TY - JOUR T1 - Genomewide association studies of stroke. JF - N Engl J Med Y1 - 2009 A1 - Ikram, M Arfan A1 - Seshadri, Sudha A1 - Bis, Joshua C A1 - Fornage, Myriam A1 - DeStefano, Anita L A1 - Aulchenko, Yurii S A1 - Debette, Stephanie A1 - Lumley, Thomas A1 - Folsom, Aaron R A1 - van den Herik, Evita G A1 - Bos, Michiel J A1 - Beiser, Alexa A1 - Cushman, Mary A1 - Launer, Lenore J A1 - Shahar, Eyal A1 - Struchalin, Maksim A1 - Du, Yangchun A1 - Glazer, Nicole L A1 - Rosamond, Wayne D A1 - Rivadeneira, Fernando A1 - Kelly-Hayes, Margaret A1 - Lopez, Oscar L A1 - Coresh, Josef A1 - Hofman, Albert A1 - DeCarli, Charles A1 - Heckbert, Susan R A1 - Koudstaal, Peter J A1 - Yang, Qiong A1 - Smith, Nicholas L A1 - Kase, Carlos S A1 - Rice, Kenneth A1 - Haritunians, Talin A1 - Roks, Gerwin A1 - de Kort, Paul L M A1 - Taylor, Kent D A1 - de Lau, Lonneke M A1 - Oostra, Ben A A1 - Uitterlinden, André G A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Mosley, Thomas H A1 - van Duijn, Cornelia M A1 - Breteler, Monique M B A1 - Longstreth, W T A1 - Wolf, Philip A KW - African Continental Ancestry Group KW - Aged KW - Chromosomes, Human, Pair 12 KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Markers KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - Risk Factors KW - Stroke AB -

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.

VL - 360 IS - 17 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19369658?dopt=Abstract ER - TY - JOUR T1 - Genome-wide analysis of genetic loci associated with Alzheimer disease. JF - JAMA Y1 - 2010 A1 - Seshadri, Sudha A1 - Fitzpatrick, Annette L A1 - Ikram, M Arfan A1 - DeStefano, Anita L A1 - Gudnason, Vilmundur A1 - Boada, Merce A1 - Bis, Joshua C A1 - Smith, Albert V A1 - Carassquillo, Minerva M A1 - Lambert, Jean Charles A1 - Harold, Denise A1 - Schrijvers, Elisabeth M C A1 - Ramirez-Lorca, Reposo A1 - Debette, Stephanie A1 - Longstreth, W T A1 - Janssens, A Cecile J W A1 - Pankratz, V Shane A1 - Dartigues, Jean François A1 - Hollingworth, Paul A1 - Aspelund, Thor A1 - Hernandez, Isabel A1 - Beiser, Alexa A1 - Kuller, Lewis H A1 - Koudstaal, Peter J A1 - Dickson, Dennis W A1 - Tzourio, Christophe A1 - Abraham, Richard A1 - Antunez, Carmen A1 - Du, Yangchun A1 - Rotter, Jerome I A1 - Aulchenko, Yurii S A1 - Harris, Tamara B A1 - Petersen, Ronald C A1 - Berr, Claudine A1 - Owen, Michael J A1 - Lopez-Arrieta, Jesus A1 - Varadarajan, Badri N A1 - Becker, James T A1 - Rivadeneira, Fernando A1 - Nalls, Michael A A1 - Graff-Radford, Neill R A1 - Campion, Dominique A1 - Auerbach, Sanford A1 - Rice, Kenneth A1 - Hofman, Albert A1 - Jonsson, Palmi V A1 - Schmidt, Helena A1 - Lathrop, Mark A1 - Mosley, Thomas H A1 - Au, Rhoda A1 - Psaty, Bruce M A1 - Uitterlinden, André G A1 - Farrer, Lindsay A A1 - Lumley, Thomas A1 - Ruiz, Agustin A1 - Williams, Julie A1 - Amouyel, Philippe A1 - Younkin, Steve G A1 - Wolf, Philip A A1 - Launer, Lenore J A1 - Lopez, Oscar L A1 - van Duijn, Cornelia M A1 - Breteler, Monique M B KW - Age of Onset KW - Aged KW - Alzheimer Disease KW - Case-Control Studies KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Odds Ratio KW - Polymorphism, Single Nucleotide AB -

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.

VL - 303 IS - 18 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20460622?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium. JF - Stroke Y1 - 2010 A1 - Debette, Stephanie A1 - Bis, Joshua C A1 - Fornage, Myriam A1 - Schmidt, Helena A1 - Ikram, M Arfan A1 - Sigurdsson, Sigurdur A1 - Heiss, Gerardo A1 - Struchalin, Maksim A1 - Smith, Albert V A1 - van der Lugt, Aad A1 - DeCarli, Charles A1 - Lumley, Thomas A1 - Knopman, David S A1 - Enzinger, Christian A1 - Eiriksdottir, Gudny A1 - Koudstaal, Peter J A1 - DeStefano, Anita L A1 - Psaty, Bruce M A1 - Dufouil, Carole A1 - Catellier, Diane J A1 - Fazekas, Franz A1 - Aspelund, Thor A1 - Aulchenko, Yurii S A1 - Beiser, Alexa A1 - Rotter, Jerome I A1 - Tzourio, Christophe A1 - Shibata, Dean K A1 - Tscherner, Maria A1 - Harris, Tamara B A1 - Rivadeneira, Fernando A1 - Atwood, Larry D A1 - Rice, Kenneth A1 - Gottesman, Rebecca F A1 - van Buchem, Mark A A1 - Uitterlinden, André G A1 - Kelly-Hayes, Margaret A1 - Cushman, Mary A1 - Zhu, Yicheng A1 - Boerwinkle, Eric A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Romero, Jose R A1 - Lopez, Oscar A1 - van Duijn, Cornelia M A1 - Au, Rhoda A1 - Heckbert, Susan R A1 - Wolf, Philip A A1 - Mosley, Thomas H A1 - Seshadri, Sudha A1 - Breteler, Monique M B A1 - Schmidt, Reinhold A1 - Launer, Lenore J A1 - Longstreth, W T KW - African Americans KW - Aged KW - Brain KW - Brain Infarction KW - Cohort Studies KW - DNA Mutational Analysis KW - Female KW - Gene Frequency KW - Genetic Markers KW - Genetic Predisposition to Disease KW - Genetic Testing KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Magnetic Resonance Imaging KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Prospective Studies AB -

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.

VL - 41 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20044523?dopt=Abstract ER - TY - JOUR T1 - A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. JF - J Gerontol A Biol Sci Med Sci Y1 - 2010 A1 - Newman, Anne B A1 - Walter, Stefan A1 - Lunetta, Kathryn L A1 - Garcia, Melissa E A1 - Slagboom, P Eline A1 - Christensen, Kaare A1 - Arnold, Alice M A1 - Aspelund, Thor A1 - Aulchenko, Yurii S A1 - Benjamin, Emelia J A1 - Christiansen, Lene A1 - D'Agostino, Ralph B A1 - Fitzpatrick, Annette L A1 - Franceschini, Nora A1 - Glazer, Nicole L A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Kaplan, Robert A1 - Karasik, David A1 - Kelly-Hayes, Margaret A1 - Kiel, Douglas P A1 - Launer, Lenore J A1 - Marciante, Kristin D A1 - Massaro, Joseph M A1 - Miljkovic, Iva A1 - Nalls, Michael A A1 - Hernandez, Dena A1 - Psaty, Bruce M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome A1 - Seshadri, Sudha A1 - Smith, Albert V A1 - Taylor, Kent D A1 - Tiemeier, Henning A1 - Uh, Hae-Won A1 - Uitterlinden, André G A1 - Vaupel, James W A1 - Walston, Jeremy A1 - Westendorp, Rudi G J A1 - Harris, Tamara B A1 - Lumley, Thomas A1 - van Duijn, Cornelia M A1 - Murabito, Joanne M KW - Adult KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Alleles KW - Cohort Studies KW - Confidence Intervals KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Longevity KW - Male KW - Middle Aged KW - Odds Ratio KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: Genome-wide association studies (GWAS) may yield insights into longevity.

METHODS: We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Longevity was defined as survival to age 90 years or older (n = 1,836); the comparison group comprised cohort members who died between the ages of 55 and 80 years (n = 1,955). In a second discovery stage, additional genotyping was conducted in the Leiden Longevity Study cohort and the Danish 1905 cohort.

RESULTS: There were 273 single-nucleotide polymorphism (SNP) associations with p < .0001, but none reached the prespecified significance level of 5 x 10(-8). Of the most significant SNPs, 24 were independent signals, and 16 of these SNPs were successfully genotyped in the second discovery stage, with one association for rs9664222, reaching 6.77 x 10(-7) for the combined meta-analysis of CHARGE and the stage 2 cohorts. The SNP lies in a region near MINPP1 (chromosome 10), a well-conserved gene involved in regulation of cellular proliferation. The minor allele was associated with lower odds of survival past age 90 (odds ratio = 0.82). Associations of interest in a homologue of the longevity assurance gene (LASS3) and PAPPA2 were not strengthened in the second stage.

CONCLUSION: Survival studies of larger size or more extreme or specific phenotypes may support or refine these initial findings.

VL - 65 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20304771?dopt=Abstract ER - TY - JOUR T1 - Association of HSP70 and its co-chaperones with Alzheimer's disease. JF - J Alzheimers Dis Y1 - 2011 A1 - Broer, Linda A1 - Ikram, Mohammad Arfan A1 - Schuur, Maaike A1 - DeStefano, Anita L A1 - Bis, Joshua C A1 - Liu, Fan A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Beiser, Alexa S A1 - Longstreth, William T A1 - Hofman, Albert A1 - Aulchenko, Yurii A1 - Seshadri, Sudha A1 - Fitzpatrick, Annette L A1 - Oostra, Ben A A1 - Breteler, Monique M B A1 - van Duijn, Cornelia M KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Cohort Studies KW - Genetic Association Studies KW - Genetic Variation KW - HSP70 Heat-Shock Proteins KW - Humans KW - Middle Aged KW - Molecular Chaperones KW - Polymorphism, Single Nucleotide AB -

The heat shock protein (HSP) 70 family has been implicated in the pathology of Alzheimer's disease (AD). In this study, we examined common genetic variations in the 80 genes encoding HSP70 and its co-chaperones. We conducted a study in a series of 462 patients and 5238 unaffected participants derived from the Rotterdam Study, a population-based study including 7983 persons aged 55 years and older. We genotyped a total of 12,053 Single Nucleotide Polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. Replication was performed in two independent cohort studies, the Framingham Heart study (FHS; n = 806) and Cardiovascular Health Study (CHS; n = 2150). When adjusting for multiple testing, we found a small but consistent, though not significant effect of rs12118313 located 32 kb from PFDN2, with an OR of 1.19 (p-value from meta-analysis = 0.003). However this SNP was in the intron of another gene, suggesting it is unlikely this SNP reflects the effect of PFDN2. In a formal pathway analysis we found nominally significant evidence for an association of BAG, DNAJA and prefoldin with AD. These findings corroborate with those of a study of 2032 AD patients and 5328 controls, in which several members of the prefoldin family showed evidence for association to AD. Our study did not reveal evidence for a genetic variant if the HSP70 family with a major effect on AD. However, our findings of the single SNP analysis and pathway analysis suggest that multiple genetic variants in prefoldin are associated with AD.

VL - 25 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21403392?dopt=Abstract ER - TY - JOUR T1 - Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. JF - Nature Y1 - 2011 A1 - Ehret, Georg B A1 - Munroe, Patricia B A1 - Rice, Kenneth M A1 - Bochud, Murielle A1 - Johnson, Andrew D A1 - Chasman, Daniel I A1 - Smith, Albert V A1 - Tobin, Martin D A1 - Verwoert, Germaine C A1 - Hwang, Shih-Jen A1 - Pihur, Vasyl A1 - Vollenweider, Peter A1 - O'Reilly, Paul F A1 - Amin, Najaf A1 - Bragg-Gresham, Jennifer L A1 - Teumer, Alexander A1 - Glazer, Nicole L A1 - Launer, Lenore A1 - Zhao, Jing Hua A1 - Aulchenko, Yurii A1 - Heath, Simon A1 - Sõber, Siim A1 - Parsa, Afshin A1 - Luan, Jian'an A1 - Arora, Pankaj A1 - Dehghan, Abbas A1 - Zhang, Feng A1 - Lucas, Gavin A1 - Hicks, Andrew A A1 - Jackson, Anne U A1 - Peden, John F A1 - Tanaka, Toshiko A1 - Wild, Sarah H A1 - Rudan, Igor A1 - Igl, Wilmar A1 - Milaneschi, Yuri A1 - Parker, Alex N A1 - Fava, Cristiano A1 - Chambers, John C A1 - Fox, Ervin R A1 - Kumari, Meena A1 - Go, Min Jin A1 - van der Harst, Pim A1 - Kao, Wen Hong Linda A1 - Sjögren, Marketa A1 - Vinay, D G A1 - Alexander, Myriam A1 - Tabara, Yasuharu A1 - Shaw-Hawkins, Sue A1 - Whincup, Peter H A1 - Liu, Yongmei A1 - Shi, Gang A1 - Kuusisto, Johanna A1 - Tayo, Bamidele A1 - Seielstad, Mark A1 - Sim, Xueling A1 - Nguyen, Khanh-Dung Hoang A1 - Lehtimäki, Terho A1 - Matullo, Giuseppe A1 - Wu, Ying A1 - Gaunt, Tom R A1 - Onland-Moret, N Charlotte A1 - Cooper, Matthew N A1 - Platou, Carl G P A1 - Org, Elin A1 - Hardy, Rebecca A1 - Dahgam, Santosh A1 - Palmen, Jutta A1 - Vitart, Veronique A1 - Braund, Peter S A1 - Kuznetsova, Tatiana A1 - Uiterwaal, Cuno S P M A1 - Adeyemo, Adebowale A1 - Palmas, Walter A1 - Campbell, Harry A1 - Ludwig, Barbara A1 - Tomaszewski, Maciej A1 - Tzoulaki, Ioanna A1 - Palmer, Nicholette D A1 - Aspelund, Thor A1 - Garcia, Melissa A1 - Chang, Yen-Pei C A1 - O'Connell, Jeffrey R A1 - Steinle, Nanette I A1 - Grobbee, Diederick E A1 - Arking, Dan E A1 - Kardia, Sharon L A1 - Morrison, Alanna C A1 - Hernandez, Dena A1 - Najjar, Samer A1 - McArdle, Wendy L A1 - Hadley, David A1 - Brown, Morris J A1 - Connell, John M A1 - Hingorani, Aroon D A1 - Day, Ian N M A1 - Lawlor, Debbie A A1 - Beilby, John P A1 - Lawrence, Robert W A1 - Clarke, Robert A1 - Hopewell, Jemma C A1 - Ongen, Halit A1 - Dreisbach, Albert W A1 - Li, Yali A1 - Young, J Hunter A1 - Bis, Joshua C A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Adair, Linda S A1 - Lee, Nanette R A1 - Chen, Ming-Huei A1 - Olden, Matthias A1 - Pattaro, Cristian A1 - Bolton, Judith A Hoffman A1 - Köttgen, Anna A1 - Bergmann, Sven A1 - Mooser, Vincent A1 - Chaturvedi, Nish A1 - Frayling, Timothy M A1 - Islam, Muhammad A1 - Jafar, Tazeen H A1 - Erdmann, Jeanette A1 - Kulkarni, Smita R A1 - Bornstein, Stefan R A1 - Grässler, Jürgen A1 - Groop, Leif A1 - Voight, Benjamin F A1 - Kettunen, Johannes A1 - Howard, Philip A1 - Taylor, Andrew A1 - Guarrera, Simonetta A1 - Ricceri, Fulvio A1 - Emilsson, Valur A1 - Plump, Andrew A1 - Barroso, Inês A1 - Khaw, Kay-Tee A1 - Weder, Alan B A1 - Hunt, Steven C A1 - Sun, Yan V A1 - Bergman, Richard N A1 - Collins, Francis S A1 - Bonnycastle, Lori L A1 - Scott, Laura J A1 - Stringham, Heather M A1 - Peltonen, Leena A1 - Perola, Markus A1 - Vartiainen, Erkki A1 - Brand, Stefan-Martin A1 - Staessen, Jan A A1 - Wang, Thomas J A1 - Burton, Paul R A1 - Soler Artigas, Maria A1 - Dong, Yanbin A1 - Snieder, Harold A1 - Wang, Xiaoling A1 - Zhu, Haidong A1 - Lohman, Kurt K A1 - Rudock, Megan E A1 - Heckbert, Susan R A1 - Smith, Nicholas L A1 - Wiggins, Kerri L A1 - Doumatey, Ayo A1 - Shriner, Daniel A1 - Veldre, Gudrun A1 - Viigimaa, Margus A1 - Kinra, Sanjay A1 - Prabhakaran, Dorairaj A1 - Tripathy, Vikal A1 - Langefeld, Carl D A1 - Rosengren, Annika A1 - Thelle, Dag S A1 - Corsi, Anna Maria A1 - Singleton, Andrew A1 - Forrester, Terrence A1 - Hilton, Gina A1 - McKenzie, Colin A A1 - Salako, Tunde A1 - Iwai, Naoharu A1 - Kita, Yoshikuni A1 - Ogihara, Toshio A1 - Ohkubo, Takayoshi A1 - Okamura, Tomonori A1 - Ueshima, Hirotsugu A1 - Umemura, Satoshi A1 - Eyheramendy, Susana A1 - Meitinger, Thomas A1 - Wichmann, H-Erich A1 - Cho, Yoon Shin A1 - Kim, Hyung-Lae A1 - Lee, Jong-Young A1 - Scott, James A1 - Sehmi, Joban S A1 - Zhang, Weihua A1 - Hedblad, Bo A1 - Nilsson, Peter A1 - Smith, George Davey A1 - Wong, Andrew A1 - Narisu, Narisu A1 - Stančáková, Alena A1 - Raffel, Leslie J A1 - Yao, Jie A1 - Kathiresan, Sekar A1 - O'Donnell, Christopher J A1 - Schwartz, Stephen M A1 - Ikram, M Arfan A1 - Longstreth, W T A1 - Mosley, Thomas H A1 - Seshadri, Sudha A1 - Shrine, Nick R G A1 - Wain, Louise V A1 - Morken, Mario A A1 - Swift, Amy J A1 - Laitinen, Jaana A1 - Prokopenko, Inga A1 - Zitting, Paavo A1 - Cooper, Jackie A A1 - Humphries, Steve E A1 - Danesh, John A1 - Rasheed, Asif A1 - Goel, Anuj A1 - Hamsten, Anders A1 - Watkins, Hugh A1 - Bakker, Stephan J L A1 - van Gilst, Wiek H A1 - Janipalli, Charles S A1 - Mani, K Radha A1 - Yajnik, Chittaranjan S A1 - Hofman, Albert A1 - Mattace-Raso, Francesco U S A1 - Oostra, Ben A A1 - Demirkan, Ayse A1 - Isaacs, Aaron A1 - Rivadeneira, Fernando A1 - Lakatta, Edward G A1 - Orrù, Marco A1 - Scuteri, Angelo A1 - Ala-Korpela, Mika A1 - Kangas, Antti J A1 - Lyytikäinen, Leo-Pekka A1 - Soininen, Pasi A1 - Tukiainen, Taru A1 - Würtz, Peter A1 - Ong, Rick Twee-Hee A1 - Dörr, Marcus A1 - Kroemer, Heyo K A1 - Völker, Uwe A1 - Völzke, Henry A1 - Galan, Pilar A1 - Hercberg, Serge A1 - Lathrop, Mark A1 - Zelenika, Diana A1 - Deloukas, Panos A1 - Mangino, Massimo A1 - Spector, Tim D A1 - Zhai, Guangju A1 - Meschia, James F A1 - Nalls, Michael A A1 - Sharma, Pankaj A1 - Terzic, Janos A1 - Kumar, M V Kranthi A1 - Denniff, Matthew A1 - Zukowska-Szczechowska, Ewa A1 - Wagenknecht, Lynne E A1 - Fowkes, F Gerald R A1 - Charchar, Fadi J A1 - Schwarz, Peter E H A1 - Hayward, Caroline A1 - Guo, Xiuqing A1 - Rotimi, Charles A1 - Bots, Michiel L A1 - Brand, Eva A1 - Samani, Nilesh J A1 - Polasek, Ozren A1 - Talmud, Philippa J A1 - Nyberg, Fredrik A1 - Kuh, Diana A1 - Laan, Maris A1 - Hveem, Kristian A1 - Palmer, Lyle J A1 - van der Schouw, Yvonne T A1 - Casas, Juan P A1 - Mohlke, Karen L A1 - Vineis, Paolo A1 - Raitakari, Olli A1 - Ganesh, Santhi K A1 - Wong, Tien Y A1 - Tai, E Shyong A1 - Cooper, Richard S A1 - Laakso, Markku A1 - Rao, Dabeeru C A1 - Harris, Tamara B A1 - Morris, Richard W A1 - Dominiczak, Anna F A1 - Kivimaki, Mika A1 - Marmot, Michael G A1 - Miki, Tetsuro A1 - Saleheen, Danish A1 - Chandak, Giriraj R A1 - Coresh, Josef A1 - Navis, Gerjan A1 - Salomaa, Veikko A1 - Han, Bok-Ghee A1 - Zhu, Xiaofeng A1 - Kooner, Jaspal S A1 - Melander, Olle A1 - Ridker, Paul M A1 - Bandinelli, Stefania A1 - Gyllensten, Ulf B A1 - Wright, Alan F A1 - Wilson, James F A1 - Ferrucci, Luigi A1 - Farrall, Martin A1 - Tuomilehto, Jaakko A1 - Pramstaller, Peter P A1 - Elosua, Roberto A1 - Soranzo, Nicole A1 - Sijbrands, Eric J G A1 - Altshuler, David A1 - Loos, Ruth J F A1 - Shuldiner, Alan R A1 - Gieger, Christian A1 - Meneton, Pierre A1 - Uitterlinden, André G A1 - Wareham, Nicholas J A1 - Gudnason, Vilmundur A1 - Rotter, Jerome I A1 - Rettig, Rainer A1 - Uda, Manuela A1 - Strachan, David P A1 - Witteman, Jacqueline C M A1 - Hartikainen, Anna-Liisa A1 - Beckmann, Jacques S A1 - Boerwinkle, Eric A1 - Vasan, Ramachandran S A1 - Boehnke, Michael A1 - Larson, Martin G A1 - Jarvelin, Marjo-Riitta A1 - Psaty, Bruce M A1 - Abecasis, Goncalo R A1 - Chakravarti, Aravinda A1 - Elliott, Paul A1 - van Duijn, Cornelia M A1 - Newton-Cheh, Christopher A1 - Levy, Daniel A1 - Caulfield, Mark J A1 - Johnson, Toby KW - Africa KW - Asia KW - Blood Pressure KW - Cardiovascular Diseases KW - Coronary Artery Disease KW - Europe KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Kidney Diseases KW - Polymorphism, Single Nucleotide KW - Stroke AB -

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

VL - 478 IS - 7367 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21909115?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium. JF - Ann Neurol Y1 - 2011 A1 - Fornage, Myriam A1 - Debette, Stephanie A1 - Bis, Joshua C A1 - Schmidt, Helena A1 - Ikram, M Arfan A1 - Dufouil, Carole A1 - Sigurdsson, Sigurdur A1 - Lumley, Thomas A1 - DeStefano, Anita L A1 - Fazekas, Franz A1 - Vrooman, Henri A A1 - Shibata, Dean K A1 - Maillard, Pauline A1 - Zijdenbos, Alex A1 - Smith, Albert V A1 - Gudnason, Haukur A1 - de Boer, Renske A1 - Cushman, Mary A1 - Mazoyer, Bernard A1 - Heiss, Gerardo A1 - Vernooij, Meike W A1 - Enzinger, Christian A1 - Glazer, Nicole L A1 - Beiser, Alexa A1 - Knopman, David S A1 - Cavalieri, Margherita A1 - Niessen, Wiro J A1 - Harris, Tamara B A1 - Petrovic, Katja A1 - Lopez, Oscar L A1 - Au, Rhoda A1 - Lambert, Jean-Charles A1 - Hofman, Albert A1 - Gottesman, Rebecca F A1 - Garcia, Melissa A1 - Heckbert, Susan R A1 - Atwood, Larry D A1 - Catellier, Diane J A1 - Uitterlinden, André G A1 - Yang, Qiong A1 - Smith, Nicholas L A1 - Aspelund, Thor A1 - Romero, Jose R A1 - Rice, Kenneth A1 - Taylor, Kent D A1 - Nalls, Michael A A1 - Rotter, Jerome I A1 - Sharrett, Richey A1 - van Duijn, Cornelia M A1 - Amouyel, Philippe A1 - Wolf, Philip A A1 - Gudnason, Vilmundur A1 - van der Lugt, Aad A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Seshadri, Sudha A1 - Tzourio, Christophe A1 - Breteler, Monique M B A1 - Mosley, Thomas H A1 - Schmidt, Reinhold A1 - Longstreth, W T A1 - DeCarli, Charles A1 - Launer, Lenore J KW - Aged KW - Aged, 80 and over KW - Cerebral Cortex KW - Chromosomes, Human, Pair 17 KW - Cognition Disorders KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Leukoencephalopathies KW - Magnetic Resonance Imaging KW - Male KW - Middle Aged KW - Movement Disorders KW - Nerve Fibers, Myelinated KW - Polymorphism, Single Nucleotide KW - Residence Characteristics KW - RNA, Messenger AB -

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.

VL - 69 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21681796?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study of aging. JF - Neurobiol Aging Y1 - 2011 A1 - Walter, Stefan A1 - Atzmon, Gil A1 - Demerath, Ellen W A1 - Garcia, Melissa E A1 - Kaplan, Robert C A1 - Kumari, Meena A1 - Lunetta, Kathryn L A1 - Milaneschi, Yuri A1 - Tanaka, Toshiko A1 - Tranah, Gregory J A1 - Völker, Uwe A1 - Yu, Lei A1 - Arnold, Alice A1 - Benjamin, Emelia J A1 - Biffar, Reiner A1 - Buchman, Aron S A1 - Boerwinkle, Eric A1 - Couper, David A1 - De Jager, Philip L A1 - Evans, Denis A A1 - Harris, Tamara B A1 - Hoffmann, Wolfgang A1 - Hofman, Albert A1 - Karasik, David A1 - Kiel, Douglas P A1 - Kocher, Thomas A1 - Kuningas, Maris A1 - Launer, Lenore J A1 - Lohman, Kurt K A1 - Lutsey, Pamela L A1 - Mackenbach, Johan A1 - Marciante, Kristin A1 - Psaty, Bruce M A1 - Reiman, Eric M A1 - Rotter, Jerome I A1 - Seshadri, Sudha A1 - Shardell, Michelle D A1 - Smith, Albert V A1 - van Duijn, Cornelia A1 - Walston, Jeremy A1 - Zillikens, M Carola A1 - Bandinelli, Stefania A1 - Baumeister, Sebastian E A1 - Bennett, David A A1 - Ferrucci, Luigi A1 - Gudnason, Vilmundur A1 - Kivimaki, Mika A1 - Liu, Yongmei A1 - Murabito, Joanne M A1 - Newman, Anne B A1 - Tiemeier, Henning A1 - Franceschini, Nora KW - Aging KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Longevity AB -

Human longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10(-8)). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10(-5)). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.

VL - 32 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21782286?dopt=Abstract ER - TY - JOUR T1 - Large-scale candidate gene analysis in whites and African Americans identifies IL6R polymorphism in relation to atrial fibrillation: the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe) project. JF - Circ Cardiovasc Genet Y1 - 2011 A1 - Schnabel, Renate B A1 - Kerr, Kathleen F A1 - Lubitz, Steven A A1 - Alkylbekova, Ermeg L A1 - Marcus, Gregory M A1 - Sinner, Moritz F A1 - Magnani, Jared W A1 - Wolf, Philip A A1 - Deo, Rajat A1 - Lloyd-Jones, Donald M A1 - Lunetta, Kathryn L A1 - Mehra, Reena A1 - Levy, Daniel A1 - Fox, Ervin R A1 - Arking, Dan E A1 - Mosley, Thomas H A1 - Müller-Nurasyid, Martina A1 - Young, Taylor R A1 - Wichmann, H-Erich A1 - Seshadri, Sudha A1 - Farlow, Deborah N A1 - Rotter, Jerome I A1 - Soliman, Elsayed Z A1 - Glazer, Nicole L A1 - Wilson, James G A1 - Breteler, Monique M B A1 - Sotoodehnia, Nona A1 - Newton-Cheh, Christopher A1 - Kääb, Stefan A1 - Ellinor, Patrick T A1 - Alonso, Alvaro A1 - Benjamin, Emelia J A1 - Heckbert, Susan R KW - African Americans KW - Aged KW - Alleles KW - Atrial Fibrillation KW - Chromosomes, Human, Pair 4 KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Humans KW - Male KW - Middle Aged KW - National Heart, Lung, and Blood Institute (U.S.) KW - Polymorphism, Single Nucleotide KW - Receptors, Interleukin-6 KW - Risk Factors KW - Stroke KW - United States AB -

BACKGROUND: The genetic background of atrial fibrillation (AF) in whites and African Americans is largely unknown. Genes in cardiovascular pathways have not been systematically investigated.

METHODS AND RESULTS: We examined a panel of approximately 50,000 common single-nucleotide polymorphisms (SNPs) in 2095 cardiovascular candidate genes and AF in 3 cohorts with participants of European (n=18,524; 2260 cases) or African American descent (n=3662; 263 cases) in the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource. Results in whites were followed up in the German Competence Network for AF (n=906, 468 cases). The top result was assessed in relation to incident ischemic stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology Stroke Consortium (n=19,602 whites, 1544 incident strokes). SNP rs4845625 in the IL6R gene was associated with AF (relative risk [RR] C allele, 0.90; 95% confidence interval [CI], 0.85-0.95; P=0.0005) in whites but did not reach statistical significance in African Americans (RR, 0.86; 95% CI, 0.72-1.03; P=0.09). The results were comparable in the German AF Network replication, (RR, 0.71; 95% CI, 0.57-0.89; P=0.003). No association between rs4845625 and stroke was observed in whites. The known chromosome 4 locus near PITX2 in whites also was associated with AF in African Americans (rs4611994; hazard ratio, 1.40; 95% CI, 1.16-1.69; P=0.0005).

CONCLUSIONS: In a community-based cohort meta-analysis, we identified genetic association in IL6R with AF in whites. Additionally, we demonstrated that the chromosome 4 locus known from recent genome-wide association studies in whites is associated with AF in African Americans.

VL - 4 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21846873?dopt=Abstract ER - TY - JOUR T1 - Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies. JF - Lancet Neurol Y1 - 2012 A1 - Traylor, Matthew A1 - Farrall, Martin A1 - Holliday, Elizabeth G A1 - Sudlow, Cathie A1 - Hopewell, Jemma C A1 - Cheng, Yu-Ching A1 - Fornage, Myriam A1 - Ikram, M Arfan A1 - Malik, Rainer A1 - Bevan, Steve A1 - Thorsteinsdottir, Unnur A1 - Nalls, Mike A A1 - Longstreth, Wt A1 - Wiggins, Kerri L A1 - Yadav, Sunaina A1 - Parati, Eugenio A A1 - DeStefano, Anita L A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Khan, Muhammad Saleem A1 - Reiner, Alex P A1 - Helgadottir, Anna A1 - Achterberg, Sefanja A1 - Fernandez-Cadenas, Israel A1 - Abboud, Sherine A1 - Schmidt, Reinhold A1 - Walters, Matthew A1 - Chen, Wei-Min A1 - Ringelstein, E Bernd A1 - O'Donnell, Martin A1 - Ho, Weang Kee A1 - Pera, Joanna A1 - Lemmens, Robin A1 - Norrving, Bo A1 - Higgins, Peter A1 - Benn, Marianne A1 - Sale, Michele A1 - Kuhlenbäumer, Gregor A1 - Doney, Alexander S F A1 - Vicente, Astrid M A1 - Delavaran, Hossein A1 - Algra, Ale A1 - Davies, Gail A1 - Oliveira, Sofia A A1 - Palmer, Colin N A A1 - Deary, Ian A1 - Schmidt, Helena A1 - Pandolfo, Massimo A1 - Montaner, Joan A1 - Carty, Cara A1 - de Bakker, Paul I W A1 - Kostulas, Konstantinos A1 - Ferro, Jose M A1 - van Zuydam, Natalie R A1 - Valdimarsson, Einar A1 - Nordestgaard, Børge G A1 - Lindgren, Arne A1 - Thijs, Vincent A1 - Slowik, Agnieszka A1 - Saleheen, Danish A1 - Paré, Guillaume A1 - Berger, Klaus A1 - Thorleifsson, Gudmar A1 - Hofman, Albert A1 - Mosley, Thomas H A1 - Mitchell, Braxton D A1 - Furie, Karen A1 - Clarke, Robert A1 - Levi, Christopher A1 - Seshadri, Sudha A1 - Gschwendtner, Andreas A1 - Boncoraglio, Giorgio B A1 - Sharma, Pankaj A1 - Bis, Joshua C A1 - Gretarsdottir, Solveig A1 - Psaty, Bruce M A1 - Rothwell, Peter M A1 - Rosand, Jonathan A1 - Meschia, James F A1 - Stefansson, Kari A1 - Dichgans, Martin A1 - Markus, Hugh S KW - Brain Ischemia KW - Databases, Genetic KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Risk Factors KW - Stroke AB -

BACKGROUND: Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.

