten, John, C1 aShulman, Joshua, M1 aBeiser, Alexa1 aRotter, Jerome1 aSchmidt, Carsten, O1 aHoffmann, Wolfgang1 aNöthen, Markus, M1 aFerrucci, Luigi1 aAttia, John1 aUitterlinden, André, G1 aAmouyel, Philippe1 aDartigues, Jean-François1 aAmieva, Hélène1 aRäikkönen, Katri1 aGarcia, Melissa1 aWolf, Philip, A1 aHofman, Albert1 aLongstreth, W T1 aPsaty, Bruce, M1 aBoerwinkle, Eric1 aDeJager, Philip, L1 aSachdev, Perminder, S1 aSchmidt, Reinhold1 aBreteler, Monique, M B1 aTeumer, Alexander1 aLopez, Oscar, L1 aCichon, Sven1 aChasman, Daniel, I1 aGrodstein, Francine1 aMüller-Myhsok, Bertram1 aTzourio, Christophe1 aPapassotiropoulos, Andreas1 aBennett, David, A1 aIkram, Arfan, M1 aDeary, Ian, J1 aDuijn, Cornelia, M1 aLauner, Lenore1 aFitzpatrick, Annette, L1 aSeshadri, Sudha1 aMosley, Thomas, H1 aCohorts for Heart and Aging Research in Genomic Epidemiology Consortium uhttps://chs-nhlbi.org/node/668403238nas a2200433 4500008004100000022001400041245012200055210006900177260001600246520194400262100001802206700002202224700002502246700001902271700001902290700001702309700002102326700002202347700002002369700002002389700002002409700002402429700002202453700002502475700001902500700002302519700002502542700002202567700001602589700002402605700001802629700002302647700002002670700002302690700001602713700002302729700001602752856003602768 2017 eng d a1534-779600aBivariate Genome-Wide Association Study of Depressive Symptoms with Type 2 Diabetes and Quantitative Glycemic Traits.0 aBivariate GenomeWide Association Study of Depressive Symptoms wi c2017 Dec 273 aOBJECTIVE: Shared genetic background may explain phenotypic associations between depression and Type-2-Diabetes (T2D). We aimed to study, on a genome-wide level, if genetic correlation and pleiotropic loci exist between depressive symptoms and T2D or glycemic traits.
METHODS: We estimated SNP-based heritability and analyzed genetic correlation between depressive symptoms and T2D and glycemic traits with the LD Score Regression (LDSC) by combining summary statistics of previously conducted meta-analyses for depressive symptoms by CHARGE consortium (N = 51,258), T2D by Diagram consortium (N = 34,840 patients and 114,981 controls), fasting glucose, fasting insulin, HOMA-β, and HOMA-IR by MAGIC consortium (N = 58,074). Finally, we investigated pleiotropic loci using a bivariate GWAS approach with summary statistics from GWAS meta-analyses and reported loci with genome-wide significant bivariate association p-value (p < 5x10). Biological annotation and function of significant pleiotropic SNPs were assessed in several databases.
RESULTS: The SNP-based heritability ranged from 0.04 to 0.10 in each individual trait. In the LDSC analyses, depressive symptoms showed no significant genetic correlation with T2D or glycemic traits (p > 0.37). Yet, we identified pleiotropic genetic variations for depressive symptoms and T2D (in the IGF2BP2, CDKAL1, CDKN2B-AS, and PLEKHA1 genes), and fasting glucose (in the MADD, CDKN2B-AS, PEX16, and MTNR1B genes).
CONCLUSIONS: We found no significant overall genetic correlations between depressive symptoms, T2D or glycemic traits suggesting major differences in underlying biology of these traits. Yet, several potential pleiotropic loci were identified between depressive symptoms, T2D and fasting glucose suggesting that previously established phenotypic associations may be partly explained by genetic variation in these specific loci.
