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1.  No Association of nineteenCOX-2 gene variants to preclinical markers of atherosclerosis The Cardiovascular Risk in Young Finns Study 
BMC Medical Genetics  2012;13:32.
Backgroud
The role of cyclooxygenase-2 (COX-2) single nucleotide polymorphisms has mostly been studied in relation to advanced atherosclerosis, but little is known how they contribute to preclinical disease. In the present study we analyzed whether COX-2 gene variants associate independently with the early subclinical markers of atherosclerosis, carotid intima-media thickness and carotid artery distensibility in a population of young healthy Caucasian adults.
Methods
SNPs for association analysis were collected from the COX-2 gene and 5 kb up- and downstream of it. There were 19 SNPs available for analysis, four genotyped and fifteen imputed. Genotype data was available for 2442 individuals participating in the Cardiovascular Risk in Young Finns Study. Genotype imputation was performed using MACH 1.0 and HapMap II CEU (release 22) samples as reference. Association analysis was performed using linear regression with an additive model. PLINK was used for true genotyped SNPs and ProbABEL for imputed genotype dosages. False discovery rate was used to take into account multiple testing bias.
Results
Two of the COX-2 variants (rs689470, rs689462) associated with distensibility (p = 0.005) under the linear regression additive model. After adjustment with gender, age, body mass index and smoking status, association between these SNPs and distensibility remained significant (p = 0.031). Subjects carrying the minor alleles had higher value of carotid artery distensibility compared to the major allele homozygotes. However, after correcting p-values for multiple testing bias using false discovery rate, association was lost. Another COX-2 variant rs4648261 associated with mean carotid intima-media thickness (p = 0.046) and maximal carotid intima-media thickness (p = 0.048) in the linear regression model. Subjects carrying the minor allele of rs4648261 had lower values of mean and maximal carotid intima-media thickness compared to subjects homozygote for major allele. After adjustments the associations were lost with both mean and maximal carotid intima-media thickness. Thus, no statistically significant associations of the studied COX-2 variants with carotid artery distensibility or carotid intima-media thickness were found.
Conclusions
Our results suggest that in a Finnish population, there are no significant associations between COX-2 variants and early atherosclerotic changes in young adulthood.
doi:10.1186/1471-2350-13-32
PMCID: PMC3388005  PMID: 22551325
2.  Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index 
Felix, Janine F. | Bradfield, Jonathan P. | Monnereau, Claire | van der Valk, Ralf J.P. | Stergiakouli, Evie | Chesi, Alessandra | Gaillard, Romy | Feenstra, Bjarke | Thiering, Elisabeth | Kreiner-Møller, Eskil | Mahajan, Anubha | Pitkänen, Niina | Joro, Raimo | Cavadino, Alana | Huikari, Ville | Franks, Steve | Groen-Blokhuis, Maria M. | Cousminer, Diana L. | Marsh, Julie A. | Lehtimäki, Terho | Curtin, John A. | Vioque, Jesus | Ahluwalia, Tarunveer S. | Myhre, Ronny | Price, Thomas S. | Vilor-Tejedor, Natalia | Yengo, Loïc | Grarup, Niels | Ntalla, Ioanna | Ang, Wei | Atalay, Mustafa | Bisgaard, Hans | Blakemore, Alexandra I. | Bonnefond, Amelie | Carstensen, Lisbeth | Eriksson, Johan | Flexeder, Claudia | Franke, Lude | Geller, Frank | Geserick, Mandy | Hartikainen, Anna-Liisa | Haworth, Claire M.A. | Hirschhorn, Joel N. | Hofman, Albert | Holm, Jens-Christian | Horikoshi, Momoko | Hottenga, Jouke Jan | Huang, Jinyan | Kadarmideen, Haja N. | Kähönen, Mika | Kiess, Wieland | Lakka, Hanna-Maaria | Lakka, Timo A. | Lewin, Alexandra M. | Liang, Liming | Lyytikäinen, Leo-Pekka | Ma, Baoshan | Magnus, Per | McCormack, Shana E. | McMahon, George | Mentch, Frank D. | Middeldorp, Christel M. | Murray, Clare S. | Pahkala, Katja | Pers, Tune H. | Pfäffle, Roland | Postma, Dirkje S. | Power, Christine | Simpson, Angela | Sengpiel, Verena | Tiesler, Carla M. T. | Torrent, Maties | Uitterlinden, André G. | van Meurs, Joyce B. | Vinding, Rebecca | Waage, Johannes | Wardle, Jane | Zeggini, Eleftheria | Zemel, Babette S. | Dedoussis, George V. | Pedersen, Oluf | Froguel, Philippe | Sunyer, Jordi | Plomin, Robert | Jacobsson, Bo | Hansen, Torben | Gonzalez, Juan R. | Custovic, Adnan | Raitakari, Olli T. | Pennell, Craig E. | Widén, Elisabeth | Boomsma, Dorret I. | Koppelman, Gerard H. | Sebert, Sylvain | Järvelin, Marjo-Riitta | Hyppönen, Elina | McCarthy, Mark I. | Lindi, Virpi | Harri, Niinikoski | Körner, Antje | Bønnelykke, Klaus | Heinrich, Joachim | Melbye, Mads | Rivadeneira, Fernando | Hakonarson, Hakon | Ring, Susan M. | Smith, George Davey | Sørensen, Thorkild I.A. | Timpson, Nicholas J. | Grant, Struan F.A. | Jaddoe, Vincent W.V.
Human Molecular Genetics  2015;25(2):389-403.
A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10−8) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10−10) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.
doi:10.1093/hmg/ddv472
PMCID: PMC4854022  PMID: 26604143
3.  Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits 
Pankratz, Nathan | Schick, Ursula M | Zhou, Yi | Zhou, Wei | Ahluwalia, Tarunveer Singh | Allende, Maria Laura | Auer, Paul L | Bork-Jensen, Jette | Brody, Jennifer A | Chen, Ming-Huei | Clavo, Vinna | Eicher, John D | Grarup, Niels | Hagedorn, Elliott J | Hu, Bella | Hunker, Kristina | Johnson, Andrew D | Leusink, Maarten | Lu, Yingchang | Lyytikäinen, Leo-Pekka | Manichaikul, Ani | Marioni, Riccardo E | Nalls, Mike A | Pazoki, Raha | Smith, Albert Vernon | van Rooij, Frank J A | Yang, Min-Lee | Zhang, Xiaoling | Zhang, Yan | Asselbergs, Folkert W | Boerwinkle, Eric | Borecki, Ingrid B | Bottinger, Erwin P | Cushman, Mary | de Bakker, Paul I W | Deary, Ian J | Dong, Liguang | Feitosa, Mary F | Floyd, James S | Franceschini, Nora | Franco, Oscar H | Garcia, Melissa E | Grove, Megan L | Gudnason, Vilmundur | Hansen, Torben | Harris, Tamara B | Hofman, Albert | Jackson, Rebecca D | Jia, Jia | Kähönen, Mika | Launer, Lenore J | Lehtimäki, Terho | Liewald, David C | Linneberg, Allan | Liu, Yongmei | Loos, Ruth J F | Nguyen, Vy M | Numans, Mattijs E | Pedersen, Oluf | Psaty, Bruce M | Raitakari, Olli T | Rich, Stephen S | Rivadeneira, Fernando | Di Sant, Amanda M Rosa | Rotter, Jerome I | Starr, John M | Taylor, Kent D | Thuesen, Betina Heinsbæk | Tracy, Russell P | Uitterlinden, Andre G | Wang, Jiansong | Wang, Judy | Dehghan, Abbas | Huo, Yong | Cupples, L Adrienne | Wilson, James G | Proia, Richard L | Zon, Leonard I | O’Donnell, Christopher J | Reiner, Alex P | Ganesh, Santhi K
Nature genetics  2016;48(8):867-876.