METHODS: We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.

FINDINGS: We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10(-16)) and ZFHX3 (p=2·28×10(-8)), and for large-vessel stroke at a 9p21 locus (p=3·32×10(-5)) and HDAC9 (p=2·03×10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10(-6). However, we were unable to replicate any of these novel associations in the replication cohort.

INTERPRETATION: Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.

FUNDING: Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).

VL - 11 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23041239?dopt=Abstract ER - TY - JOUR T1 - Ischemic stroke is associated with the ABO locus: the EuroCLOT study. JF - Ann Neurol Y1 - 2013 A1 - Williams, Frances M K A1 - Carter, Angela M A1 - Hysi, Pirro G A1 - Surdulescu, Gabriela A1 - Hodgkiss, Dylan A1 - Soranzo, Nicole A1 - Traylor, Matthew A1 - Bevan, Steve A1 - Dichgans, Martin A1 - Rothwell, Peter M W A1 - Sudlow, Cathie A1 - Farrall, Martin A1 - Silander, Kaisa A1 - Kaunisto, Mari A1 - Wagner, Peter A1 - Saarela, Olli A1 - Kuulasmaa, Kari A1 - Virtamo, Jarmo A1 - Salomaa, Veikko A1 - Amouyel, Philippe A1 - Arveiler, Dominique A1 - Ferrieres, Jean A1 - Wiklund, Per-Gunnar A1 - Ikram, M Arfan A1 - Hofman, Albert A1 - Boncoraglio, Giorgio B A1 - Parati, Eugenio A A1 - Helgadottir, Anna A1 - Gretarsdottir, Solveig A1 - Thorsteinsdottir, Unnur A1 - Thorleifsson, Gudmar A1 - Stefansson, Kari A1 - Seshadri, Sudha A1 - DeStefano, Anita A1 - Gschwendtner, Andreas A1 - Psaty, Bruce A1 - Longstreth, Will A1 - Mitchell, Braxton D A1 - Cheng, Yu-Ching A1 - Clarke, Robert A1 - Ferrario, Marco A1 - Bis, Joshua C A1 - Levi, Christopher A1 - Attia, John A1 - Holliday, Elizabeth G A1 - Scott, Rodney J A1 - Fornage, Myriam A1 - Sharma, Pankaj A1 - Furie, Karen L A1 - Rosand, Jonathan A1 - Nalls, Mike A1 - Meschia, James A1 - Mosely, Thomas H A1 - Evans, Alun A1 - Palotie, Aarno A1 - Markus, Hugh S A1 - Grant, Peter J A1 - Spector, Tim D KW - ABO Blood-Group System KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Blood Coagulation KW - Brain Ischemia KW - Cohort Studies KW - Europe KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Stroke KW - Young Adult AB -

OBJECTIVE: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.

METHODS: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3).

RESULTS: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10(-186)), rs10665 with FVII (p = 2.4 × 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10(-57)) and factor VIII (p = 1.2 × 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811).

INTERPRETATION: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.

VL - 73 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23381943?dopt=Abstract ER - TY - JOUR T1 - Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. JF - Circulation Y1 - 2013 A1 - Sabater-Lleal, Maria A1 - Huang, Jie A1 - Chasman, Daniel A1 - Naitza, Silvia A1 - Dehghan, Abbas A1 - Johnson, Andrew D A1 - Teumer, Alexander A1 - Reiner, Alex P A1 - Folkersen, Lasse A1 - Basu, Saonli A1 - Rudnicka, Alicja R A1 - Trompet, Stella A1 - Mälarstig, Anders A1 - Baumert, Jens A1 - Bis, Joshua C A1 - Guo, Xiuqing A1 - Hottenga, Jouke J A1 - Shin, So-Youn A1 - Lopez, Lorna M A1 - Lahti, Jari A1 - Tanaka, Toshiko A1 - Yanek, Lisa R A1 - Oudot-Mellakh, Tiphaine A1 - Wilson, James F A1 - Navarro, Pau A1 - Huffman, Jennifer E A1 - Zemunik, Tatijana A1 - Redline, Susan A1 - Mehra, Reena A1 - Pulanic, Drazen A1 - Rudan, Igor A1 - Wright, Alan F A1 - Kolcic, Ivana A1 - Polasek, Ozren A1 - Wild, Sarah H A1 - Campbell, Harry A1 - Curb, J David A1 - Wallace, Robert A1 - Liu, Simin A1 - Eaton, Charles B A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Bandinelli, Stefania A1 - Räikkönen, Katri A1 - Widen, Elisabeth A1 - Palotie, Aarno A1 - Fornage, Myriam A1 - Green, David A1 - Gross, Myron A1 - Davies, Gail A1 - Harris, Sarah E A1 - Liewald, David C A1 - Starr, John M A1 - Williams, Frances M K A1 - Grant, Peter J A1 - Spector, Timothy D A1 - Strawbridge, Rona J A1 - Silveira, Angela A1 - Sennblad, Bengt A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Franco, Oscar H A1 - Hofman, Albert A1 - van Dongen, Jenny A1 - Willemsen, Gonneke A1 - Boomsma, Dorret I A1 - Yao, Jie A1 - Swords Jenny, Nancy A1 - Haritunians, Talin A1 - McKnight, Barbara A1 - Lumley, Thomas A1 - Taylor, Kent D A1 - Rotter, Jerome I A1 - Psaty, Bruce M A1 - Peters, Annette A1 - Gieger, Christian A1 - Illig, Thomas A1 - Grotevendt, Anne A1 - Homuth, Georg A1 - Völzke, Henry A1 - Kocher, Thomas A1 - Goel, Anuj A1 - Franzosi, Maria Grazia A1 - Seedorf, Udo A1 - Clarke, Robert A1 - Steri, Maristella A1 - Tarasov, Kirill V A1 - Sanna, Serena A1 - Schlessinger, David A1 - Stott, David J A1 - Sattar, Naveed A1 - Buckley, Brendan M A1 - Rumley, Ann A1 - Lowe, Gordon D A1 - McArdle, Wendy L A1 - Chen, Ming-Huei A1 - Tofler, Geoffrey H A1 - Song, Jaejoon A1 - Boerwinkle, Eric A1 - Folsom, Aaron R A1 - Rose, Lynda M A1 - Franco-Cereceda, Anders A1 - Teichert, Martina A1 - Ikram, M Arfan A1 - Mosley, Thomas H A1 - Bevan, Steve A1 - Dichgans, Martin A1 - Rothwell, Peter M A1 - Sudlow, Cathie L M A1 - Hopewell, Jemma C A1 - Chambers, John C A1 - Saleheen, Danish A1 - Kooner, Jaspal S A1 - Danesh, John A1 - Nelson, Christopher P A1 - Erdmann, Jeanette A1 - Reilly, Muredach P A1 - Kathiresan, Sekar A1 - Schunkert, Heribert A1 - Morange, Pierre-Emmanuel A1 - Ferrucci, Luigi A1 - Eriksson, Johan G A1 - Jacobs, David A1 - Deary, Ian J A1 - Soranzo, Nicole A1 - Witteman, Jacqueline C M A1 - de Geus, Eco J C A1 - Tracy, Russell P A1 - Hayward, Caroline A1 - Koenig, Wolfgang A1 - Cucca, Francesco A1 - Jukema, J Wouter A1 - Eriksson, Per A1 - Seshadri, Sudha A1 - Markus, Hugh S A1 - Watkins, Hugh A1 - Samani, Nilesh J A1 - Wallaschofski, Henri A1 - Smith, Nicholas L A1 - Tregouet, David A1 - Ridker, Paul M A1 - Tang, Weihong A1 - Strachan, David P A1 - Hamsten, Anders A1 - O'Donnell, Christopher J KW - Adolescent KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Coronary Artery Disease KW - European Continental Ancestry Group KW - Female KW - Fibrinogen KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Hispanic Americans KW - Humans KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Stroke KW - Venous Thromboembolism KW - Young Adult AB -

BACKGROUND: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation.

METHODS AND RESULTS: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism.

CONCLUSIONS: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

VL - 128 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23969696?dopt=Abstract ER - TY - JOUR T1 - Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium. JF - PLoS One Y1 - 2014 A1 - Bis, Joshua C A1 - DeStefano, Anita A1 - Liu, Xiaoming A1 - Brody, Jennifer A A1 - Choi, Seung Hoan A1 - Verhaaren, Benjamin F J A1 - Debette, Stephanie A1 - Ikram, M Arfan A1 - Shahar, Eyal A1 - Butler, Kenneth R A1 - Gottesman, Rebecca F A1 - Muzny, Donna A1 - Kovar, Christie L A1 - Psaty, Bruce M A1 - Hofman, Albert A1 - Lumley, Thomas A1 - Gupta, Mayetri A1 - Wolf, Philip A A1 - van Duijn, Cornelia A1 - Gibbs, Richard A A1 - Mosley, Thomas H A1 - Longstreth, W T A1 - Boerwinkle, Eric A1 - Seshadri, Sudha A1 - Fornage, Myriam KW - Cell Adhesion Molecules, Neuronal KW - European Continental Ancestry Group KW - Female KW - Genetic Association Studies KW - Genetic Heterogeneity KW - Humans KW - Introns KW - Ischemia KW - Male KW - Myocardial Infarction KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Sequence Analysis, DNA AB -

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.

VL - 9 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24959832?dopt=Abstract ER - TY - JOUR T1 - Development and validation of a brief dementia screening indicator for primary care. JF - Alzheimers Dement Y1 - 2014 A1 - Barnes, Deborah E A1 - Beiser, Alexa S A1 - Lee, Anne A1 - Langa, Kenneth M A1 - Koyama, Alain A1 - Preis, Sarah R A1 - Neuhaus, John A1 - McCammon, Ryan J A1 - Yaffe, Kristine A1 - Seshadri, Sudha A1 - Haan, Mary N A1 - Weir, David R KW - Aged KW - Cohort Studies KW - Dementia KW - Female KW - Humans KW - Male KW - Mass Screening KW - Predictive Value of Tests KW - Primary Health Care KW - Proportional Hazards Models KW - Risk Assessment AB -

BACKGROUND: Detection of "any cognitive impairment" is mandated as part of the Medicare annual wellness visit, but screening all patients may result in excessive false positives.

METHODS: We developed and validated a brief Dementia Screening Indicator using data from four large, ongoing cohort studies (the Cardiovascular Health Study [CHS]; the Framingham Heart Study [FHS]; the Health and Retirement Study [HRS]; the Sacramento Area Latino Study on Aging [SALSA]) to help clinicians identify a subgroup of high-risk patients to target for cognitive screening.

RESULTS: The final Dementia Screening Indicator included age (1 point/year; ages, 65-79 years), less than 12 years of education (9 points), stroke (6 points), diabetes mellitus (3 points), body mass index less than 18.5 kg/m(2) (8 points), requiring assistance with money or medications (10 points), and depressive symptoms (6 points). Accuracy was good across the cohorts (Harrell's C statistic: CHS, 0.68; FHS, 0.77; HRS, 0.76; SALSA, 0.78).

CONCLUSIONS: The Dementia Screening Indicator is a simple tool that may be useful in primary care settings to identify high-risk patients to target for cognitive screening.

VL - 10 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24491321?dopt=Abstract ER - TY - JOUR T1 - Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease. JF - PLoS One Y1 - 2014 A1 - Escott-Price, Valentina A1 - Bellenguez, Céline A1 - Wang, Li-San A1 - Choi, Seung-Hoan A1 - Harold, Denise A1 - Jones, Lesley A1 - Holmans, Peter A1 - Gerrish, Amy A1 - Vedernikov, Alexey A1 - Richards, Alexander A1 - DeStefano, Anita L A1 - Lambert, Jean-Charles A1 - Ibrahim-Verbaas, Carla A A1 - Naj, Adam C A1 - Sims, Rebecca A1 - Jun, Gyungah A1 - Bis, Joshua C A1 - Beecham, Gary W A1 - Grenier-Boley, Benjamin A1 - Russo, Giancarlo A1 - Thornton-Wells, Tricia A A1 - Denning, Nicola A1 - Smith, Albert V A1 - Chouraki, Vincent A1 - Thomas, Charlene A1 - Ikram, M Arfan A1 - Zelenika, Diana A1 - Vardarajan, Badri N A1 - Kamatani, Yoichiro A1 - Lin, Chiao-Feng A1 - Schmidt, Helena A1 - Kunkle, Brian A1 - Dunstan, Melanie L A1 - Vronskaya, Maria A1 - Johnson, Andrew D A1 - Ruiz, Agustin A1 - Bihoreau, Marie-Thérèse A1 - Reitz, Christiane A1 - Pasquier, Florence A1 - Hollingworth, Paul A1 - Hanon, Olivier A1 - Fitzpatrick, Annette L A1 - Buxbaum, Joseph D A1 - Campion, Dominique A1 - Crane, Paul K A1 - Baldwin, Clinton A1 - Becker, Tim A1 - Gudnason, Vilmundur A1 - Cruchaga, Carlos A1 - Craig, David A1 - Amin, Najaf A1 - Berr, Claudine A1 - Lopez, Oscar L A1 - De Jager, Philip L A1 - Deramecourt, Vincent A1 - Johnston, Janet A A1 - Evans, Denis A1 - Lovestone, Simon A1 - Letenneur, Luc A1 - Hernandez, Isabel A1 - Rubinsztein, David C A1 - Eiriksdottir, Gudny A1 - Sleegers, Kristel A1 - Goate, Alison M A1 - Fiévet, Nathalie A1 - Huentelman, Matthew J A1 - Gill, Michael A1 - Brown, Kristelle A1 - Kamboh, M Ilyas A1 - Keller, Lina A1 - Barberger-Gateau, Pascale A1 - McGuinness, Bernadette A1 - Larson, Eric B A1 - Myers, Amanda J A1 - Dufouil, Carole A1 - Todd, Stephen A1 - Wallon, David A1 - Love, Seth A1 - Rogaeva, Ekaterina A1 - Gallacher, John A1 - George-Hyslop, Peter St A1 - Clarimon, Jordi A1 - Lleo, Alberto A1 - Bayer, Anthony A1 - Tsuang, Debby W A1 - Yu, Lei A1 - Tsolaki, Magda A1 - Bossù, Paola A1 - Spalletta, Gianfranco A1 - Proitsi, Petra A1 - Collinge, John A1 - Sorbi, Sandro A1 - Garcia, Florentino Sanchez A1 - Fox, Nick C A1 - Hardy, John A1 - Naranjo, Maria Candida Deniz A1 - Bosco, Paolo A1 - Clarke, Robert A1 - Brayne, Carol A1 - Galimberti, Daniela A1 - Scarpini, Elio A1 - Bonuccelli, Ubaldo A1 - Mancuso, Michelangelo A1 - Siciliano, Gabriele A1 - Moebus, Susanne A1 - Mecocci, Patrizia A1 - Zompo, Maria Del A1 - Maier, Wolfgang A1 - Hampel, Harald A1 - Pilotto, Alberto A1 - Frank-García, Ana A1 - Panza, Francesco A1 - Solfrizzi, Vincenzo A1 - Caffarra, Paolo A1 - Nacmias, Benedetta A1 - Perry, William A1 - Mayhaus, Manuel A1 - Lannfelt, Lars A1 - Hakonarson, Hakon A1 - Pichler, Sabrina A1 - Carrasquillo, Minerva M A1 - Ingelsson, Martin A1 - Beekly, Duane A1 - Alvarez, Victoria A1 - Zou, Fanggeng A1 - Valladares, Otto A1 - Younkin, Steven G A1 - Coto, Eliecer A1 - Hamilton-Nelson, Kara L A1 - Gu, Wei A1 - Razquin, Cristina A1 - Pastor, Pau A1 - Mateo, Ignacio A1 - Owen, Michael J A1 - Faber, Kelley M A1 - Jonsson, Palmi V A1 - Combarros, Onofre A1 - O'Donovan, Michael C A1 - Cantwell, Laura B A1 - Soininen, Hilkka A1 - Blacker, Deborah A1 - Mead, Simon A1 - Mosley, Thomas H A1 - Bennett, David A A1 - Harris, Tamara B A1 - Fratiglioni, Laura A1 - Holmes, Clive A1 - de Bruijn, Renee F A G A1 - Passmore, Peter A1 - Montine, Thomas J A1 - Bettens, Karolien A1 - Rotter, Jerome I A1 - Brice, Alexis A1 - Morgan, Kevin A1 - Foroud, Tatiana M A1 - Kukull, Walter A A1 - Hannequin, Didier A1 - Powell, John F A1 - Nalls, Michael A A1 - Ritchie, Karen A1 - Lunetta, Kathryn L A1 - Kauwe, John S K A1 - Boerwinkle, Eric A1 - Riemenschneider, Matthias A1 - Boada, Merce A1 - Hiltunen, Mikko A1 - Martin, Eden R A1 - Schmidt, Reinhold A1 - Rujescu, Dan A1 - Dartigues, Jean-François A1 - Mayeux, Richard A1 - Tzourio, Christophe A1 - Hofman, Albert A1 - Nöthen, Markus M A1 - Graff, Caroline A1 - Psaty, Bruce M A1 - Haines, Jonathan L A1 - Lathrop, Mark A1 - Pericak-Vance, Margaret A A1 - Launer, Lenore J A1 - Van Broeckhoven, Christine A1 - Farrer, Lindsay A A1 - van Duijn, Cornelia M A1 - Ramirez, Alfredo A1 - Seshadri, Sudha A1 - Schellenberg, Gerard D A1 - Amouyel, Philippe A1 - Williams, Julie KW - Alzheimer Disease KW - Carrier Proteins KW - Case-Control Studies KW - Genome-Wide Association Study KW - Heat-Shock Proteins KW - Humans KW - Polymorphism, Single Nucleotide KW - Receptors, Antigen, B-Cell AB -

BACKGROUND: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.

PRINCIPAL FINDINGS: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci.

SIGNIFICANCE: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

VL - 9 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24922517?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study of L-arginine and dimethylarginines reveals novel metabolic pathway for symmetric dimethylarginine. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - Lüneburg, Nicole A1 - Lieb, Wolfgang A1 - Zeller, Tanja A1 - Chen, Ming-Huei A1 - Maas, Renke A1 - Carter, Angela M A1 - Xanthakis, Vanessa A1 - Glazer, Nicole L A1 - Schwedhelm, Edzard A1 - Seshadri, Sudha A1 - Ikram, Mohammad Arfan A1 - Longstreth, William T A1 - Fornage, Myriam A1 - König, Inke R A1 - Loley, Christina A1 - Ojeda, Francisco M A1 - Schillert, Arne A1 - Wang, Thomas J A1 - Sticht, Heinrich A1 - Kittel, Anja A1 - König, Jörg A1 - Benjamin, Emelia J A1 - Sullivan, Lisa M A1 - Bernges, Isabel A1 - Anderssohn, Maike A1 - Ziegler, Andreas A1 - Gieger, Christian A1 - Illig, Thomas A1 - Meisinger, Christa A1 - Wichmann, H-Erich A1 - Wild, Philipp S A1 - Schunkert, Heribert A1 - Psaty, Bruce M A1 - Wiggins, Kerri L A1 - Heckbert, Susan R A1 - Smith, Nicholas A1 - Lackner, Karl A1 - Lunetta, Kathryn L A1 - Blankenberg, Stefan A1 - Erdmann, Jeanette A1 - Münzel, Thomas A1 - Grant, Peter J A1 - Vasan, Ramachandran S A1 - Böger, Rainer H KW - Adult KW - Aged KW - Amidohydrolases KW - Arginine KW - Binding Sites KW - Cohort Studies KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - HEK293 Cells KW - Humans KW - Male KW - Mediator Complex KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Protein Structure, Tertiary KW - Risk Factors KW - Stroke KW - Substrate Specificity KW - Transaminases AB -

BACKGROUND: Dimethylarginines (DMA) interfere with nitric oxide formation by inhibiting nitric oxide synthase (asymmetrical DMA [ADMA]) and l-arginine uptake into the cell (ADMA and symmetrical DMA [SDMA]). In prospective clinical studies, ADMA has been characterized as a cardiovascular risk marker, whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterize the environmental and genetic contributions to interindividual variability of these biomarkers.

METHODS AND RESULTS: This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (Framingham Heart Study [FHS; n=2992], Gutenberg Health Study [GHS; n=4354], and Multinational Monitoring of Trends and Determinants in Cardiovascular Disease Study [MONICA]/Cooperative Health Research in the Augsburg Area, Augsburg, Bavaria, Germany [KORA] F3 [n=581]) and identified replicated loci (DDAH1, MED23, Arg1, and AGXT2) associated with the interindividual variability in ADMA, l-arginine, and SDMA. Experimental in silico and in vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants, and various cardiometabolic risk factors. AGXT2 variants were not associated with poststroke survival in the Leeds study or were they associated with incident stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

CONCLUSIONS: These genome-wide association study support the importance of DDAH1 and MED23/Arg1 in regulating ADMA and l-arginine metabolism, respectively, and identify a novel regulatory renal pathway for SDMA by AGXT2. AGXT2 variants might explain part of the pathogenic link between SDMA, renal function, and outcome. An association between AGXT2 variants and stroke is unclear and warrants further investigation.

VL - 7 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25245031?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12. JF - Neurology Y1 - 2014 A1 - Kilarski, Laura L A1 - Achterberg, Sefanja A1 - Devan, William J A1 - Traylor, Matthew A1 - Malik, Rainer A1 - Lindgren, Arne A1 - Pare, Guillame A1 - Sharma, Pankaj A1 - Slowik, Agniesczka A1 - Thijs, Vincent A1 - Walters, Matthew A1 - Worrall, Bradford B A1 - Sale, Michèle M A1 - Algra, Ale A1 - Kappelle, L Jaap A1 - Wijmenga, Cisca A1 - Norrving, Bo A1 - Sandling, Johanna K A1 - Rönnblom, Lars A1 - Goris, An A1 - Franke, Andre A1 - Sudlow, Cathie A1 - Rothwell, Peter M A1 - Levi, Christopher A1 - Holliday, Elizabeth G A1 - Fornage, Myriam A1 - Psaty, Bruce A1 - Gretarsdottir, Solveig A1 - Thorsteinsdottir, Unnar A1 - Seshadri, Sudha A1 - Mitchell, Braxton D A1 - Kittner, Steven A1 - Clarke, Robert A1 - Hopewell, Jemma C A1 - Bis, Joshua C A1 - Boncoraglio, Giorgio B A1 - Meschia, James A1 - Ikram, M Arfan A1 - Hansen, Bjorn M A1 - Montaner, Joan A1 - Thorleifsson, Gudmar A1 - Stefanson, Kari A1 - Rosand, Jonathan A1 - de Bakker, Paul I W A1 - Farrall, Martin A1 - Dichgans, Martin A1 - Markus, Hugh S A1 - Bevan, Steve KW - Brain Ischemia KW - Cerebral Hemorrhage KW - Chromosomes, Human, Pair 12 KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk KW - Stroke AB -

OBJECTIVES: To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases.

METHODS: Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 cases and 5,972 controls recruited from the ischemic stroke WTCCC2 study, and with summary statistics from a further 8,480 cases and 56,032 controls in the METASTROKE consortium. A final in silico "look-up" of 2 single nucleotide polymorphisms in 2,522 cases and 1,899 controls was performed. Associations were also examined in 1,088 cases with intracerebral hemorrhage and 1,102 controls.

RESULTS: In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07-1.13], p = 7.12 × 10(-11)) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90-1.17], p = 0.695).

CONCLUSION: Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage.

VL - 83 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25031287?dopt=Abstract ER - TY - JOUR T1 - Multilocus genetic risk score associates with ischemic stroke in case-control and prospective cohort studies. JF - Stroke Y1 - 2014 A1 - Malik, Rainer A1 - Bevan, Steve A1 - Nalls, Michael A A1 - Holliday, Elizabeth G A1 - Devan, William J A1 - Cheng, Yu-Ching A1 - Ibrahim-Verbaas, Carla A A1 - Verhaaren, Benjamin F J A1 - Bis, Joshua C A1 - Joon, Aron Y A1 - de Stefano, Anita L A1 - Fornage, Myriam A1 - Psaty, Bruce M A1 - Ikram, M Arfan A1 - Launer, Lenore J A1 - van Duijn, Cornelia M A1 - Sharma, Pankaj A1 - Mitchell, Braxton D A1 - Rosand, Jonathan A1 - Meschia, James F A1 - Levi, Christopher A1 - Rothwell, Peter M A1 - Sudlow, Cathie A1 - Markus, Hugh S A1 - Seshadri, Sudha A1 - Dichgans, Martin KW - Adult KW - Aged KW - Aged, 80 and over KW - Atrial Fibrillation KW - Blood Pressure KW - Brain Ischemia KW - Case-Control Studies KW - Cohort Studies KW - Coronary Artery Disease KW - Female KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Multilocus Sequence Typing KW - Polymorphism, Single Nucleotide KW - Population KW - Prospective Studies KW - Reproducibility of Results KW - Risk Assessment KW - Risk Factors KW - Sex Factors KW - Stroke AB -

BACKGROUND AND PURPOSE: Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts.

METHODS: Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS.

RESULTS: A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case-control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification.

CONCLUSIONS: A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small.

VL - 45 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24436234?dopt=Abstract ER - TY - JOUR T1 - Predicting stroke through genetic risk functions: the CHARGE Risk Score Project. JF - Stroke Y1 - 2014 A1 - Ibrahim-Verbaas, Carla A A1 - Fornage, Myriam A1 - Bis, Joshua C A1 - Choi, Seung Hoan A1 - Psaty, Bruce M A1 - Meigs, James B A1 - Rao, Madhu A1 - Nalls, Mike A1 - Fontes, João D A1 - O'Donnell, Christopher J A1 - Kathiresan, Sekar A1 - Ehret, Georg B A1 - Fox, Caroline S A1 - Malik, Rainer A1 - Dichgans, Martin A1 - Schmidt, Helena A1 - Lahti, Jari A1 - Heckbert, Susan R A1 - Lumley, Thomas A1 - Rice, Kenneth A1 - Rotter, Jerome I A1 - Taylor, Kent D A1 - Folsom, Aaron R A1 - Boerwinkle, Eric A1 - Rosamond, Wayne D A1 - Shahar, Eyal A1 - Gottesman, Rebecca F A1 - Koudstaal, Peter J A1 - Amin, Najaf A1 - Wieberdink, Renske G A1 - Dehghan, Abbas A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - DeStefano, Anita L A1 - Debette, Stephanie A1 - Xue, Luting A1 - Beiser, Alexa A1 - Wolf, Philip A A1 - DeCarli, Charles A1 - Ikram, M Arfan A1 - Seshadri, Sudha A1 - Mosley, Thomas H A1 - Longstreth, W T A1 - van Duijn, Cornelia M A1 - Launer, Lenore J KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Area Under Curve KW - Case-Control Studies KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Regression Analysis KW - Risk Factors KW - ROC Curve KW - Sex Factors KW - Stroke AB -

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.

VL - 45 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24436238?dopt=Abstract ER - TY - JOUR T1 - Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants. JF - Stroke Y1 - 2014 A1 - Dichgans, Martin A1 - Malik, Rainer A1 - König, Inke R A1 - Rosand, Jonathan A1 - Clarke, Robert A1 - Gretarsdottir, Solveig A1 - Thorleifsson, Gudmar A1 - Mitchell, Braxton D A1 - Assimes, Themistocles L A1 - Levi, Christopher A1 - O'Donnell, Christopher J A1 - Fornage, Myriam A1 - Thorsteinsdottir, Unnur A1 - Psaty, Bruce M A1 - Hengstenberg, Christian A1 - Seshadri, Sudha A1 - Erdmann, Jeanette A1 - Bis, Joshua C A1 - Peters, Annette A1 - Boncoraglio, Giorgio B A1 - März, Winfried A1 - Meschia, James F A1 - Kathiresan, Sekar A1 - Ikram, M Arfan A1 - McPherson, Ruth A1 - Stefansson, Kari A1 - Sudlow, Cathie A1 - Reilly, Muredach P A1 - Thompson, John R A1 - Sharma, Pankaj A1 - Hopewell, Jemma C A1 - Chambers, John C A1 - Watkins, Hugh A1 - Rothwell, Peter M A1 - Roberts, Robert A1 - Markus, Hugh S A1 - Samani, Nilesh J A1 - Farrall, Martin A1 - Schunkert, Heribert KW - Brain Ischemia KW - Coronary Artery Disease KW - Data Interpretation, Statistical KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Reproducibility of Results KW - Risk Factors KW - Stroke AB -

BACKGROUND AND PURPOSE: Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases.

METHODS: Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype.

RESULTS: Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10(-8)) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10(-7)) and ABO (PIS=2.6×10(-4)), as well as at HDAC9 (PLAS=2.32×10(-12)), 9p21 (PLAS=3.70×10(-6)), RAI1-PEMT-RASD1 (PLAS=2.69×10(-5)), EDNRA (PLAS=7.29×10(-4)), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10(-4)).

CONCLUSIONS: Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.

VL - 45 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24262325?dopt=Abstract ER - TY - JOUR T1 - Association of Alzheimer's disease GWAS loci with MRI markers of brain aging. JF - Neurobiol Aging Y1 - 2015 A1 - Chauhan, Ganesh A1 - Adams, Hieab H H A1 - Bis, Joshua C A1 - Weinstein, Galit A1 - Yu, Lei A1 - Töglhofer, Anna Maria A1 - Smith, Albert Vernon A1 - van der Lee, Sven J A1 - Gottesman, Rebecca F A1 - Thomson, Russell A1 - Wang, Jing A1 - Yang, Qiong A1 - Niessen, Wiro J A1 - Lopez, Oscar L A1 - Becker, James T A1 - Phan, Thanh G A1 - Beare, Richard J A1 - Arfanakis, Konstantinos A1 - Fleischman, Debra A1 - Vernooij, Meike W A1 - Mazoyer, Bernard A1 - Schmidt, Helena A1 - Srikanth, Velandai A1 - Knopman, David S A1 - Jack, Clifford R A1 - Amouyel, Philippe A1 - Hofman, Albert A1 - DeCarli, Charles A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Bennett, David A A1 - Schmidt, Reinhold A1 - Longstreth, William T A1 - Mosley, Thomas H A1 - Fornage, Myriam A1 - Launer, Lenore J A1 - Seshadri, Sudha A1 - Ikram, M Arfan A1 - Debette, Stephanie KW - Aging KW - Alleles KW - Alzheimer Disease KW - Apolipoproteins E KW - Brain KW - Female KW - Genome-Wide Association Study KW - Hippocampus KW - Humans KW - Magnetic Resonance Imaging KW - Male KW - Organ Size KW - Polymorphism, Single Nucleotide KW - Risk KW - Sialic Acid Binding Ig-like Lectin 3 AB -

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.

VL - 36 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25670335?dopt=Abstract ER - TY - JOUR T1 - Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. JF - Neurology Y1 - 2015 A1 - Rannikmae, Kristiina A1 - Davies, Gail A1 - Thomson, Pippa A A1 - Bevan, Steve A1 - Devan, William J A1 - Falcone, Guido J A1 - Traylor, Matthew A1 - Anderson, Christopher D A1 - Battey, Thomas W K A1 - Radmanesh, Farid A1 - Deka, Ranjan A1 - Woo, Jessica G A1 - Martin, Lisa J A1 - Jimenez-Conde, Jordi A1 - Selim, Magdy A1 - Brown, Devin L A1 - Silliman, Scott L A1 - Kidwell, Chelsea S A1 - Montaner, Joan A1 - Langefeld, Carl D A1 - Slowik, Agnieszka A1 - Hansen, Bjorn M A1 - Lindgren, Arne G A1 - Meschia, James F A1 - Fornage, Myriam A1 - Bis, Joshua C A1 - Debette, Stephanie A1 - Ikram, Mohammad A A1 - Longstreth, Will T A1 - Schmidt, Reinhold A1 - Zhang, Cathy R A1 - Yang, Qiong A1 - Sharma, Pankaj A1 - Kittner, Steven J A1 - Mitchell, Braxton D A1 - Holliday, Elizabeth G A1 - Levi, Christopher R A1 - Attia, John A1 - Rothwell, Peter M A1 - Poole, Deborah L A1 - Boncoraglio, Giorgio B A1 - Psaty, Bruce M A1 - Malik, Rainer A1 - Rost, Natalia A1 - Worrall, Bradford B A1 - Dichgans, Martin A1 - Van Agtmael, Tom A1 - Woo, Daniel A1 - Markus, Hugh S A1 - Seshadri, Sudha A1 - Rosand, Jonathan A1 - Sudlow, Cathie L M KW - Cerebral Small Vessel Diseases KW - Collagen Type IV KW - Genetic Association Studies KW - Genetic Variation KW - Humans KW - Polymorphism, Single Nucleotide AB -

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.

