TY - JOUR T1 - Genetic predictors of fibrin D-dimer levels in healthy adults. JF - Circulation Y1 - 2011 A1 - Smith, Nicholas L A1 - Huffman, Jennifer E A1 - Strachan, David P A1 - Huang, Jie A1 - Dehghan, Abbas A1 - Trompet, Stella A1 - Lopez, Lorna M A1 - Shin, So-Youn A1 - Baumert, Jens A1 - Vitart, Veronique A1 - Bis, Joshua C A1 - Wild, Sarah H A1 - Rumley, Ann A1 - Yang, Qiong A1 - Uitterlinden, André G A1 - Stott, David J A1 - Davies, Gail A1 - Carter, Angela M A1 - Thorand, Barbara A1 - Polasek, Ozren A1 - McKnight, Barbara A1 - Campbell, Harry A1 - Rudnicka, Alicja R A1 - Chen, Ming-Huei A1 - Buckley, Brendan M A1 - Harris, Sarah E A1 - Peters, Annette A1 - Pulanic, Drazen A1 - Lumley, Thomas A1 - de Craen, Anton J M A1 - Liewald, David C A1 - Gieger, Christian A1 - Campbell, Susan A1 - Ford, Ian A1 - Gow, Alan J A1 - Luciano, Michelle A1 - Porteous, David J A1 - Guo, Xiuqing A1 - Sattar, Naveed A1 - Tenesa, Albert A1 - Cushman, Mary A1 - Slagboom, P Eline A1 - Visscher, Peter M A1 - Spector, Tim D A1 - Illig, Thomas A1 - Rudan, Igor A1 - Bovill, Edwin G A1 - Wright, Alan F A1 - McArdle, Wendy L A1 - Tofler, Geoffrey A1 - Hofman, Albert A1 - Westendorp, Rudi G J A1 - Starr, John M A1 - Grant, Peter J A1 - Karakas, Mahir A1 - Hastie, Nicholas D A1 - Psaty, Bruce M A1 - Wilson, James F A1 - Lowe, Gordon D O A1 - O'Donnell, Christopher J A1 - Witteman, Jacqueline C M A1 - Jukema, J Wouter A1 - Deary, Ian J A1 - Soranzo, Nicole A1 - Koenig, Wolfgang A1 - Hayward, Caroline KW - Adult KW - Aged KW - Blood Coagulation KW - European Continental Ancestry Group KW - Factor V KW - Female KW - Fibrin Fibrinogen Degradation Products KW - Fibrinogen KW - Genetic Testing KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Reference Values KW - Thromboplastin AB -

BACKGROUND: Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search.

METHODS AND RESULTS: A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ≈2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log–transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (P=6.4×10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4×10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9×10(-18)) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log–transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus.

CONCLUSIONS: Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.

VL - 123 IS - 17 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21502573?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 - New gene functions in megakaryopoiesis and platelet formation. JF - Nature Y1 - 2011 A1 - Gieger, Christian A1 - Radhakrishnan, Aparna A1 - Cvejic, Ana A1 - Tang, Weihong A1 - Porcu, Eleonora A1 - Pistis, Giorgio A1 - Serbanovic-Canic, Jovana A1 - Elling, Ulrich A1 - Goodall, Alison H A1 - Labrune, Yann A1 - Lopez, Lorna M A1 - Mägi, Reedik A1 - Meacham, Stuart A1 - Okada, Yukinori A1 - Pirastu, Nicola A1 - Sorice, Rossella A1 - Teumer, Alexander A1 - Voss, Katrin A1 - Zhang, Weihua A1 - Ramirez-Solis, Ramiro A1 - Bis, Joshua C A1 - Ellinghaus, David A1 - Gögele, Martin A1 - Hottenga, Jouke-Jan A1 - Langenberg, Claudia A1 - Kovacs, Peter A1 - O'Reilly, Paul F A1 - Shin, So-Youn A1 - Esko, Tõnu A1 - Hartiala, Jaana A1 - Kanoni, Stavroula A1 - Murgia, Federico A1 - Parsa, Afshin A1 - Stephens, Jonathan A1 - van der Harst, Pim A1 - Ellen van der Schoot, C A1 - Allayee, Hooman A1 - Attwood, Antony A1 - Balkau, Beverley A1 - Bastardot, François A1 - Basu, Saonli A1 - Baumeister, Sebastian E A1 - Biino, Ginevra A1 - Bomba, Lorenzo A1 - Bonnefond, Amélie A1 - Cambien, Francois A1 - Chambers, John C A1 - Cucca, Francesco A1 - D'Adamo, Pio A1 - Davies, Gail A1 - de Boer, Rudolf A A1 - de Geus, Eco J C A1 - Döring, Angela A1 - Elliott, Paul A1 - Erdmann, Jeanette A1 - Evans, David M A1 - Falchi, Mario A1 - Feng, Wei A1 - Folsom, Aaron R A1 - Frazer, Ian H A1 - Gibson, Quince D A1 - Glazer, Nicole L A1 - Hammond, Chris A1 - Hartikainen, Anna-Liisa A1 - Heckbert, Susan R A1 - Hengstenberg, Christian A1 - Hersch, Micha A1 - Illig, Thomas A1 - Loos, Ruth J F A1 - Jolley, Jennifer A1 - Khaw, Kay Tee A1 - Kuhnel, Brigitte A1 - Kyrtsonis, Marie-Christine A1 - Lagou, Vasiliki A1 - Lloyd-Jones, Heather A1 - Lumley, Thomas A1 - Mangino, Massimo A1 - Maschio, Andrea A1 - Mateo Leach, Irene A1 - McKnight, Barbara A1 - Memari, Yasin A1 - Mitchell, Braxton D A1 - Montgomery, Grant W A1 - Nakamura, Yusuke A1 - Nauck, Matthias A1 - Navis, Gerjan A1 - Nöthlings, Ute A1 - Nolte, Ilja M A1 - Porteous, David J A1 - Pouta, Anneli A1 - Pramstaller, Peter P A1 - Pullat, Janne A1 - Ring, Susan M A1 - Rotter, Jerome I A1 - Ruggiero, Daniela A1 - Ruokonen, Aimo A1 - Sala, Cinzia A1 - Samani, Nilesh J A1 - Sambrook, Jennifer A1 - Schlessinger, David A1 - Schreiber, Stefan A1 - Schunkert, Heribert A1 - Scott, James A1 - Smith, Nicholas L A1 - Snieder, Harold A1 - Starr, John M A1 - Stumvoll, Michael A1 - Takahashi, Atsushi A1 - Tang, W H Wilson A1 - Taylor, Kent A1 - Tenesa, Albert A1 - Lay Thein, Swee A1 - Tönjes, Anke A1 - Uda, Manuela A1 - Ulivi, Sheila A1 - van Veldhuisen, Dirk J A1 - Visscher, Peter M A1 - Völker, Uwe A1 - Wichmann, H-Erich A1 - Wiggins, Kerri L A1 - Willemsen, Gonneke A1 - Yang, Tsun-Po A1 - Hua Zhao, Jing A1 - Zitting, Paavo A1 - Bradley, John R A1 - Dedoussis, George V A1 - Gasparini, Paolo A1 - Hazen, Stanley L A1 - Metspalu, Andres A1 - Pirastu, Mario A1 - Shuldiner, Alan R A1 - Joost van Pelt, L A1 - Zwaginga, Jaap-Jan A1 - Boomsma, Dorret I A1 - Deary, Ian J A1 - Franke, Andre A1 - Froguel, Philippe A1 - Ganesh, Santhi K A1 - Jarvelin, Marjo-Riitta A1 - Martin, Nicholas G A1 - Meisinger, Christa A1 - Psaty, Bruce M A1 - Spector, Timothy D A1 - Wareham, Nicholas J A1 - Akkerman, Jan-Willem N A1 - Ciullo, Marina A1 - Deloukas, Panos A1 - Greinacher, Andreas A1 - Jupe, Steve A1 - Kamatani, Naoyuki A1 - Khadake, Jyoti A1 - Kooner, Jaspal S A1 - Penninger, Josef A1 - Prokopenko, Inga A1 - Stemple, Derek A1 - Toniolo, Daniela A1 - Wernisch, Lorenz A1 - Sanna, Serena A1 - Hicks, Andrew A A1 - Rendon, Augusto A1 - Ferreira, Manuel A A1 - Ouwehand, Willem H A1 - Soranzo, Nicole KW - Animals KW - Blood Platelets KW - Cell Size KW - Drosophila melanogaster KW - Drosophila Proteins KW - Europe KW - Gene Expression Profiling KW - Gene Silencing KW - Genome, Human KW - Genome-Wide Association Study KW - Hematopoiesis KW - Humans KW - Megakaryocytes KW - Platelet Count KW - Protein Interaction Maps KW - Transcription, Genetic KW - Zebrafish KW - Zebrafish Proteins AB -

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.

VL - 480 IS - 7376 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22139419?dopt=Abstract ER - TY - JOUR T1 - Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies. JF - Lancet Neurol Y1 - 2012 A1 - Traylor, Matthew A1 - Farrall, Martin A1 - Holliday, Elizabeth G A1 - Sudlow, Cathie A1 - Hopewell, Jemma C A1 - Cheng, Yu-Ching A1 - Fornage, Myriam A1 - Ikram, M Arfan A1 - Malik, Rainer A1 - Bevan, Steve A1 - Thorsteinsdottir, Unnur A1 - Nalls, Mike A A1 - Longstreth, Wt A1 - Wiggins, Kerri L A1 - Yadav, Sunaina A1 - Parati, Eugenio A A1 - DeStefano, Anita L A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Khan, Muhammad Saleem A1 - Reiner, Alex P A1 - Helgadottir, Anna A1 - Achterberg, Sefanja A1 - Fernandez-Cadenas, Israel A1 - Abboud, Sherine A1 - Schmidt, Reinhold A1 - Walters, Matthew A1 - Chen, Wei-Min A1 - Ringelstein, E Bernd A1 - O'Donnell, Martin A1 - Ho, Weang Kee A1 - Pera, Joanna A1 - Lemmens, Robin A1 - Norrving, Bo A1 - Higgins, Peter A1 - Benn, Marianne A1 - Sale, Michele A1 - Kuhlenbäumer, Gregor A1 - Doney, Alexander S F A1 - Vicente, Astrid M A1 - Delavaran, Hossein A1 - Algra, Ale A1 - Davies, Gail A1 - Oliveira, Sofia A A1 - Palmer, Colin N A A1 - Deary, Ian A1 - Schmidt, Helena A1 - Pandolfo, Massimo A1 - Montaner, Joan A1 - Carty, Cara A1 - de Bakker, Paul I W A1 - Kostulas, Konstantinos A1 - Ferro, Jose M A1 - van Zuydam, Natalie R A1 - Valdimarsson, Einar A1 - Nordestgaard, Børge G A1 - Lindgren, Arne A1 - Thijs, Vincent A1 - Slowik, Agnieszka A1 - Saleheen, Danish A1 - Paré, Guillaume A1 - Berger, Klaus A1 - Thorleifsson, Gudmar A1 - Hofman, Albert A1 - Mosley, Thomas H A1 - Mitchell, Braxton D A1 - Furie, Karen A1 - Clarke, Robert A1 - Levi, Christopher A1 - Seshadri, Sudha A1 - Gschwendtner, Andreas A1 - Boncoraglio, Giorgio B A1 - Sharma, Pankaj A1 - Bis, Joshua C A1 - Gretarsdottir, Solveig A1 - Psaty, Bruce M A1 - Rothwell, Peter M A1 - Rosand, Jonathan A1 - Meschia, James F A1 - Stefansson, Kari A1 - Dichgans, Martin A1 - Markus, Hugh S KW - Brain Ischemia KW - Databases, Genetic KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Risk Factors KW - Stroke AB -

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

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

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

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

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

VL - 11 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23041239?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. JF - Am J Respir Crit Care Med Y1 - 2012 A1 - Wilk, Jemma B A1 - Shrine, Nick R G A1 - Loehr, Laura R A1 - Zhao, Jing Hua A1 - Manichaikul, Ani A1 - Lopez, Lorna M A1 - Smith, Albert Vernon A1 - Heckbert, Susan R A1 - Smolonska, Joanna A1 - Tang, Wenbo A1 - Loth, Daan W A1 - Curjuric, Ivan A1 - Hui, Jennie A1 - Cho, Michael H A1 - Latourelle, Jeanne C A1 - Henry, Amanda P A1 - Aldrich, Melinda A1 - Bakke, Per A1 - Beaty, Terri H A1 - Bentley, Amy R A1 - Borecki, Ingrid B A1 - Brusselle, Guy G A1 - Burkart, Kristin M A1 - Chen, Ting-Hsu A1 - Couper, David A1 - Crapo, James D A1 - Davies, Gail A1 - Dupuis, Josée A1 - Franceschini, Nora A1 - Gulsvik, Amund A1 - Hancock, Dana B A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Imboden, Medea A1 - James, Alan L A1 - Khaw, Kay-Tee A1 - Lahousse, Lies A1 - Launer, Lenore J A1 - Litonjua, Augusto A1 - Liu, Yongmei A1 - Lohman, Kurt K A1 - Lomas, David A A1 - Lumley, Thomas A1 - Marciante, Kristin D A1 - McArdle, Wendy L A1 - Meibohm, Bernd A1 - Morrison, Alanna C A1 - Musk, Arthur W A1 - Myers, Richard H A1 - North, Kari E A1 - Postma, Dirkje S A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Rivadeneira, Fernando A1 - Rochat, Thierry A1 - Rotter, Jerome I A1 - Soler Artigas, Maria A1 - Starr, John M A1 - Uitterlinden, André G A1 - Wareham, Nicholas J A1 - Wijmenga, Cisca A1 - Zanen, Pieter A1 - Province, Michael A A1 - Silverman, Edwin K A1 - Deary, Ian J A1 - Palmer, Lyle J A1 - Cassano, Patricia A A1 - Gudnason, Vilmundur A1 - Barr, R Graham A1 - Loos, Ruth J F A1 - Strachan, David P A1 - London, Stephanie J A1 - Boezen, H Marike A1 - Probst-Hensch, Nicole A1 - Gharib, Sina A A1 - Hall, Ian P A1 - O'Connor, George T A1 - Tobin, Martin D A1 - Stricker, Bruno H KW - Aged KW - Female KW - Forced Expiratory Volume KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Nerve Tissue Proteins KW - Polymorphism, Single Nucleotide KW - Pulmonary Disease, Chronic Obstructive KW - Receptors, Nicotinic KW - Receptors, Serotonin, 5-HT4 KW - Smoking KW - Vital Capacity AB -

RATIONALE: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.