Hematologic measures such as hematocrit and white blood cell (WBC) count are heritable and clinically relevant. Erythrocyte and WBC phenotypes were analyzed with Illumina HumanExome BeadChip genotypes in 52,531 individuals (37,775 of European ancestry; 11,589 African Americans; 3,167 Hispanic Americans) from 16 population-based cohorts. We then performed replication analyses of novel discoveries in 18,018 European American women and 5,261 Han Chinese. We identified and replicated four novel erythrocyte trait-locus associations (CEP89, SHROOM3, FADS2, and APOE) and six novel WBC loci for neutrophil count (S1PR4), monocyte count (BTBD8, NLRP12, and IL17RA), eosinophil count (IRF1), and total WBC (MYB). The novel association of a rare missense variant in S1PR4 supports the role of sphingosine-1-phosphate signaling in leukocyte trafficking and circulating neutrophil counts. Loss-of-function experiments of S1pr4 in mouse and zebrafish demonstrated phenotypes consistent with the association observed in humans and altered kinetics of neutrophil recruitment and resolution in response to tissue injury.
doi:10.1038/ng.3607
PMCID: PMC5145000  PMID: 27399967
4.  No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis 
Loley, Christina | Alver, Maris | Assimes, Themistocles L. | Bjonnes, Andrew | Goel, Anuj | Gustafsson, Stefan | Hernesniemi, Jussi | Hopewell, Jemma C. | Kanoni, Stavroula | Kleber, Marcus E. | Lau, King Wai | Lu, Yingchang | Lyytikäinen, Leo-Pekka | Nelson, Christopher P. | Nikpay, Majid | Qu, Liming | Salfati, Elias | Scholz, Markus | Tukiainen, Taru | Willenborg, Christina | Won, Hong-Hee | Zeng, Lingyao | Zhang, Weihua | Anand, Sonia S. | Beutner, Frank | Bottinger, Erwin P. | Clarke, Robert | Dedoussis, George | Do, Ron | Esko, Tõnu | Eskola, Markku | Farrall, Martin | Gauguier, Dominique | Giedraitis, Vilmantas | Granger, Christopher B. | Hall, Alistair S. | Hamsten, Anders | Hazen, Stanley L. | Huang, Jie | Kähönen, Mika | Kyriakou, Theodosios | Laaksonen, Reijo | Lind, Lars | Lindgren, Cecilia | Magnusson, Patrik K. E. | Marouli, Eirini | Mihailov, Evelin | Morris, Andrew P. | Nikus, Kjell | Pedersen, Nancy | Rallidis, Loukianos | Salomaa, Veikko | Shah, Svati H. | Stewart, Alexandre F. R. | Thompson, John R. | Zalloua, Pierre A. | Chambers, John C. | Collins, Rory | Ingelsson, Erik | Iribarren, Carlos | Karhunen, Pekka J. | Kooner, Jaspal S. | Lehtimäki, Terho | Loos, Ruth J. F. | März, Winfried | McPherson, Ruth | Metspalu, Andres | Reilly, Muredach P. | Ripatti, Samuli | Sanghera, Dharambir K. | Thiery, Joachim | Watkins, Hugh | Deloukas, Panos | Kathiresan, Sekar | Samani, Nilesh J. | Schunkert, Heribert | Erdmann, Jeanette | König, Inke R.
Scientific Reports  2016;6:35278.
In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.
doi:10.1038/srep35278
PMCID: PMC5059659  PMID: 27731410
5.  Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function 
Pattaro, Cristian | Teumer, Alexander | Gorski, Mathias | Chu, Audrey Y. | Li, Man | Mijatovic, Vladan | Garnaas, Maija | Tin, Adrienne | Sorice, Rossella | Li, Yong | Taliun, Daniel | Olden, Matthias | Foster, Meredith | Yang, Qiong | Chen, Ming-Huei | Pers, Tune H. | Johnson, Andrew D. | Ko, Yi-An | Fuchsberger, Christian | Tayo, Bamidele | Nalls, Michael | Feitosa, Mary F. | Isaacs, Aaron | Dehghan, Abbas | d’Adamo, Pio | Adeyemo, Adebowale | Dieffenbach, Aida Karina | Zonderman, Alan B. | Nolte, Ilja M. | van der Most, Peter J. | Wright, Alan F. | Shuldiner, Alan R. | Morrison, Alanna C. | Hofman, Albert | Smith, Albert V. | Dreisbach, Albert W. | Franke, Andre | Uitterlinden, Andre G. | Metspalu, Andres | Tonjes, Anke | Lupo, Antonio | Robino, Antonietta | Johansson, Åsa | Demirkan, Ayse | Kollerits, Barbara | Freedman, Barry I. | Ponte, Belen | Oostra, Ben A. | Paulweber, Bernhard | Krämer, Bernhard K. | Mitchell, Braxton D. | Buckley, Brendan M. | Peralta, Carmen A. | Hayward, Caroline | Helmer, Catherine | Rotimi, Charles N. | Shaffer, Christian M. | Müller, Christian | Sala, Cinzia | van Duijn, Cornelia M. | Saint-Pierre, Aude | Ackermann, Daniel | Shriner, Daniel | Ruggiero, Daniela | Toniolo, Daniela | Lu, Yingchang | Cusi, Daniele | Czamara, Darina | Ellinghaus, David | Siscovick, David S. | Ruderfer, Douglas | Gieger, Christian | Grallert, Harald | Rochtchina, Elena | Atkinson, Elizabeth J. | Holliday, Elizabeth G. | Boerwinkle, Eric | Salvi, Erika | Bottinger, Erwin P. | Murgia, Federico | Rivadeneira, Fernando | Ernst, Florian | Kronenberg, Florian | Hu, Frank B. | Navis, Gerjan J. | Curhan, Gary C. | Ehret, George B. | Homuth, Georg | Coassin, Stefan | Thun, Gian-Andri | Pistis, Giorgio | Gambaro, Giovanni | Malerba, Giovanni | Montgomery, Grant W. | Eiriksdottir, Gudny | Jacobs, Gunnar | Li, Guo | Wichmann, H.