VL - 84 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25653287?dopt=Abstract ER - TY - JOUR T1 - Genes from a translational analysis support a multifactorial nature of white matter hyperintensities. JF - Stroke Y1 - 2015 A1 - Lopez, Lorna M A1 - Hill, W David A1 - Harris, Sarah E A1 - Valdes Hernandez, Maria A1 - Munoz Maniega, Susana A1 - Bastin, Mark E A1 - Bailey, Emma A1 - Smith, Colin A1 - McBride, Martin A1 - McClure, John A1 - Graham, Delyth A1 - Dominiczak, Anna A1 - Yang, Qiong A1 - Fornage, Myriam A1 - Ikram, M Arfan A1 - Debette, Stephanie A1 - Launer, Lenore A1 - Bis, Joshua C A1 - Schmidt, Reinhold A1 - Seshadri, Sudha A1 - Porteous, David J A1 - Starr, John A1 - Deary, Ian J A1 - Wardlaw, Joanna M KW - Aged KW - Alzheimer Disease KW - Animals KW - Brain KW - Causality KW - Dementia KW - Female KW - Genome-Wide Association Study KW - Humans KW - Leukoencephalopathies KW - Male KW - Polymorphism, Single Nucleotide KW - Rats KW - Rats, Inbred SHR KW - Rats, Wistar KW - Risk Factors KW - Translational Medical Research KW - White Matter AB -

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.

VL - 46 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25586835?dopt=Abstract ER - TY - JOUR T1 - Genetic overlap between diagnostic subtypes of ischemic stroke. JF - Stroke Y1 - 2015 A1 - Holliday, Elizabeth G A1 - Traylor, Matthew A1 - Malik, Rainer A1 - Bevan, Steve A1 - Falcone, Guido A1 - Hopewell, Jemma C A1 - Cheng, Yu-Ching A1 - Cotlarciuc, Ioana A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Boncoraglio, Giorgio B A1 - Clarke, Robert A1 - Cole, John W A1 - Fornage, Myriam A1 - Furie, Karen L A1 - Ikram, M Arfan A1 - Jannes, Jim A1 - Kittner, Steven J A1 - Lincz, Lisa F A1 - Maguire, Jane M A1 - Meschia, James F A1 - Mosley, Thomas H A1 - Nalls, Mike A A1 - Oldmeadow, Christopher A1 - Parati, Eugenio A A1 - Psaty, Bruce M A1 - Rothwell, Peter M A1 - Seshadri, Sudha A1 - Scott, Rodney J A1 - Sharma, Pankaj A1 - Sudlow, Cathie A1 - Wiggins, Kerri L A1 - Worrall, Bradford B A1 - Rosand, Jonathan A1 - Mitchell, Braxton D A1 - Dichgans, Martin A1 - Markus, Hugh S A1 - Levi, Christopher A1 - Attia, John A1 - Wray, Naomi R KW - Alleles KW - Atherosclerosis KW - Cerebral Small Vessel Diseases KW - Cohort Studies KW - Data Interpretation, Statistical KW - Embolism KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Ischemia KW - Linear Models KW - Meta-Analysis as Topic KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Stroke AB -

BACKGROUND AND PURPOSE: Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses.

METHODS: Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles.

RESULTS: High genetic correlation was identified between LAA and SVD using linear mixed models (rg=0.96, SE=0.47, P=9×10(-4)) and profile scores (rg=0.72; 95% confidence interval, 0.52-0.93). Between LAA and cardioembolism and SVD and cardioembolism, correlation was moderate using linear mixed models but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association (P=1×10(-7)) for single nucleotide polymorphisms near the opioid receptor μ1 (OPRM1) gene.

CONCLUSIONS: Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes.

VL - 46 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25613305?dopt=Abstract ER - TY - JOUR T1 - Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. JF - Biol Psychiatry Y1 - 2015 A1 - Debette, Stephanie A1 - Ibrahim Verbaas, Carla A A1 - Bressler, Jan A1 - Schuur, Maaike A1 - Smith, Albert A1 - Bis, Joshua C A1 - Davies, Gail A1 - Wolf, Christiane A1 - Gudnason, Vilmundur A1 - Chibnik, Lori B A1 - Yang, Qiong A1 - DeStefano, Anita L A1 - de Quervain, Dominique J F A1 - Srikanth, Velandai A1 - Lahti, Jari A1 - Grabe, Hans J A1 - Smith, Jennifer A A1 - Priebe, Lutz A1 - Yu, Lei A1 - Karbalai, Nazanin A1 - Hayward, Caroline A1 - Wilson, James F A1 - Campbell, Harry A1 - Petrovic, Katja A1 - Fornage, Myriam A1 - Chauhan, Ganesh A1 - Yeo, Robin A1 - Boxall, Ruth A1 - Becker, James A1 - Stegle, Oliver A1 - Mather, Karen A A1 - Chouraki, Vincent A1 - Sun, Qi A1 - Rose, Lynda M A1 - Resnick, Susan A1 - Oldmeadow, Christopher A1 - Kirin, Mirna A1 - Wright, Alan F A1 - Jonsdottir, Maria K A1 - Au, Rhoda A1 - Becker, Albert A1 - Amin, Najaf A1 - Nalls, Mike A A1 - Turner, Stephen T A1 - Kardia, Sharon L R A1 - Oostra, Ben A1 - Windham, Gwen A1 - Coker, Laura H A1 - Zhao, Wei A1 - Knopman, David S A1 - Heiss, Gerardo A1 - Griswold, Michael E A1 - Gottesman, Rebecca F A1 - Vitart, Veronique A1 - Hastie, Nicholas D A1 - Zgaga, Lina A1 - Rudan, Igor A1 - Polasek, Ozren A1 - Holliday, Elizabeth G A1 - Schofield, Peter A1 - Choi, Seung Hoan A1 - Tanaka, Toshiko A1 - An, Yang A1 - Perry, Rodney T A1 - Kennedy, Richard E A1 - Sale, Michèle M A1 - Wang, Jing A1 - Wadley, Virginia G A1 - Liewald, David C A1 - Ridker, Paul M A1 - Gow, Alan J A1 - Pattie, Alison A1 - Starr, John M A1 - Porteous, David A1 - Liu, Xuan A1 - Thomson, Russell A1 - Armstrong, Nicola J A1 - Eiriksdottir, Gudny A1 - Assareh, Arezoo A A1 - Kochan, Nicole A A1 - Widen, Elisabeth A1 - Palotie, Aarno A1 - Hsieh, Yi-Chen A1 - Eriksson, Johan G A1 - Vogler, Christian A1 - van Swieten, John C A1 - Shulman, Joshua M A1 - Beiser, Alexa A1 - Rotter, Jerome A1 - Schmidt, Carsten O A1 - Hoffmann, Wolfgang A1 - Nöthen, Markus M A1 - Ferrucci, Luigi A1 - Attia, John A1 - Uitterlinden, André G A1 - Amouyel, Philippe A1 - Dartigues, Jean-François A1 - Amieva, Hélène A1 - Räikkönen, Katri A1 - Garcia, Melissa A1 - Wolf, Philip A A1 - Hofman, Albert A1 - Longstreth, W T A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - DeJager, Philip L A1 - Sachdev, Perminder S A1 - Schmidt, Reinhold A1 - Breteler, Monique M B A1 - Teumer, Alexander A1 - Lopez, Oscar L A1 - Cichon, Sven A1 - Chasman, Daniel I A1 - Grodstein, Francine A1 - Müller-Myhsok, Bertram A1 - Tzourio, Christophe A1 - Papassotiropoulos, Andreas A1 - Bennett, David A A1 - Ikram, M Arfan A1 - Deary, Ian J A1 - van Duijn, Cornelia M A1 - Launer, Lenore A1 - Fitzpatrick, Annette L A1 - Seshadri, Sudha A1 - Mosley, Thomas H KW - Aged KW - Aged, 80 and over KW - Aging KW - Apolipoproteins E KW - Claudin-5 KW - Cohort Studies KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Memory Disorders KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Proteins KW - Proteoglycans KW - Regression Analysis KW - Sulfotransferases KW - Verbal Learning AB -

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.

VL - 77 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25648963?dopt=Abstract ER - TY - JOUR T1 - GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy. JF - J Gerontol A Biol Sci Med Sci Y1 - 2015 A1 - Broer, Linda A1 - Buchman, Aron S A1 - Deelen, Joris A1 - Evans, Daniel S A1 - Faul, Jessica D A1 - Lunetta, Kathryn L A1 - Sebastiani, Paola A1 - Smith, Jennifer A A1 - Smith, Albert V A1 - Tanaka, Toshiko A1 - Yu, Lei A1 - Arnold, Alice M A1 - Aspelund, Thor A1 - Benjamin, Emelia J A1 - De Jager, Philip L A1 - Eirkisdottir, Gudny A1 - Evans, Denis A A1 - Garcia, Melissa E A1 - Hofman, Albert A1 - Kaplan, Robert C A1 - Kardia, Sharon L R A1 - Kiel, Douglas P A1 - Oostra, Ben A A1 - Orwoll, Eric S A1 - Parimi, Neeta A1 - Psaty, Bruce M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Seshadri, Sudha A1 - Singleton, Andrew A1 - Tiemeier, Henning A1 - Uitterlinden, André G A1 - Zhao, Wei A1 - Bandinelli, Stefania A1 - Bennett, David A A1 - Ferrucci, Luigi A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Karasik, David A1 - Launer, Lenore J A1 - Perls, Thomas T A1 - Slagboom, P Eline A1 - Tranah, Gregory J A1 - Weir, David R A1 - Newman, Anne B A1 - van Duijn, Cornelia M A1 - Murabito, Joanne M KW - Aged KW - Aged, 80 and over KW - Apolipoproteins E KW - Cell Adhesion Molecules KW - Cohort Studies KW - Female KW - Forkhead Box Protein O3 KW - Forkhead Transcription Factors KW - Genome-Wide Association Study KW - Humans KW - Longevity KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Receptors, Kainic Acid AB -

BACKGROUND: The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.

METHODS: We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age ≥90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.

RESULTS: In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10(-10)).

CONCLUSIONS: We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages ≥90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.

VL - 70 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25199915?dopt=Abstract ER - TY - JOUR T1 - Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project. JF - JAMA Neurol Y1 - 2015 A1 - Auer, Paul L A1 - Nalls, Mike A1 - Meschia, James F A1 - Worrall, Bradford B A1 - Longstreth, W T A1 - Seshadri, Sudha A1 - Kooperberg, Charles A1 - Burger, Kathleen M A1 - Carlson, Christopher S A1 - Carty, Cara L A1 - Chen, Wei-Min A1 - Cupples, L Adrienne A1 - DeStefano, Anita L A1 - Fornage, Myriam A1 - Hardy, John A1 - Hsu, Li A1 - Jackson, Rebecca D A1 - Jarvik, Gail P A1 - Kim, Daniel S A1 - Lakshminarayan, Kamakshi A1 - Lange, Leslie A A1 - Manichaikul, Ani A1 - Quinlan, Aaron R A1 - Singleton, Andrew B A1 - Thornton, Timothy A A1 - Nickerson, Deborah A A1 - Peters, Ulrike A1 - Rich, Stephen S KW - Aged KW - Brain Ischemia KW - Exome KW - Female KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Muscle Proteins KW - National Heart, Lung, and Blood Institute (U.S.) KW - Nuclear Proteins KW - Open Reading Frames KW - Palmitoyl-CoA Hydrolase KW - Stroke KW - United States AB -

IMPORTANCE: Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk.

OBJECTIVE: To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome.

DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP's exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013.

MAIN OUTCOMES AND MEASURES: Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis).

RESULTS: We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 × 10(-8)) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 × 10(-7)) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke).

CONCLUSIONS AND RELEVANCE: Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.

VL - 72 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25961151?dopt=Abstract ER - TY - JOUR T1 - Shared genetic basis for migraine and ischemic stroke: A genome-wide analysis of common variants. JF - Neurology Y1 - 2015 A1 - Malik, Rainer A1 - Freilinger, Tobias A1 - Winsvold, Bendik S A1 - Anttila, Verneri A1 - Vander Heiden, Jason A1 - Traylor, Matthew A1 - de Vries, Boukje A1 - Holliday, Elizabeth G A1 - Terwindt, Gisela M A1 - Sturm, Jonathan A1 - Bis, Joshua C A1 - Hopewell, Jemma C A1 - Ferrari, Michel D A1 - Rannikmae, Kristiina A1 - Wessman, Maija A1 - Kallela, Mikko A1 - Kubisch, Christian A1 - Fornage, Myriam A1 - Meschia, James F A1 - Lehtimäki, Terho A1 - Sudlow, Cathie A1 - Clarke, Robert A1 - Chasman, Daniel I A1 - Mitchell, Braxton D A1 - Maguire, Jane A1 - Kaprio, Jaakko A1 - Farrall, Martin A1 - Raitakari, Olli T A1 - Kurth, Tobias A1 - Ikram, M Arfan A1 - Reiner, Alex P A1 - Longstreth, W T A1 - Rothwell, Peter M A1 - Strachan, David P A1 - Sharma, Pankaj A1 - Seshadri, Sudha A1 - Quaye, Lydia A1 - Cherkas, Lynn A1 - Schürks, Markus A1 - Rosand, Jonathan A1 - Ligthart, Lannie A1 - Boncoraglio, Giorgio B A1 - Davey Smith, George A1 - van Duijn, Cornelia M A1 - Stefansson, Kari A1 - Worrall, Bradford B A1 - Nyholt, Dale R A1 - Markus, Hugh S A1 - van den Maagdenberg, Arn M J M A1 - Cotsapas, Chris A1 - Zwart, John A A1 - Palotie, Aarno A1 - Dichgans, Martin KW - Brain Ischemia KW - Genome-Wide Association Study KW - Humans KW - Migraine with Aura KW - Migraine without Aura KW - Stroke AB -

OBJECTIVE: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation.

METHODS: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping.

RESULTS: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p = 6.4 × 10(-28) for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 × 10(-20) for the CE score in MO).

CONCLUSIONS: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype.

VL - 84 IS - 21 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25934857?dopt=Abstract ER - TY - JOUR T1 - White Matter Lesion Progression: Genome-Wide Search for Genetic Influences. JF - Stroke Y1 - 2015 A1 - Hofer, Edith A1 - Cavalieri, Margherita A1 - Bis, Joshua C A1 - DeCarli, Charles A1 - Fornage, Myriam A1 - Sigurdsson, Sigurdur A1 - Srikanth, Velandai A1 - Trompet, Stella A1 - Verhaaren, Benjamin F J A1 - Wolf, Christiane A1 - Yang, Qiong A1 - Adams, Hieab H H A1 - Amouyel, Philippe A1 - Beiser, Alexa A1 - Buckley, Brendan M A1 - Callisaya, Michele A1 - Chauhan, Ganesh A1 - de Craen, Anton J M A1 - Dufouil, Carole A1 - van Duijn, Cornelia M A1 - Ford, Ian A1 - Freudenberger, Paul A1 - Gottesman, Rebecca F A1 - Gudnason, Vilmundur A1 - Heiss, Gerardo A1 - Hofman, Albert A1 - Lumley, Thomas A1 - Martinez, Oliver A1 - Mazoyer, Bernard A1 - Moran, Chris A1 - Niessen, Wiro J A1 - Phan, Thanh A1 - Psaty, Bruce M A1 - Satizabal, Claudia L A1 - Sattar, Naveed A1 - Schilling, Sabrina A1 - Shibata, Dean K A1 - Slagboom, P Eline A1 - Smith, Albert A1 - Stott, David J A1 - Taylor, Kent D A1 - Thomson, Russell A1 - Töglhofer, Anna M A1 - Tzourio, Christophe A1 - van Buchem, Mark A1 - Wang, Jing A1 - Westendorp, Rudi G J A1 - Windham, B Gwen A1 - Vernooij, Meike W A1 - Zijdenbos, Alex A1 - Beare, Richard A1 - Debette, Stephanie A1 - Ikram, M Arfan A1 - Jukema, J Wouter A1 - Launer, Lenore J A1 - Longstreth, W T A1 - Mosley, Thomas H A1 - Seshadri, Sudha A1 - Schmidt, Helena A1 - Schmidt, Reinhold KW - Adult KW - Aged KW - Cohort Studies KW - Disease Progression KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Leukoencephalopathies KW - Male KW - Middle Aged KW - Prospective Studies KW - White Matter AB -

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.

VL - 46 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26451028?dopt=Abstract ER - TY - JOUR T1 - Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease. JF - J Alzheimers Dis Y1 - 2016 A1 - Chouraki, Vincent A1 - Reitz, Christiane A1 - Maury, Fleur A1 - Bis, Joshua C A1 - Bellenguez, Céline A1 - Yu, Lei A1 - Jakobsdottir, Johanna A1 - Mukherjee, Shubhabrata A1 - Adams, Hieab H A1 - Choi, Seung Hoan A1 - Larson, Eric B A1 - Fitzpatrick, Annette A1 - Uitterlinden, André G A1 - De Jager, Philip L A1 - Hofman, Albert A1 - Gudnason, Vilmundur A1 - Vardarajan, Badri A1 - Ibrahim-Verbaas, Carla A1 - van der Lee, Sven J A1 - Lopez, Oscar A1 - Dartigues, Jean-François A1 - Berr, Claudine A1 - Amouyel, Philippe A1 - Bennett, David A A1 - van Duijn, Cornelia A1 - DeStefano, Anita L A1 - Launer, Lenore J A1 - Ikram, M Arfan A1 - Crane, Paul K A1 - Lambert, Jean-Charles A1 - Mayeux, Richard A1 - Seshadri, Sudha AB -

Effective prevention of Alzheimer's disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOEɛ4. In eight prospective cohorts included in the International Genomics of Alzheimer's Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17% increase in AD risk (pooled HR = 1.17; 95% CI =   [1.13-1.21] per standard deviation increase in GRS; p-value =  2.86×10-16). This association was stronger among persons with at least one APOEɛ4 allele (HRGRS = 1.24; 95% CI =   [1.15-1.34]) than in others (HRGRS = 1.13; 95% CI =   [1.08-1.18]; pinteraction = 3.45×10-2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOEɛ4, and education (Δ-Cindex =  0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOEɛ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.

VL - 53 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27340842?dopt=Abstract ER - TY - JOUR T1 - Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2. JF - Stroke Y1 - 2016 A1 - Cheng, Yu-Ching A1 - Stanne, Tara M A1 - Giese, Anne-Katrin A1 - Ho, Weang Kee A1 - Traylor, Matthew A1 - Amouyel, Philippe A1 - Holliday, Elizabeth G A1 - Malik, Rainer A1 - Xu, Huichun A1 - Kittner, Steven J A1 - Cole, John W A1 - O'Connell, Jeffrey R A1 - Danesh, John A1 - Rasheed, Asif A1 - Zhao, Wei A1 - Engelter, Stefan A1 - Grond-Ginsbach, Caspar A1 - Kamatani, Yoichiro A1 - Lathrop, Mark A1 - Leys, Didier A1 - Thijs, Vincent A1 - Metso, Tiina M A1 - Tatlisumak, Turgut A1 - Pezzini, Alessandro A1 - Parati, Eugenio A A1 - Norrving, Bo A1 - Bevan, Steve A1 - Rothwell, Peter M A1 - Sudlow, Cathie A1 - Slowik, Agnieszka A1 - Lindgren, Arne A1 - Walters, Matthew R A1 - Jannes, Jim A1 - Shen, Jess A1 - Crosslin, David A1 - Doheny, Kimberly A1 - Laurie, Cathy C A1 - Kanse, Sandip M A1 - Bis, Joshua C A1 - Fornage, Myriam A1 - Mosley, Thomas H A1 - Hopewell, Jemma C A1 - Strauch, Konstantin A1 - Müller-Nurasyid, Martina A1 - Gieger, Christian A1 - Waldenberger, Melanie A1 - Peters, Annette A1 - Meisinger, Christine A1 - Ikram, M Arfan A1 - Longstreth, W T A1 - Meschia, James F A1 - Seshadri, Sudha A1 - Sharma, Pankaj A1 - Worrall, Bradford A1 - Jern, Christina A1 - Levi, Christopher A1 - Dichgans, Martin A1 - Boncoraglio, Giorgio B A1 - Markus, Hugh S A1 - Debette, Stephanie A1 - Rolfs, Arndt A1 - Saleheen, Danish A1 - Mitchell, Braxton D KW - Adult KW - African Continental Ancestry Group KW - Age of Onset KW - Aged KW - Asian Continental Ancestry Group KW - Brain Ischemia KW - Chromosomes, Human, Pair 10 KW - Computer Simulation KW - DNA, Intergenic KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Odds Ratio KW - Polymorphism, Single Nucleotide KW - Serine Endopeptidases KW - Stroke AB -

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.

VL - 47 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26732560?dopt=Abstract ER - TY - JOUR T1 - Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits. JF - Aging Cell Y1 - 2016 A1 - Teumer, Alexander A1 - Qi, Qibin A1 - Nethander, Maria A1 - Aschard, Hugues A1 - Bandinelli, Stefania A1 - Beekman, Marian A1 - Berndt, Sonja I A1 - Bidlingmaier, Martin A1 - Broer, Linda A1 - Cappola, Anne A1 - Ceda, Gian Paolo A1 - Chanock, Stephen A1 - Chen, Ming-Huei A1 - Chen, Tai C A1 - Chen, Yii-Der Ida A1 - Chung, Jonathan A1 - Del Greco Miglianico, Fabiola A1 - Eriksson, Joel A1 - Ferrucci, Luigi A1 - Friedrich, Nele A1 - Gnewuch, Carsten A1 - Goodarzi, Mark O A1 - Grarup, Niels A1 - Guo, Tingwei A1 - Hammer, Elke A1 - Hayes, Richard B A1 - Hicks, Andrew A A1 - Hofman, Albert A1 - Houwing-Duistermaat, Jeanine J A1 - Hu, Frank A1 - Hunter, David J A1 - Husemoen, Lise L A1 - Isaacs, Aaron A1 - Jacobs, Kevin B A1 - Janssen, Joop A M J L A1 - Jansson, John-Olov A1 - Jehmlich, Nico A1 - Johnson, Simon A1 - Juul, Anders A1 - Karlsson, Magnus A1 - Kilpeläinen, Tuomas O A1 - Kovacs, Peter A1 - Kraft, Peter A1 - Li, Chao A1 - Linneberg, Allan A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Lorentzon, Mattias A1 - Lu, Yingchang A1 - Maggio, Marcello A1 - Mägi, Reedik A1 - Meigs, James A1 - Mellström, Dan A1 - Nauck, Matthias A1 - Newman, Anne B A1 - Pollak, Michael N A1 - Pramstaller, Peter P A1 - Prokopenko, Inga A1 - Psaty, Bruce M A1 - Reincke, Martin A1 - Rimm, Eric B A1 - Rotter, Jerome I A1 - Saint Pierre, Aude A1 - Schurmann, Claudia A1 - Seshadri, Sudha A1 - Sjögren, Klara A1 - Slagboom, P Eline A1 - Strickler, Howard D A1 - Stumvoll, Michael A1 - Suh, Yousin A1 - Sun, Qi A1 - Zhang, Cuilin A1 - Svensson, Johan A1 - Tanaka, Toshiko A1 - Tare, Archana A1 - Tönjes, Anke A1 - Uh, Hae-Won A1 - van Duijn, Cornelia M A1 - van Heemst, Diana A1 - Vandenput, Liesbeth A1 - Vasan, Ramachandran S A1 - Völker, Uwe A1 - Willems, Sara M A1 - Ohlsson, Claes A1 - Wallaschofski, Henri A1 - Kaplan, Robert C AB -

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.

VL - 15 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27329260?dopt=Abstract ER - TY - JOUR T1 - GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium. JF - Aging Cell Y1 - 2016 A1 - Matteini, Amy M A1 - Tanaka, Toshiko A1 - Karasik, David A1 - Atzmon, Gil A1 - Chou, Wen-Chi A1 - Eicher, John D A1 - Johnson, Andrew D A1 - Arnold, Alice M A1 - Callisaya, Michele L A1 - Davies, Gail A1 - Evans, Daniel S A1 - Holtfreter, Birte A1 - Lohman, Kurt A1 - Lunetta, Kathryn L A1 - Mangino, Massimo A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Teumer, Alexander A1 - Yu, Lei A1 - Arking, Dan E A1 - Buchman, Aron S A1 - Chibinik, Lori B A1 - De Jager, Philip L A1 - Evans, Denis A A1 - Faul, Jessica D A1 - Garcia, Melissa E A1 - Gillham-Nasenya, Irina A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Hsu, Yi-Hsiang A1 - Ittermann, Till A1 - Lahousse, Lies A1 - Liewald, David C A1 - Liu, Yongmei A1 - Lopez, Lorna A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Siggeirsdottir, Kristin A1 - Starr, John M A1 - Thomson, Russell A1 - Tranah, Gregory J A1 - Uitterlinden, André G A1 - Völker, Uwe A1 - Völzke, Henry A1 - Weir, David R A1 - Yaffe, Kristine A1 - Zhao, Wei A1 - Zhuang, Wei Vivian A1 - Zmuda, Joseph M A1 - Bennett, David A A1 - Cummings, Steven R A1 - Deary, Ian J A1 - Ferrucci, Luigi A1 - Harris, Tamara B A1 - Kardia, Sharon L R A1 - Kocher, Thomas A1 - Kritchevsky, Stephen B A1 - Psaty, Bruce M A1 - Seshadri, Sudha A1 - Spector, Timothy D A1 - Srikanth, Velandai K A1 - Windham, B Gwen A1 - Zillikens, M Carola A1 - Newman, Anne B A1 - Walston, Jeremy D A1 - Kiel, Douglas P A1 - Murabito, Joanne M AB -

Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10(-8) ) and 39 suggestive (P-value< 5 × 10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P-value = 5.20 × 10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.

VL - 15 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27325353?dopt=Abstract ER - TY - JOUR T1 - Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. JF - PLoS Genet Y1 - 2016 A1 - Jakobsdottir, Johanna A1 - van der Lee, Sven J A1 - Bis, Joshua C A1 - Chouraki, Vincent A1 - Li-Kroeger, David A1 - Yamamoto, Shinya A1 - Grove, Megan L A1 - Naj, Adam A1 - Vronskaya, Maria A1 - Salazar, Jose L A1 - DeStefano, Anita L A1 - Brody, Jennifer A A1 - Smith, Albert V A1 - Amin, Najaf A1 - Sims, Rebecca A1 - Ibrahim-Verbaas, Carla A A1 - Choi, Seung-Hoan A1 - Satizabal, Claudia L A1 - Lopez, Oscar L A1 - Beiser, Alexa A1 - Ikram, M Arfan A1 - Garcia, Melissa E A1 - Hayward, Caroline A1 - Varga, Tibor V A1 - Ripatti, Samuli A1 - Franks, Paul W A1 - Hallmans, Göran A1 - Rolandsson, Olov A1 - Jansson, Jan-Håkon A1 - Porteous, David J A1 - Salomaa, Veikko A1 - Eiriksdottir, Gudny A1 - Rice, Kenneth M A1 - Bellen, Hugo J A1 - Levy, Daniel A1 - Uitterlinden, André G A1 - Emilsson, Valur A1 - Rotter, Jerome I A1 - Aspelund, Thor A1 - O'Donnell, Christopher J A1 - Fitzpatrick, Annette L A1 - Launer, Lenore J A1 - Hofman, Albert A1 - Wang, Li-San A1 - Williams, Julie A1 - Schellenberg, Gerard D A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Seshadri, Sudha A1 - Shulman, Joshua M A1 - Gudnason, Vilmundur A1 - van Duijn, Cornelia M AB -

We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.

