TY - JOUR T1 - Genome-wide association study of blood pressure and hypertension. JF - Nat Genet Y1 - 2009 A1 - Levy, Daniel A1 - Ehret, Georg B A1 - Rice, Kenneth A1 - Verwoert, Germaine C A1 - Launer, Lenore J A1 - Dehghan, Abbas A1 - Glazer, Nicole L A1 - Morrison, Alanna C A1 - Johnson, Andrew D A1 - Aspelund, Thor A1 - Aulchenko, Yurii A1 - Lumley, Thomas A1 - Köttgen, Anna A1 - Vasan, Ramachandran S A1 - Rivadeneira, Fernando A1 - Eiriksdottir, Gudny A1 - Guo, Xiuqing A1 - Arking, Dan E A1 - Mitchell, Gary F A1 - Mattace-Raso, Francesco U S A1 - Smith, Albert V A1 - Taylor, Kent A1 - Scharpf, Robert B A1 - Hwang, Shih-Jen A1 - Sijbrands, Eric J G A1 - Bis, Joshua A1 - Harris, Tamara B A1 - Ganesh, Santhi K A1 - O'Donnell, Christopher J A1 - Hofman, Albert A1 - Rotter, Jerome I A1 - Coresh, Josef A1 - Benjamin, Emelia J A1 - Uitterlinden, André G A1 - Heiss, Gerardo A1 - Fox, Caroline S A1 - Witteman, Jacqueline C M A1 - Boerwinkle, Eric A1 - Wang, Thomas J A1 - Gudnason, Vilmundur A1 - Larson, Martin G A1 - Chakravarti, Aravinda A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M KW - Blood Pressure KW - Cell Line KW - Chromosome Mapping KW - Chromosomes, Human KW - Diastole KW - Gene Expression Regulation KW - Genetic Association Studies KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Liver KW - Lymphocytes KW - Meta-Analysis as Topic KW - Odds Ratio KW - Phenotype KW - Prevalence KW - Risk Assessment KW - Systole AB -

Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 × 10(-7). The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 × 10(-8)) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.

VL - 41 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19430479?dopt=Abstract ER - TY - JOUR T1 - Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. JF - Nat Genet Y1 - 2009 A1 - Ganesh, Santhi K A1 - Zakai, Neil A A1 - van Rooij, Frank J A A1 - Soranzo, Nicole A1 - Smith, Albert V A1 - Nalls, Michael A A1 - Chen, Ming-Huei A1 - Köttgen, Anna A1 - Glazer, Nicole L A1 - Dehghan, Abbas A1 - Kuhnel, Brigitte A1 - Aspelund, Thor A1 - Yang, Qiong A1 - Tanaka, Toshiko A1 - Jaffe, Andrew A1 - Bis, Joshua C M A1 - Verwoert, Germaine C A1 - Teumer, Alexander A1 - Fox, Caroline S A1 - Guralnik, Jack M A1 - Ehret, Georg B A1 - Rice, Kenneth A1 - Felix, Janine F A1 - Rendon, Augusto A1 - Eiriksdottir, Gudny A1 - Levy, Daniel A1 - Patel, Kushang V A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Hofman, Albert A1 - Sambrook, Jennifer G A1 - Hernandez, Dena G A1 - Zheng, Gang A1 - Bandinelli, Stefania A1 - Singleton, Andrew B A1 - Coresh, Josef A1 - Lumley, Thomas A1 - Uitterlinden, André G A1 - Vangils, Janine M A1 - Launer, Lenore J A1 - Cupples, L Adrienne A1 - Oostra, Ben A A1 - Zwaginga, Jaap-Jan A1 - Ouwehand, Willem H A1 - Thein, Swee-Lay A1 - Meisinger, Christa A1 - Deloukas, Panos A1 - Nauck, Matthias A1 - Spector, Tim D A1 - Gieger, Christian A1 - Gudnason, Vilmundur A1 - van Duijn, Cornelia M A1 - Psaty, Bruce M A1 - Ferrucci, Luigi A1 - Chakravarti, Aravinda A1 - Greinacher, Andreas A1 - O'Donnell, Christopher J A1 - Witteman, Jacqueline C M A1 - Furth, Susan A1 - Cushman, Mary A1 - Harris, Tamara B A1 - Lin, Jing-Ping KW - Blood Pressure KW - Cell Line KW - Cohort Studies KW - Endothelial Cells KW - Erythrocytes KW - Gene Expression KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

Measurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 x 10(-8) to 7 x 10(-86)). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.

VL - 41 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19862010?dopt=Abstract ER - TY - JOUR T1 - NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium. JF - PLoS Genet Y1 - 2009 A1 - Heard-Costa, Nancy L A1 - Zillikens, M Carola A1 - Monda, Keri L A1 - Johansson, Asa A1 - Harris, Tamara B A1 - Fu, Mao A1 - Haritunians, Talin A1 - Feitosa, Mary F A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Garcia, Melissa A1 - Launer, Lenore J A1 - Smith, Albert V A1 - Mitchell, Braxton D A1 - McArdle, Patrick F A1 - Shuldiner, Alan R A1 - Bielinski, Suzette J A1 - Boerwinkle, Eric A1 - Brancati, Fred A1 - Demerath, Ellen W A1 - Pankow, James S A1 - Arnold, Alice M A1 - Chen, Yii-Der Ida A1 - Glazer, Nicole L A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Amin, Najaf A1 - Campbell, Harry A1 - Gyllensten, Ulf A1 - Pattaro, Cristian A1 - Pramstaller, Peter P A1 - Rudan, Igor A1 - Struchalin, Maksim A1 - Vitart, Veronique A1 - Gao, Xiaoyi A1 - Kraja, Aldi A1 - Province, Michael A A1 - Zhang, Qunyuan A1 - Atwood, Larry D A1 - Dupuis, Josée A1 - Hirschhorn, Joel N A1 - Jaquish, Cashell E A1 - O'Donnell, Christopher J A1 - Vasan, Ramachandran S A1 - White, Charles C A1 - Aulchenko, Yurii S A1 - Estrada, Karol A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Witteman, Jacqueline C M A1 - Oostra, Ben A A1 - Kaplan, Robert C A1 - Gudnason, Vilmundur A1 - O'Connell, Jeffrey R A1 - Borecki, Ingrid B A1 - van Duijn, Cornelia M A1 - Cupples, L Adrienne A1 - Fox, Caroline S A1 - North, Kari E KW - Aged KW - Body Mass Index KW - Cohort Studies 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 - Nerve Tissue Proteins KW - Obesity KW - Polymorphism, Single Nucleotide KW - Waist Circumference AB -

Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4x10(-7))]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3x10(-8) for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4x10(-6), 0.024 z-score units (0.10 kg/m(2)) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07-1.19; p = 3.2x10(-5) per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.

VL - 5 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19557197?dopt=Abstract ER - TY - JOUR T1 - Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. JF - Nat Genet Y1 - 2009 A1 - Benjamin, Emelia J A1 - Rice, Kenneth M A1 - Arking, Dan E A1 - Pfeufer, Arne A1 - van Noord, Charlotte A1 - Smith, Albert V A1 - Schnabel, Renate B A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Sinner, Moritz F A1 - Dehghan, Abbas A1 - Lubitz, Steven A A1 - D'Agostino, Ralph B A1 - Lumley, Thomas A1 - Ehret, Georg B A1 - Heeringa, Jan A1 - Aspelund, Thor A1 - Newton-Cheh, Christopher A1 - Larson, Martin G A1 - Marciante, Kristin D A1 - Soliman, Elsayed Z A1 - Rivadeneira, Fernando A1 - Wang, Thomas J A1 - Eiriksdottir, Gudny A1 - Levy, Daniel A1 - Psaty, Bruce M A1 - Li, Man A1 - Chamberlain, Alanna M A1 - Hofman, Albert A1 - Vasan, Ramachandran S A1 - Harris, Tamara B A1 - Rotter, Jerome I A1 - Kao, W H Linda A1 - Agarwal, Sunil K A1 - Stricker, Bruno H Ch A1 - Wang, Ke A1 - Launer, Lenore J A1 - Smith, Nicholas L A1 - Chakravarti, Aravinda A1 - Uitterlinden, André G A1 - Wolf, Philip A A1 - Sotoodehnia, Nona A1 - Köttgen, Anna A1 - van Duijn, Cornelia M A1 - Meitinger, Thomas A1 - Mueller, Martina A1 - Perz, Siegfried A1 - Steinbeck, Gerhard A1 - Wichmann, H-Erich A1 - Lunetta, Kathryn L A1 - Heckbert, Susan R A1 - Gudnason, Vilmundur A1 - Alonso, Alvaro A1 - Kääb, Stefan A1 - Ellinor, Patrick T A1 - Witteman, Jacqueline C M KW - Atrial Fibrillation KW - Chromosomes, Human, Pair 16 KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Homeodomain Proteins KW - Humans KW - Meta-Analysis as Topic KW - Mutation KW - Polymorphism, Single Nucleotide KW - Reproducibility of Results AB -

We conducted meta-analyses of genome-wide association studies for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a new locus for AF (ZFHX3, rs2106261, risk ratio RR = 1.19; P = 2.3 x 10(-7)). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 x 10(-11); combined RR = 1.25; combined P = 1.8 x 10(-15)).

VL - 41 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19597492?dopt=Abstract ER - TY - JOUR T1 - Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. JF - Nat Genet Y1 - 2010 A1 - Speliotes, Elizabeth K A1 - Willer, Cristen J A1 - Berndt, Sonja I A1 - Monda, Keri L A1 - Thorleifsson, Gudmar A1 - Jackson, Anne U A1 - Lango Allen, Hana A1 - Lindgren, Cecilia M A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Randall, Joshua C A1 - Vedantam, Sailaja A1 - Winkler, Thomas W A1 - Qi, Lu A1 - Workalemahu, Tsegaselassie A1 - Heid, Iris M A1 - Steinthorsdottir, Valgerdur A1 - Stringham, Heather M A1 - Weedon, Michael N A1 - Wheeler, Eleanor A1 - Wood, Andrew R A1 - Ferreira, Teresa A1 - Weyant, Robert J A1 - Segrè, Ayellet V A1 - Estrada, Karol A1 - Liang, Liming A1 - Nemesh, James A1 - Park, Ju-Hyun A1 - Gustafsson, Stefan A1 - Kilpeläinen, Tuomas O A1 - Yang, Jian A1 - Bouatia-Naji, Nabila A1 - Esko, Tõnu A1 - Feitosa, Mary F A1 - Kutalik, Zoltán A1 - Mangino, Massimo A1 - Raychaudhuri, Soumya A1 - Scherag, Andre A1 - Smith, Albert Vernon A1 - Welch, Ryan A1 - Zhao, Jing Hua A1 - Aben, Katja K A1 - Absher, Devin M A1 - Amin, Najaf A1 - Dixon, Anna L A1 - Fisher, Eva A1 - Glazer, Nicole L A1 - Goddard, Michael E A1 - Heard-Costa, Nancy L A1 - Hoesel, Volker A1 - Hottenga, Jouke-Jan A1 - Johansson, Asa A1 - Johnson, Toby A1 - Ketkar, Shamika A1 - Lamina, Claudia A1 - Li, Shengxu A1 - Moffatt, Miriam F A1 - Myers, Richard H A1 - Narisu, Narisu A1 - Perry, John R B A1 - Peters, Marjolein J A1 - Preuss, Michael A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Sandholt, Camilla A1 - Scott, Laura J A1 - Timpson, Nicholas J A1 - Tyrer, Jonathan P A1 - van Wingerden, Sophie A1 - Watanabe, Richard M A1 - White, Charles C A1 - Wiklund, Fredrik A1 - Barlassina, Christina A1 - Chasman, Daniel I A1 - Cooper, Matthew N A1 - Jansson, John-Olov A1 - Lawrence, Robert W A1 - Pellikka, Niina A1 - Prokopenko, Inga A1 - Shi, Jianxin A1 - Thiering, Elisabeth A1 - Alavere, Helene A1 - Alibrandi, Maria T S A1 - Almgren, Peter A1 - Arnold, Alice M A1 - Aspelund, Thor A1 - Atwood, Larry D A1 - Balkau, Beverley A1 - Balmforth, Anthony J A1 - Bennett, Amanda J A1 - Ben-Shlomo, Yoav A1 - Bergman, Richard N A1 - Bergmann, Sven A1 - Biebermann, Heike A1 - Blakemore, Alexandra I F A1 - Boes, Tanja A1 - Bonnycastle, Lori L A1 - Bornstein, Stefan R A1 - Brown, Morris J A1 - Buchanan, Thomas A A1 - Busonero, Fabio A1 - Campbell, Harry A1 - Cappuccio, Francesco P A1 - Cavalcanti-Proença, Christine A1 - Chen, Yii-Der Ida A1 - Chen, Chih-Mei A1 - Chines, Peter S A1 - Clarke, Robert A1 - Coin, Lachlan A1 - Connell, John A1 - Day, Ian N M A1 - den Heijer, Martin A1 - Duan, Jubao A1 - Ebrahim, Shah A1 - Elliott, Paul A1 - Elosua, Roberto A1 - Eiriksdottir, Gudny A1 - Erdos, Michael R A1 - Eriksson, Johan G A1 - Facheris, Maurizio F A1 - Felix, Stephan B A1 - Fischer-Posovszky, Pamela A1 - Folsom, Aaron R A1 - Friedrich, Nele A1 - Freimer, Nelson B A1 - Fu, Mao A1 - Gaget, Stefan A1 - Gejman, Pablo V A1 - Geus, Eco J C A1 - Gieger, Christian A1 - Gjesing, Anette P A1 - Goel, Anuj A1 - Goyette, Philippe A1 - Grallert, Harald A1 - Grässler, Jürgen A1 - Greenawalt, Danielle M A1 - Groves, Christopher J A1 - Gudnason, Vilmundur A1 - Guiducci, Candace A1 - Hartikainen, Anna-Liisa A1 - Hassanali, Neelam A1 - Hall, Alistair S A1 - Havulinna, Aki S A1 - Hayward, Caroline A1 - Heath, Andrew C A1 - Hengstenberg, Christian A1 - Hicks, Andrew A A1 - Hinney, Anke A1 - Hofman, Albert A1 - Homuth, Georg A1 - Hui, Jennie A1 - Igl, Wilmar A1 - Iribarren, Carlos A1 - Isomaa, Bo A1 - Jacobs, Kevin B A1 - Jarick, Ivonne A1 - Jewell, Elizabeth A1 - John, Ulrich A1 - Jørgensen, Torben A1 - Jousilahti, Pekka A1 - Jula, Antti A1 - Kaakinen, Marika A1 - Kajantie, Eero A1 - Kaplan, Lee M A1 - Kathiresan, Sekar A1 - Kettunen, Johannes A1 - Kinnunen, Leena A1 - Knowles, Joshua W A1 - Kolcic, Ivana A1 - König, Inke R A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kuusisto, Johanna A1 - Kraft, Peter A1 - Kvaløy, Kirsti A1 - Laitinen, Jaana A1 - Lantieri, Olivier A1 - Lanzani, Chiara A1 - Launer, Lenore J A1 - Lecoeur, Cécile A1 - Lehtimäki, Terho A1 - Lettre, Guillaume A1 - Liu, Jianjun A1 - Lokki, Marja-Liisa A1 - Lorentzon, Mattias A1 - Luben, Robert N A1 - Ludwig, Barbara A1 - Manunta, Paolo A1 - Marek, Diana A1 - Marre, Michel A1 - Martin, Nicholas G A1 - McArdle, Wendy L A1 - McCarthy, Anne A1 - McKnight, Barbara A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Meyre, David A1 - Midthjell, Kristian A1 - Montgomery, Grant W A1 - Morken, Mario A A1 - Morris, Andrew P A1 - Mulic, Rosanda A1 - Ngwa, Julius S A1 - Nelis, Mari A1 - Neville, Matt J A1 - Nyholt, Dale R A1 - O'Donnell, Christopher J A1 - O'Rahilly, Stephen A1 - Ong, Ken K A1 - Oostra, Ben A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Perola, Markus A1 - Pichler, Irene A1 - Pietiläinen, Kirsi H A1 - Platou, Carl G P A1 - Polasek, Ozren A1 - Pouta, Anneli A1 - Rafelt, Suzanne A1 - Raitakari, Olli A1 - Rayner, Nigel W A1 - Ridderstråle, Martin A1 - Rief, Winfried A1 - Ruokonen, Aimo A1 - Robertson, Neil R A1 - Rzehak, Peter A1 - Salomaa, Veikko A1 - Sanders, Alan R A1 - Sandhu, Manjinder S A1 - Sanna, Serena A1 - Saramies, Jouko A1 - Savolainen, Markku J A1 - Scherag, Susann A1 - Schipf, Sabine A1 - Schreiber, Stefan A1 - Schunkert, Heribert A1 - Silander, Kaisa A1 - Sinisalo, Juha A1 - Siscovick, David S A1 - Smit, Jan H A1 - Soranzo, Nicole A1 - Sovio, Ulla A1 - Stephens, Jonathan A1 - Surakka, Ida A1 - Swift, Amy J A1 - Tammesoo, Mari-Liis A1 - Tardif, Jean-Claude A1 - Teder-Laving, Maris A1 - Teslovich, Tanya M A1 - Thompson, John R A1 - Thomson, Brian A1 - Tönjes, Anke A1 - Tuomi, Tiinamaija A1 - van Meurs, Joyce B J A1 - van Ommen, Gert-Jan A1 - Vatin, Vincent A1 - Viikari, Jorma A1 - Visvikis-Siest, Sophie A1 - Vitart, Veronique A1 - Vogel, Carla I G A1 - Voight, Benjamin F A1 - Waite, Lindsay L A1 - Wallaschofski, Henri A1 - Walters, G Bragi A1 - Widen, Elisabeth A1 - Wiegand, Susanna A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witte, Daniel R A1 - Witteman, Jacqueline C A1 - Xu, Jianfeng A1 - Zhang, Qunyuan A1 - Zgaga, Lina A1 - Ziegler, Andreas A1 - Zitting, Paavo A1 - Beilby, John P A1 - Farooqi, I Sadaf A1 - Hebebrand, Johannes A1 - Huikuri, Heikki V A1 - James, Alan L A1 - Kähönen, Mika A1 - Levinson, Douglas F A1 - Macciardi, Fabio A1 - Nieminen, Markku S A1 - Ohlsson, Claes A1 - Palmer, Lyle J A1 - Ridker, Paul M A1 - Stumvoll, Michael A1 - Beckmann, Jacques S A1 - Boeing, Heiner A1 - Boerwinkle, Eric A1 - Boomsma, Dorret I A1 - Caulfield, Mark J A1 - Chanock, Stephen J A1 - Collins, Francis S A1 - Cupples, L Adrienne A1 - Smith, George Davey A1 - Erdmann, Jeanette A1 - Froguel, Philippe A1 - Grönberg, Henrik A1 - Gyllensten, Ulf A1 - Hall, Per A1 - Hansen, Torben A1 - Harris, Tamara B A1 - Hattersley, Andrew T A1 - Hayes, Richard B A1 - Heinrich, Joachim A1 - Hu, Frank B A1 - Hveem, Kristian A1 - Illig, Thomas A1 - Jarvelin, Marjo-Riitta A1 - Kaprio, Jaakko A1 - Karpe, Fredrik A1 - Khaw, Kay-Tee A1 - Kiemeney, Lambertus A A1 - Krude, Heiko A1 - Laakso, Markku A1 - Lawlor, Debbie A A1 - Metspalu, Andres A1 - Munroe, Patricia B A1 - Ouwehand, Willem H A1 - Pedersen, Oluf A1 - Penninx, Brenda W A1 - Peters, Annette A1 - Pramstaller, Peter P A1 - Quertermous, Thomas A1 - Reinehr, Thomas A1 - Rissanen, Aila A1 - Rudan, Igor A1 - Samani, Nilesh J A1 - Schwarz, Peter E H A1 - Shuldiner, Alan R A1 - Spector, Timothy D A1 - Tuomilehto, Jaakko A1 - Uda, Manuela A1 - Uitterlinden, Andre A1 - Valle, Timo T A1 - Wabitsch, Martin A1 - Waeber, Gérard A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Wilson, James F A1 - Wright, Alan F A1 - Zillikens, M Carola A1 - Chatterjee, Nilanjan A1 - McCarroll, Steven A A1 - Purcell, Shaun A1 - Schadt, Eric E A1 - Visscher, Peter M A1 - Assimes, Themistocles L A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - Fox, Caroline S A1 - Groop, Leif C A1 - Haritunians, Talin A1 - Hunter, David J A1 - Kaplan, Robert C A1 - Mohlke, Karen L A1 - O'Connell, Jeffrey R A1 - Peltonen, Leena A1 - Schlessinger, David A1 - Strachan, David P A1 - van Duijn, Cornelia M A1 - Wichmann, H-Erich A1 - Frayling, Timothy M A1 - Thorsteinsdottir, Unnur A1 - Abecasis, Goncalo R A1 - Barroso, Inês A1 - Boehnke, Michael A1 - Stefansson, Kari A1 - North, Kari E A1 - McCarthy, Mark I A1 - Hirschhorn, Joel N A1 - Ingelsson, Erik A1 - Loos, Ruth J F KW - Body Height KW - Body Mass Index KW - Body Size KW - Body Weight KW - Chromosome Mapping KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Obesity KW - Polymorphism, Single Nucleotide AB -

