05055nas a2201153 4500008004100000022001400041245009900055210006900154260001300223300001100236490000700247520175600254653000902010653002202019653002002041653003202061653002402093653001902117653004002136653001102176653001902187653003802206653003402244653001302278653001102291653002602302653003102328653000902359653001602368653002302384653002902407653003602436653003002472653001902502100002002521700002302541700001902564700002002583700002002603700002002623700002502643700001902668700002402687700001902711700002202730700002102752700002202773700002002795700002102815700002102836700002002857700001802877700002102895700001902916700002302935700002402958700002202982700001803004700002203022700002603044700002103070700002203091700002003113700002003133700001403153700002603167700001903193700002603212700002003238700002303258700002103281700002403302700002803326700001603354700002303370700001903393700002003412700001803432700002003450700002203470700002203492700002103514700002303535700002203558700002003580700002403600700002203624700002103646700002003667700002003687700002403707700002703731700002203758700002203780700002003802700002103822700002203843856003603865 2011 eng d a1531-824900aGenome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium.0 aGenomewide association studies of cerebral white matter lesion b c2011 Jun a928-390 v693 a
OBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.
METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.
RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 × 10(-9) ; p(replication) = 1.3 × 10(-7) ; p(combined) = 4.0 × 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 × 10(-9) ), rs11869977 (p = 5.7 × 10(-9) ), rs936393 (p = 6.8 × 10(-9) ), rs3744017 (p = 7.3 × 10(-9) ), and rs1055129 (p = 4.1 × 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample).
INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.
10aAged10aAged, 80 and over10aCerebral Cortex10aChromosomes, Human, Pair 1710aCognition Disorders10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aLeukoencephalopathies10aMagnetic Resonance Imaging10aMale10aMiddle Aged10aMovement Disorders10aNerve Fibers, Myelinated10aPolymorphism, Single Nucleotide10aResidence Characteristics10aRNA, Messenger1 aFornage, Myriam1 aDebette, Stephanie1 aBis, Joshua, C1 aSchmidt, Helena1 aIkram, Arfan, M1 aDufouil, Carole1 aSigurdsson, Sigurdur1 aLumley, Thomas1 aDeStefano, Anita, L1 aFazekas, Franz1 aVrooman, Henri, A1 aShibata, Dean, K1 aMaillard, Pauline1 aZijdenbos, Alex1 aSmith, Albert, V1 aGudnason, Haukur1 ade Boer, Renske1 aCushman, Mary1 aMazoyer, Bernard1 aHeiss, Gerardo1 aVernooij, Meike, W1 aEnzinger, Christian1 aGlazer, Nicole, L1 aBeiser, Alexa1 aKnopman, David, S1 aCavalieri, Margherita1 aNiessen, Wiro, J1 aHarris, Tamara, B1 aPetrovic, Katja1 aLopez, Oscar, L1 aAu, Rhoda1 aLambert, Jean-Charles1 aHofman, Albert1 aGottesman, Rebecca, F1 aGarcia, Melissa1 aHeckbert, Susan, R1 aAtwood, Larry, D1 aCatellier, Diane, J1 aUitterlinden, André, G1 aYang, Qiong1 aSmith, Nicholas, L1 aAspelund, Thor1 aRomero, Jose, R1 aRice, Kenneth1 aTaylor, Kent, D1 aNalls, Michael, A1 aRotter, Jerome, I1 aSharrett, Richey1 aDuijn, Cornelia, M1 aAmouyel, Philippe1 aWolf, Philip, A1 aGudnason, Vilmundur1 avan der Lugt, Aad1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aSeshadri, Sudha1 aTzourio, Christophe1 aBreteler, Monique, M B1 aMosley, Thomas, H1 aSchmidt, Reinhold1 aLongstreth, W T1 aDeCarli, Charles1 aLauner, Lenore, J uhttps://chs-nhlbi.org/node/129804061nas a2200781 4500008004100000022001400041245015900055210006900214260001300283300001200296490000700308520179500315653000902110653001002119653002502129653001902154653001102173653003402184653001102218653000902229653002702238653001602265653003602281653002402317653001702341653002702358100001802385700002202403700002302425700001802448700002902466700001202495700002102507700002202528700002102550700002302571700002402594700002002618700001702638700001802655700001602673700002502689700001902714700002302733700002802756700001802784700002102802700001802823700001902841700002602860700002202886700002102908700002802929700002202957700001902979700002102998700001903019700002203038700002103060700002203081700003203103700001803135700002603153700002003179700002103199700002303220856003603243 2013 eng d a1098-227200aA genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.0 agenomewide association study for venous thromboembolism the exte c2013 Jul a512-5210 v373 aVenous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10(-13) for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10(-6) ) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.
