04313nas a2200889 4500008004100000022001400041245004600055210004500101260001600146300001200162490000800174520183800182653003902020653000902059653003202068653001902100653004002119653001102159653002002170653003802190653003402228653001302262653001102275653000902286653001602295653003602311653003202347653001702379653001102396100002002407700002002427700001902447700002002466700002402486700002402510700002302534700001902557700002102576700002802597700002002625700001802645700001802663700002202681700001702703700002302720700001702743700002202760700002302782700002602805700002602831700002002857700001802877700001902895700002102914700002302935700002402958700001602982700002302998700002003021700001803041700002303059700001703082700002303099700002003122700002303142700001903165700002803184700002203212700002103234700002003255700002203275700002303297700002703320700002003347700002003367856003603387 2009 eng d a1533-440600aGenomewide association studies of stroke.0 aGenomewide association studies of stroke c2009 Apr 23 a1718-280 v3603 a
BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined.
METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons.
RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant.
CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.
10aAfrican Continental Ancestry Group10aAged10aChromosomes, Human, Pair 1210aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Markers10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProportional Hazards Models10aRisk Factors10aStroke1 aIkram, Arfan, M1 aSeshadri, Sudha1 aBis, Joshua, C1 aFornage, Myriam1 aDeStefano, Anita, L1 aAulchenko, Yurii, S1 aDebette, Stephanie1 aLumley, Thomas1 aFolsom, Aaron, R1 avan den Herik, Evita, G1 aBos, Michiel, J1 aBeiser, Alexa1 aCushman, Mary1 aLauner, Lenore, J1 aShahar, Eyal1 aStruchalin, Maksim1 aDu, Yangchun1 aGlazer, Nicole, L1 aRosamond, Wayne, D1 aRivadeneira, Fernando1 aKelly-Hayes, Margaret1 aLopez, Oscar, L1 aCoresh, Josef1 aHofman, Albert1 aDeCarli, Charles1 aHeckbert, Susan, R1 aKoudstaal, Peter, J1 aYang, Qiong1 aSmith, Nicholas, L1 aKase, Carlos, S1 aRice, Kenneth1 aHaritunians, Talin1 aRoks, Gerwin1 ade Kort, Paul, L M1 aTaylor, Kent, D1 ade Lau, Lonneke, M1 aOostra, Ben, A1 aUitterlinden, André, G1 aRotter, Jerome, I1 aBoerwinkle, Eric1 aPsaty, Bruce, M1 aMosley, Thomas, H1 aDuijn, Cornelia, M1 aBreteler, Monique, M B1 aLongstreth, W T1 aWolf, Philip, A uhttps://chs-nhlbi.org/node/109205807nas a2201045 4500008004100000022001400041245007600055210006900131260001600200300001200216490000800228520280100236653001703037653000903054653002203063653002503085653001703110653003803127653003403165653001103199653001503210653003603225100002003261700002803281700002003309700002403329700002403353700001703377700001903394700002103413700002903434700002703463700001903490700003103509700002603540700002303566700002003589700002603609700002003635700003103655700002303686700001903709700002203728700001803750700002103768700002403789700002303813700002403836700002103860700002003881700001703901700002203918700002403940700002203964700002403986700001904010700002104029700002504050700002604075700002104101700002604122700002204148700002804170700002304198700002204221700001804243700001904261700002204280700002004302700001804322700002204340700001404362700002004376700002804396700002304424700001904447700001804466700002004484700002204504700002204526700002004548700002204568700002004590700002304610700002704633710002204660710002204682710002104704856003604725 2010 eng d a1538-359800aGenome-wide analysis of genetic loci associated with Alzheimer disease.0 aGenomewide analysis of genetic loci associated with Alzheimer di c2010 May 12 a1832-400 v3033 aCONTEXT: Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD).
OBJECTIVES: To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35,000 persons (8371 AD cases).
DESIGN, SETTING, AND PARTICIPANTS: In stage 1, we identified strong genetic associations (P < 10(-3)) in a sample of 3006 AD cases and 14,642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P < 10(-3). In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P < 10(-5). In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P < 1.7x10(-8). These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009.
MAIN OUTCOME MEASURE: Presence of Alzheimer disease.
RESULTS: Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95% confidence interval [CI],1.06-1.21 per copy of the minor allele; P = 1.59x10(-11)) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR, 1.18; 95% CI, 1.07-1.29; P = 6.45x10(-9)). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P < .05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study).
CONCLUSIONS: Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.
10aAge of Onset10aAged10aAlzheimer Disease10aCase-Control Studies10aGenetic Loci10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aOdds Ratio10aPolymorphism, Single Nucleotide1 aSeshadri, Sudha1 aFitzpatrick, Annette, L1 aIkram, Arfan, M1 aDeStefano, Anita, L1 aGudnason, Vilmundur1 aBoada, Merce1 aBis, Joshua, C1 aSmith, Albert, V1 aCarassquillo, Minerva, M1 aLambert, Jean, Charles1 aHarold, Denise1 aSchrijvers, Elisabeth, M C1 aRamirez-Lorca, Reposo1 aDebette, Stephanie1 aLongstreth, W T1 aJanssens, Cecile, J W1 aPankratz, Shane1 aDartigues, Jean, François1 aHollingworth, Paul1 aAspelund, Thor1 aHernandez, Isabel1 aBeiser, Alexa1 aKuller, Lewis, H1 aKoudstaal, Peter, J1 aDickson, Dennis, W1 aTzourio, Christophe1 aAbraham, Richard1 aAntunez, Carmen1 aDu, Yangchun1 aRotter, Jerome, I1 aAulchenko, Yurii, S1 aHarris, Tamara, B1 aPetersen, Ronald, C1 aBerr, Claudine1 aOwen, Michael, J1 aLopez-Arrieta, Jesus1 aVaradarajan, Badri, N1 aBecker, James, T1 aRivadeneira, Fernando1 aNalls, Michael, A1 aGraff-Radford, Neill, R1 aCampion, Dominique1 aAuerbach, Sanford1 aRice, Kenneth1 aHofman, Albert1 aJonsson, Palmi, V1 aSchmidt, Helena1 aLathrop, Mark1 aMosley, Thomas, H1 aAu, Rhoda1 aPsaty, Bruce, M1 aUitterlinden, André, G1 aFarrer, Lindsay, A1 aLumley, Thomas1 aRuiz, Agustin1 aWilliams, Julie1 aAmouyel, Philippe1 aYounkin, Steve, G1 aWolf, Philip, A1 aLauner, Lenore, J1 aLopez, Oscar, L1 aDuijn, Cornelia, M1 aBreteler, Monique, M B1 aCHARGE Consortium1 aGERAD1 Consortium1 aEADI1 Consortium uhttps://chs-nhlbi.org/node/119904951nas a2201009 4500008004100000022001400041245010900055210006900164260001300233300001000246490000700256520207300263653002202336653000902358653001002367653002102377653001902398653002802417653001102445653001902456653002002475653003802495653002002533653002202553653003402575653001102609653002702620653003102647653000902678653001602687653003602703653002402739100002302763700001902786700002002805700002002825700002002845700002502865700001902890700002302909700002102932700002202953700002102975700001902996700002203015700002403037700002403061700002403085700002403109700002003133700002003153700002403173700001903197700001903216700002403235700001803259700002203277700002403299700002103323700002103344700002203365700002603387700002103413700001803434700002603452700002403478700002803502700002603530700001803556700001703574700002103591700002403612700001903636700002003655700001703675700002303692700001403715700002303729700002003752700002203772700002003794700002703814700002203841700002203863700002003885856003603905 2010 eng d a1524-462800aGenome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium.0 aGenomewide association studies of MRIdefined brain infarcts meta c2010 Feb a210-70 v413 aBACKGROUND AND PURPOSE: Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.
METHODS: Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >or=1 MRI infarct).
RESULTS: The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample.
CONCLUSIONS: This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.
10aAfrican Americans10aAged10aBrain10aBrain Infarction10aCohort Studies10aDNA Mutational Analysis10aFemale10aGene Frequency10aGenetic Markers10aGenetic Predisposition to Disease10aGenetic Testing10aGenetic Variation10aGenome-Wide Association Study10aHumans10aLinkage Disequilibrium10aMagnetic Resonance Imaging10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProspective Studies1 aDebette, Stephanie1 aBis, Joshua, C1 aFornage, Myriam1 aSchmidt, Helena1 aIkram, Arfan, M1 aSigurdsson, Sigurdur1 aHeiss, Gerardo1 aStruchalin, Maksim1 aSmith, Albert, V1 avan der Lugt, Aad1 aDeCarli, Charles1 aLumley, Thomas1 aKnopman, David, S1 aEnzinger, Christian1 aEiriksdottir, Gudny1 aKoudstaal, Peter, J1 aDeStefano, Anita, L1 aPsaty, Bruce, M1 aDufouil, Carole1 aCatellier, Diane, J1 aFazekas, Franz1 aAspelund, Thor1 aAulchenko, Yurii, S1 aBeiser, Alexa1 aRotter, Jerome, I1 aTzourio, Christophe1 aShibata, Dean, K1 aTscherner, Maria1 aHarris, Tamara, B1 aRivadeneira, Fernando1 aAtwood, Larry, D1 aRice, Kenneth1 aGottesman, Rebecca, F1 avan Buchem, Mark, A1 aUitterlinden, André, G1 aKelly-Hayes, Margaret1 aCushman, Mary1 aZhu, Yicheng1 aBoerwinkle, Eric1 aGudnason, Vilmundur1 aHofman, Albert1 aRomero, Jose, R1 aLopez, Oscar1 aDuijn, Cornelia, M1 aAu, Rhoda1 aHeckbert, Susan, R1 aWolf, Philip, A1 aMosley, Thomas, H1 aSeshadri, Sudha1 aBreteler, Monique, M B1 aSchmidt, Reinhold1 aLauner, Lenore, J1 aLongstreth, W T uhttps://chs-nhlbi.org/node/115604780nas a2200553 4500008004100000022001400041245014300055210006900198260001300267300001200280490000800292520317000300653000903470653002203479653001203501653001003513653003503523653001003558653001103568653002203579653003203601653001303633653001103646653001703657653003103674653000903705653001603714653001403730653003003744653002403774653002103798653002103819100002003840700002103860700001903881700002403900700002003924700002603944700001803970700002403988700002004012700002304032700002204055700002304077700002204100700002204122710004604144856003604190 2011 eng d a1460-215600aGenetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease.0 aGenetic variants of the NOTCH3 gene in the elderly and magnetic c2011 Nov a3384-970 v1343 aCerebral small vessel disease-related brain lesions such as white matter lesions and lacunes are common findings of magnetic resonance imaging in the elderly. These lesions are thought to be major contributors to disability in old age, and risk factors that include age and hypertension have been established. The radiological, histopathologic and clinical phenotypes of age-related cerebral small vessel disease remarkably resemble autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, which is caused by mutations in NOTCH3. We hypothesized that genetic variations in NOTCH3 also play a role in age-related cerebral small vessel disease. We directly sequenced all 33 exons, the promoter and 3'-untranslated region of NOTCH3 in 195 participants with either coalescent white matter lesions or lacunes and compared the results to 82 randomly selected participants with no focal changes on magnetic resonance images in the Austrian Stroke Prevention Study. We detected nine common and 33 rare single nucleotide polymorphisms, of which 20 were novel. All common single nucleotide polymorphisms were genotyped in the entire cohort (n = 888), and four of them, rs1043994, rs10404382, rs10423702 and rs1043997, were associated significantly with both the presence and progression of white matter lesions. The association was confined to hypertensives, a result which we replicated in the Cohorts for Heart and Ageing Research in Genomic Epidemiology Consortium on an independent sample of 4773 stroke-free hypertensive elderly individuals of European descent (P = 0.04). The 33 rare single nucleotide polymorphisms were scattered over the NOTCH3 gene with three being located in the promoter region, 24 in exons (18 non-synonymous), three in introns and three in the 3'-untranslated region. None of the single nucleotide polymorphisms affected a cysteine residue. Sorting Intolerant From Tolerant, PolyPhen2 analyses and protein structure simulation consistently predicted six of the non-synonymous single nucleotide polymorphisms (H170R, P496L, V1183M, L1518M, D1823N and V1952M) to be functional, with four being exclusively or mainly detected in subjects with severe white matter lesions. In four individuals with rare non-synonymous single nucleotide polymorphisms, we noted anterior temporal lobe hyperintensity, hyperintensity in the external capsule, lacunar infarcts or subcortical lacunar lesions. None of the observed abnormalities were specific to cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. This is the first comprehensive study investigating (i) the frequency of NOTCH3 variations in community-dwelling elderly and (ii) their effect on cerebral small vessel disease related magnetic resonance imaging phenotypes. We show that the NOTCH3 gene is highly variable with both common and rare single nucleotide polymorphisms spreading across the gene, and that common variants at the NOTCH3 gene increase the risk of age-related white matter lesions in hypertensives. Additional investigations are required to explore the biological mechanisms underlying the observed association.
10aAged10aAged, 80 and over10aAlleles10aBrain10aCerebral Small Vessel Diseases10aExons10aFemale10aFollow-Up Studies10aGenetic Association Studies10aGenotype10aHumans10aHypertension10aMagnetic Resonance Imaging10aMale10aMiddle Aged10aPhenotype10aPromoter Regions, Genetic10aProspective Studies10aReceptor, Notch310aReceptors, Notch1 aSchmidt, Helena1 aZeginigg, Marion1 aWiltgen, Marco1 aFreudenberger, Paul1 aPetrovic, Katja1 aCavalieri, Margherita1 aGider, Pierre1 aEnzinger, Christian1 aFornage, Myriam1 aDebette, Stephanie1 aRotter, Jerome, I1 aIkram, Mohammad, A1 aLauner, Lenore, J1 aSchmidt, Reinhold1 aCHARGE consortium Neurology working group uhttps://chs-nhlbi.org/node/134305055nas 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 aOBJECTIVE: 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/129809449nas a2203037 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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/132403656nas a2200589 4500008004100000022001400041245015400055210006900209260000900278300001100287490000600298520189800304653003802202653004002240653001102280653003202291653002602323653001102349653001202360653001302372653000902385653002602394653003602420653002402456653002702480100001902507700002102526700001802547700002302565700002202588700002902610700002302639700002002662700001702682700002302699700002602722700001702748700002302765700002002788700001902808700001902827700001902846700002002865700002002885700002202905700002202927700002002949700002102969700002002990700002003010856003603030 2014 eng d a1932-620300aAssociations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium.0 aAssociations of NINJ2 sequence variants with incident ischemic s c2014 ae997980 v93 aBACKGROUND: Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk.
METHODS AND RESULTS: We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] ≥ 1%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF≤ 1% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026).
CONCLUSION: Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings.
10aCell Adhesion Molecules, Neuronal10aEuropean Continental Ancestry Group10aFemale10aGenetic Association Studies10aGenetic Heterogeneity10aHumans10aIntrons10aIschemia10aMale10aMyocardial Infarction10aPolymorphism, Single Nucleotide10aProspective Studies10aSequence Analysis, DNA1 aBis, Joshua, C1 aDeStefano, Anita1 aLiu, Xiaoming1 aBrody, Jennifer, A1 aChoi, Seung, Hoan1 aVerhaaren, Benjamin, F J1 aDebette, Stephanie1 aIkram, Arfan, M1 aShahar, Eyal1 aButler, Kenneth, R1 aGottesman, Rebecca, F1 aMuzny, Donna1 aKovar, Christie, L1 aPsaty, Bruce, M1 aHofman, Albert1 aLumley, Thomas1 aGupta, Mayetri1 aWolf, Philip, A1 aDuijn, Cornelia1 aGibbs, Richard, A1 aMosley, Thomas, H1 aLongstreth, W T1 aBoerwinkle, Eric1 aSeshadri, Sudha1 aFornage, Myriam uhttps://chs-nhlbi.org/node/654804219nas a2200913 4500008004100000022001400041245008500055210006900140260001300209300001100222490000700233520168500240653001601925653000901941653002201950653002101972653002501993653001902018653004002037653001102077653003802088653003402126653001302160653001102173653000902184653001602193653003602209653002402245653001702269653001402286653001602300653001102316100003002327700002002357700001902377700002202396700002002418700002002438700001502458700001602473700002102489700003002510700002202540700002002562700002102582700001802603700002102621700002002642700001602662700002302678700001902701700001802720700002202738700002002760700002102780700002102801700002302822700001702845700002602862700002402888700001602912700002602928700001902954700001902973700002802992700002403020700002303044700001603067700001803083700002003101700002103121700002003142700002003162700002203182700002003204700002303224700002203247856003603269 2014 eng d a1524-462800aPredicting stroke through genetic risk functions: the CHARGE Risk Score Project.0 aPredicting stroke through genetic risk functions the CHARGE Risk c2014 Feb a403-120 v453 aBACKGROUND AND PURPOSE: Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors.
METHODS: The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke.
RESULTS: In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3×10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7×10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)).
CONCLUSIONS: The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.