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

VL - 42 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20935630?dopt=Abstract ER - TY - JOUR T1 - Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. JF - Nat Genet Y1 - 2010 A1 - Sotoodehnia, Nona A1 - Isaacs, Aaron A1 - de Bakker, Paul I W A1 - Dörr, Marcus A1 - Newton-Cheh, Christopher A1 - Nolte, Ilja M A1 - van der Harst, Pim A1 - Müller, Martina A1 - Eijgelsheim, Mark A1 - Alonso, Alvaro A1 - Hicks, Andrew A A1 - Padmanabhan, Sandosh A1 - Hayward, Caroline A1 - Smith, Albert Vernon A1 - Polasek, Ozren A1 - Giovannone, Steven A1 - Fu, Jingyuan A1 - Magnani, Jared W A1 - Marciante, Kristin D A1 - Pfeufer, Arne A1 - Gharib, Sina A A1 - Teumer, Alexander A1 - Li, Man A1 - Bis, Joshua C A1 - Rivadeneira, Fernando A1 - Aspelund, Thor A1 - Köttgen, Anna A1 - Johnson, Toby A1 - Rice, Kenneth A1 - Sie, Mark P S A1 - Wang, Ying A A1 - Klopp, Norman A1 - Fuchsberger, Christian A1 - Wild, Sarah H A1 - Mateo Leach, Irene A1 - Estrada, Karol A1 - Völker, Uwe A1 - Wright, Alan F A1 - Asselbergs, Folkert W A1 - Qu, Jiaxiang A1 - Chakravarti, Aravinda A1 - Sinner, Moritz F A1 - Kors, Jan A A1 - Petersmann, Astrid A1 - Harris, Tamara B A1 - Soliman, Elsayed Z A1 - Munroe, Patricia B A1 - Psaty, Bruce M A1 - Oostra, Ben A A1 - Cupples, L Adrienne A1 - Perz, Siegfried A1 - de Boer, Rudolf A A1 - Uitterlinden, André G A1 - Völzke, Henry A1 - Spector, Timothy D A1 - Liu, Fang-Yu A1 - Boerwinkle, Eric A1 - Dominiczak, Anna F A1 - Rotter, Jerome I A1 - van Herpen, Gé A1 - Levy, Daniel A1 - Wichmann, H-Erich A1 - van Gilst, Wiek H A1 - Witteman, Jacqueline C M A1 - Kroemer, Heyo K A1 - Kao, W H Linda A1 - Heckbert, Susan R A1 - Meitinger, Thomas A1 - Hofman, Albert A1 - Campbell, Harry A1 - Folsom, Aaron R A1 - van Veldhuisen, Dirk J A1 - Schwienbacher, Christine A1 - O'Donnell, Christopher J A1 - Volpato, Claudia Beu A1 - Caulfield, Mark J A1 - Connell, John M A1 - Launer, Lenore A1 - Lu, Xiaowen A1 - Franke, Lude A1 - Fehrmann, Rudolf S N A1 - te Meerman, Gerard A1 - Groen, Harry J M A1 - Weersma, Rinse K A1 - van den Berg, Leonard H A1 - Wijmenga, Cisca A1 - Ophoff, Roel A A1 - Navis, Gerjan A1 - Rudan, Igor A1 - Snieder, Harold A1 - Wilson, James F A1 - Pramstaller, Peter P A1 - Siscovick, David S A1 - Wang, Thomas J A1 - Gudnason, Vilmundur A1 - van Duijn, Cornelia M A1 - Felix, Stephan B A1 - Fishman, Glenn I A1 - Jamshidi, Yalda A1 - Stricker, Bruno H Ch A1 - Samani, Nilesh J A1 - Kääb, Stefan A1 - Arking, Dan E KW - Animals KW - Animals, Newborn KW - Chromosomes, Human KW - Computational Biology KW - Electrocardiography KW - Genetic Loci KW - Genome-Wide Association Study KW - Heart Conduction System KW - Humans KW - Mice KW - Mice, Transgenic KW - Models, Animal KW - Myocytes, Cardiac KW - NAV1.8 Voltage-Gated Sodium Channel KW - Polymorphism, Single Nucleotide KW - Sodium Channels AB -

The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

VL - 42 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21076409?dopt=Abstract ER - TY - JOUR T1 - Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo. JF - PLoS Genet Y1 - 2010 A1 - Ikram, M Kamran A1 - Sim, Xueling A1 - Xueling, Sim A1 - Jensen, Richard A A1 - Cotch, Mary Frances A1 - Hewitt, Alex W A1 - Ikram, M Arfan A1 - Wang, Jie Jin A1 - Klein, Ronald A1 - Klein, Barbara E K A1 - Breteler, Monique M B A1 - Cheung, Ning A1 - Liew, Gerald A1 - Mitchell, Paul A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Hofman, Albert A1 - de Jong, Paulus T V M A1 - van Duijn, Cornelia M A1 - Kao, Linda A1 - Cheng, Ching-Yu A1 - Smith, Albert Vernon A1 - Glazer, Nicole L A1 - Lumley, Thomas A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - Jonasson, Fridbert A1 - Eiriksdottir, Gudny A1 - Aspelund, Thor A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Taylor, Kent D A1 - Li, Xiaohui A1 - Iyengar, Sudha K A1 - Xi, Quansheng A1 - Sivakumaran, Theru A A1 - Mackey, David A A1 - Macgregor, Stuart A1 - Martin, Nicholas G A1 - Young, Terri L A1 - Bis, Josh C A1 - Wiggins, Kerri L A1 - Heckbert, Susan R A1 - Hammond, Christopher J A1 - Andrew, Toby A1 - Fahy, Samantha A1 - Attia, John A1 - Holliday, Elizabeth G A1 - Scott, Rodney J A1 - Islam, F M Amirul A1 - Rotter, Jerome I A1 - McAuley, Annie K A1 - Boerwinkle, Eric A1 - Tai, E Shyong A1 - Gudnason, Vilmundur A1 - Siscovick, David S A1 - Vingerling, Johannes R A1 - Wong, Tien Y KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Child KW - Child, Preschool KW - Chromosomes, Human, Pair 12 KW - Chromosomes, Human, Pair 19 KW - Chromosomes, Human, Pair 5 KW - Chromosomes, Human, Pair 6 KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Microcirculation KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Retinal Vessels KW - Young Adult AB -

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n  =  6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p  =  1.61×10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25×10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p  =  2.15×10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.

VL - 6 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21060863?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 - Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels. JF - PLoS Genet Y1 - 2010 A1 - Meyer, Tamra E A1 - Verwoert, Germaine C A1 - Hwang, Shih-Jen A1 - Glazer, Nicole L A1 - Smith, Albert V A1 - van Rooij, Frank J A A1 - Ehret, Georg B A1 - Boerwinkle, Eric A1 - Felix, Janine F A1 - Leak, Tennille S A1 - Harris, Tamara B A1 - Yang, Qiong A1 - Dehghan, Abbas A1 - Aspelund, Thor A1 - Katz, Ronit A1 - Homuth, Georg A1 - Kocher, Thomas A1 - Rettig, Rainer A1 - Ried, Janina S A1 - Gieger, Christian A1 - Prucha, Hanna A1 - Pfeufer, Arne A1 - Meitinger, Thomas A1 - Coresh, Josef A1 - Hofman, Albert A1 - Sarnak, Mark J A1 - Chen, Yii-Der Ida A1 - Uitterlinden, André G A1 - Chakravarti, Aravinda A1 - Psaty, Bruce M A1 - van Duijn, Cornelia M A1 - Kao, W H Linda A1 - Witteman, Jacqueline C M A1 - Gudnason, Vilmundur A1 - Siscovick, David S A1 - Fox, Caroline S A1 - Köttgen, Anna KW - Adult KW - Aged KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Magnesium KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Potassium KW - Sodium AB -

Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using approximately 2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p<5 x 10(-8)) or suggestive associations (p<4 x 10(-7)) were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding p<4 x 10(-7). Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels.