OBJECTIVES: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases.

METHODS: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV(1) and its ratio to FVC (FEV(1)/FVC) both less than their respective lower limits of normal as determined by published reference equations.

MEASUREMENTS AND MAIN RESULTS: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis.

CONCLUSIONS: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.

VL - 186 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22837378?dopt=Abstract 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 - Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. JF - Nat Genet Y1 - 2013 A1 - Köttgen, Anna A1 - Albrecht, Eva A1 - Teumer, Alexander A1 - Vitart, Veronique A1 - Krumsiek, Jan A1 - Hundertmark, Claudia A1 - Pistis, Giorgio A1 - Ruggiero, Daniela A1 - O'Seaghdha, Conall M A1 - Haller, Toomas A1 - Yang, Qiong A1 - Tanaka, Toshiko A1 - Johnson, Andrew D A1 - Kutalik, Zoltán A1 - Smith, Albert V A1 - Shi, Julia A1 - Struchalin, Maksim A1 - Middelberg, Rita P S A1 - Brown, Morris J A1 - Gaffo, Angelo L A1 - Pirastu, Nicola A1 - Li, Guo A1 - Hayward, Caroline A1 - Zemunik, Tatijana A1 - Huffman, Jennifer A1 - Yengo, Loic A1 - Zhao, Jing Hua A1 - Demirkan, Ayse A1 - Feitosa, Mary F A1 - Liu, Xuan A1 - Malerba, Giovanni A1 - Lopez, Lorna M A1 - van der Harst, Pim A1 - Li, Xinzhong A1 - Kleber, Marcus E A1 - Hicks, Andrew A A1 - Nolte, Ilja M A1 - Johansson, Asa A1 - Murgia, Federico A1 - Wild, Sarah H A1 - Bakker, Stephan J L A1 - Peden, John F A1 - Dehghan, Abbas A1 - Steri, Maristella A1 - Tenesa, Albert A1 - Lagou, Vasiliki A1 - Salo, Perttu A1 - Mangino, Massimo A1 - Rose, Lynda M A1 - Lehtimäki, Terho A1 - Woodward, Owen M A1 - Okada, Yukinori A1 - Tin, Adrienne A1 - Müller, Christian A1 - Oldmeadow, Christopher A1 - Putku, Margus A1 - Czamara, Darina A1 - Kraft, Peter A1 - Frogheri, Laura A1 - Thun, Gian Andri A1 - Grotevendt, Anne A1 - Gislason, Gauti Kjartan A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - McArdle, Patrick A1 - Shuldiner, Alan R A1 - Boerwinkle, Eric A1 - Coresh, Josef A1 - Schmidt, Helena A1 - Schallert, Michael A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - Kubo, Michiaki A1 - Nakamura, Yusuke A1 - Tanaka, Toshihiro A1 - Munroe, Patricia B A1 - Samani, Nilesh J A1 - Jacobs, David R A1 - Liu, Kiang A1 - D'Adamo, Pio A1 - Ulivi, Sheila A1 - Rotter, Jerome I A1 - Psaty, Bruce M A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Campbell, Susan A1 - Devuyst, Olivier A1 - Navarro, Pau A1 - Kolcic, Ivana A1 - Hastie, Nicholas A1 - Balkau, Beverley A1 - Froguel, Philippe A1 - Esko, Tõnu A1 - Salumets, Andres A1 - Khaw, Kay Tee A1 - Langenberg, Claudia A1 - Wareham, Nicholas J A1 - Isaacs, Aaron A1 - Kraja, Aldi A1 - Zhang, Qunyuan A1 - Wild, Philipp S A1 - Scott, Rodney J A1 - Holliday, Elizabeth G A1 - Org, Elin A1 - Viigimaa, Margus A1 - Bandinelli, Stefania A1 - Metter, Jeffrey E A1 - Lupo, Antonio A1 - Trabetti, Elisabetta A1 - Sorice, Rossella A1 - Döring, Angela A1 - Lattka, Eva A1 - Strauch, Konstantin A1 - Theis, Fabian A1 - Waldenberger, Melanie A1 - Wichmann, H-Erich A1 - Davies, Gail A1 - Gow, Alan J A1 - Bruinenberg, Marcel A1 - Stolk, Ronald P A1 - Kooner, Jaspal S A1 - Zhang, Weihua A1 - Winkelmann, Bernhard R A1 - Boehm, Bernhard O A1 - Lucae, Susanne A1 - Penninx, Brenda W A1 - Smit, Johannes H A1 - Curhan, Gary A1 - Mudgal, Poorva A1 - Plenge, Robert M A1 - Portas, Laura A1 - Persico, Ivana A1 - Kirin, Mirna A1 - Wilson, James F A1 - Mateo Leach, Irene A1 - van Gilst, Wiek H A1 - Goel, Anuj A1 - Ongen, Halit A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Imboden, Medea A1 - von Eckardstein, Arnold A1 - Cucca, Francesco A1 - Nagaraja, Ramaiah A1 - Piras, Maria Grazia A1 - Nauck, Matthias A1 - Schurmann, Claudia A1 - Budde, Kathrin A1 - Ernst, Florian A1 - Farrington, Susan M A1 - Theodoratou, Evropi A1 - Prokopenko, Inga A1 - Stumvoll, Michael A1 - Jula, Antti A1 - Perola, Markus A1 - Salomaa, Veikko A1 - Shin, So-Youn A1 - Spector, Tim D A1 - Sala, Cinzia A1 - Ridker, Paul M A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Hengstenberg, Christian A1 - Nelson, Christopher P A1 - Meschia, James F A1 - Nalls, Michael A A1 - Sharma, Pankaj A1 - Singleton, Andrew B A1 - Kamatani, Naoyuki A1 - Zeller, Tanja A1 - Burnier, Michel A1 - Attia, John A1 - Laan, Maris A1 - Klopp, Norman A1 - Hillege, Hans L A1 - Kloiber, Stefan A1 - Choi, Hyon A1 - Pirastu, Mario A1 - Tore, Silvia A1 - Probst-Hensch, Nicole M A1 - Völzke, Henry A1 - Gudnason, Vilmundur A1 - Parsa, Afshin A1 - Schmidt, Reinhold A1 - Whitfield, John B A1 - Fornage, Myriam A1 - Gasparini, Paolo A1 - Siscovick, David S A1 - Polasek, Ozren A1 - Campbell, Harry A1 - Rudan, Igor A1 - Bouatia-Naji, Nabila A1 - Metspalu, Andres A1 - Loos, Ruth J F A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid B A1 - Ferrucci, Luigi A1 - Gambaro, Giovanni A1 - Deary, Ian J A1 - Wolffenbuttel, Bruce H R A1 - Chambers, John C A1 - März, Winfried A1 - Pramstaller, Peter P A1 - Snieder, Harold A1 - Gyllensten, Ulf A1 - Wright, Alan F A1 - Navis, Gerjan A1 - Watkins, Hugh A1 - Witteman, Jacqueline C M A1 - Sanna, Serena A1 - Schipf, Sabine A1 - Dunlop, Malcolm G A1 - Tönjes, Anke A1 - Ripatti, Samuli A1 - Soranzo, Nicole A1 - Toniolo, Daniela A1 - Chasman, Daniel I A1 - Raitakari, Olli A1 - Kao, W H Linda A1 - Ciullo, Marina A1 - Fox, Caroline S A1 - Caulfield, Mark A1 - Bochud, Murielle A1 - Gieger, Christian KW - Analysis of Variance KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Loci KW - Genome-Wide Association Study KW - Glucose KW - Gout KW - Humans KW - Inhibins KW - Polymorphism, Single Nucleotide KW - Signal Transduction KW - Uric Acid AB -

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

VL - 45 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23263486?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations. JF - PLoS Genet Y1 - 2013 A1 - O'Seaghdha, Conall M A1 - Wu, Hongsheng A1 - Yang, Qiong A1 - Kapur, Karen A1 - Guessous, Idris A1 - Zuber, Annie Mercier A1 - Köttgen, Anna A1 - Stoudmann, Candice A1 - Teumer, Alexander A1 - Kutalik, Zoltán A1 - Mangino, Massimo A1 - Dehghan, Abbas A1 - Zhang, Weihua A1 - Eiriksdottir, Gudny A1 - Li, Guo A1 - Tanaka, Toshiko A1 - Portas, Laura A1 - Lopez, Lorna M A1 - Hayward, Caroline A1 - Lohman, Kurt A1 - Matsuda, Koichi A1 - Padmanabhan, Sandosh A1 - Firsov, Dmitri A1 - Sorice, Rossella A1 - Ulivi, Sheila A1 - Brockhaus, A Catharina A1 - Kleber, Marcus E A1 - Mahajan, Anubha A1 - Ernst, Florian D A1 - Gudnason, Vilmundur A1 - Launer, Lenore J A1 - Mace, Aurelien A1 - Boerwinckle, Eric A1 - Arking, Dan E A1 - Tanikawa, Chizu A1 - Nakamura, Yusuke A1 - Brown, Morris J A1 - Gaspoz, Jean-Michel A1 - Theler, Jean-Marc A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Bergmann, Sven A1 - Vollenweider, Peter A1 - Vitart, Veronique A1 - Wright, Alan F A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Kolcic, Ivana A1 - Navarro, Pau A1 - Brown, Edward M A1 - Estrada, Karol A1 - Ding, Jingzhong A1 - Harris, Tamara B A1 - Bandinelli, Stefania A1 - Hernandez, Dena A1 - Singleton, Andrew B A1 - Girotto, Giorgia A1 - Ruggiero, Daniela A1 - d'Adamo, Adamo Pio A1 - Robino, Antonietta A1 - Meitinger, Thomas A1 - Meisinger, Christa A1 - Davies, Gail A1 - Starr, John M A1 - Chambers, John C A1 - Boehm, Bernhard O A1 - Winkelmann, Bernhard R A1 - Huang, Jie A1 - Murgia, Federico A1 - Wild, Sarah H A1 - Campbell, Harry A1 - Morris, Andrew P A1 - Franco, Oscar H A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Völker, Uwe A1 - Hannemann, Anke A1 - Biffar, Reiner A1 - Hoffmann, Wolfgang A1 - Shin, So-Youn A1 - Lescuyer, Pierre A1 - Henry, Hughes A1 - Schurmann, Claudia A1 - Munroe, Patricia B A1 - Gasparini, Paolo A1 - Pirastu, Nicola A1 - Ciullo, Marina A1 - Gieger, Christian A1 - März, Winfried A1 - Lind, Lars A1 - Spector, Tim D A1 - Smith, Albert V A1 - Rudan, Igor A1 - Wilson, James F A1 - Polasek, Ozren A1 - Deary, Ian J A1 - Pirastu, Mario A1 - Ferrucci, Luigi A1 - Liu, Yongmei A1 - Kestenbaum, Bryan A1 - Kooner, Jaspal S A1 - Witteman, Jacqueline C M A1 - Nauck, Matthias A1 - Kao, W H Linda A1 - Wallaschofski, Henri A1 - Bonny, Olivier A1 - Fox, Caroline S A1 - Bochud, Murielle KW - Animals KW - Bone and Bones KW - Bone Density KW - Calcium KW - European Continental Ancestry Group KW - Gene Expression Regulation KW - Genome-Wide Association Study KW - Homeostasis KW - Humans KW - Kidney KW - Mice KW - Polymorphism, Single Nucleotide AB -

Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.

