%0 Journal Article %J N Engl J Med %D 2009 %T Genomewide association studies of stroke. %A Ikram, M Arfan %A Seshadri, Sudha %A Bis, Joshua C %A Fornage, Myriam %A DeStefano, Anita L %A Aulchenko, Yurii S %A Debette, Stephanie %A Lumley, Thomas %A Folsom, Aaron R %A van den Herik, Evita G %A Bos, Michiel J %A Beiser, Alexa %A Cushman, Mary %A Launer, Lenore J %A Shahar, Eyal %A Struchalin, Maksim %A Du, Yangchun %A Glazer, Nicole L %A Rosamond, Wayne D %A Rivadeneira, Fernando %A Kelly-Hayes, Margaret %A Lopez, Oscar L %A Coresh, Josef %A Hofman, Albert %A DeCarli, Charles %A Heckbert, Susan R %A Koudstaal, Peter J %A Yang, Qiong %A Smith, Nicholas L %A Kase, Carlos S %A Rice, Kenneth %A Haritunians, Talin %A Roks, Gerwin %A de Kort, Paul L M %A Taylor, Kent D %A de Lau, Lonneke M %A Oostra, Ben A %A Uitterlinden, André G %A Rotter, Jerome I %A Boerwinkle, Eric %A Psaty, Bruce M %A Mosley, Thomas H %A van Duijn, Cornelia M %A Breteler, Monique M B %A Longstreth, W T %A Wolf, Philip A %K African Continental Ancestry Group %K Aged %K Chromosomes, Human, Pair 12 %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genetic Markers %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Proportional Hazards Models %K Risk Factors %K Stroke %X

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.

%B N Engl J Med %V 360 %P 1718-28 %8 2009 Apr 23 %G eng %N 17 %1 https://www.ncbi.nlm.nih.gov/pubmed/19369658?dopt=Abstract %R 10.1056/NEJMoa0900094 %0 Journal Article %J JAMA %D 2010 %T Genome-wide analysis of genetic loci associated with Alzheimer disease. %A Seshadri, Sudha %A Fitzpatrick, Annette L %A Ikram, M Arfan %A DeStefano, Anita L %A Gudnason, Vilmundur %A Boada, Merce %A Bis, Joshua C %A Smith, Albert V %A Carassquillo, Minerva M %A Lambert, Jean Charles %A Harold, Denise %A Schrijvers, Elisabeth M C %A Ramirez-Lorca, Reposo %A Debette, Stephanie %A Longstreth, W T %A Janssens, A Cecile J W %A Pankratz, V Shane %A Dartigues, Jean François %A Hollingworth, Paul %A Aspelund, Thor %A Hernandez, Isabel %A Beiser, Alexa %A Kuller, Lewis H %A Koudstaal, Peter J %A Dickson, Dennis W %A Tzourio, Christophe %A Abraham, Richard %A Antunez, Carmen %A Du, Yangchun %A Rotter, Jerome I %A Aulchenko, Yurii S %A Harris, Tamara B %A Petersen, Ronald C %A Berr, Claudine %A Owen, Michael J %A Lopez-Arrieta, Jesus %A Varadarajan, Badri N %A Becker, James T %A Rivadeneira, Fernando %A Nalls, Michael A %A Graff-Radford, Neill R %A Campion, Dominique %A Auerbach, Sanford %A Rice, Kenneth %A Hofman, Albert %A Jonsson, Palmi V %A Schmidt, Helena %A Lathrop, Mark %A Mosley, Thomas H %A Au, Rhoda %A Psaty, Bruce M %A Uitterlinden, André G %A Farrer, Lindsay A %A Lumley, Thomas %A Ruiz, Agustin %A Williams, Julie %A Amouyel, Philippe %A Younkin, Steve G %A Wolf, Philip A %A Launer, Lenore J %A Lopez, Oscar L %A van Duijn, Cornelia M %A Breteler, Monique M B %K Age of Onset %K Aged %K Alzheimer Disease %K Case-Control Studies %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Odds Ratio %K Polymorphism, Single Nucleotide %X

CONTEXT: 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.

%B JAMA %V 303 %P 1832-40 %8 2010 May 12 %G eng %N 18 %1 http://www.ncbi.nlm.nih.gov/pubmed/20460622?dopt=Abstract %R 10.1001/jama.2010.574 %0 Journal Article %J Stroke %D 2010 %T Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium. %A Debette, Stephanie %A Bis, Joshua C %A Fornage, Myriam %A Schmidt, Helena %A Ikram, M Arfan %A Sigurdsson, Sigurdur %A Heiss, Gerardo %A Struchalin, Maksim %A Smith, Albert V %A van der Lugt, Aad %A DeCarli, Charles %A Lumley, Thomas %A Knopman, David S %A Enzinger, Christian %A Eiriksdottir, Gudny %A Koudstaal, Peter J %A DeStefano, Anita L %A Psaty, Bruce M %A Dufouil, Carole %A Catellier, Diane J %A Fazekas, Franz %A Aspelund, Thor %A Aulchenko, Yurii S %A Beiser, Alexa %A Rotter, Jerome I %A Tzourio, Christophe %A Shibata, Dean K %A Tscherner, Maria %A Harris, Tamara B %A Rivadeneira, Fernando %A Atwood, Larry D %A Rice, Kenneth %A Gottesman, Rebecca F %A van Buchem, Mark A %A Uitterlinden, André G %A Kelly-Hayes, Margaret %A Cushman, Mary %A Zhu, Yicheng %A Boerwinkle, Eric %A Gudnason, Vilmundur %A Hofman, Albert %A Romero, Jose R %A Lopez, Oscar %A van Duijn, Cornelia M %A Au, Rhoda %A Heckbert, Susan R %A Wolf, Philip A %A Mosley, Thomas H %A Seshadri, Sudha %A Breteler, Monique M B %A Schmidt, Reinhold %A Launer, Lenore J %A Longstreth, W T %K African Americans %K Aged %K Brain %K Brain Infarction %K Cohort Studies %K DNA Mutational Analysis %K Female %K Gene Frequency %K Genetic Markers %K Genetic Predisposition to Disease %K Genetic Testing %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Prospective Studies %X

BACKGROUND 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.

%B Stroke %V 41 %P 210-7 %8 2010 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/20044523?dopt=Abstract %R 10.1161/STROKEAHA.109.569194 %0 Journal Article %J Brain %D 2011 %T Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease. %A Schmidt, Helena %A Zeginigg, Marion %A Wiltgen, Marco %A Freudenberger, Paul %A Petrovic, Katja %A Cavalieri, Margherita %A Gider, Pierre %A Enzinger, Christian %A Fornage, Myriam %A Debette, Stephanie %A Rotter, Jerome I %A Ikram, Mohammad A %A Launer, Lenore J %A Schmidt, Reinhold %K Aged %K Aged, 80 and over %K Alleles %K Brain %K Cerebral Small Vessel Diseases %K Exons %K Female %K Follow-Up Studies %K Genetic Association Studies %K Genotype %K Humans %K Hypertension %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Phenotype %K Promoter Regions, Genetic %K Prospective Studies %K Receptor, Notch3 %K Receptors, Notch %X

Cerebral 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.

%B Brain %V 134 %P 3384-97 %8 2011 Nov %G eng %N Pt 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/22006983?dopt=Abstract %R 10.1093/brain/awr252 %0 Journal Article %J Ann Neurol %D 2011 %T Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium. %A Fornage, Myriam %A Debette, Stephanie %A Bis, Joshua C %A Schmidt, Helena %A Ikram, M Arfan %A Dufouil, Carole %A Sigurdsson, Sigurdur %A Lumley, Thomas %A DeStefano, Anita L %A Fazekas, Franz %A Vrooman, Henri A %A Shibata, Dean K %A Maillard, Pauline %A Zijdenbos, Alex %A Smith, Albert V %A Gudnason, Haukur %A de Boer, Renske %A Cushman, Mary %A Mazoyer, Bernard %A Heiss, Gerardo %A Vernooij, Meike W %A Enzinger, Christian %A Glazer, Nicole L %A Beiser, Alexa %A Knopman, David S %A Cavalieri, Margherita %A Niessen, Wiro J %A Harris, Tamara B %A Petrovic, Katja %A Lopez, Oscar L %A Au, Rhoda %A Lambert, Jean-Charles %A Hofman, Albert %A Gottesman, Rebecca F %A Garcia, Melissa %A Heckbert, Susan R %A Atwood, Larry D %A Catellier, Diane J %A Uitterlinden, André G %A Yang, Qiong %A Smith, Nicholas L %A Aspelund, Thor %A Romero, Jose R %A Rice, Kenneth %A Taylor, Kent D %A Nalls, Michael A %A Rotter, Jerome I %A Sharrett, Richey %A van Duijn, Cornelia M %A Amouyel, Philippe %A Wolf, Philip A %A Gudnason, Vilmundur %A van der Lugt, Aad %A Boerwinkle, Eric %A Psaty, Bruce M %A Seshadri, Sudha %A Tzourio, Christophe %A Breteler, Monique M B %A Mosley, Thomas H %A Schmidt, Reinhold %A Longstreth, W T %A DeCarli, Charles %A Launer, Lenore J %K Aged %K Aged, 80 and over %K Cerebral Cortex %K Chromosomes, Human, Pair 17 %K Cognition Disorders %K Cohort Studies %K European Continental Ancestry Group %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Leukoencephalopathies %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Movement Disorders %K Nerve Fibers, Myelinated %K Polymorphism, Single Nucleotide %K Residence Characteristics %K RNA, Messenger %X

OBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.

METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.

RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 × 10(-9) ; p(replication) = 1.3 × 10(-7) ; p(combined) = 4.0 × 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 × 10(-9) ), rs11869977 (p = 5.7 × 10(-9) ), rs936393 (p = 6.8 × 10(-9) ), rs3744017 (p = 7.3 × 10(-9) ), and rs1055129 (p = 4.1 × 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample).

INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.

%B Ann Neurol %V 69 %P 928-39 %8 2011 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/21681796?dopt=Abstract %R 10.1002/ana.22403 %0 Journal Article %J Nat Genet %D 2011 %T Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. %A Wain, Louise V %A Verwoert, Germaine C %A O'Reilly, Paul F %A Shi, Gang %A Johnson, Toby %A Johnson, Andrew D %A Bochud, Murielle %A Rice, Kenneth M %A Henneman, Peter %A Smith, Albert V %A Ehret, Georg B %A Amin, Najaf %A Larson, Martin G %A Mooser, Vincent %A Hadley, David %A Dörr, Marcus %A Bis, Joshua C %A Aspelund, Thor %A Esko, Tõnu %A Janssens, A Cecile J W %A Zhao, Jing Hua %A Heath, Simon %A Laan, Maris %A Fu, Jingyuan %A Pistis, Giorgio %A Luan, Jian'an %A Arora, Pankaj %A Lucas, Gavin %A Pirastu, Nicola %A Pichler, Irene %A Jackson, Anne U %A Webster, Rebecca J %A Zhang, Feng %A Peden, John F %A Schmidt, Helena %A Tanaka, Toshiko %A Campbell, Harry %A Igl, Wilmar %A Milaneschi, Yuri %A Hottenga, Jouke-Jan %A Vitart, Veronique %A Chasman, Daniel I %A Trompet, Stella %A Bragg-Gresham, Jennifer L %A Alizadeh, Behrooz Z %A Chambers, John C %A Guo, Xiuqing %A Lehtimäki, Terho %A Kuhnel, Brigitte %A Lopez, Lorna M %A Polasek, Ozren %A Boban, Mladen %A Nelson, Christopher P %A Morrison, Alanna C %A Pihur, Vasyl %A Ganesh, Santhi K %A Hofman, Albert %A Kundu, Suman %A Mattace-Raso, Francesco U S %A Rivadeneira, Fernando %A Sijbrands, Eric J G %A Uitterlinden, André G %A Hwang, Shih-Jen %A Vasan, Ramachandran S %A Wang, Thomas J %A Bergmann, Sven %A Vollenweider, Peter %A Waeber, Gérard %A Laitinen, Jaana %A Pouta, Anneli %A Zitting, Paavo %A McArdle, Wendy L %A Kroemer, Heyo K %A Völker, Uwe %A Völzke, Henry %A Glazer, Nicole L %A Taylor, Kent D %A Harris, Tamara B %A Alavere, Helene %A Haller, Toomas %A Keis, Aime %A Tammesoo, Mari-Liis %A Aulchenko, Yurii %A Barroso, Inês %A Khaw, Kay-Tee %A Galan, Pilar %A Hercberg, Serge %A Lathrop, Mark %A Eyheramendy, Susana %A Org, Elin %A Sõber, Siim %A Lu, Xiaowen %A Nolte, Ilja M %A Penninx, Brenda W %A Corre, Tanguy %A Masciullo, Corrado %A Sala, Cinzia %A Groop, Leif %A Voight, Benjamin F %A Melander, Olle %A O'Donnell, Christopher J %A Salomaa, Veikko %A d'Adamo, Adamo Pio %A Fabretto, Antonella %A Faletra, Flavio %A Ulivi, Sheila %A Del Greco, Fabiola M %A Facheris, Maurizio %A Collins, Francis S %A Bergman, Richard N %A Beilby, John P %A Hung, Joseph %A Musk, A William %A Mangino, Massimo %A Shin, So-Youn %A Soranzo, Nicole %A Watkins, Hugh %A Goel, Anuj %A Hamsten, Anders %A Gider, Pierre %A Loitfelder, Marisa %A Zeginigg, Marion %A Hernandez, Dena %A Najjar, Samer S %A Navarro, Pau %A Wild, Sarah H %A Corsi, Anna Maria %A Singleton, Andrew %A de Geus, Eco J C %A Willemsen, Gonneke %A Parker, Alex N %A Rose, Lynda M %A Buckley, Brendan %A Stott, David %A Orrù, Marco %A Uda, Manuela %A van der Klauw, Melanie M %A Zhang, Weihua %A Li, Xinzhong %A Scott, James %A Chen, Yii-Der Ida %A Burke, Gregory L %A Kähönen, Mika %A Viikari, Jorma %A Döring, Angela %A Meitinger, Thomas %A Davies, Gail %A Starr, John M %A Emilsson, Valur %A Plump, Andrew %A Lindeman, Jan H %A Hoen, Peter A C 't %A König, Inke R %A Felix, Janine F %A Clarke, Robert %A Hopewell, Jemma C %A Ongen, Halit %A Breteler, Monique %A Debette, Stephanie %A DeStefano, Anita L %A Fornage, Myriam %A Mitchell, Gary F %A Smith, Nicholas L %A Holm, Hilma %A Stefansson, Kari %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Samani, Nilesh J %A Preuss, Michael %A Rudan, Igor %A Hayward, Caroline %A Deary, Ian J %A Wichmann, H-Erich %A Raitakari, Olli T %A Palmas, Walter %A Kooner, Jaspal S %A Stolk, Ronald P %A Jukema, J Wouter %A Wright, Alan F %A Boomsma, Dorret I %A Bandinelli, Stefania %A Gyllensten, Ulf B %A Wilson, James F %A Ferrucci, Luigi %A Schmidt, Reinhold %A Farrall, Martin %A Spector, Tim D %A Palmer, Lyle J %A Tuomilehto, Jaakko %A Pfeufer, Arne %A Gasparini, Paolo %A Siscovick, David %A Altshuler, David %A Loos, Ruth J F %A Toniolo, Daniela %A Snieder, Harold %A Gieger, Christian %A Meneton, Pierre %A Wareham, Nicholas J %A Oostra, Ben A %A Metspalu, Andres %A Launer, Lenore %A Rettig, Rainer %A Strachan, David P %A Beckmann, Jacques S %A Witteman, Jacqueline C M %A Erdmann, Jeanette %A van Dijk, Ko Willems %A Boerwinkle, Eric %A Boehnke, Michael %A Ridker, Paul M %A Jarvelin, Marjo-Riitta %A Chakravarti, Aravinda %A Abecasis, Goncalo R %A Gudnason, Vilmundur %A Newton-Cheh, Christopher %A Levy, Daniel %A Munroe, Patricia B %A Psaty, Bruce M %A Caulfield, Mark J %A Rao, Dabeeru C %A Tobin, Martin D %A Elliott, Paul %A van Duijn, Cornelia M %K Arteries %K Blood Pressure %K Case-Control Studies %K Follow-Up Studies %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Hypertension %K Linkage Disequilibrium %K Polymorphism, Single Nucleotide %X

Numerous 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.

%B Nat Genet %V 43 %P 1005-11 %8 2011 Sep 11 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/21909110?dopt=Abstract %R 10.1038/ng.922 %0 Journal Article %J PLoS One %D 2014 %T Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium. %A Bis, Joshua C %A DeStefano, Anita %A Liu, Xiaoming %A Brody, Jennifer A %A Choi, Seung Hoan %A Verhaaren, Benjamin F J %A Debette, Stephanie %A Ikram, M Arfan %A Shahar, Eyal %A Butler, Kenneth R %A Gottesman, Rebecca F %A Muzny, Donna %A Kovar, Christie L %A Psaty, Bruce M %A Hofman, Albert %A Lumley, Thomas %A Gupta, Mayetri %A Wolf, Philip A %A van Duijn, Cornelia %A Gibbs, Richard A %A Mosley, Thomas H %A Longstreth, W T %A Boerwinkle, Eric %A Seshadri, Sudha %A Fornage, Myriam %K Cell Adhesion Molecules, Neuronal %K European Continental Ancestry Group %K Female %K Genetic Association Studies %K Genetic Heterogeneity %K Humans %K Introns %K Ischemia %K Male %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Prospective Studies %K Sequence Analysis, DNA %X

BACKGROUND: 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.

%B PLoS One %V 9 %P e99798 %8 2014 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/24959832?dopt=Abstract %R 10.1371/journal.pone.0099798 %0 Journal Article %J Stroke %D 2014 %T Predicting stroke through genetic risk functions: the CHARGE Risk Score Project. %A Ibrahim-Verbaas, Carla A %A Fornage, Myriam %A Bis, Joshua C %A Choi, Seung Hoan %A Psaty, Bruce M %A Meigs, James B %A Rao, Madhu %A Nalls, Mike %A Fontes, João D %A O'Donnell, Christopher J %A Kathiresan, Sekar %A Ehret, Georg B %A Fox, Caroline S %A Malik, Rainer %A Dichgans, Martin %A Schmidt, Helena %A Lahti, Jari %A Heckbert, Susan R %A Lumley, Thomas %A Rice, Kenneth %A Rotter, Jerome I %A Taylor, Kent D %A Folsom, Aaron R %A Boerwinkle, Eric %A Rosamond, Wayne D %A Shahar, Eyal %A Gottesman, Rebecca F %A Koudstaal, Peter J %A Amin, Najaf %A Wieberdink, Renske G %A Dehghan, Abbas %A Hofman, Albert %A Uitterlinden, André G %A DeStefano, Anita L %A Debette, Stephanie %A Xue, Luting %A Beiser, Alexa %A Wolf, Philip A %A DeCarli, Charles %A Ikram, M Arfan %A Seshadri, Sudha %A Mosley, Thomas H %A Longstreth, W T %A van Duijn, Cornelia M %A Launer, Lenore J %K Age Factors %K Aged %K Aged, 80 and over %K Area Under Curve %K Case-Control Studies %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Regression Analysis %K Risk Factors %K ROC Curve %K Sex Factors %K Stroke %X

BACKGROUND 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.