VL - 6 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20700443?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study of PR interval. JF - Nat Genet Y1 - 2010 A1 - Pfeufer, Arne A1 - van Noord, Charlotte A1 - Marciante, Kristin D A1 - Arking, Dan E A1 - Larson, Martin G A1 - Smith, Albert Vernon A1 - Tarasov, Kirill V A1 - Müller, Martina A1 - Sotoodehnia, Nona A1 - Sinner, Moritz F A1 - Verwoert, Germaine C A1 - Li, Man A1 - Kao, W H Linda A1 - Köttgen, Anna A1 - Coresh, Josef A1 - Bis, Joshua C A1 - Psaty, Bruce M A1 - Rice, Kenneth A1 - Rotter, Jerome I A1 - Rivadeneira, Fernando A1 - Hofman, Albert A1 - Kors, Jan A A1 - Stricker, Bruno H C A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Beckmann, Britt M A1 - Sauter, Wiebke A1 - Gieger, Christian A1 - Lubitz, Steven A A1 - Newton-Cheh, Christopher A1 - Wang, Thomas J A1 - Magnani, Jared W A1 - Schnabel, Renate B A1 - Chung, Mina K A1 - Barnard, John A1 - Smith, Jonathan D A1 - Van Wagoner, David R A1 - Vasan, Ramachandran S A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Najjar, Samer S A1 - Lakatta, Edward A1 - Schlessinger, David A1 - Uda, Manuela A1 - Abecasis, Goncalo R A1 - Müller-Myhsok, Bertram A1 - Ehret, Georg B A1 - Boerwinkle, Eric A1 - Chakravarti, Aravinda A1 - Soliman, Elsayed Z A1 - Lunetta, Kathryn L A1 - Perz, Siegfried A1 - Wichmann, H-Erich A1 - Meitinger, Thomas A1 - Levy, Daniel A1 - Gudnason, Vilmundur A1 - Ellinor, Patrick T A1 - Sanna, Serena A1 - Kääb, Stefan A1 - Witteman, Jacqueline C M A1 - Alonso, Alvaro A1 - Benjamin, Emelia J A1 - Heckbert, Susan R KW - Aged KW - Atrial Fibrillation KW - Cohort Studies KW - Electrocardiography KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Heart Conduction System KW - Humans KW - Male KW - Meta-Analysis as Topic AB -

The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 x 10(-8). At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

VL - 42 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20062060?dopt=Abstract ER - TY - JOUR T1 - Hundreds of variants clustered in genomic loci and biological pathways affect human height. JF - Nature Y1 - 2010 A1 - Lango Allen, Hana A1 - Estrada, Karol A1 - Lettre, Guillaume A1 - Berndt, Sonja I A1 - Weedon, Michael N A1 - Rivadeneira, Fernando A1 - Willer, Cristen J A1 - Jackson, Anne U A1 - Vedantam, Sailaja A1 - Raychaudhuri, Soumya A1 - Ferreira, Teresa A1 - Wood, Andrew R A1 - Weyant, Robert J A1 - Segrè, Ayellet V A1 - Speliotes, Elizabeth K A1 - Wheeler, Eleanor A1 - Soranzo, Nicole A1 - Park, Ju-Hyun A1 - Yang, Jian A1 - Gudbjartsson, Daniel A1 - Heard-Costa, Nancy L A1 - Randall, Joshua C A1 - Qi, Lu A1 - Vernon Smith, Albert A1 - Mägi, Reedik A1 - Pastinen, Tomi A1 - Liang, Liming A1 - Heid, Iris M A1 - Luan, Jian'an A1 - Thorleifsson, Gudmar A1 - Winkler, Thomas W A1 - Goddard, Michael E A1 - Sin Lo, Ken A1 - Palmer, Cameron A1 - Workalemahu, Tsegaselassie A1 - Aulchenko, Yurii S A1 - Johansson, Asa A1 - Zillikens, M Carola A1 - Feitosa, Mary F A1 - Esko, Tõnu A1 - Johnson, Toby A1 - Ketkar, Shamika A1 - Kraft, Peter A1 - Mangino, Massimo A1 - Prokopenko, Inga A1 - Absher, Devin A1 - Albrecht, Eva A1 - Ernst, Florian A1 - Glazer, Nicole L A1 - Hayward, Caroline A1 - Hottenga, Jouke-Jan A1 - Jacobs, Kevin B A1 - Knowles, Joshua W A1 - Kutalik, Zoltán A1 - Monda, Keri L A1 - Polasek, Ozren A1 - Preuss, Michael A1 - Rayner, Nigel W A1 - Robertson, Neil R A1 - Steinthorsdottir, Valgerdur A1 - Tyrer, Jonathan P A1 - Voight, Benjamin F A1 - Wiklund, Fredrik A1 - Xu, Jianfeng A1 - Zhao, Jing Hua A1 - Nyholt, Dale R A1 - Pellikka, Niina A1 - Perola, Markus A1 - Perry, John R B A1 - Surakka, Ida A1 - Tammesoo, Mari-Liis A1 - Altmaier, Elizabeth L A1 - Amin, Najaf A1 - Aspelund, Thor A1 - Bhangale, Tushar A1 - Boucher, Gabrielle A1 - Chasman, Daniel I A1 - Chen, Constance A1 - Coin, Lachlan A1 - Cooper, Matthew N A1 - Dixon, Anna L A1 - Gibson, Quince A1 - Grundberg, Elin A1 - Hao, Ke A1 - Juhani Junttila, M A1 - Kaplan, Lee M A1 - Kettunen, Johannes A1 - König, Inke R A1 - Kwan, Tony A1 - Lawrence, Robert W A1 - Levinson, Douglas F A1 - Lorentzon, Mattias A1 - McKnight, Barbara A1 - Morris, Andrew P A1 - Müller, Martina A1 - Suh Ngwa, Julius A1 - Purcell, Shaun A1 - Rafelt, Suzanne A1 - Salem, Rany M A1 - Salvi, Erika A1 - Sanna, Serena A1 - Shi, Jianxin A1 - Sovio, Ulla A1 - Thompson, John R A1 - Turchin, Michael C A1 - Vandenput, Liesbeth A1 - Verlaan, Dominique J A1 - Vitart, Veronique A1 - White, Charles C A1 - Ziegler, Andreas A1 - Almgren, Peter A1 - Balmforth, Anthony J A1 - Campbell, Harry A1 - Citterio, Lorena A1 - De Grandi, Alessandro A1 - Dominiczak, Anna A1 - Duan, Jubao A1 - Elliott, Paul A1 - Elosua, Roberto A1 - Eriksson, Johan G A1 - Freimer, Nelson B A1 - Geus, Eco J C A1 - Glorioso, Nicola A1 - Haiqing, Shen A1 - Hartikainen, Anna-Liisa A1 - Havulinna, Aki S A1 - Hicks, Andrew A A1 - Hui, Jennie A1 - Igl, Wilmar A1 - Illig, Thomas A1 - Jula, Antti A1 - Kajantie, Eero A1 - Kilpeläinen, Tuomas O A1 - Koiranen, Markku A1 - Kolcic, Ivana A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Laitinen, Jaana A1 - Liu, Jianjun A1 - Lokki, Marja-Liisa A1 - Marusic, Ana A1 - Maschio, Andrea A1 - Meitinger, Thomas A1 - Mulas, Antonella A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Peden, John F A1 - Petersmann, Astrid A1 - Pichler, Irene A1 - Pietiläinen, Kirsi H A1 - Pouta, Anneli A1 - Ridderstråle, Martin A1 - Rotter, Jerome I A1 - Sambrook, Jennifer G A1 - Sanders, Alan R A1 - Schmidt, Carsten Oliver A1 - Sinisalo, Juha A1 - Smit, Jan H A1 - Stringham, Heather M A1 - Bragi Walters, G A1 - Widen, Elisabeth A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Zagato, Laura A1 - Zgaga, Lina A1 - Zitting, Paavo A1 - Alavere, Helene A1 - Farrall, Martin A1 - McArdle, Wendy L A1 - Nelis, Mari A1 - Peters, Marjolein J A1 - Ripatti, Samuli A1 - van Meurs, Joyce B J A1 - Aben, Katja K A1 - Ardlie, Kristin G A1 - Beckmann, Jacques S A1 - Beilby, John P A1 - Bergman, Richard N A1 - Bergmann, Sven A1 - Collins, Francis S A1 - Cusi, Daniele A1 - den Heijer, Martin A1 - Eiriksdottir, Gudny A1 - Gejman, Pablo V A1 - Hall, Alistair S A1 - Hamsten, Anders A1 - Huikuri, Heikki V A1 - Iribarren, Carlos A1 - Kähönen, Mika A1 - Kaprio, Jaakko A1 - Kathiresan, Sekar A1 - Kiemeney, Lambertus A1 - Kocher, Thomas A1 - Launer, Lenore J A1 - Lehtimäki, Terho A1 - Melander, Olle A1 - Mosley, Tom H A1 - Musk, Arthur W A1 - Nieminen, Markku S A1 - O'Donnell, Christopher J A1 - Ohlsson, Claes A1 - Oostra, Ben A1 - Palmer, Lyle J A1 - Raitakari, Olli A1 - Ridker, Paul M A1 - Rioux, John D A1 - Rissanen, Aila A1 - Rivolta, Carlo A1 - Schunkert, Heribert A1 - Shuldiner, Alan R A1 - Siscovick, David S A1 - Stumvoll, Michael A1 - Tönjes, Anke A1 - Tuomilehto, Jaakko A1 - van Ommen, Gert-Jan A1 - Viikari, Jorma A1 - Heath, Andrew C A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - Province, Michael A A1 - Kayser, Manfred A1 - Arnold, Alice M A1 - Atwood, Larry D A1 - Boerwinkle, Eric A1 - Chanock, Stephen J A1 - Deloukas, Panos A1 - Gieger, Christian A1 - Grönberg, Henrik A1 - Hall, Per A1 - Hattersley, Andrew T A1 - Hengstenberg, Christian A1 - Hoffman, Wolfgang A1 - Lathrop, G Mark A1 - Salomaa, Veikko A1 - Schreiber, Stefan A1 - Uda, Manuela A1 - Waterworth, Dawn A1 - Wright, Alan F A1 - Assimes, Themistocles L A1 - Barroso, Inês A1 - Hofman, Albert A1 - Mohlke, Karen L A1 - Boomsma, Dorret I A1 - Caulfield, Mark J A1 - Cupples, L Adrienne A1 - Erdmann, Jeanette A1 - Fox, Caroline S A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Harris, Tamara B A1 - Hayes, Richard B A1 - Jarvelin, Marjo-Riitta A1 - Mooser, Vincent A1 - Munroe, Patricia B A1 - Ouwehand, Willem H A1 - Penninx, Brenda W A1 - Pramstaller, Peter P A1 - Quertermous, Thomas A1 - Rudan, Igor A1 - Samani, Nilesh J A1 - Spector, Timothy D A1 - Völzke, Henry A1 - Watkins, Hugh A1 - Wilson, James F A1 - Groop, Leif C A1 - Haritunians, Talin A1 - Hu, Frank B A1 - Kaplan, Robert C A1 - Metspalu, Andres A1 - North, Kari E A1 - Schlessinger, David A1 - Wareham, Nicholas J A1 - Hunter, David J A1 - O'Connell, Jeffrey R A1 - Strachan, David P A1 - Wichmann, H-Erich A1 - Borecki, Ingrid B A1 - van Duijn, Cornelia M A1 - Schadt, Eric E A1 - Thorsteinsdottir, Unnur A1 - Peltonen, Leena A1 - Uitterlinden, André G A1 - Visscher, Peter M A1 - Chatterjee, Nilanjan A1 - Loos, Ruth J F A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Ingelsson, Erik A1 - Lindgren, Cecilia M A1 - Abecasis, Goncalo R A1 - Stefansson, Kari A1 - Frayling, Timothy M A1 - Hirschhorn, Joel N KW - Body Height KW - Chromosomes, Human, Pair 3 KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Metabolic Networks and Pathways KW - Multifactorial Inheritance KW - Phenotype KW - Polymorphism, Single Nucleotide AB -

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

VL - 467 IS - 7317 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20881960?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. JF - Nat Genet Y1 - 2010 A1 - Heid, Iris M A1 - Jackson, Anne U A1 - Randall, Joshua C A1 - Winkler, Thomas W A1 - Qi, Lu A1 - Steinthorsdottir, Valgerdur A1 - Thorleifsson, Gudmar A1 - Zillikens, M Carola A1 - Speliotes, Elizabeth K A1 - Mägi, Reedik A1 - Workalemahu, Tsegaselassie A1 - White, Charles C A1 - Bouatia-Naji, Nabila A1 - Harris, Tamara B A1 - Berndt, Sonja I A1 - Ingelsson, Erik A1 - Willer, Cristen J A1 - Weedon, Michael N A1 - Luan, Jian'an A1 - Vedantam, Sailaja A1 - Esko, Tõnu A1 - Kilpeläinen, Tuomas O A1 - Kutalik, Zoltán A1 - Li, Shengxu A1 - Monda, Keri L A1 - Dixon, Anna L A1 - Holmes, Christopher C A1 - Kaplan, Lee M A1 - Liang, Liming A1 - Min, Josine L A1 - Moffatt, Miriam F A1 - Molony, Cliona A1 - Nicholson, George A1 - Schadt, Eric E A1 - Zondervan, Krina T A1 - Feitosa, Mary F A1 - Ferreira, Teresa A1 - Lango Allen, Hana A1 - Weyant, Robert J A1 - Wheeler, Eleanor A1 - Wood, Andrew R A1 - Estrada, Karol A1 - Goddard, Michael E A1 - Lettre, Guillaume A1 - Mangino, Massimo A1 - Nyholt, Dale R A1 - Purcell, Shaun A1 - Smith, Albert Vernon A1 - Visscher, Peter M A1 - Yang, Jian A1 - McCarroll, Steven A A1 - Nemesh, James A1 - Voight, Benjamin F A1 - Absher, Devin A1 - Amin, Najaf A1 - Aspelund, Thor A1 - Coin, Lachlan A1 - Glazer, Nicole L A1 - Hayward, Caroline A1 - Heard-Costa, Nancy L A1 - Hottenga, Jouke-Jan A1 - Johansson, Asa A1 - Johnson, Toby A1 - Kaakinen, Marika A1 - Kapur, Karen A1 - Ketkar, Shamika A1 - Knowles, Joshua W A1 - Kraft, Peter A1 - Kraja, Aldi T A1 - Lamina, Claudia A1 - Leitzmann, Michael F A1 - McKnight, Barbara A1 - Morris, Andrew P A1 - Ong, Ken K A1 - Perry, John R B A1 - Peters, Marjolein J A1 - Polasek, Ozren A1 - Prokopenko, Inga A1 - Rayner, Nigel W A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Robertson, Neil R A1 - Sanna, Serena A1 - Sovio, Ulla A1 - Surakka, Ida A1 - Teumer, Alexander A1 - van Wingerden, Sophie A1 - Vitart, Veronique A1 - Zhao, Jing Hua A1 - Cavalcanti-Proença, Christine A1 - Chines, Peter S A1 - Fisher, Eva A1 - Kulzer, Jennifer R A1 - Lecoeur, Cécile A1 - Narisu, Narisu A1 - Sandholt, Camilla A1 - Scott, Laura J A1 - Silander, Kaisa A1 - Stark, Klaus A1 - Tammesoo, Mari-Liis A1 - Teslovich, Tanya M A1 - Timpson, Nicholas John A1 - Watanabe, Richard M A1 - Welch, Ryan A1 - Chasman, Daniel I A1 - Cooper, Matthew N A1 - Jansson, John-Olov A1 - Kettunen, Johannes A1 - Lawrence, Robert W A1 - Pellikka, Niina A1 - Perola, Markus A1 - Vandenput, Liesbeth A1 - Alavere, Helene A1 - Almgren, Peter A1 - Atwood, Larry D A1 - Bennett, Amanda J A1 - Biffar, Reiner A1 - Bonnycastle, Lori L A1 - Bornstein, Stefan R A1 - Buchanan, Thomas A A1 - Campbell, Harry A1 - Day, Ian N M A1 - Dei, Mariano A1 - Dörr, Marcus A1 - Elliott, Paul A1 - Erdos, Michael R A1 - Eriksson, Johan G A1 - Freimer, Nelson B A1 - Fu, Mao A1 - Gaget, Stefan A1 - Geus, Eco J C A1 - Gjesing, Anette P A1 - Grallert, Harald A1 - Grässler, Jürgen A1 - Groves, Christopher J A1 - Guiducci, Candace A1 - Hartikainen, Anna-Liisa A1 - Hassanali, Neelam A1 - Havulinna, Aki S A1 - Herzig, Karl-Heinz A1 - Hicks, Andrew A A1 - Hui, Jennie A1 - Igl, Wilmar A1 - Jousilahti, Pekka A1 - Jula, Antti A1 - Kajantie, Eero A1 - Kinnunen, Leena A1 - Kolcic, Ivana A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kroemer, Heyo K A1 - Krzelj, Vjekoslav A1 - Kuusisto, Johanna A1 - Kvaloy, Kirsti A1 - Laitinen, Jaana A1 - Lantieri, Olivier A1 - Lathrop, G Mark A1 - Lokki, Marja-Liisa A1 - Luben, Robert N A1 - Ludwig, Barbara A1 - McArdle, Wendy L A1 - McCarthy, Anne A1 - Morken, Mario A A1 - Nelis, Mari A1 - Neville, Matt J A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Peden, John F A1 - Pichler, Irene A1 - Pietiläinen, Kirsi H A1 - Platou, Carl G P A1 - Pouta, Anneli A1 - Ridderstråle, Martin A1 - Samani, Nilesh J A1 - Saramies, Jouko A1 - Sinisalo, Juha A1 - Smit, Jan H A1 - Strawbridge, Rona J A1 - Stringham, Heather M A1 - Swift, Amy J A1 - Teder-Laving, Maris A1 - Thomson, Brian A1 - Usala, Gianluca A1 - van Meurs, Joyce B J A1 - van Ommen, Gert-Jan A1 - Vatin, Vincent A1 - Volpato, Claudia B A1 - Wallaschofski, Henri A1 - Walters, G Bragi A1 - Widen, Elisabeth A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witte, Daniel R A1 - Zgaga, Lina A1 - Zitting, Paavo A1 - Beilby, John P A1 - James, Alan L A1 - Kähönen, Mika A1 - Lehtimäki, Terho A1 - Nieminen, Markku S A1 - Ohlsson, Claes A1 - Palmer, Lyle J A1 - Raitakari, Olli A1 - Ridker, Paul M A1 - Stumvoll, Michael A1 - Tönjes, Anke A1 - Viikari, Jorma A1 - Balkau, Beverley A1 - Ben-Shlomo, Yoav A1 - Bergman, Richard N A1 - Boeing, Heiner A1 - Smith, George Davey A1 - Ebrahim, Shah A1 - Froguel, Philippe A1 - Hansen, Torben A1 - Hengstenberg, Christian A1 - Hveem, Kristian A1 - Isomaa, Bo A1 - Jørgensen, Torben A1 - Karpe, Fredrik A1 - Khaw, Kay-Tee A1 - Laakso, Markku A1 - Lawlor, Debbie A A1 - Marre, Michel A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Midthjell, Kristian A1 - Pedersen, Oluf A1 - Salomaa, Veikko A1 - Schwarz, Peter E H A1 - Tuomi, Tiinamaija A1 - Tuomilehto, Jaakko A1 - Valle, Timo T A1 - Wareham, Nicholas J A1 - Arnold, Alice M A1 - Beckmann, Jacques S A1 - Bergmann, Sven A1 - Boerwinkle, Eric A1 - Boomsma, Dorret I A1 - Caulfield, Mark J A1 - Collins, Francis S A1 - Eiriksdottir, Gudny A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Hattersley, Andrew T A1 - Hofman, Albert A1 - Hu, Frank B A1 - Illig, Thomas A1 - Iribarren, Carlos A1 - Jarvelin, Marjo-Riitta A1 - Kao, W H Linda A1 - Kaprio, Jaakko A1 - Launer, Lenore J A1 - Munroe, Patricia B A1 - Oostra, Ben A1 - Penninx, Brenda W A1 - Pramstaller, Peter P A1 - Psaty, Bruce M A1 - Quertermous, Thomas A1 - Rissanen, Aila A1 - Rudan, Igor A1 - Shuldiner, Alan R A1 - Soranzo, Nicole A1 - Spector, Timothy D A1 - Syvänen, Ann-Christine A1 - Uda, Manuela A1 - Uitterlinden, Andre A1 - Völzke, Henry A1 - Vollenweider, Peter A1 - Wilson, James F A1 - Witteman, Jacqueline C A1 - Wright, Alan F A1 - Abecasis, Goncalo R A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - Frayling, Timothy M A1 - Groop, Leif C A1 - Haritunians, Talin A1 - Hunter, David J A1 - Kaplan, Robert C A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Peltonen, Leena A1 - Schlessinger, David A1 - Strachan, David P A1 - Hirschhorn, Joel N A1 - Assimes, Themistocles L A1 - Wichmann, H-Erich A1 - Thorsteinsdottir, Unnur A1 - van Duijn, Cornelia M A1 - Stefansson, Kari A1 - Cupples, L Adrienne A1 - Loos, Ruth J F A1 - Barroso, Inês A1 - McCarthy, Mark I A1 - Fox, Caroline S A1 - Mohlke, Karen L A1 - Lindgren, Cecilia M KW - Adipose Tissue KW - Age Factors KW - Chromosome Mapping KW - Female KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Sex Characteristics KW - Waist-Hip Ratio AB -