10aAge Factors10aAged10aAged, 80 and over10aArea Under Curve10aCase-Control Studies10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRegression Analysis10aRisk Factors10aROC Curve10aSex Factors10aStroke1 aIbrahim-Verbaas, Carla, A1 aFornage, Myriam1 aBis, Joshua, C1 aChoi, Seung, Hoan1 aPsaty, Bruce, M1 aMeigs, James, B1 aRao, Madhu1 aNalls, Mike1 aFontes, João, D1 aO'Donnell, Christopher, J1 aKathiresan, Sekar1 aEhret, Georg, B1 aFox, Caroline, S1 aMalik, Rainer1 aDichgans, Martin1 aSchmidt, Helena1 aLahti, Jari1 aHeckbert, Susan, R1 aLumley, Thomas1 aRice, Kenneth1 aRotter, Jerome, I1 aTaylor, Kent, D1 aFolsom, Aaron, R1 aBoerwinkle, Eric1 aRosamond, Wayne, D1 aShahar, Eyal1 aGottesman, Rebecca, F1 aKoudstaal, Peter, J1 aAmin, Najaf1 aWieberdink, Renske, G1 aDehghan, Abbas1 aHofman, Albert1 aUitterlinden, André, G1 aDeStefano, Anita, L1 aDebette, Stephanie1 aXue, Luting1 aBeiser, Alexa1 aWolf, Philip, A1 aDeCarli, Charles1 aIkram, Arfan, M1 aSeshadri, Sudha1 aMosley, Thomas, H1 aLongstreth, W T1 aDuijn, Cornelia, M1 aLauner, Lenore, J uhttps://chs-nhlbi.org/node/622003472nas a2200781 4500008004100000022001400041245008200055210006900137260001300206300001500219490000700234520128200241653001001523653001201533653002201545653002201567653001001589653001101599653003401610653001601644653001101660653003101671653000901702653001501711653003601726653000901762653004101771100002001812700002201832700001901854700002101873700001201894700002801906700002601934700002501960700002601985700002102011700001502032700001602047700002102063700002002084700002102104700001902125700002202144700002802166700002202194700002302216700002102239700002002260700002302280700002202303700002202325700002202347700001902369700002102388700002402409700002302433700002202456700002202478700002702500700002202527700002002549700002202569700002002591700002002611700002302631856003602654 2015 eng d a1558-149700aAssociation of Alzheimer's disease GWAS loci with MRI markers of brain aging.0 aAssociation of Alzheimers disease GWAS loci with MRI markers of c2015 Apr a1765.e7-160 v363 aWhether novel risk variants of Alzheimer's disease (AD) identified through genome-wide association studies also influence magnetic resonance imaging-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume, total brain volume, hippocampal volume (HV), white matter hyperintensity burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N = 8175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (p = 0.0054) and CD33 (rs3865444) with smaller intracranial volume (p = 0.0058). In gene-based tests, there was associations of HLA-DRB1 with total brain volume (p = 0.0006) and BIN1 with HV (p = 0.00089). A weighted AD genetic risk score was associated with smaller HV (beta ± SE = -0.047 ± 0.013, p = 0.00041), even after excluding the APOE locus (p = 0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in nondemented older community persons.
10aAging10aAlleles10aAlzheimer Disease10aApolipoproteins E10aBrain10aFemale10aGenome-Wide Association Study10aHippocampus10aHumans10aMagnetic Resonance Imaging10aMale10aOrgan Size10aPolymorphism, Single Nucleotide10aRisk10aSialic Acid Binding Ig-like Lectin 31 aChauhan, Ganesh1 aAdams, Hieab, H H1 aBis, Joshua, C1 aWeinstein, Galit1 aYu, Lei1 aTöglhofer, Anna, Maria1 aSmith, Albert, Vernon1 avan der Lee, Sven, J1 aGottesman, Rebecca, F1 aThomson, Russell1 aWang, Jing1 aYang, Qiong1 aNiessen, Wiro, J1 aLopez, Oscar, L1 aBecker, James, T1 aPhan, Thanh, G1 aBeare, Richard, J1 aArfanakis, Konstantinos1 aFleischman, Debra1 aVernooij, Meike, W1 aMazoyer, Bernard1 aSchmidt, Helena1 aSrikanth, Velandai1 aKnopman, David, S1 aJack, Clifford, R1 aAmouyel, Philippe1 aHofman, Albert1 aDeCarli, Charles1 aTzourio, Christophe1 aDuijn, Cornelia, M1 aBennett, David, A1 aSchmidt, Reinhold1 aLongstreth, William, T1 aMosley, Thomas, H1 aFornage, Myriam1 aLauner, Lenore, J1 aSeshadri, Sudha1 aIkram, Arfan, M1 aDebette, Stephanie uhttps://chs-nhlbi.org/node/681504590nas a2200889 4500008004100000022001400041245009700055210006900152260001500221300001100236490000700247520195700254653003502211653002102246653003202267653002202299653001102321653003602332100002502368700001702393700002202410700001702432700002202449700002202471700002102493700002902514700002402543700002102567700001702588700002002605700002002625700002502645700001702670700002002687700002302707700002402730700001902754700002302773700002202796700002102818700002202839700002202861700002002883700001902903700002302922700002302945700002402968700002202992700002003014700001603034700001903050700002303069700002503092700002703117700002503144700001603169700002303185700002203208700002803230700002003258700001803278700001803296700002503314700002103339700002103360700001603381700002003397700002003417700002103437700002403458710002603482710002103508710003803529710005203567710004503619856003603664 2015 ENG d a1526-632X00aCommon variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease.0 aCommon variation in COL4A1COL4A2 is associated with sporadic cer c2015 Mar 3 a918-260 v843 aOBJECTIVES: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease.
METHODS: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084).
RESULTS: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes.
CONCLUSIONS: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.
10aCerebral Small Vessel Diseases10aCollagen Type IV10aGenetic Association Studies10aGenetic Variation10aHumans10aPolymorphism, Single Nucleotide1 aRannikmae, Kristiina1 aDavies, Gail1 aThomson, Pippa, A1 aBevan, Steve1 aDevan, William, J1 aFalcone, Guido, J1 aTraylor, Matthew1 aAnderson, Christopher, D1 aBattey, Thomas, W K1 aRadmanesh, Farid1 aDeka, Ranjan1 aWoo, Jessica, G1 aMartin, Lisa, J1 aJimenez-Conde, Jordi1 aSelim, Magdy1 aBrown, Devin, L1 aSilliman, Scott, L1 aKidwell, Chelsea, S1 aMontaner, Joan1 aLangefeld, Carl, D1 aSlowik, Agnieszka1 aHansen, Bjorn, M1 aLindgren, Arne, G1 aMeschia, James, F1 aFornage, Myriam1 aBis, Joshua, C1 aDebette, Stephanie1 aIkram, Mohammad, A1 aLongstreth, Will, T1 aSchmidt, Reinhold1 aZhang, Cathy, R1 aYang, Qiong1 aSharma, Pankaj1 aKittner, Steven, J1 aMitchell, Braxton, D1 aHolliday, Elizabeth, G1 aLevi, Christopher, R1 aAttia, John1 aRothwell, Peter, M1 aPoole, Deborah, L1 aBoncoraglio, Giorgio, B1 aPsaty, Bruce, M1 aMalik, Rainer1 aRost, Natalia1 aWorrall, Bradford, B1 aDichgans, Martin1 aVan Agtmael, Tom1 aWoo, Daniel1 aMarkus, Hugh, S1 aSeshadri, Sudha1 aRosand, Jonathan1 aSudlow, Cathie, L M1 aMETASTROKE Consortium1 aCHARGE WMH Group1 aISGC ICH GWAS Study Collaboration1 aWMH in Ischemic Stroke GWAS Study Collaboration1 aInternational Stroke Genetics Consortium uhttps://chs-nhlbi.org/node/686403799nas 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/668406153nas a2201525 4500008004100000022001400041245009600055210006900151260001300220300001200233490000600245520187500251653000902126653002202135653002302157653003402180653001102214653001702225653003402242653001102276653000902287653002702296653001602323653002002339653001102359653001702370100002902387700002302416700001902439700002302458700001802481700002002499700002302519700002002542700002002562700001902582700002402601700002602625700002102651700002402672700002402696700002302720700002702743700002002770700002102790700002202811700002102833700002202854700001602876700002002892700002902912700002202941700002502963700002202988700001803010700001803028700002403046700002003070700002603090700002003116700002403136700002603160700002503186700001903211700002303230700001903253700001703272700001703289700001903306700003003325700002203355700001903377700001703396700002403413700002203437700002203459700002403481700002003505700002103525700001603546700002003562700002103582700001903603700002003622700002103642700002203663700002703685700002003712700002503732700001903757700002303776700002503799700002003824700002203844700002503866700002203891700002803913700002103941700002003962700002303982700002404005700001604029700002804045700002304073700001804096700001804114700002304132700001804155700002404173700002104197700002304218700001604241700001404257700002004271700001904291700002004310700002404330700002204354700002204376700002004398700002404418700002304442700002204465700002204487700001904509700002304528700002004551700002004571856003604591 2015 eng d a1942-326800aMultiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.0 aMultiethnic genomewide association study of cerebral white matte c2015 Apr a398-4090 v83 aBACKGROUND: The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.
METHODS AND RESULTS: We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).
CONCLUSIONS: We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.
10aAged10aAged, 80 and over10aChromosomes, Human10aContinental Population Groups10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aMiddle Aged10aModels, Genetic10aStroke10aWhite Matter1 aVerhaaren, Benjamin, F J1 aDebette, Stephanie1 aBis, Joshua, C1 aSmith, Jennifer, A1 aIkram, Kamran1 aAdams, Hieab, H1 aBeecham, Ashley, H1 aRajan, Kumar, B1 aLopez, Lorna, M1 aBarral, Sandra1 avan Buchem, Mark, A1 avan der Grond, Jeroen1 aSmith, Albert, V1 aHegenscheid, Katrin1 aAggarwal, Neelum, T1 ade Andrade, Mariza1 aAtkinson, Elizabeth, J1 aBeekman, Marian1 aBeiser, Alexa, S1 aBlanton, Susan, H1 aBoerwinkle, Eric1 aBrickman, Adam, M1 aBryan, Nick1 aChauhan, Ganesh1 aChen, Christopher, P L H1 aChouraki, Vincent1 ade Craen, Anton, J M1 aCrivello, Fabrice1 aDeary, Ian, J1 aDeelen, Joris1 aDe Jager, Philip, L1 aDufouil, Carole1 aElkind, Mitchell, S V1 aEvans, Denis, A1 aFreudenberger, Paul1 aGottesman, Rebecca, F1 aGuðnason, Vilmundur1 aHabes, Mohamad1 aHeckbert, Susan, R1 aHeiss, Gerardo1 aHilal, Saima1 aHofer, Edith1 aHofman, Albert1 aIbrahim-Verbaas, Carla, A1 aKnopman, David, S1 aLewis, Cora, E1 aLiao, Jiemin1 aLiewald, David, C M1 aLuciano, Michelle1 avan der Lugt, Aad1 aMartinez, Oliver, O1 aMayeux, Richard1 aMazoyer, Bernard1 aNalls, Mike1 aNauck, Matthias1 aNiessen, Wiro, J1 aOostra, Ben, A1 aPsaty, Bruce, M1 aRice, Kenneth, M1 aRotter, Jerome, I1 avon Sarnowski, Bettina1 aSchmidt, Helena1 aSchreiner, Pamela, J1 aSchuur, Maaike1 aSidney, Stephen, S1 aSigurdsson, Sigurdur1 aSlagboom, Eline1 aStott, David, J M1 avan Swieten, John, C1 aTeumer, Alexander1 aTöglhofer, Anna, Maria1 aTraylor, Matthew1 aTrompet, Stella1 aTurner, Stephen, T1 aTzourio, Christophe1 aUh, Hae-Won1 aUitterlinden, André, G1 aVernooij, Meike, W1 aWang, Jing, J1 aWong, Tien, Y1 aWardlaw, Joanna, M1 aWindham, Gwen1 aWittfeld, Katharina1 aWolf, Christiane1 aWright, Clinton, B1 aYang, Qiong1 aZhao, Wei1 aZijdenbos, Alex1 aJukema, Wouter1 aSacco, Ralph, L1 aKardia, Sharon, L R1 aAmouyel, Philippe1 aMosley, Thomas, H1 aLongstreth, W T1 aDeCarli, Charles, C1 aDuijn, Cornelia, M1 aSchmidt, Reinhold1 aLauner, Lenore, J1 aGrabe, Hans, J1 aSeshadri, Sudha, S1 aIkram, Arfan, M1 aFornage, Myriam uhttps://chs-nhlbi.org/node/668304741nas a2201021 4500008004100000022001400041245008000055210006900135260001300204300001200217490000700229520186200236653001002098653000902108653001902117653002402136653001102160653003802171653003402209653001102243653002602254653000902280653001602289653002402305653001702329100001702346700002602363700001902389700002102408700002002429700002502449700002302474700002002497700002902517700002102546700001602567700002202583700002202605700001802627700002402645700002302669700002002692700002502712700002002737700002302757700001402780700002402794700002602818700002402844700001902868700001902887700001902906700002102925700002102946700001702967700002102984700001603005700002003021700002603041700001903067700002303086700002103109700002003130700001803150700002003168700002003188700002103208700002403229700002403253700002103277700001503298700002603313700001803339700002303357700002003380700001903400700002303419700002003442700001903462700002203481700002003503700002203523700002003545700002003565700002203585710007603607856003603683 2015 eng d a1524-462800aWhite Matter Lesion Progression: Genome-Wide Search for Genetic Influences.0 aWhite Matter Lesion Progression GenomeWide Search for Genetic In c2015 Nov a3048-570 v463 aBACKGROUND AND PURPOSE: White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.
METHODS: Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies.
RESULTS: A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10(-8)). Four loci were suggestive (P<1×10(-5)) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10(-6)); 12q13.13 (rs4761974, P=8.71×10(-7)); 20p12.1 (rs6135309, P=3.69×10(-6)); and 4p15.31 (rs7664442, P=2.26×10(-6)). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden.
CONCLUSIONS: Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.
10aAdult10aAged10aCohort Studies10aDisease Progression10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLeukoencephalopathies10aMale10aMiddle Aged10aProspective Studies10aWhite Matter1 aHofer, Edith1 aCavalieri, Margherita1 aBis, Joshua, C1 aDeCarli, Charles1 aFornage, Myriam1 aSigurdsson, Sigurdur1 aSrikanth, Velandai1 aTrompet, Stella1 aVerhaaren, Benjamin, F J1 aWolf, Christiane1 aYang, Qiong1 aAdams, Hieab, H H1 aAmouyel, Philippe1 aBeiser, Alexa1 aBuckley, Brendan, M1 aCallisaya, Michele1 aChauhan, Ganesh1 ade Craen, Anton, J M1 aDufouil, Carole1 aDuijn, Cornelia, M1 aFord, Ian1 aFreudenberger, Paul1 aGottesman, Rebecca, F1 aGudnason, Vilmundur1 aHeiss, Gerardo1 aHofman, Albert1 aLumley, Thomas1 aMartinez, Oliver1 aMazoyer, Bernard1 aMoran, Chris1 aNiessen, Wiro, J1 aPhan, Thanh1 aPsaty, Bruce, M1 aSatizabal, Claudia, L1 aSattar, Naveed1 aSchilling, Sabrina1 aShibata, Dean, K1 aSlagboom, Eline1 aSmith, Albert1 aStott, David, J1 aTaylor, Kent, D1 aThomson, Russell1 aTöglhofer, Anna, M1 aTzourio, Christophe1 avan Buchem, Mark1 aWang, Jing1 aWestendorp, Rudi, G J1 aWindham, Gwen1 aVernooij, Meike, W1 aZijdenbos, Alex1 aBeare, Richard1 aDebette, Stephanie1 aIkram, Arfan, M1 aJukema, Wouter1 aLauner, Lenore, J1 aLongstreth, W T1 aMosley, Thomas, H1 aSeshadri, Sudha1 aSchmidt, Helena1 aSchmidt, Reinhold1 aCohorts for Heart and Aging Research in Genomic Epidemiology Consortium uhttps://chs-nhlbi.org/node/686104818nas a2201141 4500008004100000022001400041245011000055210006900165260001300234300001100247490000700258520157500265653001001840653003901850653001701889653000901906653003701915653001901952653003201971653002402003653002002027653004002047653001102087653003802098653003402136653001102170653000902181653001602190653001502206653003602221653002602257653001102283100002002294700002002314700002302334700001902357700002102376700002202397700002702419700001802446700001602464700002302480700001802503700002602521700001702547700001802564700001402582700002102596700002702617700002302644700001802667700001702685700001902702700002002721700002302741700002402764700002302788700001702811700001702828700002302845700001902868700002202887700001902909700002402928700001602952700001502968700002002983700002103003700002103024700002103045700001903066700002003085700002203105700002303127700002403150700003003174700002203204700002603226700002003252700002503272700002003297700002003317700002203337700002003359700001903379700002203398700002003420700002203440700002103462700002803483700002003511700002303531700001703554700002103571700002503592710002303617856003603640 2016 eng d a1524-462800aGenome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2.0 aGenomeWide Association Analysis of YoungOnset Stroke Identifies c2016 Feb a307-160 v473 aBACKGROUND AND PURPOSE: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years.
METHODS: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls.
RESULTS: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2.
CONCLUSIONS: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.