VL - 9 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24068962?dopt=Abstract ER - TY - JOUR T1 - A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. JF - PLoS Genet Y1 - 2013 A1 - Porcu, Eleonora A1 - Medici, Marco A1 - Pistis, Giorgio A1 - Volpato, Claudia B A1 - Wilson, Scott G A1 - Cappola, Anne R A1 - Bos, Steffan D A1 - Deelen, Joris A1 - den Heijer, Martin A1 - Freathy, Rachel M A1 - Lahti, Jari A1 - Liu, Chunyu A1 - Lopez, Lorna M A1 - Nolte, Ilja M A1 - O'Connell, Jeffrey R A1 - Tanaka, Toshiko A1 - Trompet, Stella A1 - Arnold, Alice A1 - Bandinelli, Stefania A1 - Beekman, Marian A1 - Böhringer, Stefan A1 - Brown, Suzanne J A1 - Buckley, Brendan M A1 - Camaschella, Clara A1 - de Craen, Anton J M A1 - Davies, Gail A1 - de Visser, Marieke C H A1 - Ford, Ian A1 - Forsen, Tom A1 - Frayling, Timothy M A1 - Fugazzola, Laura A1 - Gögele, Martin A1 - Hattersley, Andrew T A1 - Hermus, Ad R A1 - Hofman, Albert A1 - Houwing-Duistermaat, Jeanine J A1 - Jensen, Richard A A1 - Kajantie, Eero A1 - Kloppenburg, Margreet A1 - Lim, Ee M A1 - Masciullo, Corrado A1 - Mariotti, Stefano A1 - Minelli, Cosetta A1 - Mitchell, Braxton D A1 - Nagaraja, Ramaiah A1 - Netea-Maier, Romana T A1 - Palotie, Aarno A1 - Persani, Luca A1 - Piras, Maria G A1 - Psaty, Bruce M A1 - Räikkönen, Katri A1 - Richards, J Brent A1 - Rivadeneira, Fernando A1 - Sala, Cinzia A1 - Sabra, Mona M A1 - Sattar, Naveed A1 - Shields, Beverley M A1 - Soranzo, Nicole A1 - Starr, John M A1 - Stott, David J A1 - Sweep, Fred C G J A1 - Usala, Gianluca A1 - van der Klauw, Melanie M A1 - van Heemst, Diana A1 - van Mullem, Alies A1 - Vermeulen, Sita H A1 - Visser, W Edward A1 - Walsh, John P A1 - Westendorp, Rudi G J A1 - Widen, Elisabeth A1 - Zhai, Guangju A1 - Cucca, Francesco A1 - Deary, Ian J A1 - Eriksson, Johan G A1 - Ferrucci, Luigi A1 - Fox, Caroline S A1 - Jukema, J Wouter A1 - Kiemeney, Lambertus A A1 - Pramstaller, Peter P A1 - Schlessinger, David A1 - Shuldiner, Alan R A1 - Slagboom, Eline P A1 - Uitterlinden, André G A1 - Vaidya, Bijay A1 - Visser, Theo J A1 - Wolffenbuttel, Bruce H R A1 - Meulenbelt, Ingrid A1 - Rotter, Jerome I A1 - Spector, Tim D A1 - Hicks, Andrew A A1 - Toniolo, Daniela A1 - Sanna, Serena A1 - Peeters, Robin P A1 - Naitza, Silvia KW - Female KW - Genome-Wide Association Study KW - Humans KW - Hyperthyroidism KW - Hypothyroidism KW - Male KW - Phenotype KW - Polymorphism, Genetic KW - Polymorphism, Single Nucleotide KW - Sex Characteristics KW - Signal Transduction KW - Thyroid Gland KW - Thyrotropin KW - Thyroxine AB -

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

VL - 9 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23408906?dopt=Abstract ER - TY - JOUR T1 - Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. JF - Circulation Y1 - 2013 A1 - Sabater-Lleal, Maria A1 - Huang, Jie A1 - Chasman, Daniel A1 - Naitza, Silvia A1 - Dehghan, Abbas A1 - Johnson, Andrew D A1 - Teumer, Alexander A1 - Reiner, Alex P A1 - Folkersen, Lasse A1 - Basu, Saonli A1 - Rudnicka, Alicja R A1 - Trompet, Stella A1 - Mälarstig, Anders A1 - Baumert, Jens A1 - Bis, Joshua C A1 - Guo, Xiuqing A1 - Hottenga, Jouke J A1 - Shin, So-Youn A1 - Lopez, Lorna M A1 - Lahti, Jari A1 - Tanaka, Toshiko A1 - Yanek, Lisa R A1 - Oudot-Mellakh, Tiphaine A1 - Wilson, James F A1 - Navarro, Pau A1 - Huffman, Jennifer E A1 - Zemunik, Tatijana A1 - Redline, Susan A1 - Mehra, Reena A1 - Pulanic, Drazen A1 - Rudan, Igor A1 - Wright, Alan F A1 - Kolcic, Ivana A1 - Polasek, Ozren A1 - Wild, Sarah H A1 - Campbell, Harry A1 - Curb, J David A1 - Wallace, Robert A1 - Liu, Simin A1 - Eaton, Charles B A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Bandinelli, Stefania A1 - Räikkönen, Katri A1 - Widen, Elisabeth A1 - Palotie, Aarno A1 - Fornage, Myriam A1 - Green, David A1 - Gross, Myron A1 - Davies, Gail A1 - Harris, Sarah E A1 - Liewald, David C A1 - Starr, John M A1 - Williams, Frances M K A1 - Grant, Peter J A1 - Spector, Timothy D A1 - Strawbridge, Rona J A1 - Silveira, Angela A1 - Sennblad, Bengt A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Franco, Oscar H A1 - Hofman, Albert A1 - van Dongen, Jenny A1 - Willemsen, Gonneke A1 - Boomsma, Dorret I A1 - Yao, Jie A1 - Swords Jenny, Nancy A1 - Haritunians, Talin A1 - McKnight, Barbara A1 - Lumley, Thomas A1 - Taylor, Kent D A1 - Rotter, Jerome I A1 - Psaty, Bruce M A1 - Peters, Annette A1 - Gieger, Christian A1 - Illig, Thomas A1 - Grotevendt, Anne A1 - Homuth, Georg A1 - Völzke, Henry A1 - Kocher, Thomas A1 - Goel, Anuj A1 - Franzosi, Maria Grazia A1 - Seedorf, Udo A1 - Clarke, Robert A1 - Steri, Maristella A1 - Tarasov, Kirill V A1 - Sanna, Serena A1 - Schlessinger, David A1 - Stott, David J A1 - Sattar, Naveed A1 - Buckley, Brendan M A1 - Rumley, Ann A1 - Lowe, Gordon D A1 - McArdle, Wendy L A1 - Chen, Ming-Huei A1 - Tofler, Geoffrey H A1 - Song, Jaejoon A1 - Boerwinkle, Eric A1 - Folsom, Aaron R A1 - Rose, Lynda M A1 - Franco-Cereceda, Anders A1 - Teichert, Martina A1 - Ikram, M Arfan A1 - Mosley, Thomas H A1 - Bevan, Steve A1 - Dichgans, Martin A1 - Rothwell, Peter M A1 - Sudlow, Cathie L M A1 - Hopewell, Jemma C A1 - Chambers, John C A1 - Saleheen, Danish A1 - Kooner, Jaspal S A1 - Danesh, John A1 - Nelson, Christopher P A1 - Erdmann, Jeanette A1 - Reilly, Muredach P A1 - Kathiresan, Sekar A1 - Schunkert, Heribert A1 - Morange, Pierre-Emmanuel A1 - Ferrucci, Luigi A1 - Eriksson, Johan G A1 - Jacobs, David A1 - Deary, Ian J A1 - Soranzo, Nicole A1 - Witteman, Jacqueline C M A1 - de Geus, Eco J C A1 - Tracy, Russell P A1 - Hayward, Caroline A1 - Koenig, Wolfgang A1 - Cucca, Francesco A1 - Jukema, J Wouter A1 - Eriksson, Per A1 - Seshadri, Sudha A1 - Markus, Hugh S A1 - Watkins, Hugh A1 - Samani, Nilesh J A1 - Wallaschofski, Henri A1 - Smith, Nicholas L A1 - Tregouet, David A1 - Ridker, Paul M A1 - Tang, Weihong A1 - Strachan, David P A1 - Hamsten, Anders A1 - O'Donnell, Christopher J KW - Adolescent KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Coronary Artery Disease KW - European Continental Ancestry Group KW - Female KW - Fibrinogen KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Hispanic Americans KW - Humans KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Stroke KW - Venous Thromboembolism KW - Young Adult AB -

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

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

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

VL - 128 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23969696?dopt=Abstract ER - TY - JOUR T1 - Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. JF - Am J Hum Genet Y1 - 2014 A1 - Peloso, Gina M A1 - Auer, Paul L A1 - Bis, Joshua C A1 - Voorman, Arend A1 - Morrison, Alanna C A1 - Stitziel, Nathan O A1 - Brody, Jennifer A A1 - Khetarpal, Sumeet A A1 - Crosby, Jacy R A1 - Fornage, Myriam A1 - Isaacs, Aaron A1 - Jakobsdottir, Johanna A1 - Feitosa, Mary F A1 - Davies, Gail A1 - Huffman, Jennifer E A1 - Manichaikul, Ani A1 - Davis, Brian A1 - Lohman, Kurt A1 - Joon, Aron Y A1 - Smith, Albert V A1 - Grove, Megan L A1 - Zanoni, Paolo A1 - Redon, Valeska A1 - Demissie, Serkalem A1 - Lawson, Kim A1 - Peters, Ulrike A1 - Carlson, Christopher A1 - Jackson, Rebecca D A1 - Ryckman, Kelli K A1 - Mackey, Rachel H A1 - Robinson, Jennifer G A1 - Siscovick, David S A1 - Schreiner, Pamela J A1 - Mychaleckyj, Josyf C A1 - Pankow, James S A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Harris, Tamara B A1 - Taylor, Kent D A1 - Stafford, Jeanette M A1 - Reynolds, Lindsay M A1 - Marioni, Riccardo E A1 - Dehghan, Abbas A1 - Franco, Oscar H A1 - Patel, Aniruddh P A1 - Lu, Yingchang A1 - Hindy, George A1 - Gottesman, Omri A1 - Bottinger, Erwin P A1 - Melander, Olle A1 - Orho-Melander, Marju A1 - Loos, Ruth J F A1 - Duga, Stefano A1 - Merlini, Piera Angelica A1 - Farrall, Martin A1 - Goel, Anuj A1 - Asselta, Rosanna A1 - Girelli, Domenico A1 - Martinelli, Nicola A1 - Shah, Svati H A1 - Kraus, William E A1 - Li, Mingyao A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - McPherson, Ruth A1 - Watkins, Hugh A1 - Ardissino, Diego A1 - Zhang, Qunyuan A1 - Wang, Judy A1 - Tsai, Michael Y A1 - Taylor, Herman A A1 - Correa, Adolfo A1 - Griswold, Michael E A1 - Lange, Leslie A A1 - Starr, John M A1 - Rudan, Igor A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - Ordovas, Jose M A1 - Levy, Daniel A1 - Chen, Y-D Ida A1 - Reiner, Alexander P A1 - Hayward, Caroline A1 - Polasek, Ozren A1 - Deary, Ian J A1 - Borecki, Ingrid B A1 - Liu, Yongmei A1 - Gudnason, Vilmundur A1 - Wilson, James G A1 - van Duijn, Cornelia M A1 - Kooperberg, Charles A1 - Rich, Stephen S A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - O'Donnell, Christopher J A1 - Rice, Kenneth A1 - Boerwinkle, Eric A1 - Kathiresan, Sekar A1 - Cupples, L Adrienne KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Alleles KW - Animals KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Coronary Disease KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Association Studies KW - Genetic Code KW - Genetic Variation KW - Humans KW - Linear Models KW - Male KW - Mice KW - Mice, Inbred C57BL KW - Microtubule-Associated Proteins KW - Middle Aged KW - Phenotype KW - Sequence Analysis, DNA KW - Subtilisins KW - Triglycerides AB -

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

VL - 94 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24507774?dopt=Abstract ER - TY - JOUR T1 - Genetic diversity is a predictor of mortality in humans. JF - BMC Genet Y1 - 2014 A1 - Bihlmeyer, Nathan A A1 - Brody, Jennifer A A1 - Smith, Albert Vernon A1 - Lunetta, Kathryn L A1 - Nalls, Mike A1 - Smith, Jennifer A A1 - Tanaka, Toshiko A1 - Davies, Gail A1 - Yu, Lei A1 - Mirza, Saira Saeed A1 - Teumer, Alexander A1 - Coresh, Josef A1 - Pankow, James S A1 - Franceschini, Nora A1 - Scaria, Anish A1 - Oshima, Junko A1 - Psaty, Bruce M A1 - Gudnason, Vilmundur A1 - Eiriksdottir, Gudny A1 - Harris, Tamara B A1 - Li, Hanyue A1 - Karasik, David A1 - Kiel, Douglas P A1 - Garcia, Melissa A1 - Liu, Yongmei A1 - Faul, Jessica D A1 - Kardia, Sharon Lr A1 - Zhao, Wei A1 - Ferrucci, Luigi A1 - Allerhand, Michael A1 - Liewald, David C A1 - Redmond, Paul A1 - Starr, John M A1 - De Jager, Philip L A1 - Evans, Denis A A1 - Direk, Nese A1 - Ikram, Mohammed Arfan A1 - Uitterlinden, Andre A1 - Homuth, Georg A1 - Lorbeer, Roberto A1 - Grabe, Hans J A1 - Launer, Lenore A1 - Murabito, Joanne M A1 - Singleton, Andrew B A1 - Weir, David R A1 - Bandinelli, Stefania A1 - Deary, Ian J A1 - Bennett, David A A1 - Tiemeier, Henning A1 - Kocher, Thomas A1 - Lumley, Thomas A1 - Arking, Dan E KW - Genome-Wide Association Study KW - Heterozygote KW - Humans KW - Mortality KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models AB -

BACKGROUND: It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease.