-Erich | Campbell, Harry | Schmidt, Helena | Wallaschofski, Henri | Völzke, Henry | Brenner, Hermann | Kroemer, Heyo K. | Kramer, Holly | Lin, Honghuang | Leach, I. Mateo | Ford, Ian | Guessous, Idris | Rudan, Igor | Prokopenko, Inga | Borecki, Ingrid | Heid, Iris M. | Kolcic, Ivana | Persico, Ivana | Jukema, J. Wouter | Wilson, James F. | Felix, Janine F. | Divers, Jasmin | Lambert, Jean-Charles | Stafford, Jeanette M. | Gaspoz, Jean-Michel | Smith, Jennifer A. | Faul, Jessica D. | Wang, Jie Jin | Ding, Jingzhong | Hirschhorn, Joel N. | Attia, John | Whitfield, John B. | Chalmers, John | Viikari, Jorma | Coresh, Josef | Denny, Joshua C. | Karjalainen, Juha | Fernandes, Jyotika K. | Endlich, Karlhans | Butterbach, Katja | Keene, Keith L. | Lohman, Kurt | Portas, Laura | Launer, Lenore J. | Lyytikäinen, Leo-Pekka | Yengo, Loic | Franke, Lude | Ferrucci, Luigi | Rose, Lynda M. | Kedenko, Lyudmyla | Rao, Madhumathi | Struchalin, Maksim | Kleber, Marcus E. | Cavalieri, Margherita | Haun, Margot | Cornelis, Marilyn C. | Ciullo, Marina | Pirastu, Mario | de Andrade, Mariza | McEvoy, Mark A. | Woodward, Mark | Adam, Martin | Cocca, Massimiliano | Nauck, Matthias | Imboden, Medea | Waldenberger, Melanie | Pruijm, Menno | Metzger, Marie | Stumvoll, Michael | Evans, Michele K. | Sale, Michele M. | Kähönen, Mika | Boban, Mladen | Bochud, Murielle | Rheinberger, Myriam | Verweij, Niek | Bouatia-Naji, Nabila | Martin, Nicholas G. | Hastie, Nick | Probst-Hensch, Nicole | Soranzo, Nicole | Devuyst, Olivier | Raitakari, Olli | Gottesman, Omri | Franco, Oscar H | Polasek, Ozren | Gasparini, Paolo | Munroe, Patricia B. | Ridker, Paul M. | Mitchell, Paul | Muntner, Paul | Meisinger, Christa | Smit, Johannes H. | Kovacs, Peter | Wild, Philipp S. | Froguel, Philippe | Rettig, Rainer | Magi, Reedik | Biffar, Reiner | Schmidt, Reinhold | Middelberg, Rita PS | Carroll, Robert J. | Penninx, Brenda W. | Scott, Rodney J. | Katz, Ronit | Sedaghat, Sanaz | Wild, Sarah H. | Kardia, Sharon L.R. | Ulivi, Sheila | Hwang, Shih-Jen | Enroth, Stefan | Kloiber, Stefan | Trompet, Stella | Stengel, Benedicte | Hancock, Stephen J. | Turner, Stephen T. | Rosas, Sylvia E. | Stracke, Sylvia | Harris, Tamara B. | Zeller, Tanja | Zemunik, Tatijana | Lehtimäki, Terho | Illig, Thomas | Aspelund, Thor | Nikopensius, Tiit | Esko, Tonu | Tanaka, Toshiko | Gyllensten, Ulf | Völker, Uwe | Emilsson, Valur | Vitart, Veronique | Aalto, Ville | Gudnason, Vilmundur | Chouraki, Vincent | Chen, Wei-Min | Igl, Wilmar | März, Winfried | Koenig, Wolfgang | Lieb, Wolfgang | Loos, Ruth J. F. | Liu, Yongmei | Snieder, Harold | Pramstaller, Peter P. | Parsa, Afshin | O’Connell, Jeffrey R. | Susztak, Katalin | Hamet, Pavel | Tremblay, Johanne | de Boer, Ian H. | Böger, Carsten A. | Goessling, Wolfram | Chasman, Daniel I. | Köttgen, Anna | Kao, WH Linda | Fox, Caroline S.
Nature communications  2016;7:10023.
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, nineteen associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biologic pathways.
doi:10.1038/ncomms10023
PMCID: PMC4735748  PMID: 26831199
6.  Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels 
van Leeuwen, Elisabeth M | Sabo, Aniko | Bis, Joshua C | Huffman, Jennifer E | Manichaikul, Ani | Smith, Albert V | Feitosa, Mary F | Demissie, Serkalem | Joshi, Peter K | Duan, Qing | Marten, Jonathan | van Klinken, Jan B | Surakka, Ida | Nolte, Ilja M | Zhang, Weihua | Mbarek, Hamdi | Li-Gao, Ruifang | Trompet, Stella | Verweij, Niek | Evangelou, Evangelos | Lyytikäinen, Leo-Pekka | Tayo, Bamidele O | Deelen, Joris | van der Most, Peter J | van der Laan, Sander W | Arking, Dan E | Morrison, Alanna | Dehghan, Abbas | Franco, Oscar H | Hofman, Albert | Rivadeneira, Fernando | Sijbrands, Eric J | Uitterlinden, Andre G | Mychaleckyj, Josyf C | Campbell, Archie | Hocking, Lynne J | Padmanabhan, Sandosh | Brody, Jennifer A | Rice, Kenneth M | White, Charles C | Harris, Tamara | Isaacs, Aaron | Campbell, Harry | Lange, Leslie A | Rudan, Igor | Kolcic, Ivana | Navarro, Pau | Zemunik, Tatijana | Salomaa, Veikko | Kooner, Angad S | Kooner, Jaspal S | Lehne, Benjamin | Scott, William R | Tan, Sian-Tsung | de Geus, Eco J | Milaneschi, Yuri | Penninx, Brenda W J H | Willemsen, Gonneke | de Mutsert, Renée | Ford, Ian | Gansevoort, Ron T | Segura-Lepe, Marcelo P | Raitakari, Olli T | Viikari, Jorma S | Nikus, Kjell | Forrester, Terrence | McKenzie, Colin A | de Craen, Anton J M | de Ruijter, Hester M | Pasterkamp, Gerard | Snieder, Harold | Oldehinkel, Albertine J | Slagboom, P Eline | Cooper, Richard S | Kähönen, Mika | Lehtimäki, Terho | Elliott, Paul | van der Harst, Pim | Jukema, J Wouter | Mook-Kanamori, Dennis O | Boomsma, Dorret I | Chambers, John C | Swertz, Morris | Ripatti, Samuli | Willems van Dijk, Ko | Vitart, Veronique | Polasek, Ozren | Hayward, Caroline | Wilson, James G | Wilson, James F | Gudnason, Vilmundur | Rich, Stephen S | Psaty, Bruce M | Borecki, Ingrid B | Boerwinkle, Eric | Rotter, Jerome I | Cupples, L Adrienne | van Duijn, Cornelia M
Journal of Medical Genetics  2016;53(7):441-449.
Background
So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.
Methods
We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage.
Results
Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.