10aAdult10aAfrican Continental Ancestry Group10aAge of Onset10aAged10aAsian Continental Ancestry Group10aBrain Ischemia10aChromosomes, Human, Pair 1010aComputer Simulation10aDNA, Intergenic10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aOdds Ratio10aPolymorphism, Single Nucleotide10aSerine Endopeptidases10aStroke1 aCheng, Yu-Ching1 aStanne, Tara, M1 aGiese, Anne-Katrin1 aHo, Weang, Kee1 aTraylor, Matthew1 aAmouyel, Philippe1 aHolliday, Elizabeth, G1 aMalik, Rainer1 aXu, Huichun1 aKittner, Steven, J1 aCole, John, W1 aO'Connell, Jeffrey, R1 aDanesh, John1 aRasheed, Asif1 aZhao, Wei1 aEngelter, Stefan1 aGrond-Ginsbach, Caspar1 aKamatani, Yoichiro1 aLathrop, Mark1 aLeys, Didier1 aThijs, Vincent1 aMetso, Tiina, M1 aTatlisumak, Turgut1 aPezzini, Alessandro1 aParati, Eugenio, A1 aNorrving, Bo1 aBevan, Steve1 aRothwell, Peter, M1 aSudlow, Cathie1 aSlowik, Agnieszka1 aLindgren, Arne1 aWalters, Matthew, R1 aJannes, Jim1 aShen, Jess1 aCrosslin, David1 aDoheny, Kimberly1 aLaurie, Cathy, C1 aKanse, Sandip, M1 aBis, Joshua, C1 aFornage, Myriam1 aMosley, Thomas, H1 aHopewell, Jemma, C1 aStrauch, Konstantin1 aMüller-Nurasyid, Martina1 aGieger, Christian1 aWaldenberger, Melanie1 aPeters, Annette1 aMeisinger, Christine1 aIkram, Arfan, M1 aLongstreth, W T1 aMeschia, James, F1 aSeshadri, Sudha1 aSharma, Pankaj1 aWorrall, Bradford1 aJern, Christina1 aLevi, Christopher1 aDichgans, Martin1 aBoncoraglio, Giorgio, B1 aMarkus, Hugh, S1 aDebette, Stephanie1 aRolfs, Arndt1 aSaleheen, Danish1 aMitchell, Braxton, D1 aWTCCC-2 Consortium uhttps://chs-nhlbi.org/node/699106999nas a2202113 4500008004100000022001400041245011100055210006900166260001300235300001200248490000700260520104100267100003001308700002201338700002201360700001701382700002301399700001801422700001901440700001901459700002101478700002501499700001801524700002201542700001501564700001801579700002501597700001801622700002001640700003001660700001801690700002301708700002601731700001801757700002001775700002201795700002301817700002301840700002201863700002801885700002101913700001801934700002801952700001701980700001901997700002602016700002702042700001302069700002102082700001802103700002202121700002202143700001802165700002202183700001502205700002102220700001902241700001602260700002302276700002302299700002002322700001602342700002502358700002102383700002302404700002602427700001802453700002302471700001902494700002302513700002602536700001902562700002002581700002002601700002002621700002202641700002202663700002202685700002402707700002502731700002202756700002002778700002602798700002002824700001902844700002102863700002002884700001802904700002302922700002002945700002002965700001502985700002103000700001803021700002403039700002303063700002503086700001903111700001503130700001903145700002203164700001403186700002003200700002203220700001703242700002203259700002503281700001203306700002103318700001803339700001903357700001803376700002903394700002003423700002103443700002503464700002003489700002203509700002703531700002303558700001703581700002503598700002003623700001803643700002103661700002203682700001903704700002903723700002303752700002503775700003203800700001903832700001903851700002203870700002403892700002803916700001903944700002103963700001703984700002404001700002204025700001804047700001704065700002104082700002004103700002404123700001904147700002004166700001904186700001704205700002104222700001504243700002304258700002204281700002304303700001904326700002204345700002204367700002004389700002204409700002304431700001904454700002204473700002404495700001904519700001804538700001904556700002304575700002304598700002404621700002204645700002404667700002204691700002404713710003804737710005304775710002104828856003604849 2017 eng d a1546-171800aLarge-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.0 aLargescale analyses of common and rare variants identify 12 new c2017 Jun a946-9520 v493 aAtrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.
1 aChristophersen, Ingrid, E1 aRienstra, Michiel1 aRoselli, Carolina1 aYin, Xiaoyan1 aGeelhoed, Bastiaan1 aBarnard, John1 aLin, Honghuang1 aArking, Dan, E1 aSmith, Albert, V1 aAlbert, Christine, M1 aChaffin, Mark1 aTucker, Nathan, R1 aLi, Molong1 aKlarin, Derek1 aBihlmeyer, Nathan, A1 aLow, Siew-Kee1 aWeeke, Peter, E1 aMüller-Nurasyid, Martina1 aSmith, Gustav1 aBrody, Jennifer, A1 aNiemeijer, Maartje, N1 aDörr, Marcus1 aTrompet, Stella1 aHuffman, Jennifer1 aGustafsson, Stefan1 aSchurmann, Claudia1 aKleber, Marcus, E1 aLyytikäinen, Leo-Pekka1 aSeppälä, Ilkka1 aMalik, Rainer1 aHorimoto, Andrea, R V R1 aPerez, Marco1 aSinisalo, Juha1 aAeschbacher, Stefanie1 aThériault, Sébastien1 aYao, Jie1 aRadmanesh, Farid1 aWeiss, Stefan1 aTeumer, Alexander1 aChoi, Seung, Hoan1 aWeng, Lu-Chen1 aClauss, Sebastian1 aDeo, Rajat1 aRader, Daniel, J1 aShah, Svati, H1 aSun, Albert1 aHopewell, Jemma, C1 aDebette, Stephanie1 aChauhan, Ganesh1 aYang, Qiong1 aWorrall, Bradford, B1 aParé, Guillaume1 aKamatani, Yoichiro1 aHagemeijer, Yanick, P1 aVerweij, Niek1 aSiland, Joylene, E1 aKubo, Michiaki1 aSmith, Jonathan, D1 aVan Wagoner, David, R1 aBis, Joshua, C1 aPerz, Siegfried1 aPsaty, Bruce, M1 aRidker, Paul, M1 aMagnani, Jared, W1 aHarris, Tamara, B1 aLauner, Lenore, J1 aShoemaker, Benjamin1 aPadmanabhan, Sandosh1 aHaessler, Jeffrey1 aBartz, Traci, M1 aWaldenberger, Melanie1 aLichtner, Peter1 aArendt, Marina1 aKrieger, Jose, E1 aKähönen, Mika1 aRisch, Lorenz1 aMansur, Alfredo, J1 aPeters, Annette1 aSmith, Blair, H1 aLind, Lars1 aScott, Stuart, A1 aLu, Yingchang1 aBottinger, Erwin, B1 aHernesniemi, Jussi1 aLindgren, Cecilia, M1 aWong, Jorge, A1 aHuang, Jie1 aEskola, Markku1 aMorris, Andrew, P1 aFord, Ian1 aReiner, Alex, P1 aDelgado, Graciela1 aChen, Lin, Y1 aChen, Yii-Der Ida1 aSandhu, Roopinder, K1 aLi, Man1 aBoerwinkle, Eric1 aEisele, Lewin1 aLannfelt, Lars1 aRost, Natalia1 aAnderson, Christopher, D1 aTaylor, Kent, D1 aCampbell, Archie1 aMagnusson, Patrik, K1 aPorteous, David1 aHocking, Lynne, J1 aVlachopoulou, Efthymia1 aPedersen, Nancy, L1 aNikus, Kjell1 aOrho-Melander, Marju1 aHamsten, Anders1 aHeeringa, Jan1 aDenny, Joshua, C1 aKriebel, Jennifer1 aDarbar, Dawood1 aNewton-Cheh, Christopher1 aShaffer, Christian1 aMacfarlane, Peter, W1 aHeilmann-Heimbach, Stefanie1 aAlmgren, Peter1 aHuang, Paul, L1 aSotoodehnia, Nona1 aSoliman, Elsayed, Z1 aUitterlinden, André, G1 aHofman, Albert1 aFranco, Oscar, H1 aVölker, Uwe1 aJöckel, Karl-Heinz1 aSinner, Moritz, F1 aLin, Henry, J1 aGuo, Xiuqing1 aDichgans, Martin1 aIngelsson, Erik1 aKooperberg, Charles1 aMelander, Olle1 aLoos, Ruth, J F1 aLaurikka, Jari1 aConen, David1 aRosand, Jonathan1 aHarst, Pim1 aLokki, Marja-Liisa1 aKathiresan, Sekar1 aPereira, Alexandre1 aJukema, Wouter1 aHayward, Caroline1 aRotter, Jerome, I1 aMärz, Winfried1 aLehtimäki, Terho1 aStricker, Bruno, H1 aChung, Mina, K1 aFelix, Stephan, B1 aGudnason, Vilmundur1 aAlonso, Alvaro1 aRoden, Dan, M1 aKääb, Stefan1 aChasman, Daniel, I1 aHeckbert, Susan, R1 aBenjamin, Emelia, J1 aTanaka, Toshihiro1 aLunetta, Kathryn, L1 aLubitz, Steven, A1 aEllinor, Patrick, T1 aMETASTROKE Consortium of the ISGC1 aNeurology Working Group of the CHARGE Consortium1 aAFGen Consortium uhttps://chs-nhlbi.org/node/739609467nas a2203025 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2017 eng d a1524-456300aNovel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.0 aNovel Blood Pressure Locus and Gene Discovery Using GenomeWide A c2017 Jul 243 aElevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
1 aWain, Louise, V1 aVaez, Ahmad1 aJansen, Rick1 aJoehanes, Roby1 avan der Most, Peter, J1 aErzurumluoglu, Mesut1 aO'Reilly, Paul, F1 aCabrera, Claudia, P1 aWarren, Helen, R1 aRose, Lynda, M1 aVerwoert, Germaine, C1 aHottenga, Jouke-Jan1 aStrawbridge, Rona, J1 aEsko, Tõnu1 aArking, Dan, E1 aHwang, Shih-Jen1 aGuo, Xiuqing1 aKutalik, Zoltán1 aTrompet, Stella1 aShrine, Nick1 aTeumer, Alexander1 aRied, Janina, S1 aBis, Joshua, C1 aSmith, Albert, V1 aAmin, Najaf1 aNolte, Ilja, M1 aLyytikäinen, Leo-Pekka1 aMahajan, Anubha1 aWareham, Nicholas, J1 aHofer, Edith1 aJoshi, Peter, K1 aKristiansson, Kati1 aTraglia, Michela1 aHavulinna, Aki, S1 aGoel, Anuj1 aNalls, Mike, A1 aSõber, Siim1 aVuckovic, Dragana1 aLuan, Jian'an1 aM, Fabiola, del Greco1 aAyers, Kristin, L1 aMarrugat, Jaume1 aRuggiero, Daniela1 aLopez, Lorna, M1 aNiiranen, Teemu1 aEnroth, Stefan1 aJackson, Anne, U1 aNelson, Christopher, P1 aHuffman, Jennifer, E1 aZhang, Weihua1 aMarten, Jonathan1 aGandin, Ilaria1 aHarris, Sarah, E1 aZemunik, Tatijana1 aLu, Yingchang1 aEvangelou, Evangelos1 aShah, Nabi1 ade Borst, Martin, H1 aMangino, Massimo1 aPrins, Bram, P1 aCampbell, Archie1 aLi-Gao, Ruifang1 aChauhan, Ganesh1 aOldmeadow, Christopher1 aAbecasis, Goncalo1 aAbedi, Maryam1 aBarbieri, Caterina, M1 aBarnes, Michael, R1 aBatini, Chiara1 aBeilby, John1 aBlake, Tineka1 aBoehnke, Michael1 aBottinger, Erwin, P1 aBraund, Peter, S1 aBrown, Morris1 aBrumat, Marco1 aCampbell, Harry1 aChambers, John, C1 aCocca, Massimiliano1 aCollins, Francis1 aConnell, John1 aCordell, Heather, J1 aDamman, Jeffrey, J1 aDavies, Gail1 ade Geus, Eco, J1 ade Mutsert, Renée1 aDeelen, Joris1 aDemirkale, Yusuf1 aDoney, Alex, S F1 aDörr, Marcus1 aFarrall, Martin1 aFerreira, Teresa1 aFrånberg, Mattias1 aGao, He1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGiulianini, Franco1 aGow, Alan, J1 aHamsten, Anders1 aHarris, Tamara, B1 aHofman, Albert1 aHolliday, Elizabeth, G1 aHui, Jennie1 aJarvelin, Marjo-Riitta1 aJohansson, Asa1 aJohnson, Andrew, D1 aJousilahti, Pekka1 aJula, Antti1 aKähönen, Mika1 aKathiresan, Sekar1 aKhaw, Kay-Tee1 aKolcic, Ivana1 aKoskinen, Seppo1 aLangenberg, Claudia1 aLarson, Marty1 aLauner, Lenore, J1 aLehne, Benjamin1 aLiewald, David, C M1 aLin, Li1 aLind, Lars1 aMach, François1 aMamasoula, Chrysovalanto1 aMenni, Cristina1 aMifsud, Borbala1 aMilaneschi, Yuri1 aMorgan, Anna1 aMorris, Andrew, D1 aMorrison, Alanna, C1 aMunson, Peter, J1 aNandakumar, Priyanka1 aNguyen, Quang, Tri1 aNutile, Teresa1 aOldehinkel, Albertine, J1 aOostra, Ben, A1 aOrg, Elin1 aPadmanabhan, Sandosh1 aPalotie, Aarno1 aParé, Guillaume1 aPattie, Alison1 aPenninx, Brenda, W J H1 aPoulter, Neil1 aPramstaller, Peter, P1 aRaitakari, Olli, T1 aRen, Meixia1 aRice, Kenneth1 aRidker, Paul, M1 aRiese, Harriëtte1 aRipatti, Samuli1 aRobino, Antonietta1 aRotter, Jerome, I1 aRudan, Igor1 aSaba, Yasaman1 aPierre, Aude, Saint1 aSala, Cinzia, F1 aSarin, Antti-Pekka1 aSchmidt, Reinhold1 aScott, Rodney1 aSeelen, Marc, A1 aShields, Denis, C1 aSiscovick, David1 aSorice, Rossella1 aStanton, Alice1 aStott, David, J1 aSundström, Johan1 aSwertz, Morris1 aTaylor, Kent, D1 aThom, Simon1 aTzoulaki, Ioanna1 aTzourio, Christophe1 aUitterlinden, André, G1 aVölker, Uwe1 aVollenweider, Peter1 aWild, Sarah1 aWillemsen, Gonneke1 aWright, Alan, F1 aYao, Jie1 aThériault, Sébastien1 aConen, David1 aAttia, John1 aSever, Peter1 aDebette, Stephanie1 aMook-Kanamori, Dennis, O1 aZeggini, Eleftheria1 aSpector, Tim, D1 aHarst, Pim1 aPalmer, Colin, N A1 aVergnaud, Anne-Claire1 aLoos, Ruth, J F1 aPolasek, Ozren1 aStarr, John, M1 aGirotto, Giorgia1 aHayward, Caroline1 aKooner, Jaspal, S1 aLindgren, Cecila, M1 aVitart, Veronique1 aSamani, Nilesh, J1 aTuomilehto, Jaakko1 aGyllensten, Ulf1 aKnekt, Paul1 aDeary, Ian, J1 aCiullo, Marina1 aElosua, Roberto1 aKeavney, Bernard, D1 aHicks, Andrew, A1 aScott, Robert, A1 aGasparini, Paolo1 aLaan, Maris1 aLiu, Yongmei1 aWatkins, Hugh1 aHartman, Catharina, A1 aSalomaa, Veikko1 aToniolo, Daniela1 aPerola, Markus1 aWilson, James, F1 aSchmidt, Helena1 aZhao, Jing Hua1 aLehtimäki, Terho1 aDuijn, Cornelia, M1 aGudnason, Vilmundur1 aPsaty, Bruce, M1 aPeters, Annette1 aRettig, Rainer1 aJames, Alan1 aJukema, Wouter1 aStrachan, David, P1 aPalmas, Walter1 aMetspalu, Andres1 aIngelsson, Erik1 aBoomsma, Dorret, I1 aFranco, Oscar, H1 aBochud, Murielle1 aNewton-Cheh, Christopher1 aMunroe, Patricia, B1 aElliott, Paul1 aChasman, Daniel, I1 aChakravarti, Aravinda1 aKnight, Joanne1 aMorris, Andrew, P1 aLevy, Daniel1 aTobin, Martin, D1 aSnieder, Harold1 aCaulfield, Mark, J1 aEhret, Georg, B uhttps://chs-nhlbi.org/node/749203062nas a2200601 4500008004100000022001400041245009700055210006900152260001300221300001200234490000700246520134100253100002101594700002201615700002501637700001801662700001901680700001901699700002101718700001601739700001801755700003001773700002601803700002301829700002901852700002001881700002001901700002001921700002401941700003501965700002202000700002002022700001802042700001602060700002102076700001902097700002002116700002002136700002202156700001902178700001702197700002002214700002602234700002002260700001802280700002602298700002402324700001702348700001902365700002102384700001902405856003602424 2017 eng d a1573-728400aTrends in the incidence of dementia: design and methods in the Alzheimer Cohorts Consortium.0 aTrends in the incidence of dementia design and methods in the Al c2017 Oct a931-9380 v323 aSeveral studies have reported a decline in incidence of dementia which may have large implications for the projected burden of disease, and provide important guidance to preventive efforts. However, reports are conflicting or inconclusive with regard to the impact of gender and education with underlying causes of a presumed declining trend remaining largely unidentified. The Alzheimer Cohorts Consortium aggregates data from nine international population-based cohorts to determine changes in the incidence of dementia since 1990. We will employ Poisson regression models to calculate incidence rates in each cohort and Cox proportional hazard regression to compare 5-year cumulative hazards across study-specific epochs. Finally, we will meta-analyse changes per decade across cohorts, and repeat all analysis stratified by sex, education and APOE genotype. In all cohorts combined, there are data on almost 69,000 people at risk of dementia with the range of follow-up years between 2 and 27. The average age at baseline is similar across cohorts ranging between 72 and 77. Uniting a wide range of disease-specific and methodological expertise in research teams, the first analyses within the Alzheimer Cohorts Consortium are underway to tackle outstanding challenges in the assessment of time-trends in dementia occurrence.
1 aChibnik, Lori, B1 aWolters, Frank, J1 aBäckman, Kristoffer1 aBeiser, Alexa1 aBerr, Claudine1 aBis, Joshua, C1 aBoerwinkle, Eric1 aBos, Daniel1 aBrayne, Carol1 aDartigues, Jean-François1 aDarweesh, Sirwan, K L1 aDebette, Stephanie1 aDavis-Plourde, Kendra, L1 aDufouil, Carole1 aFornage, Myriam1 aGrasset, Leslie1 aGudnason, Vilmundur1 aHadjichrysanthou, Christoforos1 aHelmer, Catherine1 aIkram, Arfan, M1 aIkram, Kamran1 aKern, Silke1 aKuller, Lewis, H1 aLauner, Lenore1 aLopez, Oscar, L1 aMatthews, Fiona1 aMeirelles, Osorio1 aMosley, Thomas1 aOwer, Alison1 aPsaty, Bruce, M1 aSatizabal, Claudia, L1 aSeshadri, Sudha1 aSkoog, Ingmar1 aStephan, Blossom, C M1 aTzourio, Christophe1 aWaziry, Reem1 aWong, Mei, Mei1 aZettergren, Anna1 aHofman, Albert uhttps://chs-nhlbi.org/node/755405244nas a2201057 4500008004100000022001400041245014200055210006900197260001600266520216400282100001702446700002602463700002102489700002402510700001902534700002302553700001802576700001802594700001702612700002502629700002102654700001902675700002202694700001302716700002202729700001402751700002302765700001802788700001902806700002002825700002402845700001802869700002202887700001602909700002102925700002402946700002402970700001902994700002303013700002603036700001903062700002403081700002203105700002303127700001803150700003703168700001903205700002103224700002003245700002103265700002003286700001603306700002403322700001903346700002003365700002503385700002803410700002703438700002003465700002203485700002503507700002103532700002303553700002103576700002703597700002603624700001703650700002503667700002303692700002303715700002203738700002303760700002003783700002203803700002403825700002203849700002203871700002103893700001803914700002003932700002403952700002003976700002303996700001904019700002004038700002004058700002204078700002004100710003004120856003604150 2018 eng d a1524-462800aExome Chip Analysis Identifies Low-Frequency and Rare Variants in for White Matter Hyperintensities on Brain Magnetic Resonance Imaging.0 aExome Chip Analysis Identifies LowFrequency and Rare Variants in c2018 Jul 123 aBACKGROUND AND PURPOSE: White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored.