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

VL - 42 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20935629?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 - Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. JF - Circ Cardiovasc Genet Y1 - 2010 A1 - Yang, Qiong A1 - Köttgen, Anna A1 - Dehghan, Abbas A1 - Smith, Albert V A1 - Glazer, Nicole L A1 - Chen, Ming-Huei A1 - Chasman, Daniel I A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Harris, Tamara B A1 - Launer, Lenore A1 - Nalls, Michael A1 - Hernandez, Dena A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Grove, Megan L A1 - Li, Man A1 - Linda Kao, W H A1 - Chonchol, Michel A1 - Haritunians, Talin A1 - Li, Guo A1 - Lumley, Thomas A1 - Psaty, Bruce M A1 - Shlipak, Michael A1 - Hwang, Shih-Jen A1 - Larson, Martin G A1 - O'Donnell, Christopher J A1 - Upadhyay, Ashish A1 - van Duijn, Cornelia M A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Stricker, Bruno A1 - Uitterlinden, André G A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Ridker, Paul M A1 - Siscovick, David S A1 - Gudnason, Vilmundur A1 - Witteman, Jacqueline C A1 - Fox, Caroline S A1 - Coresh, Josef KW - Cardiovascular Diseases KW - Coronary Disease KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Gout KW - Humans KW - Male KW - Risk Factors KW - Uric Acid AB -

BACKGROUND: Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed a genome-wide association study to search for genetic susceptibility loci for serum urate and gout and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD).

METHODS AND RESULTS: Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology consortium for serum urate and gout in 28 283 white participants. The effect of the most significant single-nucleotide polymorphism at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Women's Genome Health Study (n=22 054). Single-nucleotide polymorphisms at 8 genetic loci achieved genome-wide significance with serum urate levels (P=4×10(-8) to 2×10(-242) in SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, and SLC17A1). Only 2 loci (SLC2A9, ABCG2) showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio, 12.4 per 100 μmol/L; P=3×10(-39)) but not with blood pressure, glucose, estimated glomerular filtration rate, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes also was observed in the Women's Genome Health Study.

CONCLUSIONS: The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD.

VL - 3 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20884846?dopt=Abstract ER - TY - JOUR T1 - New loci associated with kidney function and chronic kidney disease. JF - Nat Genet Y1 - 2010 A1 - Köttgen, Anna A1 - Pattaro, Cristian A1 - Böger, Carsten A A1 - Fuchsberger, Christian A1 - Olden, Matthias A1 - Glazer, Nicole L A1 - Parsa, Afshin A1 - Gao, Xiaoyi A1 - Yang, Qiong A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Li, Man A1 - Schmidt, Helena A1 - Tanaka, Toshiko A1 - Isaacs, Aaron A1 - Ketkar, Shamika A1 - Hwang, Shih-Jen A1 - Johnson, Andrew D A1 - Dehghan, Abbas A1 - Teumer, Alexander A1 - Paré, Guillaume A1 - Atkinson, Elizabeth J A1 - Zeller, Tanja A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Tönjes, Anke A1 - Hayward, Caroline A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Rampersaud, Evadnie A1 - Mitchell, Braxton D A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Struchalin, Maksim A1 - Cavalieri, Margherita A1 - Singleton, Andrew A1 - Giallauria, Francesco A1 - Metter, Jeffrey A1 - de Boer, Ian H A1 - Haritunians, Talin A1 - Lumley, Thomas A1 - Siscovick, David A1 - Psaty, Bruce M A1 - Zillikens, M Carola A1 - Oostra, Ben A A1 - Feitosa, Mary A1 - Province, Michael A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Schillert, Arne A1 - Ziegler, Andreas A1 - Wild, Philipp S A1 - Schnabel, Renate B A1 - Wilde, Sandra A1 - Munzel, Thomas F A1 - Leak, Tennille S A1 - Illig, Thomas A1 - Klopp, Norman A1 - Meisinger, Christa A1 - Wichmann, H-Erich A1 - Koenig, Wolfgang A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Kolcic, Ivana A1 - Minelli, Cosetta A1 - Hu, Frank B A1 - Johansson, Asa A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Schreiber, Stefan A1 - Aulchenko, Yurii S A1 - Felix, Janine F A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Imboden, Medea A1 - Nitsch, Dorothea A1 - Brandstätter, Anita A1 - Kollerits, Barbara A1 - Kedenko, Lyudmyla A1 - Mägi, Reedik A1 - Stumvoll, Michael A1 - Kovacs, Peter A1 - Boban, Mladen A1 - Campbell, Susan A1 - Endlich, Karlhans A1 - Völzke, Henry A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Völker, Uwe A1 - Polasek, Ozren A1 - Vitart, Veronique A1 - Badola, Sunita A1 - Parker, Alexander N A1 - Ridker, Paul M A1 - Kardia, Sharon L R A1 - Blankenberg, Stefan A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Franke, Andre A1 - Rochat, Thierry A1 - Paulweber, Bernhard A1 - Prokopenko, Inga A1 - Wang, Wei A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - Shlipak, Michael G A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Krämer, Bernhard K A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Witteman, Jacqueline C A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Hastie, Nick A1 - Chasman, Daniel I A1 - Kao, W H A1 - Heid, Iris M A1 - Fox, Caroline S KW - Cohort Studies KW - Creatinine KW - Cystatin C KW - Diet KW - Europe KW - Genetic Markers KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Models, Genetic KW - Risk Factors AB -

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.

VL - 42 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20383146?dopt=Abstract ER - TY - JOUR T1 - Validation of an atrial fibrillation risk algorithm in whites and African Americans. JF - Arch Intern Med Y1 - 2010 A1 - Schnabel, Renate B A1 - Aspelund, Thor A1 - Li, Guo A1 - Sullivan, Lisa M A1 - Suchy-Dicey, Astrid A1 - Harris, Tamara B A1 - Pencina, Michael J A1 - D'Agostino, Ralph B A1 - Levy, Daniel A1 - Kannel, William B A1 - Wang, Thomas J A1 - Kronmal, Richard A A1 - Wolf, Philip A A1 - Burke, Gregory L A1 - Launer, Lenore J A1 - Vasan, Ramachandran S A1 - Psaty, Bruce M A1 - Benjamin, Emelia J A1 - Gudnason, Vilmundur A1 - Heckbert, Susan R KW - African Continental Ancestry Group KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Algorithms KW - Atrial Fibrillation KW - Blood Pressure KW - Body Mass Index KW - Cohort Studies KW - Electrocardiography KW - Europe KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Heart Failure KW - Humans KW - Hypertension KW - Incidence KW - Kaplan-Meier Estimate KW - Male KW - Middle Aged KW - Proportional Hazards Models KW - Risk Factors KW - Sex Factors KW - Systole KW - United States AB -

BACKGROUND: We sought to validate a recently published risk algorithm for incident atrial fibrillation (AF) in independent cohorts and other racial groups.

METHODS: We evaluated the performance of a Framingham Heart Study (FHS)-derived risk algorithm modified for 5-year incidence of AF in the FHS (n = 4764 participants) and 2 geographically and racially diverse cohorts in the age range 45 to 95 years: AGES (the Age, Gene/Environment Susceptibility-Reykjavik Study) (n = 4238) and CHS (the Cardiovascular Health Study) (n = 5410, of whom 874 [16.2%] were African Americans). The risk algorithm included age, sex, body mass index, systolic blood pressure, electrocardiographic PR interval, hypertension treatment, and heart failure.

RESULTS: We found 1359 incident AF events in 100 074 person-years of follow-up. Unadjusted 5-year event rates differed by cohort (AGES, 12.8 cases/1000 person-years; CHS whites, 22.7 cases/1000 person-years; and FHS, 4.5 cases/1000 person-years) and by race (CHS African Americans, 18.4 cases/1000 person-years). The strongest risk factors in all samples were age and heart failure. The relative risks for incident AF associated with risk factors were comparable across cohorts and race groups. After recalibration for baseline incidence and risk factor distribution, the Framingham algorithm, reported in C statistic, performed reasonably well in all samples: AGES, 0.67 (95% confidence interval [CI], 0.64-0.71); CHS whites, 0.68 (95% CI, 0.66-0.70); and CHS African Americans, 0.66 (95% CI, 0.61-0.71). Risk factors combined in the algorithm explained between 47.0% (AGES) and 63.6% (FHS) of the population-attributable risk.

CONCLUSIONS: Risk of incident AF in community-dwelling whites and African Americans can be assessed reliably by routinely available and potentially modifiable clinical variables. Seven risk factors accounted for up to 64% of risk.

VL - 170 IS - 21 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21098350?dopt=Abstract ER - TY - JOUR T1 - CUBN is a gene locus for albuminuria. JF - J Am Soc Nephrol Y1 - 2011 A1 - Böger, Carsten A A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Olden, Matthias A1 - Köttgen, Anna A1 - de Boer, Ian H A1 - Fuchsberger, Christian A1 - O'Seaghdha, Conall M A1 - Pattaro, Cristian A1 - Teumer, Alexander A1 - Liu, Ching-Ti A1 - Glazer, Nicole L A1 - Li, Man A1 - O'Connell, Jeffrey R A1 - Tanaka, Toshiko A1 - Peralta, Carmen A A1 - Kutalik, Zoltán A1 - Luan, Jian'an A1 - Zhao, Jing Hua A1 - Hwang, Shih-Jen A1 - Akylbekova, Ermeg A1 - Kramer, Holly A1 - van der Harst, Pim A1 - Smith, Albert V A1 - Lohman, Kurt A1 - de Andrade, Mariza A1 - Hayward, Caroline A1 - Kollerits, Barbara A1 - Tönjes, Anke A1 - Aspelund, Thor A1 - Ingelsson, Erik A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Shuldiner, Alan R A1 - Mitchell, Braxton D A1 - Arking, Dan E A1 - Franceschini, Nora A1 - Boerwinkle, Eric A1 - Egan, Josephine A1 - Hernandez, Dena A1 - Reilly, Muredach A1 - Townsend, Raymond R A1 - Lumley, Thomas A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Kestenbaum, Bryan A1 - Haritunians, Talin A1 - Bergmann, Sven A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Mooser, Vincent A1 - Waterworth, Dawn A1 - Johnson, Andrew D A1 - Florez, Jose C A1 - Meigs, James B A1 - Lu, Xiaoning A1 - Turner, Stephen T A1 - Atkinson, Elizabeth J A1 - Leak, Tennille S A1 - Aasarød, Knut A1 - Skorpen, Frank A1 - Syvänen, Ann-Christine A1 - Illig, Thomas A1 - Baumert, Jens A1 - Koenig, Wolfgang A1 - Krämer, Bernhard K A1 - Devuyst, Olivier A1 - Mychaleckyj, Josyf C A1 - Minelli, Cosetta A1 - Bakker, Stephan J L A1 - Kedenko, Lyudmyla A1 - Paulweber, Bernhard A1 - Coassin, Stefan A1 - Endlich, Karlhans A1 - Kroemer, Heyo K A1 - Biffar, Reiner A1 - Stracke, Sylvia A1 - Völzke, Henry A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Campbell, Harry A1 - Vitart, Veronique A1 - Hastie, Nicholas D A1 - Gudnason, Vilmundur A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Polasek, Ozren A1 - Curhan, Gary A1 - Kronenberg, Florian A1 - Prokopenko, Inga A1 - Rudan, Igor A1 - Arnlöv, Johan A1 - Hallan, Stein A1 - Navis, Gerjan A1 - Parsa, Afshin A1 - Ferrucci, Luigi A1 - Coresh, Josef A1 - Shlipak, Michael G A1 - Bull, Shelley B A1 - Paterson, Nicholas J A1 - Wichmann, H-Erich A1 - Wareham, Nicholas J A1 - Loos, Ruth J F A1 - Rotter, Jerome I A1 - Pramstaller, Peter P A1 - Cupples, L Adrienne A1 - Beckmann, Jacques S A1 - Yang, Qiong A1 - Heid, Iris M A1 - Rettig, Rainer A1 - Dreisbach, Albert W A1 - Bochud, Murielle A1 - Fox, Caroline S A1 - Kao, W H L KW - African Continental Ancestry Group KW - Albuminuria KW - European Continental Ancestry Group KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Humans KW - Mutation, Missense KW - Receptors, Cell Surface AB -

Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.