Conclusions
This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.
doi:10.1136/jmedgenet-2015-103439
PMCID: PMC4941146  PMID: 27036123
Complex traits; Epidemiology; Genetics; Genome-wide; circulating lipid levels
7.  A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease 
Nikpay, Majid | Goel, Anuj | Won, Hong-Hee | Hall, Leanne M | Willenborg, Christina | Kanoni, Stavroula | Saleheen, Danish | Kyriakou, Theodosios | Nelson, Christopher P | Hopewell, Jemma C | Webb, Thomas R | Zeng, Lingyao | Dehghan, Abbas | Alver, Maris | Armasu, Sebastian M | Auro, Kirsi | Bjonnes, Andrew | Chasman, Daniel I | Chen, Shufeng | Ford, Ian | Franceschini, Nora | Gieger, Christian | Grace, Christopher | Gustafsson, Stefan | Huang, Jie | Hwang, Shih-Jen | Kim, Yun Kyoung | Kleber, Marcus E | Lau, King Wai | Lu, Xiangfeng | Lu, Yingchang | Lyytikäinen, Leo-Pekka | Mihailov, Evelin | Morrison, Alanna C | Pervjakova, Natalia | Qu, Liming | Rose, Lynda M | Salfati, Elias | Saxena, Richa | Scholz, Markus | Smith, Albert V | Tikkanen, Emmi | Uitterlinden, Andre | Yang, Xueli | Zhang, Weihua | Zhao, Wei | de Andrade, Mariza | de Vries, Paul S | van Zuydam, Natalie R | Anand, Sonia S | Bertram, Lars | Beutner, Frank | Dedoussis, George | Frossard, Philippe | Gauguier, Dominique | Goodall, Alison H | Gottesman, Omri | Haber, Marc | Han, Bok-Ghee | Huang, Jianfeng | Jalilzadeh, Shapour | Kessler, Thorsten | König, Inke R | Lannfelt, Lars | Lieb, Wolfgang | Lind, Lars | Lindgren, Cecilia M | Lokki, Marja-Liisa | Magnusson, Patrik K | Mallick, Nadeem H | Mehra, Narinder | Meitinger, Thomas | Memon, Fazal-ur-Rehman | Morris, Andrew P | Nieminen, Markku S | Pedersen, Nancy L | Peters, Annette | Rallidis, Loukianos S | Rasheed, Asif | Samuel, Maria | Shah, Svati H | Sinisalo, Juha | Stirrups, Kathleen E | Trompet, Stella | Wang, Laiyuan | Zaman, Khan S | Ardissino, Diego | Boerwinkle, Eric | Borecki, Ingrid B | Bottinger, Erwin P | Buring, Julie E | Chambers, John C | Collins, Rory | Cupples, L Adrienne | Danesh, John | Demuth, Ilja | Elosua, Roberto | Epstein, Stephen E | Esko, Tõnu | Feitosa, Mary F | Franco, Oscar H | Franzosi, Maria Grazia | Granger, Christopher B | Gu, Dongfeng | Gudnason, Vilmundur | Hall, Alistair S | Hamsten, Anders | Harris, Tamara B | Hazen, Stanley L | Hengstenberg, Christian | Hofman, Albert | Ingelsson, Erik | Iribarren, Carlos | Jukema, J Wouter | Karhunen, Pekka J | Kim, Bong-Jo | Kooner, Jaspal S | Kullo, Iftikhar J | Lehtimäki, Terho | Loos, Ruth J F | Melander, Olle | Metspalu, Andres | März, Winfried | Palmer, Colin N | Perola, Markus | Quertermous, Thomas | Rader, Daniel J | Ridker, Paul M | Ripatti, Samuli | Roberts, Robert | Salomaa, Veikko | Sanghera, Dharambir K | Schwartz, Stephen M | Seedorf, Udo | Stewart, Alexandre F | Stott, David J | Thiery, Joachim | Zalloua, Pierre A | O’Donnell, Christopher J | Reilly, Muredach P | Assimes, Themistocles L | Thompson, John R | Erdmann, Jeanette | Clarke, Robert | Watkins, Hugh | Kathiresan, Sekar | McPherson, Ruth | Deloukas, Panos | Schunkert, Heribert | Samani, Nilesh J | Farrall, Martin
Nature genetics  2015;47(10):1121-1130.
Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association studies (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of 185 thousand CAD cases and controls, interrogating 6.7 million common (MAF>0.05) as well as 2.7 million low frequency (0.005
doi:10.1038/ng.3396
PMCID: PMC4589895  PMID: 26343387
Nature Communications  2016;7:11122.
Genome-wide association studies have identified numerous loci linked with complex diseases, for which the molecular mechanisms remain largely unclear. Comprehensive molecular profiling of circulating metabolites captures highly heritable traits, which can help to uncover metabolic pathophysiology underlying established disease variants. We conduct an extended genome-wide association study of genetic influences on 123 circulating metabolic traits quantified by nuclear magnetic resonance metabolomics from up to 24,925 individuals and identify eight novel loci for amino acids, pyruvate and fatty acids. The LPA locus link with cardiovascular risk exemplifies how detailed metabolic profiling may inform underlying aetiology via extensive associations with very-low-density lipoprotein and triglyceride metabolism. Genetic fine mapping and Mendelian randomization uncover wide-spread causal effects of lipoprotein(a) on overall lipoprotein metabolism and we assess potential pleiotropic consequences of genetically elevated lipoprotein(a) on diverse morbidities via electronic health-care records. Our findings strengthen the argument for safe LPA-targeted intervention to reduce cardiovascular risk.
Circulating metabolites reflect human health and disease. Here, Kettunen et al. perform a genome-wide association study on 123 circulating metabolic traits and identify novel genetic loci influencing systemic metabolism. They also link new molecular pathways with a known cardiovascular risk factor Lp(a).
doi:10.1038/ncomms11122
PMCID: PMC4814583  PMID: 27005778
Scientific Reports  2016;6:23207.
Asymmetric and symmetric dimethylarginines (ADMA and SDMA) impair nitric oxide bioavailability and have been implicated in the pathogenesis of atrial fibrillation (AF). Alanine–glyoxylate aminotransferase 2 (AGXT2) is the only enzyme capable of metabolizing both of the dimethylarginines. We hypothesized that two functional AGXT2 missense variants (rs37369, V140I; rs16899974, V498L) are associated with AF and its cardioembolic complications. Association analyses were conducted using 1,834 individulas with AF and 7,159 unaffected individuals from two coronary angiography cohorts and a cohort comprising patients undergoing clinical exercise testing. In coronary angiography patients without structural heart disease, the minor A allele of rs16899974 was associated with any AF (OR = 2.07, 95% CI 1.59-2.68), and with paroxysmal AF (OR = 1.98, 95% CI 1.44–2.74) and chronic AF (OR = 2.03, 95% CI 1.35–3.06) separately. We could not replicate the association with AF in the other two cohorts. However, the A allele of rs16899974 was nominally associated with ischemic stroke risk in the meta-analysis of WTCCC2 ischemic stroke cohorts (3,548 cases, 5,972 controls) and with earlier onset of first-ever ischemic stroke (360 cases) in the cohort of clinical exercise test patients. In conclusion, AGXT2 variations may be involved in the pathogenesis of AF and its age-related thromboembolic complications.
doi:10.1038/srep23207
PMCID: PMC4794714  PMID: 26984639
Human Molecular Genetics  2016;25(10):2093-2103.
The ST-segment and adjacent T-wave (ST-T wave) amplitudes of the electrocardiogram are quantitative characteristics of cardiac repolarization. Repolarization abnormalities have been linked to ventricular arrhythmias and sudden cardiac death. We performed the first genome-wide association meta-analysis of ST-T-wave amplitudes in up to 37 977 individuals identifying 71 robust genotype–phenotype associations clustered within 28 independent loci. Fifty-four genes were prioritized as candidates underlying the phenotypes, including genes with established roles in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) and others with as yet undefined cardiac function. These associations may provide insights in the spatiotemporal contribution of genetic variation influencing cardiac repolarization and provide novel leads for future functional follow-up.
doi:10.1093/hmg/ddw058
PMCID: PMC5062578  PMID: 26962151
Scientific Reports  2016;6:20092.