METHODS: In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies.
RESULTS: At 17q25, we confirmed the association of multiple common variants in , , and (<6×10). We also identified a novel association with 2 low-frequency nonsynonymous variants in (lead, rs34136221; =4.5×10) partially independent of known common signal (=1.4×10). We further identified a locus at 2q33 containing common variants in , , and (lead, rs2351524; =1.9×10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency variants (=2.8×10).
CONCLUSIONS: Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.
1 aJian, Xueqiu1 aSatizabal, Claudia, L1 aSmith, Albert, V1 aWittfeld, Katharina1 aBis, Joshua, C1 aSmith, Jennifer, A1 aHsu, Fang-Chi1 aNho, Kwangsik1 aHofer, Edith1 aHagenaars, Saskia, P1 aNyquist, Paul, A1 aMishra, Aniket1 aAdams, Hieab, H H1 aLi, Shuo1 aTeumer, Alexander1 aZhao, Wei1 aFreedman, Barry, I1 aSaba, Yasaman1 aYanek, Lisa, R1 aChauhan, Ganesh1 avan Buchem, Mark, A1 aCushman, Mary1 aRoyle, Natalie, A1 aBryan, Nick1 aNiessen, Wiro, J1 aWindham, Beverly, G1 aDeStefano, Anita, L1 aHabes, Mohamad1 aHeckbert, Susan, R1 aPalmer, Nicholette, D1 aLewis, Cora, E1 aEiriksdottir, Gudny1 aMaillard, Pauline1 aMathias, Rasika, A1 aHomuth, Georg1 aValdés-Hernández, Maria, Del C1 aDivers, Jasmin1 aBeiser, Alexa, S1 aLangner, Sönke1 aRice, Kenneth, M1 aBastin, Mark, E1 aYang, Qiong1 aMaldjian, Joseph, A1 aStarr, John, M1 aSidney, Stephen1 aRisacher, Shannon, L1 aUitterlinden, André, G1 aGudnason, Vilmundur, G1 aNauck, Matthias1 aRotter, Jerome, I1 aSchreiner, Pamela, J1 aBoerwinkle, Eric1 aDuijn, Cornelia, M1 aMazoyer, Bernard1 avon Sarnowski, Bettina1 aGottesman, Rebecca, F1 aLevy, Daniel1 aSigurdsson, Sigurdur1 aVernooij, Meike, W1 aTurner, Stephen, T1 aSchmidt, Reinhold1 aWardlaw, Joanna, M1 aPsaty, Bruce, M1 aMosley, Thomas, H1 aDeCarli, Charles, S1 aSaykin, Andrew, J1 aBowden, Donald, W1 aBecker, Diane, M1 aDeary, Ian, J1 aSchmidt, Helena1 aKardia, Sharon, L R1 aIkram, Arfan, M1 aDebette, Stephanie1 aGrabe, Hans, J1 aLongstreth, W T1 aSeshadri, Sudha1 aLauner, Lenore, J1 aFornage, Myriam1 aneuroCHARGE Working Group uhttps://chs-nhlbi.org/node/779610328nas a2203505 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2018 eng d a1546-171800aGenetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.0 aGenetic analysis of over 1 million people identifies 535 new loc c2018 Oct a1412-14250 v503 aHigh blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
1 aEvangelou, Evangelos1 aWarren, Helen, R1 aMosen-Ansorena, David1 aMifsud, Borbala1 aPazoki, Raha1 aGao, He1 aNtritsos, Georgios1 aDimou, Niki1 aCabrera, Claudia, P1 aKaraman, Ibrahim1 aNg, Fu, Liang1 aEvangelou, Marina1 aWitkowska, Katarzyna1 aTzanis, Evan1 aHellwege, Jacklyn, N1 aGiri, Ayush1 aEdwards, Digna, R Velez1 aSun, Yan, V1 aCho, Kelly1 aGaziano, Michael1 aWilson, Peter, W F1 aTsao, Philip, S1 aKovesdy, Csaba, P1 aEsko, Tõnu1 aMägi, Reedik1 aMilani, Lili1 aAlmgren, Peter1 aBoutin, Thibaud1 aDebette, Stephanie1 aDing, Jun1 aGiulianini, Franco1 aHolliday, Elizabeth, G1 aJackson, Anne, U1 aLi-Gao, Ruifang1 aLin, Wei-Yu1 aLuan, Jian'an1 aMangino, Massimo1 aOldmeadow, Christopher1 aPrins, Bram, Peter1 aQian, Yong1 aSargurupremraj, Muralidharan1 aShah, Nabi1 aSurendran, Praveen1 aThériault, Sébastien1 aVerweij, Niek1 aWillems, Sara, M1 aZhao, Jing-Hua1 aAmouyel, Philippe1 aConnell, John1 ade Mutsert, Renée1 aDoney, Alex, S F1 aFarrall, Martin1 aMenni, Cristina1 aMorris, Andrew, D1 aNoordam, Raymond1 aParé, Guillaume1 aPoulter, Neil, R1 aShields, Denis, C1 aStanton, Alice1 aThom, Simon1 aAbecasis, Goncalo1 aAmin, Najaf1 aArking, Dan, E1 aAyers, Kristin, L1 aBarbieri, Caterina, M1 aBatini, Chiara1 aBis, Joshua, C1 aBlake, Tineka1 aBochud, Murielle1 aBoehnke, Michael1 aBoerwinkle, Eric1 aBoomsma, Dorret, I1 aBottinger, Erwin, P1 aBraund, Peter, S1 aBrumat, Marco1 aCampbell, Archie1 aCampbell, Harry1 aChakravarti, Aravinda1 aChambers, John, C1 aChauhan, Ganesh1 aCiullo, Marina1 aCocca, Massimiliano1 aCollins, Francis1 aCordell, Heather, J1 aDavies, Gail1 ade Borst, Martin, H1 ade Geus, Eco, J1 aDeary, Ian, J1 aDeelen, Joris1 aM, Fabiola, del Greco1 aDemirkale, Cumhur, Yusuf1 aDörr, Marcus1 aEhret, Georg, B1 aElosua, Roberto1 aEnroth, Stefan1 aErzurumluoglu, Mesut1 aFerreira, Teresa1 aFrånberg, Mattias1 aFranco, Oscar, H1 aGandin, Ilaria1 aGasparini, Paolo1 aGiedraitis, Vilmantas1 aGieger, Christian1 aGirotto, Giorgia1 aGoel, Anuj1 aGow, Alan, J1 aGudnason, Vilmundur1 aGuo, Xiuqing1 aGyllensten, Ulf1 aHamsten, Anders1 aHarris, Tamara, B1 aHarris, Sarah, E1 aHartman, Catharina, A1 aHavulinna, Aki, S1 aHicks, Andrew, A1 aHofer, Edith1 aHofman, Albert1 aHottenga, Jouke-Jan1 aHuffman, Jennifer, E1 aHwang, Shih-Jen1 aIngelsson, Erik1 aJames, Alan1 aJansen, Rick1 aJarvelin, Marjo-Riitta1 aJoehanes, Roby1 aJohansson, Asa1 aJohnson, Andrew, D1 aJoshi, Peter, K1 aJousilahti, Pekka1 aJukema, Wouter1 aJula, Antti1 aKähönen, Mika1 aKathiresan, Sekar1 aKeavney, Bernard, D1 aKhaw, Kay-Tee1 aKnekt, Paul1 aKnight, Joanne1 aKolcic, Ivana1 aKooner, Jaspal, S1 aKoskinen, Seppo1 aKristiansson, Kati1 aKutalik, Zoltán1 aLaan, Maris1 aLarson, Marty1 aLauner, Lenore, J1 aLehne, Benjamin1 aLehtimäki, Terho1 aLiewald, David, C M1 aLin, Li1 aLind, Lars1 aLindgren, Cecilia, M1 aLiu, Yongmei1 aLoos, Ruth, J F1 aLopez, Lorna, M1 aLu, Yingchang1 aLyytikäinen, Leo-Pekka1 aMahajan, Anubha1 aMamasoula, Chrysovalanto1 aMarrugat, Jaume1 aMarten, Jonathan1 aMilaneschi, Yuri1 aMorgan, Anna1 aMorris, Andrew, P1 aMorrison, Alanna, C1 aMunson, Peter, J1 aNalls, Mike, A1 aNandakumar, Priyanka1 aNelson, Christopher, P1 aNiiranen, Teemu1 aNolte, Ilja, M1 aNutile, Teresa1 aOldehinkel, Albertine, J1 aOostra, Ben, A1 aO'Reilly, Paul, F1 aOrg, Elin1 aPadmanabhan, Sandosh1 aPalmas, Walter1 aPalotie, Aarno1 aPattie, Alison1 aPenninx, Brenda, W J H1 aPerola, Markus1 aPeters, Annette1 aPolasek, Ozren1 aPramstaller, Peter, P1 aNguyen, Quang, Tri1 aRaitakari, Olli, T1 aRen, Meixia1 aRettig, Rainer1 aRice, Kenneth1 aRidker, Paul, M1 aRied, Janina, S1 aRiese, Harriëtte1 aRipatti, Samuli1 aRobino, Antonietta1 aRose, Lynda, M1 aRotter, Jerome, I1 aRudan, Igor1 aRuggiero, Daniela1 aSaba, Yasaman1 aSala, Cinzia, F1 aSalomaa, Veikko1 aSamani, Nilesh, J1 aSarin, Antti-Pekka1 aSchmidt, Reinhold1 aSchmidt, Helena1 aShrine, Nick1 aSiscovick, David1 aSmith, Albert, V1 aSnieder, Harold1 aSõber, Siim1 aSorice, Rossella1 aStarr, John, M1 aStott, David, J1 aStrachan, David, P1 aStrawbridge, Rona, J1 aSundström, Johan1 aSwertz, Morris, A1 aTaylor, Kent, D1 aTeumer, Alexander1 aTobin, Martin, D1 aTomaszewski, Maciej1 aToniolo, Daniela1 aTraglia, Michela1 aTrompet, Stella1 aTuomilehto, Jaakko1 aTzourio, Christophe1 aUitterlinden, André, G1 aVaez, Ahmad1 avan der Most, Peter, J1 aDuijn, Cornelia, M1 aVergnaud, Anne-Claire1 aVerwoert, Germaine, C1 aVitart, Veronique1 aVölker, Uwe1 aVollenweider, Peter1 aVuckovic, Dragana1 aWatkins, Hugh1 aWild, Sarah, H1 aWillemsen, Gonneke1 aWilson, James, F1 aWright, Alan, F1 aYao, Jie1 aZemunik, Tatijana1 aZhang, Weihua1 aAttia, John, R1 aButterworth, Adam, S1 aChasman, Daniel, I1 aConen, David1 aCucca, Francesco1 aDanesh, John1 aHayward, Caroline1 aHowson, Joanna, M M1 aLaakso, Markku1 aLakatta, Edward, G1 aLangenberg, Claudia1 aMelander, Olle1 aMook-Kanamori, Dennis, O1 aPalmer, Colin, N A1 aRisch, Lorenz1 aScott, Robert, A1 aScott, Rodney, J1 aSever, Peter1 aSpector, Tim, D1 aHarst, Pim1 aWareham, Nicholas, J1 aZeggini, Eleftheria1 aLevy, Daniel1 aMunroe, Patricia, B1 aNewton-Cheh, Christopher1 aBrown, Morris, J1 aMetspalu, Andres1 aHung, Adriana, M1 aO'Donnell, Christopher, J1 aEdwards, Todd, L1 aPsaty, Bruce, M1 aTzoulaki, Ioanna1 aBarnes, Michael, R1 aWain, Louise, V1 aElliott, Paul1 aCaulfield, Mark, J1 aMillion Veteran Program uhttps://chs-nhlbi.org/node/784507247nas a2202185 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2018 eng d a2041-172300aGWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.0 aGWAS and colocalization analyses implicate carotid intimamedia t c2018 12 03 a51410 v93 aCarotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
10aADAMTS9 Protein10aAmino Acid Oxidoreductases10aCarotid Intima-Media Thickness10aCoronary Disease10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aLod Score10aPlaque, Atherosclerotic10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aRisk Factors1 aFranceschini, Nora1 aGiambartolomei, Claudia1 ade Vries, Paul, S1 aFinan, Chris1 aBis, Joshua, C1 aHuntley, Rachael, P1 aLovering, Ruth, C1 aTajuddin, Salman, M1 aWinkler, Thomas, W1 aGraff, Misa1 aKavousi, Maryam1 aDale, Caroline1 aSmith, Albert, V1 aHofer, Edith1 avan Leeuwen, Elisabeth, M1 aNolte, Ilja, M1 aLu, Lingyi1 aScholz, Markus1 aSargurupremraj, Muralidharan1 aPitkänen, Niina1 aFranzén, Oscar1 aJoshi, Peter, K1 aNoordam, Raymond1 aMarioni, Riccardo, E1 aHwang, Shih-Jen1 aMusani, Solomon, K1 aSchminke, Ulf1 aPalmas, Walter1 aIsaacs, Aaron1 aCorrea, Adolfo1 aZonderman, Alan, B1 aHofman, Albert1 aTeumer, Alexander1 aCox, Amanda, J1 aUitterlinden, André, G1 aWong, Andrew1 aSmit, Andries, J1 aNewman, Anne, B1 aBritton, Annie1 aRuusalepp, Arno1 aSennblad, Bengt1 aHedblad, Bo1 aPasaniuc, Bogdan1 aPenninx, Brenda, W1 aLangefeld, Carl, D1 aWassel, Christina, L1 aTzourio, Christophe1 aFava, Cristiano1 aBaldassarre, Damiano1 aO'Leary, Daniel, H1 aTeupser, Daniel1 aKuh, Diana1 aTremoli, Elena1 aMannarino, Elmo1 aGrossi, Enzo1 aBoerwinkle, Eric1 aSchadt, Eric, E1 aIngelsson, Erik1 aVeglia, Fabrizio1 aRivadeneira, Fernando1 aBeutner, Frank1 aChauhan, Ganesh1 aHeiss, Gerardo1 aSnieder, Harold1 aCampbell, Harry1 aVölzke, Henry1 aMarkus, Hugh, S1 aDeary, Ian, J1 aJukema, Wouter1 ade Graaf, Jacqueline1 aPrice, Jacqueline1 aPott, Janne1 aHopewell, Jemma, C1 aLiang, Jingjing1 aThiery, Joachim1 aEngmann, Jorgen1 aGertow, Karl1 aRice, Kenneth1 aTaylor, Kent, D1 aDhana, Klodian1 aKiemeney, Lambertus, A L M1 aLind, Lars1 aRaffield, Laura, M1 aLauner, Lenore, J1 aHoldt, Lesca, M1 aDörr, Marcus1 aDichgans, Martin1 aTraylor, Matthew1 aSitzer, Matthias1 aKumari, Meena1 aKivimaki, Mika1 aNalls, Mike, A1 aMelander, Olle1 aRaitakari, Olli1 aFranco, Oscar, H1 aRueda-Ochoa, Oscar, L1 aRoussos, Panos1 aWhincup, Peter, H1 aAmouyel, Philippe1 aGiral, Philippe1 aAnugu, Pramod1 aWong, Quenna1 aMalik, Rainer1 aRauramaa, Rainer1 aBurkhardt, Ralph1 aHardy, Rebecca1 aSchmidt, Reinhold1 ade Mutsert, Renée1 aMorris, Richard, W1 aStrawbridge, Rona, J1 aWannamethee, Goya1 aHägg, Sara1 aShah, Sonia1 aMcLachlan, Stela1 aTrompet, Stella1 aSeshadri, Sudha1 aKurl, Sudhir1 aHeckbert, Susan, R1 aRing, Susan1 aHarris, Tamara, B1 aLehtimäki, Terho1 aGalesloot, Tessel, E1 aShah, Tina1 ade Faire, Ulf1 aPlagnol, Vincent1 aRosamond, Wayne, D1 aPost, Wendy1 aZhu, Xiaofeng1 aZhang, Xiaoling1 aGuo, Xiuqing1 aSaba, Yasaman1 aDehghan, Abbas1 aSeldenrijk, Adrie1 aMorrison, Alanna, C1 aHamsten, Anders1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aLawlor, Deborah, A1 aMook-Kanamori, Dennis, O1 aBowden, Donald, W1 aSchmidt, Helena1 aWilson, James, F1 aWilson, James, G1 aRotter, Jerome, I1 aWardlaw, Joanna, M1 aDeanfield, John1 aHalcox, Julian1 aLyytikäinen, Leo-Pekka1 aLoeffler, Markus1 aEvans, Michele, K1 aDebette, Stephanie1 aHumphries, Steve, E1 aVölker, Uwe1 aGudnason, Vilmundur1 aHingorani, Aroon, D1 aBjörkegren, Johan, L M1 aCasas, Juan, P1 aO'Donnell, Christopher, J1 aMEGASTROKE Consortium uhttps://chs-nhlbi.org/node/791312060nas a2203745 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2018 eng d a1537-660500aA Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.0 aLargeScale Multiancestry Genomewide Study Accounting for Smoking c2018 Mar 01 a375-4000 v1023 aGenome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).