1 aHaljas, Kadri1 aAmare, Azmeraw, T1 aAlizadeh, Behrooz, Z1 aHsu, Yi-Hsiang1 aMosley, Thomas1 aNewman, Anne1 aMurabito, Joanne1 aTiemeier, Henning1 aTanaka, Toshiko1 aDuijn, Cornelia1 aDing, Jingzhong1 aLlewellyn, David, J1 aBennett, David, A1 aTerracciano, Antonio1 aLauner, Lenore1 aLadwig, Karl-Heinz1 aCornelis, Marylin, C1 aTeumer, Alexander1 aGrabe, Hans1 aKardia, Sharon, L R1 aWare, Erin, B1 aSmith, Jennifer, A1 aSnieder, Harold1 aEriksson, Johan, G1 aGroop, Leif1 aRäikkönen, Katri1 aLahti, Jari uhttps://chs-nhlbi.org/node/756503062nas 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/755408823nas a2202773 4500008004100000022001400041245011300055210006900168260001600237300000900253490000600262520111900268100001701387700001301404700002101417700002201438700002201460700001601482700002501498700002301523700002501546700002501571700002401596700002101620700002301641700002601664700001801690700001901708700002601727700002501753700002001778700002101798700002101819700002301840700002301863700002501886700002201911700001701933700002001950700002101970700001801991700001602009700001802025700001302043700002102056700001802077700001802095700002702113700002202140700001902162700001702181700002002198700002502218700003302243700001902276700002302295700002102318700002302339700002602362700002002388700002502408700001802433700001802451700002402469700001802493700001202511700001602523700001602539700002202555700002302577700002502600700002302625700001902648700001902667700002802686700002202714700002102736700002302757700001902780700002002799700002202819700002602841700001902867700002702886700001802913700001802931700002002949700001902969700001902988700002203007700002303029700002503052700002103077700001403098700002303112700001203135700001803147700002503165700002103190700002603211700002503237700002403262700002203286700002503308700002303333700001903356700002703375700002003402700002003422700002403442700001803466700002103484700002203505700002203527700001903549700001803568700002603586700001603612700002203628700001703650700001403667700001803681700001903699700002403718700002003742700001703762700001703779700002503796700002203821700002803843700002403871700002503895700002203920700001803942700002103960700001703981700002003998700002104018700001904039700001904058700002504077700002004102700002304122700002904145700002104174700002204195700001904217700001904236700001804255700001804273700002604291700002604317700002104343700002104364700002204385700002204407700002004429700002204449700002104471700002304492700002004515700002304535700001904558700002104577700002004598700002104618700002404639700002404663700002204687700002804709700001904737700002004756700001904776700002104795700001504816700002104831700001604852700001404868700002204882700001904904700002204923700001904945700002104964700002304985700001805008700002405026700002305050700001805073700001805091700002805109700001805137700002005155700001605175700002405191700002105215700001805236700001905254700002005273700002305293700002305316700001905339700002405358700001905382700002305401700002005424700002305444700002305467700002305490700002105513700001905534700001605553700002205569700002005591700002405611700002405635700001905659700002005678700002305698700002205721700002305743700002105766700002605787700001905813700002105832700001905853700002405872700002305896700002005919700002205939700001805961700001605979700001805995856003606013 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.