Genome-wide association studies (GWAS) of complex behavioural phenotypes such as cigarette smoking typically employ self-report phenotypes. However, precise biomarker phenotypes may afford greater statistical power and identify novel variants. Here we report the results of a GWAS meta-analysis of levels of cotinine, the primary metabolite of nicotine, in 4,548 daily smokers of European ancestry. We identified a locus close to UGT2B10 at 4q13.2 (minimum p = 5.89 × 10−10 for rs114612145), which was consequently replicated. This variant is in high linkage disequilibrium with a known functional variant in the UGT2B10 gene which is associated with reduced nicotine and cotinine glucuronidation activity, but intriguingly is not associated with nicotine intake. Additionally, we observed association between multiple variants within the 15q25.1 region and cotinine levels, all located within the CHRNA5-A3-B4 gene cluster or adjacent genes, consistent with previous much larger GWAS using self-report measures of smoking quantity. These results clearly illustrate the increase in power afforded by using precise biomarker measures in GWAS. Perhaps more importantly however, they also highlight that biomarkers do not always mark the phenotype of interest. The use of metabolite data as a proxy for environmental exposures should be carefully considered in the context of individual differences in metabolic pathways.
doi:10.1038/srep20092
PMCID: PMC4735517  PMID: 26833182
Kilpeläinen, Tuomas O. | Carli, Jayne F. Martin | Skowronski, Alicja A. | Sun, Qi | Kriebel, Jennifer | Feitosa, Mary F | Hedman, Åsa K. | Drong, Alexander W. | Hayes, James E. | Zhao, Jinghua | Pers, Tune H. | Schick, Ursula | Grarup, Niels | Kutalik, Zoltán | Trompet, Stella | Mangino, Massimo | Kristiansson, Kati | Beekman, Marian | Lyytikäinen, Leo-Pekka | Eriksson, Joel | Henneman, Peter | Lahti, Jari | Tanaka, Toshiko | Luan, Jian'an | Greco M, Fabiola Del | Pasko, Dorota | Renström, Frida | Willems, Sara M. | Mahajan, Anubha | Rose, Lynda M. | Guo, Xiuqing | Liu, Yongmei | Kleber, Marcus E. | Pérusse, Louis | Gaunt, Tom | Ahluwalia, Tarunveer S. | Ju Sung, Yun | Ramos, Yolande F. | Amin, Najaf | Amuzu, Antoinette | Barroso, Inês | Bellis, Claire | Blangero, John | Buckley, Brendan M. | Böhringer, Stefan | I Chen, Yii-Der | de Craen, Anton J. N. | Crosslin, David R. | Dale, Caroline E. | Dastani, Zari | Day, Felix R. | Deelen, Joris | Delgado, Graciela E. | Demirkan, Ayse | Finucane, Francis M. | Ford, Ian | Garcia, Melissa E. | Gieger, Christian | Gustafsson, Stefan | Hallmans, Göran | Hankinson, Susan E. | Havulinna, Aki S | Herder, Christian | Hernandez, Dena | Hicks, Andrew A. | Hunter, David J. | Illig, Thomas | Ingelsson, Erik | Ioan-Facsinay, Andreea | Jansson, John-Olov | Jenny, Nancy S. | Jørgensen, Marit E. | Jørgensen, Torben | Karlsson, Magnus | Koenig, Wolfgang | Kraft, Peter | Kwekkeboom, Joanneke | Laatikainen, Tiina | Ladwig, Karl-Heinz | LeDuc, Charles A. | Lowe, Gordon | Lu, Yingchang | Marques-Vidal, Pedro | Meisinger, Christa | Menni, Cristina | Morris, Andrew P. | Myers, Richard H. | Männistö, Satu | Nalls, Mike A. | Paternoster, Lavinia | Peters, Annette | Pradhan, Aruna D. | Rankinen, Tuomo | Rasmussen-Torvik, Laura J. | Rathmann, Wolfgang | Rice, Treva K. | Brent Richards, J | Ridker, Paul M. | Sattar, Naveed | Savage, David B. | Söderberg, Stefan | Timpson, Nicholas J. | Vandenput, Liesbeth | van Heemst, Diana | Uh, Hae-Won | Vohl, Marie-Claude | Walker, Mark | Wichmann, Heinz-Erich | Widén, Elisabeth | Wood, Andrew R. | Yao, Jie | Zeller, Tanja | Zhang, Yiying | Meulenbelt, Ingrid | Kloppenburg, Margreet | Astrup, Arne | Sørensen, Thorkild I. A. | Sarzynski, Mark A. | Rao, D. C. | Jousilahti, Pekka | Vartiainen, Erkki | Hofman, Albert | Rivadeneira, Fernando | Uitterlinden, André G. | Kajantie, Eero | Osmond, Clive | Palotie, Aarno | Eriksson, Johan G. | Heliövaara, Markku | Knekt, Paul B. | Koskinen, Seppo | Jula, Antti | Perola, Markus | Huupponen, Risto K. | Viikari, Jorma S. | Kähönen, Mika | Lehtimäki, Terho | Raitakari, Olli T. | Mellström, Dan | Lorentzon, Mattias | Casas, Juan P. | Bandinelli, Stefanie | März, Winfried | Isaacs, Aaron | van Dijk, Ko W. | van Duijn, Cornelia M. | Harris, Tamara B. | Bouchard, Claude | Allison, Matthew A. | Chasman, Daniel I. | Ohlsson, Claes | Lind, Lars | Scott, Robert A. | Langenberg, Claudia | Wareham, Nicholas J. | Ferrucci, Luigi | Frayling, Timothy M. | Pramstaller, Peter P. | Borecki, Ingrid B. | Waterworth, Dawn M. | Bergmann, Sven | Waeber, Gérard | Vollenweider, Peter | Vestergaard, Henrik | Hansen, Torben | Pedersen, Oluf | Hu, Frank B. | Eline Slagboom, P | Grallert, Harald | Spector, Tim D. | Jukema, J.W. | Klein, Robert J. | Schadt, Erik E | Franks, Paul W. | Lindgren, Cecilia M. | Leibel, Rudolph L. | Loos, Ruth J. F.
Nature Communications  2016;7:10494.
Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10−6 in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10−8) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
This meta-analysis of genome-wide association studies identifies four genetic loci associated with circulating leptin levels independent of adiposity. Examination in mouse adipose tissue explants provides functional support for the leptin-associated loci.