%B Stroke %V 45 %P 403-12 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24436238?dopt=Abstract %R 10.1161/STROKEAHA.113.003044 %0 Journal Article %J Neurobiol Aging %D 2015 %T Association of Alzheimer's disease GWAS loci with MRI markers of brain aging. %A Chauhan, Ganesh %A Adams, Hieab H H %A Bis, Joshua C %A Weinstein, Galit %A Yu, Lei %A Töglhofer, Anna Maria %A Smith, Albert Vernon %A van der Lee, Sven J %A Gottesman, Rebecca F %A Thomson, Russell %A Wang, Jing %A Yang, Qiong %A Niessen, Wiro J %A Lopez, Oscar L %A Becker, James T %A Phan, Thanh G %A Beare, Richard J %A Arfanakis, Konstantinos %A Fleischman, Debra %A Vernooij, Meike W %A Mazoyer, Bernard %A Schmidt, Helena %A Srikanth, Velandai %A Knopman, David S %A Jack, Clifford R %A Amouyel, Philippe %A Hofman, Albert %A DeCarli, Charles %A Tzourio, Christophe %A van Duijn, Cornelia M %A Bennett, David A %A Schmidt, Reinhold %A Longstreth, William T %A Mosley, Thomas H %A Fornage, Myriam %A Launer, Lenore J %A Seshadri, Sudha %A Ikram, M Arfan %A Debette, Stephanie %K Aging %K Alleles %K Alzheimer Disease %K Apolipoproteins E %K Brain %K Female %K Genome-Wide Association Study %K Hippocampus %K Humans %K Magnetic Resonance Imaging %K Male %K Organ Size %K Polymorphism, Single Nucleotide %K Risk %K Sialic Acid Binding Ig-like Lectin 3 %X

Whether 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.

%B Neurobiol Aging %V 36 %P 1765.e7-16 %8 2015 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/25670335?dopt=Abstract %R 10.1016/j.neurobiolaging.2014.12.028 %0 Journal Article %J Neurology %D 2015 %T Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. %A Rannikmae, Kristiina %A Davies, Gail %A Thomson, Pippa A %A Bevan, Steve %A Devan, William J %A Falcone, Guido J %A Traylor, Matthew %A Anderson, Christopher D %A Battey, Thomas W K %A Radmanesh, Farid %A Deka, Ranjan %A Woo, Jessica G %A Martin, Lisa J %A Jimenez-Conde, Jordi %A Selim, Magdy %A Brown, Devin L %A Silliman, Scott L %A Kidwell, Chelsea S %A Montaner, Joan %A Langefeld, Carl D %A Slowik, Agnieszka %A Hansen, Bjorn M %A Lindgren, Arne G %A Meschia, James F %A Fornage, Myriam %A Bis, Joshua C %A Debette, Stephanie %A Ikram, Mohammad A %A Longstreth, Will T %A Schmidt, Reinhold %A Zhang, Cathy R %A Yang, Qiong %A Sharma, Pankaj %A Kittner, Steven J %A Mitchell, Braxton D %A Holliday, Elizabeth G %A Levi, Christopher R %A Attia, John %A Rothwell, Peter M %A Poole, Deborah L %A Boncoraglio, Giorgio B %A Psaty, Bruce M %A Malik, Rainer %A Rost, Natalia %A Worrall, Bradford B %A Dichgans, Martin %A Van Agtmael, Tom %A Woo, Daniel %A Markus, Hugh S %A Seshadri, Sudha %A Rosand, Jonathan %A Sudlow, Cathie L M %K Cerebral Small Vessel Diseases %K Collagen Type IV %K Genetic Association Studies %K Genetic Variation %K Humans %K Polymorphism, Single Nucleotide %X

OBJECTIVES: 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.

%B Neurology %V 84 %P 918-26 %8 2015 Mar 3 %G ENG %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/25653287?dopt=Abstract %R 10.1212/WNL.0000000000001309 %0 Journal Article %J Stroke %D 2015 %T Genes from a translational analysis support a multifactorial nature of white matter hyperintensities. %A Lopez, Lorna M %A Hill, W David %A Harris, Sarah E %A Valdes Hernandez, Maria %A Munoz Maniega, Susana %A Bastin, Mark E %A Bailey, Emma %A Smith, Colin %A McBride, Martin %A McClure, John %A Graham, Delyth %A Dominiczak, Anna %A Yang, Qiong %A Fornage, Myriam %A Ikram, M Arfan %A Debette, Stephanie %A Launer, Lenore %A Bis, Joshua C %A Schmidt, Reinhold %A Seshadri, Sudha %A Porteous, David J %A Starr, John %A Deary, Ian J %A Wardlaw, Joanna M %K Aged %K Alzheimer Disease %K Animals %K Brain %K Causality %K Dementia %K Female %K Genome-Wide Association Study %K Humans %K Leukoencephalopathies %K Male %K Polymorphism, Single Nucleotide %K Rats %K Rats, Inbred SHR %K Rats, Wistar %K Risk Factors %K Translational Medical Research %K White Matter %X

BACKGROUND 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.

%B Stroke %V 46 %P 341-7 %8 2015 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25586835?dopt=Abstract %R 10.1161/STROKEAHA.114.007649 %0 Journal Article %J Biol Psychiatry %D 2015 %T Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. %A Debette, Stephanie %A Ibrahim Verbaas, Carla A %A Bressler, Jan %A Schuur, Maaike %A Smith, Albert %A Bis, Joshua C %A Davies, Gail %A Wolf, Christiane %A Gudnason, Vilmundur %A Chibnik, Lori B %A Yang, Qiong %A DeStefano, Anita L %A de Quervain, Dominique J F %A Srikanth, Velandai %A Lahti, Jari %A Grabe, Hans J %A Smith, Jennifer A %A Priebe, Lutz %A Yu, Lei %A Karbalai, Nazanin %A Hayward, Caroline %A Wilson, James F %A Campbell, Harry %A Petrovic, Katja %A Fornage, Myriam %A Chauhan, Ganesh %A Yeo, Robin %A Boxall, Ruth %A Becker, James %A Stegle, Oliver %A Mather, Karen A %A Chouraki, Vincent %A Sun, Qi %A Rose, Lynda M %A Resnick, Susan %A Oldmeadow, Christopher %A Kirin, Mirna %A Wright, Alan F %A Jonsdottir, Maria K %A Au, Rhoda %A Becker, Albert %A Amin, Najaf %A Nalls, Mike A %A Turner, Stephen T %A Kardia, Sharon L R %A Oostra, Ben %A Windham, Gwen %A Coker, Laura H %A Zhao, Wei %A Knopman, David S %A Heiss, Gerardo %A Griswold, Michael E %A Gottesman, Rebecca F %A Vitart, Veronique %A Hastie, Nicholas D %A Zgaga, Lina %A Rudan, Igor %A Polasek, Ozren %A Holliday, Elizabeth G %A Schofield, Peter %A Choi, Seung Hoan %A Tanaka, Toshiko %A An, Yang %A Perry, Rodney T %A Kennedy, Richard E %A Sale, Michèle M %A Wang, Jing %A Wadley, Virginia G %A Liewald, David C %A Ridker, Paul M %A Gow, Alan J %A Pattie, Alison %A Starr, John M %A Porteous, David %A Liu, Xuan %A Thomson, Russell %A Armstrong, Nicola J %A Eiriksdottir, Gudny %A Assareh, Arezoo A %A Kochan, Nicole A %A Widen, Elisabeth %A Palotie, Aarno %A Hsieh, Yi-Chen %A Eriksson, Johan G %A Vogler, Christian %A van Swieten, John C %A Shulman, Joshua M %A Beiser, Alexa %A Rotter, Jerome %A Schmidt, Carsten O %A Hoffmann, Wolfgang %A Nöthen, Markus M %A Ferrucci, Luigi %A Attia, John %A Uitterlinden, André G %A Amouyel, Philippe %A Dartigues, Jean-François %A Amieva, Hélène %A Räikkönen, Katri %A Garcia, Melissa %A Wolf, Philip A %A Hofman, Albert %A Longstreth, W T %A Psaty, Bruce M %A Boerwinkle, Eric %A DeJager, Philip L %A Sachdev, Perminder S %A Schmidt, Reinhold %A Breteler, Monique M B %A Teumer, Alexander %A Lopez, Oscar L %A Cichon, Sven %A Chasman, Daniel I %A Grodstein, Francine %A Müller-Myhsok, Bertram %A Tzourio, Christophe %A Papassotiropoulos, Andreas %A Bennett, David A %A Ikram, M Arfan %A Deary, Ian J %A van Duijn, Cornelia M %A Launer, Lenore %A Fitzpatrick, Annette L %A Seshadri, Sudha %A Mosley, Thomas H %K Aged %K Aged, 80 and over %K Aging %K Apolipoproteins E %K Claudin-5 %K Cohort Studies %K Female %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Memory Disorders %K Middle Aged %K Polymorphism, Single Nucleotide %K Proteins %K Proteoglycans %K Regression Analysis %K Sulfotransferases %K Verbal Learning %X

BACKGROUND: 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.

%B Biol Psychiatry %V 77 %P 749-63 %8 2015 Apr 15 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/25648963?dopt=Abstract %R 10.1016/j.biopsych.2014.08.027 %0 Journal Article %J Circ Cardiovasc Genet %D 2015 %T Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI. %A Verhaaren, Benjamin F J %A Debette, Stephanie %A Bis, Joshua C %A Smith, Jennifer A %A Ikram, M Kamran %A Adams, Hieab H %A Beecham, Ashley H %A Rajan, Kumar B %A Lopez, Lorna M %A Barral, Sandra %A van Buchem, Mark A %A van der Grond, Jeroen %A Smith, Albert V %A Hegenscheid, Katrin %A Aggarwal, Neelum T %A de Andrade, Mariza %A Atkinson, Elizabeth J %A Beekman, Marian %A Beiser, Alexa S %A Blanton, Susan H %A Boerwinkle, Eric %A Brickman, Adam M %A Bryan, R Nick %A Chauhan, Ganesh %A Chen, Christopher P L H %A Chouraki, Vincent %A de Craen, Anton J M %A Crivello, Fabrice %A Deary, Ian J %A Deelen, Joris %A De Jager, Philip L %A Dufouil, Carole %A Elkind, Mitchell S V %A Evans, Denis A %A Freudenberger, Paul %A Gottesman, Rebecca F %A Guðnason, Vilmundur %A Habes, Mohamad %A Heckbert, Susan R %A Heiss, Gerardo %A Hilal, Saima %A Hofer, Edith %A Hofman, Albert %A Ibrahim-Verbaas, Carla A %A Knopman, David S %A Lewis, Cora E %A Liao, Jiemin %A Liewald, David C M %A Luciano, Michelle %A van der Lugt, Aad %A Martinez, Oliver O %A Mayeux, Richard %A Mazoyer, Bernard %A Nalls, Mike %A Nauck, Matthias %A Niessen, Wiro J %A Oostra, Ben A %A Psaty, Bruce M %A Rice, Kenneth M %A Rotter, Jerome I %A von Sarnowski, Bettina %A Schmidt, Helena %A Schreiner, Pamela J %A Schuur, Maaike %A Sidney, Stephen S %A Sigurdsson, Sigurdur %A Slagboom, P Eline %A Stott, David J M %A van Swieten, John C %A Teumer, Alexander %A Töglhofer, Anna Maria %A Traylor, Matthew %A Trompet, Stella %A Turner, Stephen T %A Tzourio, Christophe %A Uh, Hae-Won %A Uitterlinden, André G %A Vernooij, Meike W %A Wang, Jing J %A Wong, Tien Y %A Wardlaw, Joanna M %A Windham, B Gwen %A Wittfeld, Katharina %A Wolf, Christiane %A Wright, Clinton B %A Yang, Qiong %A Zhao, Wei %A Zijdenbos, Alex %A Jukema, J Wouter %A Sacco, Ralph L %A Kardia, Sharon L R %A Amouyel, Philippe %A Mosley, Thomas H %A Longstreth, W T %A DeCarli, Charles C %A van Duijn, Cornelia M %A Schmidt, Reinhold %A Launer, Lenore J %A Grabe, Hans J %A Seshadri, Sudha S %A Ikram, M Arfan %A Fornage, Myriam %K Aged %K Aged, 80 and over %K Chromosomes, Human %K Continental Population Groups %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Middle Aged %K Models, Genetic %K Stroke %K White Matter %X

BACKGROUND: 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.

%B Circ Cardiovasc Genet %V 8 %P 398-409 %8 2015 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25663218?dopt=Abstract %R 10.1161/CIRCGENETICS.114.000858 %0 Journal Article %J Stroke %D 2015 %T White Matter Lesion Progression: Genome-Wide Search for Genetic Influences. %A Hofer, Edith %A Cavalieri, Margherita %A Bis, Joshua C %A DeCarli, Charles %A Fornage, Myriam %A Sigurdsson, Sigurdur %A Srikanth, Velandai %A Trompet, Stella %A Verhaaren, Benjamin F J %A Wolf, Christiane %A Yang, Qiong %A Adams, Hieab H H %A Amouyel, Philippe %A Beiser, Alexa %A Buckley, Brendan M %A Callisaya, Michele %A Chauhan, Ganesh %A de Craen, Anton J M %A Dufouil, Carole %A van Duijn, Cornelia M %A Ford, Ian %A Freudenberger, Paul %A Gottesman, Rebecca F %A Gudnason, Vilmundur %A Heiss, Gerardo %A Hofman, Albert %A Lumley, Thomas %A Martinez, Oliver %A Mazoyer, Bernard %A Moran, Chris %A Niessen, Wiro J %A Phan, Thanh %A Psaty, Bruce M %A Satizabal, Claudia L %A Sattar, Naveed %A Schilling, Sabrina %A Shibata, Dean K %A Slagboom, P Eline %A Smith, Albert %A Stott, David J %A Taylor, Kent D %A Thomson, Russell %A Töglhofer, Anna M %A Tzourio, Christophe %A van Buchem, Mark %A Wang, Jing %A Westendorp, Rudi G J %A Windham, B Gwen %A Vernooij, Meike W %A Zijdenbos, Alex %A Beare, Richard %A Debette, Stephanie %A Ikram, M Arfan %A Jukema, J Wouter %A Launer, Lenore J %A Longstreth, W T %A Mosley, Thomas H %A Seshadri, Sudha %A Schmidt, Helena %A Schmidt, Reinhold %K Adult %K Aged %K Cohort Studies %K Disease Progression %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Leukoencephalopathies %K Male %K Middle Aged %K Prospective Studies %K White Matter %X

BACKGROUND AND PURPOSE: White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

METHODS: Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies.

RESULTS: A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10(-8)). Four loci were suggestive (P<1×10(-5)) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10(-6)); 12q13.13 (rs4761974, P=8.71×10(-7)); 20p12.1 (rs6135309, P=3.69×10(-6)); and 4p15.31 (rs7664442, P=2.26×10(-6)). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden.

CONCLUSIONS: Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.

%B Stroke %V 46 %P 3048-57 %8 2015 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/26451028?dopt=Abstract %R 10.1161/STROKEAHA.115.009252 %0 Journal Article %J Stroke %D 2016 %T Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2. %A Cheng, Yu-Ching %A Stanne, Tara M %A Giese, Anne-Katrin %A Ho, Weang Kee %A Traylor, Matthew %A Amouyel, Philippe %A Holliday, Elizabeth G %A Malik, Rainer %A Xu, Huichun %A Kittner, Steven J %A Cole, John W %A O'Connell, Jeffrey R %A Danesh, John %A Rasheed, Asif %A Zhao, Wei %A Engelter, Stefan %A Grond-Ginsbach, Caspar %A Kamatani, Yoichiro %A Lathrop, Mark %A Leys, Didier %A Thijs, Vincent %A Metso, Tiina M %A Tatlisumak, Turgut %A Pezzini, Alessandro %A Parati, Eugenio A %A Norrving, Bo %A Bevan, Steve %A Rothwell, Peter M %A Sudlow, Cathie %A Slowik, Agnieszka %A Lindgren, Arne %A Walters, Matthew R %A Jannes, Jim %A Shen, Jess %A Crosslin, David %A Doheny, Kimberly %A Laurie, Cathy C %A Kanse, Sandip M %A Bis, Joshua C %A Fornage, Myriam %A Mosley, Thomas H %A Hopewell, Jemma C %A Strauch, Konstantin %A Müller-Nurasyid, Martina %A Gieger, Christian %A Waldenberger, Melanie %A Peters, Annette %A Meisinger, Christine %A Ikram, M Arfan %A Longstreth, W T %A Meschia, James F %A Seshadri, Sudha %A Sharma, Pankaj %A Worrall, Bradford %A Jern, Christina %A Levi, Christopher %A Dichgans, Martin %A Boncoraglio, Giorgio B %A Markus, Hugh S %A Debette, Stephanie %A Rolfs, Arndt %A Saleheen, Danish %A Mitchell, Braxton D %K Adult %K African Continental Ancestry Group %K Age of Onset %K Aged %K Asian Continental Ancestry Group %K Brain Ischemia %K Chromosomes, Human, Pair 10 %K Computer Simulation %K DNA, Intergenic %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Odds Ratio %K Polymorphism, Single Nucleotide %K Serine Endopeptidases %K Stroke %X

BACKGROUND 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.

%B Stroke %V 47 %P 307-16 %8 2016 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26732560?dopt=Abstract %R 10.1161/STROKEAHA.115.011328 %0 Journal Article %J Nat Genet %D 2017 %T Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. %A Christophersen, Ingrid E %A Rienstra, Michiel %A Roselli, Carolina %A Yin, Xiaoyan %A Geelhoed, Bastiaan %A Barnard, John %A Lin, Honghuang %A Arking, Dan E %A Smith, Albert V %A Albert, Christine M %A Chaffin, Mark %A Tucker, Nathan R %A Li, Molong %A Klarin, Derek %A Bihlmeyer, Nathan A %A Low, Siew-Kee %A Weeke, Peter E %A Müller-Nurasyid, Martina %A Smith, J Gustav %A Brody, Jennifer A %A Niemeijer, Maartje N %A Dörr, Marcus %A Trompet, Stella %A Huffman, Jennifer %A Gustafsson, Stefan %A Schurmann, Claudia %A Kleber, Marcus E %A Lyytikäinen, Leo-Pekka %A Seppälä, Ilkka %A Malik, Rainer %A Horimoto, Andrea R V R %A Perez, Marco %A Sinisalo, Juha %A Aeschbacher, Stefanie %A Thériault, Sébastien %A Yao, Jie %A Radmanesh, Farid %A Weiss, Stefan %A Teumer, Alexander %A Choi, Seung Hoan %A Weng, Lu-Chen %A Clauss, Sebastian %A Deo, Rajat %A Rader, Daniel J %A Shah, Svati H %A Sun, Albert %A Hopewell, Jemma C %A Debette, Stephanie %A Chauhan, Ganesh %A Yang, Qiong %A Worrall, Bradford B %A Paré, Guillaume %A Kamatani, Yoichiro %A Hagemeijer, Yanick P %A Verweij, Niek %A Siland, Joylene E %A Kubo, Michiaki %A Smith, Jonathan D %A Van Wagoner, David R %A Bis, Joshua C %A Perz, Siegfried %A Psaty, Bruce M %A Ridker, Paul M %A Magnani, Jared W %A Harris, Tamara B %A Launer, Lenore J %A Shoemaker, M Benjamin %A Padmanabhan, Sandosh %A Haessler, Jeffrey %A Bartz, Traci M %A Waldenberger, Melanie %A Lichtner, Peter %A Arendt, Marina %A Krieger, Jose E %A Kähönen, Mika %A Risch, Lorenz %A Mansur, Alfredo J %A Peters, Annette %A Smith, Blair H %A Lind, Lars %A Scott, Stuart A %A Lu, Yingchang %A Bottinger, Erwin B %A Hernesniemi, Jussi %A Lindgren, Cecilia M %A Wong, Jorge A %A Huang, Jie %A Eskola, Markku %A Morris, Andrew P %A Ford, Ian %A Reiner, Alex P %A Delgado, Graciela %A Chen, Lin Y %A Chen, Yii-Der Ida %A Sandhu, Roopinder K %A Li, Man %A Boerwinkle, Eric %A Eisele, Lewin %A Lannfelt, Lars %A Rost, Natalia %A Anderson, Christopher D %A Taylor, Kent D %A Campbell, Archie %A Magnusson, Patrik K %A Porteous, David %A Hocking, Lynne J %A Vlachopoulou, Efthymia %A Pedersen, Nancy L %A Nikus, Kjell %A Orho-Melander, Marju %A Hamsten, Anders %A Heeringa, Jan %A Denny, Joshua C %A Kriebel, Jennifer %A Darbar, Dawood %A Newton-Cheh, Christopher %A Shaffer, Christian %A Macfarlane, Peter W %A Heilmann-Heimbach, Stefanie %A Almgren, Peter %A Huang, Paul L %A Sotoodehnia, Nona %A Soliman, Elsayed Z %A Uitterlinden, André G %A Hofman, Albert %A Franco, Oscar H %A Völker, Uwe %A Jöckel, Karl-Heinz %A Sinner, Moritz F %A Lin, Henry J %A Guo, Xiuqing %A Dichgans, Martin %A Ingelsson, Erik %A Kooperberg, Charles %A Melander, Olle %A Loos, Ruth J F %A Laurikka, Jari %A Conen, David %A Rosand, Jonathan %A van der Harst, Pim %A Lokki, Marja-Liisa %A Kathiresan, Sekar %A Pereira, Alexandre %A Jukema, J Wouter %A Hayward, Caroline %A Rotter, Jerome I %A März, Winfried %A Lehtimäki, Terho %A Stricker, Bruno H %A Chung, Mina K %A Felix, Stephan B %A Gudnason, Vilmundur %A Alonso, Alvaro %A Roden, Dan M %A Kääb, Stefan %A Chasman, Daniel I %A Heckbert, Susan R %A Benjamin, Emelia J %A Tanaka, Toshihiro %A Lunetta, Kathryn L %A Lubitz, Steven A %A Ellinor, Patrick T %X

Atrial 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.