1 aDavies, Gail1 aLam, Max1 aHarris, Sarah, E1 aTrampush, Joey, W1 aLuciano, Michelle1 aHill, David1 aHagenaars, Saskia, P1 aRitchie, Stuart, J1 aMarioni, Riccardo, E1 aFawns-Ritchie, Chloe1 aLiewald, David, C M1 aOkely, Judith, A1 aAhola-Olli, Ari, V1 aBarnes, Catriona, L K1 aBertram, Lars1 aBis, Joshua, C1 aBurdick, Katherine, E1 aChristoforou, Andrea1 aDeRosse, Pamela1 aDjurovic, Srdjan1 aEspeseth, Thomas1 aGiakoumaki, Stella1 aGiddaluru, Sudheer1 aGustavson, Daniel, E1 aHayward, Caroline1 aHofer, Edith1 aIkram, Arfan, M1 aKarlsson, Robert1 aKnowles, Emma1 aLahti, Jari1 aLeber, Markus1 aLi, Shuo1 aMather, Karen, A1 aMelle, Ingrid1 aMorris, Derek1 aOldmeadow, Christopher1 aPalviainen, Teemu1 aPayton, Antony1 aPazoki, Raha1 aPetrovic, Katja1 aReynolds, Chandra, A1 aSargurupremraj, Muralidharan1 aScholz, Markus1 aSmith, Jennifer, A1 aSmith, Albert, V1 aTerzikhan, Natalie1 aThalamuthu, Anbupalam1 aTrompet, Stella1 avan der Lee, Sven, J1 aWare, Erin, B1 aWindham, Gwen1 aWright, Margaret, J1 aYang, Jingyun1 aYu, Jin1 aAmes, David1 aAmin, Najaf1 aAmouyel, Philippe1 aAndreassen, Ole, A1 aArmstrong, Nicola, J1 aAssareh, Amelia, A1 aAttia, John, R1 aAttix, Deborah1 aAvramopoulos, Dimitrios1 aBennett, David, A1 aBöhmer, Anne, C1 aBoyle, Patricia, A1 aBrodaty, Henry1 aCampbell, Harry1 aCannon, Tyrone, D1 aCirulli, Elizabeth, T1 aCongdon, Eliza1 aConley, Emily, Drabant1 aCorley, Janie1 aCox, Simon, R1 aDale, Anders, M1 aDehghan, Abbas1 aDick, Danielle1 aDickinson, Dwight1 aEriksson, Johan, G1 aEvangelou, Evangelos1 aFaul, Jessica, D1 aFord, Ian1 aFreimer, Nelson, A1 aGao, He1 aGiegling, Ina1 aGillespie, Nathan, A1 aGordon, Scott, D1 aGottesman, Rebecca, F1 aGriswold, Michael, E1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHartmann, Annette, M1 aHatzimanolis, Alex1 aHeiss, Gerardo1 aHolliday, Elizabeth, G1 aJoshi, Peter, K1 aKähönen, Mika1 aKardia, Sharon, L R1 aKarlsson, Ida1 aKleineidam, Luca1 aKnopman, David, S1 aKochan, Nicole, A1 aKonte, Bettina1 aKwok, John, B1 aLe Hellard, Stephanie1 aLee, Teresa1 aLehtimäki, Terho1 aLi, Shu-Chen1 aLiu, Tian1 aKoini, Marisa1 aLondon, Edythe1 aLongstreth, Will, T1 aLopez, Oscar, L1 aLoukola, Anu1 aLuck, Tobias1 aLundervold, Astri, J1 aLundquist, Anders1 aLyytikäinen, Leo-Pekka1 aMartin, Nicholas, G1 aMontgomery, Grant, W1 aMurray, Alison, D1 aNeed, Anna, C1 aNoordam, Raymond1 aNyberg, Lars1 aOllier, William1 aPapenberg, Goran1 aPattie, Alison1 aPolasek, Ozren1 aPoldrack, Russell, A1 aPsaty, Bruce, M1 aReppermund, Simone1 aRiedel-Heller, Steffi, G1 aRose, Richard, J1 aRotter, Jerome, I1 aRoussos, Panos1 aRovio, Suvi, P1 aSaba, Yasaman1 aSabb, Fred, W1 aSachdev, Perminder, S1 aSatizabal, Claudia, L1 aSchmid, Matthias1 aScott, Rodney, J1 aScult, Matthew, A1 aSimino, Jeannette1 aSlagboom, Eline1 aSmyrnis, Nikolaos1 aSoumaré, Aïcha1 aStefanis, Nikos, C1 aStott, David, J1 aStraub, Richard, E1 aSundet, Kjetil1 aTaylor, Adele, M1 