1 aSung, Yun, J1 aWinkler, Thomas, W1 aFuentes, Lisa, de Las1 aBentley, Amy, R1 aBrown, Michael, R1 aKraja, Aldi, T1 aSchwander, Karen1 aNtalla, Ioanna1 aGuo, Xiuqing1 aFranceschini, Nora1 aLu, Yingchang1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aMarten, Jonathan1 aMusani, Solomon, K1 aLi, Changwei1 aFeitosa, Mary, F1 aKilpeläinen, Tuomas, O1 aRichard, Melissa, A1 aNoordam, Raymond1 aAslibekyan, Stella1 aAschard, Hugues1 aBartz, Traci, M1 aDorajoo, Rajkumar1 aLiu, Yongmei1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, Vernon1 aTajuddin, Salman, M1 aTayo, Bamidele, O1 aWarren, Helen, R1 aZhao, Wei1 aZhou, Yanhua1 aMatoba, Nana1 aSofer, Tamar1 aAlver, Maris1 aAmini, Marzyeh1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aGandin, Ilaria1 aGao, Chuan1 aGiulianini, Franco1 aGoel, Anuj1 aHarris, Sarah, E1 aHartwig, Fernando, Pires1 aHorimoto, Andrea, R V R1 aHsu, Fang-Chi1 aJackson, Anne, U1 aKähönen, Mika1 aKasturiratne, Anuradhani1 aKuhnel, Brigitte1 aLeander, Karin1 aLee, Wen-Jane1 aLin, Keng-Hung1 aLuan, Jian, 'an1 aMcKenzie, Colin, A1 aMeian, He1 aNelson, Christopher, P1 aRauramaa, Rainer1 aSchupf, Nicole1 aScott, Robert, A1 aSheu, Wayne, H H1 aStančáková, Alena1 aTakeuchi, Fumihiko1 avan der Most, Peter, J1 aVarga, Tibor, V1 aWang, Heming1 aWang, Yajuan1 aWare, Erin, B1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAfaq, Saima1 aAlfred, Tamuno1 aAmin, Najaf1 aArking, Dan1 aAung, Tin1 aBarr, Graham1 aBielak, Lawrence, F1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aBraund, Peter, S1 aBrody, Jennifer, A1 aBroeckel, Ulrich1 aCabrera, Claudia, P1 aCade, Brian1 aCaizheng, Yu1 aCampbell, Archie1 aCanouil, Mickaël1 aChakravarti, Aravinda1 aChauhan, Ganesh1 aChristensen, Kaare1 aCocca, Massimiliano1 aCollins, Francis, S1 aConnell, John, M1 ade Mutsert, Renée1 ade Silva, Janaka1 aDebette, Stephanie1 aDörr, Marcus1 aDuan, Qing1 aEaton, Charles, B1 aEhret, Georg1 aEvangelou, Evangelos1 aFaul, Jessica, D1 aFisher, Virginia, A1 aForouhi, Nita, G1 aFranco, Oscar, H1 aFriedlander, Yechiel1 aGao, He1 aGigante, Bruna1 aGraff, Misa1 aGu, Charles1 aGu, Dongfeng1 aGupta, Preeti1 aHagenaars, Saskia, P1 aHarris, Tamara, B1 aHe, Jiang1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHofman, Albert1 aHoward, Barbara, V1 aHunt, Steven1 aIrvin, Marguerite, R1 aJia, Yucheng1 aJoehanes, Roby1 aJustice, Anne, E1 aKatsuya, Tomohiro1 aKaufman, Joel1 aKerrison, Nicola, D1 aKhor, Chiea, Chuen1 aKoh, Woon-Puay1 aKoistinen, Heikki, A1 aKomulainen, Pirjo1 aKooperberg, Charles1 aKrieger, Jose, E1 aKubo, Michiaki1 aKuusisto, Johanna1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLewis, Cora, E1 aLi, Yize1 aLim, Sing, Hui1 aLin, Shiow1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLiu, Jingmin1 aLiu, Kiang1 aLiu, Yeheng1 aLoh, Marie1 aLohman, Kurt, K1 aLong, Jirong1 aLouie, Tin1 aMägi, Reedik1 aMahajan, Anubha1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilani, Lili1 aMomozawa, Yukihide1 aMorris, Andrew, P1 aMosley, Thomas, H1 aMunson, Peter1 aMurray, Alison, D1 aNalls, Mike, A1 aNasri, Ubaydah1 aNorris, Jill, M1 aNorth, Kari1 aOgunniyi, Adesola1 aPadmanabhan, Sandosh1 aPalmas, Walter, R1 aPalmer, Nicholette, D1 aPankow, James, S1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aRaitakari, Olli, T1 aRenstrom, Frida1 aRice, Treva, K1 aRidker, Paul, M1 aRobino, Antonietta1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRudan, Igor1 aSabanayagam, Charumathi1 aSalako, Babatunde, L1 aSandow, Kevin1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aScott, William, R1 aSeshadri, Sudha1 aSever, Peter1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aTang, Hua1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aUitterlinden, André, G1 aWaldenberger, Melanie1 aWang, Lihua1 aWang, Ya, X1 aBin Wei, Wen1 aWilliams, Christine1 aWilson, Gregory1 aWojczynski, Mary, K1 aYao, Jie1 aYuan, Jian-Min1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aChen, Yii-Der Ida1 ade Faire, Ulf1 aDeary, Ian, J1 aEsko, Tõnu1 aFarrall, Martin1 aForrester, Terrence1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aHorta, Bernardo, Lessa1 aHung, Yi-Jen1 aJonas, Jost, B1 aKato, Norihiro1 aKooner, Jaspal, S1 aLaakso, Markku1 aLehtimäki, Terho1 aLiang, Kae-Woei1 aMagnusson, Patrik, K E1 aNewman, Anne, B1 aOldehinkel, Albertine, J1 aPereira, Alexandre, C1 aRedline, Susan1 aRettig, Rainer1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aWu, Tangchun1 aZheng, Wei1 aKamatani, Yoichiro1 aLaurie, Cathy, C1 aBouchard, Claude1 aCooper, Richard, S1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKardia, Sharon, L R1 aKritchevsky, Stephen, B1 aLevy, Daniel1 aO'Connell, Jeff, R1 aPsaty, Bruce, M1 avan Dam, Rob, M1 aSims, Mario1 aArnett, Donna, K1 aMook-Kanamori, Dennis, O1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aFornage, Myriam1 aRotimi, Charles, N1 aProvince, Michael, A1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aLoos, Ruth, J F1 aReiner, Alex, P1 aRotter, Jerome, I1 aZhu, Xiaofeng1 aBierut, Laura, J1 aGauderman, James1 aCaulfield, Mark, J1 aElliott, Paul1 aRice, Kenneth1 aMunroe, Patricia, B1 aMorrison, Alanna, C1 aCupples, Adrienne, L1 aRao, Dabeeru, C1 aChasman, Daniel, I1 aCHARGE Neurology Working Group1 aCOGENT-Kidney Consortium1 aGIANT Consortium1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/768616401nas a2205425 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2018 eng d a1546-171800aMultiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.0 aMultiancestry genomewide association study of 520000 subjects id c2018 Apr a524-5370 v503 aStroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.
1 aMalik, Rainer1 aChauhan, Ganesh1 aTraylor, Matthew1 aSargurupremraj, Muralidharan1 aOkada, Yukinori1 aMishra, Aniket1 aRutten-Jacobs, Loes1 aGiese, Anne-Katrin1 avan der Laan, Sander, W1 aGretarsdottir, Solveig1 aAnderson, Christopher, D1 aChong, Michael1 aAdams, Hieab, H H1 aAgo, Tetsuro1 aAlmgren, Peter1 aAmouyel, Philippe1 aAy, Hakan1 aBartz, Traci, M1 aBenavente, Oscar, R1 aBevan, Steve1 aBoncoraglio, Giorgio, B1 aBrown, Robert, D1 aButterworth, Adam, S1 aCarrera, Caty1 aCarty, Cara, L1 aChasman, Daniel, I1 aChen, Wei-Min1 aCole, John, W1 aCorrea, Adolfo1 aCotlarciuc, Ioana1 aCruchaga, Carlos1 aDanesh, John1 ade Bakker, Paul, I W1 aDeStefano, Anita, L1 aHoed, Marcel, den1 aDuan, Qing1 aEngelter, Stefan, T1 aFalcone, Guido, J1 aGottesman, Rebecca, F1 aGrewal, Raji, P1 aGudnason, Vilmundur1 aGustafsson, Stefan1 aHaessler, Jeffrey1 aHarris, Tamara, B1 aHassan, Ahamad1 aHavulinna, Aki, S1 aHeckbert, Susan, R1 aHolliday, Elizabeth, G1 aHoward, George1 aHsu, Fang-Chi1 aHyacinth, Hyacinth, I1 aIkram, Arfan, M1 aIngelsson, Erik1 aIrvin, Marguerite, R1 aJian, Xueqiu1 aJimenez-Conde, Jordi1 aJohnson, Julie, A1 aJukema, Wouter1 aKanai, Masahiro1 aKeene, Keith, L1 aKissela, Brett, M1 aKleindorfer, Dawn, O1 aKooperberg, Charles1 aKubo, Michiaki1 aLange, Leslie, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLee, Jin-Moo1 aLemmens, Robin1 aLeys, Didier1 aLewis, Cathryn, M1 aLin, Wei-Yu1 aLindgren, Arne, G1 aLorentzen, Erik1 aMagnusson, Patrik, K1 aMaguire, Jane1 aManichaikul, Ani1 aMcArdle, Patrick, F1 aMeschia, James, F1 aMitchell, Braxton, D1 aMosley, Thomas, H1 aNalls, Michael, A1 aNinomiya, Toshiharu1 aO'Donnell, Martin, J1 aPsaty, Bruce, M1 aPulit, Sara, L1 aRannikmae, Kristiina1 aReiner, Alexander, P1 aRexrode, Kathryn, M1 aRice, Kenneth1 aRich, Stephen, S1 aRidker, Paul, M1 aRost, Natalia, S1 aRothwell, Peter, M1 aRotter, Jerome, I1 aRundek, Tatjana1 aSacco, Ralph, L1 aSakaue, Saori1 aSale, Michèle, M1 aSalomaa, Veikko1 aSapkota, Bishwa, R1 aSchmidt, Reinhold1 aSchmidt, Carsten, O1 aSchminke, Ulf1 aSharma, Pankaj1 aSlowik, Agnieszka1 aSudlow, Cathie, L M1 aTanislav, Christian1 aTatlisumak, Turgut1 aTaylor, Kent, D1 aThijs, Vincent, N S1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTiedt, Steffen1 aTrompet, Stella1 aTzourio, Christophe1 aDuijn, Cornelia, M1 aWalters, Matthew1 aWareham, Nicholas, J1 aWassertheil-Smoller, Sylvia1 aWilson, James, G1 aWiggins, Kerri, L1 aYang, Qiong1 aYusuf, Salim1 aBis, Joshua, C1 aPastinen, Tomi1 aRuusalepp, Arno1 aSchadt, Eric, E1 aKoplev, Simon1 aBjörkegren, Johan, L M1 aCodoni, Veronica1 aCivelek, Mete1 aSmith, Nicholas, L1 aTrégouët, David, A1 aChristophersen, Ingrid, E1 aRoselli, Carolina1 aLubitz, Steven, A1 aEllinor, Patrick, T1 aTai, Shyong, E1 aKooner, Jaspal, S1 aKato, Norihiro1 aHe, Jiang1 aHarst, Pim1 aElliott, Paul1 aChambers, John, C1 aTakeuchi, Fumihiko1 aJohnson, Andrew, D1 aSanghera, Dharambir, K1 aMelander, Olle1 aJern, Christina1 aStrbian, Daniel1 aFernandez-Cadenas, Israel1 aLongstreth, W T1 aRolfs, Arndt1 aHata, Jun1 aWoo, Daniel1 aRosand, Jonathan1 aParé, Guillaume1 aHopewell, Jemma, C1 aSaleheen, Danish1 aStefansson, Kari1 aWorrall, Bradford, B1 aKittner, Steven, J1 aSeshadri, Sudha1 aFornage, Myriam1 aMarkus, Hugh, S1 aHowson, Joanna, M M1 aKamatani, Yoichiro1 aDebette, Stephanie1 aDichgans, Martin1 aMalik, Rainer1 aChauhan, Ganesh1 aTraylor, Matthew1 aSargurupremraj, Muralidharan1 aOkada, Yukinori1 aMishra, Aniket1 aRutten-Jacobs, Loes1 aGiese, Anne-Katrin1 avan der Laan, Sander, W1 aGretarsdottir, Solveig1 aAnderson, Christopher, D1 aChong, Michael1 aAdams, Hieab, H H1 aAgo, Tetsuro1 aAlmgren, Peter1 aAmouyel, Philippe1 aAy, Hakan1 aBartz, Traci, M1 aBenavente, Oscar, R1 aBevan, Steve1 aBoncoraglio, Giorgio, B1 aBrown, Robert, D1 aButterworth, Adam, S1 aCarrera, Caty1 aCarty, Cara, L1 aChasman, Daniel, I1 aChen, Wei-Min1 aCole, John, W1 aCorrea, Adolfo1 aCotlarciuc, Ioana1 aCruchaga, Carlos1 aDanesh, John1 ade Bakker, Paul, I W1 aDeStefano, Anita, L1 aHoed, Marcel, den1 aDuan, Qing1 aEngelter, Stefan, T1 aFalcone, Guido, J1 aGottesman, Rebecca, F1 aGrewal, Raji, P1 aGudnason, Vilmundur1 aGustafsson, Stefan1 aHaessler, Jeffrey1 aHarris, Tamara, B1 aHassan, Ahamad1 aHavulinna, Aki, S1 aHeckbert, Susan, R1 aHolliday, Elizabeth, G1 aHoward, George1 aHsu, Fang-Chi1 aHyacinth, Hyacinth, I1 aIkram, Arfan, M1 aIngelsson, Erik1 aIrvin, Marguerite, R1 aJian, Xueqiu1 aJimenez-Conde, Jordi1 aJohnson, Julie, A1 aJukema, Wouter1 aKanai, Masahiro1 aKeene, Keith, L1 aKissela, Brett, M1 aKleindorfer, Dawn, O1 aKooperberg, Charles1 aKubo, Michiaki1 aLange, Leslie, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLee, Jin-Moo1 aLemmens, Robin1 aLeys, Didier1 aLewis, Cathryn, M1 aLin, Wei-Yu1 aLindgren, Arne, G1 aLorentzen, Erik1 aMagnusson, Patrik, K1 aMaguire, Jane1 aManichaikul, Ani1 aMcArdle, Patrick, F1 aMeschia, James, F1 aMitchell, Braxton, D1 aMosley, Thomas, H1 aNalls, Michael, A1 aNinomiya, Toshiharu1 aO'Donnell, Martin, J1 aPsaty, Bruce, M1 aPulit, Sara, L1 aRannikmae, Kristiina1 aReiner, Alexander, P1 aRexrode, Kathryn, M1 aRice, Kenneth1 aRich, Stephen, S1 aRidker, Paul, M1 aRost, Natalia, S1 aRothwell, Peter, M1 aRotter, Jerome, I1 aRundek, Tatjana1 aSacco, Ralph, L1 aSakaue, Saori1 aSale, Michèle, M1 aSalomaa, Veikko1 aSapkota, Bishwa, R1 aSchmidt, Reinhold1 aSchmidt, Carsten, O1 aSchminke, Ulf1 aSharma, Pankaj1 aSlowik, Agnieszka1 aSudlow, Cathie, L M1 aTanislav, Christian1 aTatlisumak, Turgut1 aTaylor, Kent, D1 aThijs, Vincent, N S1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTiedt, Steffen1 aTrompet, Stella1 aTzourio, Christophe1 aDuijn, Cornelia, M1 aWalters, Matthew1 aWareham, Nicholas, J1 aWassertheil-Smoller, Sylvia1 aWilson, James, G1 aWiggins, Kerri, L1 aYang, Qiong1 aYusuf, Salim1 aAmin, Najaf1 aAparicio, Hugo, S1 aArnett, Donna, K1 aAttia, John1 aBeiser, Alexa, S1 aBerr, Claudine1 aBuring, Julie, E1 aBustamante, Mariana1 aCaso, Valeria1 aCheng, Yu-Ching1 aChoi, Seung, Hoan1 aChowhan, Ayesha1 aCullell, Natalia1 aDartigues, Jean-François1 aDelavaran, Hossein1 aDelgado, Pilar1 aDörr, Marcus1 aEngström, Gunnar1 aFord, Ian1 aGurpreet, Wander, S1 aHamsten, Anders1 aHeitsch, Laura1 aHozawa, Atsushi1 aIbanez, Laura1 aIlinca, Andreea1 aIngelsson, Martin1 aIwasaki, Motoki1 aJackson, Rebecca, D1 aJood, Katarina1 aJousilahti, Pekka1 aKaffashian, Sara1 aKalra, Lalit1 aKamouchi, Masahiro1 aKitazono, Takanari1 aKjartansson, Olafur1 aKloss, Manja1 aKoudstaal, Peter, J1 aKrupinski, Jerzy1 aLabovitz, Daniel, L1 aLaurie, Cathy, C1 aLevi, Christopher, R1 aLi, Linxin1 aLind, Lars1 aLindgren, Cecilia, M1 aLioutas, Vasileios1 aLiu, Yong, Mei1 aLopez, Oscar, L1 aMakoto, Hirata1 aMartinez-Majander, Nicolas1 aMatsuda, Koichi1 aMinegishi, Naoko1 aMontaner, Joan1 aMorris, Andrew, P1 aMuiño, Elena1 aMüller-Nurasyid, Martina1 aNorrving, Bo1 aOgishima, Soichi1 aParati, Eugenio, A1 aPeddareddygari, Leema, Reddy1 aPedersen, Nancy, L1 aPera, Joanna1 aPerola, Markus1 aPezzini, Alessandro1 aPileggi, Silvana1 aRabionet, Raquel1 aRiba-Llena, Iolanda1 aRibasés, Marta1 aRomero, Jose, R1 aRoquer, Jaume1 aRudd, Anthony, G1 aSarin, Antti-Pekka1 aSarju, Ralhan1 aSarnowski, Chloe1 aSasaki, Makoto1 aSatizabal, Claudia, L1 aSatoh, Mamoru1 aSattar, Naveed1 aSawada, Norie1 aSibolt, Gerli1 aSigurdsson, Ásgeir1 aSmith, Albert1 aSobue, Kenji1 aSoriano-Tárraga, Carolina1 aStanne, Tara1 aStine, Colin1 aStott, David, J1 aStrauch, Konstantin1 aTakai, Takako1 aTanaka, Hideo1 aTanno, Kozo1 aTeumer, Alexander1 aTomppo, Liisa1 aTorres-Aguila, Nuria, P1 aTouze, Emmanuel1 aTsugane, Shoichiro1 aUitterlinden, André, G1 aValdimarsson, Einar, M1 avan der Lee, Sven, J1 aVölzke, Henry1 aWakai, Kenji1 aWeir, David1 aWilliams, Stephen, R1 aWolfe, Charles, D A1 aWong, Quenna1 aXu, Huichun1 aYamaji, Taiki1 aSanghera, Dharambir, K1 aMelander, Olle1 aJern, Christina1 aStrbian, Daniel1 aFernandez-Cadenas, Israel1 aLongstreth, W T1 aRolfs, Arndt1 aHata, Jun1 aWoo, Daniel1 aRosand, Jonathan1 aParé, Guillaume1 aHopewell, Jemma, C1 aSaleheen, Danish1 aStefansson, Kari1 aWorrall, Bradford, B1 aKittner, Steven, J1 aSeshadri, Sudha1 aFornage, Myriam1 aMarkus, Hugh, S1 aHowson, Joanna, M M1 aKamatani, Yoichiro1 aDebette, Stephanie1 aDichgans, Martin1 aAFGen Consortium1 aCohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium1 aInternational Genomics of Blood Pressure (iGEN-BP) Consortium1 aINVENT Consortium1 aSTARNET1 aBioBank Japan Cooperative Hospital Group1 aCOMPASS Consortium1 aEPIC-CVD Consortium1 aEPIC-InterAct Consortium1 aInternational Stroke Genetics Consortium (ISGC)1 aMETASTROKE Consortium1 aNeurology Working Group of the CHARGE Consortium1 aNINDS Stroke Genetics Network (SiGN)1 aUK Young Lacunar DNA Study1 aMEGASTROKE Consortium1 aMEGASTROKE Consortium: uhttps://chs-nhlbi.org/node/768308823nas a2202773 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2018 eng d a2041-172300aStudy of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.0 aStudy of 300486 individuals identifies 148 independent genetic l c2018 May 29 a20980 v93 aGeneral cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
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/778805481nas 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/778503490nas a2200517 4500008004100000022001400041245012600055210006900181260001600250520197900266100001902245700002002264700002702284700002002311700001702331700001902348700001302367700001802380700002802398700001602426700002002442700001702462700002102479700001402500700003002514700001802544700002202562700002202584700002002606700002202626700002102648700001702669700002102686700001802707700002402725700002302749700002002772700002002792700002002812700002002832700002002852700001702872700002402889700002302913856003602936 2019 eng d a1460-215600aAssociation of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects.0 aAssociation of variants in HTRA1 and NOTCH3 with MRIdefined extr c2019 Mar 113 aWe report a composite extreme phenotype design using distribution of white matter hyperintensities and brain infarcts in a population-based cohort of older persons for gene-mapping of cerebral small vessel disease. We demonstrate its application in the 3C-Dijon whole exome sequencing (WES) study (n = 1924, nWESextremes = 512), with both single variant and gene-based association tests. We used other population-based cohort studies participating in the CHARGE consortium for replication, using whole exome sequencing (nWES = 2,868, nWESextremes = 956) and genome-wide genotypes (nGW = 9924, nGWextremes = 3308). We restricted our study to candidate genes known to harbour mutations for Mendelian small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2 and TREX1. We identified significant associations of a common intronic variant in HTRA1, rs2293871 using single variant association testing (Pdiscovery = 8.21 × 10-5, Preplication = 5.25 × 10-3, Pcombined = 4.72 × 10-5) and of NOTCH3 using gene-based tests (Pdiscovery = 1.61 × 10-2, Preplication = 3.99 × 10-2, Pcombined = 5.31 × 10-3). Follow-up analysis identified significant association of rs2293871 with small vessel ischaemic stroke, and two blood expression quantitative trait loci of HTRA1 in linkage disequilibrium. Additionally, we identified two participants in the 3C-Dijon cohort (0.4%) carrying heterozygote genotypes at known pathogenic variants for familial small vessel disease within NOTCH3 and HTRA1. In conclusion, our proof-of-concept study provides strong evidence that using a novel composite MRI-derived phenotype for extremes of small vessel disease can facilitate the identification of genetic variants underlying small vessel disease, both common variants and those with rare and low frequency. The findings demonstrate shared mechanisms and a continuum between genes underlying Mendelian small vessel disease and those contributing to the common, multifactorial form of the disease.