%B Nat Genet %V 49 %P 946-952 %8 2017 Jun %G eng %N 6 %R 10.1038/ng.3843 %0 Journal Article %J Hypertension %D 2017 %T Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney. %A Wain, Louise V %A Vaez, Ahmad %A Jansen, Rick %A Joehanes, Roby %A van der Most, Peter J %A Erzurumluoglu, A Mesut %A O'Reilly, Paul F %A Cabrera, Claudia P %A Warren, Helen R %A Rose, Lynda M %A Verwoert, Germaine C %A Hottenga, Jouke-Jan %A Strawbridge, Rona J %A Esko, Tõnu %A Arking, Dan E %A Hwang, Shih-Jen %A Guo, Xiuqing %A Kutalik, Zoltán %A Trompet, Stella %A Shrine, Nick %A Teumer, Alexander %A Ried, Janina S %A Bis, Joshua C %A Smith, Albert V %A Amin, Najaf %A Nolte, Ilja M %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Wareham, Nicholas J %A Hofer, Edith %A Joshi, Peter K %A Kristiansson, Kati %A Traglia, Michela %A Havulinna, Aki S %A Goel, Anuj %A Nalls, Mike A %A Sõber, Siim %A Vuckovic, Dragana %A Luan, Jian'an %A del Greco M, Fabiola %A Ayers, Kristin L %A Marrugat, Jaume %A Ruggiero, Daniela %A Lopez, Lorna M %A Niiranen, Teemu %A Enroth, Stefan %A Jackson, Anne U %A Nelson, Christopher P %A Huffman, Jennifer E %A Zhang, Weihua %A Marten, Jonathan %A Gandin, Ilaria %A Harris, Sarah E %A Zemunik, Tatijana %A Lu, Yingchang %A Evangelou, Evangelos %A Shah, Nabi %A de Borst, Martin H %A Mangino, Massimo %A Prins, Bram P %A Campbell, Archie %A Li-Gao, Ruifang %A Chauhan, Ganesh %A Oldmeadow, Christopher %A Abecasis, Goncalo %A Abedi, Maryam %A Barbieri, Caterina M %A Barnes, Michael R %A Batini, Chiara %A Beilby, John %A Blake, Tineka %A Boehnke, Michael %A Bottinger, Erwin P %A Braund, Peter S %A Brown, Morris %A Brumat, Marco %A Campbell, Harry %A Chambers, John C %A Cocca, Massimiliano %A Collins, Francis %A Connell, John %A Cordell, Heather J %A Damman, Jeffrey J %A Davies, Gail %A de Geus, Eco J %A de Mutsert, Renée %A Deelen, Joris %A Demirkale, Yusuf %A Doney, Alex S F %A Dörr, Marcus %A Farrall, Martin %A Ferreira, Teresa %A Frånberg, Mattias %A Gao, He %A Giedraitis, Vilmantas %A Gieger, Christian %A Giulianini, Franco %A Gow, Alan J %A Hamsten, Anders %A Harris, Tamara B %A Hofman, Albert %A Holliday, Elizabeth G %A Hui, Jennie %A Jarvelin, Marjo-Riitta %A Johansson, Asa %A Johnson, Andrew D %A Jousilahti, Pekka %A Jula, Antti %A Kähönen, Mika %A Kathiresan, Sekar %A Khaw, Kay-Tee %A Kolcic, Ivana %A Koskinen, Seppo %A Langenberg, Claudia %A Larson, Marty %A Launer, Lenore J %A Lehne, Benjamin %A Liewald, David C M %A Lin, Li %A Lind, Lars %A Mach, François %A Mamasoula, Chrysovalanto %A Menni, Cristina %A Mifsud, Borbala %A Milaneschi, Yuri %A Morgan, Anna %A Morris, Andrew D %A Morrison, Alanna C %A Munson, Peter J %A Nandakumar, Priyanka %A Nguyen, Quang Tri %A Nutile, Teresa %A Oldehinkel, Albertine J %A Oostra, Ben A %A Org, Elin %A Padmanabhan, Sandosh %A Palotie, Aarno %A Paré, Guillaume %A Pattie, Alison %A Penninx, Brenda W J H %A Poulter, Neil %A Pramstaller, Peter P %A Raitakari, Olli T %A Ren, Meixia %A Rice, Kenneth %A Ridker, Paul M %A Riese, Harriëtte %A Ripatti, Samuli %A Robino, Antonietta %A Rotter, Jerome I %A Rudan, Igor %A Saba, Yasaman %A Saint Pierre, Aude %A Sala, Cinzia F %A Sarin, Antti-Pekka %A Schmidt, Reinhold %A Scott, Rodney %A Seelen, Marc A %A Shields, Denis C %A Siscovick, David %A Sorice, Rossella %A Stanton, Alice %A Stott, David J %A Sundström, Johan %A Swertz, Morris %A Taylor, Kent D %A Thom, Simon %A Tzoulaki, Ioanna %A Tzourio, Christophe %A Uitterlinden, André G %A Völker, Uwe %A Vollenweider, Peter %A Wild, Sarah %A Willemsen, Gonneke %A Wright, Alan F %A Yao, Jie %A Thériault, Sébastien %A Conen, David %A Attia, John %A Sever, Peter %A Debette, Stephanie %A Mook-Kanamori, Dennis O %A Zeggini, Eleftheria %A Spector, Tim D %A van der Harst, Pim %A Palmer, Colin N A %A Vergnaud, Anne-Claire %A Loos, Ruth J F %A Polasek, Ozren %A Starr, John M %A Girotto, Giorgia %A Hayward, Caroline %A Kooner, Jaspal S %A Lindgren, Cecila M %A Vitart, Veronique %A Samani, Nilesh J %A Tuomilehto, Jaakko %A Gyllensten, Ulf %A Knekt, Paul %A Deary, Ian J %A Ciullo, Marina %A Elosua, Roberto %A Keavney, Bernard D %A Hicks, Andrew A %A Scott, Robert A %A Gasparini, Paolo %A Laan, Maris %A Liu, Yongmei %A Watkins, Hugh %A Hartman, Catharina A %A Salomaa, Veikko %A Toniolo, Daniela %A Perola, Markus %A Wilson, James F %A Schmidt, Helena %A Zhao, Jing Hua %A Lehtimäki, Terho %A van Duijn, Cornelia M %A Gudnason, Vilmundur %A Psaty, Bruce M %A Peters, Annette %A Rettig, Rainer %A James, Alan %A Jukema, J Wouter %A Strachan, David P %A Palmas, Walter %A Metspalu, Andres %A Ingelsson, Erik %A Boomsma, Dorret I %A Franco, Oscar H %A Bochud, Murielle %A Newton-Cheh, Christopher %A Munroe, Patricia B %A Elliott, Paul %A Chasman, Daniel I %A Chakravarti, Aravinda %A Knight, Joanne %A Morris, Andrew P %A Levy, Daniel %A Tobin, Martin D %A Snieder, Harold %A Caulfield, Mark J %A Ehret, Georg B %X

Elevated 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.

%B Hypertension %8 2017 Jul 24 %G eng %R 10.1161/HYPERTENSIONAHA.117.09438 %0 Journal Article %J Eur J Epidemiol %D 2017 %T Trends in the incidence of dementia: design and methods in the Alzheimer Cohorts Consortium. %A Chibnik, Lori B %A Wolters, Frank J %A Bäckman, Kristoffer %A Beiser, Alexa %A Berr, Claudine %A Bis, Joshua C %A Boerwinkle, Eric %A Bos, Daniel %A Brayne, Carol %A Dartigues, Jean-François %A Darweesh, Sirwan K L %A Debette, Stephanie %A Davis-Plourde, Kendra L %A Dufouil, Carole %A Fornage, Myriam %A Grasset, Leslie %A Gudnason, Vilmundur %A Hadjichrysanthou, Christoforos %A Helmer, Catherine %A Ikram, M Arfan %A Ikram, M Kamran %A Kern, Silke %A Kuller, Lewis H %A Launer, Lenore %A Lopez, Oscar L %A Matthews, Fiona %A Meirelles, Osorio %A Mosley, Thomas %A Ower, Alison %A Psaty, Bruce M %A Satizabal, Claudia L %A Seshadri, Sudha %A Skoog, Ingmar %A Stephan, Blossom C M %A Tzourio, Christophe %A Waziry, Reem %A Wong, Mei Mei %A Zettergren, Anna %A Hofman, Albert %X

Several 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.

%B Eur J Epidemiol %V 32 %P 931-938 %8 2017 Oct %G eng %N 10 %R 10.1007/s10654-017-0320-5 %0 Journal Article %J Stroke %D 2018 %T Exome Chip Analysis Identifies Low-Frequency and Rare Variants in for White Matter Hyperintensities on Brain Magnetic Resonance Imaging. %A Jian, Xueqiu %A Satizabal, Claudia L %A Smith, Albert V %A Wittfeld, Katharina %A Bis, Joshua C %A Smith, Jennifer A %A Hsu, Fang-Chi %A Nho, Kwangsik %A Hofer, Edith %A Hagenaars, Saskia P %A Nyquist, Paul A %A Mishra, Aniket %A Adams, Hieab H H %A Li, Shuo %A Teumer, Alexander %A Zhao, Wei %A Freedman, Barry I %A Saba, Yasaman %A Yanek, Lisa R %A Chauhan, Ganesh %A van Buchem, Mark A %A Cushman, Mary %A Royle, Natalie A %A Bryan, R Nick %A Niessen, Wiro J %A Windham, Beverly G %A DeStefano, Anita L %A Habes, Mohamad %A Heckbert, Susan R %A Palmer, Nicholette D %A Lewis, Cora E %A Eiriksdottir, Gudny %A Maillard, Pauline %A Mathias, Rasika A %A Homuth, Georg %A Valdés-Hernández, Maria Del C %A Divers, Jasmin %A Beiser, Alexa S %A Langner, Sönke %A Rice, Kenneth M %A Bastin, Mark E %A Yang, Qiong %A Maldjian, Joseph A %A Starr, John M %A Sidney, Stephen %A Risacher, Shannon L %A Uitterlinden, André G %A Gudnason, Vilmundur G %A Nauck, Matthias %A Rotter, Jerome I %A Schreiner, Pamela J %A Boerwinkle, Eric %A van Duijn, Cornelia M %A Mazoyer, Bernard %A von Sarnowski, Bettina %A Gottesman, Rebecca F %A Levy, Daniel %A Sigurdsson, Sigurdur %A Vernooij, Meike W %A Turner, Stephen T %A Schmidt, Reinhold %A Wardlaw, Joanna M %A Psaty, Bruce M %A Mosley, Thomas H %A DeCarli, Charles S %A Saykin, Andrew J %A Bowden, Donald W %A Becker, Diane M %A Deary, Ian J %A Schmidt, Helena %A Kardia, Sharon L R %A Ikram, M Arfan %A Debette, Stephanie %A Grabe, Hans J %A Longstreth, W T %A Seshadri, Sudha %A Launer, Lenore J %A Fornage, Myriam %X

BACKGROUND 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.

%B Stroke %8 2018 Jul 12 %G eng %R 10.1161/STROKEAHA.118.020689 %0 Journal Article %J Nat Genet %D 2018 %T Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. %A Evangelou, Evangelos %A Warren, Helen R %A Mosen-Ansorena, David %A Mifsud, Borbala %A Pazoki, Raha %A Gao, He %A Ntritsos, Georgios %A Dimou, Niki %A Cabrera, Claudia P %A Karaman, Ibrahim %A Ng, Fu Liang %A Evangelou, Marina %A Witkowska, Katarzyna %A Tzanis, Evan %A Hellwege, Jacklyn N %A Giri, Ayush %A Velez Edwards, Digna R %A Sun, Yan V %A Cho, Kelly %A Gaziano, J Michael %A Wilson, Peter W F %A Tsao, Philip S %A Kovesdy, Csaba P %A Esko, Tõnu %A Mägi, Reedik %A Milani, Lili %A Almgren, Peter %A Boutin, Thibaud %A Debette, Stephanie %A Ding, Jun %A Giulianini, Franco %A Holliday, Elizabeth G %A Jackson, Anne U %A Li-Gao, Ruifang %A Lin, Wei-Yu %A Luan, Jian'an %A Mangino, Massimo %A Oldmeadow, Christopher %A Prins, Bram Peter %A Qian, Yong %A Sargurupremraj, Muralidharan %A Shah, Nabi %A Surendran, Praveen %A Thériault, Sébastien %A Verweij, Niek %A Willems, Sara M %A Zhao, Jing-Hua %A Amouyel, Philippe %A Connell, John %A de Mutsert, Renée %A Doney, Alex S F %A Farrall, Martin %A Menni, Cristina %A Morris, Andrew D %A Noordam, Raymond %A Paré, Guillaume %A Poulter, Neil R %A Shields, Denis C %A Stanton, Alice %A Thom, Simon %A Abecasis, Goncalo %A Amin, Najaf %A Arking, Dan E %A Ayers, Kristin L %A Barbieri, Caterina M %A Batini, Chiara %A Bis, Joshua C %A Blake, Tineka %A Bochud, Murielle %A Boehnke, Michael %A Boerwinkle, Eric %A Boomsma, Dorret I %A Bottinger, Erwin P %A Braund, Peter S %A Brumat, Marco %A Campbell, Archie %A Campbell, Harry %A Chakravarti, Aravinda %A Chambers, John C %A Chauhan, Ganesh %A Ciullo, Marina %A Cocca, Massimiliano %A Collins, Francis %A Cordell, Heather J %A Davies, Gail %A Borst, Martin H de %A Geus, Eco J de %A Deary, Ian J %A Deelen, Joris %A del Greco M, Fabiola %A Demirkale, Cumhur Yusuf %A Dörr, Marcus %A Ehret, Georg B %A Elosua, Roberto %A Enroth, Stefan %A Erzurumluoglu, A Mesut %A Ferreira, Teresa %A Frånberg, Mattias %A Franco, Oscar H %A Gandin, Ilaria %A Gasparini, Paolo %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Goel, Anuj %A Gow, Alan J %A Gudnason, Vilmundur %A Guo, Xiuqing %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Harris, Sarah E %A Hartman, Catharina A %A Havulinna, Aki S %A Hicks, Andrew A %A Hofer, Edith %A Hofman, Albert %A Hottenga, Jouke-Jan %A Huffman, Jennifer E %A Hwang, Shih-Jen %A Ingelsson, Erik %A James, Alan %A Jansen, Rick %A Jarvelin, Marjo-Riitta %A Joehanes, Roby %A Johansson, Asa %A Johnson, Andrew D %A Joshi, Peter K %A Jousilahti, Pekka %A Jukema, J Wouter %A Jula, Antti %A Kähönen, Mika %A Kathiresan, Sekar %A Keavney, Bernard D %A Khaw, Kay-Tee %A Knekt, Paul %A Knight, Joanne %A Kolcic, Ivana %A Kooner, Jaspal S %A Koskinen, Seppo %A Kristiansson, Kati %A Kutalik, Zoltán %A Laan, Maris %A Larson, Marty %A Launer, Lenore J %A Lehne, Benjamin %A Lehtimäki, Terho %A Liewald, David C M %A Lin, Li %A Lind, Lars %A Lindgren, Cecilia M %A Liu, Yongmei %A Loos, Ruth J F %A Lopez, Lorna M %A Lu, Yingchang %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Mamasoula, Chrysovalanto %A Marrugat, Jaume %A Marten, Jonathan %A Milaneschi, Yuri %A Morgan, Anna %A Morris, Andrew P %A Morrison, Alanna C %A Munson, Peter J %A Nalls, Mike A %A Nandakumar, Priyanka %A Nelson, Christopher P %A Niiranen, Teemu %A Nolte, Ilja M %A Nutile, Teresa %A Oldehinkel, Albertine J %A Oostra, Ben A %A O'Reilly, Paul F %A Org, Elin %A Padmanabhan, Sandosh %A Palmas, Walter %A Palotie, Aarno %A Pattie, Alison %A Penninx, Brenda W J H %A Perola, Markus %A Peters, Annette %A Polasek, Ozren %A Pramstaller, Peter P %A Nguyen, Quang Tri %A Raitakari, Olli T %A Ren, Meixia %A Rettig, Rainer %A Rice, Kenneth %A Ridker, Paul M %A Ried, Janina S %A Riese, Harriëtte %A Ripatti, Samuli %A Robino, Antonietta %A Rose, Lynda M %A Rotter, Jerome I %A Rudan, Igor %A Ruggiero, Daniela %A Saba, Yasaman %A Sala, Cinzia F %A Salomaa, Veikko %A Samani, Nilesh J %A Sarin, Antti-Pekka %A Schmidt, Reinhold %A Schmidt, Helena %A Shrine, Nick %A Siscovick, David %A Smith, Albert V %A Snieder, Harold %A Sõber, Siim %A Sorice, Rossella %A Starr, John M %A Stott, David J %A Strachan, David P %A Strawbridge, Rona J %A Sundström, Johan %A Swertz, Morris A %A Taylor, Kent D %A Teumer, Alexander %A Tobin, Martin D %A Tomaszewski, Maciej %A Toniolo, Daniela %A Traglia, Michela %A Trompet, Stella %A Tuomilehto, Jaakko %A Tzourio, Christophe %A Uitterlinden, André G %A Vaez, Ahmad %A van der Most, Peter J %A van Duijn, Cornelia M %A Vergnaud, Anne-Claire %A Verwoert, Germaine C %A Vitart, Veronique %A Völker, Uwe %A Vollenweider, Peter %A Vuckovic, Dragana %A Watkins, Hugh %A Wild, Sarah H %A Willemsen, Gonneke %A Wilson, James F %A Wright, Alan F %A Yao, Jie %A Zemunik, Tatijana %A Zhang, Weihua %A Attia, John R %A Butterworth, Adam S %A Chasman, Daniel I %A Conen, David %A Cucca, Francesco %A Danesh, John %A Hayward, Caroline %A Howson, Joanna M M %A Laakso, Markku %A Lakatta, Edward G %A Langenberg, Claudia %A Melander, Olle %A Mook-Kanamori, Dennis O %A Palmer, Colin N A %A Risch, Lorenz %A Scott, Robert A %A Scott, Rodney J %A Sever, Peter %A Spector, Tim D %A van der Harst, Pim %A Wareham, Nicholas J %A Zeggini, Eleftheria %A Levy, Daniel %A Munroe, Patricia B %A Newton-Cheh, Christopher %A Brown, Morris J %A Metspalu, Andres %A Hung, Adriana M %A O'Donnell, Christopher J %A Edwards, Todd L %A Psaty, Bruce M %A Tzoulaki, Ioanna %A Barnes, Michael R %A Wain, Louise V %A Elliott, Paul %A Caulfield, Mark J %X

High 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.