10aAged10aAging10aCase-Control Studies10aCohort Studies10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aMiddle Aged10aPolymorphism, Single Nucleotide10aRegression Analysis10aRisk Factors10aVenous Thromboembolism1 aTang, Weihong1 aTeichert, Martina1 aChasman, Daniel, I1 aHeit, John, A1 aMorange, Pierre-Emmanuel1 aLi, Guo1 aPankratz, Nathan1 aLeebeek, Frank, W1 aParé, Guillaume1 ade Andrade, Mariza1 aTzourio, Christophe1 aPsaty, Bruce, M1 aBasu, Saonli1 aRuiter, Rikje1 aRose, Lynda1 aArmasu, Sebastian, M1 aLumley, Thomas1 aHeckbert, Susan, R1 aUitterlinden, André, G1 aLathrop, Mark1 aRice, Kenneth, M1 aCushman, Mary1 aHofman, Albert1 aLambert, Jean-Charles1 aGlazer, Nicole, L1 aPankow, James, S1 aWitteman, Jacqueline, C1 aAmouyel, Philippe1 aBis, Joshua, C1 aBovill, Edwin, G1 aKong, Xiaoxiao1 aTracy, Russell, P1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aTrégouët, David-Alexandre1 aLoth, Daan, W1 aStricker, Bruno, H Ch1 aRidker, Paul, M1 aFolsom, Aaron, R1 aSmith, Nicholas, L uhttps://chs-nhlbi.org/node/602908236nas a2202509 4500008004100000022001400041245008500055210006900140260000900209300001100218490000600229520112800235653002201363653002101385653002501406653003401431653002401465653001101489653003601500653003101536100002801567700002401595700001801619700002101637700001901658700001801677700001901695700001701714700002301731700002401754700002401778700002601802700003001828700001701858700001801875700001701893700001901910700002101929700002801950700002101978700003001999700002002029700002102049700002202070700002102092700002002113700002002133700002502153700002302178700002002201700002002221700001802241700002402259700002102283700002302304700001802327700003002345700002202375700002302397700002302420700001902443700002802462700002302490700002302513700001902536700002102555700001602576700002402592700002102616700001702637700001602654700001902670700002002689700002402709700002502733700002302758700001702781700002102798700001902819700002202838700002602860700002402886700002202910700002102932700002202953700002702975700001803002700002103020700001803041700001703059700003003076700002703106700002003133700002103153700002003174700001803194700001803212700001503230700002303245700002003268700002803288700002003316700001803336700001903354700002103373700001203394700001903406700001803425700002603443700001903469700001903488700001803507700003203525700001703557700001603574700003103590700001703621700001903638700001803657700002403675700001903699700002303718700002603741700002403767700002003791700002203811700002103833700002003854700001903874700002103893700002303914700002103937700002403958700002003982700002304002700001904025700002004044700001904064700002204083700002104105700002904126700002204155700001804177700002204195700001804217700002104235700002304256700001804279700002904297700001204326700002204338700001604360700001904376700002104395700002104416700002204437700002204459700002604481700002304507700002104530700002104551700001604572700002204588700002204610700002204632700002304654700001804677700002804695700002004723700002304743700002204766700002204788700001804810700001804828700002304846700002204869700002204891700002004913700002204933700001904955700002404974700002104998700002105019700003005040700001705070700002005087700002005107700002205127700001705149700003005166700002005196700002405216700001905240700002305259700002005282700002005302700002405322700001805346700003105364700002205395700003105417700002305448700002305471700002105494700002005515700002805535700002205563700002005585710004705605710003805652856003605690 2014 eng d a1932-620300aGene-wide analysis detects two new susceptibility genes for Alzheimer's disease.0 aGenewide analysis detects two new susceptibility genes for Alzhe c2014 ae946610 v93 aBACKGROUND: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
PRINCIPAL FINDINGS: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci.
SIGNIFICANCE: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
10aAlzheimer Disease10aCarrier Proteins10aCase-Control Studies10aGenome-Wide Association Study10aHeat-Shock Proteins10aHumans10aPolymorphism, Single Nucleotide10aReceptors, Antigen, B-Cell1 aEscott-Price, Valentina1 aBellenguez, Céline1 aSan Wang, Li-1 aChoi, Seung-Hoan1 aHarold, Denise1 aJones, Lesley1 aHolmans, Peter1 aGerrish, Amy1 aVedernikov, Alexey1 aRichards, Alexander1 aDeStefano, Anita, L1 aLambert, Jean-Charles1 aIbrahim-Verbaas, Carla, A1 aNaj, Adam, C1 aSims, Rebecca1 aJun, Gyungah1 aBis, Joshua, C1 aBeecham, Gary, W1 aGrenier-Boley, Benjamin1 aRusso, Giancarlo1 aThornton-Wells, Tricia, A1 aDenning, Nicola1 aSmith, Albert, V1 aChouraki, Vincent1 aThomas, Charlene1 aIkram, Arfan, M1 aZelenika, Diana1 