VL - 22 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21355061?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 - 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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 and large-scale follow up identifies 16 new loci influencing lung function. JF - Nat Genet Y1 - 2011 A1 - Soler Artigas, Maria A1 - Loth, Daan W A1 - Wain, Louise V A1 - Gharib, Sina A A1 - Obeidat, Ma'en A1 - Tang, Wenbo A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Smith, Albert Vernon A1 - Huffman, Jennifer E A1 - Albrecht, Eva A1 - Jackson, Catherine M A1 - Evans, David M A1 - Cadby, Gemma A1 - Fornage, Myriam A1 - Manichaikul, Ani A1 - Lopez, Lorna M A1 - Johnson, Toby A1 - Aldrich, Melinda C A1 - Aspelund, Thor A1 - Barroso, Inês A1 - Campbell, Harry A1 - Cassano, Patricia A A1 - Couper, David J A1 - Eiriksdottir, Gudny A1 - Franceschini, Nora A1 - Garcia, Melissa A1 - Gieger, Christian A1 - Gislason, Gauti Kjartan A1 - Grkovic, Ivica A1 - Hammond, Christopher J A1 - Hancock, Dana B A1 - Harris, Tamara B A1 - Ramasamy, Adaikalavan A1 - Heckbert, Susan R A1 - Heliövaara, Markku A1 - Homuth, Georg A1 - Hysi, Pirro G A1 - James, Alan L A1 - Jankovic, Stipan A1 - Joubert, Bonnie R A1 - Karrasch, Stefan A1 - Klopp, Norman A1 - Koch, Beate A1 - Kritchevsky, Stephen B A1 - Launer, Lenore J A1 - Liu, Yongmei A1 - Loehr, Laura R A1 - Lohman, Kurt A1 - Loos, Ruth J F A1 - Lumley, Thomas A1 - Al Balushi, Khalid A A1 - Ang, Wei Q A1 - Barr, R Graham A1 - Beilby, John A1 - Blakey, John D A1 - Boban, Mladen A1 - Boraska, Vesna A1 - Brisman, Jonas A1 - Britton, John R A1 - Brusselle, Guy G A1 - Cooper, Cyrus A1 - Curjuric, Ivan A1 - Dahgam, Santosh A1 - Deary, Ian J A1 - Ebrahim, Shah A1 - Eijgelsheim, Mark A1 - Francks, Clyde A1 - Gaysina, Darya A1 - Granell, Raquel A1 - Gu, Xiangjun A1 - Hankinson, John L A1 - Hardy, Rebecca A1 - Harris, Sarah E A1 - Henderson, John A1 - Henry, Amanda A1 - Hingorani, Aroon D A1 - Hofman, Albert A1 - Holt, Patrick G A1 - Hui, Jennie A1 - Hunter, Michael L A1 - Imboden, Medea A1 - Jameson, Karen A A1 - Kerr, Shona M A1 - Kolcic, Ivana A1 - Kronenberg, Florian A1 - Liu, Jason Z A1 - Marchini, Jonathan A1 - McKeever, Tricia A1 - Morris, Andrew D A1 - Olin, Anna-Carin A1 - Porteous, David J A1 - Postma, Dirkje S A1 - Rich, Stephen S A1 - Ring, Susan M A1 - Rivadeneira, Fernando A1 - Rochat, Thierry A1 - Sayer, Avan Aihie A1 - Sayers, Ian A1 - Sly, Peter D A1 - Smith, George Davey A1 - Sood, Akshay A1 - Starr, John M A1 - Uitterlinden, André G A1 - Vonk, Judith M A1 - Wannamethee, S Goya A1 - Whincup, Peter H A1 - Wijmenga, Cisca A1 - Williams, O Dale A1 - Wong, Andrew A1 - Mangino, Massimo A1 - Marciante, Kristin D A1 - McArdle, Wendy L A1 - Meibohm, Bernd A1 - Morrison, Alanna C A1 - North, Kari E A1 - Omenaas, Ernst A1 - Palmer, Lyle J A1 - Pietiläinen, Kirsi H A1 - Pin, Isabelle A1 - Pola Sbreve Ek, Ozren A1 - Pouta, Anneli A1 - Psaty, Bruce M A1 - Hartikainen, Anna-Liisa A1 - Rantanen, Taina A1 - Ripatti, Samuli A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Rudnicka, Alicja R A1 - Schulz, Holger A1 - Shin, So-Youn A1 - Spector, Tim D A1 - Surakka, Ida A1 - Vitart, Veronique A1 - Völzke, Henry A1 - Wareham, Nicholas J A1 - Warrington, Nicole M A1 - Wichmann, H-Erich A1 - Wild, Sarah H A1 - Wilk, Jemma B A1 - Wjst, Matthias A1 - Wright, Alan F A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Pennell, Craig E A1 - Nyberg, Fredrik A1 - Kuh, Diana A1 - Holloway, John W A1 - Boezen, H Marike A1 - Lawlor, Debbie A A1 - Morris, Richard W A1 - Probst-Hensch, Nicole A1 - Kaprio, Jaakko A1 - Wilson, James F A1 - Hayward, Caroline A1 - Kähönen, Mika A1 - Heinrich, Joachim A1 - Musk, Arthur W A1 - Jarvis, Deborah L A1 - Gläser, Sven A1 - Jarvelin, Marjo-Riitta A1 - Ch Stricker, Bruno H A1 - Elliott, Paul A1 - O'Connor, George T A1 - Strachan, David P A1 - London, Stephanie J A1 - Hall, Ian P A1 - Gudnason, Vilmundur A1 - Tobin, Martin D KW - Child KW - European Continental Ancestry Group KW - Genome-Wide Association Study KW - Humans KW - Pulmonary Disease, Chronic Obstructive KW - Respiratory Function Tests AB -

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

VL - 43 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21946350?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 - Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. JF - Nat Genet Y1 - 2011 A1 - Wain, Louise V A1 - Verwoert, Germaine C A1 - O'Reilly, Paul F A1 - Shi, Gang A1 - Johnson, Toby A1 - Johnson, Andrew D A1 - Bochud, Murielle A1 - Rice, Kenneth M A1 - Henneman, Peter A1 - Smith, Albert V A1 - Ehret, Georg B A1 - Amin, Najaf A1 - Larson, Martin G A1 - Mooser, Vincent A1 - Hadley, David A1 - Dörr, Marcus A1 - Bis, Joshua C A1 - Aspelund, Thor A1 - Esko, Tõnu A1 - Janssens, A Cecile J W A1 - Zhao, Jing Hua A1 - Heath, Simon A1 - Laan, Maris A1 - Fu, Jingyuan A1 - Pistis, Giorgio A1 - Luan, Jian'an A1 - Arora, Pankaj A1 - Lucas, Gavin A1 - Pirastu, Nicola A1 - Pichler, Irene A1 - Jackson, Anne U A1 - Webster, Rebecca J A1 - Zhang, Feng A1 - Peden, John F A1 - Schmidt, Helena A1 - Tanaka, Toshiko A1 - Campbell, Harry A1 - Igl, Wilmar A1 - Milaneschi, Yuri A1 - Hottenga, Jouke-Jan A1 - Vitart, Veronique A1 - Chasman, Daniel I A1 - Trompet, Stella A1 - Bragg-Gresham, Jennifer L A1 - Alizadeh, Behrooz Z A1 - Chambers, John C A1 - Guo, Xiuqing A1 - Lehtimäki, Terho A1 - Kuhnel, Brigitte A1 - Lopez, Lorna M A1 - Polasek, Ozren A1 - Boban, Mladen A1 - Nelson, Christopher P A1 - Morrison, Alanna C A1 - Pihur, Vasyl A1 - Ganesh, Santhi K A1 - Hofman, Albert A1 - Kundu, Suman A1 - Mattace-Raso, Francesco U S A1 - Rivadeneira, Fernando A1 - Sijbrands, Eric J G A1 - Uitterlinden, André G A1 - Hwang, Shih-Jen A1 - Vasan, Ramachandran S A1 - Wang, Thomas J A1 - Bergmann, Sven A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Laitinen, Jaana A1 - Pouta, Anneli A1 - Zitting, Paavo A1 - McArdle, Wendy L A1 - Kroemer, Heyo K A1 - Völker, Uwe A1 - Völzke, Henry A1 - Glazer, Nicole L A1 - Taylor, Kent D A1 - Harris, Tamara B A1 - Alavere, Helene A1 - Haller, Toomas A1 - Keis, Aime A1 - Tammesoo, Mari-Liis A1 - Aulchenko, Yurii A1 - Barroso, Inês A1 - Khaw, Kay-Tee A1 - Galan, Pilar A1 - Hercberg, Serge A1 - Lathrop, Mark A1 - Eyheramendy, Susana A1 - Org, Elin A1 - Sõber, Siim A1 - Lu, Xiaowen A1 - Nolte, Ilja M A1 - Penninx, Brenda W A1 - Corre, Tanguy A1 - Masciullo, Corrado A1 - Sala, Cinzia A1 - Groop, Leif A1 - Voight, Benjamin F A1 - Melander, Olle A1 - O'Donnell, Christopher J A1 - Salomaa, Veikko A1 - d'Adamo, Adamo Pio A1 - Fabretto, Antonella A1 - Faletra, Flavio A1 - Ulivi, Sheila A1 - Del Greco, Fabiola M A1 - Facheris, Maurizio A1 - Collins, Francis S A1 - Bergman, Richard N A1 - Beilby, John P A1 - Hung, Joseph A1 - Musk, A William A1 - Mangino, Massimo A1 - Shin, So-Youn A1 - Soranzo, Nicole A1 - Watkins, Hugh A1 - Goel, Anuj A1 - Hamsten, Anders A1 - Gider, Pierre A1 - Loitfelder, Marisa A1 - Zeginigg, Marion A1 - Hernandez, Dena A1 - Najjar, Samer S A1 - Navarro, Pau A1 - Wild, Sarah H A1 - Corsi, Anna Maria A1 - Singleton, Andrew A1 - de Geus, Eco J C A1 - Willemsen, Gonneke A1 - Parker, Alex N A1 - Rose, Lynda M A1 - Buckley, Brendan A1 - Stott, David A1 - Orrù, Marco A1 - Uda, Manuela A1 - van der Klauw, Melanie M A1 - Zhang, Weihua A1 - Li, Xinzhong A1 - Scott, James A1 - Chen, Yii-Der Ida A1 - Burke, Gregory L A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Döring, Angela A1 - Meitinger, Thomas A1 - Davies, Gail A1 - Starr, John M A1 - Emilsson, Valur A1 - Plump, Andrew A1 - Lindeman, Jan H A1 - Hoen, Peter A C 't A1 - König, Inke R A1 - Felix, Janine F A1 - Clarke, Robert A1 - Hopewell, Jemma C A1 - Ongen, Halit A1 - Breteler, Monique A1 - Debette, Stephanie A1 - DeStefano, Anita L A1 - Fornage, Myriam A1 - Mitchell, Gary F A1 - Smith, Nicholas L A1 - Holm, Hilma A1 - Stefansson, Kari A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Samani, Nilesh J A1 - Preuss, Michael A1 - Rudan, Igor A1 - Hayward, Caroline A1 - Deary, Ian J A1 - Wichmann, H-Erich A1 - Raitakari, Olli T A1 - Palmas, Walter A1 - Kooner, Jaspal S A1 - Stolk, Ronald P A1 - Jukema, J Wouter A1 - Wright, Alan F A1 - Boomsma, Dorret I A1 - Bandinelli, Stefania A1 - Gyllensten, Ulf B A1 - Wilson, James F A1 - Ferrucci, Luigi A1 - Schmidt, Reinhold A1 - Farrall, Martin A1 - Spector, Tim D A1 - Palmer, Lyle J A1 - Tuomilehto, Jaakko A1 - Pfeufer, Arne A1 - Gasparini, Paolo A1 - Siscovick, David A1 - Altshuler, David A1 - Loos, Ruth J F A1 - Toniolo, Daniela A1 - Snieder, Harold A1 - Gieger, Christian A1 - Meneton, Pierre A1 - Wareham, Nicholas J A1 - Oostra, Ben A A1 - Metspalu, Andres A1 - Launer, Lenore A1 - Rettig, Rainer A1 - Strachan, David P A1 - Beckmann, Jacques S A1 - Witteman, Jacqueline C M A1 - Erdmann, Jeanette A1 - van Dijk, Ko Willems A1 - Boerwinkle, Eric A1 - Boehnke, Michael A1 - Ridker, Paul M A1 - Jarvelin, Marjo-Riitta A1 - Chakravarti, Aravinda A1 - Abecasis, Goncalo R A1 - Gudnason, Vilmundur A1 - Newton-Cheh, Christopher A1 - Levy, Daniel A1 - Munroe, Patricia B A1 - Psaty, Bruce M A1 - Caulfield, Mark J A1 - Rao, Dabeeru C A1 - Tobin, Martin D A1 - Elliott, Paul A1 - van Duijn, Cornelia M KW - Arteries KW - Blood Pressure KW - Case-Control Studies KW - Follow-Up Studies KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Linkage Disequilibrium KW - Polymorphism, Single Nucleotide AB -

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

VL - 43 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21909110?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque. JF - Nat Genet Y1 - 2011 A1 - Bis, Joshua C A1 - Kavousi, Maryam A1 - Franceschini, Nora A1 - Isaacs, Aaron A1 - Abecasis, Goncalo R A1 - Schminke, Ulf A1 - Post, Wendy S A1 - Smith, Albert V A1 - Cupples, L Adrienne A1 - Markus, Hugh S A1 - Schmidt, Reinhold A1 - Huffman, Jennifer E A1 - Lehtimäki, Terho A1 - Baumert, Jens A1 - Münzel, Thomas A1 - Heckbert, Susan R A1 - Dehghan, Abbas A1 - North, Kari A1 - Oostra, Ben A1 - Bevan, Steve A1 - Stoegerer, Eva-Maria A1 - Hayward, Caroline A1 - Raitakari, Olli A1 - Meisinger, Christa A1 - Schillert, Arne A1 - Sanna, Serena A1 - Völzke, Henry A1 - Cheng, Yu-Ching A1 - Thorsson, Bolli A1 - Fox, Caroline S A1 - Rice, Kenneth A1 - Rivadeneira, Fernando A1 - Nambi, Vijay A1 - Halperin, Eran A1 - Petrovic, Katja E A1 - Peltonen, Leena A1 - Wichmann, H Erich A1 - Schnabel, Renate B A1 - Dörr, Marcus A1 - Parsa, Afshin A1 - Aspelund, Thor A1 - Demissie, Serkalem A1 - Kathiresan, Sekar A1 - Reilly, Muredach P A1 - Taylor, Kent A1 - Uitterlinden, Andre A1 - Couper, David J A1 - Sitzer, Matthias A1 - Kähönen, Mika A1 - Illig, Thomas A1 - Wild, Philipp S A1 - Orrù, Marco A1 - Lüdemann, Jan A1 - Shuldiner, Alan R A1 - Eiriksdottir, Gudny A1 - White, Charles C A1 - Rotter, Jerome I A1 - Hofman, Albert A1 - Seissler, Jochen A1 - Zeller, Tanja A1 - Usala, Gianluca A1 - Ernst, Florian A1 - Launer, Lenore J A1 - D'Agostino, Ralph B A1 - O'Leary, Daniel H A1 - Ballantyne, Christie A1 - Thiery, Joachim A1 - Ziegler, Andreas A1 - Lakatta, Edward G A1 - Chilukoti, Ravi Kumar A1 - Harris, Tamara B A1 - Wolf, Philip A A1 - Psaty, Bruce M A1 - Polak, Joseph F A1 - Li, Xia A1 - Rathmann, Wolfgang A1 - Uda, Manuela A1 - Boerwinkle, Eric A1 - Klopp, Norman A1 - Schmidt, Helena A1 - Wilson, James F A1 - Viikari, Jorma A1 - Koenig, Wolfgang A1 - Blankenberg, Stefan A1 - Newman, Anne B A1 - Witteman, Jacqueline A1 - Heiss, Gerardo A1 - Duijn, Cornelia van A1 - Scuteri, Angelo A1 - Homuth, Georg A1 - Mitchell, Braxton D A1 - Gudnason, Vilmundur A1 - O'Donnell, Christopher J KW - Adult KW - Aged KW - Aging KW - Atherosclerosis KW - Carotid Intima-Media Thickness KW - Cohort Studies KW - Coronary Artery Disease KW - European Continental Ancestry Group KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Genotype KW - Heart KW - Humans KW - Middle Aged KW - Phenotype KW - Plaque, Atherosclerotic KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.