VL - 12 IS - 10 ER - TY - JOUR T1 - Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. JF - Nat Genet Y1 - 2017 A1 - Sims, Rebecca A1 - van der Lee, Sven J A1 - Naj, Adam C A1 - Bellenguez, Céline A1 - Badarinarayan, Nandini A1 - Jakobsdottir, Johanna A1 - Kunkle, Brian W A1 - Boland, Anne A1 - Raybould, Rachel A1 - Bis, Joshua C A1 - Martin, Eden R A1 - Grenier-Boley, Benjamin A1 - Heilmann-Heimbach, Stefanie A1 - Chouraki, Vincent A1 - Kuzma, Amanda B A1 - Sleegers, Kristel A1 - Vronskaya, Maria A1 - Ruiz, Agustin A1 - Graham, Robert R A1 - Olaso, Robert A1 - Hoffmann, Per A1 - Grove, Megan L A1 - Vardarajan, Badri N A1 - Hiltunen, Mikko A1 - Nöthen, Markus M A1 - White, Charles C A1 - Hamilton-Nelson, Kara L A1 - Epelbaum, Jacques A1 - Maier, Wolfgang A1 - Choi, Seung-Hoan A1 - Beecham, Gary W A1 - Dulary, Cécile A1 - Herms, Stefan A1 - Smith, Albert V A1 - Funk, Cory C A1 - Derbois, Céline A1 - Forstner, Andreas J A1 - Ahmad, Shahzad A1 - Li, Hongdong A1 - Bacq, Delphine A1 - Harold, Denise A1 - Satizabal, Claudia L A1 - Valladares, Otto A1 - Squassina, Alessio A1 - Thomas, Rhodri A1 - Brody, Jennifer A A1 - Qu, Liming A1 - Sánchez-Juan, Pascual A1 - Morgan, Taniesha A1 - Wolters, Frank J A1 - Zhao, Yi A1 - Garcia, Florentino Sanchez A1 - Denning, Nicola A1 - Fornage, Myriam A1 - Malamon, John A1 - Naranjo, Maria Candida Deniz A1 - Majounie, Elisa A1 - Mosley, Thomas H A1 - Dombroski, Beth A1 - Wallon, David A1 - Lupton, Michelle K A1 - Dupuis, Josée A1 - Whitehead, Patrice A1 - Fratiglioni, Laura A1 - Medway, Christopher A1 - Jian, Xueqiu A1 - Mukherjee, Shubhabrata A1 - Keller, Lina A1 - Brown, Kristelle A1 - Lin, Honghuang A1 - Cantwell, Laura B A1 - Panza, Francesco A1 - McGuinness, Bernadette A1 - Moreno-Grau, Sonia A1 - Burgess, Jeremy D A1 - Solfrizzi, Vincenzo A1 - Proitsi, Petra A1 - Adams, Hieab H A1 - Allen, Mariet A1 - Seripa, Davide A1 - Pastor, Pau A1 - Cupples, L Adrienne A1 - Price, Nathan D A1 - Hannequin, Didier A1 - Frank-García, Ana A1 - Levy, Daniel A1 - Chakrabarty, Paramita A1 - Caffarra, Paolo A1 - Giegling, Ina A1 - Beiser, Alexa S A1 - Giedraitis, Vilmantas A1 - Hampel, Harald A1 - Garcia, Melissa E A1 - Wang, Xue A1 - Lannfelt, Lars A1 - Mecocci, Patrizia A1 - Eiriksdottir, Gudny A1 - Crane, Paul K A1 - Pasquier, Florence A1 - Boccardi, Virginia A1 - Henández, Isabel A1 - Barber, Robert C A1 - Scherer, Martin A1 - Tarraga, Lluis A1 - Adams, Perrie M A1 - Leber, Markus A1 - Chen, Yuning A1 - Albert, Marilyn S A1 - Riedel-Heller, Steffi A1 - Emilsson, Valur A1 - Beekly, Duane A1 - Braae, Anne A1 - Schmidt, Reinhold A1 - Blacker, Deborah A1 - Masullo, Carlo A1 - Schmidt, Helena A1 - Doody, Rachelle S A1 - Spalletta, Gianfranco A1 - Jr, W T Longstreth A1 - Fairchild, Thomas J A1 - Bossù, Paola A1 - Lopez, Oscar L A1 - Frosch, Matthew P A1 - Sacchinelli, Eleonora A1 - Ghetti, Bernardino A1 - Yang, Qiong A1 - Huebinger, Ryan M A1 - Jessen, Frank A1 - Li, Shuo A1 - Kamboh, M Ilyas A1 - Morris, John A1 - Sotolongo-Grau, Oscar A1 - Katz, Mindy J A1 - Corcoran, Chris A1 - Dunstan, Melanie A1 - Braddel, Amy A1 - Thomas, Charlene A1 - Meggy, Alun A1 - Marshall, Rachel A1 - Gerrish, Amy A1 - Chapman, Jade A1 - Aguilar, Miquel A1 - Taylor, Sarah A1 - Hill, Matt A1 - Fairén, Mònica Díez A1 - Hodges, Angela A1 - Vellas, Bruno A1 - Soininen, Hilkka A1 - Kloszewska, Iwona A1 - Daniilidou, Makrina A1 - Uphill, James A1 - Patel, Yogen A1 - Hughes, Joseph T A1 - Lord, Jenny A1 - Turton, James A1 - Hartmann, Annette M A1 - Cecchetti, Roberta A1 - Fenoglio, Chiara A1 - Serpente, Maria A1 - Arcaro, Marina A1 - Caltagirone, Carlo A1 - Orfei, Maria Donata A1 - Ciaramella, Antonio A1 - Pichler, Sabrina A1 - Mayhaus, Manuel A1 - Gu, Wei A1 - Lleo, Alberto A1 - Fortea, Juan A1 - Blesa, Rafael A1 - Barber, Imelda S A1 - Brookes, Keeley A1 - Cupidi, Chiara A1 - Maletta, Raffaele Giovanni A1 - Carrell, David A1 - Sorbi, Sandro A1 - Moebus, Susanne A1 - Urbano, Maria A1 - Pilotto, Alberto A1 - Kornhuber, Johannes A1 - Bosco, Paolo A1 - Todd, Stephen A1 - Craig, David A1 - Johnston, Janet A1 - Gill, Michael A1 - Lawlor, Brian A1 - Lynch, Aoibhinn A1 - Fox, Nick C A1 - Hardy, John A1 - Albin, Roger L A1 - Apostolova, Liana G A1 - Arnold, Steven E A1 - Asthana, Sanjay A1 - Atwood, Craig S A1 - Baldwin, Clinton T A1 - Barnes, Lisa L A1 - Barral, Sandra A1 - Beach, Thomas G A1 - Becker, James T A1 - Bigio, Eileen H A1 - Bird, Thomas D A1 - Boeve, Bradley F A1 - Bowen, James D A1 - Boxer, Adam A1 - Burke, James R A1 - Burns, Jeffrey M A1 - Buxbaum, Joseph D A1 - Cairns, Nigel J A1 - Cao, Chuanhai A1 - Carlson, Chris S A1 - Carlsson, Cynthia M A1 - Carney, Regina M A1 - Carrasquillo, Minerva M A1 - Carroll, Steven L A1 - Diaz, Carolina Ceballos A1 - Chui, Helena C A1 - Clark, David G A1 - Cribbs, David H A1 - Crocco, Elizabeth A A1 - DeCarli, Charles A1 - Dick, Malcolm A1 - Duara, Ranjan A1 - Evans, Denis A A1 - Faber, Kelley M A1 - Fallon, Kenneth B A1 - Fardo, David W A1 - Farlow, Martin R A1 - Ferris, Steven A1 - Foroud, Tatiana M A1 - Galasko, Douglas R A1 - Gearing, Marla A1 - Geschwind, Daniel H A1 - Gilbert, John R A1 - Graff-Radford, Neill R A1 - Green, Robert C A1 - Growdon, John H A1 - Hamilton, Ronald L A1 - Harrell, Lindy E A1 - Honig, Lawrence S A1 - Huentelman, Matthew J A1 - Hulette, Christine M A1 - Hyman, Bradley T A1 - Jarvik, Gail P A1 - Abner, Erin A1 - Jin, Lee-Way A1 - Jun, Gyungah A1 - Karydas, Anna A1 - Kaye, Jeffrey A A1 - Kim, Ronald A1 - Kowall, Neil W A1 - Kramer, Joel H A1 - LaFerla, Frank M A1 - Lah, James J A1 - Leverenz, James B A1 - Levey, Allan I A1 - Li, Ge A1 - Lieberman, Andrew P A1 - Lunetta, Kathryn L A1 - Lyketsos, Constantine G A1 - Marson, Daniel C A1 - Martiniuk, Frank A1 - Mash, Deborah C A1 - Masliah, Eliezer A1 - McCormick, Wayne C A1 - McCurry, Susan M A1 - McDavid, Andrew N A1 - McKee, Ann C A1 - Mesulam, Marsel A1 - Miller, Bruce L A1 - Miller, Carol A A1 - Miller, Joshua W A1 - Morris, John C A1 - Murrell, Jill R A1 - Myers, Amanda J A1 - O'Bryant, Sid A1 - Olichney, John M A1 - Pankratz, Vernon S A1 - Parisi, Joseph E A1 - Paulson, Henry L A1 - Perry, William A1 - Peskind, Elaine A1 - Pierce, Aimee A1 - Poon, Wayne W A1 - Potter, Huntington A1 - Quinn, Joseph F A1 - Raj, Ashok A1 - Raskind, Murray A1 - Reisberg, Barry A1 - Reitz, Christiane A1 - Ringman, John M A1 - Roberson, Erik D A1 - Rogaeva, Ekaterina A1 - Rosen, Howard J A1 - Rosenberg, Roger N A1 - Sager, Mark A A1 - Saykin, Andrew J A1 - Schneider, Julie A A1 - Schneider, Lon S A1 - Seeley, William W A1 - Smith, Amanda G A1 - Sonnen, Joshua A A1 - Spina, Salvatore A1 - Stern, Robert A A1 - Swerdlow, Russell H A1 - Tanzi, Rudolph E A1 - Thornton-Wells, Tricia A A1 - Trojanowski, John Q A1 - Troncoso, Juan C A1 - Van Deerlin, Vivianna M A1 - Van Eldik, Linda J A1 - Vinters, Harry V A1 - Vonsattel, Jean Paul A1 - Weintraub, Sandra A1 - Welsh-Bohmer, Kathleen A A1 - Wilhelmsen, Kirk C A1 - Williamson, Jennifer A1 - Wingo, Thomas S A1 - Woltjer, Randall L A1 - Wright, Clinton B A1 - Yu, Chang-En A1 - Yu, Lei A1 - Garzia, Fabienne A1 - Golamaully, Feroze A1 - Septier, Gislain A1 - Engelborghs, Sebastien A1 - Vandenberghe, Rik A1 - De Deyn, Peter P A1 - Fernadez, Carmen Muñoz A1 - Benito, Yoland Aladro A1 - Thonberg, Håkan A1 - Forsell, Charlotte A1 - Lilius, Lena A1 - Kinhult-Ståhlbom, Anne A1 - Kilander, Lena A1 - Brundin, RoseMarie A1 - Concari, Letizia A1 - Helisalmi, Seppo A1 - Koivisto, Anne Maria A1 - Haapasalo, Annakaisa A1 - Dermecourt, Vincent A1 - Fiévet, Nathalie A1 - Hanon, Olivier A1 - Dufouil, Carole A1 - Brice, Alexis A1 - Ritchie, Karen A1 - Dubois, Bruno A1 - Himali, Jayanadra J A1 - Keene, C Dirk A1 - Tschanz, JoAnn A1 - Fitzpatrick, Annette L A1 - Kukull, Walter A A1 - Norton, Maria A1 - Aspelund, Thor A1 - Larson, Eric B A1 - Munger, Ron A1 - Rotter, Jerome I A1 - Lipton, Richard B A1 - Bullido, María J A1 - Hofman, Albert A1 - Montine, Thomas J A1 - Coto, Eliecer A1 - Boerwinkle, Eric A1 - Petersen, Ronald C A1 - Alvarez, Victoria A1 - Rivadeneira, Fernando A1 - Reiman, Eric M A1 - Gallo, Maura A1 - O'Donnell, Christopher J A1 - Reisch, Joan S A1 - Bruni, Amalia Cecilia A1 - Royall, Donald R A1 - Dichgans, Martin A1 - Sano, Mary A1 - Galimberti, Daniela A1 - St George-Hyslop, Peter A1 - Scarpini, Elio A1 - Tsuang, Debby W A1 - Mancuso, Michelangelo A1 - Bonuccelli, Ubaldo A1 - Winslow, Ashley R A1 - Daniele, Antonio A1 - Wu, Chuang-Kuo A1 - Peters, Oliver A1 - Nacmias, Benedetta A1 - Riemenschneider, Matthias A1 - Heun, Reinhard A1 - Brayne, Carol A1 - Rubinsztein, David C A1 - Bras, Jose A1 - Guerreiro, Rita A1 - Al-Chalabi, Ammar A1 - Shaw, Christopher E A1 - Collinge, John A1 - Mann, David A1 - Tsolaki, Magda A1 - Clarimon, Jordi A1 - Sussams, Rebecca A1 - Lovestone, Simon A1 - O'Donovan, Michael C A1 - Owen, Michael J A1 - Behrens, Timothy W A1 - Mead, Simon A1 - Goate, Alison M A1 - Uitterlinden, André G A1 - Holmes, Clive A1 - Cruchaga, Carlos A1 - Ingelsson, Martin A1 - Bennett, David A A1 - Powell, John A1 - Golde, Todd E A1 - Graff, Caroline A1 - De Jager, Philip L A1 - Morgan, Kevin A1 - Ertekin-Taner, Nilufer A1 - Combarros, Onofre A1 - Psaty, Bruce M A1 - Passmore, Peter A1 - Younkin, Steven G A1 - Berr, Claudine A1 - Gudnason, Vilmundur A1 - Rujescu, Dan A1 - Dickson, Dennis W A1 - Dartigues, Jean-François A1 - DeStefano, Anita L A1 - Ortega-Cubero, Sara A1 - Hakonarson, Hakon A1 - Campion, Dominique A1 - Boada, Merce A1 - Kauwe, John Keoni A1 - Farrer, Lindsay A A1 - Van Broeckhoven, Christine A1 - Ikram, M Arfan A1 - Jones, Lesley A1 - Haines, Jonathan L A1 - Tzourio, Christophe A1 - Launer, Lenore J A1 - Escott-Price, Valentina A1 - Mayeux, Richard A1 - Deleuze, Jean-Francois A1 - Amin, Najaf A1 - Holmans, Peter A A1 - Pericak-Vance, Margaret A A1 - Amouyel, Philippe A1 - van Duijn, Cornelia M A1 - Ramirez, Alfredo A1 - Wang, Li-San A1 - Lambert, Jean-Charles A1 - Seshadri, Sudha A1 - Williams, Julie A1 - Schellenberg, Gerard D KW - Adaptor Proteins, Signal Transducing KW - Alzheimer Disease KW - Amino Acid Sequence KW - Case-Control Studies KW - Exome KW - Gene Expression Profiling KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genotype KW - Humans KW - Immunity, Innate KW - Linkage Disequilibrium KW - Membrane Glycoproteins KW - Microglia KW - Odds Ratio KW - Phospholipase C gamma KW - Polymorphism, Single Nucleotide KW - Protein Interaction Maps KW - Receptors, Immunologic KW - Sequence Homology, Amino Acid AB -

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

VL - 49 IS - 9 ER - TY - JOUR T1 - Trends in the incidence of dementia: design and methods in the Alzheimer Cohorts Consortium. JF - Eur J Epidemiol Y1 - 2017 A1 - Chibnik, Lori B A1 - Wolters, Frank J A1 - Bäckman, Kristoffer A1 - Beiser, Alexa A1 - Berr, Claudine A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Bos, Daniel A1 - Brayne, Carol A1 - Dartigues, Jean-François A1 - Darweesh, Sirwan K L A1 - Debette, Stephanie A1 - Davis-Plourde, Kendra L A1 - Dufouil, Carole A1 - Fornage, Myriam A1 - Grasset, Leslie A1 - Gudnason, Vilmundur A1 - Hadjichrysanthou, Christoforos A1 - Helmer, Catherine A1 - Ikram, M Arfan A1 - Ikram, M Kamran A1 - Kern, Silke A1 - Kuller, Lewis H A1 - Launer, Lenore A1 - Lopez, Oscar L A1 - Matthews, Fiona A1 - Meirelles, Osorio A1 - Mosley, Thomas A1 - Ower, Alison A1 - Psaty, Bruce M A1 - Satizabal, Claudia L A1 - Seshadri, Sudha A1 - Skoog, Ingmar A1 - Stephan, Blossom C M A1 - Tzourio, Christophe A1 - Waziry, Reem A1 - Wong, Mei Mei A1 - Zettergren, Anna A1 - Hofman, Albert AB -

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.

VL - 32 IS - 10 ER - TY - JOUR T1 - Exome Chip Analysis Identifies Low-Frequency and Rare Variants in for White Matter Hyperintensities on Brain Magnetic Resonance Imaging. JF - Stroke Y1 - 2018 A1 - Jian, Xueqiu A1 - Satizabal, Claudia L A1 - Smith, Albert V A1 - Wittfeld, Katharina A1 - Bis, Joshua C A1 - Smith, Jennifer A A1 - Hsu, Fang-Chi A1 - Nho, Kwangsik A1 - Hofer, Edith A1 - Hagenaars, Saskia P A1 - Nyquist, Paul A A1 - Mishra, Aniket A1 - Adams, Hieab H H A1 - Li, Shuo A1 - Teumer, Alexander A1 - Zhao, Wei A1 - Freedman, Barry I A1 - Saba, Yasaman A1 - Yanek, Lisa R A1 - Chauhan, Ganesh A1 - van Buchem, Mark A A1 - Cushman, Mary A1 - Royle, Natalie A A1 - Bryan, R Nick A1 - Niessen, Wiro J A1 - Windham, Beverly G A1 - DeStefano, Anita L A1 - Habes, Mohamad A1 - Heckbert, Susan R A1 - Palmer, Nicholette D A1 - Lewis, Cora E A1 - Eiriksdottir, Gudny A1 - Maillard, Pauline A1 - Mathias, Rasika A A1 - Homuth, Georg A1 - Valdés-Hernández, Maria Del C A1 - Divers, Jasmin A1 - Beiser, Alexa S A1 - Langner, Sönke A1 - Rice, Kenneth M A1 - Bastin, Mark E A1 - Yang, Qiong A1 - Maldjian, Joseph A A1 - Starr, John M A1 - Sidney, Stephen A1 - Risacher, Shannon L A1 - Uitterlinden, André G A1 - Gudnason, Vilmundur G A1 - Nauck, Matthias A1 - Rotter, Jerome I A1 - Schreiner, Pamela J A1 - Boerwinkle, Eric A1 - van Duijn, Cornelia M A1 - Mazoyer, Bernard A1 - von Sarnowski, Bettina A1 - Gottesman, Rebecca F A1 - Levy, Daniel A1 - Sigurdsson, Sigurdur A1 - Vernooij, Meike W A1 - Turner, Stephen T A1 - Schmidt, Reinhold A1 - Wardlaw, Joanna M A1 - Psaty, Bruce M A1 - Mosley, Thomas H A1 - DeCarli, Charles S A1 - Saykin, Andrew J A1 - Bowden, Donald W A1 - Becker, Diane M A1 - Deary, Ian J A1 - Schmidt, Helena A1 - Kardia, Sharon L R A1 - Ikram, M Arfan A1 - Debette, Stephanie A1 - Grabe, Hans J A1 - Longstreth, W T A1 - Seshadri, Sudha A1 - Launer, Lenore J A1 - Fornage, Myriam AB -

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.

ER - TY - JOUR T1 - Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project. JF - Dement Geriatr Cogn Disord Y1 - 2018 A1 - Blue, Elizabeth E A1 - Bis, Joshua C A1 - Dorschner, Michael O A1 - Tsuang, Debby W A1 - Barral, Sandra M A1 - Beecham, Gary A1 - Below, Jennifer E A1 - Bush, William S A1 - Butkiewicz, Mariusz A1 - Cruchaga, Carlos A1 - DeStefano, Anita A1 - Farrer, Lindsay A A1 - Goate, Alison A1 - Haines, Jonathan A1 - Jaworski, Jim A1 - Jun, Gyungah A1 - Kunkle, Brian A1 - Kuzma, Amanda A1 - Lee, Jenny J A1 - Lunetta, Kathryn L A1 - Ma, Yiyi A1 - Martin, Eden A1 - Naj, Adam A1 - Nato, Alejandro Q A1 - Navas, Patrick A1 - Nguyen, Hiep A1 - Reitz, Christiane A1 - Reyes, Dolly A1 - Salerno, William A1 - Schellenberg, Gerard D A1 - Seshadri, Sudha A1 - Sohi, Harkirat A1 - Thornton, Timothy A A1 - Valadares, Otto A1 - van Duijn, Cornelia A1 - Vardarajan, Badri N A1 - Wang, Li-San A1 - Boerwinkle, Eric A1 - Dupuis, Josée A1 - Pericak-Vance, Margaret A A1 - Mayeux, Richard A1 - Wijsman, Ellen M AB -

BACKGROUND/AIMS: The Alzheimer's Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimer's disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP.

METHODS: We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as "pathogenic" in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study. The participants were clinically evaluated for AD, and they represent European, Caribbean Hispanic, and isolate Dutch populations.

RESULTS/CONCLUSIONS: Pathogenic variants in dementia genes were predominantly rare and conserved coding changes. Pathogenic variants within ARSA, CSF1R, and GRN were observed, and candidate variants in GRN and CHMP2B were nominated in ADSP families. An independent case-control study provided evidence of an association between variants in TREM2, APOE, ARSA, CSF1R, PSEN1, and MAPT and risk of AD. Variants in genes which cause dementing disorders may influence the clinical diagnosis of AD in a small proportion of cases within the ADSP.

VL - 45 IS - 1-2 ER - TY - JOUR T1 - Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume. JF - Nat Commun Y1 - 2018 A1 - Vojinovic, Dina A1 - Adams, Hieab H A1 - Jian, Xueqiu A1 - Yang, Qiong A1 - Smith, Albert Vernon A1 - Bis, Joshua C A1 - Teumer, Alexander A1 - Scholz, Markus A1 - Armstrong, Nicola J A1 - Hofer, Edith A1 - Saba, Yasaman A1 - Luciano, Michelle A1 - Bernard, Manon A1 - Trompet, Stella A1 - Yang, Jingyun A1 - Gillespie, Nathan A A1 - van der Lee, Sven J A1 - Neumann, Alexander A1 - Ahmad, Shahzad A1 - Andreassen, Ole A A1 - Ames, David A1 - Amin, Najaf A1 - Arfanakis, Konstantinos A1 - Bastin, Mark E A1 - Becker, Diane M A1 - Beiser, Alexa S A1 - Beyer, Frauke A1 - Brodaty, Henry A1 - Bryan, R Nick A1 - Bülow, Robin A1 - Dale, Anders M A1 - De Jager, Philip L A1 - Deary, Ian J A1 - DeCarli, Charles A1 - Fleischman, Debra A A1 - Gottesman, Rebecca F A1 - van der Grond, Jeroen A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Homuth, Georg A1 - Knopman, David S A1 - Kwok, John B A1 - Lewis, Cora E A1 - Li, Shuo A1 - Loeffler, Markus A1 - Lopez, Oscar L A1 - Maillard, Pauline A1 - El Marroun, Hanan A1 - Mather, Karen A A1 - Mosley, Thomas H A1 - Muetzel, Ryan L A1 - Nauck, Matthias A1 - Nyquist, Paul A A1 - Panizzon, Matthew S A1 - Pausova, Zdenka A1 - Psaty, Bruce M A1 - Rice, Ken A1 - Rotter, Jerome I A1 - Royle, Natalie A1 - Satizabal, Claudia L A1 - Schmidt, Reinhold A1 - Schofield, Peter R A1 - Schreiner, Pamela J A1 - Sidney, Stephen A1 - Stott, David J A1 - Thalamuthu, Anbupalam A1 - Uitterlinden, André G A1 - Valdés Hernández, Maria C A1 - Vernooij, Meike W A1 - Wen, Wei A1 - White, Tonya A1 - Witte, A Veronica A1 - Wittfeld, Katharina A1 - Wright, Margaret J A1 - Yanek, Lisa R A1 - Tiemeier, Henning A1 - Kremen, William S A1 - Bennett, David A A1 - Jukema, J Wouter A1 - Paus, Tomáš A1 - Wardlaw, Joanna M A1 - Schmidt, Helena A1 - Sachdev, Perminder S A1 - Villringer, Arno A1 - Grabe, Hans Jörgen A1 - Longstreth, W T A1 - van Duijn, Cornelia M A1 - Launer, Lenore J A1 - Seshadri, Sudha A1 - Ikram, M Arfan A1 - Fornage, Myriam AB -

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρ = -0.59, p-value = 3.14 × 10), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.

VL - 9 IS - 1 ER - TY - JOUR T1 - GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes. JF - Nat Commun Y1 - 2018 A1 - Franceschini, Nora A1 - Giambartolomei, Claudia A1 - de Vries, Paul S A1 - Finan, Chris A1 - Bis, Joshua C A1 - Huntley, Rachael P A1 - Lovering, Ruth C A1 - Tajuddin, Salman M A1 - Winkler, Thomas W A1 - Graff, Misa A1 - Kavousi, Maryam A1 - Dale, Caroline A1 - Smith, Albert V A1 - Hofer, Edith A1 - van Leeuwen, Elisabeth M A1 - Nolte, Ilja M A1 - Lu, Lingyi A1 - Scholz, Markus A1 - Sargurupremraj, Muralidharan A1 - Pitkänen, Niina A1 - Franzén, Oscar A1 - Joshi, Peter K A1 - Noordam, Raymond A1 - Marioni, Riccardo E A1 - Hwang, Shih-Jen A1 - Musani, Solomon K A1 - Schminke, Ulf A1 - Palmas, Walter A1 - Isaacs, Aaron A1 - Correa, Adolfo A1 - Zonderman, Alan B A1 - Hofman, Albert A1 - Teumer, Alexander A1 - Cox, Amanda J A1 - Uitterlinden, André G A1 - Wong, Andrew A1 - Smit, Andries J A1 - Newman, Anne B A1 - Britton, Annie A1 - Ruusalepp, Arno A1 - Sennblad, Bengt A1 - Hedblad, Bo A1 - Pasaniuc, Bogdan A1 - Penninx, Brenda W A1 - Langefeld, Carl D A1 - Wassel, Christina L A1 - Tzourio, Christophe A1 - Fava, Cristiano A1 - Baldassarre, Damiano A1 - O'Leary, Daniel H A1 - Teupser, Daniel A1 - Kuh, Diana A1 - Tremoli, Elena A1 - Mannarino, Elmo A1 - Grossi, Enzo A1 - Boerwinkle, Eric A1 - Schadt, Eric E A1 - Ingelsson, Erik A1 - Veglia, Fabrizio A1 - Rivadeneira, Fernando A1 - Beutner, Frank A1 - Chauhan, Ganesh A1 - Heiss, Gerardo A1 - Snieder, Harold A1 - Campbell, Harry A1 - Völzke, Henry A1 - Markus, Hugh S A1 - Deary, Ian J A1 - Jukema, J Wouter A1 - de Graaf, Jacqueline A1 - Price, Jacqueline A1 - Pott, Janne A1 - Hopewell, Jemma C A1 - Liang, Jingjing A1 - Thiery, Joachim A1 - Engmann, Jorgen A1 - Gertow, Karl A1 - Rice, Kenneth A1 - Taylor, Kent D A1 - Dhana, Klodian A1 - Kiemeney, Lambertus A L M A1 - Lind, Lars A1 - Raffield, Laura M A1 - Launer, Lenore J A1 - Holdt, Lesca M A1 - Dörr, Marcus A1 - Dichgans, Martin A1 - Traylor, Matthew A1 - Sitzer, Matthias A1 - Kumari, Meena A1 - Kivimaki, Mika A1 - Nalls, Mike A A1 - Melander, Olle A1 - Raitakari, Olli A1 - Franco, Oscar H A1 - Rueda-Ochoa, Oscar L A1 - Roussos, Panos A1 - Whincup, Peter H A1 - Amouyel, Philippe A1 - Giral, Philippe A1 - Anugu, Pramod A1 - Wong, Quenna A1 - Malik, Rainer A1 - Rauramaa, Rainer A1 - Burkhardt, Ralph A1 - Hardy, Rebecca A1 - Schmidt, Reinhold A1 - de Mutsert, Renée A1 - Morris, Richard W A1 - Strawbridge, Rona J A1 - Wannamethee, S Goya A1 - Hägg, Sara A1 - Shah, Sonia A1 - McLachlan, Stela A1 - Trompet, Stella A1 - Seshadri, Sudha A1 - Kurl, Sudhir A1 - Heckbert, Susan R A1 - Ring, Susan A1 - Harris, Tamara B A1 - Lehtimäki, Terho A1 - Galesloot, Tessel E A1 - Shah, Tina A1 - de Faire, Ulf A1 - Plagnol, Vincent A1 - Rosamond, Wayne D A1 - Post, Wendy A1 - Zhu, Xiaofeng A1 - Zhang, Xiaoling A1 - Guo, Xiuqing A1 - Saba, Yasaman A1 - Dehghan, Abbas A1 - Seldenrijk, Adrie A1 - Morrison, Alanna C A1 - Hamsten, Anders A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Lawlor, Deborah A A1 - Mook-Kanamori, Dennis O A1 - Bowden, Donald W A1 - Schmidt, Helena A1 - Wilson, James F A1 - Wilson, James G A1 - Rotter, Jerome I A1 - Wardlaw, Joanna M A1 - Deanfield, John A1 - Halcox, Julian A1 - Lyytikäinen, Leo-Pekka A1 - Loeffler, Markus A1 - Evans, Michele K A1 - Debette, Stephanie A1 - Humphries, Steve E A1 - Völker, Uwe A1 - Gudnason, Vilmundur A1 - Hingorani, Aroon D A1 - Björkegren, Johan L M A1 - Casas, Juan P A1 - O'Donnell, Christopher J KW - ADAMTS9 Protein KW - Amino Acid Oxidoreductases KW - Carotid Intima-Media Thickness KW - Coronary Disease KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Lod Score KW - Plaque, Atherosclerotic KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Risk Factors AB -

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.

VL - 9 IS - 1 ER - TY - JOUR T1 - A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. JF - Am J Hum Genet Y1 - 2018 A1 - Sung, Yun J A1 - Winkler, Thomas W A1 - de Las Fuentes, Lisa A1 - Bentley, Amy R A1 - Brown, Michael R A1 - Kraja, Aldi T A1 - Schwander, Karen A1 - Ntalla, Ioanna A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Lu, Yingchang A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Li, Changwei A1 - Feitosa, Mary F A1 - Kilpeläinen, Tuomas O A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Aslibekyan, Stella A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Dorajoo, Rajkumar A1 - Liu, Yongmei A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert Vernon A1 - Tajuddin, Salman M A1 - Tayo, Bamidele O A1 - Warren, Helen R A1 - Zhao, Wei A1 - Zhou, Yanhua A1 - Matoba, Nana A1 - Sofer, Tamar A1 - Alver, Maris A1 - Amini, Marzyeh A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Gandin, Ilaria A1 - Gao, Chuan A1 - Giulianini, Franco A1 - Goel, Anuj A1 - Harris, Sarah E A1 - Hartwig, Fernando Pires A1 - Horimoto, Andrea R V R A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Kähönen, Mika A1 - Kasturiratne, Anuradhani A1 - Kuhnel, Brigitte A1 - Leander, Karin A1 - Lee, Wen-Jane A1 - Lin, Keng-Hung A1 - 'an Luan, Jian A1 - McKenzie, Colin A A1 - Meian, He A1 - Nelson, Christopher P A1 - Rauramaa, Rainer A1 - Schupf, Nicole A1 - Scott, Robert A A1 - Sheu, Wayne H H A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Wang, Heming A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Afaq, Saima A1 - Alfred, Tamuno A1 - Amin, Najaf A1 - Arking, Dan A1 - Aung, Tin A1 - Barr, R Graham A1 - Bielak, Lawrence F A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Braund, Peter S A1 - Brody, Jennifer A A1 - Broeckel, Ulrich A1 - Cabrera, Claudia P A1 - Cade, Brian A1 - Caizheng, Yu A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Chakravarti, Aravinda A1 - Chauhan, Ganesh A1 - Christensen, Kaare A1 - Cocca, Massimiliano A1 - Collins, Francis S A1 - Connell, John M A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - Debette, Stephanie A1 - Dörr, Marcus A1 - Duan, Qing A1 - Eaton, Charles B A1 - Ehret, Georg A1 - Evangelou, Evangelos A1 - Faul, Jessica D A1 - Fisher, Virginia A A1 - Forouhi, Nita G A1 - Franco, Oscar H A1 - Friedlander, Yechiel A1 - Gao, He A1 - Gigante, Bruna A1 - Graff, Misa A1 - Gu, C Charles A1 - Gu, Dongfeng A1 - Gupta, Preeti A1 - Hagenaars, Saskia P A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Hofman, Albert A1 - Howard, Barbara V A1 - Hunt, Steven A1 - Irvin, Marguerite R A1 - Jia, Yucheng A1 - Joehanes, Roby A1 - Justice, Anne E A1 - Katsuya, Tomohiro A1 - Kaufman, Joel A1 - Kerrison, Nicola D A1 - Khor, Chiea Chuen A1 - Koh, Woon-Puay A1 - Koistinen, Heikki A A1 - Komulainen, Pirjo A1 - Kooperberg, Charles A1 - Krieger, Jose E A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lewis, Cora E A1 - Li, Yize A1 - Lim, Sing Hui A1 - Lin, Shiow A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Liu, Jingmin A1 - Liu, Kiang A1 - Liu, Yeheng A1 - Loh, Marie A1 - Lohman, Kurt K A1 - Long, Jirong A1 - Louie, Tin A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milani, Lili A1 - Momozawa, Yukihide A1 - Morris, Andrew P A1 - Mosley, Thomas H A1 - Munson, Peter A1 - Murray, Alison D A1 - Nalls, Mike A A1 - Nasri, Ubaydah A1 - Norris, Jill M A1 - North, Kari A1 - Ogunniyi, Adesola A1 - Padmanabhan, Sandosh A1 - Palmas, Walter R A1 - Palmer, Nicholette D A1 - Pankow, James S A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Raitakari, Olli T A1 - Renstrom, Frida A1 - Rice, Treva K A1 - Ridker, Paul M A1 - Robino, Antonietta A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rudan, Igor A1 - Sabanayagam, Charumathi A1 - Salako, Babatunde L A1 - Sandow, Kevin A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Scott, William R A1 - Seshadri, Sudha A1 - Sever, Peter A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Tang, Hua A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Uitterlinden, André G A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Ya X A1 - Wei, Wen Bin A1 - Williams, Christine A1 - Wilson, Gregory A1 - Wojczynski, Mary K A1 - Yao, Jie A1 - Yuan, Jian-Min A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Chen, Yii-Der Ida A1 - de Faire, Ulf A1 - Deary, Ian J A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Forrester, Terrence A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Horta, Bernardo Lessa A1 - Hung, Yi-Jen A1 - Jonas, Jost B A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Laakso, Markku A1 - Lehtimäki, Terho A1 - Liang, Kae-Woei A1 - Magnusson, Patrik K E A1 - Newman, Anne B A1 - Oldehinkel, Albertine J A1 - Pereira, Alexandre C A1 - Redline, Susan A1 - Rettig, Rainer A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Kamatani, Yoichiro A1 - Laurie, Cathy C A1 - Bouchard, Claude A1 - Cooper, Richard S A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Kardia, Sharon L R A1 - Kritchevsky, Stephen B A1 - Levy, Daniel A1 - O'Connell, Jeff R A1 - Psaty, Bruce M A1 - van Dam, Rob M A1 - Sims, Mario A1 - Arnett, Donna K A1 - Mook-Kanamori, Dennis O A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - Fornage, Myriam A1 - Rotimi, Charles N A1 - Province, Michael A A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Loos, Ruth J F A1 - Reiner, Alex P A1 - Rotter, Jerome I A1 - Zhu, Xiaofeng A1 - Bierut, Laura J A1 - Gauderman, W James A1 - Caulfield, Mark J A1 - Elliott, Paul A1 - Rice, Kenneth A1 - Munroe, Patricia B A1 - Morrison, Alanna C A1 - Cupples, L Adrienne A1 - Rao, Dabeeru C A1 - Chasman, Daniel I AB -

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).