aVardarajan, Badri, N1 aKamatani, Yoichiro1 aLin, Chiao-Feng1 aSchmidt, Helena1 aKunkle, Brian1 aDunstan, Melanie, L1 aVronskaya, Maria1 aJohnson, Andrew, D1 aRuiz, Agustin1 aBihoreau, Marie-Thérèse1 aReitz, Christiane1 aPasquier, Florence1 aHollingworth, Paul1 aHanon, Olivier1 aFitzpatrick, Annette, L1 aBuxbaum, Joseph, D1 aCampion, Dominique1 aCrane, Paul, K1 aBaldwin, Clinton1 aBecker, Tim1 aGudnason, Vilmundur1 aCruchaga, Carlos1 aCraig, David1 aAmin, Najaf1 aBerr, Claudine1 aLopez, Oscar, L1 aDe Jager, Philip, L1 aDeramecourt, Vincent1 aJohnston, Janet, A1 aEvans, Denis1 aLovestone, Simon1 aLetenneur, Luc1 aHernandez, Isabel1 aRubinsztein, David, C1 aEiriksdottir, Gudny1 aSleegers, Kristel1 aGoate, Alison, M1 aFiévet, Nathalie1 aHuentelman, Matthew, J1 aGill, Michael1 aBrown, Kristelle1 aKamboh, Ilyas1 aKeller, Lina1 aBarberger-Gateau, Pascale1 aMcGuinness, Bernadette1 aLarson, Eric, B1 aMyers, Amanda, J1 aDufouil, Carole1 aTodd, Stephen1 aWallon, David1 aLove, Seth1 aRogaeva, Ekaterina1 aGallacher, John1 aSt George-Hyslop, Peter1 aClarimon, Jordi1 aLleo, Alberto1 aBayer, Anthony1 aTsuang, Debby, W1 aYu, Lei1 aTsolaki, Magda1 aBossù, Paola1 aSpalletta, Gianfranco1 aProitsi, Petra1 aCollinge, John1 aSorbi, Sandro1 aGarcia, Florentino, Sanchez1 aFox, Nick, C1 aHardy, John1 aNaranjo, Maria, Candida De1 aBosco, Paolo1 aClarke, Robert1 aBrayne, Carol1 aGalimberti, Daniela1 aScarpini, Elio1 aBonuccelli, Ubaldo1 aMancuso, Michelangelo1 aSiciliano, Gabriele1 aMoebus, Susanne1 aMecocci, Patrizia1 aDel Zompo, Maria1 aMaier, Wolfgang1 aHampel, Harald1 aPilotto, Alberto1 aFrank-García, Ana1 aPanza, Francesco1 aSolfrizzi, Vincenzo1 aCaffarra, Paolo1 aNacmias, Benedetta1 aPerry, William1 aMayhaus, Manuel1 aLannfelt, Lars1 aHakonarson, Hakon1 aPichler, Sabrina1 aCarrasquillo, Minerva, M1 aIngelsson, Martin1 aBeekly, Duane1 aAlvarez, Victoria1 aZou, Fanggeng1 aValladares, Otto1 aYounkin, Steven, G1 aCoto, Eliecer1 aHamilton-Nelson, Kara, L1 aGu, Wei1 aRazquin, Cristina1 aPastor, Pau1 aMateo, Ignacio1 aOwen, Michael, J1 aFaber, Kelley, M1 aJonsson, Palmi, V1 aCombarros, Onofre1 aO'Donovan, Michael, C1 aCantwell, Laura, B1 aSoininen, Hilkka1 aBlacker, Deborah1 aMead, Simon1 aMosley, Thomas, H1 aBennett, David, A1 aHarris, Tamara, B1 aFratiglioni, Laura1 aHolmes, Clive1 ade Bruijn, Renee, F A G1 aPassmore, Peter1 aMontine, Thomas, J1 aBettens, Karolien1 aRotter, Jerome, I1 aBrice, Alexis1 aMorgan, Kevin1 aForoud, Tatiana, M1 aKukull, Walter, A1 aHannequin, Didier1 aPowell, John, F1 aNalls, Michael, A1 aRitchie, Karen1 aLunetta, Kathryn, L1 aKauwe, John, S K1 aBoerwinkle, Eric1 aRiemenschneider, Matthias1 aBoada, Merce1 aHiltunen, Mikko1 aMartin, Eden, R1 aSchmidt, Reinhold1 aRujescu, Dan1 aDartigues, Jean-François1 aMayeux, Richard1 aTzourio, Christophe1 aHofman, Albert1 aNöthen, Markus, M1 aGraff, Caroline1 aPsaty, Bruce, M1 aHaines, Jonathan, L1 aLathrop, Mark1 aPericak-Vance, Margaret, A1 aLauner, Lenore, J1 aVan Broeckhoven, Christine1 aFarrer, Lindsay, A1 aDuijn, Cornelia, M1 aRamirez, Alfredo1 aSeshadri, Sudha1 aSchellenberg, Gerard, D1 aAmouyel, Philippe1 aWilliams, Julie1 aUnited Kingdom Brain Expression Consortium1 aCardiovascular Health Study (CHS) uhttps://chs-nhlbi.org/node/661703355nas a2200529 4500008004100000022001400041245009100055210006900146260001600215300001100231490000700242520178200249100002202031700002202053700001702075700001902092700002402111700001202135700002602147700002702173700002002200700002202220700002002242700002502262700002802287700002402315700001902339700002402358700002202382700002702404700002502431700001702456700003002473700001902503700002202522700002202544700002002566700002402586700002202610700002002632700001902652700002602671700002002697700002002717710005202737856003602789 2016 eng d a1875-890800aEvaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease.0 aEvaluation of a Genetic Risk Score to Improve Risk Prediction fo c2016 Jun 18 a921-320 v533 aEffective prevention of Alzheimer's disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOEɛ4. In eight prospective cohorts included in the International Genomics of Alzheimer's Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17% increase in AD risk (pooled HR = 1.17; 95% CI = [1.13-1.21] per standard deviation increase in GRS; p-value = 2.86×10-16). This association was stronger among persons with at least one APOEɛ4 allele (HRGRS = 1.24; 95% CI = [1.15-1.34]) than in others (HRGRS = 1.13; 95% CI = [1.08-1.18]; pinteraction = 3.45×10-2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOEɛ4, and education (Δ-Cindex = 0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOEɛ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.
