TY - JOUR T1 - Effects of long-term averaging of quantitative blood pressure traits on the detection of genetic associations. JF - Am J Hum Genet Y1 - 2014 A1 - Ganesh, Santhi K A1 - Chasman, Daniel I A1 - Larson, Martin G A1 - Guo, Xiuqing A1 - Verwoert, Germain A1 - Bis, Joshua C A1 - Gu, Xiangjun A1 - Smith, Albert V A1 - Yang, Min-Lee A1 - Zhang, Yan A1 - Ehret, Georg A1 - Rose, Lynda M A1 - Hwang, Shih-Jen A1 - Papanicolau, George J A1 - Sijbrands, Eric J A1 - Rice, Kenneth A1 - Eiriksdottir, Gudny A1 - Pihur, Vasyl A1 - Ridker, Paul M A1 - Vasan, Ramachandran S A1 - Newton-Cheh, Christopher A1 - Raffel, Leslie J A1 - Amin, Najaf A1 - Rotter, Jerome I A1 - Liu, Kiang A1 - Launer, Lenore J A1 - Xu, Ming A1 - Caulfield, Mark A1 - Morrison, Alanna C A1 - Johnson, Andrew D A1 - Vaidya, Dhananjay A1 - Dehghan, Abbas A1 - Li, Guo A1 - Bouchard, Claude A1 - Harris, Tamara B A1 - Zhang, He A1 - Boerwinkle, Eric A1 - Siscovick, David S A1 - Gao, Wei A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Hofman, Albert A1 - Willer, Cristen J A1 - Franco, Oscar H A1 - Huo, Yong A1 - Witteman, Jacqueline C M A1 - Munroe, Patricia B A1 - Gudnason, Vilmundur A1 - Palmas, Walter A1 - van Duijn, Cornelia A1 - Fornage, Myriam A1 - Levy, Daniel A1 - Psaty, Bruce M A1 - Chakravarti, Aravinda KW - Blood Pressure KW - Genome-Wide Association Study KW - Humans KW - Longitudinal Studies KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

Blood pressure (BP) is a heritable, quantitative trait with intraindividual variability and susceptibility to measurement error. Genetic studies of BP generally use single-visit measurements and thus cannot remove variability occurring over months or years. We leveraged the idea that averaging BP measured across time would improve phenotypic accuracy and thereby increase statistical power to detect genetic associations. We studied systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) averaged over multiple years in 46,629 individuals of European ancestry. We identified 39 trait-variant associations across 19 independent loci (p < 5 × 10(-8)); five associations (in four loci) uniquely identified by our LTA analyses included those of SBP and MAP at 2p23 (rs1275988, near KCNK3), DBP at 2q11.2 (rs7599598, in FER1L5), and PP at 6p21 (rs10948071, near CRIP3) and 7p13 (rs2949837, near IGFBP3). Replication analyses conducted in cohorts with single-visit BP data showed positive replication of associations and a nominal association (p < 0.05). We estimated a 20% gain in statistical power with long-term average (LTA) as compared to single-visit BP association studies. Using LTA analysis, we identified genetic loci influencing BP. LTA might be one way of increasing the power of genetic associations for continuous traits in extant samples for other phenotypes that are measured serially over time.

VL - 95 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24975945?dopt=Abstract ER - TY - JOUR T1 - Loss-of-function mutations in APOC3, triglycerides, and coronary disease. JF - N Engl J Med Y1 - 2014 A1 - Crosby, Jacy A1 - Peloso, Gina M A1 - Auer, Paul L A1 - Crosslin, David R A1 - Stitziel, Nathan O A1 - Lange, Leslie A A1 - Lu, Yingchang A1 - Tang, Zheng-Zheng A1 - Zhang, He A1 - Hindy, George A1 - Masca, Nicholas A1 - Stirrups, Kathleen A1 - Kanoni, Stavroula A1 - Do, Ron A1 - Jun, Goo A1 - Hu, Youna A1 - Kang, Hyun Min A1 - Xue, Chenyi A1 - Goel, Anuj A1 - Farrall, Martin A1 - Duga, Stefano A1 - Merlini, Pier Angelica A1 - Asselta, Rosanna A1 - Girelli, Domenico A1 - Olivieri, Oliviero A1 - Martinelli, Nicola A1 - Yin, Wu A1 - Reilly, Dermot A1 - Speliotes, Elizabeth A1 - Fox, Caroline S A1 - Hveem, Kristian A1 - Holmen, Oddgeir L A1 - Nikpay, Majid A1 - Farlow, Deborah N A1 - Assimes, Themistocles L A1 - Franceschini, Nora A1 - Robinson, Jennifer A1 - North, Kari E A1 - Martin, Lisa W A1 - DePristo, Mark A1 - Gupta, Namrata A1 - Escher, Stefan A A1 - Jansson, Jan-Håkan A1 - Van Zuydam, Natalie A1 - Palmer, Colin N A A1 - Wareham, Nicholas A1 - Koch, Werner A1 - Meitinger, Thomas A1 - Peters, Annette A1 - Lieb, Wolfgang A1 - Erbel, Raimund A1 - König, Inke R A1 - Kruppa, Jochen A1 - Degenhardt, Franziska A1 - Gottesman, Omri A1 - Bottinger, Erwin P A1 - O'Donnell, Christopher J A1 - Psaty, Bruce M A1 - Ballantyne, Christie M A1 - Abecasis, Goncalo A1 - Ordovas, Jose M A1 - Melander, Olle A1 - Watkins, Hugh A1 - Orho-Melander, Marju A1 - Ardissino, Diego A1 - Loos, Ruth J F A1 - McPherson, Ruth A1 - Willer, Cristen J A1 - Erdmann, Jeanette A1 - Hall, Alistair S A1 - Samani, Nilesh J A1 - Deloukas, Panos A1 - Schunkert, Heribert A1 - Wilson, James G A1 - Kooperberg, Charles A1 - Rich, Stephen S A1 - Tracy, Russell P A1 - Lin, Dan-Yu A1 - Altshuler, David A1 - Gabriel, Stacey A1 - Nickerson, Deborah A A1 - Jarvik, Gail P A1 - Cupples, L Adrienne A1 - Reiner, Alex P A1 - Boerwinkle, Eric A1 - Kathiresan, Sekar KW - African Continental Ancestry Group KW - Apolipoprotein C-III KW - Coronary Disease KW - European Continental Ancestry Group KW - Exome KW - Genotype KW - Heterozygote KW - Humans KW - Liver KW - Mutation KW - Risk Factors KW - Sequence Analysis, DNA KW - Triglycerides AB -