VL - 102 IS - 3 ER - TY - JOUR T1 - Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. JF - Nat Genet Y1 - 2018 A1 - Malik, Rainer A1 - Chauhan, Ganesh A1 - Traylor, Matthew A1 - Sargurupremraj, Muralidharan A1 - Okada, Yukinori A1 - Mishra, Aniket A1 - Rutten-Jacobs, Loes A1 - Giese, Anne-Katrin A1 - van der Laan, Sander W A1 - Gretarsdottir, Solveig A1 - Anderson, Christopher D A1 - Chong, Michael A1 - Adams, Hieab H H A1 - Ago, Tetsuro A1 - Almgren, Peter A1 - Amouyel, Philippe A1 - Ay, Hakan A1 - Bartz, Traci M A1 - Benavente, Oscar R A1 - Bevan, Steve A1 - Boncoraglio, Giorgio B A1 - Brown, Robert D A1 - Butterworth, Adam S A1 - Carrera, Caty A1 - Carty, Cara L A1 - Chasman, Daniel I A1 - Chen, Wei-Min A1 - Cole, John W A1 - Correa, Adolfo A1 - Cotlarciuc, Ioana A1 - Cruchaga, Carlos A1 - Danesh, John A1 - de Bakker, Paul I W A1 - DeStefano, Anita L A1 - den Hoed, Marcel A1 - Duan, Qing A1 - Engelter, Stefan T A1 - Falcone, Guido J A1 - Gottesman, Rebecca F A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Haessler, Jeffrey A1 - Harris, Tamara B A1 - Hassan, Ahamad A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Holliday, Elizabeth G A1 - Howard, George A1 - Hsu, Fang-Chi A1 - Hyacinth, Hyacinth I A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Irvin, Marguerite R A1 - Jian, Xueqiu A1 - Jimenez-Conde, Jordi A1 - Johnson, Julie A A1 - Jukema, J Wouter A1 - Kanai, Masahiro A1 - Keene, Keith L A1 - Kissela, Brett M A1 - Kleindorfer, Dawn O A1 - Kooperberg, Charles A1 - Kubo, Michiaki A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lee, Jin-Moo A1 - Lemmens, Robin A1 - Leys, Didier A1 - Lewis, Cathryn M A1 - Lin, Wei-Yu A1 - Lindgren, Arne G A1 - Lorentzen, Erik A1 - Magnusson, Patrik K A1 - Maguire, Jane A1 - Manichaikul, Ani A1 - McArdle, Patrick F A1 - Meschia, James F A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - Nalls, Michael A A1 - Ninomiya, Toshiharu A1 - O'Donnell, Martin J A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Rannikmae, Kristiina A1 - Reiner, Alexander P A1 - Rexrode, Kathryn M A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rost, Natalia S A1 - Rothwell, Peter M A1 - Rotter, Jerome I A1 - Rundek, Tatjana A1 - Sacco, Ralph L A1 - Sakaue, Saori A1 - Sale, Michèle M A1 - Salomaa, Veikko A1 - Sapkota, Bishwa R A1 - Schmidt, Reinhold A1 - Schmidt, Carsten O A1 - Schminke, Ulf A1 - Sharma, Pankaj A1 - Slowik, Agnieszka A1 - Sudlow, Cathie L M A1 - Tanislav, Christian A1 - Tatlisumak, Turgut A1 - Taylor, Kent D A1 - Thijs, Vincent N S A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tiedt, Steffen A1 - Trompet, Stella A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Walters, Matthew A1 - Wareham, Nicholas J A1 - Wassertheil-Smoller, Sylvia A1 - Wilson, James G A1 - Wiggins, Kerri L A1 - Yang, Qiong A1 - Yusuf, Salim A1 - Bis, Joshua C A1 - Pastinen, Tomi A1 - Ruusalepp, Arno A1 - Schadt, Eric E A1 - Koplev, Simon A1 - Björkegren, Johan L M A1 - Codoni, Veronica A1 - Civelek, Mete A1 - Smith, Nicholas L A1 - Trégouët, David A A1 - Christophersen, Ingrid E A1 - Roselli, Carolina A1 - Lubitz, Steven A A1 - Ellinor, Patrick T A1 - Tai, E Shyong A1 - Kooner, Jaspal S A1 - Kato, Norihiro A1 - He, Jiang A1 - van der Harst, Pim A1 - Elliott, Paul A1 - Chambers, John C A1 - Takeuchi, Fumihiko A1 - Johnson, Andrew D A1 - Sanghera, Dharambir K A1 - Melander, Olle A1 - Jern, Christina A1 - Strbian, Daniel A1 - Fernandez-Cadenas, Israel A1 - Longstreth, W T A1 - Rolfs, Arndt A1 - Hata, Jun A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Paré, Guillaume A1 - Hopewell, Jemma C A1 - Saleheen, Danish A1 - Stefansson, Kari A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Seshadri, Sudha A1 - Fornage, Myriam A1 - Markus, Hugh S A1 - Howson, Joanna M M A1 - Kamatani, Yoichiro A1 - Debette, Stephanie A1 - Dichgans, Martin A1 - Malik, Rainer A1 - Chauhan, Ganesh A1 - Traylor, Matthew A1 - Sargurupremraj, Muralidharan A1 - Okada, Yukinori A1 - Mishra, Aniket A1 - Rutten-Jacobs, Loes A1 - Giese, Anne-Katrin A1 - van der Laan, Sander W A1 - Gretarsdottir, Solveig A1 - Anderson, Christopher D A1 - Chong, Michael A1 - Adams, Hieab H H A1 - Ago, Tetsuro A1 - Almgren, Peter A1 - Amouyel, Philippe A1 - Ay, Hakan A1 - Bartz, Traci M A1 - Benavente, Oscar R A1 - Bevan, Steve A1 - Boncoraglio, Giorgio B A1 - Brown, Robert D A1 - Butterworth, Adam S A1 - Carrera, Caty A1 - Carty, Cara L A1 - Chasman, Daniel I A1 - Chen, Wei-Min A1 - Cole, John W A1 - Correa, Adolfo A1 - Cotlarciuc, Ioana A1 - Cruchaga, Carlos A1 - Danesh, John A1 - de Bakker, Paul I W A1 - DeStefano, Anita L A1 - Hoed, Marcel den A1 - Duan, Qing A1 - Engelter, Stefan T A1 - Falcone, Guido J A1 - Gottesman, Rebecca F A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Haessler, Jeffrey A1 - Harris, Tamara B A1 - Hassan, Ahamad A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Holliday, Elizabeth G A1 - Howard, George A1 - Hsu, Fang-Chi A1 - Hyacinth, Hyacinth I A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Irvin, Marguerite R A1 - Jian, Xueqiu A1 - Jimenez-Conde, Jordi A1 - Johnson, Julie A A1 - Jukema, J Wouter A1 - Kanai, Masahiro A1 - Keene, Keith L A1 - Kissela, Brett M A1 - Kleindorfer, Dawn O A1 - Kooperberg, Charles A1 - Kubo, Michiaki A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lee, Jin-Moo A1 - Lemmens, Robin A1 - Leys, Didier A1 - Lewis, Cathryn M A1 - Lin, Wei-Yu A1 - Lindgren, Arne G A1 - Lorentzen, Erik A1 - Magnusson, Patrik K A1 - Maguire, Jane A1 - Manichaikul, Ani A1 - McArdle, Patrick F A1 - Meschia, James F A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - Nalls, Michael A A1 - Ninomiya, Toshiharu A1 - O'Donnell, Martin J A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Rannikmae, Kristiina A1 - Reiner, Alexander P A1 - Rexrode, Kathryn M A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rost, Natalia S A1 - Rothwell, Peter M A1 - Rotter, Jerome I A1 - Rundek, Tatjana A1 - Sacco, Ralph L A1 - Sakaue, Saori A1 - Sale, Michèle M A1 - Salomaa, Veikko A1 - Sapkota, Bishwa R A1 - Schmidt, Reinhold A1 - Schmidt, Carsten O A1 - Schminke, Ulf A1 - Sharma, Pankaj A1 - Slowik, Agnieszka A1 - Sudlow, Cathie L M A1 - Tanislav, Christian A1 - Tatlisumak, Turgut A1 - Taylor, Kent D A1 - Thijs, Vincent N S A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tiedt, Steffen A1 - Trompet, Stella A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Walters, Matthew A1 - Wareham, Nicholas J A1 - Wassertheil-Smoller, Sylvia A1 - Wilson, James G A1 - Wiggins, Kerri L A1 - Yang, Qiong A1 - Yusuf, Salim A1 - Amin, Najaf A1 - Aparicio, Hugo S A1 - Arnett, Donna K A1 - Attia, John A1 - Beiser, Alexa S A1 - Berr, Claudine A1 - Buring, Julie E A1 - Bustamante, Mariana A1 - Caso, Valeria A1 - Cheng, Yu-Ching A1 - Choi, Seung Hoan A1 - Chowhan, Ayesha A1 - Cullell, Natalia A1 - Dartigues, Jean-François A1 - Delavaran, Hossein A1 - Delgado, Pilar A1 - Dörr, Marcus A1 - Engström, Gunnar A1 - Ford, Ian A1 - Gurpreet, Wander S A1 - Hamsten, Anders A1 - Heitsch, Laura A1 - Hozawa, Atsushi A1 - Ibanez, Laura A1 - Ilinca, Andreea A1 - Ingelsson, Martin A1 - Iwasaki, Motoki A1 - Jackson, Rebecca D A1 - Jood, Katarina A1 - Jousilahti, Pekka A1 - Kaffashian, Sara A1 - Kalra, Lalit A1 - Kamouchi, Masahiro A1 - Kitazono, Takanari A1 - Kjartansson, Olafur A1 - Kloss, Manja A1 - Koudstaal, Peter J A1 - Krupinski, Jerzy A1 - Labovitz, Daniel L A1 - Laurie, Cathy C A1 - Levi, Christopher R A1 - Li, Linxin A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Lioutas, Vasileios A1 - Liu, Yong Mei A1 - Lopez, Oscar L A1 - Makoto, Hirata A1 - Martinez-Majander, Nicolas A1 - Matsuda, Koichi A1 - Minegishi, Naoko A1 - Montaner, Joan A1 - Morris, Andrew P A1 - Muiño, Elena A1 - Müller-Nurasyid, Martina A1 - Norrving, Bo A1 - Ogishima, Soichi A1 - Parati, Eugenio A A1 - Peddareddygari, Leema Reddy A1 - Pedersen, Nancy L A1 - Pera, Joanna A1 - Perola, Markus A1 - Pezzini, Alessandro A1 - Pileggi, Silvana A1 - Rabionet, Raquel A1 - Riba-Llena, Iolanda A1 - Ribasés, Marta A1 - Romero, Jose R A1 - Roquer, Jaume A1 - Rudd, Anthony G A1 - Sarin, Antti-Pekka A1 - Sarju, Ralhan A1 - Sarnowski, Chloe A1 - Sasaki, Makoto A1 - Satizabal, Claudia L A1 - Satoh, Mamoru A1 - Sattar, Naveed A1 - Sawada, Norie A1 - Sibolt, Gerli A1 - Sigurdsson, Ásgeir A1 - Smith, Albert A1 - Sobue, Kenji A1 - Soriano-Tárraga, Carolina A1 - Stanne, Tara A1 - Stine, O Colin A1 - Stott, David J A1 - Strauch, Konstantin A1 - Takai, Takako A1 - Tanaka, Hideo A1 - Tanno, Kozo A1 - Teumer, Alexander A1 - Tomppo, Liisa A1 - Torres-Aguila, Nuria P A1 - Touze, Emmanuel A1 - Tsugane, Shoichiro A1 - Uitterlinden, André G A1 - Valdimarsson, Einar M A1 - van der Lee, Sven J A1 - Völzke, Henry A1 - Wakai, Kenji A1 - Weir, David A1 - Williams, Stephen R A1 - Wolfe, Charles D A A1 - Wong, Quenna A1 - Xu, Huichun A1 - Yamaji, Taiki A1 - Sanghera, Dharambir K A1 - Melander, Olle A1 - Jern, Christina A1 - Strbian, Daniel A1 - Fernandez-Cadenas, Israel A1 - Longstreth, W T A1 - Rolfs, Arndt A1 - Hata, Jun A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Paré, Guillaume A1 - Hopewell, Jemma C A1 - Saleheen, Danish A1 - Stefansson, Kari A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Seshadri, Sudha A1 - Fornage, Myriam A1 - Markus, Hugh S A1 - Howson, Joanna M M A1 - Kamatani, Yoichiro A1 - Debette, Stephanie A1 - Dichgans, Martin AB -

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.

VL - 50 IS - 4 ER - TY - JOUR T1 - Omega-3 Fatty Acids and Genome-wide Interaction Analyses Reveal DPP10-Pulmonary Function Association. JF - Am J Respir Crit Care Med Y1 - 2018 A1 - Xu, Jiayi A1 - Gaddis, Nathan C A1 - Bartz, Traci M A1 - Hou, Ruixue A1 - Manichaikul, Ani W A1 - Pankratz, Nathan A1 - Smith, Albert V A1 - Sun, Fangui A1 - Terzikhan, Natalie A1 - Markunas, Christina A A1 - Patchen, Bonnie K A1 - Schu, Matthew A1 - Beydoun, May A A1 - Brusselle, Guy G A1 - Eiriksdottir, Gudny A1 - Zhou, Xia A1 - Wood, Alexis C A1 - Graff, Mariaelisa A1 - Harris, Tamara B A1 - Ikram, M Arfan A1 - Jacobs, David R A1 - Launer, Lenore J A1 - Lemaitre, Rozenn N A1 - O'Connor, George A1 - Oelsner, Elizabeth C A1 - Psaty, Bruce M A1 - Ramachandran, Vasan S A1 - Rohde, Rebecca R A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Seshadri, Sudha A1 - Smith, Lewis J A1 - Tiemeier, Henning A1 - Tsai, Michael Y A1 - Uitterlinden, André G A1 - Voruganti, V Saroja A1 - Xu, Hanfei A1 - Zilhão, Nuno R A1 - Fornage, Myriam A1 - Zillikens, M Carola A1 - London, Stephanie J A1 - Barr, R Graham A1 - Dupuis, Josée A1 - Gharib, Sina A A1 - Gudnason, Vilmundur A1 - Lahousse, Lies A1 - North, Kari E A1 - Steffen, Lyn M A1 - Cassano, Patricia A A1 - Hancock, Dana B AB -

RATIONALE: Omega-3 poly-unsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health.

OBJECTIVE: To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility.

METHODS: Associations of n-3 PUFA biomarkers (alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (forced expiratory volume in the first second [FEV], forced vital capacity [FVC], and [FEV/FVC]) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N=16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N=11,962) and replicated in one cohort (N=1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of single nucleotide polymorphism (SNP) associations and their interactions with n-3 PUFAs.

RESULTS: DPA and DHA were positively associated with FEV1 and FVC (P<0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320-an intronic DPP10 SNP-with FVC when incorporating an interaction with DHA, and the finding was replicated (P=9.4×10 across discovery and replication cohorts). The rs11693320-A allele (frequency~80%) was associated with lower FVC (P=2.1×10; β= -161.0mL), and the association was attenuated by higher DHA levels (P=2.1×10; β=36.2mL).

CONCLUSIONS: We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction.

ER - TY - JOUR T1 - Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. JF - Nat Commun Y1 - 2018 A1 - Davies, Gail A1 - Lam, Max A1 - Harris, Sarah E A1 - Trampush, Joey W A1 - Luciano, Michelle A1 - Hill, W David A1 - Hagenaars, Saskia P A1 - Ritchie, Stuart J A1 - Marioni, Riccardo E A1 - Fawns-Ritchie, Chloe A1 - Liewald, David C M A1 - Okely, Judith A A1 - Ahola-Olli, Ari V A1 - Barnes, Catriona L K A1 - Bertram, Lars A1 - Bis, Joshua C A1 - Burdick, Katherine E A1 - Christoforou, Andrea A1 - DeRosse, Pamela A1 - Djurovic, Srdjan A1 - Espeseth, Thomas A1 - Giakoumaki, Stella A1 - Giddaluru, Sudheer A1 - Gustavson, Daniel E A1 - Hayward, Caroline A1 - Hofer, Edith A1 - Ikram, M Arfan A1 - Karlsson, Robert A1 - Knowles, Emma A1 - Lahti, Jari A1 - Leber, Markus A1 - Li, Shuo A1 - Mather, Karen A A1 - Melle, Ingrid A1 - Morris, Derek A1 - Oldmeadow, Christopher A1 - Palviainen, Teemu A1 - Payton, Antony A1 - Pazoki, Raha A1 - Petrovic, Katja A1 - Reynolds, Chandra A A1 - Sargurupremraj, Muralidharan A1 - Scholz, Markus A1 - Smith, Jennifer A A1 - Smith, Albert V A1 - Terzikhan, Natalie A1 - Thalamuthu, Anbupalam A1 - Trompet, Stella A1 - van der Lee, Sven J A1 - Ware, Erin B A1 - Windham, B Gwen A1 - Wright, Margaret J A1 - Yang, Jingyun A1 - Yu, Jin A1 - Ames, David A1 - Amin, Najaf A1 - Amouyel, Philippe A1 - Andreassen, Ole A A1 - Armstrong, Nicola J A1 - Assareh, Amelia A A1 - Attia, John R A1 - Attix, Deborah A1 - Avramopoulos, Dimitrios A1 - Bennett, David A A1 - Böhmer, Anne C A1 - Boyle, Patricia A A1 - Brodaty, Henry A1 - Campbell, Harry A1 - Cannon, Tyrone D A1 - Cirulli, Elizabeth T A1 - Congdon, Eliza A1 - Conley, Emily Drabant A1 - Corley, Janie A1 - Cox, Simon R A1 - Dale, Anders M A1 - Dehghan, Abbas A1 - Dick, Danielle A1 - Dickinson, Dwight A1 - Eriksson, Johan G A1 - Evangelou, Evangelos A1 - Faul, Jessica D A1 - Ford, Ian A1 - Freimer, Nelson A A1 - Gao, He A1 - Giegling, Ina A1 - Gillespie, Nathan A A1 - Gordon, Scott D A1 - Gottesman, Rebecca F A1 - Griswold, Michael E A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hartmann, Annette M A1 - Hatzimanolis, Alex A1 - Heiss, Gerardo A1 - Holliday, Elizabeth G A1 - Joshi, Peter K A1 - Kähönen, Mika A1 - Kardia, Sharon L R A1 - Karlsson, Ida A1 - Kleineidam, Luca A1 - Knopman, David S A1 - Kochan, Nicole A A1 - Konte, Bettina A1 - Kwok, John B A1 - Le Hellard, Stephanie A1 - Lee, Teresa A1 - Lehtimäki, Terho A1 - Li, Shu-Chen A1 - Liu, Tian A1 - Koini, Marisa A1 - London, Edythe A1 - Longstreth, Will T A1 - Lopez, Oscar L A1 - Loukola, Anu A1 - Luck, Tobias A1 - Lundervold, Astri J A1 - Lundquist, Anders A1 - Lyytikäinen, Leo-Pekka A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - Murray, Alison D A1 - Need, Anna C A1 - Noordam, Raymond A1 - Nyberg, Lars A1 - Ollier, William A1 - Papenberg, Goran A1 - Pattie, Alison A1 - Polasek, Ozren A1 - Poldrack, Russell A A1 - Psaty, Bruce M A1 - Reppermund, Simone A1 - Riedel-Heller, Steffi G A1 - Rose, Richard J A1 - Rotter, Jerome I A1 - Roussos, Panos A1 - Rovio, Suvi P A1 - Saba, Yasaman A1 - Sabb, Fred W A1 - Sachdev, Perminder S A1 - Satizabal, Claudia L A1 - Schmid, Matthias A1 - Scott, Rodney J A1 - Scult, Matthew A A1 - Simino, Jeannette A1 - Slagboom, P Eline A1 - Smyrnis, Nikolaos A1 - Soumaré, Aïcha A1 - Stefanis, Nikos C A1 - Stott, David J A1 - Straub, Richard E A1 - Sundet, Kjetil A1 - Taylor, Adele M A1 - Taylor, Kent D A1 - Tzoulaki, Ioanna A1 - Tzourio, Christophe A1 - Uitterlinden, Andre A1 - Vitart, Veronique A1 - Voineskos, Aristotle N A1 - Kaprio, Jaakko A1 - Wagner, Michael A1 - Wagner, Holger A1 - Weinhold, Leonie A1 - Wen, K Hoyan A1 - Widen, Elisabeth A1 - Yang, Qiong A1 - Zhao, Wei A1 - Adams, Hieab H H A1 - Arking, Dan E A1 - Bilder, Robert M A1 - Bitsios, Panos A1 - Boerwinkle, Eric A1 - Chiba-Falek, Ornit A1 - Corvin, Aiden A1 - De Jager, Philip L A1 - Debette, Stephanie A1 - Donohoe, Gary A1 - Elliott, Paul A1 - Fitzpatrick, Annette L A1 - Gill, Michael A1 - Glahn, David C A1 - Hägg, Sara A1 - Hansell, Narelle K A1 - Hariri, Ahmad R A1 - Ikram, M Kamran A1 - Jukema, J Wouter A1 - Vuoksimaa, Eero A1 - Keller, Matthew C A1 - Kremen, William S A1 - Launer, Lenore A1 - Lindenberger, Ulman A1 - Palotie, Aarno A1 - Pedersen, Nancy L A1 - Pendleton, Neil A1 - Porteous, David J A1 - Räikkönen, Katri A1 - Raitakari, Olli T A1 - Ramirez, Alfredo A1 - Reinvang, Ivar A1 - Rudan, Igor A1 - Schmidt, Reinhold A1 - Schmidt, Helena A1 - Schofield, Peter W A1 - Schofield, Peter R A1 - Starr, John M A1 - Steen, Vidar M A1 - Trollor, Julian N A1 - Turner, Steven T A1 - van Duijn, Cornelia M A1 - Villringer, Arno A1 - Weinberger, Daniel R A1 - Weir, David R A1 - Wilson, James F A1 - Malhotra, Anil A1 - McIntosh, Andrew M A1 - Gale, Catharine R A1 - Seshadri, Sudha A1 - Mosley, Thomas H A1 - Bressler, Jan A1 - Lencz, Todd A1 - Deary, Ian J AB -

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.

VL - 9 IS - 1 ER - TY - JOUR T1 - Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation. JF - Mol Psychiatry Y1 - 2018 A1 - Bis, Joshua C A1 - Jian, Xueqiu A1 - Kunkle, Brian W A1 - Chen, Yuning A1 - Hamilton-Nelson, Kara L A1 - Bush, William S A1 - Salerno, William J A1 - Lancour, Daniel A1 - Ma, Yiyi A1 - Renton, Alan E A1 - Marcora, Edoardo A1 - Farrell, John J A1 - Zhao, Yi A1 - Qu, Liming A1 - Ahmad, Shahzad A1 - Amin, Najaf A1 - Amouyel, Philippe A1 - Beecham, Gary W A1 - Below, Jennifer E A1 - Campion, Dominique A1 - Charbonnier, Camille A1 - Chung, Jaeyoon A1 - Crane, Paul K A1 - Cruchaga, Carlos A1 - Cupples, L Adrienne A1 - Dartigues, Jean-François A1 - Debette, Stephanie A1 - Deleuze, Jean-Francois A1 - Fulton, Lucinda A1 - Gabriel, Stacey B A1 - Genin, Emmanuelle A1 - Gibbs, Richard A A1 - Goate, Alison A1 - Grenier-Boley, Benjamin A1 - Gupta, Namrata A1 - Haines, Jonathan L A1 - Havulinna, Aki S A1 - Helisalmi, Seppo A1 - Hiltunen, Mikko A1 - Howrigan, Daniel P A1 - Ikram, M Arfan A1 - Kaprio, Jaakko A1 - Konrad, Jan A1 - Kuzma, Amanda A1 - Lander, Eric S A1 - Lathrop, Mark A1 - Lehtimäki, Terho A1 - Lin, Honghuang A1 - Mattila, Kari A1 - Mayeux, Richard A1 - Muzny, Donna M A1 - Nasser, Waleed A1 - Neale, Benjamin A1 - Nho, Kwangsik A1 - Nicolas, Gaël A1 - Patel, Devanshi A1 - Pericak-Vance, Margaret A A1 - Perola, Markus A1 - Psaty, Bruce M A1 - Quenez, Olivier A1 - Rajabli, Farid A1 - Redon, Richard A1 - Reitz, Christiane A1 - Remes, Anne M A1 - Salomaa, Veikko A1 - Sarnowski, Chloe A1 - Schmidt, Helena A1 - Schmidt, Michael A1 - Schmidt, Reinhold A1 - Soininen, Hilkka A1 - Thornton, Timothy A A1 - Tosto, Giuseppe A1 - Tzourio, Christophe A1 - van der Lee, Sven J A1 - van Duijn, Cornelia M A1 - Vardarajan, Badri A1 - Wang, Weixin A1 - Wijsman, Ellen A1 - Wilson, Richard K A1 - Witten, Daniela A1 - Worley, Kim C A1 - Zhang, Xiaoling A1 - Bellenguez, Céline A1 - Lambert, Jean-Charles A1 - Kurki, Mitja I A1 - Palotie, Aarno A1 - Daly, Mark A1 - Boerwinkle, Eric A1 - Lunetta, Kathryn L A1 - DeStefano, Anita L A1 - Dupuis, Josée A1 - Martin, Eden R A1 - Schellenberg, Gerard D A1 - Seshadri, Sudha A1 - Naj, Adam C A1 - Fornage, Myriam A1 - Farrer, Lindsay A AB -

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.

ER - TY - JOUR T1 - Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects. JF - Brain Y1 - 2019 A1 - Mishra, Aniket A1 - Chauhan, Ganesh A1 - Violleau, Marie-Helene A1 - Vojinovic, Dina A1 - Jian, Xueqiu A1 - Bis, Joshua C A1 - Li, Shuo A1 - Saba, Yasaman A1 - Grenier-Boley, Benjamin A1 - Yang, Qiong A1 - Bartz, Traci M A1 - Hofer, Edith A1 - Soumaré, Aïcha A1 - Peng, Fen A1 - Duperron, Marie-Gabrielle A1 - Foglio, Mario A1 - Mosley, Thomas H A1 - Schmidt, Reinhold A1 - Psaty, Bruce M A1 - Launer, Lenore J A1 - Boerwinkle, Eric A1 - Zhu, Yicheng A1 - Mazoyer, Bernard A1 - Lathrop, Mark A1 - Bellenguez, Céline A1 - van Duijn, Cornelia M A1 - Ikram, M Arfan A1 - Schmidt, Helena A1 - Longstreth, W T A1 - Fornage, Myriam A1 - Seshadri, Sudha A1 - Joutel, Anne A1 - Tzourio, Christophe A1 - Debette, Stephanie AB -

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.

ER - TY - JOUR T1 - Genetic architecture of subcortical brain structures in 38,851 individuals. JF - Nat Genet Y1 - 2019 A1 - Satizabal, Claudia L A1 - Adams, Hieab H H A1 - Hibar, Derrek P A1 - White, Charles C A1 - Knol, Maria J A1 - Stein, Jason L A1 - Scholz, Markus A1 - Sargurupremraj, Muralidharan A1 - Jahanshad, Neda A1 - Roshchupkin, Gennady V A1 - Smith, Albert V A1 - Bis, Joshua C A1 - Jian, Xueqiu A1 - Luciano, Michelle A1 - Hofer, Edith A1 - Teumer, Alexander A1 - van der Lee, Sven J A1 - Yang, Jingyun A1 - Yanek, Lisa R A1 - Lee, Tom V A1 - Li, Shuo A1 - Hu, Yanhui A1 - Koh, Jia Yu A1 - Eicher, John D A1 - Desrivières, Sylvane A1 - Arias-Vasquez, Alejandro A1 - Chauhan, Ganesh A1 - Athanasiu, Lavinia A1 - Rentería, Miguel E A1 - Kim, Sungeun A1 - Hoehn, David A1 - Armstrong, Nicola J A1 - Chen, Qiang A1 - Holmes, Avram J A1 - den Braber, Anouk A1 - Kloszewska, Iwona A1 - Andersson, Micael A1 - Espeseth, Thomas A1 - Grimm, Oliver A1 - Abramovic, Lucija A1 - Alhusaini, Saud A1 - Milaneschi, Yuri A1 - Papmeyer, Martina A1 - Axelsson, Tomas A1 - Ehrlich, Stefan A1 - Roiz-Santiañez, Roberto A1 - Kraemer, Bernd A1 - Håberg, Asta K A1 - Jones, Hannah J A1 - Pike, G Bruce A1 - Stein, Dan J A1 - Stevens, Allison A1 - Bralten, Janita A1 - Vernooij, Meike W A1 - Harris, Tamara B A1 - Filippi, Irina A1 - Witte, A Veronica A1 - Guadalupe, Tulio A1 - Wittfeld, Katharina A1 - Mosley, Thomas H A1 - Becker, James T A1 - Doan, Nhat Trung A1 - Hagenaars, Saskia P A1 - Saba, Yasaman A1 - Cuellar-Partida, Gabriel A1 - Amin, Najaf A1 - Hilal, Saima A1 - Nho, Kwangsik A1 - Mirza-Schreiber, Nazanin A1 - Arfanakis, Konstantinos A1 - Becker, Diane M A1 - Ames, David A1 - Goldman, Aaron L A1 - Lee, Phil H A1 - Boomsma, Dorret I A1 - Lovestone, Simon A1 - Giddaluru, Sudheer A1 - Le Hellard, Stephanie A1 - Mattheisen, Manuel A1 - Bohlken, Marc M A1 - Kasperaviciute, Dalia A1 - Schmaal, Lianne A1 - Lawrie, Stephen M A1 - Agartz, Ingrid A1 - Walton, Esther A1 - Tordesillas-Gutierrez, Diana A1 - Davies, Gareth E A1 - Shin, Jean A1 - Ipser, Jonathan C A1 - Vinke, Louis N A1 - Hoogman, Martine A1 - Jia, Tianye A1 - Burkhardt, Ralph A1 - Klein, Marieke A1 - Crivello, Fabrice A1 - Janowitz, Deborah A1 - Carmichael, Owen A1 - Haukvik, Unn K A1 - Aribisala, Benjamin S A1 - Schmidt, Helena A1 - Strike, Lachlan T A1 - Cheng, Ching-Yu A1 - Risacher, Shannon L A1 - Pütz, Benno A1 - Fleischman, Debra A A1 - Assareh, Amelia A A1 - Mattay, Venkata S A1 - Buckner, Randy L A1 - Mecocci, Patrizia A1 - Dale, Anders M A1 - Cichon, Sven A1 - Boks, Marco P A1 - Matarin, Mar A1 - Penninx, Brenda W J H A1 - Calhoun, Vince D A1 - Chakravarty, M Mallar A1 - Marquand, Andre F A1 - Macare, Christine A1 - Kharabian Masouleh, Shahrzad A1 - Oosterlaan, Jaap A1 - Amouyel, Philippe A1 - Hegenscheid, Katrin A1 - Rotter, Jerome I A1 - Schork, Andrew J A1 - Liewald, David C M A1 - de Zubicaray, Greig I A1 - Wong, Tien Yin A1 - Shen, Li A1 - Sämann, Philipp G A1 - Brodaty, Henry A1 - Roffman, Joshua L A1 - de Geus, Eco J C A1 - Tsolaki, Magda A1 - Erk, Susanne A1 - van Eijk, Kristel R A1 - Cavalleri, Gianpiero L A1 - van der Wee, Nic J A A1 - McIntosh, Andrew M A1 - Gollub, Randy L A1 - Bulayeva, Kazima B A1 - Bernard, Manon A1 - Richards, Jennifer S A1 - Himali, Jayandra J A1 - Loeffler, Markus A1 - Rommelse, Nanda A1 - Hoffmann, Wolfgang A1 - Westlye, Lars T A1 - Valdés Hernández, Maria C A1 - Hansell, Narelle K A1 - van Erp, Theo G M A1 - Wolf, Christiane A1 - Kwok, John B J A1 - Vellas, Bruno A1 - Heinz, Andreas A1 - Olde Loohuis, Loes M A1 - Delanty, Norman A1 - Ho, Beng-Choon A1 - Ching, Christopher R K A1 - Shumskaya, Elena A1 - Singh, Baljeet A1 - Hofman, Albert A1 - van der Meer, Dennis A1 - Homuth, Georg A1 - Psaty, Bruce M A1 - Bastin, Mark E A1 - Montgomery, Grant W A1 - Foroud, Tatiana M A1 - Reppermund, Simone A1 - Hottenga, Jouke-Jan A1 - Simmons, Andrew A1 - Meyer-Lindenberg, Andreas A1 - Cahn, Wiepke A1 - Whelan, Christopher D A1 - van Donkelaar, Marjolein M J A1 - Yang, Qiong A1 - Hosten, Norbert A1 - Green, Robert C A1 - Thalamuthu, Anbupalam A1 - Mohnke, Sebastian A1 - Hulshoff Pol, Hilleke E A1 - Lin, Honghuang A1 - Jack, Clifford R A1 - Schofield, Peter R A1 - Mühleisen, Thomas W A1 - Maillard, Pauline A1 - Potkin, Steven G A1 - Wen, Wei A1 - Fletcher, Evan A1 - Toga, Arthur W A1 - Gruber, Oliver A1 - Huentelman, Matthew A1 - Davey Smith, George A1 - Launer, Lenore J A1 - Nyberg, Lars A1 - Jönsson, Erik G A1 - Crespo-Facorro, Benedicto A1 - Koen, Nastassja A1 - Greve, Douglas N A1 - Uitterlinden, André G A1 - Weinberger, Daniel R A1 - Steen, Vidar M A1 - Fedko, Iryna O A1 - Groenewold, Nynke A A1 - Niessen, Wiro J A1 - Toro, Roberto A1 - Tzourio, Christophe A1 - Longstreth, William T A1 - Ikram, M Kamran A1 - Smoller, Jordan W A1 - van Tol, Marie-Jose A1 - Sussmann, Jessika E A1 - Paus, Tomáš A1 - Lemaître, Hervé A1 - Schroeter, Matthias L A1 - Mazoyer, Bernard A1 - Andreassen, Ole A A1 - Holsboer, Florian A1 - Depondt, Chantal A1 - Veltman, Dick J A1 - Turner, Jessica A A1 - Pausova, Zdenka A1 - Schumann, Gunter A1 - van Rooij, Daan A1 - Djurovic, Srdjan A1 - Deary, Ian J A1 - McMahon, Katie L A1 - Müller-Myhsok, Bertram A1 - Brouwer, Rachel M A1 - Soininen, Hilkka A1 - Pandolfo, Massimo A1 - Wassink, Thomas H A1 - Cheung, Joshua W A1 - Wolfers, Thomas A1 - Martinot, Jean-Luc A1 - Zwiers, Marcel P A1 - Nauck, Matthias A1 - Melle, Ingrid A1 - Martin, Nicholas G A1 - Kanai, Ryota A1 - Westman, Eric A1 - Kahn, René S A1 - Sisodiya, Sanjay M A1 - White, Tonya A1 - Saremi, Arvin A1 - van Bokhoven, Hans A1 - Brunner, Han G A1 - Völzke, Henry A1 - Wright, Margaret J A1 - van 't Ent, Dennis A1 - Nöthen, Markus M A1 - Ophoff, Roel A A1 - Buitelaar, Jan K A1 - Fernández, Guillén A1 - Sachdev, Perminder S A1 - Rietschel, Marcella A1 - van Haren, Neeltje E M A1 - Fisher, Simon E A1 - Beiser, Alexa S A1 - Francks, Clyde A1 - Saykin, Andrew J A1 - Mather, Karen A A1 - Romanczuk-Seiferth, Nina A1 - Hartman, Catharina A A1 - DeStefano, Anita L A1 - Heslenfeld, Dirk J A1 - Weiner, Michael W A1 - Walter, Henrik A1 - Hoekstra, Pieter J A1 - Nyquist, Paul A A1 - Franke, Barbara A1 - Bennett, David A A1 - Grabe, Hans J A1 - Johnson, Andrew D A1 - Chen, Christopher A1 - van Duijn, Cornelia M A1 - Lopez, Oscar L A1 - Fornage, Myriam A1 - Wardlaw, Joanna M A1 - Schmidt, Reinhold A1 - DeCarli, Charles A1 - De Jager, Philip L A1 - Villringer, Arno A1 - Debette, Stephanie A1 - Gudnason, Vilmundur A1 - Medland, Sarah E A1 - Shulman, Joshua M A1 - Thompson, Paul M A1 - Seshadri, Sudha A1 - Ikram, M Arfan AB -

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.