doi:10.1038/ncomms10494
PMCID: PMC4740377  PMID: 26833098
Lu, Yingchang | Day, Felix R. | Gustafsson, Stefan | Buchkovich, Martin L. | Na, Jianbo | Bataille, Veronique | Cousminer, Diana L. | Dastani, Zari | Drong, Alexander W. | Esko, Tõnu | Evans, David M. | Falchi, Mario | Feitosa, Mary F. | Ferreira, Teresa | Hedman, Åsa K. | Haring, Robin | Hysi, Pirro G. | Iles, Mark M. | Justice, Anne E. | Kanoni, Stavroula | Lagou, Vasiliki | Li, Rui | Li, Xin | Locke, Adam | Lu, Chen | Mägi, Reedik | Perry, John R. B. | Pers, Tune H. | Qi, Qibin | Sanna, Marianna | Schmidt, Ellen M. | Scott, William R. | Shungin, Dmitry | Teumer, Alexander | Vinkhuyzen, Anna A. E. | Walker, Ryan W. | Westra, Harm-Jan | Zhang, Mingfeng | Zhang, Weihua | Zhao, Jing Hua | Zhu, Zhihong | Afzal, Uzma | Ahluwalia, Tarunveer Singh | Bakker, Stephan J. L. | Bellis, Claire | Bonnefond, Amélie | Borodulin, Katja | Buchman, Aron S. | Cederholm, Tommy | Choh, Audrey C. | Choi, Hyung Jin | Curran, Joanne E. | de Groot, Lisette C. P. G. M. | De Jager, Philip L. | Dhonukshe-Rutten, Rosalie A. M. | Enneman, Anke W. | Eury, Elodie | Evans, Daniel S. | Forsen, Tom | Friedrich, Nele | Fumeron, Frédéric | Garcia, Melissa E. | Gärtner, Simone | Han, Bok-Ghee | Havulinna, Aki S. | Hayward, Caroline | Hernandez, Dena | Hillege, Hans | Ittermann, Till | Kent, Jack W. | Kolcic, Ivana | Laatikainen, Tiina | Lahti, Jari | Leach, Irene Mateo | Lee, Christine G. | Lee, Jong-Young | Liu, Tian | Liu, Youfang | Lobbens, Stéphane | Loh, Marie | Lyytikäinen, Leo-Pekka | Medina-Gomez, Carolina | Michaëlsson, Karl | Nalls, Mike A. | Nielson, Carrie M. | Oozageer, Laticia | Pascoe, Laura | Paternoster, Lavinia | Polašek, Ozren | Ripatti, Samuli | Sarzynski, Mark A. | Shin, Chan Soo | Narančić, Nina Smolej | Spira, Dominik | Srikanth, Priya | Steinhagen-Thiessen, Elisabeth | Sung, Yun Ju | Swart, Karin M. A. | Taittonen, Leena | Tanaka, Toshiko | Tikkanen, Emmi | van der Velde, Nathalie | van Schoor, Natasja M. | Verweij, Niek | Wright, Alan F. | Yu, Lei | Zmuda, Joseph M. | Eklund, Niina | Forrester, Terrence | Grarup, Niels | Jackson, Anne U. | Kristiansson, Kati | Kuulasmaa, Teemu | Kuusisto, Johanna | Lichtner, Peter | Luan, Jian'an | Mahajan, Anubha | Männistö, Satu | Palmer, Cameron D. | Ried, Janina S. | Scott, Robert A. | Stancáková, Alena | Wagner, Peter J. | Demirkan, Ayse | Döring, Angela | Gudnason, Vilmundur | Kiel, Douglas P. | Kühnel, Brigitte | Mangino, Massimo | Mcknight, Barbara | Menni, Cristina | O'Connell, Jeffrey R. | Oostra, Ben A. | Shuldiner, Alan R. | Song, Kijoung | Vandenput, Liesbeth | van Duijn, Cornelia M. | Vollenweider, Peter | White, Charles C. | Boehnke, Michael | Boettcher, Yvonne | Cooper, Richard S. | Forouhi, Nita G. | Gieger, Christian | Grallert, Harald | Hingorani, Aroon | Jørgensen, Torben | Jousilahti, Pekka | Kivimaki, Mika | Kumari, Meena | Laakso, Markku | Langenberg, Claudia | Linneberg, Allan | Luke, Amy | Mckenzie, Colin A. | Palotie, Aarno | Pedersen, Oluf | Peters, Annette | Strauch, Konstantin | Tayo, Bamidele O. | Wareham, Nicholas J. | Bennett, David A. | Bertram, Lars | Blangero, John | Blüher, Matthias | Bouchard, Claude | Campbell, Harry | Cho, Nam H. | Cummings, Steven R. | Czerwinski, Stefan A. | Demuth, Ilja | Eckardt, Rahel | Eriksson, Johan G. | Ferrucci, Luigi | Franco, Oscar H. | Froguel, Philippe | Gansevoort, Ron T. | Hansen, Torben | Harris, Tamara B. | Hastie, Nicholas | Heliövaara, Markku | Hofman, Albert | Jordan, Joanne M. | Jula, Antti | Kähönen, Mika | Kajantie, Eero | Knekt, Paul B. | Koskinen, Seppo | Kovacs, Peter | Lehtimäki, Terho | Lind, Lars | Liu, Yongmei | Orwoll, Eric S. | Osmond, Clive | Perola, Markus | Pérusse, Louis | Raitakari, Olli T. | Rankinen, Tuomo | Rao, D. C. | Rice, Treva K. | Rivadeneira, Fernando | Rudan, Igor | Salomaa, Veikko | Sørensen, Thorkild I. A. | Stumvoll, Michael | Tönjes, Anke | Towne, Bradford | Tranah, Gregory J. | Tremblay, Angelo | Uitterlinden, André G. | van der Harst, Pim | Vartiainen, Erkki | Viikari, Jorma S. | Vitart, Veronique | Vohl, Marie-Claude | Völzke, Henry | Walker, Mark | Wallaschofski, Henri | Wild, Sarah | Wilson, James F. | Yengo, Loïc | Bishop, D. Timothy | Borecki, Ingrid B. | Chambers, John C. | Cupples, L. Adrienne | Dehghan, Abbas | Deloukas, Panos | Fatemifar, Ghazaleh | Fox, Caroline | Furey, Terrence S. | Franke, Lude | Han, Jiali | Hunter, David J. | Karjalainen, Juha | Karpe, Fredrik | Kaplan, Robert C. | Kooner, Jaspal S. | McCarthy, Mark I. | Murabito, Joanne M. | Morris, Andrew P. | Bishop, Julia A. N. | North, Kari E. | Ohlsson, Claes | Ong, Ken K. | Prokopenko, Inga | Richards, J. Brent | Schadt, Eric E. | Spector, Tim D. | Widén, Elisabeth | Willer, Cristen J. | Yang, Jian | Ingelsson, Erik | Mohlke, Karen L. | Hirschhorn, Joel N. | Pospisilik, John Andrew | Zillikens, M. Carola | Lindgren, Cecilia | Kilpeläinen, Tuomas Oskari | Loos, Ruth J. F.
Nature Communications  2016;7:10495.