VL - 43 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21909108?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. JF - Circulation Y1 - 2011 A1 - Dehghan, Abbas A1 - Dupuis, Josée A1 - Barbalic, Maja A1 - Bis, Joshua C A1 - Eiriksdottir, Gudny A1 - Lu, Chen A1 - Pellikka, Niina A1 - Wallaschofski, Henri A1 - Kettunen, Johannes A1 - Henneman, Peter A1 - Baumert, Jens A1 - Strachan, David P A1 - Fuchsberger, Christian A1 - Vitart, Veronique A1 - Wilson, James F A1 - Paré, Guillaume A1 - Naitza, Silvia A1 - Rudock, Megan E A1 - Surakka, Ida A1 - de Geus, Eco J C A1 - Alizadeh, Behrooz Z A1 - Guralnik, Jack A1 - Shuldiner, Alan A1 - Tanaka, Toshiko A1 - Zee, Robert Y L A1 - Schnabel, Renate B A1 - Nambi, Vijay A1 - Kavousi, Maryam A1 - Ripatti, Samuli A1 - Nauck, Matthias A1 - Smith, Nicholas L A1 - Smith, Albert V A1 - Sundvall, Jouko A1 - Scheet, Paul A1 - Liu, Yongmei A1 - Ruokonen, Aimo A1 - Rose, Lynda M A1 - Larson, Martin G A1 - Hoogeveen, Ron C A1 - Freimer, Nelson B A1 - Teumer, Alexander A1 - Tracy, Russell P A1 - Launer, Lenore J A1 - Buring, Julie E A1 - Yamamoto, Jennifer F A1 - Folsom, Aaron R A1 - Sijbrands, Eric J G A1 - Pankow, James A1 - Elliott, Paul A1 - Keaney, John F A1 - Sun, Wei A1 - Sarin, Antti-Pekka A1 - Fontes, João D A1 - Badola, Sunita A1 - Astor, Brad C A1 - Hofman, Albert A1 - Pouta, Anneli A1 - Werdan, Karl A1 - Greiser, Karin H A1 - Kuss, Oliver A1 - Meyer zu Schwabedissen, Henriette E A1 - Thiery, Joachim A1 - Jamshidi, Yalda A1 - Nolte, Ilja M A1 - Soranzo, Nicole A1 - Spector, Timothy D A1 - Völzke, Henry A1 - Parker, Alexander N A1 - Aspelund, Thor A1 - Bates, David A1 - Young, Lauren A1 - Tsui, Kim A1 - Siscovick, David S A1 - Guo, Xiuqing A1 - Rotter, Jerome I A1 - Uda, Manuela A1 - Schlessinger, David A1 - Rudan, Igor A1 - Hicks, Andrew A A1 - Penninx, Brenda W A1 - Thorand, Barbara A1 - Gieger, Christian A1 - Coresh, Joe A1 - Willemsen, Gonneke A1 - Harris, Tamara B A1 - Uitterlinden, André G A1 - Jarvelin, Marjo-Riitta A1 - Rice, Kenneth A1 - Radke, Dörte A1 - Salomaa, Veikko A1 - Willems van Dijk, Ko A1 - Boerwinkle, Eric A1 - Vasan, Ramachandran S A1 - Ferrucci, Luigi A1 - Gibson, Quince D A1 - Bandinelli, Stefania A1 - Snieder, Harold A1 - Boomsma, Dorret I A1 - Xiao, Xiangjun A1 - Campbell, Harry A1 - Hayward, Caroline A1 - Pramstaller, Peter P A1 - van Duijn, Cornelia M A1 - Peltonen, Leena A1 - Psaty, Bruce M A1 - Gudnason, Vilmundur A1 - Ridker, Paul M A1 - Homuth, Georg A1 - Koenig, Wolfgang A1 - Ballantyne, Christie M A1 - Witteman, Jacqueline C M A1 - Benjamin, Emelia J A1 - Perola, Markus A1 - Chasman, Daniel I KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Risk Factors KW - Vasculitis AB -

BACKGROUND: C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels.

METHODS AND RESULTS: We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P<2.9×10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease.

CONCLUSIONS: We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.

VL - 123 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21300955?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association and functional follow-up reveals new loci for kidney function. JF - PLoS Genet Y1 - 2012 A1 - Pattaro, Cristian A1 - Köttgen, Anna A1 - Teumer, Alexander A1 - Garnaas, Maija A1 - Böger, Carsten A A1 - Fuchsberger, Christian A1 - Olden, Matthias A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Taliun, Daniel A1 - Li, Man A1 - Gao, Xiaoyi A1 - Gorski, Mathias A1 - Yang, Qiong A1 - Hundertmark, Claudia A1 - Foster, Meredith C A1 - O'Seaghdha, Conall M A1 - Glazer, Nicole A1 - Isaacs, Aaron A1 - Liu, Ching-Ti A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Struchalin, Maksim A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Johnson, Andrew D A1 - Gierman, Hinco J A1 - Feitosa, Mary A1 - Hwang, Shih-Jen A1 - Atkinson, Elizabeth J A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Johansson, Asa A1 - Tönjes, Anke A1 - Dehghan, Abbas A1 - Chouraki, Vincent A1 - Holliday, Elizabeth G A1 - Sorice, Rossella A1 - Kutalik, Zoltán A1 - Lehtimäki, Terho A1 - Esko, Tõnu A1 - Deshmukh, Harshal A1 - Ulivi, Sheila A1 - Chu, Audrey Y A1 - Murgia, Federico A1 - Trompet, Stella A1 - Imboden, Medea A1 - Kollerits, Barbara A1 - Pistis, Giorgio A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Mitchell, Braxton D A1 - Boerwinkle, Eric A1 - Schmidt, Helena A1 - Cavalieri, Margherita A1 - Rao, Madhumathi A1 - Hu, Frank B A1 - Demirkan, Ayse A1 - Oostra, Ben A A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Ding, Jingzhong A1 - Andrews, Jeanette S A1 - Freedman, Barry I A1 - Koenig, Wolfgang A1 - Illig, Thomas A1 - Döring, Angela A1 - Wichmann, H-Erich A1 - Kolcic, Ivana A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Minelli, Cosetta A1 - Wheeler, Heather E A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Nöthlings, Ute A1 - Jacobs, Gunnar A1 - Biffar, Reiner A1 - Endlich, Karlhans A1 - Ernst, Florian A1 - Homuth, Georg A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Stracke, Sylvia A1 - Völker, Uwe A1 - Völzke, Henry A1 - Kovacs, Peter A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Aulchenko, Yurii S A1 - Polasek, Ozren A1 - Hastie, Nick A1 - Vitart, Veronique A1 - Helmer, Catherine A1 - Wang, Jie Jin A1 - Ruggiero, Daniela A1 - Bergmann, Sven A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Nikopensius, Tiit A1 - Province, Michael A1 - Ketkar, Shamika A1 - Colhoun, Helen A1 - Doney, Alex A1 - Robino, Antonietta A1 - Giulianini, Franco A1 - Krämer, Bernhard K A1 - Portas, Laura A1 - Ford, Ian A1 - Buckley, Brendan M A1 - Adam, Martin A1 - Thun, Gian-Andri A1 - Paulweber, Bernhard A1 - Haun, Margot A1 - Sala, Cinzia A1 - Metzger, Marie A1 - Mitchell, Paul A1 - Ciullo, Marina A1 - Kim, Stuart K A1 - Vollenweider, Peter A1 - Raitakari, Olli A1 - Metspalu, Andres A1 - Palmer, Colin A1 - Gasparini, Paolo A1 - Pirastu, Mario A1 - Jukema, J Wouter A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Toniolo, Daniela A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - Siscovick, David S A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Franke, Andre A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Prokopenko, Inga A1 - Witteman, Jacqueline C M A1 - Hayward, Caroline A1 - Ridker, Paul A1 - Parsa, Afshin A1 - Bochud, Murielle A1 - Heid, Iris M A1 - Goessling, Wolfram A1 - Chasman, Daniel I A1 - Kao, W H Linda A1 - Fox, Caroline S KW - African Americans KW - Aged KW - Animals KW - Caspase 9 KW - Cyclin-Dependent Kinases KW - DEAD-box RNA Helicases KW - DNA Helicases KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Gene Knockdown Techniques KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Phosphoric Diester Hydrolases KW - Zebrafish AB -

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

VL - 8 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22479191?dopt=Abstract ER - TY - JOUR T1 - Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. JF - Nat Genet Y1 - 2012 A1 - Estrada, Karol A1 - Styrkarsdottir, Unnur A1 - Evangelou, Evangelos A1 - Hsu, Yi-Hsiang A1 - Duncan, Emma L A1 - Ntzani, Evangelia E A1 - Oei, Ling A1 - Albagha, Omar M E A1 - Amin, Najaf A1 - Kemp, John P A1 - Koller, Daniel L A1 - Li, Guo A1 - Liu, Ching-Ti A1 - Minster, Ryan L A1 - Moayyeri, Alireza A1 - Vandenput, Liesbeth A1 - Willner, Dana A1 - Xiao, Su-Mei A1 - Yerges-Armstrong, Laura M A1 - Zheng, Hou-Feng A1 - Alonso, Nerea A1 - Eriksson, Joel A1 - Kammerer, Candace M A1 - Kaptoge, Stephen K A1 - Leo, Paul J A1 - Thorleifsson, Gudmar A1 - Wilson, Scott G A1 - Wilson, James F A1 - Aalto, Ville A1 - Alen, Markku A1 - Aragaki, Aaron K A1 - Aspelund, Thor A1 - Center, Jacqueline R A1 - Dailiana, Zoe A1 - Duggan, David J A1 - Garcia, Melissa A1 - García-Giralt, Natalia A1 - Giroux, Sylvie A1 - Hallmans, Göran A1 - Hocking, Lynne J A1 - Husted, Lise Bjerre A1 - Jameson, Karen A A1 - Khusainova, Rita A1 - Kim, Ghi Su A1 - Kooperberg, Charles A1 - Koromila, Theodora A1 - Kruk, Marcin A1 - Laaksonen, Marika A1 - LaCroix, Andrea Z A1 - Lee, Seung Hun A1 - Leung, Ping C A1 - Lewis, Joshua R A1 - Masi, Laura A1 - Mencej-Bedrac, Simona A1 - Nguyen, Tuan V A1 - Nogues, Xavier A1 - Patel, Millan S A1 - Prezelj, Janez A1 - Rose, Lynda M A1 - Scollen, Serena A1 - Siggeirsdottir, Kristin A1 - Smith, Albert V A1 - Svensson, Olle A1 - Trompet, Stella A1 - Trummer, Olivia A1 - van Schoor, Natasja M A1 - Woo, Jean A1 - Zhu, Kun A1 - Balcells, Susana A1 - Brandi, Maria Luisa A1 - Buckley, Brendan M A1 - Cheng, Sulin A1 - Christiansen, Claus A1 - Cooper, Cyrus A1 - Dedoussis, George A1 - Ford, Ian A1 - Frost, Morten A1 - Goltzman, David A1 - González-Macías, Jesús A1 - Kähönen, Mika A1 - Karlsson, Magnus A1 - Khusnutdinova, Elza A1 - Koh, Jung-Min A1 - Kollia, Panagoula A1 - Langdahl, Bente Lomholt A1 - Leslie, William D A1 - Lips, Paul A1 - Ljunggren, Osten A1 - Lorenc, Roman S A1 - Marc, Janja A1 - Mellström, Dan A1 - Obermayer-Pietsch, Barbara A1 - Olmos, José M A1 - Pettersson-Kymmer, Ulrika A1 - Reid, David M A1 - Riancho, José A A1 - Ridker, Paul M A1 - Rousseau, François A1 - Slagboom, P Eline A1 - Tang, Nelson L S A1 - Urreizti, Roser A1 - Van Hul, Wim A1 - Viikari, Jorma A1 - Zarrabeitia, María T A1 - Aulchenko, Yurii S A1 - Castano-Betancourt, Martha A1 - Grundberg, Elin A1 - Herrera, Lizbeth A1 - Ingvarsson, Thorvaldur A1 - Johannsdottir, Hrefna A1 - Kwan, Tony A1 - Li, Rui A1 - Luben, Robert A1 - Medina-Gómez, Carolina A1 - Palsson, Stefan Th A1 - Reppe, Sjur A1 - Rotter, Jerome I A1 - Sigurdsson, Gunnar A1 - van Meurs, Joyce B J A1 - Verlaan, Dominique A1 - Williams, Frances M K A1 - Wood, Andrew R A1 - Zhou, Yanhua A1 - Gautvik, Kaare M A1 - Pastinen, Tomi A1 - Raychaudhuri, Soumya A1 - Cauley, Jane A A1 - Chasman, Daniel I A1 - Clark, Graeme R A1 - Cummings, Steven R A1 - Danoy, Patrick A1 - Dennison, Elaine M A1 - Eastell, Richard A1 - Eisman, John A A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Jackson, Rebecca D A1 - Jones, Graeme A1 - Jukema, J Wouter A1 - Khaw, Kay-Tee A1 - Lehtimäki, Terho A1 - Liu, Yongmei A1 - Lorentzon, Mattias A1 - McCloskey, Eugene A1 - Mitchell, Braxton D A1 - Nandakumar, Kannabiran A1 - Nicholson, Geoffrey C A1 - Oostra, Ben A A1 - Peacock, Munro A1 - Pols, Huibert A P A1 - Prince, Richard L A1 - Raitakari, Olli A1 - Reid, Ian R A1 - Robbins, John A1 - Sambrook, Philip N A1 - Sham, Pak Chung A1 - Shuldiner, Alan R A1 - Tylavsky, Frances A A1 - van Duijn, Cornelia M A1 - Wareham, Nick J A1 - Cupples, L Adrienne A1 - Econs, Michael J A1 - Evans, David M A1 - Harris, Tamara B A1 - Kung, Annie Wai Chee A1 - Psaty, Bruce M A1 - Reeve, Jonathan A1 - Spector, Timothy D A1 - Streeten, Elizabeth A A1 - Zillikens, M Carola A1 - Thorsteinsdottir, Unnur A1 - Ohlsson, Claes A1 - Karasik, David A1 - Richards, J Brent A1 - Brown, Matthew A A1 - Stefansson, Kari A1 - Uitterlinden, André G A1 - Ralston, Stuart H A1 - Ioannidis, John P A A1 - Kiel, Douglas P A1 - Rivadeneira, Fernando KW - Bone Density KW - Computational Biology KW - European Continental Ancestry Group KW - Extracellular Matrix Proteins KW - Female KW - Femur Neck KW - Fractures, Bone KW - Gene Expression Profiling KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Glycoproteins KW - Humans KW - Intercellular Signaling Peptides and Proteins KW - Low Density Lipoprotein Receptor-Related Protein-5 KW - Lumbar Vertebrae KW - Male KW - Mitochondrial Membrane Transport Proteins KW - Osteoporosis KW - Phosphoproteins KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Risk Factors KW - Spectrin AB -