%B Nat Genet %V 50 %P 1412-1425 %8 2018 Oct %G eng %N 10 %R 10.1038/s41588-018-0205-x %0 Journal Article %J Nat Commun %D 2018 %T GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes. %A Franceschini, Nora %A Giambartolomei, Claudia %A de Vries, Paul S %A Finan, Chris %A Bis, Joshua C %A Huntley, Rachael P %A Lovering, Ruth C %A Tajuddin, Salman M %A Winkler, Thomas W %A Graff, Misa %A Kavousi, Maryam %A Dale, Caroline %A Smith, Albert V %A Hofer, Edith %A van Leeuwen, Elisabeth M %A Nolte, Ilja M %A Lu, Lingyi %A Scholz, Markus %A Sargurupremraj, Muralidharan %A Pitkänen, Niina %A Franzén, Oscar %A Joshi, Peter K %A Noordam, Raymond %A Marioni, Riccardo E %A Hwang, Shih-Jen %A Musani, Solomon K %A Schminke, Ulf %A Palmas, Walter %A Isaacs, Aaron %A Correa, Adolfo %A Zonderman, Alan B %A Hofman, Albert %A Teumer, Alexander %A Cox, Amanda J %A Uitterlinden, André G %A Wong, Andrew %A Smit, Andries J %A Newman, Anne B %A Britton, Annie %A Ruusalepp, Arno %A Sennblad, Bengt %A Hedblad, Bo %A Pasaniuc, Bogdan %A Penninx, Brenda W %A Langefeld, Carl D %A Wassel, Christina L %A Tzourio, Christophe %A Fava, Cristiano %A Baldassarre, Damiano %A O'Leary, Daniel H %A Teupser, Daniel %A Kuh, Diana %A Tremoli, Elena %A Mannarino, Elmo %A Grossi, Enzo %A Boerwinkle, Eric %A Schadt, Eric E %A Ingelsson, Erik %A Veglia, Fabrizio %A Rivadeneira, Fernando %A Beutner, Frank %A Chauhan, Ganesh %A Heiss, Gerardo %A Snieder, Harold %A Campbell, Harry %A Völzke, Henry %A Markus, Hugh S %A Deary, Ian J %A Jukema, J Wouter %A de Graaf, Jacqueline %A Price, Jacqueline %A Pott, Janne %A Hopewell, Jemma C %A Liang, Jingjing %A Thiery, Joachim %A Engmann, Jorgen %A Gertow, Karl %A Rice, Kenneth %A Taylor, Kent D %A Dhana, Klodian %A Kiemeney, Lambertus A L M %A Lind, Lars %A Raffield, Laura M %A Launer, Lenore J %A Holdt, Lesca M %A Dörr, Marcus %A Dichgans, Martin %A Traylor, Matthew %A Sitzer, Matthias %A Kumari, Meena %A Kivimaki, Mika %A Nalls, Mike A %A Melander, Olle %A Raitakari, Olli %A Franco, Oscar H %A Rueda-Ochoa, Oscar L %A Roussos, Panos %A Whincup, Peter H %A Amouyel, Philippe %A Giral, Philippe %A Anugu, Pramod %A Wong, Quenna %A Malik, Rainer %A Rauramaa, Rainer %A Burkhardt, Ralph %A Hardy, Rebecca %A Schmidt, Reinhold %A de Mutsert, Renée %A Morris, Richard W %A Strawbridge, Rona J %A Wannamethee, S Goya %A Hägg, Sara %A Shah, Sonia %A McLachlan, Stela %A Trompet, Stella %A Seshadri, Sudha %A Kurl, Sudhir %A Heckbert, Susan R %A Ring, Susan %A Harris, Tamara B %A Lehtimäki, Terho %A Galesloot, Tessel E %A Shah, Tina %A de Faire, Ulf %A Plagnol, Vincent %A Rosamond, Wayne D %A Post, Wendy %A Zhu, Xiaofeng %A Zhang, Xiaoling %A Guo, Xiuqing %A Saba, Yasaman %A Dehghan, Abbas %A Seldenrijk, Adrie %A Morrison, Alanna C %A Hamsten, Anders %A Psaty, Bruce M %A van Duijn, Cornelia M %A Lawlor, Deborah A %A Mook-Kanamori, Dennis O %A Bowden, Donald W %A Schmidt, Helena %A Wilson, James F %A Wilson, James G %A Rotter, Jerome I %A Wardlaw, Joanna M %A Deanfield, John %A Halcox, Julian %A Lyytikäinen, Leo-Pekka %A Loeffler, Markus %A Evans, Michele K %A Debette, Stephanie %A Humphries, Steve E %A Völker, Uwe %A Gudnason, Vilmundur %A Hingorani, Aroon D %A Björkegren, Johan L M %A Casas, Juan P %A O'Donnell, Christopher J %K ADAMTS9 Protein %K Amino Acid Oxidoreductases %K Carotid Intima-Media Thickness %K Coronary Disease %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Lod Score %K Plaque, Atherosclerotic %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Risk Factors %X

Carotid 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.

%B Nat Commun %V 9 %P 5141 %8 2018 12 03 %G eng %N 1 %R 10.1038/s41467-018-07340-5 %0 Journal Article %J Am J Hum Genet %D 2018 %T A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. %A Sung, Yun J %A Winkler, Thomas W %A de Las Fuentes, Lisa %A Bentley, Amy R %A Brown, Michael R %A Kraja, Aldi T %A Schwander, Karen %A Ntalla, Ioanna %A Guo, Xiuqing %A Franceschini, Nora %A Lu, Yingchang %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Marten, Jonathan %A Musani, Solomon K %A Li, Changwei %A Feitosa, Mary F %A Kilpeläinen, Tuomas O %A Richard, Melissa A %A Noordam, Raymond %A Aslibekyan, Stella %A Aschard, Hugues %A Bartz, Traci M %A Dorajoo, Rajkumar %A Liu, Yongmei %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert Vernon %A Tajuddin, Salman M %A Tayo, Bamidele O %A Warren, Helen R %A Zhao, Wei %A Zhou, Yanhua %A Matoba, Nana %A Sofer, Tamar %A Alver, Maris %A Amini, Marzyeh %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Gandin, Ilaria %A Gao, Chuan %A Giulianini, Franco %A Goel, Anuj %A Harris, Sarah E %A Hartwig, Fernando Pires %A Horimoto, Andrea R V R %A Hsu, Fang-Chi %A Jackson, Anne U %A Kähönen, Mika %A Kasturiratne, Anuradhani %A Kuhnel, Brigitte %A Leander, Karin %A Lee, Wen-Jane %A Lin, Keng-Hung %A 'an Luan, Jian %A McKenzie, Colin A %A Meian, He %A Nelson, Christopher P %A Rauramaa, Rainer %A Schupf, Nicole %A Scott, Robert A %A Sheu, Wayne H H %A Stančáková, Alena %A Takeuchi, Fumihiko %A van der Most, Peter J %A Varga, Tibor V %A Wang, Heming %A Wang, Yajuan %A Ware, Erin B %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Afaq, Saima %A Alfred, Tamuno %A Amin, Najaf %A Arking, Dan %A Aung, Tin %A Barr, R Graham %A Bielak, Lawrence F %A Boerwinkle, Eric %A Bottinger, Erwin P %A Braund, Peter S %A Brody, Jennifer A %A Broeckel, Ulrich %A Cabrera, Claudia P %A Cade, Brian %A Caizheng, Yu %A Campbell, Archie %A Canouil, Mickaël %A Chakravarti, Aravinda %A Chauhan, Ganesh %A Christensen, Kaare %A Cocca, Massimiliano %A Collins, Francis S %A Connell, John M %A de Mutsert, Renée %A de Silva, H Janaka %A Debette, Stephanie %A Dörr, Marcus %A Duan, Qing %A Eaton, Charles B %A Ehret, Georg %A Evangelou, Evangelos %A Faul, Jessica D %A Fisher, Virginia A %A Forouhi, Nita G %A Franco, Oscar H %A Friedlander, Yechiel %A Gao, He %A Gigante, Bruna %A Graff, Misa %A Gu, C Charles %A Gu, Dongfeng %A Gupta, Preeti %A Hagenaars, Saskia P %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Hofman, Albert %A Howard, Barbara V %A Hunt, Steven %A Irvin, Marguerite R %A Jia, Yucheng %A Joehanes, Roby %A Justice, Anne E %A Katsuya, Tomohiro %A Kaufman, Joel %A Kerrison, Nicola D %A Khor, Chiea Chuen %A Koh, Woon-Puay %A Koistinen, Heikki A %A Komulainen, Pirjo %A Kooperberg, Charles %A Krieger, Jose E %A Kubo, Michiaki %A Kuusisto, Johanna %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lewis, Cora E %A Li, Yize %A Lim, Sing Hui %A Lin, Shiow %A Liu, Ching-Ti %A Liu, Jianjun %A Liu, Jingmin %A Liu, Kiang %A Liu, Yeheng %A Loh, Marie %A Lohman, Kurt K %A Long, Jirong %A Louie, Tin %A Mägi, Reedik %A Mahajan, Anubha %A Meitinger, Thomas %A Metspalu, Andres %A Milani, Lili %A Momozawa, Yukihide %A Morris, Andrew P %A Mosley, Thomas H %A Munson, Peter %A Murray, Alison D %A Nalls, Mike A %A Nasri, Ubaydah %A Norris, Jill M %A North, Kari %A Ogunniyi, Adesola %A Padmanabhan, Sandosh %A Palmas, Walter R %A Palmer, Nicholette D %A Pankow, James S %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Raitakari, Olli T %A Renstrom, Frida %A Rice, Treva K %A Ridker, Paul M %A Robino, Antonietta %A Robinson, Jennifer G %A Rose, Lynda M %A Rudan, Igor %A Sabanayagam, Charumathi %A Salako, Babatunde L %A Sandow, Kevin %A Schmidt, Carsten O %A Schreiner, Pamela J %A Scott, William R %A Seshadri, Sudha %A Sever, Peter %A Sitlani, Colleen M %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Tang, Hua %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Uitterlinden, André G %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya X %A Wei, Wen Bin %A Williams, Christine %A Wilson, Gregory %A Wojczynski, Mary K %A Yao, Jie %A Yuan, Jian-Min %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Chen, Yii-Der Ida %A de Faire, Ulf %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Forrester, Terrence %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Horta, Bernardo Lessa %A Hung, Yi-Jen %A Jonas, Jost B %A Kato, Norihiro %A Kooner, Jaspal S %A Laakso, Markku %A Lehtimäki, Terho %A Liang, Kae-Woei %A Magnusson, Patrik K E %A Newman, Anne B %A Oldehinkel, Albertine J %A Pereira, Alexandre C %A Redline, Susan %A Rettig, Rainer %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Zheng, Wei %A Kamatani, Yoichiro %A Laurie, Cathy C %A Bouchard, Claude %A Cooper, Richard S %A Evans, Michele K %A Gudnason, Vilmundur %A Kardia, Sharon L R %A Kritchevsky, Stephen B %A Levy, Daniel %A O'Connell, Jeff R %A Psaty, Bruce M %A van Dam, Rob M %A Sims, Mario %A Arnett, Donna K %A Mook-Kanamori, Dennis O %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A Fornage, Myriam %A Rotimi, Charles N %A Province, Michael A %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Loos, Ruth J F %A Reiner, Alex P %A Rotter, Jerome I %A Zhu, Xiaofeng %A Bierut, Laura J %A Gauderman, W James %A Caulfield, Mark J %A Elliott, Paul %A Rice, Kenneth %A Munroe, Patricia B %A Morrison, Alanna C %A Cupples, L Adrienne %A Rao, Dabeeru C %A Chasman, Daniel I %X

Genome-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).

%B Am J Hum Genet %V 102 %P 375-400 %8 2018 Mar 01 %G eng %N 3 %R 10.1016/j.ajhg.2018.01.015 %0 Journal Article %J Nat Genet %D 2018 %T Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. %A Malik, Rainer %A Chauhan, Ganesh %A Traylor, Matthew %A Sargurupremraj, Muralidharan %A Okada, Yukinori %A Mishra, Aniket %A Rutten-Jacobs, Loes %A Giese, Anne-Katrin %A van der Laan, Sander W %A Gretarsdottir, Solveig %A Anderson, Christopher D %A Chong, Michael %A Adams, Hieab H H %A Ago, Tetsuro %A Almgren, Peter %A Amouyel, Philippe %A Ay, Hakan %A Bartz, Traci M %A Benavente, Oscar R %A Bevan, Steve %A Boncoraglio, Giorgio B %A Brown, Robert D %A Butterworth, Adam S %A Carrera, Caty %A Carty, Cara L %A Chasman, Daniel I %A Chen, Wei-Min %A Cole, John W %A Correa, Adolfo %A Cotlarciuc, Ioana %A Cruchaga, Carlos %A Danesh, John %A de Bakker, Paul I W %A DeStefano, Anita L %A den Hoed, Marcel %A Duan, Qing %A Engelter, Stefan T %A Falcone, Guido J %A Gottesman, Rebecca F %A Grewal, Raji P %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Haessler, Jeffrey %A Harris, Tamara B %A Hassan, Ahamad %A Havulinna, Aki S %A Heckbert, Susan R %A Holliday, Elizabeth G %A Howard, George %A Hsu, Fang-Chi %A Hyacinth, Hyacinth I %A Ikram, M Arfan %A Ingelsson, Erik %A Irvin, Marguerite R %A Jian, Xueqiu %A Jimenez-Conde, Jordi %A Johnson, Julie A %A Jukema, J Wouter %A Kanai, Masahiro %A Keene, Keith L %A Kissela, Brett M %A Kleindorfer, Dawn O %A Kooperberg, Charles %A Kubo, Michiaki %A Lange, Leslie A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lee, Jin-Moo %A Lemmens, Robin %A Leys, Didier %A Lewis, Cathryn M %A Lin, Wei-Yu %A Lindgren, Arne G %A Lorentzen, Erik %A Magnusson, Patrik K %A Maguire, Jane %A Manichaikul, Ani %A McArdle, Patrick F %A Meschia, James F %A Mitchell, Braxton D %A Mosley, Thomas H %A Nalls, Michael A %A Ninomiya, Toshiharu %A O'Donnell, Martin J %A Psaty, Bruce M %A Pulit, Sara L %A Rannikmae, Kristiina %A Reiner, Alexander P %A Rexrode, Kathryn M %A Rice, Kenneth %A Rich, Stephen S %A Ridker, Paul M %A Rost, Natalia S %A Rothwell, Peter M %A Rotter, Jerome I %A Rundek, Tatjana %A Sacco, Ralph L %A Sakaue, Saori %A Sale, Michèle M %A Salomaa, Veikko %A Sapkota, Bishwa R %A Schmidt, Reinhold %A Schmidt, Carsten O %A Schminke, Ulf %A Sharma, Pankaj %A Slowik, Agnieszka %A Sudlow, Cathie L M %A Tanislav, Christian %A Tatlisumak, Turgut %A Taylor, Kent D %A Thijs, Vincent N S %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tiedt, Steffen %A Trompet, Stella %A Tzourio, Christophe %A van Duijn, Cornelia M %A Walters, Matthew %A Wareham, Nicholas J %A Wassertheil-Smoller, Sylvia %A Wilson, James G %A Wiggins, Kerri L %A Yang, Qiong %A Yusuf, Salim %A Bis, Joshua C %A Pastinen, Tomi %A Ruusalepp, Arno %A Schadt, Eric E %A Koplev, Simon %A Björkegren, Johan L M %A Codoni, Veronica %A Civelek, Mete %A Smith, Nicholas L %A Trégouët, David A %A Christophersen, Ingrid E %A Roselli, Carolina %A Lubitz, Steven A %A Ellinor, Patrick T %A Tai, E Shyong %A Kooner, Jaspal S %A Kato, Norihiro %A He, Jiang %A van der Harst, Pim %A Elliott, Paul %A Chambers, John C %A Takeuchi, Fumihiko %A Johnson, Andrew D %A Sanghera, Dharambir K %A Melander, Olle %A Jern, Christina %A Strbian, Daniel %A Fernandez-Cadenas, Israel %A Longstreth, W T %A Rolfs, Arndt %A Hata, Jun %A Woo, Daniel %A Rosand, Jonathan %A Paré, Guillaume %A Hopewell, Jemma C %A Saleheen, Danish %A Stefansson, Kari %A Worrall, Bradford B %A Kittner, Steven J %A Seshadri, Sudha %A Fornage, Myriam %A Markus, Hugh S %A Howson, Joanna M M %A Kamatani, Yoichiro %A Debette, Stephanie %A Dichgans, Martin %A Malik, Rainer %A Chauhan, Ganesh %A Traylor, Matthew %A Sargurupremraj, Muralidharan %A Okada, Yukinori %A Mishra, Aniket %A Rutten-Jacobs, Loes %A Giese, Anne-Katrin %A van der Laan, Sander W %A Gretarsdottir, Solveig %A Anderson, Christopher D %A Chong, Michael %A Adams, Hieab H H %A Ago, Tetsuro %A Almgren, Peter %A Amouyel, Philippe %A Ay, Hakan %A Bartz, Traci M %A Benavente, Oscar R %A Bevan, Steve %A Boncoraglio, Giorgio B %A Brown, Robert D %A Butterworth, Adam S %A Carrera, Caty %A Carty, Cara L %A Chasman, Daniel I %A Chen, Wei-Min %A Cole, John W %A Correa, Adolfo %A Cotlarciuc, Ioana %A Cruchaga, Carlos %A Danesh, John %A de Bakker, Paul I W %A DeStefano, Anita L %A Hoed, Marcel den %A Duan, Qing %A Engelter, Stefan T %A Falcone, Guido J %A Gottesman, Rebecca F %A Grewal, Raji P %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Haessler, Jeffrey %A Harris, Tamara B %A Hassan, Ahamad %A Havulinna, Aki S %A Heckbert, Susan R %A Holliday, Elizabeth G %A Howard, George %A Hsu, Fang-Chi %A Hyacinth, Hyacinth I %A Ikram, M Arfan %A Ingelsson, Erik %A Irvin, Marguerite R %A Jian, Xueqiu %A Jimenez-Conde, Jordi %A Johnson, Julie A %A Jukema, J Wouter %A Kanai, Masahiro %A Keene, Keith L %A Kissela, Brett M %A Kleindorfer, Dawn O %A Kooperberg, Charles %A Kubo, Michiaki %A Lange, Leslie A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lee, Jin-Moo %A Lemmens, Robin %A Leys, Didier %A Lewis, Cathryn M %A Lin, Wei-Yu %A Lindgren, Arne G %A Lorentzen, Erik %A Magnusson, Patrik K %A Maguire, Jane %A Manichaikul, Ani %A McArdle, Patrick F %A Meschia, James F %A Mitchell, Braxton D %A Mosley, Thomas H %A Nalls, Michael A %A Ninomiya, Toshiharu %A O'Donnell, Martin J %A Psaty, Bruce M %A Pulit, Sara L %A Rannikmae, Kristiina %A Reiner, Alexander P %A Rexrode, Kathryn M %A Rice, Kenneth %A Rich, Stephen S %A Ridker, Paul M %A Rost, Natalia S %A Rothwell, Peter M %A Rotter, Jerome I %A Rundek, Tatjana %A Sacco, Ralph L %A Sakaue, Saori %A Sale, Michèle M %A Salomaa, Veikko %A Sapkota, Bishwa R %A Schmidt, Reinhold %A Schmidt, Carsten O %A Schminke, Ulf %A Sharma, Pankaj %A Slowik, Agnieszka %A Sudlow, Cathie L M %A Tanislav, Christian %A Tatlisumak, Turgut %A Taylor, Kent D %A Thijs, Vincent N S %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tiedt, Steffen %A Trompet, Stella %A Tzourio, Christophe %A van Duijn, Cornelia M %A Walters, Matthew %A Wareham, Nicholas J %A Wassertheil-Smoller, Sylvia %A Wilson, James G %A Wiggins, Kerri L %A Yang, Qiong %A Yusuf, Salim %A Amin, Najaf %A Aparicio, Hugo S %A Arnett, Donna K %A Attia, John %A Beiser, Alexa S %A Berr, Claudine %A Buring, Julie E %A Bustamante, Mariana %A Caso, Valeria %A Cheng, Yu-Ching %A Choi, Seung Hoan %A Chowhan, Ayesha %A Cullell, Natalia %A Dartigues, Jean-François %A Delavaran, Hossein %A Delgado, Pilar %A Dörr, Marcus %A Engström, Gunnar %A Ford, Ian %A Gurpreet, Wander S %A Hamsten, Anders %A Heitsch, Laura %A Hozawa, Atsushi %A Ibanez, Laura %A Ilinca, Andreea %A Ingelsson, Martin %A Iwasaki, Motoki %A Jackson, Rebecca D %A Jood, Katarina %A Jousilahti, Pekka %A Kaffashian, Sara %A Kalra, Lalit %A Kamouchi, Masahiro %A Kitazono, Takanari %A Kjartansson, Olafur %A Kloss, Manja %A Koudstaal, Peter J %A Krupinski, Jerzy %A Labovitz, Daniel L %A Laurie, Cathy C %A Levi, Christopher R %A Li, Linxin %A Lind, Lars %A Lindgren, Cecilia M %A Lioutas, Vasileios %A Liu, Yong Mei %A Lopez, Oscar L %A Makoto, Hirata %A Martinez-Majander, Nicolas %A Matsuda, Koichi %A Minegishi, Naoko %A Montaner, Joan %A Morris, Andrew P %A Muiño, Elena %A Müller-Nurasyid, Martina %A Norrving, Bo %A Ogishima, Soichi %A Parati, Eugenio A %A Peddareddygari, Leema Reddy %A Pedersen, Nancy L %A Pera, Joanna %A Perola, Markus %A Pezzini, Alessandro %A Pileggi, Silvana %A Rabionet, Raquel %A Riba-Llena, Iolanda %A Ribasés, Marta %A Romero, Jose R %A Roquer, Jaume %A Rudd, Anthony G %A Sarin, Antti-Pekka %A Sarju, Ralhan %A Sarnowski, Chloe %A Sasaki, Makoto %A Satizabal, Claudia L %A Satoh, Mamoru %A Sattar, Naveed %A Sawada, Norie %A Sibolt, Gerli %A Sigurdsson, Ásgeir %A Smith, Albert %A Sobue, Kenji %A Soriano-Tárraga, Carolina %A Stanne, Tara %A Stine, O Colin %A Stott, David J %A Strauch, Konstantin %A Takai, Takako %A Tanaka, Hideo %A Tanno, Kozo %A Teumer, Alexander %A Tomppo, Liisa %A Torres-Aguila, Nuria P %A Touze, Emmanuel %A Tsugane, Shoichiro %A Uitterlinden, André G %A Valdimarsson, Einar M %A van der Lee, Sven J %A Völzke, Henry %A Wakai, Kenji %A Weir, David %A Williams, Stephen R %A Wolfe, Charles D A %A Wong, Quenna %A Xu, Huichun %A Yamaji, Taiki %A Sanghera, Dharambir K %A Melander, Olle %A Jern, Christina %A Strbian, Daniel %A Fernandez-Cadenas, Israel %A Longstreth, W T %A Rolfs, Arndt %A Hata, Jun %A Woo, Daniel %A Rosand, Jonathan %A Paré, Guillaume %A Hopewell, Jemma C %A Saleheen, Danish %A Stefansson, Kari %A Worrall, Bradford B %A Kittner, Steven J %A Seshadri, Sudha %A Fornage, Myriam %A Markus, Hugh S %A Howson, Joanna M M %A Kamatani, Yoichiro %A Debette, Stephanie %A Dichgans, Martin %X