To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10−8), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
A genome-wide association meta-analysis study here shows novel genetic loci to be associated to body fat percentage, and describes cross-phenotype association that further demonstrate a close relationship between adiposity and cardiovascular disease risk.
doi:10.1038/ncomms10495
PMCID: PMC4740398  PMID: 26833246
Pattaro, Cristian | Teumer, Alexander | Gorski, Mathias | Chu, Audrey Y. | Li, Man | Mijatovic, Vladan | Garnaas, Maija | Tin, Adrienne | Sorice, Rossella | Li, Yong | Taliun, Daniel | Olden, Matthias | Foster, Meredith | Yang, Qiong | Chen, Ming-Huei | Pers, Tune H. | Johnson, Andrew D. | Ko, Yi-An | Fuchsberger, Christian | Tayo, Bamidele | Nalls, Michael | Feitosa, Mary F. | Isaacs, Aaron | Dehghan, Abbas | d'Adamo, Pio | Adeyemo, Adebowale | Dieffenbach, Aida Karina | Zonderman, Alan B. | Nolte, Ilja M. | van der Most, Peter J. | Wright, Alan F. | Shuldiner, Alan R. | Morrison, Alanna C. | Hofman, Albert | Smith, Albert V. | Dreisbach, Albert W. | Franke, Andre | Uitterlinden, Andre G. | Metspalu, Andres | Tonjes, Anke | Lupo, Antonio | Robino, Antonietta | Johansson, Åsa | Demirkan, Ayse | Kollerits, Barbara | Freedman, Barry I. | Ponte, Belen | Oostra, Ben A. | Paulweber, Bernhard | Krämer, Bernhard K. | Mitchell, Braxton D. | Buckley, Brendan M. | Peralta, Carmen A. | Hayward, Caroline | Helmer, Catherine | Rotimi, Charles N. | Shaffer, Christian M. | Müller, Christian | Sala, Cinzia | van Duijn, Cornelia M. | Saint-Pierre, Aude | Ackermann, Daniel | Shriner, Daniel | Ruggiero, Daniela | Toniolo, Daniela | Lu, Yingchang | Cusi, Daniele | Czamara, Darina | Ellinghaus, David | Siscovick, David S. | Ruderfer, Douglas | Gieger, Christian | Grallert, Harald | Rochtchina, Elena | Atkinson, Elizabeth J. | Holliday, Elizabeth G. | Boerwinkle, Eric | Salvi, Erika | Bottinger, Erwin P. | Murgia, Federico | Rivadeneira, Fernando | Ernst, Florian | Kronenberg, Florian | Hu, Frank B. | Navis, Gerjan J. | Curhan, Gary C. | Ehret, George B. | Homuth, Georg | Coassin, Stefan | Thun, Gian-Andri | Pistis, Giorgio | Gambaro, Giovanni | Malerba, Giovanni | Montgomery, Grant W. | Eiriksdottir, Gudny | Jacobs, Gunnar | Li, Guo | Wichmann, H-Erich | Campbell, Harry | Schmidt, Helena | Wallaschofski, Henri | Völzke, Henry | Brenner, Hermann | Kroemer, Heyo K. | Kramer, Holly | Lin, Honghuang | Leach, I. Mateo | Ford, Ian | Guessous, Idris | Rudan, Igor | Prokopenko, Inga | Borecki, Ingrid | Heid, Iris M. | Kolcic, Ivana | Persico, Ivana | Jukema, J. Wouter | Wilson, James F. | Felix, Janine F. | Divers, Jasmin | Lambert, Jean-Charles | Stafford, Jeanette M. | Gaspoz, Jean-Michel | Smith, Jennifer A. | Faul, Jessica D. | Wang, Jie Jin | Ding, Jingzhong | Hirschhorn, Joel N. | Attia, John | Whitfield, John B. | Chalmers, John | Viikari, Jorma | Coresh, Josef | Denny, Joshua C. | Karjalainen, Juha | Fernandes, Jyotika K. | Endlich, Karlhans | Butterbach, Katja | Keene, Keith L. | Lohman, Kurt | Portas, Laura | Launer, Lenore J. | Lyytikäinen, Leo-Pekka | Yengo, Loic | Franke, Lude | Ferrucci, Luigi | Rose, Lynda M. | Kedenko, Lyudmyla | Rao, Madhumathi | Struchalin, Maksim | Kleber, Marcus E. | Cavalieri, Margherita | Haun, Margot | Cornelis, Marilyn C. | Ciullo, Marina | Pirastu, Mario | de Andrade, Mariza | McEvoy, Mark A. | Woodward, Mark | Adam, Martin | Cocca, Massimiliano | Nauck, Matthias | Imboden, Medea | Waldenberger, Melanie | Pruijm, Menno | Metzger, Marie | Stumvoll, Michael | Evans, Michele K. | Sale, Michele M. | Kähönen, Mika | Boban, Mladen | Bochud, Murielle | Rheinberger, Myriam | Verweij, Niek | Bouatia-Naji, Nabila | Martin, Nicholas G. | Hastie, Nick | Probst-Hensch, Nicole | Soranzo, Nicole | Devuyst, Olivier | Raitakari, Olli | Gottesman, Omri | Franco, Oscar H. | Polasek, Ozren | Gasparini, Paolo | Munroe, Patricia B. | Ridker, Paul M. | Mitchell, Paul | Muntner, Paul | Meisinger, Christa | Smit, Johannes H. | Kovacs, Peter | Wild, Philipp S. | Froguel, Philippe | Rettig, Rainer | Mägi, Reedik | Biffar, Reiner | Schmidt, Reinhold | Middelberg, Rita P. S. | Carroll, Robert J. | Penninx, Brenda W. | Scott, Rodney J. | Katz, Ronit | Sedaghat, Sanaz | Wild, Sarah H. | Kardia, Sharon L. R. | Ulivi, Sheila | Hwang, Shih-Jen | Enroth, Stefan | Kloiber, Stefan | Trompet, Stella | Stengel, Benedicte | Hancock, Stephen J. | Turner, Stephen T. | Rosas, Sylvia E. | Stracke, Sylvia | Harris, Tamara B. | Zeller, Tanja | Zemunik, Tatijana | Lehtimäki, Terho | Illig, Thomas | Aspelund, Thor | Nikopensius, Tiit | Esko, Tonu | Tanaka, Toshiko | Gyllensten, Ulf | Völker, Uwe | Emilsson, Valur | Vitart, Veronique | Aalto, Ville | Gudnason, Vilmundur | Chouraki, Vincent | Chen, Wei-Min | Igl, Wilmar | März, Winfried | Koenig, Wolfgang | Lieb, Wolfgang | Loos, Ruth J. F. | Liu, Yongmei | Snieder, Harold | Pramstaller, Peter P. | Parsa, Afshin | O'Connell, Jeffrey R. | Susztak, Katalin | Hamet, Pavel | Tremblay, Johanne | de Boer, Ian H. | Böger, Carsten A. | Goessling, Wolfram | Chasman, Daniel I. | Köttgen, Anna | Kao, W. H. Linda | Fox, Caroline S.
Nature Communications  2016;7:10023.
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.