1 aMishra, Aniket1 aChauhan, Ganesh1 aViolleau, Marie-Helene1 aVojinovic, Dina1 aJian, Xueqiu1 aBis, Joshua, C1 aLi, Shuo1 aSaba, Yasaman1 aGrenier-Boley, Benjamin1 aYang, Qiong1 aBartz, Traci, M1 aHofer, Edith1 aSoumaré, Aïcha1 aPeng, Fen1 aDuperron, Marie-Gabrielle1 aFoglio, Mario1 aMosley, Thomas, H1 aSchmidt, Reinhold1 aPsaty, Bruce, M1 aLauner, Lenore, J1 aBoerwinkle, Eric1 aZhu, Yicheng1 aMazoyer, Bernard1 aLathrop, Mark1 aBellenguez, Céline1 aDuijn, Cornelia, M1 aIkram, Arfan, M1 aSchmidt, Helena1 aLongstreth, W T1 aFornage, Myriam1 aSeshadri, Sudha1 aJoutel, Anne1 aTzourio, Christophe1 aDebette, Stephanie uhttps://chs-nhlbi.org/node/798911242nas a2203601 4500008004100000022001400041245008000055210006900135260001300204300001400217490000700231520105900238100002601297700002201323700002101345700002201366700001901388700002001407700001901427700003301446700002001479700002801499700002101527700001901548700001701567700002201584700001701606700002201623700002501645700001801670700001901688700001601707700001301723700001501736700001701751700002001768700002601788700002901814700002001843700002301863700002501886700001701911700001701928700002501945700001601970700002101986700002302007700002202030700002202052700002102074700001802095700002202113700002002135700002102155700002202176700002002198700002002218700002902238700001902267700002102286700002102307700001602328700001802344700002102362700002002383700002302403700002202426700001902448700002002467700002102487700002402508700002202532700002102554700002202575700002502597700001802622700002902640700001602669700001702685700001802702700002902720700002802749700002102777700001602798700002202814700001702836700002302853700002102876700002302897700002602920700002302946700002102969700002602990700002003016700002303036700001903059700001903078700003303097700002203130700001503152700002303167700002003190700002103210700001603231700002103247700001903268700002203287700002203309700002103331700002003352700002703372700002003399700002303419700002003442700002503462700001703487700002503504700002303529700002303552700002203575700002203597700002003619700001703639700001903656700001703675700002703692700002203719700002403741700002303765700002203788700003403810700002103844700002203865700002403887700002203911700002203933700002403955700002703979700002004006700001304026700002404039700001904063700002304082700001904105700001904124700001704143700002504160700002804185700002604213700002404239700002104263700002404284700001904308700002604327700002404353700002104377700002004398700002304418700002104441700003304462700002404495700002304519700002104542700002004563700001804583700001904601700002604620700002004646700001904666700002804685700002104713700001904734700001904753700002504772700001804797700002004815700002004835700002504855700002304880700002304903700002404926700002004950700003004970700001705000700002705017700003405044700001605078700002005094700002105114700002605135700002205161700002905183700001905212700002205231700002405253700002605277700002205303700002205325700001305347700001905360700002005379700001905399700002405418700002505442700002205467700001705489700002205506700003005528700002005558700002205578700002805600700002605628700002005654700002005674700002505694700002105719700001805740700002405758700002705782700001805809700002305827700002405850700002505874700001805899700002205917700002705939700002105966700002305987700002206010700002106032700002106053700002306074700002006097700002106117700002006138700002106158700001806179700002206197700002806219700002306247700002106270700002206291700002306313700002206336700002006358700002306378700002206401700002006423700001806443700002406461700001706485700001806502700001906520700002406539700001706563700001806580700002306598700002006621700001906641700002406660700002406684700002306708700002006731700002206751700002506773700002606798700002406824700002806848700002106876700002106897700001906918700002206937700002106959700002906980700002607009700002407035700002407059700002307083700001907106700002407125700002107149700002007170700002207190700001907212700002307231700002207254700002307276700002007299700002007319700002307339700002207362700002107384700002407405700002107429700002307450700002407473700002207497700002307519700002207542700002007564700002007584856003607604 2019 eng d a1546-171800aGenetic architecture of subcortical brain structures in 38,851 individuals.0 aGenetic architecture of subcortical brain structures in 38851 in c2019 Nov a1624-16360 v513 aSubcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
1 aSatizabal, Claudia, L1 aAdams, Hieab, H H1 aHibar, Derrek, P1 aWhite, Charles, C1 aKnol, Maria, J1 aStein, Jason, L1 aScholz, Markus1 aSargurupremraj, Muralidharan1 aJahanshad, Neda1 aRoshchupkin, Gennady, V1 aSmith, Albert, V1 aBis, Joshua, C1 aJian, Xueqiu1 aLuciano, Michelle1 aHofer, Edith1 aTeumer, Alexander1 avan der Lee, Sven, J1 aYang, Jingyun1 aYanek, Lisa, R1 aLee, Tom, V1 aLi, Shuo1 aHu, Yanhui1 aKoh, Jia, Yu1 aEicher, John, D1 aDesrivières, Sylvane1 aArias-Vasquez, Alejandro1 aChauhan, Ganesh1 aAthanasiu, Lavinia1 aRentería, Miguel, E1 aKim, Sungeun1 aHoehn, David1 aArmstrong, Nicola, J1 aChen, Qiang1 aHolmes, Avram, J1 aBraber, Anouk, den1 aKloszewska, Iwona1 aAndersson, Micael1 aEspeseth, Thomas1 aGrimm, Oliver1 aAbramovic, Lucija1 aAlhusaini, Saud1 aMilaneschi, Yuri1 aPapmeyer, Martina1 aAxelsson, Tomas1 aEhrlich, Stefan1 aRoiz-Santiañez, Roberto1 aKraemer, Bernd1 aHåberg, Asta, K1 aJones, Hannah, J1 aPike, Bruce1 aStein, Dan, J1 aStevens, Allison1 aBralten, Janita1 aVernooij, Meike, W1 aHarris, Tamara, B1 aFilippi, Irina1 aWitte, Veronica1 aGuadalupe, Tulio1 aWittfeld, Katharina1 aMosley, Thomas, H1 aBecker, James, T1 aDoan, Nhat, Trung1 aHagenaars, Saskia, P1 aSaba, Yasaman1 aCuellar-Partida, Gabriel1 aAmin, Najaf1 aHilal, Saima1 aNho, Kwangsik1 aMirza-Schreiber, Nazanin1 aArfanakis, Konstantinos1 aBecker, Diane, M1 aAmes, David1 aGoldman, Aaron, L1 aLee, Phil, H1 aBoomsma, Dorret, I1 aLovestone, Simon1 aGiddaluru, Sudheer1 aLe Hellard, Stephanie1 aMattheisen, Manuel1 aBohlken, Marc, M1 aKasperaviciute, Dalia1 aSchmaal, Lianne1 aLawrie, Stephen, M1 aAgartz, Ingrid1 aWalton, Esther1 aTordesillas-Gutierrez, Diana1 aDavies, Gareth, E1 aShin, Jean1 aIpser, Jonathan, C1 aVinke, Louis, N1 aHoogman, Martine1 aJia, Tianye1 aBurkhardt, Ralph1 aKlein, Marieke1 aCrivello, Fabrice1 aJanowitz, Deborah1 aCarmichael, Owen1 aHaukvik, Unn, K1 aAribisala, Benjamin, S1 aSchmidt, Helena1 aStrike, Lachlan, T1 aCheng, Ching-Yu1 aRisacher, Shannon, L1 aPütz, Benno1 aFleischman, Debra, A1 aAssareh, Amelia, A1 aMattay, Venkata, S1 aBuckner, Randy, L1 aMecocci, Patrizia1 aDale, Anders, M1 aCichon, Sven1 aBoks, Marco, P1 aMatarin, Mar1 aPenninx, Brenda, W J H1 aCalhoun, Vince, D1 aChakravarty, Mallar1 aMarquand, Andre, F1 aMacare, Christine1 aMasouleh, Shahrzad, Kharabian1 aOosterlaan, Jaap1 aAmouyel, Philippe1 aHegenscheid, Katrin1 aRotter, Jerome, I1 aSchork, Andrew, J1 aLiewald, David, C M1 ade Zubicaray, Greig, I1 aWong, Tien, Yin1 aShen, Li1 aSämann, Philipp, G1 aBrodaty, Henry1 aRoffman, Joshua, L1 aGeus, Eco, J C1 aTsolaki, Magda1 aErk, Susanne1 avan Eijk, Kristel, R1 aCavalleri, Gianpiero, L1 avan der Wee, Nic, J A1 aMcIntosh, Andrew, M1 aGollub, Randy, L1 aBulayeva, Kazima, B1 aBernard, Manon1 aRichards, Jennifer, S1 aHimali, Jayandra, J1 aLoeffler, Markus1 aRommelse, Nanda1 aHoffmann, Wolfgang1 aWestlye, Lars, T1 aHernández, Maria, C Valdés1 aHansell, Narelle, K1 avan Erp, Theo, G M1 aWolf, Christiane1 aKwok, John, B J1 aVellas, Bruno1 aHeinz, Andreas1 aLoohuis, Loes, M Olde1 aDelanty, Norman1 aHo, Beng-Choon1 aChing, Christopher, R K1 aShumskaya, Elena1 aSingh, Baljeet1 aHofman, Albert1 avan der Meer, Dennis1 aHomuth, Georg1 aPsaty, Bruce, M1 aBastin, Mark, E1 aMontgomery, Grant, W1 aForoud, Tatiana, M1 aReppermund, Simone1 aHottenga, Jouke-Jan1 aSimmons, Andrew1 aMeyer-Lindenberg, Andreas1 aCahn, Wiepke1 aWhelan, Christopher, D1 avan Donkelaar, Marjolein, M J1 aYang, Qiong1 aHosten, Norbert1 aGreen, Robert, C1 aThalamuthu, Anbupalam1 aMohnke, Sebastian1 aPol, Hilleke, E Hulshoff1 aLin, Honghuang1 aJack, Clifford, R1 aSchofield, Peter, R1 aMühleisen, Thomas, W1 aMaillard, Pauline1 aPotkin, Steven, G1 aWen, Wei1 aFletcher, Evan1 aToga, Arthur, W1 aGruber, Oliver1 aHuentelman, Matthew1 aSmith, George, Davey1 aLauner, Lenore, J1 aNyberg, Lars1 aJönsson, Erik, G1 aCrespo-Facorro, Benedicto1 aKoen, Nastassja1 aGreve, Douglas, N1 aUitterlinden, André, G1 aWeinberger, Daniel, R1 aSteen, Vidar, M1 aFedko, Iryna, O1 aGroenewold, Nynke, A1 aNiessen, Wiro, J1 aToro, Roberto1 aTzourio, Christophe1 aLongstreth, William, T1 aIkram, Kamran1 aSmoller, Jordan, W1 avan Tol, Marie-Jose1 aSussmann, Jessika, E1 aPaus, Tomáš1 aLemaître, Hervé1 aSchroeter, Matthias, L1 aMazoyer, Bernard1 aAndreassen, Ole, A1 aHolsboer, Florian1 aDepondt, Chantal1 aVeltman, Dick, J1 aTurner, Jessica, A1 aPausova, Zdenka1 aSchumann, Gunter1 avan Rooij, Daan1 aDjurovic, Srdjan1 aDeary, Ian, J1 aMcMahon, Katie, L1 aMüller-Myhsok, Bertram1 aBrouwer, Rachel, M1 aSoininen, Hilkka1 aPandolfo, Massimo1 aWassink, Thomas, H1 aCheung, Joshua, W1 aWolfers, Thomas1 aMartinot, Jean-Luc1 aZwiers, Marcel, P1 aNauck, Matthias1 aMelle, Ingrid1 aMartin, Nicholas, G1 aKanai, Ryota1 aWestman, Eric1 aKahn, René, S1 aSisodiya, Sanjay, M1 aWhite, Tonya1 aSaremi, Arvin1 avan Bokhoven, Hans1 aBrunner, Han, G1 aVölzke, Henry1 aWright, Margaret, J1 aEnt, Dennis, van 't1 aNöthen, Markus, M1 aOphoff, Roel, A1 aBuitelaar, Jan, K1 aFernández, Guillén1 aSachdev, Perminder, S1 aRietschel, Marcella1 avan Haren, Neeltje, E M1 aFisher, Simon, E1 aBeiser, Alexa, S1 aFrancks, Clyde1 aSaykin, Andrew, J1 aMather, Karen, A1 aRomanczuk-Seiferth, Nina1 aHartman, Catharina, A1 aDeStefano, Anita, L1 aHeslenfeld, Dirk, J1 aWeiner, Michael, W1 aWalter, Henrik1 aHoekstra, Pieter, J1 aNyquist, Paul, A1 aFranke, Barbara1 aBennett, David, A1 aGrabe, Hans, J1 aJohnson, Andrew, D1 aChen, Christopher1 aDuijn, Cornelia, M1 aLopez, Oscar, L1 aFornage, Myriam1 aWardlaw, Joanna, M1 aSchmidt, Reinhold1 aDeCarli, Charles1 aDe Jager, Philip, L1 aVillringer, Arno1 aDebette, Stephanie1 aGudnason, Vilmundur1 aMedland, Sarah, E1 aShulman, Joshua, M1 aThompson, Paul, M1 aSeshadri, Sudha1 aIkram, Arfan, M uhttps://chs-nhlbi.org/node/820617696nas 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/797704711nas a2201357 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2019 eng d a1546-171800aTrans-ethnic association study of blood pressure determinants in over 750,000 individuals.0 aTransethnic association study of blood pressure determinants in c2019 Jan a51-620 v513 aIn this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.