1 aChouraki, Vincent1 aReitz, Christiane1 aMaury, Fleur1 aBis, Joshua, C1 aBellenguez, Céline1 aYu, Lei1 aJakobsdottir, Johanna1 aMukherjee, Shubhabrata1 aAdams, Hieab, H1 aChoi, Seung, Hoan1 aLarson, Eric, B1 aFitzpatrick, Annette1 aUitterlinden, André, G1 aDe Jager, Philip, L1 aHofman, Albert1 aGudnason, Vilmundur1 aVardarajan, Badri1 aIbrahim-Verbaas, Carla1 avan der Lee, Sven, J1 aLopez, Oscar1 aDartigues, Jean-François1 aBerr, Claudine1 aAmouyel, Philippe1 aBennett, David, A1 aDuijn, Cornelia1 aDeStefano, Anita, L1 aLauner, Lenore, J1 aIkram, Arfan, M1 aCrane, Paul, K1 aLambert, Jean-Charles1 aMayeux, Richard1 aSeshadri, Sudha1 aInternational Genomics of Alzheimer’s Project uhttps://chs-nhlbi.org/node/718505111nas a2200877 4500008004100000022001400041245025000055210006900305260001300374300001100387490000800398520248000406653002202886653003902908653002102947653001902968653000902987653002002996653002603016653002403042653001603066653003103082653001103113653001103124653003603135653003003171653001803201100001303219700002003232700002003252700002003272700002403292700001903316700002103335700001403356700001703370700001303387700001903400700002103419700002303440700002003463700002303483700002103506700002003527700002803547700002303575700001503598700002203613700002103635700001303656700002503669700002003694700002503714700001603739700002203755700002603777700002003803700001903823700002503842700002203867700002503889700002103914700002003935700002003955700002503975700001704000700002204017700003004039700002004069700002404089700001804113700002104131700002104152700002404173856003604197 2016 eng d a1938-320700aInteraction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies and methylation analysis of 3 studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.0 aInteraction of methylationrelated genetic variants with circulat c2016 Feb a567-780 v1033 aBACKGROUND: DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression.
OBJECTIVE: We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation.
DESIGN: We selected 7 SNPs on the basis of predicted relations in fatty acids, methylation, and lipids. We conducted a meta-analysis and a methylation and mediation analysis with the use of data from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium and the ENCODE (Encyclopedia of DNA Elements) consortium.
RESULTS: On the basis of the meta-analysis of 7 cohorts in the CHARGE consortium, higher plasma HDL cholesterol was associated with fewer C alleles at ATP-binding cassette subfamily A member 1 (ABCA1) rs2246293 (β = -0.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (β = 3.87 mg/dL, P = 5.62 × 10(21)). The difference in HDL cholesterol associated with higher circulating EPA was dependent on genotypes at rs2246293, and it was greater for each additional C allele (β = 1.69 mg/dL, P = 0.006). In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study, higher ABCA1 promoter cg14019050 methylation was associated with more C alleles at rs2246293 (β = 8.84%, P = 3.51 × 10(18)) and lower circulating EPA (β = -1.46%, P = 0.009), and the mean difference in methylation of cg14019050 that was associated with higher EPA was smaller with each additional C allele of rs2246293 (β = -2.83%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r = -0.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r = -0.12, P = 0.0002). An additional mediation analysis was meta-analyzed across the GOLDN study, Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Compared with the model without the adjustment of cg14019050 methylation, the model with such adjustment provided smaller estimates of the mean plasma HDL cholesterol concentration in association with both the rs2246293 C allele and EPA and a smaller difference by rs2246293 genotypes in the EPA-associated HDL cholesterol. However, the differences between 2 nested models were NS (P > 0.05).
CONCLUSION: We obtained little evidence that the gene-by-fatty acid interactions on blood lipids act through DNA methylation.