RESULTS: We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person's risk of death by 1.57%.

CONCLUSIONS: This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.

VL - 15 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25543667?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 - Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function. JF - PLoS One Y1 - 2014 A1 - Tang, Wenbo A1 - Kowgier, Matthew A1 - Loth, Daan W A1 - Soler Artigas, Maria A1 - Joubert, Bonnie R A1 - Hodge, Emily A1 - Gharib, Sina A A1 - Smith, Albert V A1 - Ruczinski, Ingo A1 - Gudnason, Vilmundur A1 - Mathias, Rasika A A1 - Harris, Tamara B A1 - Hansel, Nadia N A1 - Launer, Lenore J A1 - Barnes, Kathleen C A1 - Hansen, Joyanna G A1 - Albrecht, Eva A1 - Aldrich, Melinda C A1 - Allerhand, Michael A1 - Barr, R Graham A1 - Brusselle, Guy G A1 - Couper, David J A1 - Curjuric, Ivan A1 - Davies, Gail A1 - Deary, Ian J A1 - Dupuis, Josée A1 - Fall, Tove A1 - Foy, Millennia A1 - Franceschini, Nora A1 - Gao, Wei A1 - Gläser, Sven A1 - Gu, Xiangjun A1 - Hancock, Dana B A1 - Heinrich, Joachim A1 - Hofman, Albert A1 - Imboden, Medea A1 - Ingelsson, Erik A1 - James, Alan A1 - Karrasch, Stefan A1 - Koch, Beate A1 - Kritchevsky, Stephen B A1 - Kumar, Ashish A1 - Lahousse, Lies A1 - Li, Guo A1 - Lind, Lars A1 - Lindgren, Cecilia A1 - Liu, Yongmei A1 - Lohman, Kurt A1 - Lumley, Thomas A1 - McArdle, Wendy L A1 - Meibohm, Bernd A1 - Morris, Andrew P A1 - Morrison, Alanna C A1 - Musk, Bill A1 - North, Kari E A1 - Palmer, Lyle J A1 - Probst-Hensch, Nicole M A1 - Psaty, Bruce M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Schulz, Holger A1 - Smith, Lewis J A1 - Sood, Akshay A1 - Starr, John M A1 - Strachan, David P A1 - Teumer, Alexander A1 - Uitterlinden, André G A1 - Völzke, Henry A1 - Voorman, Arend A1 - Wain, Louise V A1 - Wells, Martin T A1 - Wilk, Jemma B A1 - Williams, O Dale A1 - Heckbert, Susan R A1 - Stricker, Bruno H A1 - London, Stephanie J A1 - Fornage, Myriam A1 - Tobin, Martin D A1 - O'Connor, George T A1 - Hall, Ian P A1 - Cassano, Patricia A KW - Adult KW - Chromosomes, Human, Pair 11 KW - Female KW - Gene Expression Regulation KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Longitudinal Studies KW - Male KW - Respiration AB -

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.

METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.

RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.

CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.

VL - 9 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24983941?dopt=Abstract ER - TY - JOUR T1 - No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects. JF - PLoS One Y1 - 2014 A1 - Baumert, Jens A1 - Huang, Jie A1 - McKnight, Barbara A1 - Sabater-Lleal, Maria A1 - Steri, Maristella A1 - Chu, Audrey Y A1 - Trompet, Stella A1 - Lopez, Lorna M A1 - Fornage, Myriam A1 - Teumer, Alexander A1 - Tang, Weihong A1 - Rudnicka, Alicja R A1 - Mälarstig, Anders A1 - Hottenga, Jouke-Jan A1 - Kavousi, Maryam A1 - Lahti, Jari A1 - Tanaka, Toshiko A1 - Hayward, Caroline A1 - Huffman, Jennifer E A1 - Morange, Pierre-Emmanuel A1 - Rose, Lynda M A1 - Basu, Saonli A1 - Rumley, Ann A1 - Stott, David J A1 - Buckley, Brendan M A1 - de Craen, Anton J M A1 - Sanna, Serena A1 - Masala, Marco A1 - Biffar, Reiner A1 - Homuth, Georg A1 - Silveira, Angela A1 - Sennblad, Bengt A1 - Goel, Anuj A1 - Watkins, Hugh A1 - Müller-Nurasyid, Martina A1 - Rückerl, Regina A1 - Taylor, Kent A1 - Chen, Ming-Huei A1 - de Geus, Eco J C A1 - Hofman, Albert A1 - Witteman, Jacqueline C M A1 - de Maat, Moniek P M A1 - Palotie, Aarno A1 - Davies, Gail A1 - Siscovick, David S A1 - Kolcic, Ivana A1 - Wild, Sarah H A1 - Song, Jaejoon A1 - McArdle, Wendy L A1 - Ford, Ian A1 - Sattar, Naveed A1 - Schlessinger, David A1 - Grotevendt, Anne A1 - Franzosi, Maria Grazia A1 - Illig, Thomas A1 - Waldenberger, Melanie A1 - Lumley, Thomas A1 - Tofler, Geoffrey H A1 - Willemsen, Gonneke A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Räikkönen, Katri A1 - Chasman, Daniel I A1 - Folsom, Aaron R A1 - Lowe, Gordon D A1 - Westendorp, Rudi G J A1 - Slagboom, P Eline A1 - Cucca, Francesco A1 - Wallaschofski, Henri A1 - Strawbridge, Rona J A1 - Seedorf, Udo A1 - Koenig, Wolfgang A1 - Bis, Joshua C A1 - Mukamal, Kenneth J A1 - van Dongen, Jenny A1 - Widen, Elisabeth A1 - Franco, Oscar H A1 - Starr, John M A1 - Liu, Kiang A1 - Ferrucci, Luigi A1 - Polasek, Ozren A1 - Wilson, James F A1 - Oudot-Mellakh, Tiphaine A1 - Campbell, Harry A1 - Navarro, Pau A1 - Bandinelli, Stefania A1 - Eriksson, Johan A1 - Boomsma, Dorret I A1 - Dehghan, Abbas A1 - Clarke, Robert A1 - Hamsten, Anders A1 - Boerwinkle, Eric A1 - Jukema, J Wouter A1 - Naitza, Silvia A1 - Ridker, Paul M A1 - Völzke, Henry A1 - Deary, Ian J A1 - Reiner, Alexander P A1 - Trégouët, David-Alexandre A1 - O'Donnell, Christopher J A1 - Strachan, David P A1 - Peters, Annette A1 - Smith, Nicholas L KW - Alcohol Drinking KW - Body Mass Index KW - Fibrinogen KW - Gene-Environment Interaction KW - Genomics KW - Humans KW - Smoking AB -

Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 × 10(-8). This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.

VL - 9 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25551457?dopt=Abstract ER - TY - JOUR T1 - Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. JF - Neurology Y1 - 2015 A1 - Rannikmae, Kristiina A1 - Davies, Gail A1 - Thomson, Pippa A A1 - Bevan, Steve A1 - Devan, William J A1 - Falcone, Guido J A1 - Traylor, Matthew A1 - Anderson, Christopher D A1 - Battey, Thomas W K A1 - Radmanesh, Farid A1 - Deka, Ranjan A1 - Woo, Jessica G A1 - Martin, Lisa J A1 - Jimenez-Conde, Jordi A1 - Selim, Magdy A1 - Brown, Devin L A1 - Silliman, Scott L A1 - Kidwell, Chelsea S A1 - Montaner, Joan A1 - Langefeld, Carl D A1 - Slowik, Agnieszka A1 - Hansen, Bjorn M A1 - Lindgren, Arne G A1 - Meschia, James F A1 - Fornage, Myriam A1 - Bis, Joshua C A1 - Debette, Stephanie A1 - Ikram, Mohammad A A1 - Longstreth, Will T A1 - Schmidt, Reinhold A1 - Zhang, Cathy R A1 - Yang, Qiong A1 - Sharma, Pankaj A1 - Kittner, Steven J A1 - Mitchell, Braxton D A1 - Holliday, Elizabeth G A1 - Levi, Christopher R A1 - Attia, John A1 - Rothwell, Peter M A1 - Poole, Deborah L A1 - Boncoraglio, Giorgio B A1 - Psaty, Bruce M A1 - Malik, Rainer A1 - Rost, Natalia A1 - Worrall, Bradford B A1 - Dichgans, Martin A1 - Van Agtmael, Tom A1 - Woo, Daniel A1 - Markus, Hugh S A1 - Seshadri, Sudha A1 - Rosand, Jonathan A1 - Sudlow, Cathie L M KW - Cerebral Small Vessel Diseases KW - Collagen Type IV KW - Genetic Association Studies KW - Genetic Variation KW - Humans KW - Polymorphism, Single Nucleotide AB -

OBJECTIVES: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease.

METHODS: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084).

RESULTS: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes.

CONCLUSIONS: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.

VL - 84 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25653287?dopt=Abstract ER - TY - JOUR T1 - Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. JF - Biol Psychiatry Y1 - 2015 A1 - Debette, Stephanie A1 - Ibrahim Verbaas, Carla A A1 - Bressler, Jan A1 - Schuur, Maaike A1 - Smith, Albert A1 - Bis, Joshua C A1 - Davies, Gail A1 - Wolf, Christiane A1 - Gudnason, Vilmundur A1 - Chibnik, Lori B A1 - Yang, Qiong A1 - DeStefano, Anita L A1 - de Quervain, Dominique J F A1 - Srikanth, Velandai A1 - Lahti, Jari A1 - Grabe, Hans J A1 - Smith, Jennifer A A1 - Priebe, Lutz A1 - Yu, Lei A1 - Karbalai, Nazanin A1 - Hayward, Caroline A1 - Wilson, James F A1 - Campbell, Harry A1 - Petrovic, Katja A1 - Fornage, Myriam A1 - Chauhan, Ganesh A1 - Yeo, Robin A1 - Boxall, Ruth A1 - Becker, James A1 - Stegle, Oliver A1 - Mather, Karen A A1 - Chouraki, Vincent A1 - Sun, Qi A1 - Rose, Lynda M A1 - Resnick, Susan A1 - Oldmeadow, Christopher A1 - Kirin, Mirna A1 - Wright, Alan F A1 - Jonsdottir, Maria K A1 - Au, Rhoda A1 - Becker, Albert A1 - Amin, Najaf A1 - Nalls, Mike A A1 - Turner, Stephen T A1 - Kardia, Sharon L R A1 - Oostra, Ben A1 - Windham, Gwen A1 - Coker, Laura H A1 - Zhao, Wei A1 - Knopman, David S A1 - Heiss, Gerardo A1 - Griswold, Michael E A1 - Gottesman, Rebecca F A1 - Vitart, Veronique A1 - Hastie, Nicholas D A1 - Zgaga, Lina A1 - Rudan, Igor A1 - Polasek, Ozren A1 - Holliday, Elizabeth G A1 - Schofield, Peter A1 - Choi, Seung Hoan A1 - Tanaka, Toshiko A1 - An, Yang A1 - Perry, Rodney T A1 - Kennedy, Richard E A1 - Sale, Michèle M A1 - Wang, Jing A1 - Wadley, Virginia G A1 - Liewald, David C A1 - Ridker, Paul M A1 - Gow, Alan J A1 - Pattie, Alison A1 - Starr, John M A1 - Porteous, David A1 - Liu, Xuan A1 - Thomson, Russell A1 - Armstrong, Nicola J A1 - Eiriksdottir, Gudny A1 - Assareh, Arezoo A A1 - Kochan, Nicole A A1 - Widen, Elisabeth A1 - Palotie, Aarno A1 - Hsieh, Yi-Chen A1 - Eriksson, Johan G A1 - Vogler, Christian A1 - van Swieten, John C A1 - Shulman, Joshua M A1 - Beiser, Alexa A1 - Rotter, Jerome A1 - Schmidt, Carsten O A1 - Hoffmann, Wolfgang A1 - Nöthen, Markus M A1 - Ferrucci, Luigi A1 - Attia, John A1 - Uitterlinden, André G A1 - Amouyel, Philippe A1 - Dartigues, Jean-François A1 - Amieva, Hélène A1 - Räikkönen, Katri A1 - Garcia, Melissa A1 - Wolf, Philip A A1 - Hofman, Albert A1 - Longstreth, W T A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - DeJager, Philip L A1 - Sachdev, Perminder S A1 - Schmidt, Reinhold A1 - Breteler, Monique M B A1 - Teumer, Alexander A1 - Lopez, Oscar L A1 - Cichon, Sven A1 - Chasman, Daniel I A1 - Grodstein, Francine A1 - Müller-Myhsok, Bertram A1 - Tzourio, Christophe A1 - Papassotiropoulos, Andreas A1 - Bennett, David A A1 - Ikram, M Arfan A1 - Deary, Ian J A1 - van Duijn, Cornelia M A1 - Launer, Lenore A1 - Fitzpatrick, Annette L A1 - Seshadri, Sudha A1 - Mosley, Thomas H KW - Aged KW - Aged, 80 and over KW - Aging KW - Apolipoproteins E KW - Claudin-5 KW - Cohort Studies KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Memory Disorders KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Proteins KW - Proteoglycans KW - Regression Analysis KW - Sulfotransferases KW - Verbal Learning AB -

BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.

METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.

RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.

CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

VL - 77 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25648963?dopt=Abstract ER - TY - JOUR T1 - GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium. JF - Aging Cell Y1 - 2016 A1 - Matteini, Amy M A1 - Tanaka, Toshiko A1 - Karasik, David A1 - Atzmon, Gil A1 - Chou, Wen-Chi A1 - Eicher, John D A1 - Johnson, Andrew D A1 - Arnold, Alice M A1 - Callisaya, Michele L A1 - Davies, Gail A1 - Evans, Daniel S A1 - Holtfreter, Birte A1 - Lohman, Kurt A1 - Lunetta, Kathryn L A1 - Mangino, Massimo A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Teumer, Alexander A1 - Yu, Lei A1 - Arking, Dan E A1 - Buchman, Aron S A1 - Chibinik, Lori B A1 - De Jager, Philip L A1 - Evans, Denis A A1 - Faul, Jessica D A1 - Garcia, Melissa E A1 - Gillham-Nasenya, Irina A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Hsu, Yi-Hsiang A1 - Ittermann, Till A1 - Lahousse, Lies A1 - Liewald, David C A1 - Liu, Yongmei A1 - Lopez, Lorna A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Siggeirsdottir, Kristin A1 - Starr, John M A1 - Thomson, Russell A1 - Tranah, Gregory J A1 - Uitterlinden, André G A1 - Völker, Uwe A1 - Völzke, Henry A1 - Weir, David R A1 - Yaffe, Kristine A1 - Zhao, Wei A1 - Zhuang, Wei Vivian A1 - Zmuda, Joseph M A1 - Bennett, David A A1 - Cummings, Steven R A1 - Deary, Ian J A1 - Ferrucci, Luigi A1 - Harris, Tamara B A1 - Kardia, Sharon L R A1 - Kocher, Thomas A1 - Kritchevsky, Stephen B A1 - Psaty, Bruce M A1 - Seshadri, Sudha A1 - Spector, Timothy D A1 - Srikanth, Velandai K A1 - Windham, B Gwen A1 - Zillikens, M Carola A1 - Newman, Anne B A1 - Walston, Jeremy D A1 - Kiel, Douglas P A1 - Murabito, Joanne M AB -

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

VL - 15 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27325353?dopt=Abstract ER - TY - JOUR T1 - The complex genetics of gait speed: genome-wide meta-analysis approach. JF - Aging (Albany NY) Y1 - 2017 A1 - Ben-Avraham, Dan A1 - Karasik, David A1 - Verghese, Joe A1 - Lunetta, Kathryn L A1 - Smith, Jennifer A A1 - Eicher, John D A1 - Vered, Rotem A1 - Deelen, Joris A1 - Arnold, Alice M A1 - Buchman, Aron S A1 - Tanaka, Toshiko A1 - Faul, Jessica D A1 - Nethander, Maria A1 - Fornage, Myriam A1 - Adams, Hieab H A1 - Matteini, Amy M A1 - Callisaya, Michele L A1 - Smith, Albert V A1 - Yu, Lei A1 - De Jager, Philip L A1 - Evans, Denis A A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Pattie, Alison A1 - Corley, Janie A1 - Launer, Lenore J A1 - Knopman, Davis S A1 - Parimi, Neeta A1 - Turner, Stephen T A1 - Bandinelli, Stefania A1 - Beekman, Marian A1 - Gutman, Danielle A1 - Sharvit, Lital A1 - Mooijaart, Simon P A1 - Liewald, David C A1 - Houwing-Duistermaat, Jeanine J A1 - Ohlsson, Claes A1 - Moed, Matthijs A1 - Verlinden, Vincent J A1 - Mellström, Dan A1 - van der Geest, Jos N A1 - Karlsson, Magnus A1 - Hernandez, Dena A1 - McWhirter, Rebekah A1 - Liu, Yongmei A1 - Thomson, Russell A1 - Tranah, Gregory J A1 - Uitterlinden, André G A1 - Weir, David R A1 - Zhao, Wei A1 - Starr, John M A1 - Johnson, Andrew D A1 - Ikram, M Arfan A1 - Bennett, David A A1 - Cummings, Steven R A1 - Deary, Ian J A1 - Harris, Tamara B A1 - Kardia, Sharon L R A1 - Mosley, Thomas H A1 - Srikanth, Velandai K A1 - Windham, Beverly G A1 - Newman, Ann B A1 - Walston, Jeremy D A1 - Davies, Gail A1 - Evans, Daniel S A1 - Slagboom, Eline P A1 - Ferrucci, Luigi A1 - Kiel, Douglas P A1 - Murabito, Joanne M A1 - Atzmon, Gil AB -

Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging.

VL - 9 IS - 1 ER - TY - JOUR T1 - Exome-wide association study of plasma lipids in >300,000 individuals. JF - Nat Genet Y1 - 2017 A1 - Liu, Dajiang J A1 - Peloso, Gina M A1 - Yu, Haojie A1 - Butterworth, Adam S A1 - Wang, Xiao A1 - Mahajan, Anubha A1 - Saleheen, Danish A1 - Emdin, Connor A1 - Alam, Dewan A1 - Alves, Alexessander Couto A1 - Amouyel, Philippe A1 - Di Angelantonio, Emanuele A1 - Arveiler, Dominique A1 - Assimes, Themistocles L A1 - Auer, Paul L A1 - Baber, Usman A1 - Ballantyne, Christie M A1 - Bang, Lia E A1 - Benn, Marianne A1 - Bis, Joshua C A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Bork-Jensen, Jette A1 - Bottinger, Erwin P A1 - Brandslund, Ivan A1 - Brown, Morris A1 - Busonero, Fabio A1 - Caulfield, Mark J A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Chen, Y Eugene A1 - Chen, Yii-Der Ida A1 - Chowdhury, Rajiv A1 - Christensen, Cramer A1 - Chu, Audrey Y A1 - Connell, John M A1 - Cucca, Francesco A1 - Cupples, L Adrienne A1 - Damrauer, Scott M A1 - Davies, Gail A1 - Deary, Ian J A1 - Dedoussis, George A1 - Denny, Joshua C A1 - Dominiczak, Anna A1 - Dubé, Marie-Pierre A1 - Ebeling, Tapani A1 - Eiriksdottir, Gudny A1 - Esko, Tõnu A1 - Farmaki, Aliki-Eleni A1 - Feitosa, Mary F A1 - Ferrario, Marco A1 - Ferrieres, Jean A1 - Ford, Ian A1 - Fornage, Myriam A1 - Franks, Paul W A1 - Frayling, Timothy M A1 - Frikke-Schmidt, Ruth A1 - Fritsche, Lars G A1 - Frossard, Philippe A1 - Fuster, Valentin A1 - Ganesh, Santhi K A1 - Gao, Wei A1 - Garcia, Melissa E A1 - Gieger, Christian A1 - Giulianini, Franco A1 - Goodarzi, Mark O A1 - Grallert, Harald A1 - Grarup, Niels A1 - Groop, Leif A1 - Grove, Megan L A1 - Gudnason, Vilmundur A1 - Hansen, Torben A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Hirschhorn, Joel N A1 - Holmen, Oddgeir L A1 - Huffman, Jennifer A1 - Huo, Yong A1 - Hveem, Kristian A1 - Jabeen, Sehrish A1 - Jackson, Anne U A1 - Jakobsdottir, Johanna A1 - Jarvelin, Marjo-Riitta A1 - Jensen, Gorm B A1 - Jørgensen, Marit E A1 - Jukema, J Wouter A1 - Justesen, Johanne M A1 - Kamstrup, Pia R A1 - Kanoni, Stavroula A1 - Karpe, Fredrik A1 - Kee, Frank A1 - Khera, Amit V A1 - Klarin, Derek A1 - Koistinen, Heikki A A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Kuulasmaa, Kari A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lakka, Timo A1 - Langenberg, Claudia A1 - Langsted, Anne A1 - Launer, Lenore J A1 - Lauritzen, Torsten A1 - Liewald, David C M A1 - Lin, Li An A1 - Linneberg, Allan A1 - Loos, Ruth J F A1 - Lu, Yingchang A1 - Lu, Xiangfeng A1 - Mägi, Reedik A1 - Mälarstig, Anders A1 - Manichaikul, Ani A1 - Manning, Alisa K A1 - Mäntyselkä, Pekka A1 - Marouli, Eirini A1 - Masca, Nicholas G D A1 - Maschio, Andrea A1 - Meigs, James B A1 - Melander, Olle A1 - Metspalu, Andres A1 - Morris, Andrew P A1 - Morrison, Alanna C A1 - Mulas, Antonella A1 - Müller-Nurasyid, Martina A1 - Munroe, Patricia B A1 - Neville, Matt J A1 - Nielsen, Jonas B A1 - Nielsen, Sune F A1 - Nordestgaard, Børge G A1 - Ordovas, Jose M A1 - Mehran, Roxana A1 - O'Donnell, Christoper J A1 - Orho-Melander, Marju A1 - Molony, Cliona M A1 - Muntendam, Pieter A1 - Padmanabhan, Sandosh A1 - Palmer, Colin N A A1 - Pasko, Dorota A1 - Patel, Aniruddh P A1 - Pedersen, Oluf A1 - Perola, Markus A1 - Peters, Annette A1 - Pisinger, Charlotta A1 - Pistis, Giorgio A1 - Polasek, Ozren A1 - Poulter, Neil A1 - Psaty, Bruce M A1 - Rader, Daniel J A1 - Rasheed, Asif A1 - Rauramaa, Rainer A1 - Reilly, Dermot F A1 - Reiner, Alex P A1 - Renstrom, Frida A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rioux, John D A1 - Robertson, Neil R A1 - Roden, Dan M A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Sanna, Serena A1 - Sattar, Naveed A1 - Schmidt, Ellen M A1 - Scott, Robert A A1 - Sever, Peter A1 - Sevilla, Raquel S A1 - Shaffer, Christian M A1 - Sim, Xueling A1 - Sivapalaratnam, Suthesh A1 - Small, Kerrin S A1 - Smith, Albert V A1 - Smith, Blair H A1 - Somayajula, Sangeetha A1 - Southam, Lorraine A1 - Spector, Timothy D A1 - Speliotes, Elizabeth K A1 - Starr, John M A1 - Stirrups, Kathleen E A1 - Stitziel, Nathan A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Surendran, Praveen A1 - Tada, Hayato A1 - Tall, Alan R A1 - Tang, Hua A1 - Tardif, Jean-Claude A1 - Taylor, Kent D A1 - Trompet, Stella A1 - Tsao, Philip S A1 - Tuomilehto, Jaakko A1 - Tybjaerg-Hansen, Anne A1 - van Zuydam, Natalie R A1 - Varbo, Anette A1 - Varga, Tibor V A1 - Virtamo, Jarmo A1 - Waldenberger, Melanie A1 - Wang, Nan A1 - Wareham, Nick J A1 - Warren, Helen R A1 - Weeke, Peter E A1 - Weinstock, Joshua A1 - Wessel, Jennifer A1 - Wilson, James G A1 - Wilson, Peter W F A1 - Xu, Ming A1 - Yaghootkar, Hanieh A1 - Young, Robin A1 - Zeggini, Eleftheria A1 - Zhang, He A1 - Zheng, Neil S A1 - Zhang, Weihua A1 - Zhang, Yan A1 - Zhou, Wei A1 - Zhou, Yanhua A1 - Zoledziewska, Magdalena A1 - Howson, Joanna M M A1 - Danesh, John A1 - McCarthy, Mark I A1 - Cowan, Chad A A1 - Abecasis, Goncalo A1 - Deloukas, Panos A1 - Musunuru, Kiran A1 - Willer, Cristen J A1 - Kathiresan, Sekar KW - Coronary Artery Disease KW - Diabetes Mellitus, Type 2 KW - Exome KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genotype KW - Humans KW - Lipids KW - Macular Degeneration KW - Phenotype KW - Risk Factors AB -

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

VL - 49 IS - 12 ER - TY - JOUR T1 - Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets. JF - Cell Rep Y1 - 2017 A1 - Lam, Max A1 - Trampush, Joey W A1 - Yu, Jin A1 - Knowles, Emma A1 - Davies, Gail A1 - Liewald, David C A1 - Starr, John M A1 - Djurovic, Srdjan A1 - Melle, Ingrid A1 - Sundet, Kjetil A1 - Christoforou, Andrea A1 - Reinvang, Ivar A1 - DeRosse, Pamela A1 - Lundervold, Astri J A1 - Steen, Vidar M A1 - Espeseth, Thomas A1 - Räikkönen, Katri A1 - Widen, Elisabeth A1 - Palotie, Aarno A1 - Eriksson, Johan G A1 - Giegling, Ina A1 - Konte, Bettina A1 - Roussos, Panos A1 - Giakoumaki, Stella A1 - Burdick, Katherine E A1 - Payton, Antony A1 - Ollier, William A1 - Chiba-Falek, Ornit A1 - Attix, Deborah K A1 - Need, Anna C A1 - Cirulli, Elizabeth T A1 - Voineskos, Aristotle N A1 - Stefanis, Nikos C A1 - Avramopoulos, Dimitrios A1 - Hatzimanolis, Alex A1 - Arking, Dan E A1 - Smyrnis, Nikolaos A1 - Bilder, Robert M A1 - Freimer, Nelson A A1 - Cannon, Tyrone D A1 - London, Edythe A1 - Poldrack, Russell A A1 - Sabb, Fred W A1 - Congdon, Eliza A1 - Conley, Emily Drabant A1 - Scult, Matthew A A1 - Dickinson, Dwight A1 - Straub, Richard E A1 - Donohoe, Gary A1 - Morris, Derek A1 - Corvin, Aiden A1 - Gill, Michael A1 - Hariri, Ahmad R A1 - Weinberger, Daniel R A1 - Pendleton, Neil A1 - Bitsios, Panos A1 - Rujescu, Dan A1 - Lahti, Jari A1 - Le Hellard, Stephanie A1 - Keller, Matthew C A1 - Andreassen, Ole A A1 - Deary, Ian J A1 - Glahn, David C A1 - Malhotra, Anil K A1 - Lencz, Todd AB -

Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth.