Stroke 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.

%B Nat Genet %V 50 %P 524-537 %8 2018 Apr %G eng %N 4 %R 10.1038/s41588-018-0058-3 %0 Journal Article %J Nat Commun %D 2018 %T Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. %A Davies, Gail %A Lam, Max %A Harris, Sarah E %A Trampush, Joey W %A Luciano, Michelle %A Hill, W David %A Hagenaars, Saskia P %A Ritchie, Stuart J %A Marioni, Riccardo E %A Fawns-Ritchie, Chloe %A Liewald, David C M %A Okely, Judith A %A Ahola-Olli, Ari V %A Barnes, Catriona L K %A Bertram, Lars %A Bis, Joshua C %A Burdick, Katherine E %A Christoforou, Andrea %A DeRosse, Pamela %A Djurovic, Srdjan %A Espeseth, Thomas %A Giakoumaki, Stella %A Giddaluru, Sudheer %A Gustavson, Daniel E %A Hayward, Caroline %A Hofer, Edith %A Ikram, M Arfan %A Karlsson, Robert %A Knowles, Emma %A Lahti, Jari %A Leber, Markus %A Li, Shuo %A Mather, Karen A %A Melle, Ingrid %A Morris, Derek %A Oldmeadow, Christopher %A Palviainen, Teemu %A Payton, Antony %A Pazoki, Raha %A Petrovic, Katja %A Reynolds, Chandra A %A Sargurupremraj, Muralidharan %A Scholz, Markus %A Smith, Jennifer A %A Smith, Albert V %A Terzikhan, Natalie %A Thalamuthu, Anbupalam %A Trompet, Stella %A van der Lee, Sven J %A Ware, Erin B %A Windham, B Gwen %A Wright, Margaret J %A Yang, Jingyun %A Yu, Jin %A Ames, David %A Amin, Najaf %A Amouyel, Philippe %A Andreassen, Ole A %A Armstrong, Nicola J %A Assareh, Amelia A %A Attia, John R %A Attix, Deborah %A Avramopoulos, Dimitrios %A Bennett, David A %A Böhmer, Anne C %A Boyle, Patricia A %A Brodaty, Henry %A Campbell, Harry %A Cannon, Tyrone D %A Cirulli, Elizabeth T %A Congdon, Eliza %A Conley, Emily Drabant %A Corley, Janie %A Cox, Simon R %A Dale, Anders M %A Dehghan, Abbas %A Dick, Danielle %A Dickinson, Dwight %A Eriksson, Johan G %A Evangelou, Evangelos %A Faul, Jessica D %A Ford, Ian %A Freimer, Nelson A %A Gao, He %A Giegling, Ina %A Gillespie, Nathan A %A Gordon, Scott D %A Gottesman, Rebecca F %A Griswold, Michael E %A Gudnason, Vilmundur %A Harris, Tamara B %A Hartmann, Annette M %A Hatzimanolis, Alex %A Heiss, Gerardo %A Holliday, Elizabeth G %A Joshi, Peter K %A Kähönen, Mika %A Kardia, Sharon L R %A Karlsson, Ida %A Kleineidam, Luca %A Knopman, David S %A Kochan, Nicole A %A Konte, Bettina %A Kwok, John B %A Le Hellard, Stephanie %A Lee, Teresa %A Lehtimäki, Terho %A Li, Shu-Chen %A Liu, Tian %A Koini, Marisa %A London, Edythe %A Longstreth, Will T %A Lopez, Oscar L %A Loukola, Anu %A Luck, Tobias %A Lundervold, Astri J %A Lundquist, Anders %A Lyytikäinen, Leo-Pekka %A Martin, Nicholas G %A Montgomery, Grant W %A Murray, Alison D %A Need, Anna C %A Noordam, Raymond %A Nyberg, Lars %A Ollier, William %A Papenberg, Goran %A Pattie, Alison %A Polasek, Ozren %A Poldrack, Russell A %A Psaty, Bruce M %A Reppermund, Simone %A Riedel-Heller, Steffi G %A Rose, Richard J %A Rotter, Jerome I %A Roussos, Panos %A Rovio, Suvi P %A Saba, Yasaman %A Sabb, Fred W %A Sachdev, Perminder S %A Satizabal, Claudia L %A Schmid, Matthias %A Scott, Rodney J %A Scult, Matthew A %A Simino, Jeannette %A Slagboom, P Eline %A Smyrnis, Nikolaos %A Soumaré, Aïcha %A Stefanis, Nikos C %A Stott, David J %A Straub, Richard E %A Sundet, Kjetil %A Taylor, Adele M %A Taylor, Kent D %A Tzoulaki, Ioanna %A Tzourio, Christophe %A Uitterlinden, Andre %A Vitart, Veronique %A Voineskos, Aristotle N %A Kaprio, Jaakko %A Wagner, Michael %A Wagner, Holger %A Weinhold, Leonie %A Wen, K Hoyan %A Widen, Elisabeth %A Yang, Qiong %A Zhao, Wei %A Adams, Hieab H H %A Arking, Dan E %A Bilder, Robert M %A Bitsios, Panos %A Boerwinkle, Eric %A Chiba-Falek, Ornit %A Corvin, Aiden %A De Jager, Philip L %A Debette, Stephanie %A Donohoe, Gary %A Elliott, Paul %A Fitzpatrick, Annette L %A Gill, Michael %A Glahn, David C %A Hägg, Sara %A Hansell, Narelle K %A Hariri, Ahmad R %A Ikram, M Kamran %A Jukema, J Wouter %A Vuoksimaa, Eero %A Keller, Matthew C %A Kremen, William S %A Launer, Lenore %A Lindenberger, Ulman %A Palotie, Aarno %A Pedersen, Nancy L %A Pendleton, Neil %A Porteous, David J %A Räikkönen, Katri %A Raitakari, Olli T %A Ramirez, Alfredo %A Reinvang, Ivar %A Rudan, Igor %A Schmidt, Reinhold %A Schmidt, Helena %A Schofield, Peter W %A Schofield, Peter R %A Starr, John M %A Steen, Vidar M %A Trollor, Julian N %A Turner, Steven T %A van Duijn, Cornelia M %A Villringer, Arno %A Weinberger, Daniel R %A Weir, David R %A Wilson, James F %A Malhotra, Anil %A McIntosh, Andrew M %A Gale, Catharine R %A Seshadri, Sudha %A Mosley, Thomas H %A Bressler, Jan %A Lencz, Todd %A Deary, Ian J %X

General 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.

%B Nat Commun %V 9 %P 2098 %8 2018 May 29 %G eng %N 1 %R 10.1038/s41467-018-04362-x %0 Journal Article %J Mol Psychiatry %D 2018 %T Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation. %A Bis, Joshua C %A Jian, Xueqiu %A Kunkle, Brian W %A Chen, Yuning %A Hamilton-Nelson, Kara L %A Bush, William S %A Salerno, William J %A Lancour, Daniel %A Ma, Yiyi %A Renton, Alan E %A Marcora, Edoardo %A Farrell, John J %A Zhao, Yi %A Qu, Liming %A Ahmad, Shahzad %A Amin, Najaf %A Amouyel, Philippe %A Beecham, Gary W %A Below, Jennifer E %A Campion, Dominique %A Charbonnier, Camille %A Chung, Jaeyoon %A Crane, Paul K %A Cruchaga, Carlos %A Cupples, L Adrienne %A Dartigues, Jean-François %A Debette, Stephanie %A Deleuze, Jean-Francois %A Fulton, Lucinda %A Gabriel, Stacey B %A Genin, Emmanuelle %A Gibbs, Richard A %A Goate, Alison %A Grenier-Boley, Benjamin %A Gupta, Namrata %A Haines, Jonathan L %A Havulinna, Aki S %A Helisalmi, Seppo %A Hiltunen, Mikko %A Howrigan, Daniel P %A Ikram, M Arfan %A Kaprio, Jaakko %A Konrad, Jan %A Kuzma, Amanda %A Lander, Eric S %A Lathrop, Mark %A Lehtimäki, Terho %A Lin, Honghuang %A Mattila, Kari %A Mayeux, Richard %A Muzny, Donna M %A Nasser, Waleed %A Neale, Benjamin %A Nho, Kwangsik %A Nicolas, Gaël %A Patel, Devanshi %A Pericak-Vance, Margaret A %A Perola, Markus %A Psaty, Bruce M %A Quenez, Olivier %A Rajabli, Farid %A Redon, Richard %A Reitz, Christiane %A Remes, Anne M %A Salomaa, Veikko %A Sarnowski, Chloe %A Schmidt, Helena %A Schmidt, Michael %A Schmidt, Reinhold %A Soininen, Hilkka %A Thornton, Timothy A %A Tosto, Giuseppe %A Tzourio, Christophe %A van der Lee, Sven J %A van Duijn, Cornelia M %A Vardarajan, Badri %A Wang, Weixin %A Wijsman, Ellen %A Wilson, Richard K %A Witten, Daniela %A Worley, Kim C %A Zhang, Xiaoling %A Bellenguez, Céline %A Lambert, Jean-Charles %A Kurki, Mitja I %A Palotie, Aarno %A Daly, Mark %A Boerwinkle, Eric %A Lunetta, Kathryn L %A DeStefano, Anita L %A Dupuis, Josée %A Martin, Eden R %A Schellenberg, Gerard D %A Seshadri, Sudha %A Naj, Adam C %A Fornage, Myriam %A Farrer, Lindsay A %X

The 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.

%B Mol Psychiatry %8 2018 Aug 14 %G eng %R 10.1038/s41380-018-0112-7 %0 Journal Article %J Brain %D 2019 %T Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects. %A Mishra, Aniket %A Chauhan, Ganesh %A Violleau, Marie-Helene %A Vojinovic, Dina %A Jian, Xueqiu %A Bis, Joshua C %A Li, Shuo %A Saba, Yasaman %A Grenier-Boley, Benjamin %A Yang, Qiong %A Bartz, Traci M %A Hofer, Edith %A Soumaré, Aïcha %A Peng, Fen %A Duperron, Marie-Gabrielle %A Foglio, Mario %A Mosley, Thomas H %A Schmidt, Reinhold %A Psaty, Bruce M %A Launer, Lenore J %A Boerwinkle, Eric %A Zhu, Yicheng %A Mazoyer, Bernard %A Lathrop, Mark %A Bellenguez, Céline %A van Duijn, Cornelia M %A Ikram, M Arfan %A Schmidt, Helena %A Longstreth, W T %A Fornage, Myriam %A Seshadri, Sudha %A Joutel, Anne %A Tzourio, Christophe %A Debette, Stephanie %X

We 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.