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

VL - 44 IS - 5 ER - TY - JOUR T1 - Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. JF - Nat Genet Y1 - 2012 A1 - Stolk, Lisette A1 - Perry, John R B A1 - Chasman, Daniel I A1 - He, Chunyan A1 - Mangino, Massimo A1 - Sulem, Patrick A1 - Barbalic, Maja A1 - Broer, Linda A1 - Byrne, Enda M A1 - Ernst, Florian A1 - Esko, Tõnu A1 - Franceschini, Nora A1 - Gudbjartsson, Daniel F A1 - Hottenga, Jouke-Jan A1 - Kraft, Peter A1 - McArdle, Patrick F A1 - Porcu, Eleonora A1 - Shin, So-Youn A1 - Smith, Albert V A1 - van Wingerden, Sophie A1 - Zhai, Guangju A1 - Zhuang, Wei V A1 - Albrecht, Eva A1 - Alizadeh, Behrooz Z A1 - Aspelund, Thor A1 - Bandinelli, Stefania A1 - Lauc, Lovorka Barac A1 - Beckmann, Jacques S A1 - Boban, Mladen A1 - Boerwinkle, Eric A1 - Broekmans, Frank J A1 - Burri, Andrea A1 - Campbell, Harry A1 - Chanock, Stephen J A1 - Chen, Constance A1 - Cornelis, Marilyn C A1 - Corre, Tanguy A1 - Coviello, Andrea D A1 - D'Adamo, Pio A1 - Davies, Gail A1 - de Faire, Ulf A1 - de Geus, Eco J C A1 - Deary, Ian J A1 - Dedoussis, George V Z A1 - Deloukas, Panagiotis A1 - Ebrahim, Shah A1 - Eiriksdottir, Gudny A1 - Emilsson, Valur A1 - Eriksson, Johan G A1 - Fauser, Bart C J M A1 - Ferreli, Liana A1 - Ferrucci, Luigi A1 - Fischer, Krista A1 - Folsom, Aaron R A1 - Garcia, Melissa E A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Glazer, Nicole A1 - Grobbee, Diederick E A1 - Hall, Per A1 - Haller, Toomas A1 - Hankinson, Susan E A1 - Hass, Merli A1 - Hayward, Caroline A1 - Heath, Andrew C A1 - Hofman, Albert A1 - Ingelsson, Erik A1 - Janssens, A Cecile J W A1 - Johnson, Andrew D A1 - Karasik, David A1 - Kardia, Sharon L R A1 - Keyzer, Jules A1 - Kiel, Douglas P A1 - Kolcic, Ivana A1 - Kutalik, Zoltán A1 - Lahti, Jari A1 - Lai, Sandra A1 - Laisk, Triin A1 - Laven, Joop S E A1 - Lawlor, Debbie A A1 - Liu, Jianjun A1 - Lopez, Lorna M A1 - Louwers, Yvonne V A1 - Magnusson, Patrik K E A1 - Marongiu, Mara A1 - Martin, Nicholas G A1 - Klaric, Irena Martinovic A1 - Masciullo, Corrado A1 - McKnight, Barbara A1 - Medland, Sarah E A1 - Melzer, David A1 - Mooser, Vincent A1 - Navarro, Pau A1 - Newman, Anne B A1 - Nyholt, Dale R A1 - Onland-Moret, N Charlotte A1 - Palotie, Aarno A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Pedersen, Nancy L A1 - Peeters, Petra H M A1 - Pistis, Giorgio A1 - Plump, Andrew S A1 - Polasek, Ozren A1 - Pop, Victor J M A1 - Psaty, Bruce M A1 - Räikkönen, Katri A1 - Rehnberg, Emil A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Sala, Cinzia A1 - Salumets, Andres A1 - Scuteri, Angelo A1 - Singleton, Andrew A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Soranzo, Nicole A1 - Stacey, Simon N A1 - Starr, John M A1 - Stathopoulou, Maria G A1 - Stirrups, Kathleen A1 - Stolk, Ronald P A1 - Styrkarsdottir, Unnur A1 - Sun, Yan V A1 - Tenesa, Albert A1 - Thorand, Barbara A1 - Toniolo, Daniela A1 - Tryggvadottir, Laufey A1 - Tsui, Kim A1 - Ulivi, Sheila A1 - van Dam, Rob M A1 - van der Schouw, Yvonne T A1 - van Gils, Carla H A1 - van Nierop, Peter A1 - Vink, Jacqueline M A1 - Visscher, Peter M A1 - Voorhuis, Marlies A1 - Waeber, Gérard A1 - Wallaschofski, Henri A1 - Wichmann, H Erich A1 - Widen, Elisabeth A1 - Wijnands-van Gent, Colette J M A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Wolffenbuttel, Bruce H R A1 - Wright, Alan F A1 - Yerges-Armstrong, Laura M A1 - Zemunik, Tatijana A1 - Zgaga, Lina A1 - Zillikens, M Carola A1 - Zygmunt, Marek A1 - Arnold, Alice M A1 - Boomsma, Dorret I A1 - Buring, Julie E A1 - Crisponi, Laura A1 - Demerath, Ellen W A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hu, Frank B A1 - Hunter, David J A1 - Launer, Lenore J A1 - Metspalu, Andres A1 - Montgomery, Grant W A1 - Oostra, Ben A A1 - Ridker, Paul M A1 - Sanna, Serena A1 - Schlessinger, David A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Streeten, Elizabeth A A1 - Thorsteinsdottir, Unnur A1 - Uda, Manuela A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Völzke, Henry A1 - Murray, Anna A1 - Murabito, Joanne M A1 - Visser, Jenny A A1 - Lunetta, Kathryn L KW - Age Factors KW - DNA Helicases KW - DNA Polymerase gamma KW - DNA Primase KW - DNA Repair KW - DNA Repair Enzymes KW - DNA-Directed DNA Polymerase KW - European Continental Ancestry Group KW - Exodeoxyribonucleases KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Immunity KW - Menopause KW - Polymorphism, Single Nucleotide KW - Proteins AB -

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

VL - 44 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22267201?dopt=Abstract ER - TY - JOUR T1 - Common variants in Mendelian kidney disease genes and their association with renal function. JF - J Am Soc Nephrol Y1 - 2013 A1 - Parsa, Afshin A1 - Fuchsberger, Christian A1 - Köttgen, Anna A1 - O'Seaghdha, Conall M A1 - Pattaro, Cristian A1 - de Andrade, Mariza A1 - Chasman, Daniel I A1 - Teumer, Alexander A1 - Endlich, Karlhans A1 - Olden, Matthias A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Kim, Young J A1 - Taliun, Daniel A1 - Li, Man A1 - Feitosa, Mary A1 - Gorski, Mathias A1 - Yang, Qiong A1 - Hundertmark, Claudia A1 - Foster, Meredith C A1 - Glazer, Nicole A1 - Isaacs, Aaron A1 - Rao, Madhumathi A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Struchalin, Maksim A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Hwang, Shih-Jen A1 - Atkinson, Elizabeth J A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Johansson, Asa A1 - Tönjes, Anke A1 - Dehghan, Abbas A1 - Couraki, Vincent A1 - Holliday, Elizabeth G A1 - Sorice, Rossella A1 - Kutalik, Zoltán A1 - Lehtimäki, Terho A1 - Esko, Tõnu A1 - Deshmukh, Harshal A1 - Ulivi, Sheila A1 - Chu, Audrey Y A1 - Murgia, Federico A1 - Trompet, Stella A1 - Imboden, Medea A1 - Kollerits, Barbara A1 - Pistis, Giorgio A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Mitchell, Braxton D A1 - Boerwinkle, Eric A1 - Schmidt, Helena A1 - Hofer, Edith A1 - Hu, Frank A1 - Demirkan, Ayse A1 - Oostra, Ben A A1 - Turner, Stephen T A1 - Ding, Jingzhong A1 - Andrews, Jeanette S A1 - Freedman, Barry I A1 - Giulianini, Franco A1 - Koenig, Wolfgang A1 - Illig, Thomas A1 - Döring, Angela A1 - Wichmann, H-Erich A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Minelli, Cosetta A1 - Wheeler, Heather E A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Nöthlings, Ute A1 - Jacobs, Gunnar A1 - Biffar, Reiner A1 - Ernst, Florian A1 - Homuth, Georg A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Stracke, Sylvia A1 - Völker, Uwe A1 - Völzke, Henry A1 - Kovacs, Peter A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Aulchenko, Yurii S A1 - Polasek, Ozren A1 - Hastie, Nick A1 - Vitart, Veronique A1 - Helmer, Catherine A1 - Wang, Jie Jin A1 - Stengel, Bénédicte A1 - Ruggiero, Daniela A1 - Bergmann, Sven A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Nikopensius, Tiit A1 - Province, Michael A1 - Colhoun, Helen A1 - Doney, Alex A1 - Robino, Antonietta A1 - Krämer, Bernhard K A1 - Portas, Laura A1 - Ford, Ian A1 - Buckley, Brendan M A1 - Adam, Martin A1 - Thun, Gian-Andri A1 - Paulweber, Bernhard A1 - Haun, Margot A1 - Sala, Cinzia A1 - Mitchell, Paul A1 - Ciullo, Marina A1 - Vollenweider, Peter A1 - Raitakari, Olli A1 - Metspalu, Andres A1 - Palmer, Colin A1 - Gasparini, Paolo A1 - Pirastu, Mario A1 - Jukema, J Wouter A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Toniolo, Daniela A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Franke, Andre A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Prokopenko, Inga A1 - Witteman, Jacqueline A1 - Hayward, Caroline A1 - Ridker, Paul M A1 - Bochud, Murielle A1 - Heid, Iris M A1 - Siscovick, David S A1 - Fox, Caroline S A1 - Kao, W Linda A1 - Böger, Carsten A KW - Databases, Genetic KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Kidney KW - Mendelian Randomization Analysis KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Renal Insufficiency, Chronic AB -

Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

VL - 24 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24029420?dopt=Abstract ER - TY - JOUR T1 - Genetic loci for retinal arteriolar microcirculation. JF - PLoS One Y1 - 2013 A1 - Sim, Xueling A1 - Jensen, Richard A A1 - Ikram, M Kamran A1 - Cotch, Mary Frances A1 - Li, Xiaohui A1 - Macgregor, Stuart A1 - Xie, Jing A1 - Smith, Albert Vernon A1 - Boerwinkle, Eric A1 - Mitchell, Paul A1 - Klein, Ronald A1 - Klein, Barbara E K A1 - Glazer, Nicole L A1 - Lumley, Thomas A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - de Jong, Paulus T V M A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Harris, Tamara B A1 - Jonasson, Fridbert A1 - Launer, Lenore J A1 - Attia, John A1 - Baird, Paul N A1 - Harrap, Stephen A1 - Holliday, Elizabeth G A1 - Inouye, Michael A1 - Rochtchina, Elena A1 - Scott, Rodney J A1 - Viswanathan, Ananth A1 - Li, Guo A1 - Smith, Nicholas L A1 - Wiggins, Kerri L A1 - Kuo, Jane Z A1 - Taylor, Kent D A1 - Hewitt, Alex W A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - Sun, Cong A1 - Young, Terri L A1 - Mackey, David A A1 - van Zuydam, Natalie R A1 - Doney, Alex S F A1 - Palmer, Colin N A A1 - Morris, Andrew D A1 - Rotter, Jerome I A1 - Tai, E Shyong A1 - Gudnason, Vilmundur A1 - Vingerling, Johannes R A1 - Siscovick, David S A1 - Wang, Jie Jin A1 - Wong, Tien Y KW - Aged KW - Aged, 80 and over KW - Arterioles KW - Chromosomes, Human, Pair 5 KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - MEF2 Transcription Factors KW - Microcirculation KW - Middle Aged KW - Models, Genetic KW - Retinal Vessels AB -

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.

VL - 8 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23776548?dopt=Abstract ER - TY - JOUR T1 - Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis. JF - PLoS One Y1 - 2013 A1 - Holliday, Elizabeth G A1 - Smith, Albert V A1 - Cornes, Belinda K A1 - Buitendijk, Gabriëlle H S A1 - Jensen, Richard A A1 - Sim, Xueling A1 - Aspelund, Thor A1 - Aung, Tin A1 - Baird, Paul N A1 - Boerwinkle, Eric A1 - Cheng, Ching Yu A1 - van Duijn, Cornelia M A1 - Eiriksdottir, Gudny A1 - Gudnason, Vilmundur A1 - Harris, Tamara A1 - Hewitt, Alex W A1 - Inouye, Michael A1 - Jonasson, Fridbert A1 - Klein, Barbara E K A1 - Launer, Lenore A1 - Li, Xiaohui A1 - Liew, Gerald A1 - Lumley, Thomas A1 - McElduff, Patrick A1 - McKnight, Barbara A1 - Mitchell, Paul A1 - Psaty, Bruce M A1 - Rochtchina, Elena A1 - Rotter, Jerome I A1 - Scott, Rodney J A1 - Tay, Wanting A1 - Taylor, Kent A1 - Teo, Yik Ying A1 - Uitterlinden, André G A1 - Viswanathan, Ananth A1 - Xie, Sophia A1 - Vingerling, Johannes R A1 - Klaver, Caroline C W A1 - Tai, E Shyong A1 - Siscovick, David A1 - Klein, Ronald A1 - Cotch, Mary Frances A1 - Wong, Tien Y A1 - Attia, John A1 - Wang, Jie Jin KW - Apolipoproteins E KW - Complement Factor H KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Kruppel-Like Transcription Factors KW - Macular Degeneration KW - Nerve Tissue Proteins KW - Polymorphism, Single Nucleotide KW - Proteins KW - Risk Factors KW - Zinc Finger Protein Gli3 AB -

Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10(-6)) and upstream of GLI2 (rs6721654; P = 6.5×10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.

VL - 8 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23326517?dopt=Abstract ER - TY - JOUR T1 - Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium. JF - J Am Heart Assoc Y1 - 2013 A1 - Alonso, Alvaro A1 - Krijthe, Bouwe P A1 - Aspelund, Thor A1 - Stepas, Katherine A A1 - Pencina, Michael J A1 - Moser, Carlee B A1 - Sinner, Moritz F A1 - Sotoodehnia, Nona A1 - Fontes, João D A1 - Janssens, A Cecile J W A1 - Kronmal, Richard A A1 - Magnani, Jared W A1 - Witteman, Jacqueline C A1 - Chamberlain, Alanna M A1 - Lubitz, Steven A A1 - Schnabel, Renate B A1 - Agarwal, Sunil K A1 - McManus, David D A1 - Ellinor, Patrick T A1 - Larson, Martin G A1 - Burke, Gregory L A1 - Launer, Lenore J A1 - Hofman, Albert A1 - Levy, Daniel A1 - Gottdiener, John S A1 - Kääb, Stefan A1 - Couper, David A1 - Harris, Tamara B A1 - Soliman, Elsayed Z A1 - Stricker, Bruno H C A1 - Gudnason, Vilmundur A1 - Heckbert, Susan R A1 - Benjamin, Emelia J KW - African Americans KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Atrial Fibrillation KW - Cohort Studies KW - Diabetes Mellitus KW - European Continental Ancestry Group KW - Female KW - Heart Failure KW - Humans KW - Hypertension KW - Iceland KW - Incidence KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Netherlands KW - Proportional Hazards Models KW - Risk Assessment KW - Smoking KW - United States AB -

BACKGROUND: Tools for the prediction of atrial fibrillation (AF) may identify high-risk individuals more likely to benefit from preventive interventions and serve as a benchmark to test novel putative risk factors.