VL - 51 IS - 11 ER - TY - JOUR T1 - Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. JF - Nat Genet Y1 - 2019 A1 - Kunkle, Brian W A1 - Grenier-Boley, Benjamin A1 - Sims, Rebecca A1 - Bis, Joshua C A1 - Damotte, Vincent A1 - Naj, Adam C A1 - Boland, Anne A1 - Vronskaya, Maria A1 - van der Lee, Sven J A1 - Amlie-Wolf, Alexandre A1 - Bellenguez, Céline A1 - Frizatti, Aura A1 - Chouraki, Vincent A1 - Martin, Eden R A1 - Sleegers, Kristel A1 - Badarinarayan, Nandini A1 - Jakobsdottir, Johanna A1 - Hamilton-Nelson, Kara L A1 - Moreno-Grau, Sonia A1 - Olaso, Robert A1 - Raybould, Rachel A1 - Chen, Yuning A1 - Kuzma, Amanda B A1 - Hiltunen, Mikko A1 - Morgan, Taniesha A1 - Ahmad, Shahzad A1 - Vardarajan, Badri N A1 - Epelbaum, Jacques A1 - Hoffmann, Per A1 - Boada, Merce A1 - Beecham, Gary W A1 - Garnier, Jean-Guillaume A1 - Harold, Denise A1 - Fitzpatrick, Annette L A1 - Valladares, Otto A1 - Moutet, Marie-Laure A1 - Gerrish, Amy A1 - Smith, Albert V A1 - Qu, Liming A1 - Bacq, Delphine A1 - Denning, Nicola A1 - Jian, Xueqiu A1 - Zhao, Yi A1 - Del Zompo, Maria A1 - Fox, Nick C A1 - Choi, Seung-Hoan A1 - Mateo, Ignacio A1 - Hughes, Joseph T A1 - Adams, Hieab H A1 - Malamon, John A1 - Sanchez-Garcia, Florentino A1 - Patel, Yogen A1 - Brody, Jennifer A A1 - Dombroski, Beth A A1 - Naranjo, Maria Candida Deniz A1 - Daniilidou, Makrina A1 - Eiriksdottir, Gudny A1 - Mukherjee, Shubhabrata A1 - Wallon, David A1 - Uphill, James A1 - Aspelund, Thor A1 - Cantwell, Laura B A1 - Garzia, Fabienne A1 - Galimberti, Daniela A1 - Hofer, Edith A1 - Butkiewicz, Mariusz A1 - Fin, Bertrand A1 - Scarpini, Elio A1 - Sarnowski, Chloe A1 - Bush, Will S A1 - Meslage, Stéphane A1 - Kornhuber, Johannes A1 - White, Charles C A1 - Song, Yuenjoo A1 - Barber, Robert C A1 - Engelborghs, Sebastiaan A1 - Sordon, Sabrina A1 - Voijnovic, Dina A1 - Adams, Perrie M A1 - Vandenberghe, Rik A1 - Mayhaus, Manuel A1 - Cupples, L Adrienne A1 - Albert, Marilyn S A1 - De Deyn, Peter P A1 - Gu, Wei A1 - Himali, Jayanadra J A1 - Beekly, Duane A1 - Squassina, Alessio A1 - Hartmann, Annette M A1 - Orellana, Adelina A1 - Blacker, Deborah A1 - Rodriguez-Rodriguez, Eloy A1 - Lovestone, Simon A1 - Garcia, Melissa E A1 - Doody, Rachelle S A1 - Munoz-Fernadez, Carmen A1 - Sussams, Rebecca A1 - Lin, Honghuang A1 - Fairchild, Thomas J A1 - Benito, Yolanda A A1 - Holmes, Clive A1 - Karamujić-Čomić, Hata A1 - Frosch, Matthew P A1 - Thonberg, Håkan A1 - Maier, Wolfgang A1 - Roschupkin, Gena A1 - Ghetti, Bernardino A1 - Giedraitis, Vilmantas A1 - Kawalia, Amit A1 - Li, Shuo A1 - Huebinger, Ryan M A1 - Kilander, Lena A1 - Moebus, Susanne A1 - Hernandez, Isabel A1 - Kamboh, M Ilyas A1 - Brundin, RoseMarie A1 - Turton, James A1 - Yang, Qiong A1 - Katz, Mindy J A1 - Concari, Letizia A1 - Lord, Jenny A1 - Beiser, Alexa S A1 - Keene, C Dirk A1 - Helisalmi, Seppo A1 - Kloszewska, Iwona A1 - Kukull, Walter A A1 - Koivisto, Anne Maria A1 - Lynch, Aoibhinn A1 - Tarraga, Lluis A1 - Larson, Eric B A1 - Haapasalo, Annakaisa A1 - Lawlor, Brian A1 - Mosley, Thomas H A1 - Lipton, Richard B A1 - Solfrizzi, Vincenzo A1 - Gill, Michael A1 - Longstreth, W T A1 - Montine, Thomas J A1 - Frisardi, Vincenza A1 - Diez-Fairen, Monica A1 - Rivadeneira, Fernando A1 - Petersen, Ronald C A1 - Deramecourt, Vincent A1 - Alvarez, Ignacio A1 - Salani, Francesca A1 - Ciaramella, Antonio A1 - Boerwinkle, Eric A1 - Reiman, Eric M A1 - Fiévet, Nathalie A1 - Rotter, Jerome I A1 - Reisch, Joan S A1 - Hanon, Olivier A1 - Cupidi, Chiara A1 - Andre Uitterlinden, A G A1 - Royall, Donald R A1 - Dufouil, Carole A1 - Maletta, Raffaele Giovanni A1 - de Rojas, Itziar A1 - Sano, Mary A1 - Brice, Alexis A1 - Cecchetti, Roberta A1 - George-Hyslop, Peter St A1 - Ritchie, Karen A1 - Tsolaki, Magda A1 - Tsuang, Debby W A1 - Dubois, Bruno A1 - Craig, David A1 - Wu, Chuang-Kuo A1 - Soininen, Hilkka A1 - Avramidou, Despoina A1 - Albin, Roger L A1 - Fratiglioni, Laura A1 - Germanou, Antonia A1 - Apostolova, Liana G A1 - Keller, Lina A1 - Koutroumani, Maria A1 - Arnold, Steven E A1 - Panza, Francesco A1 - Gkatzima, Olymbia A1 - Asthana, Sanjay A1 - Hannequin, Didier A1 - Whitehead, Patrice A1 - Atwood, Craig S A1 - Caffarra, Paolo A1 - Hampel, Harald A1 - Quintela, Inés A1 - Carracedo, Angel A1 - Lannfelt, Lars A1 - Rubinsztein, David C A1 - Barnes, Lisa L A1 - Pasquier, Florence A1 - Frölich, Lutz A1 - Barral, Sandra A1 - McGuinness, Bernadette A1 - Beach, Thomas G A1 - Johnston, Janet A A1 - Becker, James T A1 - Passmore, Peter A1 - Bigio, Eileen H A1 - Schott, Jonathan M A1 - Bird, Thomas D A1 - Warren, Jason D A1 - Boeve, Bradley F A1 - Lupton, Michelle K A1 - Bowen, James D A1 - Proitsi, Petra A1 - Boxer, Adam A1 - Powell, John F A1 - Burke, James R A1 - Kauwe, John S K A1 - Burns, Jeffrey M A1 - Mancuso, Michelangelo A1 - Buxbaum, Joseph D A1 - Bonuccelli, Ubaldo A1 - Cairns, Nigel J A1 - McQuillin, Andrew A1 - Cao, Chuanhai A1 - Livingston, Gill A1 - Carlson, Chris S A1 - Bass, Nicholas J A1 - Carlsson, Cynthia M A1 - Hardy, John A1 - Carney, Regina M A1 - Bras, Jose A1 - Carrasquillo, Minerva M A1 - Guerreiro, Rita A1 - Allen, Mariet A1 - Chui, Helena C A1 - Fisher, Elizabeth A1 - Masullo, Carlo A1 - Crocco, Elizabeth A A1 - DeCarli, Charles A1 - Bisceglio, Gina A1 - Dick, Malcolm A1 - Ma, Li A1 - Duara, Ranjan A1 - Graff-Radford, Neill R A1 - Evans, Denis A A1 - Hodges, Angela A1 - Faber, Kelley M A1 - Scherer, Martin A1 - Fallon, Kenneth B A1 - Riemenschneider, Matthias A1 - Fardo, David W A1 - Heun, Reinhard A1 - Farlow, Martin R A1 - Kölsch, Heike A1 - Ferris, Steven A1 - Leber, Markus A1 - Foroud, Tatiana M A1 - Heuser, Isabella A1 - Galasko, Douglas R A1 - Giegling, Ina A1 - Gearing, Marla A1 - Hüll, Michael A1 - Geschwind, Daniel H A1 - Gilbert, John R A1 - Morris, John A1 - Green, Robert C A1 - Mayo, Kevin A1 - Growdon, John H A1 - Feulner, Thomas A1 - Hamilton, Ronald L A1 - Harrell, Lindy E A1 - Drichel, Dmitriy A1 - Honig, Lawrence S A1 - Cushion, Thomas D A1 - Huentelman, Matthew J A1 - Hollingworth, Paul A1 - Hulette, Christine M A1 - Hyman, Bradley T A1 - Marshall, Rachel A1 - Jarvik, Gail P A1 - Meggy, Alun A1 - Abner, Erin A1 - Menzies, Georgina E A1 - Jin, Lee-Way A1 - Leonenko, Ganna A1 - Real, Luis M A1 - Jun, Gyungah R A1 - Baldwin, Clinton T A1 - Grozeva, Detelina A1 - Karydas, Anna A1 - Russo, Giancarlo A1 - Kaye, Jeffrey A A1 - Kim, Ronald A1 - Jessen, Frank A1 - Kowall, Neil W A1 - Vellas, Bruno A1 - Kramer, Joel H A1 - Vardy, Emma A1 - LaFerla, Frank M A1 - Jöckel, Karl-Heinz A1 - Lah, James J A1 - Dichgans, Martin A1 - Leverenz, James B A1 - Mann, David A1 - Levey, Allan I A1 - Pickering-Brown, Stuart A1 - Lieberman, Andrew P A1 - Klopp, Norman A1 - Lunetta, Kathryn L A1 - Wichmann, H-Erich A1 - Lyketsos, Constantine G A1 - Morgan, Kevin A1 - Marson, Daniel C A1 - Brown, Kristelle A1 - Martiniuk, Frank A1 - Medway, Christopher A1 - Mash, Deborah C A1 - Nöthen, Markus M A1 - Masliah, Eliezer A1 - Hooper, Nigel M A1 - McCormick, Wayne C A1 - Daniele, Antonio A1 - McCurry, Susan M A1 - Bayer, Anthony A1 - McDavid, Andrew N A1 - Gallacher, John A1 - McKee, Ann C A1 - van den Bussche, Hendrik A1 - Mesulam, Marsel A1 - Brayne, Carol A1 - Miller, Bruce L A1 - Riedel-Heller, Steffi A1 - Miller, Carol A A1 - Miller, Joshua W A1 - Al-Chalabi, Ammar A1 - Morris, John C A1 - Shaw, Christopher E A1 - Myers, Amanda J A1 - Wiltfang, Jens A1 - O'Bryant, Sid A1 - Olichney, John M A1 - Alvarez, Victoria A1 - Parisi, Joseph E A1 - Singleton, Andrew B A1 - Paulson, Henry L A1 - Collinge, John A1 - Perry, William R A1 - Mead, Simon A1 - Peskind, Elaine A1 - Cribbs, David H A1 - Rossor, Martin A1 - Pierce, Aimee A1 - Ryan, Natalie S A1 - Poon, Wayne W A1 - Nacmias, Benedetta A1 - Potter, Huntington A1 - Sorbi, Sandro A1 - Quinn, Joseph F A1 - Sacchinelli, Eleonora A1 - Raj, Ashok A1 - Spalletta, Gianfranco A1 - Raskind, Murray A1 - Caltagirone, Carlo A1 - Bossù, Paola A1 - Orfei, Maria Donata A1 - Reisberg, Barry A1 - Clarke, Robert A1 - Reitz, Christiane A1 - Smith, A David A1 - Ringman, John M A1 - Warden, Donald A1 - Roberson, Erik D A1 - Wilcock, Gordon A1 - Rogaeva, Ekaterina A1 - Bruni, Amalia Cecilia A1 - Rosen, Howard J A1 - Gallo, Maura A1 - Rosenberg, Roger N A1 - Ben-Shlomo, Yoav A1 - Sager, Mark A A1 - Mecocci, Patrizia A1 - Saykin, Andrew J A1 - Pastor, Pau A1 - Cuccaro, Michael L A1 - Vance, Jeffery M A1 - Schneider, Julie A A1 - Schneider, Lori S A1 - Slifer, Susan A1 - Seeley, William W A1 - Smith, Amanda G A1 - Sonnen, Joshua A A1 - Spina, Salvatore A1 - Stern, Robert A A1 - Swerdlow, Russell H A1 - Tang, Mitchell A1 - Tanzi, Rudolph E A1 - Trojanowski, John Q A1 - Troncoso, Juan C A1 - Van Deerlin, Vivianna M A1 - Van Eldik, Linda J A1 - Vinters, Harry V A1 - Vonsattel, Jean Paul A1 - Weintraub, Sandra A1 - Welsh-Bohmer, Kathleen A A1 - Wilhelmsen, Kirk C A1 - Williamson, Jennifer A1 - Wingo, Thomas S A1 - Woltjer, Randall L A1 - Wright, Clinton B A1 - Yu, Chang-En A1 - Yu, Lei A1 - Saba, Yasaman A1 - Pilotto, Alberto A1 - Bullido, María J A1 - Peters, Oliver A1 - Crane, Paul K A1 - Bennett, David A1 - Bosco, Paola A1 - Coto, Eliecer A1 - Boccardi, Virginia A1 - De Jager, Phil L A1 - Lleo, Alberto A1 - Warner, Nick A1 - Lopez, Oscar L A1 - Ingelsson, Martin A1 - Deloukas, Panagiotis A1 - Cruchaga, Carlos A1 - Graff, Caroline A1 - Gwilliam, Rhian A1 - Fornage, Myriam A1 - Goate, Alison M A1 - Sánchez-Juan, Pascual A1 - Kehoe, Patrick G A1 - Amin, Najaf A1 - Ertekin-Taner, Nilifur A1 - Berr, Claudine A1 - Debette, Stephanie A1 - Love, Seth A1 - Launer, Lenore J A1 - Younkin, Steven G A1 - Dartigues, Jean-François A1 - Corcoran, Chris A1 - Ikram, M Arfan A1 - Dickson, Dennis W A1 - Nicolas, Gaël A1 - Campion, Dominique A1 - Tschanz, JoAnn A1 - Schmidt, Helena A1 - Hakonarson, Hakon A1 - Clarimon, Jordi A1 - Munger, Ron A1 - Schmidt, Reinhold A1 - Farrer, Lindsay A A1 - Van Broeckhoven, Christine A1 - C O'Donovan, Michael A1 - DeStefano, Anita L A1 - Jones, Lesley A1 - Haines, Jonathan L A1 - Deleuze, Jean-Francois A1 - Owen, Michael J A1 - Gudnason, Vilmundur A1 - Mayeux, Richard A1 - Escott-Price, Valentina A1 - Psaty, Bruce M A1 - Ramirez, Alfredo A1 - Wang, Li-San A1 - Ruiz, Agustin A1 - van Duijn, Cornelia M A1 - Holmans, Peter A A1 - Seshadri, Sudha A1 - Williams, Julie A1 - Amouyel, Phillippe A1 - Schellenberg, Gerard D A1 - Lambert, Jean-Charles A1 - Pericak-Vance, Margaret A AB -

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.

VL - 51 IS - 3 ER - TY - JOUR T1 - A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology. JF - Blood Y1 - 2019 A1 - de Vries, Paul S A1 - Sabater-Lleal, Maria A1 - Huffman, Jennifer E A1 - Marten, Jonathan A1 - Song, Ci A1 - Pankratz, Nathan A1 - Bartz, Traci M A1 - de Haan, Hugoline G A1 - Delgado, Graciela E A1 - Eicher, John D A1 - Martinez-Perez, Angel A1 - Ward-Caviness, Cavin K A1 - Brody, Jennifer A A1 - Chen, Ming-Huei A1 - de Maat, Moniek P M A1 - Frånberg, Mattias A1 - Gill, Dipender A1 - Kleber, Marcus E A1 - Rivadeneira, Fernando A1 - Soria, José Manuel A1 - Tang, Weihong A1 - Tofler, Geoffrey H A1 - Uitterlinden, André G A1 - van Hylckama Vlieg, Astrid A1 - Seshadri, Sudha A1 - Boerwinkle, Eric A1 - Davies, Neil M A1 - Giese, Anne-Katrin A1 - Ikram, M Kamran A1 - Kittner, Steven J A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - Reiner, Alex P A1 - Sargurupremraj, Muralidharan A1 - Taylor, Kent D A1 - Fornage, Myriam A1 - Hamsten, Anders A1 - März, Winfried A1 - Rosendaal, Frits R A1 - Souto, Juan Carlos A1 - Dehghan, Abbas A1 - Johnson, Andrew D A1 - Morrison, Alanna C A1 - O'Donnell, Christopher J A1 - Smith, Nicholas L AB -

Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27 495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a -ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel ( and ) and 6 known loci associated with FVII activity, explaining 19.0% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing in HuH7 cells upregulated FVII, whereas silencing downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at and contribute to FVII activity by regulating expression levels. FVII activity appears to contribute to the etiology of IS in the general population.

VL - 133 IS - 9 ER - TY - JOUR T1 - Association of CD14 with incident dementia and markers of brain aging and injury. JF - Neurology Y1 - 2020 A1 - Pase, Matthew P A1 - Himali, Jayandra J A1 - Beiser, Alexa S A1 - DeCarli, Charles A1 - McGrath, Emer R A1 - Satizabal, Claudia L A1 - Aparicio, Hugo J A1 - Adams, Hieab H H A1 - Reiner, Alexander P A1 - Longstreth, W T A1 - Fornage, Myriam A1 - Tracy, Russell P A1 - Lopez, Oscar A1 - Psaty, Bruce M A1 - Levy, Daniel A1 - Seshadri, Sudha A1 - Bis, Joshua C AB -

OBJECTIVE: To test the hypothesis that the inflammatory marker plasma soluble CD14 (sCD14) associates with incident dementia and related endophenotypes in 2 community-based cohorts.

METHODS: Our samples included the prospective community-based Framingham Heart Study (FHS) and Cardiovascular Health Study (CHS) cohorts. Plasma sCD14 was measured at baseline and related to the incidence of dementia, domains of cognitive function, and MRI-defined brain volumes. Follow-up for dementia occurred over a mean of 10 years (SD 4) in the FHS and a mean of 6 years (SD 3) in the CHS.

RESULTS: We studied 1,588 participants from the FHS (mean age 69 ± 6 years, 47% male, 131 incident events) and 3,129 participants from the CHS (mean age 72 ± 5 years, 41% male, 724 incident events) for the risk of incident dementia. Meta-analysis across the 2 cohorts showed that each SD unit increase in sCD14 was associated with a 12% increase in the risk of incident dementia (95% confidence interval 1.03-1.23; = 0.01) following adjustments for age, sex, ε4 status, and vascular risk factors. Higher levels of sCD14 were associated with various cognitive and MRI markers of accelerated brain aging in both cohorts and with a greater progression of brain atrophy and a decline in executive function in the FHS.

CONCLUSION: sCD14 is an inflammatory marker related to brain atrophy, cognitive decline, and incident dementia.

VL - 94 IS - 3 ER - TY - JOUR T1 - The genetic architecture of the human cerebral cortex JF - Science Y1 - 2020 A1 - Grasby, Katrina L. A1 - Jahanshad, Neda A1 - Painter, Jodie N. A1 - Colodro-Conde, Lucía A1 - Bralten, Janita A1 - Hibar, Derrek P. A1 - Lind, Penelope A. A1 - Pizzagalli, Fabrizio A1 - Ching, Christopher R. K. A1 - McMahon, Mary Agnes B. A1 - Shatokhina, Natalia A1 - Zsembik, Leo C. P. A1 - Thomopoulos, Sophia I. A1 - Zhu, Alyssa H. A1 - Strike, Lachlan T. A1 - Agartz, Ingrid A1 - Alhusaini, Saud A1 - Almeida, Marcio A. A. A1 - Alnæs, Dag A1 - Amlien, Inge K. A1 - Andersson, Micael A1 - Ard, Tyler A1 - Armstrong, Nicola J. A1 - Ashley-Koch, Allison A1 - Atkins, Joshua R. A1 - Bernard, Manon A1 - Brouwer, Rachel M. A1 - Buimer, Elizabeth E. L. A1 - Bülow, Robin A1 - Bürger, Christian A1 - Cannon, Dara M. A1 - Chakravarty, Mallar A1 - Chen, Qiang A1 - Cheung, Joshua W. A1 - Couvy-Duchesne, Baptiste A1 - Dale, Anders M. A1 - Dalvie, Shareefa A1 - de Araujo, Tânia K. A1 - de Zubicaray, Greig I. A1 - de Zwarte, Sonja M. C. A1 - den Braber, Anouk A1 - Doan, Nhat Trung A1 - Dohm, Katharina A1 - Ehrlich, Stefan A1 - Engelbrecht, Hannah-Ruth A1 - Erk, Susanne A1 - Fan, Chun Chieh A1 - Fedko, Iryna O. A1 - Foley, Sonya F. A1 - Ford, Judith M. A1 - Fukunaga, Masaki A1 - Garrett, Melanie E. A1 - Ge, Tian A1 - Giddaluru, Sudheer A1 - Goldman, Aaron L. A1 - Green, Melissa J. A1 - Groenewold, Nynke A. A1 - Grotegerd, Dominik A1 - Gurholt, Tiril P. A1 - Gutman, Boris A. A1 - Hansell, Narelle K. A1 - Harris, Mathew A. A1 - Harrison, Marc B. A1 - Haswell, Courtney C. A1 - Hauser, Michael A1 - Herms, Stefan A1 - Heslenfeld, Dirk J. A1 - Ho, New Fei A1 - Hoehn, David A1 - Hoffmann, Per A1 - Holleran, Laurena A1 - Hoogman, Martine A1 - Hottenga, Jouke-Jan A1 - Ikeda, Masashi A1 - Janowitz, Deborah A1 - Jansen, Iris E. A1 - Jia, Tianye A1 - Jockwitz, Christiane A1 - Kanai, Ryota A1 - Karama, Sherif A1 - Kasperaviciute, Dalia A1 - Kaufmann, Tobias A1 - Kelly, Sinead A1 - Kikuchi, Masataka A1 - Klein, Marieke A1 - Knapp, Michael A1 - Knodt, Annchen R. A1 - Krämer, Bernd A1 - Lam, Max A1 - Lancaster, Thomas M. A1 - Lee, Phil H. A1 - Lett, Tristram A. A1 - Lewis, Lindsay B. A1 - Lopes-Cendes, Iscia A1 - Luciano, Michelle A1 - Macciardi, Fabio A1 - Marquand, Andre F. A1 - Mathias, Samuel R. A1 - Melzer, Tracy R. A1 - Milaneschi, Yuri A1 - Mirza-Schreiber, Nazanin A1 - Moreira, Jose C. V. A1 - Mühleisen, Thomas W. A1 - Müller-Myhsok, Bertram A1 - Najt, Pablo A1 - Nakahara, Soichiro A1 - Nho, Kwangsik A1 - Olde Loohuis, Loes M. A1 - Orfanos, Dimitri Papadopoulos A1 - Pearson, John F. A1 - Pitcher, Toni L. A1 - Pütz, Benno A1 - Quidé, Yann A1 - Ragothaman, Anjanibhargavi A1 - Rashid, Faisal M. A1 - Reay, William R. A1 - Redlich, Ronny A1 - Reinbold, Céline S. A1 - Repple, Jonathan A1 - Richard, Geneviève A1 - Riedel, Brandalyn C. A1 - Risacher, Shannon L. A1 - Rocha, Cristiane S. A1 - Mota, Nina Roth A1 - Salminen, Lauren A1 - Saremi, Arvin A1 - Saykin, Andrew J. A1 - Schlag, Fenja A1 - Schmaal, Lianne A1 - Schofield, Peter R. A1 - Secolin, Rodrigo A1 - Shapland, Chin Yang A1 - Shen, Li A1 - Shin, Jean A1 - Shumskaya, Elena A1 - Sønderby, Ida E. A1 - Sprooten, Emma A1 - Tansey, Katherine E. A1 - Teumer, Alexander A1 - Thalamuthu, Anbupalam A1 - Tordesillas-Gutierrez, Diana A1 - Turner, Jessica A. A1 - Uhlmann, Anne A1 - Vallerga, Costanza Ludovica A1 - van der Meer, Dennis A1 - van Donkelaar, Marjolein M. J. A1 - van Eijk, Liza A1 - van Erp, Theo G. M. A1 - van Haren, Neeltje E. M. A1 - van Rooij, Daan A1 - van Tol, Marie-Jose A1 - Veldink, Jan H. A1 - Verhoef, Ellen A1 - Walton, Esther A1 - Wang, Mingyuan A1 - Wang, Yunpeng A1 - Wardlaw, Joanna M. A1 - Wen, Wei A1 - Westlye, Lars T. A1 - Whelan, Christopher D. A1 - Witt, Stephanie H. A1 - Wittfeld, Katharina A1 - Wolf, Christiane A1 - Wolfers, Thomas A1 - Wu, Jing Qin A1 - Yasuda, Clarissa L. A1 - Zaremba, Dario A1 - Zhang, Zuo A1 - Zwiers, Marcel P. A1 - Artiges, Eric A1 - Assareh, Amelia A. A1 - Ayesa-Arriola, Rosa A1 - Belger, Aysenil A1 - Brandt, Christine L. A1 - Brown, Gregory G. A1 - Cichon, Sven A1 - Curran, Joanne E. A1 - Davies, Gareth E. A1 - Degenhardt, Franziska A1 - Dennis, Michelle F. A1 - Dietsche, Bruno A1 - Djurovic, Srdjan A1 - Doherty, Colin P. A1 - Espiritu, Ryan A1 - Garijo, Daniel A1 - Gil, Yolanda A1 - Gowland, Penny A. A1 - Green, Robert C. A1 - Häusler, Alexander N. A1 - Heindel, Walter A1 - Ho, Beng-Choon A1 - Hoffmann, Wolfgang U. A1 - Holsboer, Florian A1 - Homuth, Georg A1 - Hosten, Norbert A1 - Jack, Clifford R. A1 - Jang, MiHyun A1 - Jansen, Andreas A1 - Kimbrel, Nathan A. A1 - Kolskår, Knut A1 - Koops, Sanne A1 - Krug, Axel A1 - Lim, Kelvin O. A1 - Luykx, Jurjen J. A1 - Mathalon, Daniel H. A1 - Mather, Karen A. A1 - Mattay, Venkata S. A1 - Matthews, Sarah A1 - Mayoral Van Son, Jaqueline A1 - McEwen, Sarah C. A1 - Melle, Ingrid A1 - Morris, Derek W. A1 - Mueller, Bryon A. A1 - Nauck, Matthias A1 - Nordvik, Jan E. A1 - Nöthen, Markus M. A1 - O’Leary, Daniel S. A1 - Opel, Nils A1 - Martinot, Marie-Laure Paillère A1 - Pike, G. Bruce A1 - Preda, Adrian A1 - Quinlan, Erin B. A1 - Rasser, Paul E. A1 - Ratnakar, Varun A1 - Reppermund, Simone A1 - Steen, Vidar M. A1 - Tooney, Paul A. A1 - Torres, Fábio R. A1 - Veltman, Dick J. A1 - Voyvodic, James T. A1 - Whelan, Robert A1 - White, Tonya A1 - Yamamori, Hidenaga A1 - Adams, Hieab H. H. A1 - Bis, Joshua C. A1 - Debette, Stephanie A1 - DeCarli, Charles A1 - Fornage, Myriam A1 - Gudnason, Vilmundur A1 - Hofer, Edith A1 - Ikram, M. Arfan A1 - Launer, Lenore A1 - Longstreth, W. T. A1 - Lopez, Oscar L. A1 - Mazoyer, Bernard A1 - Mosley, Thomas H. A1 - Roshchupkin, Gennady V. A1 - Satizabal, Claudia L. A1 - Schmidt, Reinhold A1 - Seshadri, Sudha A1 - Yang, Qiong A1 - Alvim, Marina K. M. A1 - Ames, David A1 - Anderson, Tim J. A1 - Andreassen, Ole A. A1 - Arias-Vasquez, Alejandro A1 - Bastin, Mark E. A1 - Baune, Bernhard T. A1 - Beckham, Jean C. A1 - Blangero, John A1 - Boomsma, Dorret I. A1 - Brodaty, Henry A1 - Brunner, Han G. A1 - Buckner, Randy L. A1 - Buitelaar, Jan K. A1 - Bustillo, Juan R. A1 - Cahn, Wiepke A1 - Cairns, Murray J. A1 - Calhoun, Vince A1 - Carr, Vaughan J. A1 - Caseras, Xavier A1 - Caspers, Svenja A1 - Cavalleri, Gianpiero L. A1 - Cendes, Fernando A1 - Corvin, Aiden A1 - Crespo-Facorro, Benedicto A1 - Dalrymple-Alford, John C. A1 - Dannlowski, Udo A1 - de Geus, Eco J. C. A1 - Deary, Ian J. A1 - Delanty, Norman A1 - Depondt, Chantal A1 - Desrivières, Sylvane A1 - Donohoe, Gary A1 - Espeseth, Thomas A1 - Fernández, Guillén A1 - Fisher, Simon E. A1 - Flor, Herta A1 - Forstner, Andreas J. A1 - Francks, Clyde A1 - Franke, Barbara A1 - Glahn, David C. A1 - Gollub, Randy L. A1 - Grabe, Hans J. A1 - Gruber, Oliver A1 - Håberg, Asta K. A1 - Hariri, Ahmad R. A1 - Hartman, Catharina A. A1 - Hashimoto, Ryota A1 - Heinz, Andreas A1 - Henskens, Frans A. A1 - Hillegers, Manon H. J. A1 - Hoekstra, Pieter J. A1 - Holmes, Avram J. A1 - Hong, L. Elliot A1 - Hopkins, William D. A1 - Hulshoff Pol, Hilleke E. A1 - Jernigan, Terry L. A1 - Jönsson, Erik G. A1 - Kahn, René S. A1 - Kennedy, Martin A. A1 - Kircher, Tilo T. J. A1 - Kochunov, Peter A1 - Kwok, John B. J. A1 - Le Hellard, Stephanie A1 - Loughland, Carmel M. A1 - Martin, Nicholas G. A1 - Martinot, Jean-Luc A1 - McDonald, Colm A1 - McMahon, Katie L. A1 - Meyer-Lindenberg, Andreas A1 - Michie, Patricia T. A1 - Morey, Rajendra A. A1 - Mowry, Bryan A1 - Nyberg, Lars A1 - Oosterlaan, Jaap A1 - Ophoff, Roel A. A1 - Pantelis, Christos A1 - Paus, Tomáš A1 - Pausova, Zdenka A1 - Penninx, Brenda W. J. H. A1 - Polderman, Tinca J. C. A1 - Posthuma, Danielle A1 - Rietschel, Marcella A1 - Roffman, Joshua L. A1 - Rowland, Laura M. A1 - Sachdev, Perminder S. A1 - Sämann, Philipp G. A1 - Schall, Ulrich A1 - Schumann, Gunter A1 - Scott, Rodney J. A1 - Sim, Kang A1 - Sisodiya, Sanjay M. A1 - Smoller, Jordan W. A1 - Sommer, Iris E. A1 - St Pourcain, Beate A1 - Stein, Dan J. A1 - Toga, Arthur W. A1 - Trollor, Julian N. A1 - Van der Wee, Nic J. A. A1 - van ’t Ent, Dennis A1 - Völzke, Henry A1 - Walter, Henrik A1 - Weber, Bernd A1 - Weinberger, Daniel R. A1 - Wright, Margaret J. A1 - Zhou, Juan A1 - Stein, Jason L. A1 - Thompson, Paul M. A1 - Medland, Sarah E. VL - 367 UR - 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 IS - 6484 JO - Science ER - TY - JOUR T1 - Association of low-frequency and rare coding variants with information processing speed. JF - Transl Psychiatry Y1 - 2021 A1 - Bressler, Jan A1 - Davies, Gail A1 - Smith, Albert V A1 - Saba, Yasaman A1 - Bis, Joshua C A1 - Jian, Xueqiu A1 - Hayward, Caroline A1 - Yanek, Lisa A1 - Smith, Jennifer A A1 - Mirza, Saira S A1 - Wang, Ruiqi A1 - Adams, Hieab H H A1 - Becker, Diane A1 - Boerwinkle, Eric A1 - Campbell, Archie A1 - Cox, Simon R A1 - Eiriksdottir, Gudny A1 - Fawns-Ritchie, Chloe A1 - Gottesman, Rebecca F A1 - Grove, Megan L A1 - Guo, Xiuqing A1 - Hofer, Edith A1 - Kardia, Sharon L R A1 - Knol, Maria J A1 - Koini, Marisa A1 - Lopez, Oscar L A1 - Marioni, Riccardo E A1 - Nyquist, Paul A1 - Pattie, Alison A1 - Polasek, Ozren A1 - Porteous, David J A1 - Rudan, Igor A1 - Satizabal, Claudia L A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Sidney, Stephen A1 - Simino, Jeannette A1 - Smith, Blair H A1 - Turner, Stephen T A1 - van der Lee, Sven J A1 - Ware, Erin B A1 - Whitmer, Rachel A A1 - Yaffe, Kristine A1 - Yang, Qiong A1 - Zhao, Wei A1 - Gudnason, Vilmundur A1 - Launer, Lenore J A1 - Fitzpatrick, Annette L A1 - Psaty, Bruce M A1 - Fornage, Myriam A1 - Arfan Ikram, M A1 - van Duijn, Cornelia M A1 - Seshadri, Sudha A1 - Mosley, Thomas H A1 - Deary, Ian J KW - Adult KW - Aging KW - Cognition KW - Genome-Wide Association Study KW - Geroscience KW - Humans KW - Polymorphism, Single Nucleotide KW - Ubiquitin-Protein Ligases AB -

Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.