10aApolipoproteins E10aATP Binding Cassette Transporter 110aCholesterol, HDL10aCohort Studies10aDiet10aDNA Methylation10aEicosapentaenoic Acid10aEpigenesis, Genetic10aFatty Acids10aGene Expression Regulation10aHumans10aLipids10aPolymorphism, Single Nucleotide10aPromoter Regions, Genetic10aTriglycerides1 aMa, Yiyi1 aFollis, Jack, L1 aSmith, Caren, E1 aTanaka, Toshiko1 aManichaikul, Ani, W1 aChu, Audrey, Y1 aSamieri, Cecilia1 aZhou, Xia1 aGuan, Weihua1 aWang, Lu1 aBiggs, Mary, L1 aChen, Yii-der, I1 aHernandez, Dena, G1 aBorecki, Ingrid1 aChasman, Daniel, I1 aRich, Stephen, S1 aFerrucci, Luigi1 aIrvin, Marguerite, Ryan1 aAslibekyan, Stella1 aZhi, Degui1 aTiwari, Hemant, K1 aClaas, Steven, A1 aSha, Jin1 aKabagambe, Edmond, K1 aLai, Chao-Qiang1 aParnell, Laurence, D1 aLee, Yu-Chi1 aAmouyel, Philippe1 aLambert, Jean-Charles1 aPsaty, Bruce, M1 aKing, Irena, B1 aMozaffarian, Dariush1 aMcKnight, Barbara1 aBandinelli, Stefania1 aTsai, Michael, Y1 aRidker, Paul, M1 aDing, Jingzhong1 aMstat, Kurt, Lohmant1 aLiu, Yongmei1 aSotoodehnia, Nona1 aBarberger-Gateau, Pascale1 aSteffen, Lyn, M1 aSiscovick, David, S1 aAbsher, Devin1 aArnett, Donna, K1 aOrdovas, Jose, M1 aLemaitre, Rozenn, N uhttps://chs-nhlbi.org/node/695117687nas a2205785 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2017 eng d a1546-171800aRare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.0 aRare coding variants in PLCG2 ABI3 and TREM2 implicate microglia c2017 Sep a1373-13840 v493 aWe identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
10aAdaptor Proteins, Signal Transducing10aAlzheimer Disease10aAmino Acid Sequence10aCase-Control Studies10aExome10aGene Expression Profiling10aGene Frequency10aGenetic Predisposition to Disease10aGenotype10aHumans10aImmunity, Innate10aLinkage Disequilibrium10aMembrane Glycoproteins10aMicroglia10aOdds Ratio10aPhospholipase C gamma10aPolymorphism, Single Nucleotide10aProtein Interaction Maps10aReceptors, Immunologic10aSequence Homology, Amino Acid1 aSims, Rebecca1 avan der Lee, Sven, J1 aNaj, Adam, C1 aBellenguez, Céline1 aBadarinarayan, Nandini1 aJakobsdottir, Johanna1 aKunkle, Brian, W1 aBoland, Anne1 aRaybould, Rachel1 aBis, Joshua, C1 aMartin, Eden, R1 aGrenier-Boley, Benjamin1 aHeilmann-Heimbach, Stefanie1 aChouraki, Vincent1 aKuzma, Amanda, B1 aSleegers, Kristel1 aVronskaya, Maria1 aRuiz, Agustin1 aGraham, Robert, R1 aOlaso, Robert1 aHoffmann, Per1 aGrove, Megan, L1 aVardarajan, Badri, N1 aHiltunen, Mikko1 aNöthen, Markus, M1 aWhite, Charles, C1 aHamilton-Nelson, Kara, L1 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aMann, David1 aTsolaki, Magda1 aClarimon, Jordi1 aSussams, Rebecca1 aLovestone, Simon1 aO'Donovan, Michael, C1 aOwen, Michael, J1 aBehrens, Timothy, W1 aMead, Simon1 aGoate, Alison, M1 aUitterlinden, André, G1 aHolmes, Clive1 aCruchaga, Carlos1 aIngelsson, Martin1 aBennett, David, A1 aPowell, John1 aGolde, Todd, E1 aGraff, Caroline1 aDe Jager, Philip, L1 aMorgan, Kevin1 aErtekin-Taner, Nilufer1 aCombarros, Onofre1 aPsaty, Bruce, M1 aPassmore, Peter1 aYounkin, Steven, G1 aBerr, Claudine1 aGudnason, Vilmundur1 aRujescu, Dan1 aDickson, Dennis, W1 aDartigues, Jean-François1 aDeStefano, Anita, L1 aOrtega-Cubero, Sara1 aHakonarson, Hakon1 aCampion, Dominique1 aBoada, Merce1 aKauwe, John, Keoni1 aFarrer, Lindsay, A1 aVan Broeckhoven, Christine1 aIkram, Arfan, M1 aJones, Lesley1 aHaines, Jonathan, L1 aTzourio, Christophe1 aLauner, Lenore, J1 aEscott-Price, Valentina1 aMayeux, Richard1 aDeleuze, Jean-Francois1 aAmin, Najaf1 aHolmans, Peter, A1 aPericak-Vance, Margaret, A1 aAmouyel, Philippe1 aDuijn, Cornelia, M1 aRamirez, Alfredo1 aSan Wang, Li-1 aLambert, Jean-Charles1 aSeshadri, Sudha1 aWilliams, Julie1 aSchellenberg, Gerard, D1 aARUK Consortium1 aGERAD/PERADES, CHARGE, ADGC, EADI uhttps://chs-nhlbi.org/node/758705481nas a2201285 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2018 eng d a1476-557800aWhole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.0 aWhole exome sequencing study identifies novel rare and common Al c2018 Aug 143 aThe Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.