%B Brain %8 2019 Mar 11 %G eng %R 10.1093/brain/awz024 %0 Journal Article %J Nat Genet %D 2019 %T Genetic architecture of subcortical brain structures in 38,851 individuals. %A Satizabal, Claudia L %A Adams, Hieab H H %A Hibar, Derrek P %A White, Charles C %A Knol, Maria J %A Stein, Jason L %A Scholz, Markus %A Sargurupremraj, Muralidharan %A Jahanshad, Neda %A Roshchupkin, Gennady V %A Smith, Albert V %A Bis, Joshua C %A Jian, Xueqiu %A Luciano, Michelle %A Hofer, Edith %A Teumer, Alexander %A van der Lee, Sven J %A Yang, Jingyun %A Yanek, Lisa R %A Lee, Tom V %A Li, Shuo %A Hu, Yanhui %A Koh, Jia Yu %A Eicher, John D %A Desrivières, Sylvane %A Arias-Vasquez, Alejandro %A Chauhan, Ganesh %A Athanasiu, Lavinia %A Rentería, Miguel E %A Kim, Sungeun %A Hoehn, David %A Armstrong, Nicola J %A Chen, Qiang %A Holmes, Avram J %A den Braber, Anouk %A Kloszewska, Iwona %A Andersson, Micael %A Espeseth, Thomas %A Grimm, Oliver %A Abramovic, Lucija %A Alhusaini, Saud %A Milaneschi, Yuri %A Papmeyer, Martina %A Axelsson, Tomas %A Ehrlich, Stefan %A Roiz-Santiañez, Roberto %A Kraemer, Bernd %A Håberg, Asta K %A Jones, Hannah J %A Pike, G Bruce %A Stein, Dan J %A Stevens, Allison %A Bralten, Janita %A Vernooij, Meike W %A Harris, Tamara B %A Filippi, Irina %A Witte, A Veronica %A Guadalupe, Tulio %A Wittfeld, Katharina %A Mosley, Thomas H %A Becker, James T %A Doan, Nhat Trung %A Hagenaars, Saskia P %A Saba, Yasaman %A Cuellar-Partida, Gabriel %A Amin, Najaf %A Hilal, Saima %A Nho, Kwangsik %A Mirza-Schreiber, Nazanin %A Arfanakis, Konstantinos %A Becker, Diane M %A Ames, David %A Goldman, Aaron L %A Lee, Phil H %A Boomsma, Dorret I %A Lovestone, Simon %A Giddaluru, Sudheer %A Le Hellard, Stephanie %A Mattheisen, Manuel %A Bohlken, Marc M %A Kasperaviciute, Dalia %A Schmaal, Lianne %A Lawrie, Stephen M %A Agartz, Ingrid %A Walton, Esther %A Tordesillas-Gutierrez, Diana %A Davies, Gareth E %A Shin, Jean %A Ipser, Jonathan C %A Vinke, Louis N %A Hoogman, Martine %A Jia, Tianye %A Burkhardt, Ralph %A Klein, Marieke %A Crivello, Fabrice %A Janowitz, Deborah %A Carmichael, Owen %A Haukvik, Unn K %A Aribisala, Benjamin S %A Schmidt, Helena %A Strike, Lachlan T %A Cheng, Ching-Yu %A Risacher, Shannon L %A Pütz, Benno %A Fleischman, Debra A %A Assareh, Amelia A %A Mattay, Venkata S %A Buckner, Randy L %A Mecocci, Patrizia %A Dale, Anders M %A Cichon, Sven %A Boks, Marco P %A Matarin, Mar %A Penninx, Brenda W J H %A Calhoun, Vince D %A Chakravarty, M Mallar %A Marquand, Andre F %A Macare, Christine %A Kharabian Masouleh, Shahrzad %A Oosterlaan, Jaap %A Amouyel, Philippe %A Hegenscheid, Katrin %A Rotter, Jerome I %A Schork, Andrew J %A Liewald, David C M %A de Zubicaray, Greig I %A Wong, Tien Yin %A Shen, Li %A Sämann, Philipp G %A Brodaty, Henry %A Roffman, Joshua L %A de Geus, Eco J C %A Tsolaki, Magda %A Erk, Susanne %A van Eijk, Kristel R %A Cavalleri, Gianpiero L %A van der Wee, Nic J A %A McIntosh, Andrew M %A Gollub, Randy L %A Bulayeva, Kazima B %A Bernard, Manon %A Richards, Jennifer S %A Himali, Jayandra J %A Loeffler, Markus %A Rommelse, Nanda %A Hoffmann, Wolfgang %A Westlye, Lars T %A Valdés Hernández, Maria C %A Hansell, Narelle K %A van Erp, Theo G M %A Wolf, Christiane %A Kwok, John B J %A Vellas, Bruno %A Heinz, Andreas %A Olde Loohuis, Loes M %A Delanty, Norman %A Ho, Beng-Choon %A Ching, Christopher R K %A Shumskaya, Elena %A Singh, Baljeet %A Hofman, Albert %A van der Meer, Dennis %A Homuth, Georg %A Psaty, Bruce M %A Bastin, Mark E %A Montgomery, Grant W %A Foroud, Tatiana M %A Reppermund, Simone %A Hottenga, Jouke-Jan %A Simmons, Andrew %A Meyer-Lindenberg, Andreas %A Cahn, Wiepke %A Whelan, Christopher D %A van Donkelaar, Marjolein M J %A Yang, Qiong %A Hosten, Norbert %A Green, Robert C %A Thalamuthu, Anbupalam %A Mohnke, Sebastian %A Hulshoff Pol, Hilleke E %A Lin, Honghuang %A Jack, Clifford R %A Schofield, Peter R %A Mühleisen, Thomas W %A Maillard, Pauline %A Potkin, Steven G %A Wen, Wei %A Fletcher, Evan %A Toga, Arthur W %A Gruber, Oliver %A Huentelman, Matthew %A Davey Smith, George %A Launer, Lenore J %A Nyberg, Lars %A Jönsson, Erik G %A Crespo-Facorro, Benedicto %A Koen, Nastassja %A Greve, Douglas N %A Uitterlinden, André G %A Weinberger, Daniel R %A Steen, Vidar M %A Fedko, Iryna O %A Groenewold, Nynke A %A Niessen, Wiro J %A Toro, Roberto %A Tzourio, Christophe %A Longstreth, William T %A Ikram, M Kamran %A Smoller, Jordan W %A van Tol, Marie-Jose %A Sussmann, Jessika E %A Paus, Tomáš %A Lemaître, Hervé %A Schroeter, Matthias L %A Mazoyer, Bernard %A Andreassen, Ole A %A Holsboer, Florian %A Depondt, Chantal %A Veltman, Dick J %A Turner, Jessica A %A Pausova, Zdenka %A Schumann, Gunter %A van Rooij, Daan %A Djurovic, Srdjan %A Deary, Ian J %A McMahon, Katie L %A Müller-Myhsok, Bertram %A Brouwer, Rachel M %A Soininen, Hilkka %A Pandolfo, Massimo %A Wassink, Thomas H %A Cheung, Joshua W %A Wolfers, Thomas %A Martinot, Jean-Luc %A Zwiers, Marcel P %A Nauck, Matthias %A Melle, Ingrid %A Martin, Nicholas G %A Kanai, Ryota %A Westman, Eric %A Kahn, René S %A Sisodiya, Sanjay M %A White, Tonya %A Saremi, Arvin %A van Bokhoven, Hans %A Brunner, Han G %A Völzke, Henry %A Wright, Margaret J %A van 't Ent, Dennis %A Nöthen, Markus M %A Ophoff, Roel A %A Buitelaar, Jan K %A Fernández, Guillén %A Sachdev, Perminder S %A Rietschel, Marcella %A van Haren, Neeltje E M %A Fisher, Simon E %A Beiser, Alexa S %A Francks, Clyde %A Saykin, Andrew J %A Mather, Karen A %A Romanczuk-Seiferth, Nina %A Hartman, Catharina A %A DeStefano, Anita L %A Heslenfeld, Dirk J %A Weiner, Michael W %A Walter, Henrik %A Hoekstra, Pieter J %A Nyquist, Paul A %A Franke, Barbara %A Bennett, David A %A Grabe, Hans J %A Johnson, Andrew D %A Chen, Christopher %A van Duijn, Cornelia M %A Lopez, Oscar L %A Fornage, Myriam %A Wardlaw, Joanna M %A Schmidt, Reinhold %A DeCarli, Charles %A De Jager, Philip L %A Villringer, Arno %A Debette, Stephanie %A Gudnason, Vilmundur %A Medland, Sarah E %A Shulman, Joshua M %A Thompson, Paul M %A Seshadri, Sudha %A Ikram, M Arfan %X

Subcortical 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.

%B Nat Genet %V 51 %P 1624-1636 %8 2019 Nov %G eng %N 11 %R 10.1038/s41588-019-0511-y %0 Journal Article %J Nat Genet %D 2019 %T Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. %A Kunkle, Brian W %A Grenier-Boley, Benjamin %A Sims, Rebecca %A Bis, Joshua C %A Damotte, Vincent %A Naj, Adam C %A Boland, Anne %A Vronskaya, Maria %A van der Lee, Sven J %A Amlie-Wolf, Alexandre %A Bellenguez, Céline %A Frizatti, Aura %A Chouraki, Vincent %A Martin, Eden R %A Sleegers, Kristel %A Badarinarayan, Nandini %A Jakobsdottir, Johanna %A Hamilton-Nelson, Kara L %A Moreno-Grau, Sonia %A Olaso, Robert %A Raybould, Rachel %A Chen, Yuning %A Kuzma, Amanda B %A Hiltunen, Mikko %A Morgan, Taniesha %A Ahmad, Shahzad %A Vardarajan, Badri N %A Epelbaum, Jacques %A Hoffmann, Per %A Boada, Merce %A Beecham, Gary W %A Garnier, Jean-Guillaume %A Harold, Denise %A Fitzpatrick, Annette L %A Valladares, Otto %A Moutet, Marie-Laure %A Gerrish, Amy %A Smith, Albert V %A Qu, Liming %A Bacq, Delphine %A Denning, Nicola %A Jian, Xueqiu %A Zhao, Yi %A Del Zompo, Maria %A Fox, Nick C %A Choi, Seung-Hoan %A Mateo, Ignacio %A Hughes, Joseph T %A Adams, Hieab H %A Malamon, John %A Sanchez-Garcia, Florentino %A Patel, Yogen %A Brody, Jennifer A %A Dombroski, Beth A %A Naranjo, Maria Candida Deniz %A Daniilidou, Makrina %A Eiriksdottir, Gudny %A Mukherjee, Shubhabrata %A Wallon, David %A Uphill, James %A Aspelund, Thor %A Cantwell, Laura B %A Garzia, Fabienne %A Galimberti, Daniela %A Hofer, Edith %A Butkiewicz, Mariusz %A Fin, Bertrand %A Scarpini, Elio %A Sarnowski, Chloe %A Bush, Will S %A Meslage, Stéphane %A Kornhuber, Johannes %A White, Charles C %A Song, Yuenjoo %A Barber, Robert C %A Engelborghs, Sebastiaan %A Sordon, Sabrina %A Voijnovic, Dina %A Adams, Perrie M %A Vandenberghe, Rik %A Mayhaus, Manuel %A Cupples, L Adrienne %A Albert, Marilyn S %A De Deyn, Peter P %A Gu, Wei %A Himali, Jayanadra J %A Beekly, Duane %A Squassina, Alessio %A Hartmann, Annette M %A Orellana, Adelina %A Blacker, Deborah %A Rodriguez-Rodriguez, Eloy %A Lovestone, Simon %A Garcia, Melissa E %A Doody, Rachelle S %A Munoz-Fernadez, Carmen %A Sussams, Rebecca %A Lin, Honghuang %A Fairchild, Thomas J %A Benito, Yolanda A %A Holmes, Clive %A Karamujić-Čomić, Hata %A Frosch, Matthew P %A Thonberg, Håkan %A Maier, Wolfgang %A Roschupkin, Gena %A Ghetti, Bernardino %A Giedraitis, Vilmantas %A Kawalia, Amit %A Li, Shuo %A Huebinger, Ryan M %A Kilander, Lena %A Moebus, Susanne %A Hernandez, Isabel %A Kamboh, M Ilyas %A Brundin, RoseMarie %A Turton, James %A Yang, Qiong %A Katz, Mindy J %A Concari, Letizia %A Lord, Jenny %A Beiser, Alexa S %A Keene, C Dirk %A Helisalmi, Seppo %A Kloszewska, Iwona %A Kukull, Walter A %A Koivisto, Anne Maria %A Lynch, Aoibhinn %A Tarraga, Lluis %A Larson, Eric B %A Haapasalo, Annakaisa %A Lawlor, Brian %A Mosley, Thomas H %A Lipton, Richard B %A Solfrizzi, Vincenzo %A Gill, Michael %A Longstreth, W T %A Montine, Thomas J %A Frisardi, Vincenza %A Diez-Fairen, Monica %A Rivadeneira, Fernando %A Petersen, Ronald C %A Deramecourt, Vincent %A Alvarez, Ignacio %A Salani, Francesca %A Ciaramella, Antonio %A Boerwinkle, Eric %A Reiman, Eric M %A Fiévet, Nathalie %A Rotter, Jerome I %A Reisch, Joan S %A Hanon, Olivier %A Cupidi, Chiara %A Andre Uitterlinden, A G %A Royall, Donald R %A Dufouil, Carole %A Maletta, Raffaele Giovanni %A de Rojas, Itziar %A Sano, Mary %A Brice, Alexis %A Cecchetti, Roberta %A George-Hyslop, Peter St %A Ritchie, Karen %A Tsolaki, Magda %A Tsuang, Debby W %A Dubois, Bruno %A Craig, David %A Wu, Chuang-Kuo %A Soininen, Hilkka %A Avramidou, Despoina %A Albin, Roger L %A Fratiglioni, Laura %A Germanou, Antonia %A Apostolova, Liana G %A Keller, Lina %A Koutroumani, Maria %A Arnold, Steven E %A Panza, Francesco %A Gkatzima, Olymbia %A Asthana, Sanjay %A Hannequin, Didier %A Whitehead, Patrice %A Atwood, Craig S %A Caffarra, Paolo %A Hampel, Harald %A Quintela, Inés %A Carracedo, Angel %A Lannfelt, Lars %A Rubinsztein, David C %A Barnes, Lisa L %A Pasquier, Florence %A Frölich, Lutz %A Barral, Sandra %A McGuinness, Bernadette %A Beach, Thomas G %A Johnston, Janet A %A Becker, James T %A Passmore, Peter %A Bigio, Eileen H %A Schott, Jonathan M %A Bird, Thomas D %A Warren, Jason D %A Boeve, Bradley F %A Lupton, Michelle K %A Bowen, James D %A Proitsi, Petra %A Boxer, Adam %A Powell, John F %A Burke, James R %A Kauwe, John S K %A Burns, Jeffrey M %A Mancuso, Michelangelo %A Buxbaum, Joseph D %A Bonuccelli, Ubaldo %A Cairns, Nigel J %A McQuillin, Andrew %A Cao, Chuanhai %A Livingston, Gill %A Carlson, Chris S %A Bass, Nicholas J %A Carlsson, Cynthia M %A Hardy, John %A Carney, Regina M %A Bras, Jose %A Carrasquillo, Minerva M %A Guerreiro, Rita %A Allen, Mariet %A Chui, Helena C %A Fisher, Elizabeth %A Masullo, Carlo %A Crocco, Elizabeth A %A DeCarli, Charles %A Bisceglio, Gina %A Dick, Malcolm %A Ma, Li %A Duara, Ranjan %A Graff-Radford, Neill R %A Evans, Denis A %A Hodges, Angela %A Faber, Kelley M %A Scherer, Martin %A Fallon, Kenneth B %A Riemenschneider, Matthias %A Fardo, David W %A Heun, Reinhard %A Farlow, Martin R %A Kölsch, Heike %A Ferris, Steven %A Leber, Markus %A Foroud, Tatiana M %A Heuser, Isabella %A Galasko, Douglas R %A Giegling, Ina %A Gearing, Marla %A Hüll, Michael %A Geschwind, Daniel H %A Gilbert, John R %A Morris, John %A Green, Robert C %A Mayo, Kevin %A Growdon, John H %A Feulner, Thomas %A Hamilton, Ronald L %A Harrell, Lindy E %A Drichel, Dmitriy %A Honig, Lawrence S %A Cushion, Thomas D %A Huentelman, Matthew J %A Hollingworth, Paul %A Hulette, Christine M %A Hyman, Bradley T %A Marshall, Rachel %A Jarvik, Gail P %A Meggy, Alun %A Abner, Erin %A Menzies, Georgina E %A Jin, Lee-Way %A Leonenko, Ganna %A Real, Luis M %A Jun, Gyungah R %A Baldwin, Clinton T %A Grozeva, Detelina %A Karydas, Anna %A Russo, Giancarlo %A Kaye, Jeffrey A %A Kim, Ronald %A Jessen, Frank %A Kowall, Neil W %A Vellas, Bruno %A Kramer, Joel H %A Vardy, Emma %A LaFerla, Frank M %A Jöckel, Karl-Heinz %A Lah, James J %A Dichgans, Martin %A Leverenz, James B %A Mann, David %A Levey, Allan I %A Pickering-Brown, Stuart %A Lieberman, Andrew P %A Klopp, Norman %A Lunetta, Kathryn L %A Wichmann, H-Erich %A Lyketsos, Constantine G %A Morgan, Kevin %A Marson, Daniel C %A Brown, Kristelle %A Martiniuk, Frank %A Medway, Christopher %A Mash, Deborah C %A Nöthen, Markus M %A Masliah, Eliezer %A Hooper, Nigel M %A McCormick, Wayne C %A Daniele, Antonio %A McCurry, Susan M %A Bayer, Anthony %A McDavid, Andrew N %A Gallacher, John %A McKee, Ann C %A van den Bussche, Hendrik %A Mesulam, Marsel %A Brayne, Carol %A Miller, Bruce L %A Riedel-Heller, Steffi %A Miller, Carol A %A Miller, Joshua W %A Al-Chalabi, Ammar %A Morris, John C %A Shaw, Christopher E %A Myers, Amanda J %A Wiltfang, Jens %A O'Bryant, Sid %A Olichney, John M %A Alvarez, Victoria %A Parisi, Joseph E %A Singleton, Andrew B %A Paulson, Henry L %A Collinge, John %A Perry, William R %A Mead, Simon %A Peskind, Elaine %A Cribbs, David H %A Rossor, Martin %A Pierce, Aimee %A Ryan, Natalie S %A Poon, Wayne W %A Nacmias, Benedetta %A Potter, Huntington %A Sorbi, Sandro %A Quinn, Joseph F %A Sacchinelli, Eleonora %A Raj, Ashok %A Spalletta, Gianfranco %A Raskind, Murray %A Caltagirone, Carlo %A Bossù, Paola %A Orfei, Maria Donata %A Reisberg, Barry %A Clarke, Robert %A Reitz, Christiane %A Smith, A David %A Ringman, John M %A Warden, Donald %A Roberson, Erik D %A Wilcock, Gordon %A Rogaeva, Ekaterina %A Bruni, Amalia Cecilia %A Rosen, Howard J %A Gallo, Maura %A Rosenberg, Roger N %A Ben-Shlomo, Yoav %A Sager, Mark A %A Mecocci, Patrizia %A Saykin, Andrew J %A Pastor, Pau %A Cuccaro, Michael L %A Vance, Jeffery M %A Schneider, Julie A %A Schneider, Lori S %A Slifer, Susan %A Seeley, William W %A Smith, Amanda G %A Sonnen, Joshua A %A Spina, Salvatore %A Stern, Robert A %A Swerdlow, Russell H %A Tang, Mitchell %A Tanzi, Rudolph E %A Trojanowski, John Q %A Troncoso, Juan C %A Van Deerlin, Vivianna M %A Van Eldik, Linda J %A Vinters, Harry V %A Vonsattel, Jean Paul %A Weintraub, Sandra %A Welsh-Bohmer, Kathleen A %A Wilhelmsen, Kirk C %A Williamson, Jennifer %A Wingo, Thomas S %A Woltjer, Randall L %A Wright, Clinton B %A Yu, Chang-En %A Yu, Lei %A Saba, Yasaman %A Pilotto, Alberto %A Bullido, María J %A Peters, Oliver %A Crane, Paul K %A Bennett, David %A Bosco, Paola %A Coto, Eliecer %A Boccardi, Virginia %A De Jager, Phil L %A Lleo, Alberto %A Warner, Nick %A Lopez, Oscar L %A Ingelsson, Martin %A Deloukas, Panagiotis %A Cruchaga, Carlos %A Graff, Caroline %A Gwilliam, Rhian %A Fornage, Myriam %A Goate, Alison M %A Sánchez-Juan, Pascual %A Kehoe, Patrick G %A Amin, Najaf %A Ertekin-Taner, Nilifur %A Berr, Claudine %A Debette, Stephanie %A Love, Seth %A Launer, Lenore J %A Younkin, Steven G %A Dartigues, Jean-François %A Corcoran, Chris %A Ikram, M Arfan %A Dickson, Dennis W %A Nicolas, Gaël %A Campion, Dominique %A Tschanz, JoAnn %A Schmidt, Helena %A Hakonarson, Hakon %A Clarimon, Jordi %A Munger, Ron %A Schmidt, Reinhold %A Farrer, Lindsay A %A Van Broeckhoven, Christine %A C O'Donovan, Michael %A DeStefano, Anita L %A Jones, Lesley %A Haines, Jonathan L %A Deleuze, Jean-Francois %A Owen, Michael J %A Gudnason, Vilmundur %A Mayeux, Richard %A Escott-Price, Valentina %A Psaty, Bruce M %A Ramirez, Alfredo %A Wang, Li-San %A Ruiz, Agustin %A van Duijn, Cornelia M %A Holmans, Peter A %A Seshadri, Sudha %A Williams, Julie %A Amouyel, Phillippe %A Schellenberg, Gerard D %A Lambert, Jean-Charles %A Pericak-Vance, Margaret A %X

Risk 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.

%B Nat Genet %V 51 %P 414-430 %8 2019 Mar %G eng %N 3 %R 10.1038/s41588-019-0358-2 %0 Journal Article %J Nat Genet %D 2019 %T Trans-ethnic association study of blood pressure determinants in over 750,000 individuals. %A Giri, Ayush %A Hellwege, Jacklyn N %A Keaton, Jacob M %A Park, Jihwan %A Qiu, Chengxiang %A Warren, Helen R %A Torstenson, Eric S %A Kovesdy, Csaba P %A Sun, Yan V %A Wilson, Otis D %A Robinson-Cohen, Cassianne %A Roumie, Christianne L %A Chung, Cecilia P %A Birdwell, Kelly A %A Damrauer, Scott M %A DuVall, Scott L %A Klarin, Derek %A Cho, Kelly %A Wang, Yu %A Evangelou, Evangelos %A Cabrera, Claudia P %A Wain, Louise V %A Shrestha, Rojesh %A Mautz, Brian S %A Akwo, Elvis A %A Sargurupremraj, Muralidharan %A Debette, Stephanie %A Boehnke, Michael %A Scott, Laura J %A Luan, Jian'an %A Zhao, Jing-Hua %A Willems, Sara M %A Thériault, Sébastien %A Shah, Nabi %A Oldmeadow, Christopher %A Almgren, Peter %A Li-Gao, Ruifang %A Verweij, Niek %A Boutin, Thibaud S %A Mangino, Massimo %A Ntalla, Ioanna %A Feofanova, Elena %A Surendran, Praveen %A Cook, James P %A Karthikeyan, Savita %A Lahrouchi, Najim %A Liu, Chunyu %A Sepúlveda, Nuno %A Richardson, Tom G %A Kraja, Aldi %A Amouyel, Philippe %A Farrall, Martin %A Poulter, Neil R %A Laakso, Markku %A Zeggini, Eleftheria %A Sever, Peter %A Scott, Robert A %A Langenberg, Claudia %A Wareham, Nicholas J %A Conen, David %A Palmer, Colin Neil Alexander %A Attia, John %A Chasman, Daniel I %A Ridker, Paul M %A Melander, Olle %A Mook-Kanamori, Dennis Owen %A Harst, Pim van der %A Cucca, Francesco %A Schlessinger, David %A Hayward, Caroline %A Spector, Tim D %A Jarvelin, Marjo-Riitta %A Hennig, Branwen J %A Timpson, Nicholas J %A Wei, Wei-Qi %A Smith, Joshua C %A Xu, Yaomin %A Matheny, Michael E %A Siew, Edward E %A Lindgren, Cecilia %A Herzig, Karl-Heinz %A Dedoussis, George %A Denny, Joshua C %A Psaty, Bruce M %A Howson, Joanna M M %A Munroe, Patricia B %A Newton-Cheh, Christopher %A Caulfield, Mark J %A Elliott, Paul %A Gaziano, J Michael %A Concato, John %A Wilson, Peter W F %A Tsao, Philip S %A Velez Edwards, Digna R %A Susztak, Katalin %A O'Donnell, Christopher J %A Hung, Adriana M %A Edwards, Todd L %X

In 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.