aTaylor, Kent, D1 aTzoulaki, Ioanna1 aTzourio, Christophe1 aUitterlinden, Andre1 aVitart, 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/778813215nas a2204525 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2020 eng d a0036-807500aThe genetic architecture of the human cerebral cortex0 agenetic architecture of the human cerebral cortex cAug-03-2021 aeaay66900 v3671 aGrasby, Katrina, L.1 aJahanshad, Neda1 aPainter, Jodie, N.1 aColodro-Conde, Lucía1 aBralten, Janita1 aHibar, Derrek, P.1 aLind, Penelope, A.1 aPizzagalli, Fabrizio1 aChing, Christopher, R. K.1 aMcMahon, Mary, Agnes B.1 aShatokhina, Natalia1 aZsembik, Leo, C. P.1 aThomopoulos, Sophia, I.1 aZhu, Alyssa, H.1 aStrike, Lachlan, T.1 aAgartz, Ingrid1 aAlhusaini, Saud1 aAlmeida, Marcio, A. A.1 aAlnæs, Dag1 aAmlien, Inge, K.1 aAndersson, Micael1 aArd, Tyler1 aArmstrong, Nicola, J.1 aAshley-Koch, Allison1 aAtkins, Joshua, R.1 aBernard, Manon1 aBrouwer, Rachel, M.1 aBuimer, Elizabeth, E. L.1 aBülow, Robin1 aBürger, Christian1 aCannon, Dara, M.1 aChakravarty, Mallar1 aChen, Qiang1 aCheung, Joshua, W.1 aCouvy-Duchesne, Baptiste1 aDale, Anders, M.1 aDalvie, Shareefa1 ade Araujo, Tânia, K.1 ade Zubicaray, Greig, I.1 ade Zwarte, Sonja, M. C.1 aBraber, Anouk, den1 aDoan, Nhat, Trung1 aDohm, Katharina1 aEhrlich, Stefan1 aEngelbrecht, Hannah-Ruth1 aErk, Susanne1 aFan, Chun, Chieh1 aFedko, Iryna, O.1 aFoley, Sonya, F.1 aFord, Judith, M.1 aFukunaga, Masaki1 aGarrett, Melanie, E.1 aGe, Tian1 aGiddaluru, Sudheer1 aGoldman, Aaron, L.1 aGreen, Melissa, J.1 aGroenewold, Nynke, A.1 aGrotegerd, Dominik1 aGurholt, Tiril, P.1 aGutman, Boris, A.1 aHansell, Narelle, K.1 aHarris, Mathew, A.1 aHarrison, Marc, B.1 aHaswell, Courtney, C.1 aHauser, Michael1 aHerms, Stefan1 aHeslenfeld, Dirk, J.1 aHo, New, Fei1 aHoehn, David1 aHoffmann, Per1 aHolleran, Laurena1 aHoogman, Martine1 aHottenga, Jouke-Jan1 aIkeda, Masashi1 aJanowitz, Deborah1 aJansen, Iris, E.1 aJia, Tianye1 aJockwitz, Christiane1 aKanai, Ryota1 aKarama, Sherif1 aKasperaviciute, Dalia1 aKaufmann, Tobias1 aKelly, Sinead1 aKikuchi, Masataka1 aKlein, Marieke1 aKnapp, Michael1 aKnodt, Annchen, R.1 aKrämer, Bernd1 aLam, Max1 aLancaster, Thomas, M.1 aLee, Phil, H.1 aLett, Tristram, A.1 aLewis, Lindsay, B.1 aLopes-Cendes, Iscia1 aLuciano, Michelle1 aMacciardi, Fabio1 aMarquand, Andre, F.1 aMathias, Samuel, R.1 aMelzer, Tracy, R.1 aMilaneschi, Yuri1 aMirza-Schreiber, Nazanin1 aMoreira, Jose, C. V.1 aMühleisen, Thomas, W.1 aMüller-Myhsok, Bertram1 aNajt, Pablo1 aNakahara, Soichiro1 aNho, Kwangsik1 aLoohuis, Loes, M. Olde1 aOrfanos, Dimitri, Papadopoul1 aPearson, John, F.1 aPitcher, Toni, L.1 aPütz, Benno1 aQuidé, Yann1 aRagothaman, Anjanibhargavi1 aRashid, Faisal, M.1 aReay, William, R.1 aRedlich, Ronny1 aReinbold, Céline, S.1 aRepple, Jonathan1 aRichard, Geneviève1 aRiedel, Brandalyn, C.1 aRisacher, Shannon, L.1 aRocha, Cristiane, S.1 aMota, Nina, Roth1 aSalminen, Lauren1 