1 aBis, Joshua, C1 aJian, Xueqiu1 aKunkle, Brian, W1 aChen, Yuning1 aHamilton-Nelson, Kara, L1 aBush, William, S1 aSalerno, William, J1 aLancour, Daniel1 aMa, Yiyi1 aRenton, Alan, E1 aMarcora, Edoardo1 aFarrell, John, J1 aZhao, Yi1 aQu, Liming1 aAhmad, Shahzad1 aAmin, Najaf1 aAmouyel, Philippe1 aBeecham, Gary, W1 aBelow, Jennifer, E1 aCampion, Dominique1 aCharbonnier, Camille1 aChung, Jaeyoon1 aCrane, Paul, K1 aCruchaga, Carlos1 aCupples, Adrienne, L1 aDartigues, Jean-François1 aDebette, Stephanie1 aDeleuze, Jean-Francois1 aFulton, Lucinda1 aGabriel, Stacey, B1 aGenin, Emmanuelle1 aGibbs, Richard, A1 aGoate, Alison1 aGrenier-Boley, Benjamin1 aGupta, Namrata1 aHaines, Jonathan, L1 aHavulinna, Aki, S1 aHelisalmi, Seppo1 aHiltunen, Mikko1 aHowrigan, Daniel, P1 aIkram, Arfan, M1 aKaprio, Jaakko1 aKonrad, Jan1 aKuzma, Amanda1 aLander, Eric, S1 aLathrop, Mark1 aLehtimäki, Terho1 aLin, Honghuang1 aMattila, Kari1 aMayeux, Richard1 aMuzny, Donna, M1 aNasser, Waleed1 aNeale, Benjamin1 aNho, Kwangsik1 aNicolas, Gaël1 aPatel, Devanshi1 aPericak-Vance, Margaret, A1 aPerola, Markus1 aPsaty, Bruce, M1 aQuenez, Olivier1 aRajabli, Farid1 aRedon, Richard1 aReitz, Christiane1 aRemes, Anne, M1 aSalomaa, Veikko1 aSarnowski, Chloe1 aSchmidt, Helena1 aSchmidt, Michael1 aSchmidt, Reinhold1 aSoininen, Hilkka1 aThornton, Timothy, A1 aTosto, Giuseppe1 aTzourio, Christophe1 avan der Lee, Sven, J1 aDuijn, Cornelia, M1 aVardarajan, Badri1 aWang, Weixin1 aWijsman, Ellen1 aWilson, Richard, K1 aWitten, Daniela1 aWorley, Kim, C1 aZhang, Xiaoling1 aBellenguez, Céline1 aLambert, Jean-Charles1 aKurki, Mitja, I1 aPalotie, Aarno1 aDaly, Mark1 aBoerwinkle, Eric1 aLunetta, Kathryn, L1 aDeStefano, Anita, L1 aDupuis, Josée1 aMartin, Eden, R1 aSchellenberg, Gerard, D1 aSeshadri, Sudha1 aNaj, Adam, C1 aFornage, Myriam1 aFarrer, Lindsay, A1 aAlzheimer’s Disease Sequencing Project uhttps://chs-nhlbi.org/node/778517696nas a2205797 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2019 eng d a1546-171800aGenetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.0 aGenetic metaanalysis of diagnosed Alzheimers disease identifies c2019 Mar a414-4300 v513 aRisk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
1 aKunkle, Brian, W1 aGrenier-Boley, Benjamin1 aSims, Rebecca1 aBis, Joshua, C1 aDamotte, Vincent1 aNaj, Adam, C1 aBoland, Anne1 aVronskaya, Maria1 avan der Lee, Sven, J1 aAmlie-Wolf, Alexandre1 aBellenguez, Céline1 aFrizatti, Aura1 aChouraki, Vincent1 aMartin, Eden, R1 aSleegers, Kristel1 aBadarinarayan, Nandini1 aJakobsdottir, Johanna1 aHamilton-Nelson, Kara, L1 aMoreno-Grau, Sonia1 aOlaso, Robert1 aRaybould, Rachel1 aChen, Yuning1 aKuzma, Amanda, B1 aHiltunen, Mikko1 aMorgan, Taniesha1 aAhmad, Shahzad1 aVardarajan, Badri, N1 aEpelbaum, Jacques1 aHoffmann, Per1 aBoada, Merce1 aBeecham, Gary, W1 aGarnier, Jean-Guillaume1 aHarold, Denise1 aFitzpatrick, Annette, L1 aValladares, Otto1 aMoutet, Marie-Laure1 aGerrish, Amy1 aSmith, Albert, V1 aQu, Liming1 aBacq, Delphine1 aDenning, Nicola1 aJian, Xueqiu1 aZhao, Yi1 aDel Zompo, Maria1 aFox, Nick, C1 aChoi, Seung-Hoan1 aMateo, Ignacio1 aHughes, Joseph, T1 aAdams, Hieab, H1 aMalamon, John1 aSanchez-Garcia, Florentino1 aPatel, Yogen1 aBrody, Jennifer, A1 aDombroski, Beth, A1 aNaranjo, Maria, Candida De1 aDaniilidou, Makrina1 aEiriksdottir, Gudny1 aMukherjee, Shubhabrata1 aWallon, David1 aUphill, James1 aAspelund, Thor1 aCantwell, Laura, B1 aGarzia, Fabienne1 aGalimberti, Daniela1 aHofer, Edith1 aButkiewicz, Mariusz1 aFin, Bertrand1 aScarpini, Elio1 aSarnowski, Chloe1 aBush, Will, S1 aMeslage, Stéphane1 aKornhuber, Johannes1 aWhite, Charles, C1 aSong, Yuenjoo1 aBarber, Robert, C1 aEngelborghs, Sebastiaan1 aSordon, Sabrina1 aVoijnovic, Dina1 aAdams, Perrie, M1 