VL - 21 IS - 9 ER - TY - JOUR T1 - Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney. JF - Hypertension Y1 - 2017 A1 - Wain, Louise V A1 - Vaez, Ahmad A1 - Jansen, Rick A1 - Joehanes, Roby A1 - van der Most, Peter J A1 - Erzurumluoglu, A Mesut A1 - O'Reilly, Paul F A1 - Cabrera, Claudia P A1 - Warren, Helen R A1 - Rose, Lynda M A1 - Verwoert, Germaine C A1 - Hottenga, Jouke-Jan A1 - Strawbridge, Rona J A1 - Esko, Tõnu A1 - Arking, Dan E A1 - Hwang, Shih-Jen A1 - Guo, Xiuqing A1 - Kutalik, Zoltán A1 - Trompet, Stella A1 - Shrine, Nick A1 - Teumer, Alexander A1 - Ried, Janina S A1 - Bis, Joshua C A1 - Smith, Albert V A1 - Amin, Najaf A1 - Nolte, Ilja M A1 - Lyytikäinen, Leo-Pekka A1 - Mahajan, Anubha A1 - Wareham, Nicholas J A1 - Hofer, Edith A1 - Joshi, Peter K A1 - Kristiansson, Kati A1 - Traglia, Michela A1 - Havulinna, Aki S A1 - Goel, Anuj A1 - Nalls, Mike A A1 - Sõber, Siim A1 - Vuckovic, Dragana A1 - Luan, Jian'an A1 - del Greco M, Fabiola A1 - Ayers, Kristin L A1 - Marrugat, Jaume A1 - Ruggiero, Daniela A1 - Lopez, Lorna M A1 - Niiranen, Teemu A1 - Enroth, Stefan A1 - Jackson, Anne U A1 - Nelson, Christopher P A1 - Huffman, Jennifer E A1 - Zhang, Weihua A1 - Marten, Jonathan A1 - Gandin, Ilaria A1 - Harris, Sarah E A1 - Zemunik, Tatijana A1 - Lu, Yingchang A1 - Evangelou, Evangelos A1 - Shah, Nabi A1 - de Borst, Martin H A1 - Mangino, Massimo A1 - Prins, Bram P A1 - Campbell, Archie A1 - Li-Gao, Ruifang A1 - Chauhan, Ganesh A1 - Oldmeadow, Christopher A1 - Abecasis, Goncalo A1 - Abedi, Maryam A1 - Barbieri, Caterina M A1 - Barnes, Michael R A1 - Batini, Chiara A1 - Beilby, John A1 - Blake, Tineka A1 - Boehnke, Michael A1 - Bottinger, Erwin P A1 - Braund, Peter S A1 - Brown, Morris A1 - Brumat, Marco A1 - Campbell, Harry A1 - Chambers, John C A1 - Cocca, Massimiliano A1 - Collins, Francis A1 - Connell, John A1 - Cordell, Heather J A1 - Damman, Jeffrey J A1 - Davies, Gail A1 - de Geus, Eco J A1 - de Mutsert, Renée A1 - Deelen, Joris A1 - Demirkale, Yusuf A1 - Doney, Alex S F A1 - Dörr, Marcus A1 - Farrall, Martin A1 - Ferreira, Teresa A1 - Frånberg, Mattias A1 - Gao, He A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Giulianini, Franco A1 - Gow, Alan J A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Holliday, Elizabeth G A1 - Hui, Jennie A1 - Jarvelin, Marjo-Riitta A1 - Johansson, Asa A1 - Johnson, Andrew D A1 - Jousilahti, Pekka A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kathiresan, Sekar A1 - Khaw, Kay-Tee A1 - Kolcic, Ivana A1 - Koskinen, Seppo A1 - Langenberg, Claudia A1 - Larson, Marty A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Liewald, David C M A1 - Lin, Li A1 - Lind, Lars A1 - Mach, François A1 - Mamasoula, Chrysovalanto A1 - Menni, Cristina A1 - Mifsud, Borbala A1 - Milaneschi, Yuri A1 - Morgan, Anna A1 - Morris, Andrew D A1 - Morrison, Alanna C A1 - Munson, Peter J A1 - Nandakumar, Priyanka A1 - Nguyen, Quang Tri A1 - Nutile, Teresa A1 - Oldehinkel, Albertine J A1 - Oostra, Ben A A1 - Org, Elin A1 - Padmanabhan, Sandosh A1 - Palotie, Aarno A1 - Paré, Guillaume A1 - Pattie, Alison A1 - Penninx, Brenda W J H A1 - Poulter, Neil A1 - Pramstaller, Peter P A1 - Raitakari, Olli T A1 - Ren, Meixia A1 - Rice, Kenneth A1 - Ridker, Paul M A1 - Riese, Harriëtte A1 - Ripatti, Samuli A1 - Robino, Antonietta A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Saba, Yasaman A1 - Saint Pierre, Aude A1 - Sala, Cinzia F A1 - Sarin, Antti-Pekka A1 - Schmidt, Reinhold A1 - Scott, Rodney A1 - Seelen, Marc A A1 - Shields, Denis C A1 - Siscovick, David A1 - Sorice, Rossella A1 - Stanton, Alice A1 - Stott, David J A1 - Sundström, Johan A1 - Swertz, Morris A1 - Taylor, Kent D A1 - Thom, Simon A1 - Tzoulaki, Ioanna A1 - Tzourio, Christophe A1 - Uitterlinden, André G A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Wild, Sarah A1 - Willemsen, Gonneke A1 - Wright, Alan F A1 - Yao, Jie A1 - Thériault, Sébastien A1 - Conen, David A1 - Attia, John A1 - Sever, Peter A1 - Debette, Stephanie A1 - Mook-Kanamori, Dennis O A1 - Zeggini, Eleftheria A1 - Spector, Tim D A1 - van der Harst, Pim A1 - Palmer, Colin N A A1 - Vergnaud, Anne-Claire A1 - Loos, Ruth J F A1 - Polasek, Ozren A1 - Starr, John M A1 - Girotto, Giorgia A1 - Hayward, Caroline A1 - Kooner, Jaspal S A1 - Lindgren, Cecila M A1 - Vitart, Veronique A1 - Samani, Nilesh J A1 - Tuomilehto, Jaakko A1 - Gyllensten, Ulf A1 - Knekt, Paul A1 - Deary, Ian J A1 - Ciullo, Marina A1 - Elosua, Roberto A1 - Keavney, Bernard D A1 - Hicks, Andrew A A1 - Scott, Robert A A1 - Gasparini, Paolo A1 - Laan, Maris A1 - Liu, Yongmei A1 - Watkins, Hugh A1 - Hartman, Catharina A A1 - Salomaa, Veikko A1 - Toniolo, Daniela A1 - Perola, Markus A1 - Wilson, James F A1 - Schmidt, Helena A1 - Zhao, Jing Hua A1 - Lehtimäki, Terho A1 - van Duijn, Cornelia M A1 - Gudnason, Vilmundur A1 - Psaty, Bruce M A1 - Peters, Annette A1 - Rettig, Rainer A1 - James, Alan A1 - Jukema, J Wouter A1 - Strachan, David P A1 - Palmas, Walter A1 - Metspalu, Andres A1 - Ingelsson, Erik A1 - Boomsma, Dorret I A1 - Franco, Oscar H A1 - Bochud, Murielle A1 - Newton-Cheh, Christopher A1 - Munroe, Patricia B A1 - Elliott, Paul A1 - Chasman, Daniel I A1 - Chakravarti, Aravinda A1 - Knight, Joanne A1 - Morris, Andrew P A1 - Levy, Daniel A1 - Tobin, Martin D A1 - Snieder, Harold A1 - Caulfield, Mark J A1 - Ehret, Georg B AB -

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

ER - TY - JOUR T1 - Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. JF - Nat Genet Y1 - 2018 A1 - Evangelou, Evangelos A1 - Warren, Helen R A1 - Mosen-Ansorena, David A1 - Mifsud, Borbala A1 - Pazoki, Raha A1 - Gao, He A1 - Ntritsos, Georgios A1 - Dimou, Niki A1 - Cabrera, Claudia P A1 - Karaman, Ibrahim A1 - Ng, Fu Liang A1 - Evangelou, Marina A1 - Witkowska, Katarzyna A1 - Tzanis, Evan A1 - Hellwege, Jacklyn N A1 - Giri, Ayush A1 - Velez Edwards, Digna R A1 - Sun, Yan V A1 - Cho, Kelly A1 - Gaziano, J Michael A1 - Wilson, Peter W F A1 - Tsao, Philip S A1 - Kovesdy, Csaba P A1 - Esko, Tõnu A1 - Mägi, Reedik A1 - Milani, Lili A1 - Almgren, Peter A1 - Boutin, Thibaud A1 - Debette, Stephanie A1 - Ding, Jun A1 - Giulianini, Franco A1 - Holliday, Elizabeth G A1 - Jackson, Anne U A1 - Li-Gao, Ruifang A1 - Lin, Wei-Yu A1 - Luan, Jian'an A1 - Mangino, Massimo A1 - Oldmeadow, Christopher A1 - Prins, Bram Peter A1 - Qian, Yong A1 - Sargurupremraj, Muralidharan A1 - Shah, Nabi A1 - Surendran, Praveen A1 - Thériault, Sébastien A1 - Verweij, Niek A1 - Willems, Sara M A1 - Zhao, Jing-Hua A1 - Amouyel, Philippe A1 - Connell, John A1 - de Mutsert, Renée A1 - Doney, Alex S F A1 - Farrall, Martin A1 - Menni, Cristina A1 - Morris, Andrew D A1 - Noordam, Raymond A1 - Paré, Guillaume A1 - Poulter, Neil R A1 - Shields, Denis C A1 - Stanton, Alice A1 - Thom, Simon A1 - Abecasis, Goncalo A1 - Amin, Najaf A1 - Arking, Dan E A1 - Ayers, Kristin L A1 - Barbieri, Caterina M A1 - Batini, Chiara A1 - Bis, Joshua C A1 - Blake, Tineka A1 - Bochud, Murielle A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Boomsma, Dorret I A1 - Bottinger, Erwin P A1 - Braund, Peter S A1 - Brumat, Marco A1 - Campbell, Archie A1 - Campbell, Harry A1 - Chakravarti, Aravinda A1 - Chambers, John C A1 - Chauhan, Ganesh A1 - Ciullo, Marina A1 - Cocca, Massimiliano A1 - Collins, Francis A1 - Cordell, Heather J A1 - Davies, Gail A1 - Borst, Martin H de A1 - Geus, Eco J de A1 - Deary, Ian J A1 - Deelen, Joris A1 - del Greco M, Fabiola A1 - Demirkale, Cumhur Yusuf A1 - Dörr, Marcus A1 - Ehret, Georg B A1 - Elosua, Roberto A1 - Enroth, Stefan A1 - Erzurumluoglu, A Mesut A1 - Ferreira, Teresa A1 - Frånberg, Mattias A1 - Franco, Oscar H A1 - Gandin, Ilaria A1 - Gasparini, Paolo A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Girotto, Giorgia A1 - Goel, Anuj A1 - Gow, Alan J A1 - Gudnason, Vilmundur A1 - Guo, Xiuqing A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Harris, Sarah E A1 - Hartman, Catharina A A1 - Havulinna, Aki S A1 - Hicks, Andrew A A1 - Hofer, Edith A1 - Hofman, Albert A1 - Hottenga, Jouke-Jan A1 - Huffman, Jennifer E A1 - Hwang, Shih-Jen A1 - Ingelsson, Erik A1 - James, Alan A1 - Jansen, Rick A1 - Jarvelin, Marjo-Riitta A1 - Joehanes, Roby A1 - Johansson, Asa A1 - Johnson, Andrew D A1 - Joshi, Peter K A1 - Jousilahti, Pekka A1 - Jukema, J Wouter A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kathiresan, Sekar A1 - Keavney, Bernard D A1 - Khaw, Kay-Tee A1 - Knekt, Paul A1 - Knight, Joanne A1 - Kolcic, Ivana A1 - Kooner, Jaspal S A1 - Koskinen, Seppo A1 - Kristiansson, Kati A1 - Kutalik, Zoltán A1 - Laan, Maris A1 - Larson, Marty A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lehtimäki, Terho A1 - Liewald, David C M A1 - Lin, Li A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Lopez, Lorna M A1 - Lu, Yingchang A1 - Lyytikäinen, Leo-Pekka A1 - Mahajan, Anubha A1 - Mamasoula, Chrysovalanto A1 - Marrugat, Jaume A1 - Marten, Jonathan A1 - Milaneschi, Yuri A1 - Morgan, Anna A1 - Morris, Andrew P A1 - Morrison, Alanna C A1 - Munson, Peter J A1 - Nalls, Mike A A1 - Nandakumar, Priyanka A1 - Nelson, Christopher P A1 - Niiranen, Teemu A1 - Nolte, Ilja M A1 - Nutile, Teresa A1 - Oldehinkel, Albertine J A1 - Oostra, Ben A A1 - O'Reilly, Paul F A1 - Org, Elin A1 - Padmanabhan, Sandosh A1 - Palmas, Walter A1 - Palotie, Aarno A1 - Pattie, Alison A1 - Penninx, Brenda W J H A1 - Perola, Markus A1 - Peters, Annette A1 - Polasek, Ozren A1 - Pramstaller, Peter P A1 - Nguyen, Quang Tri A1 - Raitakari, Olli T A1 - Ren, Meixia A1 - Rettig, Rainer A1 - Rice, Kenneth A1 - Ridker, Paul M A1 - Ried, Janina S A1 - Riese, Harriëtte A1 - Ripatti, Samuli A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Ruggiero, Daniela A1 - Saba, Yasaman A1 - Sala, Cinzia F A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Sarin, Antti-Pekka A1 - Schmidt, Reinhold A1 - Schmidt, Helena A1 - Shrine, Nick A1 - Siscovick, David A1 - Smith, Albert V A1 - Snieder, Harold A1 - Sõber, Siim A1 - Sorice, Rossella A1 - Starr, John M A1 - Stott, David J A1 - Strachan, David P A1 - Strawbridge, Rona J A1 - Sundström, Johan A1 - Swertz, Morris A A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Tobin, Martin D A1 - Tomaszewski, Maciej A1 - Toniolo, Daniela A1 - Traglia, Michela A1 - Trompet, Stella A1 - Tuomilehto, Jaakko A1 - Tzourio, Christophe A1 - Uitterlinden, André G A1 - Vaez, Ahmad A1 - van der Most, Peter J A1 - van Duijn, Cornelia M A1 - Vergnaud, Anne-Claire A1 - Verwoert, Germaine C A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Vuckovic, Dragana A1 - Watkins, Hugh A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Wright, Alan F A1 - Yao, Jie A1 - Zemunik, Tatijana A1 - Zhang, Weihua A1 - Attia, John R A1 - Butterworth, Adam S A1 - Chasman, Daniel I A1 - Conen, David A1 - Cucca, Francesco A1 - Danesh, John A1 - Hayward, Caroline A1 - Howson, Joanna M M A1 - Laakso, Markku A1 - Lakatta, Edward G A1 - Langenberg, Claudia A1 - Melander, Olle A1 - Mook-Kanamori, Dennis O A1 - Palmer, Colin N A A1 - Risch, Lorenz A1 - Scott, Robert A A1 - Scott, Rodney J A1 - Sever, Peter A1 - Spector, Tim D A1 - van der Harst, Pim A1 - Wareham, Nicholas J A1 - Zeggini, Eleftheria A1 - Levy, Daniel A1 - Munroe, Patricia B A1 - Newton-Cheh, Christopher A1 - Brown, Morris J A1 - Metspalu, Andres A1 - Hung, Adriana M A1 - O'Donnell, Christopher J A1 - Edwards, Todd L A1 - Psaty, Bruce M A1 - Tzoulaki, Ioanna A1 - Barnes, Michael R A1 - Wain, Louise V A1 - Elliott, Paul A1 - Caulfield, Mark J AB -