aSaremi, Arvin1 aSaykin, Andrew, J.1 aSchlag, Fenja1 aSchmaal, Lianne1 aSchofield, Peter, R.1 aSecolin, Rodrigo1 aShapland, Chin, Yang1 aShen, Li1 aShin, Jean1 aShumskaya, Elena1 aSønderby, Ida, E.1 aSprooten, Emma1 aTansey, Katherine, E.1 aTeumer, Alexander1 aThalamuthu, Anbupalam1 aTordesillas-Gutierrez, Diana1 aTurner, Jessica, A.1 aUhlmann, Anne1 aVallerga, Costanza, Ludovica1 avan der Meer, Dennis1 avan Donkelaar, Marjolein, M. J.1 avan Eijk, Liza1 avan Erp, Theo, G. M.1 avan Haren, Neeltje, E. M.1 avan Rooij, Daan1 avan Tol, Marie-Jose1 aVeldink, Jan, H.1 aVerhoef, Ellen1 aWalton, Esther1 aWang, Mingyuan1 aWang, Yunpeng1 aWardlaw, Joanna, M.1 aWen, Wei1 aWestlye, Lars, T.1 aWhelan, Christopher, D.1 aWitt, Stephanie, H.1 aWittfeld, Katharina1 aWolf, Christiane1 aWolfers, Thomas1 aWu, Jing, Qin1 aYasuda, Clarissa, L.1 aZaremba, Dario1 aZhang, Zuo1 aZwiers, Marcel, P.1 aArtiges, Eric1 aAssareh, Amelia, A.1 aAyesa-Arriola, Rosa1 aBelger, Aysenil1 aBrandt, Christine, L.1 aBrown, Gregory, G.1 aCichon, Sven1 aCurran, Joanne, E.1 aDavies, Gareth, E.1 aDegenhardt, Franziska1 aDennis, Michelle, F.1 aDietsche, Bruno1 aDjurovic, Srdjan1 aDoherty, Colin, P.1 aEspiritu, Ryan1 aGarijo, Daniel1 aGil, Yolanda1 aGowland, Penny, A.1 aGreen, Robert, C.1 aHäusler, Alexander, N.1 aHeindel, Walter1 aHo, Beng-Choon1 aHoffmann, Wolfgang, U.1 aHolsboer, Florian1 aHomuth, Georg1 aHosten, Norbert1 aJack, Clifford, R.1 aJang, MiHyun1 aJansen, Andreas1 aKimbrel, Nathan, A.1 aKolskår, Knut1 aKoops, Sanne1 aKrug, Axel1 aLim, Kelvin, O.1 aLuykx, Jurjen, J.1 aMathalon, Daniel, H.1 aMather, Karen, A.1 aMattay, Venkata, S.1 aMatthews, Sarah1 aVan Son, Jaqueline, Mayoral1 aMcEwen, Sarah, C.1 aMelle, Ingrid1 aMorris, Derek, W.1 aMueller, Bryon, A.1 aNauck, Matthias1 aNordvik, Jan, E.1 aNöthen, Markus, M.1 aO’Leary, Daniel, S.1 aOpel, Nils1 aMartinot, Marie-Laure, Paillère1 aPike, Bruce1 aPreda, Adrian1 aQuinlan, Erin, B.1 aRasser, Paul, E.1 aRatnakar, Varun1 aReppermund, Simone1 aSteen, Vidar, M.1 aTooney, Paul, A.1 aTorres, Fábio, R.1 aVeltman, Dick, J.1 aVoyvodic, James, T.1 aWhelan, Robert1 aWhite, Tonya1 aYamamori, Hidenaga1 aAdams, Hieab, H. H.1 aBis, Joshua, C.1 aDebette, Stephanie1 aDeCarli, Charles1 aFornage, Myriam1 aGudnason, Vilmundur1 aHofer, Edith1 aIkram, Arfan1 aLauner, Lenore1 aLongstreth, W., T.1 aLopez, Oscar, L.1 aMazoyer, Bernard1 aMosley, Thomas, H.1 aRoshchupkin, Gennady, V.1 aSatizabal, Claudia, L.1 aSchmidt, Reinhold1 aSeshadri, Sudha1 aYang, Qiong1 aAlvim, Marina, K. M.1 aAmes, David1 aAnderson, Tim, J.1 aAndreassen, Ole, A.1 aArias-Vasquez, Alejandro1 aBastin, Mark, E.1 aBaune, Bernhard, T.1 aBeckham, Jean, C.1 aBlangero, John1 aBoomsma, Dorret, I.1 aBrodaty, Henry1 aBrunner, Han, G.1 aBuckner, Randy, L.1 aBuitelaar, Jan, K.1 aBustillo, Juan, R.1 aCahn, Wiepke1 aCairns, Murray, J.1 aCalhoun, Vince1 aCarr, Vaughan, J.1 aCaseras, Xavier1 aCaspers, Svenja1 