1 aGiri, Ayush1 aHellwege, Jacklyn, N1 aKeaton, Jacob, M1 aPark, Jihwan1 aQiu, Chengxiang1 aWarren, Helen, R1 aTorstenson, Eric, S1 aKovesdy, Csaba, P1 aSun, Yan, V1 aWilson, Otis, D1 aRobinson-Cohen, Cassianne1 aRoumie, Christianne, L1 aChung, Cecilia, P1 aBirdwell, Kelly, A1 aDamrauer, Scott, M1 aDuVall, Scott, L1 aKlarin, Derek1 aCho, Kelly1 aWang, Yu1 aEvangelou, Evangelos1 aCabrera, Claudia, P1 aWain, Louise, V1 aShrestha, Rojesh1 aMautz, Brian, S1 aAkwo, Elvis, A1 aSargurupremraj, Muralidharan1 aDebette, Stephanie1 aBoehnke, Michael1 aScott, Laura, J1 aLuan, Jian'an1 aZhao, Jing-Hua1 aWillems, Sara, M1 aThériault, Sébastien1 aShah, Nabi1 aOldmeadow, Christopher1 aAlmgren, Peter1 aLi-Gao, Ruifang1 aVerweij, Niek1 aBoutin, Thibaud, S1 aMangino, Massimo1 aNtalla, Ioanna1 aFeofanova, Elena1 aSurendran, Praveen1 aCook, James, P1 aKarthikeyan, Savita1 aLahrouchi, Najim1 aLiu, Chunyu1 aSepúlveda, Nuno1 aRichardson, Tom, G1 aKraja, Aldi1 aAmouyel, Philippe1 aFarrall, Martin1 aPoulter, Neil, R1 aLaakso, Markku1 aZeggini, Eleftheria1 aSever, Peter1 aScott, Robert, A1 aLangenberg, Claudia1 aWareham, Nicholas, J1 aConen, David1 aPalmer, Colin, Neil Alexa1 aAttia, John1 aChasman, Daniel, I1 aRidker, Paul, M1 aMelander, Olle1 aMook-Kanamori, Dennis, Owen1 avan der Harst, Pim1 aCucca, Francesco1 aSchlessinger, David1 aHayward, Caroline1 aSpector, Tim, D1 aJarvelin, Marjo-Riitta1 aHennig, Branwen, J1 aTimpson, Nicholas, J1 aWei, Wei-Qi1 aSmith, Joshua, C1 aXu, Yaomin1 aMatheny, Michael, E1 aSiew, Edward, E1 aLindgren, Cecilia1 aHerzig, Karl-Heinz1 aDedoussis, George1 aDenny, Joshua, C1 aPsaty, Bruce, M1 aHowson, Joanna, M M1 aMunroe, Patricia, B1 aNewton-Cheh, Christopher1 aCaulfield, Mark, J1 aElliott, Paul1 aGaziano, Michael1 aConcato, John1 aWilson, Peter, W F1 aTsao, Philip, S1 aEdwards, Digna, R Velez1 aSusztak, Katalin1 aO'Donnell, Christopher, J1 aHung, Adriana, M1 aEdwards, Todd, L1 aUnderstanding Society Scientific Group1 aInternational Consortium for Blood Pressure1 aBlood Pressure-International Consortium of Exome Chip Studies1 aMillion Veteran Program uhttps://chs-nhlbi.org/node/791413215nas 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.aay669004975nas a2200733 4500008004100000022001400041245010200055210006900157260001600226520287800242100001603120700001903136700001603155700001903171700001303190700002203203700002203225700002203247700001903269700001703288700001303305700002203318700002303340700002003363700002103383700002303404700002003427700002603447700002003473700001603493700002403509700002003533700002103553700002803574700002603602700002403628700003303652700002303685700002303708700002403731700001603755700001403771700002103785700001703806700001803823700001803841700002103859700002203880700002003902700002603922700002303948700002203971700002403993700002704017700001704044700001904061700002004080700002004100700002204120700002004142700002304162700002004185856003604205 2022 eng d a1460-215600aEpigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI.0 aEpigenetic and integrative crossomics analyses of cerebral white c2022 Aug 093 aCerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at approximately 450,000 CpG sites in 9,732 middle-aged to older adults from 14 community-based studies. Single-CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single-CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5), and colocalized with FOLH1 expression in brain (posterior probability =0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single-CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis, and multi-omics colocalization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug repositioning analysis indicated antihyperlipidemic agents, more specifically peroxisome proliferator-activated receptor alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood brain barrier disruption.
1 aYang, Yunju1 aKnol, Maria, J1 aWang, Ruiqi1 aMishra, Aniket1 aLiu, Dan1 aLuciano, Michelle1 aTeumer, Alexander1 aArmstrong, Nicola1 aBis, Joshua, C1 aJhun, Min, A1 aLi, Shuo1 aAdams, Hieab, H H1 aAziz, Nasir, Ahmad1 aBastin, Mark, E1 aBourgey, Mathieu1 aBrody, Jennifer, A1 aFrenzel, Stefan1 aGottesman, Rebecca, F1 aHosten, Norbert1 aHou, Lifang1 aKardia, Sharon, L R1 aLohner, Valerie1 aMarquis, Pascale1 aManiega, Susana, Muñoz1 aSatizabal, Claudia, L1 aSorond, Farzaneh, A1 aHernández, Maria, C Valdés1 aDuijn, Cornelia, M1 aVernooij, Meike, W1 aWittfeld, Katharina1 aYang, Qiong1 aZhao, Wei1 aBoerwinkle, Eric1 aLevy, Daniel1 aDeary, Ian, J1 aJiang, Jiyang1 aMather, Karen, A1 aMosley, Thomas, H1 aPsaty, Bruce, M1 aSachdev, Perminder, S1 aSmith, Jennifer, A1 aSotoodehnia, Nona1 aDeCarli, Charles, S1 aBreteler, Monique, M B1 aIkram, Arfan1 aGrabe, Hans, J1 aWardlaw, Joanna1 aLongstreth, W T1 aLauner, Lenore, J1 aSeshadri, Sudha1 aDebette, Stephanie1 aFornage, Myriam uhttps://chs-nhlbi.org/node/918405288nas a2201585 4500008004100000022001400041245009100055210006900146260001600215520091300231100001601144700002101160700001601181700002001197700001901217700001601236700002501252700001801277700001901295700001901314700002101333700001801354700002101372700002001393700001601413700001801429700001801447700001701465700002401482700001901506700002101525700002801546700002201574700001401596700002001610700002101630700001901651700002401670700002401694700002301718700002701741700002001768700001901788700001901807700002101826700002101847700001901868700002201887700001801909700001801927700001301945700001601958700001301974700001701987700001702004700002502021700002102046700001902067700002002086700001902106700001802125700002402143700002702167700001902194700001902213700002302232700002502255700002102280700002402301700001902325700002602344700002402370700002602394700002102420700002202441700002102463700002302484700002002507700001702527700002202544700002602566700002002592700002302612700002502635700002102660700001702681700002202698700002402720700002002744700001302764700002002777700001202797700001602809700001402825700001602839700001602855700002202871700001902893700002302912700002202935700002202957700002002979700001902999700002403018700001603042700002103058700002303079700001903102700002003121700002103141700002003162700002903182700002603211700002203237700002003259700002403279700002003303700001903323700002003342700002003362700002003382700001903402700002103421700002403442700002603466700002303492700002303515700002203538700002203560700002303582700001803605700002003623700002303643856003603666 2022 eng d a1476-557800aGenome-wide meta-analyses reveal novel loci for verbal short-term memory and learning.0 aGenomewide metaanalyses reveal novel loci for verbal shortterm m c2022 Aug 163 aUnderstanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.
1 aLahti, Jari1 aTuominen, Samuli1 aYang, Qiong1 aPergola, Giulio1 aAhmad, Shahzad1 aAmin, Najaf1 aArmstrong, Nicola, J1 aBeiser, Alexa1 aBey, Katharina1 aBis, Joshua, C1 aBoerwinkle, Eric1 aBressler, Jan1 aCampbell, Archie1 aCampbell, Harry1 aChen, Qiang1 aCorley, Janie1 aCox, Simon, R1 aDavies, Gail1 aDe Jager, Philip, L1 aDerks, Eske, M1 aFaul, Jessica, D1 aFitzpatrick, Annette, L1 aFohner, Alison, E1 aFord, Ian1 aFornage, Myriam1 aGerring, Zachary1 aGrabe, Hans, J1 aGrodstein, Francine1 aGudnason, Vilmundur1 aSimonsick, Eleanor1 aHolliday, Elizabeth, G1 aJoshi, Peter, K1 aKajantie, Eero1 aKaprio, Jaakko1 aKarell, Pauliina1 aKleineidam, Luca1 aKnol, Maria, J1 aKochan, Nicole, A1 aKwok, John, B1 aLeber, Markus1 aLam, Max1 aLee, Teresa1 aLi, Shuo1 aLoukola, Anu1 aLuck, Tobias1 aMarioni, Riccardo, E1 aMather, Karen, A1 aMedland, Sarah1 aMirza, Saira, S1 aNalls, Mike, A1 aNho, Kwangsik1 aO'Donnell, Adrienne1 aOldmeadow, Christopher1 aPainter, Jodie1 aPattie, Alison1 aReppermund, Simone1 aRisacher, Shannon, L1 aRose, Richard, J1 aSadashivaiah, Vijay1 aScholz, Markus1 aSatizabal, Claudia, L1 aSchofield, Peter, W1 aSchraut, Katharina, E1 aScott, Rodney, J1 aSimino, Jeannette1 aSmith, Albert, V1 aSmith, Jennifer, A1 aStott, David, J1 aSurakka, Ida1 aTeumer, Alexander1 aThalamuthu, Anbupalam1 aTrompet, Stella1 aTurner, Stephen, T1 avan der Lee, Sven, J1 aVillringer, Arno1 aVölker, Uwe1 aWilson, Robert, S1 aWittfeld, Katharina1 aVuoksimaa, Eero1 aXia, Rui1 aYaffe, Kristine1 aYu, Lei1 aZare, Habil1 aZhao, Wei1 aAmes, David1 aAttia, John1 aBennett, David, A1 aBrodaty, Henry1 aChasman, Daniel, I1 aGoldman, Aaron, L1 aHayward, Caroline1 aIkram, Arfan, M1 aJukema, Wouter1 aKardia, Sharon, L R1 aLencz, Todd1 aLoeffler, Markus1 aMattay, Venkata, S1 aPalotie, Aarno1 aPsaty, Bruce, M1 aRamirez, Alfredo1 aRidker, Paul, M1 aRiedel-Heller, Steffi, G1 aSachdev, Perminder, S1 aSaykin, Andrew, J1 aScherer, Martin1 aSchofield, Peter, R1 aSidney, Stephen1 aStarr, John, M1 aTrollor, Julian1 aUlrich, William1 aWagner, Michael1 aWeir, David, R1 aWilson, James, F1 aWright, Margaret, J1 aWeinberger, Daniel, R1 aDebette, Stephanie1 aEriksson, Johan, G1 aMosley, Thomas, H1 aLauner, Lenore, J1 aDuijn, Cornelia, M1 aDeary, Ian, J1 aSeshadri, Sudha1 aRäikkönen, Katri uhttps://chs-nhlbi.org/node/916915436nas a2205137 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2022 eng d a1546-171800aNew insights into the genetic etiology of Alzheimer's disease and related dementias.0 aNew insights into the genetic etiology of Alzheimers disease and c2022 Apr a412-4360 v543 aCharacterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
10aAlzheimer Disease10aCognitive Dysfunction10aGenome-Wide Association Study10aHumans10atau Proteins1 aBellenguez, Céline1 aKüçükali, Fahri1 aJansen, Iris, E1 aKleineidam, Luca1 aMoreno-Grau, Sonia1 aAmin, Najaf1 aNaj, Adam, C1 aCampos-Martin, Rafael1 aGrenier-Boley, Benjamin1 aAndrade, Victor1 aHolmans, Peter, A1 aBoland, Anne1 aDamotte, Vincent1 avan der Lee, Sven, J1 aCosta, Marcos, R1 aKuulasmaa, Teemu1 aYang, Qiong1 ade Rojas, Itziar1 aBis, Joshua, C1 aYaqub, Amber1 aProkic, Ivana1 aChapuis, Julien1 aAhmad, Shahzad1 aGiedraitis, Vilmantas1 aAarsland, Dag1 aGarcia-Gonzalez, Pablo1 aAbdelnour, Carla1 aAlarcón-Martín, Emilio1 aAlcolea, Daniel1 aAlegret, Montserrat1 aAlvarez, Ignacio1 aAlvarez, Victoria1 aArmstrong, Nicola, J1 aTsolaki, Anthoula1 aAntunez, Carmen1 aAppollonio, Ildebrando1 aArcaro, Marina1 aArchetti, Silvana1 aPastor, Alfonso, Arias1 aArosio, Beatrice1 aAthanasiu, Lavinia1 aBailly, Henri1 aBanaj, Nerisa1 aBaquero, Miquel1 aBarral, Sandra1 aBeiser, Alexa1 aPastor, Ana, Belén1 aBelow, Jennifer, E1 aBenchek, Penelope1 aBenussi, Luisa1 aBerr, Claudine1 aBesse, Céline1 aBessi, Valentina1 aBinetti, Giuliano1 aBizarro, Alessandra1 aBlesa, Rafael1 aBoada, Merce1 aBoerwinkle, Eric1 aBorroni, Barbara1 aBoschi, Silvia1 aBossù, Paola1 aBråthen, Geir1 aBressler, Jan1 aBresner, Catherine1 aBrodaty, Henry1 aBrookes, Keeley, J1 aBrusco, Luis, Ignacio1 aBuiza-Rueda, Dolores1 aBûrger, Katharina1 aBurholt, Vanessa1 aBush, William, S1 aCalero, Miguel1 aCantwell, Laura, B1 aChene, Geneviève1 aChung, Jaeyoon1 aCuccaro, Michael, L1 aCarracedo, Angel1 aCecchetti, Roberta1 aCervera-Carles, Laura1 aCharbonnier, Camille1 aChen, Hung-Hsin1 aChillotti, Caterina1 aCiccone, Simona1 aClaassen, Jurgen, A H R1 aClark, Christopher1 aConti, Elisa1 aCorma-Gómez, Anaïs1 aCostantini, Emanuele1 aCustodero, Carlo1 aDaian, Delphine1 aDalmasso, Maria, Carolina1 aDaniele, Antonio1 aDardiotis, Efthimios1 aDartigues, Jean-François1 ade Deyn, Peter, Paul1 aLopes, Katia, de Paiva1 ade Witte, Lot, D1 aDebette, Stephanie1 aDeckert, Jürgen1 aDel Ser, Teodoro1 aDenning, Nicola1 aDeStefano, Anita1 aDichgans, Martin1 aDiehl-Schmid, Janine1 aDiez-Fairen, Monica1 aRossi, Paolo, Dionigi1 aDjurovic, Srdjan1 aDuron, Emmanuelle1 aDüzel, Emrah1 aDufouil, Carole1 aEiriksdottir, Gudny1 aEngelborghs, Sebastiaan1 aEscott-Price, Valentina1 aEspinosa, Ana1 aEwers, Michael1 aFaber, Kelley, M1 aFabrizio, Tagliavini1 aNielsen, Sune, Fallgaard1 aFardo, David, W1 aFarotti, Lucia1 aFenoglio, Chiara1 aFernández-Fuertes, Marta1 aFerrari, Raffaele1 aFerreira, Catarina, B1 aFerri, Evelyn1 aFin, Bertrand1 aFischer, Peter1 aFladby, Tormod1 aFließbach, Klaus1 aFongang, Bernard1 aFornage, Myriam1 aFortea, Juan1 aForoud, Tatiana, M1 aFostinelli, Silvia1 aFox, Nick, C1 aFranco-Macías, Emlio1 aBullido, María, J1 aFrank-García, Ana1 aFroelich, Lutz1 aFulton-Howard, Brian1 aGalimberti, Daniela1 aGarcía-Alberca, Jose, Maria1 aGarcia-Gonzalez, Pablo1 aGarcia-Madrona, Sebastian1 aGarcia-Ribas, Guillermo1 aGhidoni, Roberta1 aGiegling, Ina1 aGiorgio, Giaccone1 aGoate, Alison, M1 aGoldhardt, Oliver1 aGomez-Fonseca, Duber1 aGonzález-Perez, Antonio1 aGraff, Caroline1 aGrande, Giulia1 aGreen, Emma1 aGrimmer, Timo1 aGrünblatt, Edna1 aGrunin, Michelle1 aGudnason, Vilmundur1 aGuetta-Baranes, Tamar1 aHaapasalo, Annakaisa1 aHadjigeorgiou, Georgios1 aHaines, Jonathan, L1 aHamilton-Nelson, Kara, L1 aHampel, Harald1 aHanon, Olivier1 aHardy, John1 aHartmann, Annette, M1 aHausner, Lucrezia1 aHarwood, Janet1 aHeilmann-Heimbach, Stefanie1 aHelisalmi, Seppo1 aHeneka, Michael, T1 aHernandez, Isabel1 aHerrmann, Martin, J1 aHoffmann, Per1 aHolmes, Clive1 aHolstege, Henne1 aVilas, Raquel, Huerto1 aHulsman, Marc1 aHumphrey, Jack1 aBiessels, Geert, Jan1 aJian, Xueqiu1 aJohansson, Charlotte1 aJun, Gyungah, R1 aKastumata, Yuriko1 aKauwe, John1 aKehoe, Patrick, G1 aKilander, Lena1 aStåhlbom, Anne, Kinhult1 aKivipelto, Miia1 aKoivisto, Anne1 aKornhuber, Johannes1 aKosmidis, Mary, H1 aKukull, Walter, A1 aKuksa, Pavel, P1 aKunkle, Brian, W1 aKuzma, Amanda, B1 aLage, Carmen1 aLaukka, Erika, J1 aLauner, Lenore1 aLauria, Alessandra1 aLee, Chien-Yueh1 aLehtisalo, Jenni1 aLerch, Ondrej1 aLleo, Alberto1 aLongstreth, William1 aLopez, Oscar1 ade Munain, Adolfo, Lopez1 aLove, Seth1 aLöwemark, Malin1 aLuckcuck, Lauren1 aLunetta, Kathryn, L1 aMa, Yiyi1 aMacías, Juan1 aMacLeod, Catherine, A1 aMaier, Wolfgang1 aMangialasche, Francesca1 aSpallazzi, Marco1 aMarquié, Marta1 aMarshall, Rachel1 aMartin, Eden, R1 