aVandenberghe, Rik1 aMayhaus, Manuel1 aCupples, Adrienne, L1 aAlbert, Marilyn, S1 aDe Deyn, Peter, P1 aGu, Wei1 aHimali, Jayanadra, J1 aBeekly, Duane1 aSquassina, Alessio1 aHartmann, Annette, M1 aOrellana, Adelina1 aBlacker, Deborah1 aRodriguez-Rodriguez, Eloy1 aLovestone, Simon1 aGarcia, Melissa, E1 aDoody, Rachelle, S1 aMunoz-Fernadez, Carmen1 aSussams, Rebecca1 aLin, Honghuang1 aFairchild, Thomas, J1 aBenito, Yolanda, A1 aHolmes, Clive1 aKaramujić-Čomić, Hata1 aFrosch, Matthew, P1 aThonberg, Håkan1 aMaier, Wolfgang1 aRoschupkin, Gena1 aGhetti, Bernardino1 aGiedraitis, Vilmantas1 aKawalia, Amit1 aLi, Shuo1 aHuebinger, Ryan, M1 aKilander, Lena1 aMoebus, Susanne1 aHernandez, Isabel1 aKamboh, Ilyas1 aBrundin, RoseMarie1 aTurton, James1 aYang, Qiong1 aKatz, Mindy, J1 aConcari, Letizia1 aLord, Jenny1 aBeiser, Alexa, S1 aKeene, Dirk1 aHelisalmi, Seppo1 aKloszewska, Iwona1 aKukull, Walter, A1 aKoivisto, Anne, Maria1 aLynch, Aoibhinn1 aTarraga, Lluis1 aLarson, Eric, B1 aHaapasalo, Annakaisa1 aLawlor, Brian1 aMosley, Thomas, H1 aLipton, Richard, B1 aSolfrizzi, Vincenzo1 aGill, Michael1 aLongstreth, W T1 aMontine, Thomas, J1 aFrisardi, Vincenza1 aDiez-Fairen, Monica1 aRivadeneira, Fernando1 aPetersen, Ronald, C1 aDeramecourt, Vincent1 aAlvarez, Ignacio1 aSalani, Francesca1 aCiaramella, Antonio1 aBoerwinkle, Eric1 aReiman, Eric, M1 aFiévet, Nathalie1 aRotter, Jerome, I1 aReisch, Joan, S1 aHanon, Olivier1 aCupidi, Chiara1 aUitterlinden, A, G Andre1 aRoyall, Donald, R1 aDufouil, Carole1 aMaletta, Raffaele, Giovanni1 ade Rojas, Itziar1 aSano, Mary1 aBrice, Alexis1 aCecchetti, Roberta1 aSt George-Hyslop, Peter1 aRitchie, Karen1 aTsolaki, Magda1 aTsuang, Debby, W1 aDubois, Bruno1 aCraig, David1 aWu, Chuang-Kuo1 aSoininen, Hilkka1 aAvramidou, Despoina1 aAlbin, Roger, L1 aFratiglioni, Laura1 aGermanou, Antonia1 aApostolova, Liana, G1 aKeller, Lina1 aKoutroumani, Maria1 aArnold, Steven, E1 aPanza, Francesco1 aGkatzima, Olymbia1 aAsthana, Sanjay1 aHannequin, Didier1 aWhitehead, Patrice1 aAtwood, Craig, S1 aCaffarra, Paolo1 aHampel, Harald1 aQuintela, Inés1 aCarracedo, Angel1 aLannfelt, Lars1 aRubinsztein, David, C1 aBarnes, Lisa, L1 aPasquier, Florence1 aFrölich, Lutz1 aBarral, Sandra1 aMcGuinness, Bernadette1 aBeach, Thomas, G1 aJohnston, Janet, A1 aBecker, James, T1 aPassmore, Peter1 aBigio, Eileen, H1 aSchott, Jonathan, M1 aBird, Thomas, D1 aWarren, Jason, D1 aBoeve, Bradley, F1 aLupton, Michelle, K1 aBowen, James, D1 aProitsi, Petra1 aBoxer, Adam1 aPowell, John, F1 aBurke, James, R1 aKauwe, John, S K1 aBurns, Jeffrey, M1 aMancuso, Michelangelo1 aBuxbaum, Joseph, D1 aBonuccelli, Ubaldo1 aCairns, Nigel, J1 aMcQuillin, Andrew1 aCao, Chuanhai1 aLivingston, Gill1 aCarlson, Chris, S1 aBass, Nicholas, J1 aCarlsson, Cynthia, M1 aHardy, John1 aCarney, Regina, M1 aBras, Jose1 aCarrasquillo, Minerva, M1 aGuerreiro, Rita1 aAllen, Mariet1 aChui, Helena, C1 aFisher, Elizabeth1 aMasullo, Carlo1 aCrocco, Elizabeth, A1 aDeCarli, Charles1 aBisceglio, Gina1 aDick, Malcolm1 aMa, Li1 aDuara, Ranjan1 aGraff-Radford, Neill, R1 aEvans, Denis, A1 aHodges, Angela1 aFaber, Kelley, M1 aScherer, Martin1 aFallon, Kenneth, B1 aRiemenschneider, Matthias1 aFardo, David, W1 aHeun, Reinhard1 aFarlow, Martin, R1 aKölsch, Heike1 aFerris, Steven1 aLeber, Markus1 aForoud, Tatiana, M1 aHeuser, Isabella1 aGalasko, Douglas, R1 aGiegling, Ina1 aGearing, Marla1 aHüll, Michael1 aGeschwind, Daniel, H1 aGilbert, John, R1 aMorris, John1 aGreen, Robert, C1 aMayo, Kevin1 aGrowdon, John, H1 aFeulner, Thomas1 aHamilton, Ronald, L1 aHarrell, Lindy, E1 aDrichel, Dmitriy1 aHonig, Lawrence, S1 aCushion, Thomas, D1 aHuentelman, Matthew, J1 aHollingworth, Paul1 aHulette, Christine, M1 aHyman, Bradley, T1 aMarshall, Rachel1 aJarvik, Gail, P1 aMeggy, Alun1 aAbner, Erin1 aMenzies, Georgina, E1 aJin, Lee-Way1 aLeonenko, Ganna1 aReal, Luis, M1 aJun, Gyungah, R1 aBaldwin, Clinton, T1 aGrozeva, Detelina1 aKarydas, Anna1 aRusso, Giancarlo1 aKaye, Jeffrey, A1 