aCavalleri, Gianpiero, L.1 aCendes, Fernando1 aCorvin, Aiden1 aCrespo-Facorro, Benedicto1 aDalrymple-Alford, John, C.1 aDannlowski, Udo1 ade Geus, Eco, J. C.1 aDeary, Ian, J.1 aDelanty, Norman1 aDepondt, Chantal1 aDesrivières, Sylvane1 aDonohoe, Gary1 aEspeseth, Thomas1 aFernández, Guillén1 aFisher, Simon, E.1 aFlor, Herta1 aForstner, Andreas, J.1 aFrancks, Clyde1 aFranke, Barbara1 aGlahn, David, C.1 aGollub, Randy, L.1 aGrabe, Hans, J.1 aGruber, Oliver1 aHåberg, Asta, K.1 aHariri, Ahmad, R.1 aHartman, Catharina, A.1 aHashimoto, Ryota1 aHeinz, Andreas1 aHenskens, Frans, A.1 aHillegers, Manon, H. J.1 aHoekstra, Pieter, J.1 aHolmes, Avram, J.1 aHong, Elliot1 aHopkins, William, D.1 aPol, Hilleke, E. Hulshof1 aJernigan, Terry, L.1 aJönsson, Erik, G.1 aKahn, René, S.1 aKennedy, Martin, A.1 aKircher, Tilo, T. J.1 aKochunov, Peter1 aKwok, John, B. J.1 aLe Hellard, Stephanie1 aLoughland, Carmel, M.1 aMartin, Nicholas, G.1 aMartinot, Jean-Luc1 aMcDonald, Colm1 aMcMahon, Katie, L.1 aMeyer-Lindenberg, Andreas1 aMichie, Patricia, T.1 aMorey, Rajendra, A.1 aMowry, Bryan1 aNyberg, Lars1 aOosterlaan, Jaap1 aOphoff, Roel, A.1 aPantelis, Christos1 aPaus, Tomáš1 aPausova, Zdenka1 aPenninx, Brenda, W. J. H.1 aPolderman, Tinca, J. C.1 aPosthuma, Danielle1 aRietschel, Marcella1 aRoffman, Joshua, L.1 aRowland, Laura, M.1 aSachdev, Perminder, S.1 aSämann, Philipp, G.1 aSchall, Ulrich1 aSchumann, Gunter1 aScott, Rodney, J.1 aSim, Kang1 aSisodiya, Sanjay, M.1 aSmoller, Jordan, W.1 aSommer, Iris, E.1 aSt Pourcain, Beate1 aStein, Dan, J.1 aToga, Arthur, W.1 aTrollor, Julian, N.1 aVan der Wee, Nic, J. A.1 aEnt, Dennis, van ’t1 aVölzke, Henry1 aWalter, Henrik1 aWeber, Bernd1 aWeinberger, Daniel, R.1 aWright, Margaret, J.1 aZhou, Juan1 aStein, Jason, L.1 aThompson, Paul, M.1 aMedland, Sarah, E.1 aAlzheimer’s Disease Neuroimaging Initiative¶1 aCHARGE Consortium¶1 aEPIGEN Consortium¶1 aIMAGEN Consortium¶1 aSYS Consortium¶1 aParkinson’s Progression Markers Initiative¶1 aEnhancing NeuroImaging Genetics through Meta-Analysis Consortium (ENIGMA)—Genetics working group uhttps://www.sciencemag.org/lookup/doi/10.1126/science.aay6690https://syndication.highwire.org/content/doi/10.1126/science.aay6690https://syndication.highwire.org/content/doi/10.1126/science.aay669015436nas 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 aEADB1 aGR@ACE1 aDEGESCO1 aEADI1 aGERAD1 aDemgene1 aFinnGen1 aADGC1 aCHARGE uhttps://chs-nhlbi.org/node/903504492nas 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/932303409nas a2200433 4500008004100000022001400041245010900055210006900164260001600233490000700249520207000256653002402326653001502350653005502365653001102420653003102431653005002462653002202512653001402534653002402548653001502572653001702587100002702604700002902631700002202660700002302682700002302705700001902728700002002747700002102767700002102788700001902809700002002828700002002848700001902868700002402887700002802911856003602939 