VL - 11 IS - 1 ER - TY - JOUR T1 - Association of mitochondrial DNA copy number with cardiometabolic diseases. JF - Cell Genom Y1 - 2021 A1 - Liu, Xue A1 - Longchamps, Ryan J A1 - Wiggins, Kerri L A1 - Raffield, Laura M A1 - Bielak, Lawrence F A1 - Zhao, Wei A1 - Pitsillides, Achilleas A1 - Blackwell, Thomas W A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Kurniansyah, Nuzulul A1 - Thyagarajan, Bharat A1 - Pankratz, Nathan A1 - Rich, Stephen S A1 - Taylor, Kent D A1 - Peyser, Patricia A A1 - Heckbert, Susan R A1 - Seshadri, Sudha A1 - Cupples, L Adrienne A1 - Boerwinkle, Eric A1 - Grove, Megan L A1 - Larson, Nicholas B A1 - Smith, Jennifer A A1 - Vasan, Ramachandran S A1 - Sofer, Tamar A1 - Fitzpatrick, Annette L A1 - Fornage, Myriam A1 - Ding, Jun A1 - Correa, Adolfo A1 - Abecasis, Goncalo A1 - Psaty, Bruce M A1 - Wilson, James G A1 - Levy, Daniel A1 - Rotter, Jerome I A1 - Bis, Joshua C A1 - Satizabal, Claudia L A1 - Arking, Dan E A1 - Liu, Chunyu AB -

Mitochondrial DNA (mtDNA) is present in multiple copies in human cells. We evaluated cross-sectional associations of whole blood mtDNA copy number (CN) with several cardiometabolic disease traits in 408,361 participants of multiple ancestries in TOPMed and UK Biobank. Age showed a threshold association with mtDNA CN: among younger participants (<65 years of age), each additional 10 years of age was associated with 0.03 standard deviation (s.d.) higher level of mtDNA CN ( = 0.0014) versus a 0.14 s.d. lower level of mtDNA CN ( = 1.82 × 10) among older participants (≥65 years). At lower mtDNA CN levels, we found age-independent associations with increased odds of obesity ( = 5.6 × 10), hypertension ( = 2.8 × 10), diabetes ( = 3.6 × 10), and hyperlipidemia ( = 6.3 × 10). The observed decline in mtDNA CN after 65 years of age may be a key to understanding age-related diseases.

VL - 1 IS - 1 ER - TY - JOUR T1 - Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. JF - Nature Y1 - 2021 A1 - Taliun, Daniel A1 - Harris, Daniel N A1 - Kessler, Michael D A1 - Carlson, Jedidiah A1 - Szpiech, Zachary A A1 - Torres, Raul A1 - Taliun, Sarah A Gagliano A1 - Corvelo, André A1 - Gogarten, Stephanie M A1 - Kang, Hyun Min A1 - Pitsillides, Achilleas N A1 - LeFaive, Jonathon A1 - Lee, Seung-Been A1 - Tian, Xiaowen A1 - Browning, Brian L A1 - Das, Sayantan A1 - Emde, Anne-Katrin A1 - Clarke, Wayne E A1 - Loesch, Douglas P A1 - Shetty, Amol C A1 - Blackwell, Thomas W A1 - Smith, Albert V A1 - Wong, Quenna A1 - Liu, Xiaoming A1 - Conomos, Matthew P A1 - Bobo, Dean M A1 - Aguet, Francois A1 - Albert, Christine A1 - Alonso, Alvaro A1 - Ardlie, Kristin G A1 - Arking, Dan E A1 - Aslibekyan, Stella A1 - Auer, Paul L A1 - Barnard, John A1 - Barr, R Graham A1 - Barwick, Lucas A1 - Becker, Lewis C A1 - Beer, Rebecca L A1 - Benjamin, Emelia J A1 - Bielak, Lawrence F A1 - Blangero, John A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Brody, Jennifer A A1 - Burchard, Esteban G A1 - Cade, Brian E A1 - Casella, James F A1 - Chalazan, Brandon A1 - Chasman, Daniel I A1 - Chen, Yii-Der Ida A1 - Cho, Michael H A1 - Choi, Seung Hoan A1 - Chung, Mina K A1 - Clish, Clary B A1 - Correa, Adolfo A1 - Curran, Joanne E A1 - Custer, Brian A1 - Darbar, Dawood A1 - Daya, Michelle A1 - de Andrade, Mariza A1 - DeMeo, Dawn L A1 - Dutcher, Susan K A1 - Ellinor, Patrick T A1 - Emery, Leslie S A1 - Eng, Celeste A1 - Fatkin, Diane A1 - Fingerlin, Tasha A1 - Forer, Lukas A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Fuchsberger, Christian A1 - Fullerton, Stephanie M A1 - Germer, Soren A1 - Gladwin, Mark T A1 - Gottlieb, Daniel J A1 - Guo, Xiuqing A1 - Hall, Michael E A1 - He, Jiang A1 - Heard-Costa, Nancy L A1 - Heckbert, Susan R A1 - Irvin, Marguerite R A1 - Johnsen, Jill M A1 - Johnson, Andrew D A1 - Kaplan, Robert A1 - Kardia, Sharon L R A1 - Kelly, Tanika A1 - Kelly, Shannon A1 - Kenny, Eimear E A1 - Kiel, Douglas P A1 - Klemmer, Robert A1 - Konkle, Barbara A A1 - Kooperberg, Charles A1 - Köttgen, Anna A1 - Lange, Leslie A A1 - Lasky-Su, Jessica A1 - Levy, Daniel A1 - Lin, Xihong A1 - Lin, Keng-Han A1 - Liu, Chunyu A1 - Loos, Ruth J F A1 - Garman, Lori A1 - Gerszten, Robert A1 - Lubitz, Steven A A1 - Lunetta, Kathryn L A1 - Mak, Angel C Y A1 - Manichaikul, Ani A1 - Manning, Alisa K A1 - Mathias, Rasika A A1 - McManus, David D A1 - McGarvey, Stephen T A1 - Meigs, James B A1 - Meyers, Deborah A A1 - Mikulla, Julie L A1 - Minear, Mollie A A1 - Mitchell, Braxton D A1 - Mohanty, Sanghamitra A1 - Montasser, May E A1 - Montgomery, Courtney A1 - Morrison, Alanna C A1 - Murabito, Joanne M A1 - Natale, Andrea A1 - Natarajan, Pradeep A1 - Nelson, Sarah C A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Pankratz, Nathan A1 - Peloso, Gina M A1 - Peyser, Patricia A A1 - Pleiness, Jacob A1 - Post, Wendy S A1 - Psaty, Bruce M A1 - Rao, D C A1 - Redline, Susan A1 - Reiner, Alexander P A1 - Roden, Dan A1 - Rotter, Jerome I A1 - Ruczinski, Ingo A1 - Sarnowski, Chloe A1 - Schoenherr, Sebastian A1 - Schwartz, David A A1 - Seo, Jeong-Sun A1 - Seshadri, Sudha A1 - Sheehan, Vivien A A1 - Sheu, Wayne H A1 - Shoemaker, M Benjamin A1 - Smith, Nicholas L A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Stilp, Adrienne M A1 - Tang, Weihong A1 - Taylor, Kent D A1 - Telen, Marilyn A1 - Thornton, Timothy A A1 - Tracy, Russell P A1 - Van Den Berg, David J A1 - Vasan, Ramachandran S A1 - Viaud-Martinez, Karine A A1 - Vrieze, Scott A1 - Weeks, Daniel E A1 - Weir, Bruce S A1 - Weiss, Scott T A1 - Weng, Lu-Chen A1 - Willer, Cristen J A1 - Zhang, Yingze A1 - Zhao, Xutong A1 - Arnett, Donna K A1 - Ashley-Koch, Allison E A1 - Barnes, Kathleen C A1 - Boerwinkle, Eric A1 - Gabriel, Stacey A1 - Gibbs, Richard A1 - Rice, Kenneth M A1 - Rich, Stephen S A1 - Silverman, Edwin K A1 - Qasba, Pankaj A1 - Gan, Weiniu A1 - Papanicolaou, George J A1 - Nickerson, Deborah A A1 - Browning, Sharon R A1 - Zody, Michael C A1 - Zöllner, Sebastian A1 - Wilson, James G A1 - Cupples, L Adrienne A1 - Laurie, Cathy C A1 - Jaquish, Cashell E A1 - Hernandez, Ryan D A1 - O'Connor, Timothy D A1 - Abecasis, Goncalo R AB -

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

VL - 590 IS - 7845 ER - TY - JOUR T1 - Association of Serum Neurofilament Light Chain Concentration and MRI Findings in Older Adults: The Cardiovascular Health Study. JF - Neurology Y1 - 2022 A1 - Fohner, Alison E A1 - Bartz, Traci M A1 - Tracy, Russell P A1 - Adams, Hieab H H A1 - Bis, Joshua C A1 - Djoussé, Luc A1 - Satizabal, Claudia L A1 - Lopez, Oscar L A1 - Seshadri, Sudha A1 - Mukamal, Kenneth J A1 - Kuller, Lewis H A1 - Psaty, Bruce M A1 - Longstreth, W T AB -

BACKGROUND AND OBJECTIVES: Neurofilament light chain (NfL) in blood is a sensitive but nonspecific marker of brain injury. This study sought to evaluate associations between NfL concentration and MRI findings of vascular brain injury in older adults.

METHODS: A longitudinal cohort study included 2 cranial MRI scans performed about 5 years apart and assessed for white matter hyperintensities (WMH) and infarcts. About 1 year before their second MRI, 1,362 participants (median age 77 years, 61.4% women) without a history of TIA or stroke had measurement of 4 biomarkers: NfL, total tau, glial fibrillary acidic protein (GFAP), and ubiquitin carboxyl-terminal hydrolase L1. Most (n = 1,279) also had the first MRI scan, and some (n = 633) had quantitative measurements of hippocampal and WMH. In primary analyses, we assessed associations of NfL with a 10-point white matter grade (WMG) and prevalent infarcts on second MRI and with worsening WMG and incident infarct comparing the 2 scans. A value <0.0125 (0.05/4) was considered significant for these analyses. We also assessed associations with hippocampal and WMH volume.

RESULTS: In fully adjusted models, log(NfL) concentration was associated with WMG (β = 0.27; = 2.3 × 10) and worsening WMG (relative risk [RR] 1.24; = 0.0022), but less strongly with prevalent brain infarcts (RR 1.18; = 0.013) and not with incident brain infarcts (RR 1.18; = 0.18). Associations were also present with WMH volume (β = 2,242.9, = 0.0036). For the other 3 biomarkers, the associations for log (GFAP) concentration with WMG and worsening WMG were significant.

DISCUSSION: Among older adults without a history of stroke, higher serum NfL concentration was associated with covert MRI findings of vascular brain injury, especially the burden of WMH and its worsening. Whether these results offer opportunities for the use of NfL as a noninvasive biomarker of WMH or to control vascular risk factors remains to be determined.

VL - 98 IS - 9 ER - TY - JOUR T1 - Associations of Pulmonary Function with MRI Brain Volumes: A Coordinated Multi-Study Analysis. JF - J Alzheimers Dis Y1 - 2022 A1 - Frenzel, Stefan A1 - Bis, Josh C A1 - Gudmundsson, Elias F A1 - O'Donnell, Adrienne A1 - Simino, Jeannette A1 - Yaqub, Amber A1 - Bartz, Traci M A1 - Brusselle, Guy G O A1 - Bülow, Robin A1 - DeCarli, Charles S A1 - Ewert, Ralf A1 - Gharib, Sina A A1 - Ghosh, Saptaparni A1 - Gireud-Goss, Monica A1 - Gottesman, Rebecca F A1 - Ikram, M Arfan A1 - Knopman, David S A1 - Launer, Lenore J A1 - London, Stephanie J A1 - Longstreth, W T A1 - Lopez, Oscar L A1 - Melo van Lent, Debora A1 - O'Connor, George A1 - Satizabal, Claudia L A1 - Shrestha, Srishti A1 - Sigurdsson, Sigurdur A1 - Stubbe, Beate A1 - Talluri, Rajesh A1 - Vasan, Ramachandran S A1 - Vernooij, Meike W A1 - Völzke, Henry A1 - Wiggins, Kerri L A1 - Yu, Bing A1 - Beiser, Alexa S A1 - Gudnason, Vilmundur A1 - Mosley, Thomas A1 - Psaty, Bruce M A1 - Wolters, Frank J A1 - Grabe, Hans J A1 - Seshadri, Sudha AB -

BACKGROUND: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent.

OBJECTIVE: To study the cross-sectional associations of pulmonary function with structural brain variables.

METHODS: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses.

RESULTS: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume.

CONCLUSION: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.

ER - TY - JOUR T1 - Clonal Hematopoiesis Is Associated With Higher Risk of Stroke. JF - Stroke Y1 - 2022 A1 - Bhattacharya, Romit A1 - Zekavat, Seyedeh M A1 - Haessler, Jeffrey A1 - Fornage, Myriam A1 - Raffield, Laura A1 - Uddin, Md Mesbah A1 - Bick, Alexander G A1 - Niroula, Abhishek A1 - Yu, Bing A1 - Gibson, Christopher A1 - Griffin, Gabriel A1 - Morrison, Alanna C A1 - Psaty, Bruce M A1 - Longstreth, William T A1 - Bis, Joshua C A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Tracy, Russell P A1 - Correa, Adolfo A1 - Seshadri, Sudha A1 - Johnson, Andrew A1 - Collins, Jason M A1 - Hayden, Kathleen M A1 - Madsen, Tracy E A1 - Ballantyne, Christie M A1 - Jaiswal, Siddhartha A1 - Ebert, Benjamin L A1 - Kooperberg, Charles A1 - Manson, JoAnn E A1 - Whitsel, Eric A A1 - Natarajan, Pradeep A1 - Reiner, Alexander P AB -

BACKGROUND AND PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke.

METHODS: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes (, , and ) with any stroke, ischemic stroke, and hemorrhagic stroke.

RESULTS: CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03-1.27]; =0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01-1.51]; =0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, showed the strongest association with total stroke and ischemic stroke, whereas and were each associated with increased risk of hemorrhagic stroke.

CONCLUSIONS: CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.

VL - 53 IS - 3 ER - TY - JOUR T1 - Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI. JF - Brain Y1 - 2022 A1 - Yang, Yunju A1 - Knol, Maria J A1 - Wang, Ruiqi A1 - Mishra, Aniket A1 - Liu, Dan A1 - Luciano, Michelle A1 - Teumer, Alexander A1 - Armstrong, Nicola A1 - Bis, Joshua C A1 - Jhun, Min A A1 - Li, Shuo A1 - Adams, Hieab H H A1 - Aziz, Nasir Ahmad A1 - Bastin, Mark E A1 - Bourgey, Mathieu A1 - Brody, Jennifer A A1 - Frenzel, Stefan A1 - Gottesman, Rebecca F A1 - Hosten, Norbert A1 - Hou, Lifang A1 - Kardia, Sharon L R A1 - Lohner, Valerie A1 - Marquis, Pascale A1 - Maniega, Susana Muñoz A1 - Satizabal, Claudia L A1 - Sorond, Farzaneh A A1 - Valdés Hernández, Maria C A1 - van Duijn, Cornelia M A1 - Vernooij, Meike W A1 - Wittfeld, Katharina A1 - Yang, Qiong A1 - Zhao, Wei A1 - Boerwinkle, Eric A1 - Levy, Daniel A1 - Deary, Ian J A1 - Jiang, Jiyang A1 - Mather, Karen A A1 - Mosley, Thomas H A1 - Psaty, Bruce M A1 - Sachdev, Perminder S A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - DeCarli, Charles S A1 - Breteler, Monique M B A1 - Arfan Ikram, M A1 - Grabe, Hans J A1 - Wardlaw, Joanna A1 - Longstreth, W T A1 - Launer, Lenore J A1 - Seshadri, Sudha A1 - Debette, Stephanie A1 - Fornage, Myriam AB -

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.

ER - TY - JOUR T1 - Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning. JF - Mol Psychiatry Y1 - 2022 A1 - Lahti, Jari A1 - Tuominen, Samuli A1 - Yang, Qiong A1 - Pergola, Giulio A1 - Ahmad, Shahzad A1 - Amin, Najaf A1 - Armstrong, Nicola J A1 - Beiser, Alexa A1 - Bey, Katharina A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Bressler, Jan A1 - Campbell, Archie A1 - Campbell, Harry A1 - Chen, Qiang A1 - Corley, Janie A1 - Cox, Simon R A1 - Davies, Gail A1 - De Jager, Philip L A1 - Derks, Eske M A1 - Faul, Jessica D A1 - Fitzpatrick, Annette L A1 - Fohner, Alison E A1 - Ford, Ian A1 - Fornage, Myriam A1 - Gerring, Zachary A1 - Grabe, Hans J A1 - Grodstein, Francine A1 - Gudnason, Vilmundur A1 - Simonsick, Eleanor A1 - Holliday, Elizabeth G A1 - Joshi, Peter K A1 - Kajantie, Eero A1 - Kaprio, Jaakko A1 - Karell, Pauliina A1 - Kleineidam, Luca A1 - Knol, Maria J A1 - Kochan, Nicole A A1 - Kwok, John B A1 - Leber, Markus A1 - Lam, Max A1 - Lee, Teresa A1 - Li, Shuo A1 - Loukola, Anu A1 - Luck, Tobias A1 - Marioni, Riccardo E A1 - Mather, Karen A A1 - Medland, Sarah A1 - Mirza, Saira S A1 - Nalls, Mike A A1 - Nho, Kwangsik A1 - O'Donnell, Adrienne A1 - Oldmeadow, Christopher A1 - Painter, Jodie A1 - Pattie, Alison A1 - Reppermund, Simone A1 - Risacher, Shannon L A1 - Rose, Richard J A1 - Sadashivaiah, Vijay A1 - Scholz, Markus A1 - Satizabal, Claudia L A1 - Schofield, Peter W A1 - Schraut, Katharina E A1 - Scott, Rodney J A1 - Simino, Jeannette A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Stott, David J A1 - Surakka, Ida A1 - Teumer, Alexander A1 - Thalamuthu, Anbupalam A1 - Trompet, Stella A1 - Turner, Stephen T A1 - van der Lee, Sven J A1 - Villringer, Arno A1 - Völker, Uwe A1 - Wilson, Robert S A1 - Wittfeld, Katharina A1 - Vuoksimaa, Eero A1 - Xia, Rui A1 - Yaffe, Kristine A1 - Yu, Lei A1 - Zare, Habil A1 - Zhao, Wei A1 - Ames, David A1 - Attia, John A1 - Bennett, David A A1 - Brodaty, Henry A1 - Chasman, Daniel I A1 - Goldman, Aaron L A1 - Hayward, Caroline A1 - Ikram, M Arfan A1 - Jukema, J Wouter A1 - Kardia, Sharon L R A1 - Lencz, Todd A1 - Loeffler, Markus A1 - Mattay, Venkata S A1 - Palotie, Aarno A1 - Psaty, Bruce M A1 - Ramirez, Alfredo A1 - Ridker, Paul M A1 - Riedel-Heller, Steffi G A1 - Sachdev, Perminder S A1 - Saykin, Andrew J A1 - Scherer, Martin A1 - Schofield, Peter R A1 - Sidney, Stephen A1 - Starr, John M A1 - Trollor, Julian A1 - Ulrich, William A1 - Wagner, Michael A1 - Weir, David R A1 - Wilson, James F A1 - Wright, Margaret J A1 - Weinberger, Daniel R A1 - Debette, Stephanie A1 - Eriksson, Johan G A1 - Mosley, Thomas H A1 - Launer, Lenore J A1 - van Duijn, Cornelia M A1 - Deary, Ian J A1 - Seshadri, Sudha A1 - Räikkönen, Katri AB -

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.

ER - TY - JOUR T1 - New insights into the genetic etiology of Alzheimer's disease and related dementias. JF - Nat Genet Y1 - 2022 A1 - Bellenguez, Céline A1 - Küçükali, Fahri A1 - Jansen, Iris E A1 - Kleineidam, Luca A1 - Moreno-Grau, Sonia A1 - Amin, Najaf A1 - Naj, Adam C A1 - Campos-Martin, Rafael A1 - Grenier-Boley, Benjamin A1 - Andrade, Victor A1 - Holmans, Peter A A1 - Boland, Anne A1 - Damotte, Vincent A1 - van der Lee, Sven J A1 - Costa, Marcos R A1 - Kuulasmaa, Teemu A1 - Yang, Qiong A1 - de Rojas, Itziar A1 - Bis, Joshua C A1 - Yaqub, Amber A1 - Prokic, Ivana A1 - Chapuis, Julien A1 - Ahmad, Shahzad A1 - Giedraitis, Vilmantas A1 - Aarsland, Dag A1 - Garcia-Gonzalez, Pablo A1 - Abdelnour, Carla A1 - Alarcón-Martín, Emilio A1 - Alcolea, Daniel A1 - Alegret, Montserrat A1 - Alvarez, Ignacio A1 - Alvarez, Victoria A1 - Armstrong, Nicola J A1 - Tsolaki, Anthoula A1 - Antunez, Carmen A1 - Appollonio, Ildebrando A1 - Arcaro, Marina A1 - Archetti, Silvana A1 - Pastor, Alfonso Arias A1 - Arosio, Beatrice A1 - Athanasiu, Lavinia A1 - Bailly, Henri A1 - Banaj, Nerisa A1 - Baquero, Miquel A1 - Barral, Sandra A1 - Beiser, Alexa A1 - Pastor, Ana Belén A1 - Below, Jennifer E A1 - Benchek, Penelope A1 - Benussi, Luisa A1 - Berr, Claudine A1 - Besse, Céline A1 - Bessi, Valentina A1 - Binetti, Giuliano A1 - Bizarro, Alessandra A1 - Blesa, Rafael A1 - Boada, Merce A1 - Boerwinkle, Eric A1 - Borroni, Barbara A1 - Boschi, Silvia A1 - Bossù, Paola A1 - Bråthen, Geir A1 - Bressler, Jan A1 - Bresner, Catherine A1 - Brodaty, Henry A1 - Brookes, Keeley J A1 - Brusco, Luis Ignacio A1 - Buiza-Rueda, Dolores A1 - Bûrger, Katharina A1 - Burholt, Vanessa A1 - Bush, William S A1 - Calero, Miguel A1 - Cantwell, Laura B A1 - Chene, Geneviève A1 - Chung, Jaeyoon A1 - Cuccaro, Michael L A1 - Carracedo, Angel A1 - Cecchetti, Roberta A1 - Cervera-Carles, Laura A1 - Charbonnier, Camille A1 - Chen, Hung-Hsin A1 - Chillotti, Caterina A1 - Ciccone, Simona A1 - Claassen, Jurgen A H R A1 - Clark, Christopher A1 - Conti, Elisa A1 - Corma-Gómez, Anaïs A1 - Costantini, Emanuele A1 - Custodero, Carlo A1 - Daian, Delphine A1 - Dalmasso, Maria Carolina A1 - Daniele, Antonio A1 - Dardiotis, Efthimios A1 - Dartigues, Jean-François A1 - de Deyn, Peter Paul A1 - de Paiva Lopes, Katia A1 - de Witte, Lot D A1 - Debette, Stephanie A1 - Deckert, Jürgen A1 - Del Ser, Teodoro A1 - Denning, Nicola A1 - DeStefano, Anita A1 - Dichgans, Martin A1 - Diehl-Schmid, Janine A1 - Diez-Fairen, Monica A1 - Rossi, Paolo Dionigi A1 - Djurovic, Srdjan A1 - Duron, Emmanuelle A1 - Düzel, Emrah A1 - Dufouil, Carole A1 - Eiriksdottir, Gudny A1 - Engelborghs, Sebastiaan A1 - Escott-Price, Valentina A1 - Espinosa, Ana A1 - Ewers, Michael A1 - Faber, Kelley M A1 - Fabrizio, Tagliavini A1 - Nielsen, Sune Fallgaard A1 - Fardo, David W A1 - Farotti, Lucia A1 - Fenoglio, Chiara A1 - Fernández-Fuertes, Marta A1 - Ferrari, Raffaele A1 - Ferreira, Catarina B A1 - Ferri, Evelyn A1 - Fin, Bertrand A1 - Fischer, Peter A1 - Fladby, Tormod A1 - Fließbach, Klaus A1 - Fongang, Bernard A1 - Fornage, Myriam A1 - Fortea, Juan A1 - Foroud, Tatiana M A1 - Fostinelli, Silvia A1 - Fox, Nick C A1 - Franco-Macías, Emlio A1 - Bullido, María J A1 - Frank-García, Ana A1 - Froelich, Lutz A1 - Fulton-Howard, Brian A1 - Galimberti, Daniela A1 - García-Alberca, Jose Maria A1 - Garcia-Gonzalez, Pablo A1 - Garcia-Madrona, Sebastian A1 - Garcia-Ribas, Guillermo A1 - Ghidoni, Roberta A1 - Giegling, Ina A1 - Giorgio, Giaccone A1 - Goate, Alison M A1 - Goldhardt, Oliver A1 - Gomez-Fonseca, Duber A1 - González-Perez, Antonio A1 - Graff, Caroline A1 - Grande, Giulia A1 - Green, Emma A1 - Grimmer, Timo A1 - Grünblatt, Edna A1 - Grunin, Michelle A1 - Gudnason, Vilmundur A1 - Guetta-Baranes, Tamar A1 - Haapasalo, Annakaisa A1 - Hadjigeorgiou, Georgios A1 - Haines, Jonathan L A1 - Hamilton-Nelson, Kara L A1 - Hampel, Harald A1 - Hanon, Olivier A1 - Hardy, John A1 - Hartmann, Annette M A1 - Hausner, Lucrezia A1 - Harwood, Janet A1 - Heilmann-Heimbach, Stefanie A1 - Helisalmi, Seppo A1 - Heneka, Michael T A1 - Hernandez, Isabel A1 - Herrmann, Martin J A1 - Hoffmann, Per A1 - Holmes, Clive A1 - Holstege, Henne A1 - Vilas, Raquel Huerto A1 - Hulsman, Marc A1 - Humphrey, Jack A1 - Biessels, Geert Jan A1 - Jian, Xueqiu A1 - Johansson, Charlotte A1 - Jun, Gyungah R A1 - Kastumata, Yuriko A1 - Kauwe, John A1 - Kehoe, Patrick G A1 - Kilander, Lena A1 - Ståhlbom, Anne Kinhult A1 - Kivipelto, Miia A1 - Koivisto, Anne A1 - Kornhuber, Johannes A1 - Kosmidis, Mary H A1 - Kukull, Walter A A1 - Kuksa, Pavel P A1 - Kunkle, Brian W A1 - Kuzma, Amanda B A1 - Lage, Carmen A1 - Laukka, Erika J A1 - Launer, Lenore A1 - Lauria, Alessandra A1 - Lee, Chien-Yueh A1 - Lehtisalo, Jenni A1 - Lerch, Ondrej A1 - Lleo, Alberto A1 - Longstreth, William A1 - Lopez, Oscar A1 - de Munain, Adolfo Lopez A1 - Love, Seth A1 - Löwemark, Malin A1 - Luckcuck, Lauren A1 - Lunetta, Kathryn L A1 - Ma, Yiyi A1 - Macías, Juan A1 - MacLeod, Catherine A A1 - Maier, Wolfgang A1 - Mangialasche, Francesca A1 - Spallazzi, Marco A1 - Marquié, Marta A1 - Marshall, Rachel A1 - Martin, Eden R A1 - Montes, Angel Martín A1 - Rodríguez, Carmen Martínez A1 - Masullo, Carlo A1 - Mayeux, Richard A1 - Mead, Simon A1 - Mecocci, Patrizia A1 - Medina, Miguel A1 - Meggy, Alun A1 - Mehrabian, Shima A1 - Mendoza, Silvia A1 - Menéndez-González, Manuel A1 - Mir, Pablo A1 - Moebus, Susanne A1 - Mol, Merel A1 - Molina-Porcel, Laura A1 - Montrreal, Laura A1 - Morelli, Laura A1 - Moreno, Fermin A1 - Morgan, Kevin A1 - Mosley, Thomas A1 - Nöthen, Markus M A1 - Muchnik, Carolina A1 - Mukherjee, Shubhabrata A1 - Nacmias, Benedetta A1 - Ngandu, Tiia A1 - Nicolas, Gaël A1 - Nordestgaard, Børge G A1 - Olaso, Robert A1 - Orellana, Adelina A1 - Orsini, Michela A1 - Ortega, Gemma A1 - Padovani, Alessandro A1 - Paolo, Caffarra A1 - Papenberg, Goran A1 - Parnetti, Lucilla A1 - Pasquier, Florence A1 - Pastor, Pau A1 - Peloso, Gina A1 - Pérez-Cordón, Alba A1 - Pérez-Tur, Jordi A1 - Pericard, Pierre A1 - Peters, Oliver A1 - Pijnenburg, Yolande A L A1 - Pineda, Juan A A1 - Piñol-Ripoll, Gerard A1 - Pisanu, Claudia A1 - Polak, Thomas A1 - Popp, Julius A1 - Posthuma, Danielle A1 - Priller, Josef A1 - Puerta, Raquel A1 - Quenez, Olivier A1 - Quintela, Inés A1 - Thomassen, Jesper Qvist A1 - Rábano, Alberto A1 - Rainero, Innocenzo A1 - Rajabli, Farid A1 - Ramakers, Inez A1 - Real, Luis M A1 - Reinders, Marcel J T A1 - Reitz, Christiane A1 - Reyes-Dumeyer, Dolly A1 - Ridge, Perry A1 - Riedel-Heller, Steffi A1 - Riederer, Peter A1 - Roberto, Natalia A1 - Rodriguez-Rodriguez, Eloy A1 - Rongve, Arvid A1 - Allende, Irene Rosas A1 - Rosende-Roca, Maitée A1 - Royo, Jose Luis A1 - Rubino, Elisa A1 - Rujescu, Dan A1 - Sáez, María Eugenia A1 - Sakka, Paraskevi A1 - Saltvedt, Ingvild A1 - Sanabria, Ángela A1 - Sánchez-Arjona, María Bernal A1 - Sanchez-Garcia, Florentino A1 - Juan, Pascual Sánchez A1 - Sánchez-Valle, Raquel A1 - Sando, Sigrid B A1 - Sarnowski, Chloe A1 - Satizabal, Claudia L A1 - Scamosci, Michela A1 - Scarmeas, Nikolaos A1 - Scarpini, Elio A1 - Scheltens, Philip A1 - Scherbaum, Norbert A1 - Scherer, Martin A1 - Schmid, Matthias A1 - Schneider, Anja A1 - Schott, Jonathan M A1 - Selbæk, Geir A1 - Seripa, Davide A1 - Serrano, Manuel A1 - Sha, Jin A1 - Shadrin, Alexey A A1 - Skrobot, Olivia A1 - Slifer, Susan A1 - Snijders, Gijsje J L A1 - Soininen, Hilkka A1 - Solfrizzi, Vincenzo A1 - Solomon, Alina A1 - Song, Yeunjoo A1 - Sorbi, Sandro A1 - Sotolongo-Grau, Oscar A1 - Spalletta, Gianfranco A1 - Spottke, Annika A1 - Squassina, Alessio A1 - Stordal, Eystein A1 - Tartan, Juan Pablo A1 - Tarraga, Lluis A1 - Tesí, Niccolo A1 - Thalamuthu, Anbupalam A1 - Thomas, Tegos A1 - Tosto, Giuseppe A1 - Traykov, Latchezar A1 - Tremolizzo, Lucio A1 - Tybjærg-Hansen, Anne A1 - Uitterlinden, Andre A1 - Ullgren, Abbe A1 - Ulstein, Ingun A1 - Valero, Sergi A1 - Valladares, Otto A1 - Broeckhoven, Christine Van A1 - Vance, Jeffery A1 - Vardarajan, Badri N A1 - van der Lugt, Aad A1 - Dongen, Jasper Van A1 - van Rooij, Jeroen A1 - van Swieten, John A1 - Vandenberghe, Rik A1 - Verhey, Frans A1 - Vidal, Jean-Sébastien A1 - Vogelgsang, Jonathan A1 - Vyhnalek, Martin A1 - Wagner, Michael A1 - Wallon, David A1 - Wang, Li-San A1 - Wang, Ruiqi A1 - Weinhold, Leonie A1 - Wiltfang, Jens A1 - Windle, Gill A1 - Woods, Bob A1 - Yannakoulia, Mary A1 - Zare, Habil A1 - Zhao, Yi A1 - Zhang, Xiaoling A1 - Zhu, Congcong A1 - Zulaica, Miren A1 - Farrer, Lindsay A A1 - Psaty, Bruce M A1 - Ghanbari, Mohsen A1 - Raj, Towfique A1 - Sachdev, Perminder A1 - Mather, Karen A1 - Jessen, Frank A1 - Ikram, M Arfan A1 - de Mendonça, Alexandre A1 - Hort, Jakub A1 - Tsolaki, Magda A1 - Pericak-Vance, Margaret A A1 - Amouyel, Philippe A1 - Williams, Julie A1 - Frikke-Schmidt, Ruth A1 - Clarimon, Jordi A1 - Deleuze, Jean-Francois A1 - Rossi, Giacomina A1 - Seshadri, Sudha A1 - Andreassen, Ole A A1 - Ingelsson, Martin A1 - Hiltunen, Mikko A1 - Sleegers, Kristel A1 - Schellenberg, Gerard D A1 - van Duijn, Cornelia M A1 - Sims, Rebecca A1 - van der Flier, Wiesje M A1 - Ruiz, Agustin A1 - Ramirez, Alfredo A1 - Lambert, Jean-Charles KW - Alzheimer Disease KW - Cognitive Dysfunction KW - Genome-Wide Association Study KW - Humans KW - tau Proteins AB -