%B Nat Genet %V 51 %P 51-62 %8 2019 Jan %G eng %N 1 %R 10.1038/s41588-018-0303-9 %0 Journal Article %J Science %D 2020 %T The genetic architecture of the human cerebral cortex %A Grasby, Katrina L. %A Jahanshad, Neda %A Painter, Jodie N. %A Colodro-Conde, Lucía %A Bralten, Janita %A Hibar, Derrek P. %A Lind, Penelope A. %A Pizzagalli, Fabrizio %A Ching, Christopher R. K. %A McMahon, Mary Agnes B. %A Shatokhina, Natalia %A Zsembik, Leo C. P. %A Thomopoulos, Sophia I. %A Zhu, Alyssa H. %A Strike, Lachlan T. %A Agartz, Ingrid %A Alhusaini, Saud %A Almeida, Marcio A. A. %A Alnæs, Dag %A Amlien, Inge K. %A Andersson, Micael %A Ard, Tyler %A Armstrong, Nicola J. %A Ashley-Koch, Allison %A Atkins, Joshua R. %A Bernard, Manon %A Brouwer, Rachel M. %A Buimer, Elizabeth E. L. %A Bülow, Robin %A Bürger, Christian %A Cannon, Dara M. %A Chakravarty, Mallar %A Chen, Qiang %A Cheung, Joshua W. %A Couvy-Duchesne, Baptiste %A Dale, Anders M. %A Dalvie, Shareefa %A de Araujo, Tânia K. %A de Zubicaray, Greig I. %A de Zwarte, Sonja M. C. %A den Braber, Anouk %A Doan, Nhat Trung %A Dohm, Katharina %A Ehrlich, Stefan %A Engelbrecht, Hannah-Ruth %A Erk, Susanne %A Fan, Chun Chieh %A Fedko, Iryna O. %A Foley, Sonya F. %A Ford, Judith M. %A Fukunaga, Masaki %A Garrett, Melanie E. %A Ge, Tian %A Giddaluru, Sudheer %A Goldman, Aaron L. %A Green, Melissa J. %A Groenewold, Nynke A. %A Grotegerd, Dominik %A Gurholt, Tiril P. %A Gutman, Boris A. %A Hansell, Narelle K. %A Harris, Mathew A. %A Harrison, Marc B. %A Haswell, Courtney C. %A Hauser, Michael %A Herms, Stefan %A Heslenfeld, Dirk J. %A Ho, New Fei %A Hoehn, David %A Hoffmann, Per %A Holleran, Laurena %A Hoogman, Martine %A Hottenga, Jouke-Jan %A Ikeda, Masashi %A Janowitz, Deborah %A Jansen, Iris E. %A Jia, Tianye %A Jockwitz, Christiane %A Kanai, Ryota %A Karama, Sherif %A Kasperaviciute, Dalia %A Kaufmann, Tobias %A Kelly, Sinead %A Kikuchi, Masataka %A Klein, Marieke %A Knapp, Michael %A Knodt, Annchen R. %A Krämer, Bernd %A Lam, Max %A Lancaster, Thomas M. %A Lee, Phil H. %A Lett, Tristram A. %A Lewis, Lindsay B. %A Lopes-Cendes, Iscia %A Luciano, Michelle %A Macciardi, Fabio %A Marquand, Andre F. %A Mathias, Samuel R. %A Melzer, Tracy R. %A Milaneschi, Yuri %A Mirza-Schreiber, Nazanin %A Moreira, Jose C. V. %A Mühleisen, Thomas W. %A Müller-Myhsok, Bertram %A Najt, Pablo %A Nakahara, Soichiro %A Nho, Kwangsik %A Olde Loohuis, Loes M. %A Orfanos, Dimitri Papadopoulos %A Pearson, John F. %A Pitcher, Toni L. %A Pütz, Benno %A Quidé, Yann %A Ragothaman, Anjanibhargavi %A Rashid, Faisal M. %A Reay, William R. %A Redlich, Ronny %A Reinbold, Céline S. %A Repple, Jonathan %A Richard, Geneviève %A Riedel, Brandalyn C. %A Risacher, Shannon L. %A Rocha, Cristiane S. %A Mota, Nina Roth %A Salminen, Lauren %A Saremi, Arvin %A Saykin, Andrew J. %A Schlag, Fenja %A Schmaal, Lianne %A Schofield, Peter R. %A Secolin, Rodrigo %A Shapland, Chin Yang %A Shen, Li %A Shin, Jean %A Shumskaya, Elena %A Sønderby, Ida E. %A Sprooten, Emma %A Tansey, Katherine E. %A Teumer, Alexander %A Thalamuthu, Anbupalam %A Tordesillas-Gutierrez, Diana %A Turner, Jessica A. %A Uhlmann, Anne %A Vallerga, Costanza Ludovica %A van der Meer, Dennis %A van Donkelaar, Marjolein M. J. %A van Eijk, Liza %A van Erp, Theo G. M. %A van Haren, Neeltje E. M. %A van Rooij, Daan %A van Tol, Marie-Jose %A Veldink, Jan H. %A Verhoef, Ellen %A Walton, Esther %A Wang, Mingyuan %A Wang, Yunpeng %A Wardlaw, Joanna M. %A Wen, Wei %A Westlye, Lars T. %A Whelan, Christopher D. %A Witt, Stephanie H. %A Wittfeld, Katharina %A Wolf, Christiane %A Wolfers, Thomas %A Wu, Jing Qin %A Yasuda, Clarissa L. %A Zaremba, Dario %A Zhang, Zuo %A Zwiers, Marcel P. %A Artiges, Eric %A Assareh, Amelia A. %A Ayesa-Arriola, Rosa %A Belger, Aysenil %A Brandt, Christine L. %A Brown, Gregory G. %A Cichon, Sven %A Curran, Joanne E. %A Davies, Gareth E. %A Degenhardt, Franziska %A Dennis, Michelle F. %A Dietsche, Bruno %A Djurovic, Srdjan %A Doherty, Colin P. %A Espiritu, Ryan %A Garijo, Daniel %A Gil, Yolanda %A Gowland, Penny A. %A Green, Robert C. %A Häusler, Alexander N. %A Heindel, Walter %A Ho, Beng-Choon %A Hoffmann, Wolfgang U. %A Holsboer, Florian %A Homuth, Georg %A Hosten, Norbert %A Jack, Clifford R. %A Jang, MiHyun %A Jansen, Andreas %A Kimbrel, Nathan A. %A Kolskår, Knut %A Koops, Sanne %A Krug, Axel %A Lim, Kelvin O. %A Luykx, Jurjen J. %A Mathalon, Daniel H. %A Mather, Karen A. %A Mattay, Venkata S. %A Matthews, Sarah %A Mayoral Van Son, Jaqueline %A McEwen, Sarah C. %A Melle, Ingrid %A Morris, Derek W. %A Mueller, Bryon A. %A Nauck, Matthias %A Nordvik, Jan E. %A Nöthen, Markus M. %A O’Leary, Daniel S. %A Opel, Nils %A Martinot, Marie-Laure Paillère %A Pike, G. Bruce %A Preda, Adrian %A Quinlan, Erin B. %A Rasser, Paul E. %A Ratnakar, Varun %A Reppermund, Simone %A Steen, Vidar M. %A Tooney, Paul A. %A Torres, Fábio R. %A Veltman, Dick J. %A Voyvodic, James T. %A Whelan, Robert %A White, Tonya %A Yamamori, Hidenaga %A Adams, Hieab H. H. %A Bis, Joshua C. %A Debette, Stephanie %A DeCarli, Charles %A Fornage, Myriam %A Gudnason, Vilmundur %A Hofer, Edith %A Ikram, M. Arfan %A Launer, Lenore %A Longstreth, W. T. %A Lopez, Oscar L. %A Mazoyer, Bernard %A Mosley, Thomas H. %A Roshchupkin, Gennady V. %A Satizabal, Claudia L. %A Schmidt, Reinhold %A Seshadri, Sudha %A Yang, Qiong %A Alvim, Marina K. M. %A Ames, David %A Anderson, Tim J. %A Andreassen, Ole A. %A Arias-Vasquez, Alejandro %A Bastin, Mark E. %A Baune, Bernhard T. %A Beckham, Jean C. %A Blangero, John %A Boomsma, Dorret I. %A Brodaty, Henry %A Brunner, Han G. %A Buckner, Randy L. %A Buitelaar, Jan K. %A Bustillo, Juan R. %A Cahn, Wiepke %A Cairns, Murray J. %A Calhoun, Vince %A Carr, Vaughan J. %A Caseras, Xavier %A Caspers, Svenja %A Cavalleri, Gianpiero L. %A Cendes, Fernando %A Corvin, Aiden %A Crespo-Facorro, Benedicto %A Dalrymple-Alford, John C. %A Dannlowski, Udo %A de Geus, Eco J. C. %A Deary, Ian J. %A Delanty, Norman %A Depondt, Chantal %A Desrivières, Sylvane %A Donohoe, Gary %A Espeseth, Thomas %A Fernández, Guillén %A Fisher, Simon E. %A Flor, Herta %A Forstner, Andreas J. %A Francks, Clyde %A Franke, Barbara %A Glahn, David C. %A Gollub, Randy L. %A Grabe, Hans J. %A Gruber, Oliver %A Håberg, Asta K. %A Hariri, Ahmad R. %A Hartman, Catharina A. %A Hashimoto, Ryota %A Heinz, Andreas %A Henskens, Frans A. %A Hillegers, Manon H. J. %A Hoekstra, Pieter J. %A Holmes, Avram J. %A Hong, L. Elliot %A Hopkins, William D. %A Hulshoff Pol, Hilleke E. %A Jernigan, Terry L. %A Jönsson, Erik G. %A Kahn, René S. %A Kennedy, Martin A. %A Kircher, Tilo T. J. %A Kochunov, Peter %A Kwok, John B. J. %A Le Hellard, Stephanie %A Loughland, Carmel M. %A Martin, Nicholas G. %A Martinot, Jean-Luc %A McDonald, Colm %A McMahon, Katie L. %A Meyer-Lindenberg, Andreas %A Michie, Patricia T. %A Morey, Rajendra A. %A Mowry, Bryan %A Nyberg, Lars %A Oosterlaan, Jaap %A Ophoff, Roel A. %A Pantelis, Christos %A Paus, Tomáš %A Pausova, Zdenka %A Penninx, Brenda W. J. H. %A Polderman, Tinca J. C. %A Posthuma, Danielle %A Rietschel, Marcella %A Roffman, Joshua L. %A Rowland, Laura M. %A Sachdev, Perminder S. %A Sämann, Philipp G. %A Schall, Ulrich %A Schumann, Gunter %A Scott, Rodney J. %A Sim, Kang %A Sisodiya, Sanjay M. %A Smoller, Jordan W. %A Sommer, Iris E. %A St Pourcain, Beate %A Stein, Dan J. %A Toga, Arthur W. %A Trollor, Julian N. %A Van der Wee, Nic J. A. %A van ’t Ent, Dennis %A Völzke, Henry %A Walter, Henrik %A Weber, Bernd %A Weinberger, Daniel R. %A Wright, Margaret J. %A Zhou, Juan %A Stein, Jason L. %A Thompson, Paul M. %A Medland, Sarah E. %B Science %V 367 %P eaay6690 %8 Aug-03-2021 %G eng %U https://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.aay6690 %N 6484 %! Science %R 10.1126/science.aay6690 %0 Journal Article %J Brain %D 2022 %T Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI. %A Yang, Yunju %A Knol, Maria J %A Wang, Ruiqi %A Mishra, Aniket %A Liu, Dan %A Luciano, Michelle %A Teumer, Alexander %A Armstrong, Nicola %A Bis, Joshua C %A Jhun, Min A %A Li, Shuo %A Adams, Hieab H H %A Aziz, Nasir Ahmad %A Bastin, Mark E %A Bourgey, Mathieu %A Brody, Jennifer A %A Frenzel, Stefan %A Gottesman, Rebecca F %A Hosten, Norbert %A Hou, Lifang %A Kardia, Sharon L R %A Lohner, Valerie %A Marquis, Pascale %A Maniega, Susana Muñoz %A Satizabal, Claudia L %A Sorond, Farzaneh A %A Valdés Hernández, Maria C %A van Duijn, Cornelia M %A Vernooij, Meike W %A Wittfeld, Katharina %A Yang, Qiong %A Zhao, Wei %A Boerwinkle, Eric %A Levy, Daniel %A Deary, Ian J %A Jiang, Jiyang %A Mather, Karen A %A Mosley, Thomas H %A Psaty, Bruce M %A Sachdev, Perminder S %A Smith, Jennifer A %A Sotoodehnia, Nona %A DeCarli, Charles S %A Breteler, Monique M B %A Arfan Ikram, M %A Grabe, Hans J %A Wardlaw, Joanna %A Longstreth, W T %A Launer, Lenore J %A Seshadri, Sudha %A Debette, Stephanie %A Fornage, Myriam %X

Cerebral 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.

%B Brain %8 2022 Aug 09 %G eng %R 10.1093/brain/awac290 %0 Journal Article %J Mol Psychiatry %D 2022 %T Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning. %A Lahti, Jari %A Tuominen, Samuli %A Yang, Qiong %A Pergola, Giulio %A Ahmad, Shahzad %A Amin, Najaf %A Armstrong, Nicola J %A Beiser, Alexa %A Bey, Katharina %A Bis, Joshua C %A Boerwinkle, Eric %A Bressler, Jan %A Campbell, Archie %A Campbell, Harry %A Chen, Qiang %A Corley, Janie %A Cox, Simon R %A Davies, Gail %A De Jager, Philip L %A Derks, Eske M %A Faul, Jessica D %A Fitzpatrick, Annette L %A Fohner, Alison E %A Ford, Ian %A Fornage, Myriam %A Gerring, Zachary %A Grabe, Hans J %A Grodstein, Francine %A Gudnason, Vilmundur %A Simonsick, Eleanor %A Holliday, Elizabeth G %A Joshi, Peter K %A Kajantie, Eero %A Kaprio, Jaakko %A Karell, Pauliina %A Kleineidam, Luca %A Knol, Maria J %A Kochan, Nicole A %A Kwok, John B %A Leber, Markus %A Lam, Max %A Lee, Teresa %A Li, Shuo %A Loukola, Anu %A Luck, Tobias %A Marioni, Riccardo E %A Mather, Karen A %A Medland, Sarah %A Mirza, Saira S %A Nalls, Mike A %A Nho, Kwangsik %A O'Donnell, Adrienne %A Oldmeadow, Christopher %A Painter, Jodie %A Pattie, Alison %A Reppermund, Simone %A Risacher, Shannon L %A Rose, Richard J %A Sadashivaiah, Vijay %A Scholz, Markus %A Satizabal, Claudia L %A Schofield, Peter W %A Schraut, Katharina E %A Scott, Rodney J %A Simino, Jeannette %A Smith, Albert V %A Smith, Jennifer A %A Stott, David J %A Surakka, Ida %A Teumer, Alexander %A Thalamuthu, Anbupalam %A Trompet, Stella %A Turner, Stephen T %A van der Lee, Sven J %A Villringer, Arno %A Völker, Uwe %A Wilson, Robert S %A Wittfeld, Katharina %A Vuoksimaa, Eero %A Xia, Rui %A Yaffe, Kristine %A Yu, Lei %A Zare, Habil %A Zhao, Wei %A Ames, David %A Attia, John %A Bennett, David A %A Brodaty, Henry %A Chasman, Daniel I %A Goldman, Aaron L %A Hayward, Caroline %A Ikram, M Arfan %A Jukema, J Wouter %A Kardia, Sharon L R %A Lencz, Todd %A Loeffler, Markus %A Mattay, Venkata S %A Palotie, Aarno %A Psaty, Bruce M %A Ramirez, Alfredo %A Ridker, Paul M %A Riedel-Heller, Steffi G %A Sachdev, Perminder S %A Saykin, Andrew J %A Scherer, Martin %A Schofield, Peter R %A Sidney, Stephen %A Starr, John M %A Trollor, Julian %A Ulrich, William %A Wagner, Michael %A Weir, David R %A Wilson, James F %A Wright, Margaret J %A Weinberger, Daniel R %A Debette, Stephanie %A Eriksson, Johan G %A Mosley, Thomas H %A Launer, Lenore J %A van Duijn, Cornelia M %A Deary, Ian J %A Seshadri, Sudha %A Räikkönen, Katri %X

Understanding 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.