METHODS AND RESULTS: Individual-level data from 3 large cohorts in the United States (Atherosclerosis Risk in Communities [ARIC] study, the Cardiovascular Health Study [CHS], and the Framingham Heart Study [FHS]), including 18 556 men and women aged 46 to 94 years (19% African Americans, 81% whites) were pooled to derive predictive models for AF using clinical variables. Validation of the derived models was performed in 7672 participants from the Age, Gene and Environment-Reykjavik study (AGES) and the Rotterdam Study (RS). The analysis included 1186 incident AF cases in the derivation cohorts and 585 in the validation cohorts. A simple 5-year predictive model including the variables age, race, height, weight, systolic and diastolic blood pressure, current smoking, use of antihypertensive medication, diabetes, and history of myocardial infarction and heart failure had good discrimination (C-statistic, 0.765; 95% CI, 0.748 to 0.781). Addition of variables from the electrocardiogram did not improve the overall model discrimination (C-statistic, 0.767; 95% CI, 0.750 to 0.783; categorical net reclassification improvement, -0.0032; 95% CI, -0.0178 to 0.0113). In the validation cohorts, discrimination was acceptable (AGES C-statistic, 0.664; 95% CI, 0.632 to 0.697 and RS C-statistic, 0.705; 95% CI, 0.664 to 0.747) and calibration was adequate.

CONCLUSION: A risk model including variables readily available in primary care settings adequately predicted AF in diverse populations from the United States and Europe.

VL - 2 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23537808?dopt=Abstract ER - TY - JOUR T1 - B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies. JF - Europace Y1 - 2014 A1 - Sinner, Moritz F A1 - Stepas, Katherine A A1 - Moser, Carlee B A1 - Krijthe, Bouwe P A1 - Aspelund, Thor A1 - Sotoodehnia, Nona A1 - Fontes, João D A1 - Janssens, A Cecile J W A1 - Kronmal, Richard A A1 - Magnani, Jared W A1 - Witteman, Jacqueline C A1 - Chamberlain, Alanna M A1 - Lubitz, Steven A A1 - Schnabel, Renate B A1 - Vasan, Ramachandran S A1 - Wang, Thomas J A1 - Agarwal, Sunil K A1 - McManus, David D A1 - Franco, Oscar H A1 - Yin, Xiaoyan A1 - Larson, Martin G A1 - Burke, Gregory L A1 - Launer, Lenore J A1 - Hofman, Albert A1 - Levy, Daniel A1 - Gottdiener, John S A1 - Kääb, Stefan A1 - Couper, David A1 - Harris, Tamara B A1 - Astor, Brad C A1 - Ballantyne, Christie M A1 - Hoogeveen, Ron C A1 - Arai, Andrew E A1 - Soliman, Elsayed Z A1 - Ellinor, Patrick T A1 - Stricker, Bruno H C A1 - Gudnason, Vilmundur A1 - Heckbert, Susan R A1 - Pencina, Michael J A1 - Benjamin, Emelia J A1 - Alonso, Alvaro KW - Aged KW - Atrial Fibrillation KW - Biomarkers KW - C-Reactive Protein KW - Europe KW - Female KW - Humans KW - Incidence KW - Male KW - Natriuretic Peptide, Brain KW - Peptide Fragments KW - Predictive Value of Tests KW - Risk Assessment KW - Risk Factors KW - United States AB -

AIMS: B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information.

METHODS AND RESULTS: We ascertained AF incidence in 18 556 Whites and African Americans from the Atherosclerosis Risk in Communities Study (ARIC, n=10 675), Cardiovascular Health Study (CHS, n = 5043), and Framingham Heart Study (FHS, n = 2838), followed for 5 years (prediction horizon). We added BNP (ARIC/CHS: N-terminal pro-B-type natriuretic peptide; FHS: BNP), CRP, or both to a previously reported AF risk score, and assessed model calibration and predictive ability [C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI)]. We replicated models in two independent European cohorts: Age, Gene/Environment Susceptibility Reykjavik Study (AGES), n = 4467; Rotterdam Study (RS), n = 3203. B-type natriuretic peptide and CRP were significantly associated with AF incidence (n = 1186): hazard ratio per 1-SD ln-transformed biomarker 1.66 [95% confidence interval (CI), 1.56-1.76], P < 0.0001 and 1.18 (95% CI, 1.11-1.25), P < 0.0001, respectively. Model calibration was sufficient (BNP, χ(2) = 17.0; CRP, χ(2) = 10.5; BNP and CRP, χ(2) = 13.1). B-type natriuretic peptide improved the C-statistic from 0.765 to 0.790, yielded an IDI of 0.027 (95% CI, 0.022-0.032), a relative IDI of 41.5%, and a continuous NRI of 0.389 (95% CI, 0.322-0.455). The predictive ability of CRP was limited (C-statistic increment 0.003). B-type natriuretic peptide consistently improved prediction in AGES and RS.

CONCLUSION: B-type natriuretic peptide, not CRP, substantially improved AF risk prediction beyond clinical factors in an independently replicated, heterogeneous population. B-type natriuretic peptide may serve as a benchmark to evaluate novel putative AF risk biomarkers.

VL - 16 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25037055?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analysis identifies six new loci associated with forced vital capacity. JF - Nat Genet Y1 - 2014 A1 - Loth, Daan W A1 - Soler Artigas, Maria A1 - Gharib, Sina A A1 - Wain, Louise V A1 - Franceschini, Nora A1 - Koch, Beate A1 - Pottinger, Tess D A1 - Smith, Albert Vernon A1 - Duan, Qing A1 - Oldmeadow, Chris A1 - Lee, Mi Kyeong A1 - Strachan, David P A1 - James, Alan L A1 - Huffman, Jennifer E A1 - Vitart, Veronique A1 - Ramasamy, Adaikalavan A1 - Wareham, Nicholas J A1 - Kaprio, Jaakko A1 - Wang, Xin-Qun A1 - Trochet, Holly A1 - Kähönen, Mika A1 - Flexeder, Claudia A1 - Albrecht, Eva A1 - Lopez, Lorna M A1 - de Jong, Kim A1 - Thyagarajan, Bharat A1 - Alves, Alexessander Couto A1 - Enroth, Stefan A1 - Omenaas, Ernst A1 - Joshi, Peter K A1 - Fall, Tove A1 - Viñuela, Ana A1 - Launer, Lenore J A1 - Loehr, Laura R A1 - Fornage, Myriam A1 - Li, Guo A1 - Wilk, Jemma B A1 - Tang, Wenbo A1 - Manichaikul, Ani A1 - Lahousse, Lies A1 - Harris, Tamara B A1 - North, Kari E A1 - Rudnicka, Alicja R A1 - Hui, Jennie A1 - Gu, Xiangjun A1 - Lumley, Thomas A1 - Wright, Alan F A1 - Hastie, Nicholas D A1 - Campbell, Susan A1 - Kumar, Rajesh A1 - Pin, Isabelle A1 - Scott, Robert A A1 - Pietiläinen, Kirsi H A1 - Surakka, Ida A1 - Liu, Yongmei A1 - Holliday, Elizabeth G A1 - Schulz, Holger A1 - Heinrich, Joachim A1 - Davies, Gail A1 - Vonk, Judith M A1 - Wojczynski, Mary A1 - Pouta, Anneli A1 - Johansson, Asa A1 - Wild, Sarah H A1 - Ingelsson, Erik A1 - Rivadeneira, Fernando A1 - Völzke, Henry A1 - Hysi, Pirro G A1 - Eiriksdottir, Gudny A1 - Morrison, Alanna C A1 - Rotter, Jerome I A1 - Gao, Wei A1 - Postma, Dirkje S A1 - White, Wendy B A1 - Rich, Stephen S A1 - Hofman, Albert A1 - Aspelund, Thor A1 - Couper, David A1 - Smith, Lewis J A1 - Psaty, Bruce M A1 - Lohman, Kurt A1 - Burchard, Esteban G A1 - Uitterlinden, André G A1 - Garcia, Melissa A1 - Joubert, Bonnie R A1 - McArdle, Wendy L A1 - Musk, A Bill A1 - Hansel, Nadia A1 - Heckbert, Susan R A1 - Zgaga, Lina A1 - van Meurs, Joyce B J A1 - Navarro, Pau A1 - Rudan, Igor A1 - Oh, Yeon-Mok A1 - Redline, Susan A1 - Jarvis, Deborah L A1 - Zhao, Jing Hua A1 - Rantanen, Taina A1 - O'Connor, George T A1 - Ripatti, Samuli A1 - Scott, Rodney J A1 - Karrasch, Stefan A1 - Grallert, Harald A1 - Gaddis, Nathan C A1 - Starr, John M A1 - Wijmenga, Cisca A1 - Minster, Ryan L A1 - Lederer, David J A1 - Pekkanen, Juha A1 - Gyllensten, Ulf A1 - Campbell, Harry A1 - Morris, Andrew P A1 - Gläser, Sven A1 - Hammond, Christopher J A1 - Burkart, Kristin M A1 - Beilby, John A1 - Kritchevsky, Stephen B A1 - Gudnason, Vilmundur A1 - Hancock, Dana B A1 - Williams, O Dale A1 - Polasek, Ozren A1 - Zemunik, Tatijana A1 - Kolcic, Ivana A1 - Petrini, Marcy F A1 - Wjst, Matthias A1 - Kim, Woo Jin A1 - Porteous, David J A1 - Scotland, Generation A1 - Smith, Blair H A1 - Viljanen, Anne A1 - Heliövaara, Markku A1 - Attia, John R A1 - Sayers, Ian A1 - Hampel, Regina A1 - Gieger, Christian A1 - Deary, Ian J A1 - Boezen, H Marike A1 - Newman, Anne A1 - Jarvelin, Marjo-Riitta A1 - Wilson, James F A1 - Lind, Lars A1 - Stricker, Bruno H A1 - Teumer, Alexander A1 - Spector, Timothy D A1 - Melén, Erik A1 - Peters, Marjolein J A1 - Lange, Leslie A A1 - Barr, R Graham A1 - Bracke, Ken R A1 - Verhamme, Fien M A1 - Sung, Joohon A1 - Hiemstra, Pieter S A1 - Cassano, Patricia A A1 - Sood, Akshay A1 - Hayward, Caroline A1 - Dupuis, Josée A1 - Hall, Ian P A1 - Brusselle, Guy G A1 - Tobin, Martin D A1 - London, Stephanie J KW - Cohort Studies KW - Databases, Genetic KW - Follow-Up Studies KW - Forced Expiratory Volume KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Lung Diseases KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Prognosis KW - Quantitative Trait Loci KW - Respiratory Function Tests KW - Spirometry KW - Vital Capacity AB -

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

VL - 46 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24929828?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 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 - 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 proteomic analysis of atrial fibrillation in a prospective longitudinal cohort (AGES-Reykjavik study). JF - Europace Y1 - 2023 A1 - Jonmundsson, Thorarinn A1 - Steindorsdottir, Anna E A1 - Austin, Thomas R A1 - Frick, Elisabet A A1 - Axelsson, Gisli T A1 - Launer, Lenore A1 - Psaty, Bruce M A1 - Loureiro, Joseph A1 - Orth, Anthony P A1 - Aspelund, Thor A1 - Emilsson, Valur A1 - Floyd, James S A1 - Jennings, Lori A1 - Gudnason, Vilmundur A1 - Gudmundsdottir, Valborg KW - Atrial Fibrillation KW - Biomarkers KW - Endosomal Sorting Complexes Required for Transport KW - Humans KW - Natriuretic Peptide, Brain KW - Oxidoreductases Acting on Sulfur Group Donors KW - Peptide Fragments KW - Prognosis KW - Prospective Studies KW - Proteomics KW - Risk Factors AB -

AIMS: Atrial fibrillation (AF) is associated with high risk of comorbidities and mortality. Our aim was to examine causal and predictive relationships between 4137 serum proteins and incident AF in the prospective population-based Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik) study.

METHODS AND RESULTS: The study included 4765 participants, of whom 1172 developed AF. Cox proportional hazards regression models were fitted for 4137 baseline protein measurements adjusting for known risk factors. Protein associations were tested for replication in the Cardiovascular Health Study (CHS). Causal relationships were examined in a bidirectional, two-sample Mendelian randomization analysis. The time-dependent area under the receiver operating characteristic curve (AUC)-statistic was examined as protein levels and an AF-polygenic risk score (PRS) were added to clinical risk models. The proteomic signature of incident AF consisted of 76 proteins, of which 63 (83%) were novel and 29 (38%) were replicated in CHS. The signature included both N-terminal prohormone of brain natriuretic peptide (NT-proBNP)-dependent (e.g. CHST15, ATP1B1, and SVEP1) and independent components (e.g. ASPN, AKR1B, and LAMA1/LAMB1/LAMC1). Nine causal candidates were identified (TAGLN, WARS, CHST15, CHMP3, COL15A1, DUSP13, MANBA, QSOX2, and SRL). The reverse causal analysis suggested that most AF-associated proteins were affected by the genetic liability to AF. N-terminal prohormone of brain natriuretic peptide improved the prediction of incident AF events close to baseline with further improvements gained by the AF-PRS at all time points.

CONCLUSION: The AF proteomic signature includes biologically relevant proteins, some of which may be causal. It mainly reflects an NT-proBNP-dependent consequence of the genetic liability to AF. N-terminal prohormone of brain natriuretic peptide is a promising marker for incident AF in the short term, but risk assessment incorporating a PRS may improve long-term risk assessment.

VL - 25 IS - 11 ER - TY - JOUR T1 - Proteomic prediction of incident heart failure and its main subtypes. JF - Eur J Heart Fail Y1 - 2023 A1 - Emilsson, Valur A1 - Jonsson, Brynjolfur G A1 - Austin, Thomas R A1 - Gudmundsdottir, Valborg A1 - Axelsson, Gisli T A1 - Frick, Elisabet A A1 - Jonmundsson, Thorarinn A1 - Steindorsdottir, Anna E A1 - Loureiro, Joseph A1 - Brody, Jennifer A A1 - Aspelund, Thor A1 - Launer, Lenore J A1 - Thorgeirsson, Gudmundur A1 - Kortekaas, Kirsten A A1 - Lindeman, Jan H A1 - Orth, Anthony P A1 - Lamb, John R A1 - Psaty, Bruce M A1 - Kizer, Jorge R A1 - Jennings, Lori L A1 - Gudnason, Vilmundur AB -

AIM: To examine the ability of serum proteins in predicting future heart failure (HF) events, including HF with reduced or preserved ejection fraction (HFrEF or HFpEF), in relation to event time, and with or without considering established HF-associated clinical variables.

METHODS AND RESULTS: In the prospective population-based Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS), 440 individuals developed HF after their first visit with a median follow-up of 5.45 years. Among them, 167 were diagnosed with HFrEF and 188 with HFpEF. A least absolute shrinkage and selection operator regression model with nonparametric bootstrap were used to select predictors from an analysis of 4782 serum proteins, and several pre-established clinical parameters linked to HF. A subset of 8-10 distinct or overlapping serum proteins predicted different future HF outcomes, and C-statistics were used to assess discrimination, revealing proteins combined with a C-index of 0.80 for all incident HF, 0.78 and 0.80 for incident HFpEF or HFrEF, respectively. In the AGES-RS, protein panels alone encompassed the risk contained in the clinical information and improved the performance characteristics of prediction models based on NT-proBNP and clinical risk factors. Finally, the protein predictors performed particularly well close to the time of an HF event, an outcome that was replicated in the Cardiovascular Health Study (CHS).

CONCLUSION: A small number of circulating proteins accurately predicted future HF in the AGES-RS cohort of older adults, and they alone encompass the risk information found in a collection of clinical data. Incident HF events were predicted up to eight years, with predictor performance significantly improving for events occurring less than one year ahead, a finding replicated in an external cohort study. This article is protected by copyright. All rights reserved.

ER -