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.

VL - 54 IS - 4 ER - TY - JOUR T1 - Stroke genetics informs drug discovery and risk prediction across ancestries. JF - Nature Y1 - 2022 A1 - Mishra, Aniket A1 - Malik, Rainer A1 - Hachiya, Tsuyoshi A1 - Jürgenson, Tuuli A1 - Namba, Shinichi A1 - Posner, Daniel C A1 - Kamanu, Frederick K A1 - Koido, Masaru A1 - Le Grand, Quentin A1 - Shi, Mingyang A1 - He, Yunye A1 - Georgakis, Marios K A1 - Caro, Ilana A1 - Krebs, Kristi A1 - Liaw, Yi-Ching A1 - Vaura, Felix C A1 - Lin, Kuang A1 - Winsvold, Bendik Slagsvold A1 - Srinivasasainagendra, Vinodh A1 - Parodi, Livia A1 - Bae, Hee-Joon A1 - Chauhan, Ganesh A1 - Chong, Michael R A1 - Tomppo, Liisa A1 - Akinyemi, Rufus A1 - Roshchupkin, Gennady V A1 - Habib, Naomi A1 - Jee, Yon Ho A1 - Thomassen, Jesper Qvist A1 - Abedi, Vida A1 - Cárcel-Márquez, Jara A1 - Nygaard, Marianne A1 - Leonard, Hampton L A1 - Yang, Chaojie A1 - Yonova-Doing, Ekaterina A1 - Knol, Maria J A1 - Lewis, Adam J A1 - Judy, Renae L A1 - Ago, Tetsuro A1 - Amouyel, Philippe A1 - Armstrong, Nicole D A1 - Bakker, Mark K A1 - Bartz, Traci M A1 - Bennett, David A A1 - Bis, Joshua C A1 - Bordes, Constance A1 - Børte, Sigrid A1 - Cain, Anael A1 - Ridker, Paul M A1 - Cho, Kelly A1 - Chen, Zhengming A1 - Cruchaga, Carlos A1 - Cole, John W A1 - De Jager, Phil L A1 - de Cid, Rafael A1 - Endres, Matthias A1 - Ferreira, Leslie E A1 - Geerlings, Mirjam I A1 - Gasca, Natalie C A1 - Gudnason, Vilmundur A1 - Hata, Jun A1 - He, Jing A1 - Heath, Alicia K A1 - Ho, Yuk-Lam A1 - Havulinna, Aki S A1 - Hopewell, Jemma C A1 - Hyacinth, Hyacinth I A1 - Inouye, Michael A1 - Jacob, Mina A A1 - Jeon, Christina E A1 - Jern, Christina A1 - Kamouchi, Masahiro A1 - Keene, Keith L A1 - Kitazono, Takanari A1 - Kittner, Steven J A1 - Konuma, Takahiro A1 - Kumar, Amit A1 - Lacaze, Paul A1 - Launer, Lenore J A1 - Lee, Keon-Joo A1 - Lepik, Kaido A1 - Li, Jiang A1 - Li, Liming A1 - Manichaikul, Ani A1 - Markus, Hugh S A1 - Marston, Nicholas A A1 - Meitinger, Thomas A1 - Mitchell, Braxton D A1 - Montellano, Felipe A A1 - Morisaki, Takayuki A1 - Mosley, Thomas H A1 - Nalls, Mike A A1 - Nordestgaard, Børge G A1 - O'Donnell, Martin J A1 - Okada, Yukinori A1 - Onland-Moret, N Charlotte A1 - Ovbiagele, Bruce A1 - Peters, Annette A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Rosand, Jonathan A1 - Sabatine, Marc S A1 - Sacco, Ralph L A1 - Saleheen, Danish A1 - Sandset, Else Charlotte A1 - Salomaa, Veikko A1 - Sargurupremraj, Muralidharan A1 - Sasaki, Makoto A1 - Satizabal, Claudia L A1 - Schmidt, Carsten O A1 - Shimizu, Atsushi A1 - Smith, Nicholas L A1 - Sloane, Kelly L A1 - Sutoh, Yoichi A1 - Sun, Yan V A1 - Tanno, Kozo A1 - Tiedt, Steffen A1 - Tatlisumak, Turgut A1 - Torres-Aguila, Nuria P A1 - Tiwari, Hemant K A1 - Trégouët, David-Alexandre A1 - Trompet, Stella A1 - Tuladhar, Anil Man A1 - Tybjærg-Hansen, Anne A1 - van Vugt, Marion A1 - Vibo, Riina A1 - Verma, Shefali S A1 - Wiggins, Kerri L A1 - Wennberg, Patrik A1 - Woo, Daniel A1 - Wilson, Peter W F A1 - Xu, Huichun A1 - Yang, Qiong A1 - Yoon, Kyungheon A1 - Millwood, Iona Y A1 - Gieger, Christian A1 - Ninomiya, Toshiharu A1 - Grabe, Hans J A1 - Jukema, J Wouter A1 - Rissanen, Ina L A1 - Strbian, Daniel A1 - Kim, Young Jin A1 - Chen, Pei-Hsin A1 - Mayerhofer, Ernst A1 - Howson, Joanna M M A1 - Irvin, Marguerite R A1 - Adams, Hieab A1 - Wassertheil-Smoller, Sylvia A1 - Christensen, Kaare A1 - Ikram, Mohammad A A1 - Rundek, Tatjana A1 - Worrall, Bradford B A1 - Lathrop, G Mark A1 - Riaz, Moeen A1 - Simonsick, Eleanor M A1 - Kõrv, Janika A1 - França, Paulo H C A1 - Zand, Ramin A1 - Prasad, Kameshwar A1 - Frikke-Schmidt, Ruth A1 - de Leeuw, Frank-Erik A1 - Liman, Thomas A1 - Haeusler, Karl Georg A1 - Ruigrok, Ynte M A1 - Heuschmann, Peter Ulrich A1 - Longstreth, W T A1 - Jung, Keum Ji A1 - Bastarache, Lisa A1 - Paré, Guillaume A1 - Damrauer, Scott M A1 - Chasman, Daniel I A1 - Rotter, Jerome I A1 - Anderson, Christopher D A1 - Zwart, John-Anker A1 - Niiranen, Teemu J A1 - Fornage, Myriam A1 - Liaw, Yung-Po A1 - Seshadri, Sudha A1 - Fernandez-Cadenas, Israel A1 - Walters, Robin G A1 - Ruff, Christian T A1 - Owolabi, Mayowa O A1 - Huffman, Jennifer E A1 - Milani, Lili A1 - Kamatani, Yoichiro A1 - Dichgans, Martin A1 - Debette, Stephanie AB -

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.

ER - TY - JOUR T1 - Association Between Whole Blood-Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk. JF - J Am Heart Assoc Y1 - 2023 A1 - Liu, Xue A1 - Sun, Xianbang A1 - Zhang, Yuankai A1 - Jiang, Wenqing A1 - Lai, Meng A1 - Wiggins, Kerri L A1 - Raffield, Laura M A1 - Bielak, Lawrence F A1 - Zhao, Wei A1 - Pitsillides, Achilleas A1 - Haessler, Jeffrey A1 - Zheng, Yinan A1 - Blackwell, Thomas W A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Qian, Yong A1 - Thyagarajan, Bharat A1 - Pankratz, Nathan A1 - Rich, Stephen S A1 - Taylor, Kent D A1 - Peyser, Patricia A A1 - Heckbert, Susan R A1 - Seshadri, Sudha A1 - Boerwinkle, Eric A1 - Grove, Megan L A1 - Larson, Nicholas B A1 - Smith, Jennifer A A1 - Vasan, Ramachandran S A1 - Fitzpatrick, Annette L A1 - Fornage, Myriam A1 - Ding, Jun A1 - Carson, April P A1 - Abecasis, Goncalo A1 - Dupuis, Josée A1 - Reiner, Alexander A1 - Kooperberg, Charles A1 - Hou, Lifang A1 - Psaty, Bruce M A1 - Wilson, James G A1 - Levy, Daniel A1 - Rotter, Jerome I A1 - Bis, Joshua C A1 - Satizabal, Claudia L A1 - Arking, Dan E A1 - Liu, Chunyu AB -

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1-SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04-1.12; <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; =0.11) or in the reverse direction (β=-0.012; =0.076). Additional bidirectional Mendelian randomization analyses revealed that low-density lipoprotein cholesterol had a causal effect on mtDNA CN (β=-0.084; <0.001), but the reverse direction was not significant (=0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low-density lipoprotein cholesterol level (=0.52), whereas there was a strong direct causal effect of higher low-density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=-0.092; <0.001). Conclusions Our findings indicate that high low-density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

ER - TY - JOUR T1 - Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts. JF - Neurology Y1 - 2023 A1 - Zhang, Yuankai A1 - Liu, Xue A1 - Wiggins, Kerri L A1 - Kurniansyah, Nuzulul A1 - Guo, Xiuqing A1 - Rodrigue, Amanda L A1 - Zhao, Wei A1 - Yanek, Lisa R A1 - Ratliff, Scott M A1 - Pitsillides, Achilleas A1 - Aguirre Patiño, Juan Sebastian A1 - Sofer, Tamar A1 - Arking, Dan E A1 - Austin, Thomas R A1 - Beiser, Alexa S A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bressler, Jan A1 - Curran, Joanne E A1 - Hou, Lifang A1 - Hughes, Timothy M A1 - Kardia, Sharon L A1 - Launer, Lenore A1 - Levy, Daniel A1 - Mosley, Tom H A1 - Nasrallah, Ilya M A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Seshadri, Sudha A1 - Tarraf, Wassim A1 - González, Kevin A A1 - Ramachandran, Vasan A1 - Yaffe, Kristine A1 - Nyquist, Paul A A1 - Psaty, Bruce M A1 - DeCarli, Charles S A1 - Smith, Jennifer A A1 - Glahn, David C A1 - González, Hector M A1 - Bis, Joshua C A1 - Fornage, Myriam A1 - Heckbert, Susan R A1 - Fitzpatrick, Annette L A1 - Liu, Chunyu A1 - Satizabal, Claudia L AB -

BACKGROUND AND OBJECTIVES: Previous studies suggest lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer's disease (AD) and AD related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.

METHODS: We included dementia-free participants from nine diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5 to 20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs. ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed Mendelian randomization (MR) analyses to assess causality.

RESULTS: We included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (Beta=0.04; 95% CI 0.02, 0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition.

DISCUSSION: Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the US. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.

ER - TY - JOUR T1 - Carriers of rare damaging genetic variants are at lower risk of atherosclerotic disease. JF - medRxiv Y1 - 2023 A1 - Georgakis, Marios K A1 - Malik, Rainer A1 - Hasbani, Natalie R A1 - Shakt, Gabrielle A1 - Morrison, Alanna C A1 - Tsao, Noah L A1 - Judy, Renae A1 - Mitchell, Braxton D A1 - Xu, Huichun A1 - Montasser, May E A1 - Do, Ron A1 - Kenny, Eimear E A1 - Loos, Ruth J F A1 - Terry, James G A1 - Carr, John Jeffrey A1 - Bis, Joshua C A1 - Psaty, Bruce M A1 - Longstreth, W T A1 - Young, Kendra A A1 - Lutz, Sharon M A1 - Cho, Michael H A1 - Broome, Jai A1 - Khan, Alyna T A1 - Wang, Fei Fei A1 - Heard-Costa, Nancy A1 - Seshadri, Sudha A1 - Vasan, Ramachandran S A1 - Palmer, Nicholette D A1 - Freedman, Barry I A1 - Bowden, Donald W A1 - Yanek, Lisa R A1 - Kral, Brian G A1 - Becker, Lewis C A1 - Peyser, Patricia A A1 - Bielak, Lawrence F A1 - Ammous, Farah A1 - Carson, April P A1 - Hall, Michael E A1 - Raffield, Laura M A1 - Rich, Stephen S A1 - Post, Wendy S A1 - Tracy, Russel P A1 - Taylor, Kent D A1 - Guo, Xiuqing A1 - Mahaney, Michael C A1 - Curran, Joanne E A1 - Blangero, John A1 - Clarke, Shoa L A1 - Haessler, Jeffrey W A1 - Hu, Yao A1 - Assimes, Themistocles L A1 - Kooperberg, Charles A1 - Damrauer, Scott M A1 - Rotter, Jerome I A1 - de Vries, Paul S A1 - Dichgans, Martin AB -

BACKGROUND: The CCL2/CCR2 axis governs monocyte trafficking and recruitment to atherosclerotic lesions. Human genetic analyses and population-based studies support an association between circulating CCL2 levels and atherosclerosis. Still, it remains unknown whether pharmacological targeting of CCR2, the main CCL2 receptor, would provide protection against human atherosclerotic disease.

METHODS: In whole-exome sequencing data from 454,775 UK Biobank participants (40-69 years), we identified predicted loss-of-function (LoF) or damaging missense (REVEL score >0.5) variants within the gene. We prioritized variants associated with lower monocyte count (p<0.05) and tested associations with vascular risk factors and risk of atherosclerotic disease over a mean follow-up of 14 years. The results were replicated in a pooled cohort of three independent datasets (TOPMed, deCODE and Penn Medicine BioBank; total n=441,445) and the effect of the most frequent damaging variant was experimentally validated.

RESULTS: A total of 45 predicted LoF or damaging missense variants were identified in the gene, 4 of which were also significantly associated with lower monocyte count, but not with other white blood cell counts. Heterozygous carriers of these variants were at a lower risk of a combined atherosclerosis outcome, showed a lower burden of atherosclerosis across four vascular beds, and were at a lower lifetime risk of coronary artery disease and myocardial infarction. There was no evidence of association with vascular risk factors including LDL-cholesterol, blood pressure, glycemic status, or C-reactive protein. Using a cAMP assay, we found that cells transfected with the most frequent damaging variant (3:46358273:T:A, M249K, 547 carriers, frequency: 0.14%) show a decrease in signaling in response to CCL2. The associations of the M249K variant with myocardial infarction were consistent across cohorts (OR : 0.62 95%CI: 0.39-0.96; OR : 0.64 95%CI: 0.34-1.19; OR : 0.64 95%CI: 0.45-0.90). In a phenome-wide association study, we found no evidence for higher risk of common infections or mortality among carriers of damaging variants.

CONCLUSIONS: Heterozygous carriers of damaging variants have a lower burden of atherosclerosis and lower lifetime risk of myocardial infarction. In conjunction with previous evidence from experimental and epidemiological studies, our findings highlight the translational potential of CCR2-targeting as an atheroprotective approach.

ER - TY - JOUR T1 - Clonal hematopoiesis is associated with protection from Alzheimer's disease. JF - Nat Med Y1 - 2023 A1 - Bouzid, Hind A1 - Belk, Julia A A1 - Jan, Max A1 - Qi, Yanyan A1 - Sarnowski, Chloe A1 - Wirth, Sara A1 - Ma, Lisa A1 - Chrostek, Matthew R A1 - Ahmad, Herra A1 - Nachun, Daniel A1 - Yao, Winnie A1 - Beiser, Alexa A1 - Bick, Alexander G A1 - Bis, Joshua C A1 - Fornage, Myriam A1 - Longstreth, William T A1 - Lopez, Oscar L A1 - Natarajan, Pradeep A1 - Psaty, Bruce M A1 - Satizabal, Claudia L A1 - Weinstock, Joshua A1 - Larson, Eric B A1 - Crane, Paul K A1 - Keene, C Dirk A1 - Seshadri, Sudha A1 - Satpathy, Ansuman T A1 - Montine, Thomas J A1 - Jaiswal, Siddhartha AB -

Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant expansion of mutated hematopoietic stem cells. As CHIP-associated mutations are known to alter the development and function of myeloid cells, we hypothesized that CHIP may also be associated with the risk of Alzheimer's disease (AD), a disease in which brain-resident myeloid cells are thought to have a major role. To perform association tests between CHIP and AD dementia, we analyzed blood DNA sequencing data from 1,362 individuals with AD and 4,368 individuals without AD. Individuals with CHIP had a lower risk of AD dementia (meta-analysis odds ratio (OR) = 0.64, P = 3.8 × 10), and Mendelian randomization analyses supported a potential causal association. We observed that the same mutations found in blood were also detected in microglia-enriched fraction of the brain in seven of eight CHIP carriers. Single-nucleus chromatin accessibility profiling of brain-derived nuclei in six CHIP carriers revealed that the mutated cells comprised a large proportion of the microglial pool in the samples examined. While additional studies are required to validate the mechanistic findings, these results suggest that CHIP may have a role in attenuating the risk of AD.

VL - 29 IS - 7 ER - TY - JOUR T1 - Complexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics. JF - medRxiv Y1 - 2023 A1 - Sargurupremraj, Muralidharan A1 - Soumaré, Aïcha A1 - Bis, Joshua C A1 - Surakka, Ida A1 - Jürgenson, Tuuli A1 - Joly, Pierre A1 - Knol, Maria J A1 - Wang, Ruiqi A1 - Yang, Qiong A1 - Satizabal, Claudia L A1 - Gudjonsson, Alexander A1 - Mishra, Aniket A1 - Bouteloup, Vincent A1 - Phuah, Chia-Ling A1 - van Duijn, Cornelia M A1 - Cruchaga, Carlos A1 - Dufouil, Carole A1 - Chene, Geneviève A1 - Lopez, Oscar A1 - Psaty, Bruce M A1 - Tzourio, Christophe A1 - Amouyel, Philippe A1 - Adams, Hieab H A1 - Jacqmin-Gadda, Hélène A1 - Ikram, Mohammad Arfan A1 - Gudnason, Vilmundur A1 - Milani, Lili A1 - Winsvold, Bendik S A1 - Hveem, Kristian A1 - Matthews, Paul M A1 - Longstreth, W T A1 - Seshadri, Sudha A1 - Launer, Lenore J A1 - Debette, Stephanie AB -

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.

ER - TY - JOUR T1 - Sleep Architecture, Obstructive Sleep Apnea, and Cognitive Function in Adults. JF - JAMA Netw Open Y1 - 2023 A1 - Pase, Matthew P A1 - Harrison, Stephanie A1 - Misialek, Jeffrey R A1 - Kline, Christopher E A1 - Cavuoto, Marina A1 - Baril, Andree-Ann A1 - Yiallourou, Stephanie A1 - Bisson, Alycia A1 - Himali, Dibya A1 - Leng, Yue A1 - Yang, Qiong A1 - Seshadri, Sudha A1 - Beiser, Alexa A1 - Gottesman, Rebecca F A1 - Redline, Susan A1 - Lopez, Oscar A1 - Lutsey, Pamela L A1 - Yaffe, Kristine A1 - Stone, Katie L A1 - Purcell, Shaun M A1 - Himali, Jayandra J AB -

IMPORTANCE: Good sleep is essential for health, yet associations between sleep and dementia risk remain incompletely understood. The Sleep and Dementia Consortium was established to study associations between polysomnography (PSG)-derived sleep and the risk of dementia and related cognitive and brain magnetic resonance imaging endophenotypes.

OBJECTIVE: To investigate association of sleep architecture and obstructive sleep apnea (OSA) with cognitive function in the Sleep and Dementia Consortium.

DESIGN, SETTING, AND PARTICIPANTS: The Sleep and Dementia Consortium curated data from 5 population-based cohorts across the US with methodologically consistent, overnight, home-based type II PSG and neuropsychological assessments over 5 years of follow-up: the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, Framingham Heart Study (FHS), Osteoporotic Fractures in Men Study, and Study of Osteoporotic Fractures. Sleep metrics were harmonized centrally and then distributed to participating cohorts for cohort-specific analysis using linear regression; study-level estimates were pooled in random effects meta-analyses. Results were adjusted for demographic variables, the time between PSG and neuropsychological assessment (0-5 years), body mass index, antidepressant use, and sedative use. There were 5946 participants included in the pooled analyses without stroke or dementia. Data were analyzed from March 2020 to June 2023.

EXPOSURES: Measures of sleep architecture and OSA derived from in-home PSG.

MAIN OUTCOMES AND MEASURES: The main outcomes were global cognitive composite z scores derived from principal component analysis, with cognitive domains investigated as secondary outcomes. Higher scores indicated better performance.

RESULTS: Across cohorts, 5946 adults (1875 females [31.5%]; mean age range, 58-89 years) were included. The median (IQR) wake after sleep onset time ranged from 44 (27-73) to 101 (66-147) minutes, and the prevalence of moderate to severe OSA ranged from 16.9% to 28.9%. Across cohorts, higher sleep maintenance efficiency (pooled β per 1% increase, 0.08; 95% CI, 0.03 to 0.14; P < .01) and lower wake after sleep onset (pooled β per 1-min increase, -0.07; 95% CI, -0.13 to -0.01 per 1-min increase; P = .02) were associated with better global cognition. Mild to severe OSA (apnea-hypopnea index [AHI] ≥5) was associated with poorer global cognition (pooled β, -0.06; 95% CI, -0.11 to -0.01; P = .01) vs AHI less than 5; comparable results were found for moderate to severe OSA (pooled β, -0.06; 95% CI, -0.11 to -0.01; P = .02) vs AHI less than 5. Differences in sleep stages were not associated with cognition.

CONCLUSIONS AND RELEVANCE: This study found that better sleep consolidation and the absence of OSA were associated with better global cognition over 5 years of follow-up. These findings suggest that the role of interventions to improve sleep for maintaining cognitive function requires investigation.

VL - 6 IS - 7 ER - TY - JOUR T1 - Associations of Neurological Biomarkers in Serum with Gait Measures: The Cardiovascular Health Study. JF - J Gerontol A Biol Sci Med Sci Y1 - 2024 A1 - Nadkarni, Abhijay A1 - Mukamal, Kenneth J A1 - Zhu, Xiaonan A1 - Siscovick, David A1 - Brach, Jennifer S A1 - Jacob, Mini A1 - Seshadri, Sudha A1 - Abe, Temidayo A1 - Rosano, Caterina A1 - Djoussé, Luc A1 - Rosso, Andrea L AB -

BACKGROUND: Gait impairment leads to increased mobility decline and may have neurological contributions. This study explores how neurological biomarkers are related to gait in older adults.

METHODS: We studied participants in the Cardiovascular Health Study, a population-based cohort of older Americans, who underwent a serum biomarker assessment from samples collected in 1996-97 for neurofilament light-chain (NfL), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and total tau (n=1959, mean age=78.0 years, 60.8% female). In a subsample (n=380), cross-sectional associations with quantitative gait measures were explored. This subsample was assessed on a mat for gait speed, step length, double support time, step time, step length variability and step time variability. Gait speed was also measured over a 15-ft walkway annually from 1996-97 to 1998-99, for longitudinal analyses. Linear regression models assessed cross-sectional associations of biomarkers with gait measures, while mixed effects models assessed longitudinal gait speed change from baseline to 1998-99.

RESULTS: NfL was significantly associated with annual gait speed decline (standardized β = -0.64 m/s, 95% CI: [-1.23, -0.06]) after adjustment for demographic and health factors. Among gait mat-assessed phenotypes, NfL was also cross-sectionally associated with gait speed (β = 0.001 m/s [0.0003, 0.002]) but not with other gait measures. None of the remaining biomarkers were significantly related to gait in either longitudinal or cross-sectional analyses.

CONCLUSION: Higher NfL levels were related to greater annual gait speed decline. Gait speed decline may be related to axonal degeneration. The clinical utility of NfL should be explored.

ER - TY - JOUR T1 - Human whole-exome genotype data for Alzheimer's disease. JF - Nat Commun Y1 - 2024 A1 - Leung, Yuk Yee A1 - Naj, Adam C A1 - Chou, Yi-Fan A1 - Valladares, Otto A1 - Schmidt, Michael A1 - Hamilton-Nelson, Kara A1 - Wheeler, Nicholas A1 - Lin, Honghuang A1 - Gangadharan, Prabhakaran A1 - Qu, Liming A1 - Clark, Kaylyn A1 - Kuzma, Amanda B A1 - Lee, Wan-Ping A1 - Cantwell, Laura A1 - Nicaretta, Heather A1 - Haines, Jonathan A1 - Farrer, Lindsay A1 - Seshadri, Sudha A1 - Brkanac, Zoran A1 - Cruchaga, Carlos A1 - Pericak-Vance, Margaret A1 - Mayeux, Richard P A1 - Bush, William S A1 - DeStefano, Anita A1 - Martin, Eden A1 - Schellenberg, Gerard D A1 - Wang, Li-San KW - Alzheimer Disease KW - Computational Biology KW - Data Accuracy KW - Exome KW - Genotype KW - Humans AB -

The heterogeneity of the whole-exome sequencing (WES) data generation methods present a challenge to a joint analysis. Here we present a bioinformatics strategy for joint-calling 20,504 WES samples collected across nine studies and sequenced using ten capture kits in fourteen sequencing centers in the Alzheimer's Disease Sequencing Project. The joint-genotype called variant-called format (VCF) file contains only positions within the union of capture kits. The VCF was then processed specifically to account for the batch effects arising from the use of different capture kits from different studies. We identified 8.2 million autosomal variants. 96.82% of the variants are high-quality, and are located in 28,579 Ensembl transcripts. 41% of the variants are intronic and 1.8% of the variants are with CADD > 30, indicating they are of high predicted pathogenicity. Here we show our new strategy can generate high-quality data from processing these diversely generated WES samples. The improved ability to combine data sequenced in different batches benefits the whole genomics research community.

VL - 15 IS - 1 ER - TY - JOUR T1 - Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance. JF - Alzheimers Res Ther Y1 - 2024 A1 - Mei, Hao A1 - Simino, Jeannette A1 - Li, Lianna A1 - Jiang, Fan A1 - Bis, Joshua C A1 - Davies, Gail A1 - Hill, W David A1 - Xia, Charley A1 - Gudnason, Vilmundur A1 - Yang, Qiong A1 - Lahti, Jari A1 - Smith, Jennifer A A1 - Kirin, Mirna A1 - De Jager, Philip A1 - Armstrong, Nicola J A1 - Ghanbari, Mohsen A1 - Kolcic, Ivana A1 - Moran, Christopher A1 - Teumer, Alexander A1 - Sargurupremraj, Murali A1 - Mahmud, Shamsed A1 - Fornage, Myriam A1 - Zhao, Wei A1 - Satizabal, Claudia L A1 - Polasek, Ozren A1 - Räikkönen, Katri A1 - Liewald, David C A1 - Homuth, Georg A1 - Callisaya, Michele A1 - Mather, Karen A A1 - Windham, B Gwen A1 - Zemunik, Tatijana A1 - Palotie, Aarno A1 - Pattie, Alison A1 - van der Auwera, Sandra A1 - Thalamuthu, Anbupalam A1 - Knopman, David S A1 - Rudan, Igor A1 - Starr, John M A1 - Wittfeld, Katharina A1 - Kochan, Nicole A A1 - Griswold, Michael E A1 - Vitart, Veronique A1 - Brodaty, Henry A1 - Gottesman, Rebecca A1 - Cox, Simon R A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Chasman, Daniel I A1 - Grodstein, Francine A1 - Sachdev, Perminder S A1 - Srikanth, Velandai A1 - Hayward, Caroline A1 - Wilson, James F A1 - Eriksson, Johan G A1 - Kardia, Sharon L R A1 - Grabe, Hans J A1 - Bennett, David A A1 - Ikram, M Arfan A1 - Deary, Ian J A1 - van Duijn, Cornelia M A1 - Launer, Lenore A1 - Fitzpatrick, Annette L A1 - Seshadri, Sudha A1 - Bressler, Jan A1 - Debette, Stephanie A1 - Mosley, Thomas H KW - Aged KW - Cognition KW - Genome-Wide Association Study KW - Humans KW - Memory KW - MicroRNAs KW - Multiomics KW - Polymorphism, Single Nucleotide AB -

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.

VL - 16 IS - 1 ER -