%B Mol Psychiatry %8 2022 Aug 16 %G eng %R 10.1038/s41380-022-01710-8 %0 Journal Article %J Nat Genet %D 2022 %T New insights into the genetic etiology of Alzheimer's disease and related dementias. %A Bellenguez, Céline %A Küçükali, Fahri %A Jansen, Iris E %A Kleineidam, Luca %A Moreno-Grau, Sonia %A Amin, Najaf %A Naj, Adam C %A Campos-Martin, Rafael %A Grenier-Boley, Benjamin %A Andrade, Victor %A Holmans, Peter A %A Boland, Anne %A Damotte, Vincent %A van der Lee, Sven J %A Costa, Marcos R %A Kuulasmaa, Teemu %A Yang, Qiong %A de Rojas, Itziar %A Bis, Joshua C %A Yaqub, Amber %A Prokic, Ivana %A Chapuis, Julien %A Ahmad, Shahzad %A Giedraitis, Vilmantas %A Aarsland, Dag %A Garcia-Gonzalez, Pablo %A Abdelnour, Carla %A Alarcón-Martín, Emilio %A Alcolea, Daniel %A Alegret, Montserrat %A Alvarez, Ignacio %A Alvarez, Victoria %A Armstrong, Nicola J %A Tsolaki, Anthoula %A Antunez, Carmen %A Appollonio, Ildebrando %A Arcaro, Marina %A Archetti, Silvana %A Pastor, Alfonso Arias %A Arosio, Beatrice %A Athanasiu, Lavinia %A Bailly, Henri %A Banaj, Nerisa %A Baquero, Miquel %A Barral, Sandra %A Beiser, Alexa %A Pastor, Ana Belén %A Below, Jennifer E %A Benchek, Penelope %A Benussi, Luisa %A Berr, Claudine %A Besse, Céline %A Bessi, Valentina %A Binetti, Giuliano %A Bizarro, Alessandra %A Blesa, Rafael %A Boada, Merce %A Boerwinkle, Eric %A Borroni, Barbara %A Boschi, Silvia %A Bossù, Paola %A Bråthen, Geir %A Bressler, Jan %A Bresner, Catherine %A Brodaty, Henry %A Brookes, Keeley J %A Brusco, Luis Ignacio %A Buiza-Rueda, Dolores %A Bûrger, Katharina %A Burholt, Vanessa %A Bush, William S %A Calero, Miguel %A Cantwell, Laura B %A Chene, Geneviève %A Chung, Jaeyoon %A Cuccaro, Michael L %A Carracedo, Angel %A Cecchetti, Roberta %A Cervera-Carles, Laura %A Charbonnier, Camille %A Chen, Hung-Hsin %A Chillotti, Caterina %A Ciccone, Simona %A Claassen, Jurgen A H R %A Clark, Christopher %A Conti, Elisa %A Corma-Gómez, Anaïs %A Costantini, Emanuele %A Custodero, Carlo %A Daian, Delphine %A Dalmasso, Maria Carolina %A Daniele, Antonio %A Dardiotis, Efthimios %A Dartigues, Jean-François %A de Deyn, Peter Paul %A de Paiva Lopes, Katia %A de Witte, Lot D %A Debette, Stephanie %A Deckert, Jürgen %A Del Ser, Teodoro %A Denning, Nicola %A DeStefano, Anita %A Dichgans, Martin %A Diehl-Schmid, Janine %A Diez-Fairen, Monica %A Rossi, Paolo Dionigi %A Djurovic, Srdjan %A Duron, Emmanuelle %A Düzel, Emrah %A Dufouil, Carole %A Eiriksdottir, Gudny %A Engelborghs, Sebastiaan %A Escott-Price, Valentina %A Espinosa, Ana %A Ewers, Michael %A Faber, Kelley M %A Fabrizio, Tagliavini %A Nielsen, Sune Fallgaard %A Fardo, David W %A Farotti, Lucia %A Fenoglio, Chiara %A Fernández-Fuertes, Marta %A Ferrari, Raffaele %A Ferreira, Catarina B %A Ferri, Evelyn %A Fin, Bertrand %A Fischer, Peter %A Fladby, Tormod %A Fließbach, Klaus %A Fongang, Bernard %A Fornage, Myriam %A Fortea, Juan %A Foroud, Tatiana M %A Fostinelli, Silvia %A Fox, Nick C %A Franco-Macías, Emlio %A Bullido, María J %A Frank-García, Ana %A Froelich, Lutz %A Fulton-Howard, Brian %A Galimberti, Daniela %A García-Alberca, Jose Maria %A Garcia-Gonzalez, Pablo %A Garcia-Madrona, Sebastian %A Garcia-Ribas, Guillermo %A Ghidoni, Roberta %A Giegling, Ina %A Giorgio, Giaccone %A Goate, Alison M %A Goldhardt, Oliver %A Gomez-Fonseca, Duber %A González-Perez, Antonio %A Graff, Caroline %A Grande, Giulia %A Green, Emma %A Grimmer, Timo %A Grünblatt, Edna %A Grunin, Michelle %A Gudnason, Vilmundur %A Guetta-Baranes, Tamar %A Haapasalo, Annakaisa %A Hadjigeorgiou, Georgios %A Haines, Jonathan L %A Hamilton-Nelson, Kara L %A Hampel, Harald %A Hanon, Olivier %A Hardy, John %A Hartmann, Annette M %A Hausner, Lucrezia %A Harwood, Janet %A Heilmann-Heimbach, Stefanie %A Helisalmi, Seppo %A Heneka, Michael T %A Hernandez, Isabel %A Herrmann, Martin J %A Hoffmann, Per %A Holmes, Clive %A Holstege, Henne %A Vilas, Raquel Huerto %A Hulsman, Marc %A Humphrey, Jack %A Biessels, Geert Jan %A Jian, Xueqiu %A Johansson, Charlotte %A Jun, Gyungah R %A Kastumata, Yuriko %A Kauwe, John %A Kehoe, Patrick G %A Kilander, Lena %A Ståhlbom, Anne Kinhult %A Kivipelto, Miia %A Koivisto, Anne %A Kornhuber, Johannes %A Kosmidis, Mary H %A Kukull, Walter A %A Kuksa, Pavel P %A Kunkle, Brian W %A Kuzma, Amanda B %A Lage, Carmen %A Laukka, Erika J %A Launer, Lenore %A Lauria, Alessandra %A Lee, Chien-Yueh %A Lehtisalo, Jenni %A Lerch, Ondrej %A Lleo, Alberto %A Longstreth, William %A Lopez, Oscar %A de Munain, Adolfo Lopez %A Love, Seth %A Löwemark, Malin %A Luckcuck, Lauren %A Lunetta, Kathryn L %A Ma, Yiyi %A Macías, Juan %A MacLeod, Catherine A %A Maier, Wolfgang %A Mangialasche, Francesca %A Spallazzi, Marco %A Marquié, Marta %A Marshall, Rachel %A Martin, Eden R %A Montes, Angel Martín %A Rodríguez, Carmen Martínez %A Masullo, Carlo %A Mayeux, Richard %A Mead, Simon %A Mecocci, Patrizia %A Medina, Miguel %A Meggy, Alun %A Mehrabian, Shima %A Mendoza, Silvia %A Menéndez-González, Manuel %A Mir, Pablo %A Moebus, Susanne %A Mol, Merel %A Molina-Porcel, Laura %A Montrreal, Laura %A Morelli, Laura %A Moreno, Fermin %A Morgan, Kevin %A Mosley, Thomas %A Nöthen, Markus M %A Muchnik, Carolina %A Mukherjee, Shubhabrata %A Nacmias, Benedetta %A Ngandu, Tiia %A Nicolas, Gaël %A Nordestgaard, Børge G %A Olaso, Robert %A Orellana, Adelina %A Orsini, Michela %A Ortega, Gemma %A Padovani, Alessandro %A Paolo, Caffarra %A Papenberg, Goran %A Parnetti, Lucilla %A Pasquier, Florence %A Pastor, Pau %A Peloso, Gina %A Pérez-Cordón, Alba %A Pérez-Tur, Jordi %A Pericard, Pierre %A Peters, Oliver %A Pijnenburg, Yolande A L %A Pineda, Juan A %A Piñol-Ripoll, Gerard %A Pisanu, Claudia %A Polak, Thomas %A Popp, Julius %A Posthuma, Danielle %A Priller, Josef %A Puerta, Raquel %A Quenez, Olivier %A Quintela, Inés %A Thomassen, Jesper Qvist %A Rábano, Alberto %A Rainero, Innocenzo %A Rajabli, Farid %A Ramakers, Inez %A Real, Luis M %A Reinders, Marcel J T %A Reitz, Christiane %A Reyes-Dumeyer, Dolly %A Ridge, Perry %A Riedel-Heller, Steffi %A Riederer, Peter %A Roberto, Natalia %A Rodriguez-Rodriguez, Eloy %A Rongve, Arvid %A Allende, Irene Rosas %A Rosende-Roca, Maitée %A Royo, Jose Luis %A Rubino, Elisa %A Rujescu, Dan %A Sáez, María Eugenia %A Sakka, Paraskevi %A Saltvedt, Ingvild %A Sanabria, Ángela %A Sánchez-Arjona, María Bernal %A Sanchez-Garcia, Florentino %A Juan, Pascual Sánchez %A Sánchez-Valle, Raquel %A Sando, Sigrid B %A Sarnowski, Chloe %A Satizabal, Claudia L %A Scamosci, Michela %A Scarmeas, Nikolaos %A Scarpini, Elio %A Scheltens, Philip %A Scherbaum, Norbert %A Scherer, Martin %A Schmid, Matthias %A Schneider, Anja %A Schott, Jonathan M %A Selbæk, Geir %A Seripa, Davide %A Serrano, Manuel %A Sha, Jin %A Shadrin, Alexey A %A Skrobot, Olivia %A Slifer, Susan %A Snijders, Gijsje J L %A Soininen, Hilkka %A Solfrizzi, Vincenzo %A Solomon, Alina %A Song, Yeunjoo %A Sorbi, Sandro %A Sotolongo-Grau, Oscar %A Spalletta, Gianfranco %A Spottke, Annika %A Squassina, Alessio %A Stordal, Eystein %A Tartan, Juan Pablo %A Tarraga, Lluis %A Tesí, Niccolo %A Thalamuthu, Anbupalam %A Thomas, Tegos %A Tosto, Giuseppe %A Traykov, Latchezar %A Tremolizzo, Lucio %A Tybjærg-Hansen, Anne %A Uitterlinden, Andre %A Ullgren, Abbe %A Ulstein, Ingun %A Valero, Sergi %A Valladares, Otto %A Broeckhoven, Christine Van %A Vance, Jeffery %A Vardarajan, Badri N %A van der Lugt, Aad %A Dongen, Jasper Van %A van Rooij, Jeroen %A van Swieten, John %A Vandenberghe, Rik %A Verhey, Frans %A Vidal, Jean-Sébastien %A Vogelgsang, Jonathan %A Vyhnalek, Martin %A Wagner, Michael %A Wallon, David %A Wang, Li-San %A Wang, Ruiqi %A Weinhold, Leonie %A Wiltfang, Jens %A Windle, Gill %A Woods, Bob %A Yannakoulia, Mary %A Zare, Habil %A Zhao, Yi %A Zhang, Xiaoling %A Zhu, Congcong %A Zulaica, Miren %A Farrer, Lindsay A %A Psaty, Bruce M %A Ghanbari, Mohsen %A Raj, Towfique %A Sachdev, Perminder %A Mather, Karen %A Jessen, Frank %A Ikram, M Arfan %A de Mendonça, Alexandre %A Hort, Jakub %A Tsolaki, Magda %A Pericak-Vance, Margaret A %A Amouyel, Philippe %A Williams, Julie %A Frikke-Schmidt, Ruth %A Clarimon, Jordi %A Deleuze, Jean-Francois %A Rossi, Giacomina %A Seshadri, Sudha %A Andreassen, Ole A %A Ingelsson, Martin %A Hiltunen, Mikko %A Sleegers, Kristel %A Schellenberg, Gerard D %A van Duijn, Cornelia M %A Sims, Rebecca %A van der Flier, Wiesje M %A Ruiz, Agustin %A Ramirez, Alfredo %A Lambert, Jean-Charles %K Alzheimer Disease %K Cognitive Dysfunction %K Genome-Wide Association Study %K Humans %K tau Proteins %X

Characterization 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.

%B Nat Genet %V 54 %P 412-436 %8 2022 Apr %G eng %N 4 %R 10.1038/s41588-022-01024-z %0 Journal Article %J Nature %D 2022 %T Stroke genetics informs drug discovery and risk prediction across ancestries. %A Mishra, Aniket %A Malik, Rainer %A Hachiya, Tsuyoshi %A Jürgenson, Tuuli %A Namba, Shinichi %A Posner, Daniel C %A Kamanu, Frederick K %A Koido, Masaru %A Le Grand, Quentin %A Shi, Mingyang %A He, Yunye %A Georgakis, Marios K %A Caro, Ilana %A Krebs, Kristi %A Liaw, Yi-Ching %A Vaura, Felix C %A Lin, Kuang %A Winsvold, Bendik Slagsvold %A Srinivasasainagendra, Vinodh %A Parodi, Livia %A Bae, Hee-Joon %A Chauhan, Ganesh %A Chong, Michael R %A Tomppo, Liisa %A Akinyemi, Rufus %A Roshchupkin, Gennady V %A Habib, Naomi %A Jee, Yon Ho %A Thomassen, Jesper Qvist %A Abedi, Vida %A Cárcel-Márquez, Jara %A Nygaard, Marianne %A Leonard, Hampton L %A Yang, Chaojie %A Yonova-Doing, Ekaterina %A Knol, Maria J %A Lewis, Adam J %A Judy, Renae L %A Ago, Tetsuro %A Amouyel, Philippe %A Armstrong, Nicole D %A Bakker, Mark K %A Bartz, Traci M %A Bennett, David A %A Bis, Joshua C %A Bordes, Constance %A Børte, Sigrid %A Cain, Anael %A Ridker, Paul M %A Cho, Kelly %A Chen, Zhengming %A Cruchaga, Carlos %A Cole, John W %A De Jager, Phil L %A de Cid, Rafael %A Endres, Matthias %A Ferreira, Leslie E %A Geerlings, Mirjam I %A Gasca, Natalie C %A Gudnason, Vilmundur %A Hata, Jun %A He, Jing %A Heath, Alicia K %A Ho, Yuk-Lam %A Havulinna, Aki S %A Hopewell, Jemma C %A Hyacinth, Hyacinth I %A Inouye, Michael %A Jacob, Mina A %A Jeon, Christina E %A Jern, Christina %A Kamouchi, Masahiro %A Keene, Keith L %A Kitazono, Takanari %A Kittner, Steven J %A Konuma, Takahiro %A Kumar, Amit %A Lacaze, Paul %A Launer, Lenore J %A Lee, Keon-Joo %A Lepik, Kaido %A Li, Jiang %A Li, Liming %A Manichaikul, Ani %A Markus, Hugh S %A Marston, Nicholas A %A Meitinger, Thomas %A Mitchell, Braxton D %A Montellano, Felipe A %A Morisaki, Takayuki %A Mosley, Thomas H %A Nalls, Mike A %A Nordestgaard, Børge G %A O'Donnell, Martin J %A Okada, Yukinori %A Onland-Moret, N Charlotte %A Ovbiagele, Bruce %A Peters, Annette %A Psaty, Bruce M %A Rich, Stephen S %A Rosand, Jonathan %A Sabatine, Marc S %A Sacco, Ralph L %A Saleheen, Danish %A Sandset, Else Charlotte %A Salomaa, Veikko %A Sargurupremraj, Muralidharan %A Sasaki, Makoto %A Satizabal, Claudia L %A Schmidt, Carsten O %A Shimizu, Atsushi %A Smith, Nicholas L %A Sloane, Kelly L %A Sutoh, Yoichi %A Sun, Yan V %A Tanno, Kozo %A Tiedt, Steffen %A Tatlisumak, Turgut %A Torres-Aguila, Nuria P %A Tiwari, Hemant K %A Trégouët, David-Alexandre %A Trompet, Stella %A Tuladhar, Anil Man %A Tybjærg-Hansen, Anne %A van Vugt, Marion %A Vibo, Riina %A Verma, Shefali S %A Wiggins, Kerri L %A Wennberg, Patrik %A Woo, Daniel %A Wilson, Peter W F %A Xu, Huichun %A Yang, Qiong %A Yoon, Kyungheon %A Millwood, Iona Y %A Gieger, Christian %A Ninomiya, Toshiharu %A Grabe, Hans J %A Jukema, J Wouter %A Rissanen, Ina L %A Strbian, Daniel %A Kim, Young Jin %A Chen, Pei-Hsin %A Mayerhofer, Ernst %A Howson, Joanna M M %A Irvin, Marguerite R %A Adams, Hieab %A Wassertheil-Smoller, Sylvia %A Christensen, Kaare %A Ikram, Mohammad A %A Rundek, Tatjana %A Worrall, Bradford B %A Lathrop, G Mark %A Riaz, Moeen %A Simonsick, Eleanor M %A Kõrv, Janika %A França, Paulo H C %A Zand, Ramin %A Prasad, Kameshwar %A Frikke-Schmidt, Ruth %A de Leeuw, Frank-Erik %A Liman, Thomas %A Haeusler, Karl Georg %A Ruigrok, Ynte M %A Heuschmann, Peter Ulrich %A Longstreth, W T %A Jung, Keum Ji %A Bastarache, Lisa %A Paré, Guillaume %A Damrauer, Scott M %A Chasman, Daniel I %A Rotter, Jerome I %A Anderson, Christopher D %A Zwart, John-Anker %A Niiranen, Teemu J %A Fornage, Myriam %A Liaw, Yung-Po %A Seshadri, Sudha %A Fernandez-Cadenas, Israel %A Walters, Robin G %A Ruff, Christian T %A Owolabi, Mayowa O %A Huffman, Jennifer E %A Milani, Lili %A Kamatani, Yoichiro %A Dichgans, Martin %A Debette, Stephanie %X

Previous 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.

%B Nature %8 2022 Sep 30 %G eng %R 10.1038/s41586-022-05165-3 %0 Journal Article %J medRxiv %D 2023 %T Complexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics. %A Sargurupremraj, Muralidharan %A Soumaré, Aïcha %A Bis, Joshua C %A Surakka, Ida %A Jürgenson, Tuuli %A Joly, Pierre %A Knol, Maria J %A Wang, Ruiqi %A Yang, Qiong %A Satizabal, Claudia L %A Gudjonsson, Alexander %A Mishra, Aniket %A Bouteloup, Vincent %A Phuah, Chia-Ling %A van Duijn, Cornelia M %A Cruchaga, Carlos %A Dufouil, Carole %A Chene, Geneviève %A Lopez, Oscar %A Psaty, Bruce M %A Tzourio, Christophe %A Amouyel, Philippe %A Adams, Hieab H %A Jacqmin-Gadda, Hélène %A Ikram, Mohammad Arfan %A Gudnason, Vilmundur %A Milani, Lili %A Winsvold, Bendik S %A Hveem, Kristian %A Matthews, Paul M %A Longstreth, W T %A Seshadri, Sudha %A Launer, Lenore J %A Debette, Stephanie %X

IMPORTANCE: 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.

%B medRxiv %8 2023 Aug 13 %G eng %R 10.1101/2023.08.08.23293761 %0 Journal Article %J Alzheimers Res Ther %D 2024 %T Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance. %A Mei, Hao %A Simino, Jeannette %A Li, Lianna %A Jiang, Fan %A Bis, Joshua C %A Davies, Gail %A Hill, W David %A Xia, Charley %A Gudnason, Vilmundur %A Yang, Qiong %A Lahti, Jari %A Smith, Jennifer A %A Kirin, Mirna %A De Jager, Philip %A Armstrong, Nicola J %A Ghanbari, Mohsen %A Kolcic, Ivana %A Moran, Christopher %A Teumer, Alexander %A Sargurupremraj, Murali %A Mahmud, Shamsed %A Fornage, Myriam %A Zhao, Wei %A Satizabal, Claudia L %A Polasek, Ozren %A Räikkönen, Katri %A Liewald, David C %A Homuth, Georg %A Callisaya, Michele %A Mather, Karen A %A Windham, B Gwen %A Zemunik, Tatijana %A Palotie, Aarno %A Pattie, Alison %A van der Auwera, Sandra %A Thalamuthu, Anbupalam %A Knopman, David S %A Rudan, Igor %A Starr, John M %A Wittfeld, Katharina %A Kochan, Nicole A %A Griswold, Michael E %A Vitart, Veronique %A Brodaty, Henry %A Gottesman, Rebecca %A Cox, Simon R %A Psaty, Bruce M %A Boerwinkle, Eric %A Chasman, Daniel I %A Grodstein, Francine %A Sachdev, Perminder S %A Srikanth, Velandai %A Hayward, Caroline %A Wilson, James F %A Eriksson, Johan G %A Kardia, Sharon L R %A Grabe, Hans J %A Bennett, David A %A Ikram, M Arfan %A Deary, Ian J %A van Duijn, Cornelia M %A Launer, Lenore %A Fitzpatrick, Annette L %A Seshadri, Sudha %A Bressler, Jan %A Debette, Stephanie %A Mosley, Thomas H %K Aged %K Cognition %K Genome-Wide Association Study %K Humans %K Memory %K MicroRNAs %K Multiomics %K Polymorphism, Single Nucleotide %X

BACKGROUND: 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.

%B Alzheimers Res Ther %V 16 %P 14 %8 2024 Jan 20 %G eng %N 1 %R 10.1186/s13195-023-01376-6