BACKGROUND: Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype.

METHODS: We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons.

RESULTS: An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P=8×10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P=4×10(-6)).

CONCLUSIONS: Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.).

VL - 371 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24941081?dopt=Abstract ER - TY - JOUR T1 - Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. JF - Am J Hum Genet Y1 - 2014 A1 - Lange, Leslie A A1 - Hu, Youna A1 - Zhang, He A1 - Xue, Chenyi A1 - Schmidt, Ellen M A1 - Tang, Zheng-Zheng A1 - Bizon, Chris A1 - Lange, Ethan M A1 - Smith, Joshua D A1 - Turner, Emily H A1 - Jun, Goo A1 - Kang, Hyun Min A1 - Peloso, Gina A1 - Auer, Paul A1 - Li, Kuo-Ping A1 - Flannick, Jason A1 - Zhang, Ji A1 - Fuchsberger, Christian A1 - Gaulton, Kyle A1 - Lindgren, Cecilia A1 - Locke, Adam A1 - Manning, Alisa A1 - Sim, Xueling A1 - Rivas, Manuel A A1 - Holmen, Oddgeir L A1 - Gottesman, Omri A1 - Lu, Yingchang A1 - Ruderfer, Douglas A1 - Stahl, Eli A A1 - Duan, Qing A1 - Li, Yun A1 - Durda, Peter A1 - Jiao, Shuo A1 - Isaacs, Aaron A1 - Hofman, Albert A1 - Bis, Joshua C A1 - Correa, Adolfo A1 - Griswold, Michael E A1 - Jakobsdottir, Johanna A1 - Smith, Albert V A1 - Schreiner, Pamela J A1 - Feitosa, Mary F A1 - Zhang, Qunyuan A1 - Huffman, Jennifer E A1 - Crosby, Jacy A1 - Wassel, Christina L A1 - Do, Ron A1 - Franceschini, Nora A1 - Martin, Lisa W A1 - Robinson, Jennifer G A1 - Assimes, Themistocles L A1 - Crosslin, David R A1 - Rosenthal, Elisabeth A A1 - Tsai, Michael A1 - Rieder, Mark J A1 - Farlow, Deborah N A1 - Folsom, Aaron R A1 - Lumley, Thomas A1 - Fox, Ervin R A1 - Carlson, Christopher S A1 - Peters, Ulrike A1 - Jackson, Rebecca D A1 - van Duijn, Cornelia M A1 - Uitterlinden, André G A1 - Levy, Daniel A1 - Rotter, Jerome I A1 - Taylor, Herman A A1 - Gudnason, Vilmundur A1 - Siscovick, David S A1 - Fornage, Myriam A1 - Borecki, Ingrid B A1 - Hayward, Caroline A1 - Rudan, Igor A1 - Chen, Y Eugene A1 - Bottinger, Erwin P A1 - Loos, Ruth J F A1 - Sætrom, Pål A1 - Hveem, Kristian A1 - Boehnke, Michael A1 - Groop, Leif A1 - McCarthy, Mark A1 - Meitinger, Thomas A1 - Ballantyne, Christie M A1 - Gabriel, Stacey B A1 - O'Donnell, Christopher J A1 - Post, Wendy S A1 - North, Kari E A1 - Reiner, Alexander P A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Altshuler, David A1 - Kathiresan, Sekar A1 - Lin, Dan-Yu A1 - Jarvik, Gail P A1 - Cupples, L Adrienne A1 - Kooperberg, Charles A1 - Wilson, James G A1 - Nickerson, Deborah A A1 - Abecasis, Goncalo R A1 - Rich, Stephen S A1 - Tracy, Russell P A1 - Willer, Cristen J KW - Adult KW - Aged KW - Apolipoproteins E KW - Cholesterol, LDL KW - Cohort Studies KW - Dyslipidemias KW - Exome KW - Female KW - Follow-Up Studies KW - Gene Frequency KW - Genetic Code KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Lipase KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Proprotein Convertase 9 KW - Proprotein Convertases KW - Receptors, LDL KW - Sequence Analysis, DNA KW - Serine Endopeptidases AB -

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.