aKim, Ronald1 aJessen, Frank1 aKowall, Neil, W1 aVellas, Bruno1 aKramer, Joel, H1 aVardy, Emma1 aLaFerla, Frank, M1 aJöckel, Karl-Heinz1 aLah, James, J1 aDichgans, Martin1 aLeverenz, James, B1 aMann, David1 aLevey, Allan, I1 aPickering-Brown, Stuart1 aLieberman, Andrew, P1 aKlopp, Norman1 aLunetta, Kathryn, L1 aWichmann, H-Erich1 aLyketsos, Constantine, G1 aMorgan, Kevin1 aMarson, Daniel, C1 aBrown, Kristelle1 aMartiniuk, Frank1 aMedway, Christopher1 aMash, Deborah, C1 aNöthen, Markus, M1 aMasliah, Eliezer1 aHooper, Nigel, M1 aMcCormick, Wayne, C1 aDaniele, Antonio1 aMcCurry, Susan, M1 aBayer, Anthony1 aMcDavid, Andrew, N1 aGallacher, John1 aMcKee, Ann, C1 avan den Bussche, Hendrik1 aMesulam, Marsel1 aBrayne, Carol1 aMiller, Bruce, L1 aRiedel-Heller, Steffi1 aMiller, Carol, A1 aMiller, Joshua, W1 aAl-Chalabi, Ammar1 aMorris, John, C1 aShaw, Christopher, E1 aMyers, Amanda, J1 aWiltfang, Jens1 aO'Bryant, Sid1 aOlichney, John, M1 aAlvarez, Victoria1 aParisi, Joseph, E1 aSingleton, Andrew, B1 aPaulson, Henry, L1 aCollinge, John1 aPerry, William, R1 aMead, Simon1 aPeskind, Elaine1 aCribbs, David, H1 aRossor, Martin1 aPierce, Aimee1 aRyan, Natalie, S1 aPoon, Wayne, W1 aNacmias, Benedetta1 aPotter, Huntington1 aSorbi, Sandro1 aQuinn, Joseph, F1 aSacchinelli, Eleonora1 aRaj, Ashok1 aSpalletta, Gianfranco1 aRaskind, Murray1 aCaltagirone, Carlo1 aBossù, Paola1 aOrfei, Maria, Donata1 aReisberg, Barry1 aClarke, Robert1 aReitz, Christiane1 aSmith, David1 aRingman, John, M1 aWarden, Donald1 aRoberson, Erik, D1 aWilcock, Gordon1 aRogaeva, Ekaterina1 aBruni, Amalia, Cecilia1 aRosen, Howard, J1 aGallo, Maura1 aRosenberg, Roger, N1 aBen-Shlomo, Yoav1 aSager, Mark, A1 aMecocci, Patrizia1 aSaykin, Andrew, J1 aPastor, Pau1 aCuccaro, Michael, L1 aVance, Jeffery, M1 aSchneider, Julie, A1 aSchneider, Lori, S1 aSlifer, Susan1 aSeeley, William, W1 aSmith, Amanda, G1 aSonnen, Joshua, A1 aSpina, Salvatore1 aStern, Robert, A1 aSwerdlow, Russell, H1 aTang, Mitchell1 aTanzi, Rudolph, E1 aTrojanowski, John, Q1 aTroncoso, Juan, C1 aVan Deerlin, Vivianna, M1 aVan Eldik, Linda, J1 aVinters, Harry, V1 aVonsattel, Jean, Paul1 aWeintraub, Sandra1 aWelsh-Bohmer, Kathleen, A1 aWilhelmsen, Kirk, C1 aWilliamson, Jennifer1 aWingo, Thomas, S1 aWoltjer, Randall, L1 aWright, Clinton, B1 aYu, Chang-En1 aYu, Lei1 aSaba, Yasaman1 aPilotto, Alberto1 aBullido, María, J1 aPeters, Oliver1 aCrane, Paul, K1 aBennett, David1 aBosco, Paola1 aCoto, Eliecer1 aBoccardi, Virginia1 aDe Jager, Phil, L1 aLleo, Alberto1 aWarner, Nick1 aLopez, Oscar, L1 aIngelsson, Martin1 aDeloukas, Panagiotis1 aCruchaga, Carlos1 aGraff, Caroline1 aGwilliam, Rhian1 aFornage, Myriam1 aGoate, Alison, M1 aSánchez-Juan, Pascual1 aKehoe, Patrick, G1 aAmin, Najaf1 aErtekin-Taner, Nilifur1 aBerr, Claudine1 aDebette, Stephanie1 aLove, Seth1 aLauner, Lenore, J1 aYounkin, Steven, G1 aDartigues, Jean-François1 aCorcoran, Chris1 aIkram, Arfan, M1 aDickson, Dennis, W1 aNicolas, Gaël1 aCampion, Dominique1 aTschanz, JoAnn1 aSchmidt, Helena1 aHakonarson, Hakon1 aClarimon, Jordi1 aMunger, Ron1 aSchmidt, Reinhold1 aFarrer, Lindsay, A1 aVan Broeckhoven, Christine1 aO'Donovan, Michael, C1 aDeStefano, Anita, L1 aJones, Lesley1 aHaines, Jonathan, L1 aDeleuze, Jean-Francois1 aOwen, Michael, J1 aGudnason, Vilmundur1 aMayeux, Richard1 aEscott-Price, Valentina1 aPsaty, Bruce, M1 aRamirez, Alfredo1 aSan Wang, Li-1 aRuiz, Agustin1 aDuijn, Cornelia, M1 aHolmans, Peter, A1 aSeshadri, Sudha1 aWilliams, Julie1 aAmouyel, Phillippe1 aSchellenberg, Gerard, D1 aLambert, Jean-Charles1 aPericak-Vance, Margaret, A1 aAlzheimer Disease Genetics Consortium (ADGC),1 aEuropean Alzheimer’s Disease Initiative (EADI),1 aCohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE),1 aGenetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD/PERADES), uhttps://chs-nhlbi.org/node/797715436nas 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, 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