aMontes, Angel, Martín1 aRodríguez, Carmen, Martínez1 aMasullo, Carlo1 aMayeux, Richard1 aMead, Simon1 aMecocci, Patrizia1 aMedina, Miguel1 aMeggy, Alun1 aMehrabian, Shima1 aMendoza, Silvia1 aMenéndez-González, Manuel1 aMir, Pablo1 aMoebus, Susanne1 aMol, Merel1 aMolina-Porcel, Laura1 aMontrreal, Laura1 aMorelli, Laura1 aMoreno, Fermin1 aMorgan, Kevin1 aMosley, Thomas1 aNöthen, Markus, M1 aMuchnik, Carolina1 aMukherjee, Shubhabrata1 aNacmias, Benedetta1 aNgandu, Tiia1 aNicolas, Gaël1 aNordestgaard, Børge, G1 aOlaso, Robert1 aOrellana, Adelina1 aOrsini, Michela1 aOrtega, Gemma1 aPadovani, Alessandro1 aPaolo, Caffarra1 aPapenberg, Goran1 aParnetti, Lucilla1 aPasquier, Florence1 aPastor, Pau1 aPeloso, Gina1 aPérez-Cordón, Alba1 aPérez-Tur, Jordi1 aPericard, Pierre1 aPeters, Oliver1 aPijnenburg, Yolande, A L1 aPineda, Juan, A1 aPiñol-Ripoll, Gerard1 aPisanu, Claudia1 aPolak, Thomas1 aPopp, Julius1 aPosthuma, Danielle1 aPriller, Josef1 aPuerta, Raquel1 aQuenez, Olivier1 aQuintela, Inés1 aThomassen, Jesper, Qvist1 aRábano, Alberto1 aRainero, Innocenzo1 aRajabli, Farid1 aRamakers, Inez1 aReal, Luis, M1 aReinders, Marcel, J T1 aReitz, Christiane1 aReyes-Dumeyer, Dolly1 aRidge, Perry1 aRiedel-Heller, Steffi1 aRiederer, Peter1 aRoberto, Natalia1 aRodriguez-Rodriguez, Eloy1 aRongve, Arvid1 aAllende, Irene, Rosas1 aRosende-Roca, Maitée1 aRoyo, Jose, Luis1 aRubino, Elisa1 aRujescu, Dan1 aSáez, María, Eugenia1 aSakka, Paraskevi1 aSaltvedt, Ingvild1 aSanabria, Ángela1 aSánchez-Arjona, María, Bernal1 aSanchez-Garcia, Florentino1 aJuan, Pascual, Sánchez1 aSánchez-Valle, Raquel1 aSando, Sigrid, B1 aSarnowski, Chloe1 aSatizabal, Claudia, L1 aScamosci, Michela1 aScarmeas, Nikolaos1 aScarpini, Elio1 aScheltens, Philip1 aScherbaum, Norbert1 aScherer, Martin1 aSchmid, Matthias1 aSchneider, Anja1 aSchott, Jonathan, M1 aSelbæk, Geir1 aSeripa, Davide1 aSerrano, Manuel1 aSha, Jin1 aShadrin, Alexey, A1 aSkrobot, Olivia1 aSlifer, Susan1 aSnijders, Gijsje, J L1 aSoininen, Hilkka1 aSolfrizzi, Vincenzo1 aSolomon, Alina1 aSong, Yeunjoo1 aSorbi, Sandro1 aSotolongo-Grau, Oscar1 aSpalletta, Gianfranco1 aSpottke, Annika1 aSquassina, Alessio1 aStordal, Eystein1 aTartan, Juan, Pablo1 aTarraga, Lluis1 aTesí, Niccolo1 aThalamuthu, Anbupalam1 aThomas, Tegos1 aTosto, Giuseppe1 aTraykov, Latchezar1 aTremolizzo, Lucio1 aTybjærg-Hansen, Anne1 aUitterlinden, Andre1 aUllgren, Abbe1 aUlstein, Ingun1 aValero, Sergi1 aValladares, Otto1 aVan Broeckhoven, Christine1 aVance, Jeffery1 aVardarajan, Badri, N1 avan der Lugt, Aad1 aVan Dongen, Jasper1 avan Rooij, Jeroen1 avan Swieten, John1 aVandenberghe, Rik1 aVerhey, Frans1 aVidal, Jean-Sébastien1 aVogelgsang, Jonathan1 aVyhnalek, Martin1 aWagner, Michael1 aWallon, David1 aSan Wang, Li-1 aWang, Ruiqi1 aWeinhold, Leonie1 aWiltfang, Jens1 aWindle, Gill1 aWoods, Bob1 aYannakoulia, Mary1 aZare, Habil1 aZhao, Yi1 aZhang, Xiaoling1 aZhu, Congcong1 aZulaica, Miren1 aFarrer, Lindsay, A1 aPsaty, Bruce, M1 aGhanbari, Mohsen1 aRaj, Towfique1 aSachdev, Perminder1 aMather, Karen1 aJessen, Frank1 aIkram, Arfan, M1 ade Mendonça, Alexandre1 aHort, Jakub1 aTsolaki, Magda1 aPericak-Vance, Margaret, A1 aAmouyel, Philippe1 aWilliams, Julie1 aFrikke-Schmidt, Ruth1 aClarimon, Jordi1 aDeleuze, Jean-Francois1 aRossi, Giacomina1 aSeshadri, Sudha1 aAndreassen, Ole, A1 aIngelsson, Martin1 aHiltunen, Mikko1 aSleegers, Kristel1 aSchellenberg, Gerard, D1 aDuijn, Cornelia, M1 aSims, Rebecca1 avan der Flier, Wiesje, M1 aRuiz, Agustin1 aRamirez, Alfredo1 aLambert, Jean-Charles1 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2022 eng d a1476-468700aStroke genetics informs drug discovery and risk prediction across ancestries.0 aStroke genetics informs drug discovery and risk prediction acros c2022 Sep 303 aPrevious genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
1 aMishra, Aniket1 aMalik, Rainer1 aHachiya, Tsuyoshi1 aJürgenson, Tuuli1 aNamba, Shinichi1 aPosner, Daniel, C1 aKamanu, Frederick, K1 aKoido, Masaru1 aLe Grand, Quentin1 aShi, Mingyang1 aHe, Yunye1 aGeorgakis, Marios, K1 aCaro, Ilana1 aKrebs, Kristi1 aLiaw, Yi-Ching1 aVaura, Felix, C1 aLin, Kuang1 aWinsvold, Bendik, Slagsvold1 aSrinivasasainagendra, Vinodh1 aParodi, Livia1 aBae, Hee-Joon1 aChauhan, Ganesh1 aChong, Michael, R1 aTomppo, Liisa1 aAkinyemi, Rufus1 aRoshchupkin, Gennady, V1 aHabib, Naomi1 aJee, Yon, Ho1 aThomassen, Jesper, Qvist1 aAbedi, Vida1 aCárcel-Márquez, Jara1 aNygaard, Marianne1 aLeonard, Hampton, L1 aYang, Chaojie1 aYonova-Doing, Ekaterina1 aKnol, Maria, J1 aLewis, Adam, J1 aJudy, Renae, L1 aAgo, Tetsuro1 aAmouyel, Philippe1 aArmstrong, Nicole, D1 aBakker, Mark, K1 aBartz, Traci, M1 aBennett, David, A1 aBis, Joshua, C1 aBordes, Constance1 aBørte, Sigrid1 aCain, Anael1 aRidker, Paul, M1 aCho, Kelly1 aChen, Zhengming1 aCruchaga, Carlos1 aCole, John, W1 aDe Jager, Phil, L1 ade Cid, Rafael1 aEndres, Matthias1 aFerreira, Leslie, E1 aGeerlings, Mirjam, I1 aGasca, Natalie, C1 aGudnason, Vilmundur1 aHata, Jun1 aHe, Jing1 aHeath, Alicia, K1 aHo, Yuk-Lam1 aHavulinna, Aki, S1 aHopewell, Jemma, C1 aHyacinth, Hyacinth, I1 aInouye, Michael1 aJacob, Mina, A1 aJeon, Christina, E1 aJern, Christina1 aKamouchi, Masahiro1 aKeene, Keith, L1 aKitazono, Takanari1 aKittner, Steven, J1 aKonuma, Takahiro1 aKumar, Amit1 aLacaze, Paul1 aLauner, Lenore, J1 aLee, Keon-Joo1 aLepik, Kaido1 aLi, Jiang1 aLi, Liming1 aManichaikul, Ani1 aMarkus, Hugh, S1 aMarston, Nicholas, A1 aMeitinger, Thomas1 aMitchell, Braxton, D1 aMontellano, Felipe, A1 aMorisaki, Takayuki1 aMosley, Thomas, H1 aNalls, Mike, A1 aNordestgaard, Børge, G1 aO'Donnell, Martin, J1 aOkada, Yukinori1 aOnland-Moret, Charlotte, N1 aOvbiagele, Bruce1 aPeters, Annette1 aPsaty, Bruce, M1 aRich, Stephen, S1 aRosand, Jonathan1 aSabatine, Marc, S1 aSacco, Ralph, L1 aSaleheen, Danish1 aSandset, Else, Charlotte1 aSalomaa, Veikko1 aSargurupremraj, Muralidharan1 aSasaki, Makoto1 aSatizabal, Claudia, L1 aSchmidt, Carsten, O1 aShimizu, Atsushi1 aSmith, Nicholas, L1 aSloane, Kelly, L1 aSutoh, Yoichi1 aSun, Yan, V1 aTanno, Kozo1 aTiedt, Steffen1 aTatlisumak, Turgut1 aTorres-Aguila, Nuria, P1 aTiwari, Hemant, K1 aTrégouët, David-Alexandre1 aTrompet, Stella1 aTuladhar, Anil, Man1 aTybjærg-Hansen, Anne1 avan Vugt, Marion1 aVibo, Riina1 aVerma, Shefali, S1 aWiggins, Kerri, L1 aWennberg, Patrik1 aWoo, Daniel1 aWilson, Peter, W F1 aXu, Huichun1 aYang, Qiong1 aYoon, Kyungheon1 aMillwood, Iona, Y1 aGieger, Christian1 aNinomiya, Toshiharu1 aGrabe, Hans, J1 aJukema, Wouter1 aRissanen, Ina, L1 aStrbian, Daniel1 aKim, Young, Jin1 aChen, Pei-Hsin1 aMayerhofer, Ernst1 aHowson, Joanna, M M1 aIrvin, Marguerite, R1 aAdams, Hieab1 aWassertheil-Smoller, Sylvia1 aChristensen, Kaare1 aIkram, Mohammad, A1 aRundek, Tatjana1 aWorrall, Bradford, B1 aLathrop, Mark, G1 aRiaz, Moeen1 aSimonsick, Eleanor, M1 aKõrv, Janika1 aFrança, Paulo, H C1 aZand, Ramin1 aPrasad, Kameshwar1 aFrikke-Schmidt, Ruth1 ade Leeuw, Frank-Erik1 aLiman, Thomas1 aHaeusler, Karl, Georg1 aRuigrok, Ynte, M1 aHeuschmann, Peter, Ulrich1 aLongstreth, W T1 aJung, Keum, Ji1 aBastarache, Lisa1 aParé, Guillaume1 aDamrauer, Scott, M1 aChasman, Daniel, I1 aRotter, Jerome, I1 aAnderson, Christopher, D1 aZwart, John-Anker1 aNiiranen, Teemu, J1 aFornage, Myriam1 aLiaw, Yung-Po1 aSeshadri, Sudha1 aFernandez-Cadenas, Israel1 aWalters, Robin, G1 aRuff, Christian, T1 aOwolabi, Mayowa, O1 aHuffman, Jennifer, E1 aMilani, Lili1 aKamatani, Yoichiro1 aDichgans, Martin1 aDebette, Stephanie1 aCOMPASS Consortium1 aINVENT Consortium1 aDutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study Group1 aEstonian Biobank1 aPRECISEQ Consortium1 aFinnGen Consortium1 aNINDS Stroke Genetics Network (SiGN)1 aMEGASTROKE Consortium1 aSIREN Consortium1 aChina Kadoorie Biobank Collaborative Group1 aVA Million Veteran Program1 aInternational Stroke Genetics Consortium (ISGC)1 aBiobank Japan1 aCHARGE Consortium1 aGIGASTROKE Consortium uhttps://chs-nhlbi.org/node/917206165nas a2200505 4500008004100000245012200041210006900163260001600232520464400248100003304892700002104925700001904946700001704965700002204982700001705004700001905021700001605040700001605056700002605072700002605098700001905124700002305143700002105166700002305187700002105210700002005231700002205251700001705273700002005290700002405310700002205334700002005356700002805376700002705404700002405431700001705455700002405472700002005496700002205516700002005538700002005558700002205578700002305600856003605623 2023 eng d00aComplexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics.0 aComplexities of cerebral small vessel disease blood pressure and c2023 Aug 133 aIMPORTANCE: There is increasing recognition that vascular disease, which can be treated, is a key contributor to dementia risk. However, the contribution of specific markers of vascular disease is unclear and, as a consequence, optimal prevention strategies remain unclear.
OBJECTIVE: To disentangle the causal relation of several key vascular traits to dementia risk: (i) white matter hyperintensity (WMH) burden, a highly prevalent imaging marker of covert cerebral small vessel disease (cSVD); (ii) clinical stroke; and (iii) blood pressure (BP), the leading risk factor for cSVD and stroke, for which efficient therapies exist. To account for potential epidemiological biases inherent to late-onset conditions like dementia.
DESIGN SETTING AND PARTICIPANTS: This study first explored the association of genetically determined WMH, BP levels and stroke risk with AD using summary-level data from large genome-wide association studies (GWASs) in a two-sample Mendelian randomization (MR) framework. Second, leveraging individual-level data from large longitudinal population-based cohorts and biobanks with prospective dementia surveillance, the association of weighted genetic risk scores (wGRSs) for WMH, BP, and stroke with incident all-cause-dementia was explored using Cox-proportional hazard and multi-state models. The data analysis was performed from July 26, 2020, through July 24, 2022.
EXPOSURES: Genetically determined levels of WMH volume and BP (systolic, diastolic and pulse blood pressures) and genetic liability to stroke.
MAIN OUTCOMES AND MEASURES: The summary-level MR analyses focused on the outcomes from GWAS of clinically diagnosed AD (n-cases=21,982) and GWAS additionally including self-reported parental history of dementia as a proxy for AD diagnosis (AD , n-cases=53,042). For the longitudinal analyses, individual-level data of 157,698 participants with 10,699 incident all-cause-dementia were studied, exploring AD, vascular or mixed dementia in secondary analyses.
RESULTS: In the two-sample MR analyses, WMH showed strong evidence for a causal association with increased risk of AD (OR, 1.16; 95%CI:1.05-1.28; P=.003) and AD (OR, 1.28; 95%CI:1.07-1.53; P=.008), after accounting for genetically determined pulse pressure for the latter. Genetically predicted BP traits showed evidence for a protective association with both clinically defined AD and AD , with evidence for confounding by shared genetic instruments. In longitudinal analyses the wGRSs for WMH, but not BP or stroke, showed suggestive association with incident all-cause-dementia (HR, 1.02; 95%CI:1.00-1.04; P=.06). BP and stroke wGRSs were strongly associated with mortality but there was no evidence for selective survival bias during follow-up. In secondary analyses, polygenic scores with more liberal instrument definition showed association of both WMH and stroke with all-cause-dementia, AD, and vascular or mixed dementia; associations of stroke, but not WMH, with dementia outcomes were markedly attenuated after adjusting for interim stroke.
CONCLUSION: These findings provide converging evidence that WMH is a leading vascular contributor to dementia risk, which may better capture the brain damage caused by BP (and other etiologies) than BP itself and should be targeted in priority for dementia prevention in the population.
KEY POINTS: Do instrumental variable analyses leveraging genetic information provide evidence for a causal association of various vascular traits with Alzheimer's disease (AD) and all-cause-dementia? How do these associations compare for white matter hyperintensity (WMH) burden, a highly prevalent marker of covert cerebral small vessel disease (cSVD), stroke, and blood pressure traits, the strongest known risk factor for cSVD and stroke? Using Mendelian randomization (MR) leveraging large, published genome-wide association studies, this study showed a putative causal association of larger WMH burden with increased AD risk after accounting for pulse pressure effects, and some evidence for association of lower BP with AD risk with possible confounding by shared genetic instruments. Longitudinal analyses on individual-level data also supported association of genetically determined WMH with incident all-cause-dementia and AD, independently of interim stroke. This study using complementary genetic epidemiology approaches, identified increasing WMH burden to be associated with dementia and AD risk, suggesting the association as specific for cSVD and independent of BP and stroke.
1 aSargurupremraj, Muralidharan1 aSoumaré, Aïcha1 aBis, Joshua, C1 aSurakka, Ida1 aJürgenson, Tuuli1 aJoly, Pierre1 aKnol, Maria, J1 aWang, Ruiqi1 aYang, Qiong1 aSatizabal, Claudia, L1 aGudjonsson, Alexander1 aMishra, Aniket1 aBouteloup, Vincent1 aPhuah, Chia-Ling1 aDuijn, Cornelia, M1 aCruchaga, Carlos1 aDufouil, Carole1 aChene, Geneviève1 aLopez, Oscar1 aPsaty, Bruce, M1 aTzourio, Christophe1 aAmouyel, Philippe1 aAdams, Hieab, H1 aJacqmin-Gadda, Hélène1 aIkram, Mohammad, Arfan1 aGudnason, Vilmundur1 aMilani, Lili1 aWinsvold, Bendik, S1 aHveem, Kristian1 aMatthews, Paul, M1 aLongstreth, W T1 aSeshadri, Sudha1 aLauner, Lenore, J1 aDebette, Stephanie uhttps://chs-nhlbi.org/node/950504874nas 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