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

VL - 50 IS - 10 ER - TY - JOUR T1 - Meta-analysis of exome array data identifies six novel genetic loci for lung function. JF - Wellcome Open Res Y1 - 2018 A1 - Jackson, Victoria E A1 - Latourelle, Jeanne C A1 - Wain, Louise V A1 - Smith, Albert V A1 - Grove, Megan L A1 - Bartz, Traci M A1 - Obeidat, Ma'en A1 - Province, Michael A A1 - Gao, Wei A1 - Qaiser, Beenish A1 - Porteous, David J A1 - Cassano, Patricia A A1 - Ahluwalia, Tarunveer S A1 - Grarup, Niels A1 - Li, Jin A1 - Altmaier, Elisabeth A1 - Marten, Jonathan A1 - Harris, Sarah E A1 - Manichaikul, Ani A1 - Pottinger, Tess D A1 - Li-Gao, Ruifang A1 - Lind-Thomsen, Allan A1 - Mahajan, Anubha A1 - Lahousse, Lies A1 - Imboden, Medea A1 - Teumer, Alexander A1 - Prins, Bram A1 - Lyytikäinen, Leo-Pekka A1 - Eiriksdottir, Gudny A1 - Franceschini, Nora A1 - Sitlani, Colleen M A1 - Brody, Jennifer A A1 - Bossé, Yohan A1 - Timens, Wim A1 - Kraja, Aldi A1 - Loukola, Anu A1 - Tang, Wenbo A1 - Liu, Yongmei A1 - Bork-Jensen, Jette A1 - Justesen, Johanne M A1 - Linneberg, Allan A1 - Lange, Leslie A A1 - Rawal, Rajesh A1 - Karrasch, Stefan A1 - Huffman, Jennifer E A1 - Smith, Blair H A1 - Davies, Gail A1 - Burkart, Kristin M A1 - Mychaleckyj, Josyf C A1 - Bonten, Tobias N A1 - Enroth, Stefan A1 - Lind, Lars A1 - Brusselle, Guy G A1 - Kumar, Ashish A1 - Stubbe, Beate A1 - Kähönen, Mika A1 - Wyss, Annah B A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Hao, Ke A1 - Rantanen, Taina A1 - Kritchevsky, Stephen B A1 - Lohman, Kurt A1 - Skaaby, Tea A1 - Pisinger, Charlotta A1 - Hansen, Torben A1 - Schulz, Holger A1 - Polasek, Ozren A1 - Campbell, Archie A1 - Starr, John M A1 - Rich, Stephen S A1 - Mook-Kanamori, Dennis O A1 - Johansson, Asa A1 - Ingelsson, Erik A1 - Uitterlinden, André G A1 - Weiss, Stefan A1 - Raitakari, Olli T A1 - Gudnason, Vilmundur A1 - North, Kari E A1 - Gharib, Sina A A1 - Sin, Don D A1 - Taylor, Kent D A1 - O'Connor, George T A1 - Kaprio, Jaakko A1 - Harris, Tamara B A1 - Pederson, Oluf A1 - Vestergaard, Henrik A1 - Wilson, James G A1 - Strauch, Konstantin A1 - Hayward, Caroline A1 - Kerr, Shona A1 - Deary, Ian J A1 - Barr, R Graham A1 - de Mutsert, Renée A1 - Gyllensten, Ulf A1 - Morris, Andrew P A1 - Ikram, M Arfan A1 - Probst-Hensch, Nicole A1 - Gläser, Sven A1 - Zeggini, Eleftheria A1 - Lehtimäki, Terho A1 - Strachan, David P A1 - Dupuis, Josée A1 - Morrison, Alanna C A1 - Hall, Ian P A1 - Tobin, Martin D A1 - London, Stephanie J AB -

Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV ), forced vital capacity (FVC) and the ratio of FEV to FVC (FEV /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. We identified significant (P<2·8x10 ) associations with six SNPs: a nonsynonymous variant in , which is predicted to be damaging, three intronic SNPs ( and ) and two intergenic SNPs near to and Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including and . Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

VL - 3 ER - TY - JOUR T1 - Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. JF - Nat Commun Y1 - 2018 A1 - Davies, Gail A1 - Lam, Max A1 - Harris, Sarah E A1 - Trampush, Joey W A1 - Luciano, Michelle A1 - Hill, W David A1 - Hagenaars, Saskia P A1 - Ritchie, Stuart J A1 - Marioni, Riccardo E A1 - Fawns-Ritchie, Chloe A1 - Liewald, David C M A1 - Okely, Judith A A1 - Ahola-Olli, Ari V A1 - Barnes, Catriona L K A1 - Bertram, Lars A1 - Bis, Joshua C A1 - Burdick, Katherine E A1 - Christoforou, Andrea A1 - DeRosse, Pamela A1 - Djurovic, Srdjan A1 - Espeseth, Thomas A1 - Giakoumaki, Stella A1 - Giddaluru, Sudheer A1 - Gustavson, Daniel E A1 - Hayward, Caroline A1 - Hofer, Edith A1 - Ikram, M Arfan A1 - Karlsson, Robert A1 - Knowles, Emma A1 - Lahti, Jari A1 - Leber, Markus A1 - Li, Shuo A1 - Mather, Karen A A1 - Melle, Ingrid A1 - Morris, Derek A1 - Oldmeadow, Christopher A1 - Palviainen, Teemu A1 - Payton, Antony A1 - Pazoki, Raha A1 - Petrovic, Katja A1 - Reynolds, Chandra A A1 - Sargurupremraj, Muralidharan A1 - Scholz, Markus A1 - Smith, Jennifer A A1 - Smith, Albert V A1 - Terzikhan, Natalie A1 - Thalamuthu, Anbupalam A1 - Trompet, Stella A1 - van der Lee, Sven J A1 - Ware, Erin B A1 - Windham, B Gwen A1 - Wright, Margaret J A1 - Yang, Jingyun A1 - Yu, Jin A1 - Ames, David A1 - Amin, Najaf A1 - Amouyel, Philippe A1 - Andreassen, Ole A A1 - Armstrong, Nicola J A1 - Assareh, Amelia A A1 - Attia, John R A1 - Attix, Deborah A1 - Avramopoulos, Dimitrios A1 - Bennett, David A A1 - Böhmer, Anne C A1 - Boyle, Patricia A A1 - Brodaty, Henry A1 - Campbell, Harry A1 - Cannon, Tyrone D A1 - Cirulli, Elizabeth T A1 - Congdon, Eliza A1 - Conley, Emily Drabant A1 - Corley, Janie A1 - Cox, Simon R A1 - Dale, Anders M A1 - Dehghan, Abbas A1 - Dick, Danielle A1 - Dickinson, Dwight A1 - Eriksson, Johan G A1 - Evangelou, Evangelos A1 - Faul, Jessica D A1 - Ford, Ian A1 - Freimer, Nelson A A1 - Gao, He A1 - Giegling, Ina A1 - Gillespie, Nathan A A1 - Gordon, Scott D A1 - Gottesman, Rebecca F A1 - Griswold, Michael E A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hartmann, Annette M A1 - Hatzimanolis, Alex A1 - Heiss, Gerardo A1 - Holliday, Elizabeth G A1 - Joshi, Peter K A1 - Kähönen, Mika A1 - Kardia, Sharon L R A1 - Karlsson, Ida A1 - Kleineidam, Luca A1 - Knopman, David S A1 - Kochan, Nicole A A1 - Konte, Bettina A1 - Kwok, John B A1 - Le Hellard, Stephanie A1 - Lee, Teresa A1 - Lehtimäki, Terho A1 - Li, Shu-Chen A1 - Liu, Tian A1 - Koini, Marisa A1 - London, Edythe A1 - Longstreth, Will T A1 - Lopez, Oscar L A1 - Loukola, Anu A1 - Luck, Tobias A1 - Lundervold, Astri J A1 - Lundquist, Anders A1 - Lyytikäinen, Leo-Pekka A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - Murray, Alison D A1 - Need, Anna C A1 - Noordam, Raymond A1 - Nyberg, Lars A1 - Ollier, William A1 - Papenberg, Goran A1 - Pattie, Alison A1 - Polasek, Ozren A1 - Poldrack, Russell A A1 - Psaty, Bruce M A1 - Reppermund, Simone A1 - Riedel-Heller, Steffi G A1 - Rose, Richard J A1 - Rotter, Jerome I A1 - Roussos, Panos A1 - Rovio, Suvi P A1 - Saba, Yasaman A1 - Sabb, Fred W A1 - Sachdev, Perminder S A1 - Satizabal, Claudia L A1 - Schmid, Matthias A1 - Scott, Rodney J A1 - Scult, Matthew A A1 - Simino, Jeannette A1 - Slagboom, P Eline A1 - Smyrnis, Nikolaos A1 - Soumaré, Aïcha A1 - Stefanis, Nikos C A1 - Stott, David J A1 - Straub, Richard E A1 - Sundet, Kjetil A1 - Taylor, Adele M A1 - Taylor, Kent D A1 - Tzoulaki, Ioanna A1 - Tzourio, Christophe A1 - Uitterlinden, Andre A1 - Vitart, Veronique A1 - Voineskos, Aristotle N A1 - Kaprio, Jaakko A1 - Wagner, Michael A1 - Wagner, Holger A1 - Weinhold, Leonie A1 - Wen, K Hoyan A1 - Widen, Elisabeth A1 - Yang, Qiong A1 - Zhao, Wei A1 - Adams, Hieab H H A1 - Arking, Dan E A1 - Bilder, Robert M A1 - Bitsios, Panos A1 - Boerwinkle, Eric A1 - Chiba-Falek, Ornit A1 - Corvin, Aiden A1 - De Jager, Philip L A1 - Debette, Stephanie A1 - Donohoe, Gary A1 - Elliott, Paul A1 - Fitzpatrick, Annette L A1 - Gill, Michael A1 - Glahn, David C A1 - Hägg, Sara A1 - Hansell, Narelle K A1 - Hariri, Ahmad R A1 - Ikram, M Kamran A1 - Jukema, J Wouter A1 - Vuoksimaa, Eero A1 - Keller, Matthew C A1 - Kremen, William S A1 - Launer, Lenore A1 - Lindenberger, Ulman A1 - Palotie, Aarno A1 - Pedersen, Nancy L A1 - Pendleton, Neil A1 - Porteous, David J A1 - Räikkönen, Katri A1 - Raitakari, Olli T A1 - Ramirez, Alfredo A1 - Reinvang, Ivar A1 - Rudan, Igor A1 - Schmidt, Reinhold A1 - Schmidt, Helena A1 - Schofield, Peter W A1 - Schofield, Peter R A1 - Starr, John M A1 - Steen, Vidar M A1 - Trollor, Julian N A1 - Turner, Steven T A1 - van Duijn, Cornelia M A1 - Villringer, Arno A1 - Weinberger, Daniel R A1 - Weir, David R A1 - Wilson, James F A1 - Malhotra, Anil A1 - McIntosh, Andrew M A1 - Gale, Catharine R A1 - Seshadri, Sudha A1 - Mosley, Thomas H A1 - Bressler, Jan A1 - Lencz, Todd A1 - Deary, Ian J AB -