2023 eng d a1532-209200aA proteomic analysis of atrial fibrillation in a prospective longitudinal cohort (AGES-Reykjavik study).0 aproteomic analysis of atrial fibrillation in a prospective longi c2023 Nov 020 v253 aAIMS: Atrial fibrillation (AF) is associated with high risk of comorbidities and mortality. Our aim was to examine causal and predictive relationships between 4137 serum proteins and incident AF in the prospective population-based Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik) study.
METHODS AND RESULTS: The study included 4765 participants, of whom 1172 developed AF. Cox proportional hazards regression models were fitted for 4137 baseline protein measurements adjusting for known risk factors. Protein associations were tested for replication in the Cardiovascular Health Study (CHS). Causal relationships were examined in a bidirectional, two-sample Mendelian randomization analysis. The time-dependent area under the receiver operating characteristic curve (AUC)-statistic was examined as protein levels and an AF-polygenic risk score (PRS) were added to clinical risk models. The proteomic signature of incident AF consisted of 76 proteins, of which 63 (83%) were novel and 29 (38%) were replicated in CHS. The signature included both N-terminal prohormone of brain natriuretic peptide (NT-proBNP)-dependent (e.g. CHST15, ATP1B1, and SVEP1) and independent components (e.g. ASPN, AKR1B, and LAMA1/LAMB1/LAMC1). Nine causal candidates were identified (TAGLN, WARS, CHST15, CHMP3, COL15A1, DUSP13, MANBA, QSOX2, and SRL). The reverse causal analysis suggested that most AF-associated proteins were affected by the genetic liability to AF. N-terminal prohormone of brain natriuretic peptide improved the prediction of incident AF events close to baseline with further improvements gained by the AF-PRS at all time points.
CONCLUSION: The AF proteomic signature includes biologically relevant proteins, some of which may be causal. It mainly reflects an NT-proBNP-dependent consequence of the genetic liability to AF. N-terminal prohormone of brain natriuretic peptide is a promising marker for incident AF in the short term, but risk assessment incorporating a PRS may improve long-term risk assessment.
10aAtrial Fibrillation10aBiomarkers10aEndosomal Sorting Complexes Required for Transport10aHumans10aNatriuretic Peptide, Brain10aOxidoreductases Acting on Sulfur Group Donors10aPeptide Fragments10aPrognosis10aProspective Studies10aProteomics10aRisk Factors1 aJonmundsson, Thorarinn1 aSteindorsdottir, Anna, E1 aAustin, Thomas, R1 aFrick, Elisabet, A1 aAxelsson, Gisli, T1 aLauner, Lenore1 aPsaty, Bruce, M1 aLoureiro, Joseph1 aOrth, Anthony, P1 aAspelund, Thor1 aEmilsson, Valur1 aFloyd, James, S1 aJennings, Lori1 aGudnason, Vilmundur1 aGudmundsdottir, Valborg uhttps://chs-nhlbi.org/node/953904874nas 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