VL - 94 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24507775?dopt=Abstract 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 - New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals. JF - Circ Cardiovasc Genet Y1 - 2017 A1 - Kraja, Aldi T A1 - Cook, James P A1 - Warren, Helen R A1 - Surendran, Praveen A1 - Liu, Chunyu A1 - Evangelou, Evangelos A1 - Manning, Alisa K A1 - Grarup, Niels A1 - Drenos, Fotios A1 - Sim, Xueling A1 - Smith, Albert Vernon A1 - Amin, Najaf A1 - Blakemore, Alexandra I F A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Farmaki, Aliki-Eleni A1 - Fava, Cristiano A1 - Ferreira, Teresa A1 - Herzig, Karl-Heinz A1 - Giri, Ayush A1 - Giulianini, Franco A1 - Grove, Megan L A1 - Guo, Xiuqing A1 - Harris, Sarah E A1 - Have, Christian T A1 - Havulinna, Aki S A1 - Zhang, He A1 - Jørgensen, Marit E A1 - Käräjämäki, AnneMari A1 - Kooperberg, Charles A1 - Linneberg, Allan A1 - Little, Louis A1 - Liu, Yongmei A1 - Bonnycastle, Lori L A1 - Lu, Yingchang A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Malerba, Giovanni A1 - Marioni, Riccardo E A1 - Mei, Hao A1 - Menni, Cristina A1 - Morrison, Alanna C A1 - Padmanabhan, Sandosh A1 - Palmas, Walter A1 - Poveda, Alaitz A1 - Rauramaa, Rainer A1 - Rayner, Nigel William A1 - Riaz, Muhammad A1 - Rice, Ken A1 - Richard, Melissa A A1 - Smith, Jennifer A A1 - Southam, Lorraine A1 - Stančáková, Alena A1 - Stirrups, Kathleen E A1 - Tragante, Vinicius A1 - Tuomi, Tiinamaija A1 - Tzoulaki, Ioanna A1 - Varga, Tibor V A1 - Weiss, Stefan A1 - Yiorkas, Andrianos M A1 - Young, Robin A1 - Zhang, Weihua A1 - Barnes, Michael R A1 - Cabrera, Claudia P A1 - Gao, He A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Chambers, John C A1 - Connell, John M A1 - Christensen, Cramer K A1 - de Boer, Rudolf A A1 - Deary, Ian J A1 - Dedoussis, George A1 - Deloukas, Panos A1 - Dominiczak, Anna F A1 - Dörr, Marcus A1 - Joehanes, Roby A1 - Edwards, Todd L A1 - Esko, Tõnu A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Franks, Paul W A1 - Gambaro, Giovanni A1 - Groop, Leif A1 - Hallmans, Göran A1 - Hansen, Torben A1 - Hayward, Caroline A1 - Heikki, Oksa A1 - Ingelsson, Erik A1 - Tuomilehto, Jaakko A1 - Jarvelin, Marjo-Riitta A1 - Kardia, Sharon L R A1 - Karpe, Fredrik A1 - Kooner, Jaspal S A1 - Lakka, Timo A A1 - Langenberg, Claudia A1 - Lind, Lars A1 - Loos, Ruth J F A1 - Laakso, Markku A1 - McCarthy, Mark I A1 - Melander, Olle A1 - Mohlke, Karen L A1 - Morris, Andrew P A1 - Palmer, Colin N A A1 - Pedersen, Oluf A1 - Polasek, Ozren A1 - Poulter, Neil R A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Sever, Peter J A1 - Skaaby, Tea A1 - Stafford, Jeanette M A1 - Starr, John M A1 - van der Harst, Pim A1 - van der Meer, Peter A1 - van Duijn, Cornelia M A1 - Vergnaud, Anne-Claire A1 - Gudnason, Vilmundur A1 - Wareham, Nicholas J A1 - Wilson, James G A1 - Willer, Cristen J A1 - Witte, Daniel R A1 - Zeggini, Eleftheria A1 - Saleheen, Danish A1 - Butterworth, Adam S A1 - Danesh, John A1 - Asselbergs, Folkert W A1 - Wain, Louise V A1 - Ehret, Georg B A1 - Chasman, Daniel I A1 - Caulfield, Mark J A1 - Elliott, Paul A1 - Lindgren, Cecilia M A1 - Levy, Daniel A1 - Newton-Cheh, Christopher A1 - Munroe, Patricia B A1 - Howson, Joanna M M AB -

BACKGROUND: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.

METHODS AND RESULTS: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.

CONCLUSIONS: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

VL - 10 IS - 5 ER -