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

VL - 9 IS - 1 ER - TY - JOUR T1 - Association of low-frequency and rare coding variants with information processing speed. JF - Transl Psychiatry Y1 - 2021 A1 - Bressler, Jan A1 - Davies, Gail A1 - Smith, Albert V A1 - Saba, Yasaman A1 - Bis, Joshua C A1 - Jian, Xueqiu A1 - Hayward, Caroline A1 - Yanek, Lisa A1 - Smith, Jennifer A A1 - Mirza, Saira S A1 - Wang, Ruiqi A1 - Adams, Hieab H H A1 - Becker, Diane A1 - Boerwinkle, Eric A1 - Campbell, Archie A1 - Cox, Simon R A1 - Eiriksdottir, Gudny A1 - Fawns-Ritchie, Chloe A1 - Gottesman, Rebecca F A1 - Grove, Megan L A1 - Guo, Xiuqing A1 - Hofer, Edith A1 - Kardia, Sharon L R A1 - Knol, Maria J A1 - Koini, Marisa A1 - Lopez, Oscar L A1 - Marioni, Riccardo E A1 - Nyquist, Paul A1 - Pattie, Alison A1 - Polasek, Ozren A1 - Porteous, David J A1 - Rudan, Igor A1 - Satizabal, Claudia L A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Sidney, Stephen A1 - Simino, Jeannette A1 - Smith, Blair H A1 - Turner, Stephen T A1 - van der Lee, Sven J A1 - Ware, Erin B A1 - Whitmer, Rachel A A1 - Yaffe, Kristine A1 - Yang, Qiong A1 - Zhao, Wei A1 - Gudnason, Vilmundur A1 - Launer, Lenore J A1 - Fitzpatrick, Annette L A1 - Psaty, Bruce M A1 - Fornage, Myriam A1 - Arfan Ikram, M A1 - van Duijn, Cornelia M A1 - Seshadri, Sudha A1 - Mosley, Thomas H A1 - Deary, Ian J KW - Adult KW - Aging KW - Cognition KW - Genome-Wide Association Study KW - Geroscience KW - Humans KW - Polymorphism, Single Nucleotide KW - Ubiquitin-Protein Ligases AB -

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

VL - 11 IS - 1 ER - TY - JOUR T1 - Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning. JF - Mol Psychiatry Y1 - 2022 A1 - Lahti, Jari A1 - Tuominen, Samuli A1 - Yang, Qiong A1 - Pergola, Giulio A1 - Ahmad, Shahzad A1 - Amin, Najaf A1 - Armstrong, Nicola J A1 - Beiser, Alexa A1 - Bey, Katharina A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Bressler, Jan A1 - Campbell, Archie A1 - Campbell, Harry A1 - Chen, Qiang A1 - Corley, Janie A1 - Cox, Simon R A1 - Davies, Gail A1 - De Jager, Philip L A1 - Derks, Eske M A1 - Faul, Jessica D A1 - Fitzpatrick, Annette L A1 - Fohner, Alison E A1 - Ford, Ian A1 - Fornage, Myriam A1 - Gerring, Zachary A1 - Grabe, Hans J A1 - Grodstein, Francine A1 - Gudnason, Vilmundur A1 - Simonsick, Eleanor A1 - Holliday, Elizabeth G A1 - Joshi, Peter K A1 - Kajantie, Eero A1 - Kaprio, Jaakko A1 - Karell, Pauliina A1 - Kleineidam, Luca A1 - Knol, Maria J A1 - Kochan, Nicole A A1 - Kwok, John B A1 - Leber, Markus A1 - Lam, Max A1 - Lee, Teresa A1 - Li, Shuo A1 - Loukola, Anu A1 - Luck, Tobias A1 - Marioni, Riccardo E A1 - Mather, Karen A A1 - Medland, Sarah A1 - Mirza, Saira S A1 - Nalls, Mike A A1 - Nho, Kwangsik A1 - O'Donnell, Adrienne A1 - Oldmeadow, Christopher A1 - Painter, Jodie A1 - Pattie, Alison A1 - Reppermund, Simone A1 - Risacher, Shannon L A1 - Rose, Richard J A1 - Sadashivaiah, Vijay A1 - Scholz, Markus A1 - Satizabal, Claudia L A1 - Schofield, Peter W A1 - Schraut, Katharina E A1 - Scott, Rodney J A1 - Simino, Jeannette A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Stott, David J A1 - Surakka, Ida A1 - Teumer, Alexander A1 - Thalamuthu, Anbupalam A1 - Trompet, Stella A1 - Turner, Stephen T A1 - van der Lee, Sven J A1 - Villringer, Arno A1 - Völker, Uwe A1 - Wilson, Robert S A1 - Wittfeld, Katharina A1 - Vuoksimaa, Eero A1 - Xia, Rui A1 - Yaffe, Kristine A1 - Yu, Lei A1 - Zare, Habil A1 - Zhao, Wei A1 - Ames, David A1 - Attia, John A1 - Bennett, David A A1 - Brodaty, Henry A1 - Chasman, Daniel I A1 - Goldman, Aaron L A1 - Hayward, Caroline A1 - Ikram, M Arfan A1 - Jukema, J Wouter A1 - Kardia, Sharon L R A1 - Lencz, Todd A1 - Loeffler, Markus A1 - Mattay, Venkata S A1 - Palotie, Aarno A1 - Psaty, Bruce M A1 - Ramirez, Alfredo A1 - Ridker, Paul M A1 - Riedel-Heller, Steffi G A1 - Sachdev, Perminder S A1 - Saykin, Andrew J A1 - Scherer, Martin A1 - Schofield, Peter R A1 - Sidney, Stephen A1 - Starr, John M A1 - Trollor, Julian A1 - Ulrich, William A1 - Wagner, Michael A1 - Weir, David R A1 - Wilson, James F A1 - Wright, Margaret J A1 - Weinberger, Daniel R A1 - Debette, Stephanie A1 - Eriksson, Johan G A1 - Mosley, Thomas H A1 - Launer, Lenore J A1 - van Duijn, Cornelia M A1 - Deary, Ian J A1 - Seshadri, Sudha A1 - Räikkönen, Katri AB -

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

ER - TY - JOUR T1 - Whole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles. JF - medRxiv Y1 - 2023 A1 - Huffman, Jennifer E A1 - Nicolas, Jayna A1 - Hahn, Julie A1 - Heath, Adam S A1 - Raffield, Laura M A1 - Yanek, Lisa R A1 - Brody, Jennifer A A1 - Thibord, Florian A1 - Almasy, Laura A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Bowler, Russell P A1 - Carrasquilla, Germán D A1 - Chasman, Daniel I A1 - Chen, Ming-Huei A1 - Emmert, David B A1 - Ghanbari, Mohsen A1 - Haessle, Jeffery A1 - Hottenga, Jouke-Jan A1 - Kleber, Marcus E A1 - Le, Ngoc-Quynh A1 - Lee, Jiwon A1 - Lewis, Joshua P A1 - Li-Gao, Ruifang A1 - Luan, Jian'an A1 - Malmberg, Anni A1 - Mangino, Massimo A1 - Marioni, Riccardo E A1 - Martinez-Perez, Angel A1 - Pankratz, Nathan A1 - Polasek, Ozren A1 - Richmond, Anne A1 - Rodriguez, Benjamin At A1 - Rotter, Jerome I A1 - Steri, Maristella A1 - Suchon, Pierre A1 - Trompet, Stella A1 - Weiss, Stefan A1 - Zare, Marjan A1 - Auer, Paul A1 - Cho, Michael H A1 - Christofidou, Paraskevi A1 - Davies, Gail A1 - de Geus, Eco A1 - Deleuze, Jean-Francois A1 - Delgado, Graciela E A1 - Ekunwe, Lynette A1 - Faraday, Nauder A1 - Gögele, Martin A1 - Greinacher, Andreas A1 - He, Gao A1 - Howard, Tom A1 - Joshi, Peter K A1 - Kilpeläinen, Tuomas O A1 - Lahti, Jari A1 - Linneberg, Allan A1 - Naitza, Silvia A1 - Noordam, Raymond A1 - Paüls-Vergés, Ferran A1 - Rich, Stephen S A1 - Rosendaal, Frits R A1 - Rudan, Igor A1 - Ryan, Kathleen A A1 - Souto, Juan Carlos A1 - van Rooij, Frank Ja A1 - Wang, Heming A1 - Zhao, Wei A1 - Becker, Lewis C A1 - Beswick, Andrew A1 - Brown, Michael R A1 - Cade, Brian E A1 - Campbell, Harry A1 - Cho, Kelly A1 - Crapo, James D A1 - Curran, Joanne E A1 - de Maat, Moniek Pm A1 - Doyle, Margaret A1 - Elliott, Paul A1 - Floyd, James S A1 - Fuchsberger, Christian A1 - Grarup, Niels A1 - Guo, Xiuqing A1 - Harris, Sarah E A1 - Hou, Lifang A1 - Kolcic, Ivana A1 - Kooperberg, Charles A1 - Menni, Cristina A1 - Nauck, Matthias A1 - O'Connell, Jeffrey R A1 - Orrù, Valeria A1 - Psaty, Bruce M A1 - Räikkönen, Katri A1 - Smith, Jennifer A A1 - Soria, José Manuel A1 - Stott, David J A1 - van Hylckama Vlieg, Astrid A1 - Watkins, Hugh A1 - Willemsen, Gonneke A1 - Wilson, Peter A1 - Ben-Shlomo, Yoav A1 - Blangero, John A1 - Boomsma, Dorret A1 - Cox, Simon R A1 - Dehghan, Abbas A1 - Eriksson, Johan G A1 - Fiorillo, Edoardo A1 - Fornage, Myriam A1 - Hansen, Torben A1 - Hayward, Caroline A1 - Ikram, M Arfan A1 - Jukema, J Wouter A1 - Kardia, Sharon Lr A1 - Lange, Leslie A A1 - März, Winfried A1 - Mathias, Rasika A A1 - Mitchell, Braxton D A1 - Mook-Kanamori, Dennis O A1 - Morange, Pierre-Emmanuel A1 - Pedersen, Oluf A1 - Pramstaller, Peter P A1 - Redline, Susan A1 - Reiner, Alexander A1 - Ridker, Paul M A1 - Silverman, Edwin K A1 - Spector, Tim D A1 - Völker, Uwe A1 - Wareham, Nick A1 - Wilson, James F A1 - Yao, Jie A1 - Trégouët, David-Alexandre A1 - Johnson, Andrew D A1 - Wolberg, Alisa S A1 - de Vries, Paul S A1 - Sabater-Lleal, Maria A1 - Morrison, Alanna C A1 - Smith, Nicholas L AB -

UNLABELLED: Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI's Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10% higher in African populations. Three ( , and signals contain predicted deleterious missense variants. Two loci, and , each harbor two conditionally distinct, non-coding variants. The gene region encoding the protein chain subunits ( ), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common (MAF=0.180) in African reference panels but extremely rare (MAF=0.008) in Europeans. Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.

KEY POINTS: Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 conditionally distinct variants (20 novel).Sufficient power achieved to identify signal driven by African population variant.Links to (1) liver enzyme, blood cell and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.

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

BACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia.

METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes.

RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues.

CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.

VL - 16 IS - 1 ER -