doi:10.1038/ncomms10023
PMCID: PMC4735748  PMID: 26831199
Kato, Norihiro | Loh, Marie | Takeuchi, Fumihiko | Verweij, Niek | Wang, Xu | Zhang, Weihua | Kelly, Tanika N | Saleheen, Danish | Lehne, Benjamin | Leach, Irene Mateo | Drong, Alexander W | Abbott, James | Wahl, Simone | Tan, Sian-Tsung | Scott, William R | Campanella, Gianluca | Chadeau-Hyam, Marc | Afzal, Uzma | Ahluwalia, Tarunveer S | Bonder, Marc Jan | Chen, Peng | Dehghan, Abbas | Edwards, Todd L | Esko, Tõnu | Go, Min Jin | Harris, Sarah E | Hartiala, Jaana | Kasela, Silva | Kasturiratne, Anuradhani | Khor, Chiea-Chuen | Kleber, Marcus E | Li, Huaixing | Yu Mok, Zuan | Nakatochi, Masahiro | Sapari, Nur Sabrina | Saxena, Richa | Stewart, Alexandre F R | Stolk, Lisette | Tabara, Yasuharu | Teh, Ai Ling | Wu, Ying | Wu, Jer-Yuarn | Zhang, Yi | Aits, Imke | Da Silva Couto Alves, Alexessander | Das, Shikta | Dorajoo, Rajkumar | Hopewell, Jemma C | Kim, Yun Kyoung | Koivula, Robert W | Luan, Jian’an | Lyytikäinen, Leo-Pekka | Nguyen, Quang N | Pereira, Mark A | Postmus, Iris | Raitakari, Olli T | Bryan, Molly Scannell | Scott, Robert A | Sorice, Rossella | Tragante, Vinicius | Traglia, Michela | White, Jon | Yamamoto, Ken | Zhang, Yonghong | Adair, Linda S | Ahmed, Alauddin | Akiyama, Koichi | Asif, Rasheed | Aung, Tin | Barroso, Inês | Bjonnes, Andrew | Braun, Timothy R | Cai, Hui | Chang, Li-Ching | Chen, Chien-Hsiun | Cheng, Ching-Yu | Chong, Yap-Seng | Collins, Rory | Courtney, Regina | Davies, Gail | Delgado, Graciela | Do, Loi D | Doevendans, Pieter A | Gansevoort, Ron T | Gao, Yu-Tang | Grammer, Tanja B | Grarup, Niels | Grewal, Jagvir | Gu, Dongfeng | Wander, Gurpreet S | Hartikainen, Anna-Liisa | Hazen, Stanley L | He, Jing | Heng, Chew-Kiat | Hixson, James E | Hofman, Albert | Hsu, Chris | Huang, Wei | Husemoen, Lise L N | Hwang, Joo-Yeon | Ichihara, Sahoko | Igase, Michiya | Isono, Masato | Justesen, Johanne M | Katsuya, Tomohiro | Kibriya, Muhammad G | Kim, Young Jin | Kishimoto, Miyako | Koh, Woon-Puay | Kohara, Katsuhiko | Kumari, Meena | Kwek, Kenneth | Lee, Nanette R | Lee, Jeannette | Liao, Jiemin | Lieb, Wolfgang | Liewald, David C M | Matsubara, Tatsuaki | Matsushita, Yumi | Meitinger, Thomas | Mihailov, Evelin | Milani, Lili | Mills, Rebecca | Mononen, Nina | Müller-Nurasyid, Martina | Nabika, Toru | Nakashima, Eitaro | Ng, Hong Kiat | Nikus, Kjell | Nutile, Teresa | Ohkubo, Takayoshi | Ohnaka, Keizo | Parish, Sarah | Paternoster, Lavinia | Peng, Hao | Peters, Annette | Pham, Son T | Pinidiyapathirage, Mohitha J | Rahman, Mahfuzar | Rakugi, Hiromi | Rolandsson, Olov | Ann Rozario, Michelle | Ruggiero, Daniela | Sala, Cinzia F | Sarju, Ralhan | Shimokawa, Kazuro | Snieder, Harold | Sparsø, Thomas | Spiering, Wilko | Starr, John M | Stott, David J | Stram, Daniel O | Sugiyama, Takao | Szymczak, Silke | Tang, W H Wilson | Tong, Lin | Trompet, Stella | Turjanmaa, Väinö | Ueshima, Hirotsugu | Uitterlinden, André G | Umemura, Satoshi | Vaarasmaki, Marja | van Dam, Rob M | van Gilst, Wiek H | van Veldhuisen, Dirk J | Viikari, Jorma S | Waldenberger, Melanie | Wang, Yiqin | Wang, Aili | Wilson, Rory | Wong, Tien-Yin | Xiang, Yong-Bing | Yamaguchi, Shuhei | Ye, Xingwang | Young, Robin D | Young, Terri L | Yuan, Jian-Min | Zhou, Xueya | Asselbergs, Folkert W | Ciullo, Marina | Clarke, Robert | Deloukas, Panos | Franke, Andre | Franks, Paul W | Franks, Steve | Friedlander, Yechiel | Gross, Myron D | Guo, Zhirong | Hansen, Torben | Jarvelin, Marjo-Riitta | Jørgensen, Torben | Jukema, J Wouter | kähönen, Mika | Kajio, Hiroshi | Kivimaki, Mika | Lee, Jong-Young | Lehtimäki, Terho | Linneberg, Allan | Miki, Tetsuro | Pedersen, Oluf | Samani, Nilesh J | Sørensen, Thorkild I A | Takayanagi, Ryoichi | Toniolo, Daniela | Ahsan, Habibul | Allayee, Hooman | Chen, Yuan-Tsong | Danesh, John | Deary, Ian J | Franco, Oscar H | Franke, Lude | Heijman, Bastiaan T | Holbrook, Joanna D | Isaacs, Aaron | Kim, Bong-Jo | Lin, Xu | Liu, Jianjun | März, Winfried | Metspalu, Andres | Mohlke, Karen L | Sanghera, Dharambir K | Shu, Xiao-Ou | van Meurs, Joyce B J | Vithana, Eranga | Wickremasinghe, Ananda R | Wijmenga, Cisca | Wolffenbuttel, Bruce H W | Yokota, Mitsuhiro | Zheng, Wei | Zhu, Dingliang | Vineis, Paolo | Kyrtopoulos, Soterios A | Kleinjans, Jos C S | McCarthy, Mark I | Soong, Richie | Gieger, Christian | Scott, James | Teo, Yik-Ying | He, Jiang | Elliott, Paul | Tai, E Shyong | van der Harst, Pim | Kooner, Jaspal S | Chambers, John C
Nature genetics  2015;47(11):1282-1293.
We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
doi:10.1038/ng.3405
PMCID: PMC4719169  PMID: 26390057
Artigas, María Soler | Wain, Louise V. | Miller, Suzanne | Kheirallah, Abdul Kader | Huffman, Jennifer E. | Ntalla, Ioanna | Shrine, Nick | Obeidat, Ma'en | Trochet, Holly | McArdle, Wendy L. | Alves, Alexessander Couto | Hui, Jennie | Zhao, Jing Hua | Joshi, Peter K. | Teumer, Alexander | Albrecht, Eva | Imboden, Medea | Rawal, Rajesh | Lopez, Lorna M. | Marten, Jonathan | Enroth, Stefan | Surakka, Ida | Polasek, Ozren | Lyytikäinen, Leo-Pekka | Granell, Raquel | Hysi, Pirro G. | Flexeder, Claudia | Mahajan, Anubha | Beilby, John | Bossé, Yohan | Brandsma, Corry-Anke | Campbell, Harry | Gieger, Christian | Gläser, Sven | González, Juan R. | Grallert, Harald | Hammond, Chris J. | Harris, Sarah E. | Hartikainen, Anna-Liisa | Heliövaara, Markku | Henderson, John | Hocking, Lynne | Horikoshi, Momoko | Hutri-Kähönen, Nina | Ingelsson, Erik | Johansson, Åsa | Kemp, John P. | Kolcic, Ivana | Kumar, Ashish | Lind, Lars | Melén, Erik | Musk, Arthur W. | Navarro, Pau | Nickle, David C. | Padmanabhan, Sandosh | Raitakari, Olli T. | Ried, Janina S. | Ripatti, Samuli | Schulz, Holger | Scott, Robert A. | Sin, Don D. | Starr, John M. | Viñuela, Ana | Völzke, Henry | Wild, Sarah H. | Wright, Alan F. | Zemunik, Tatijana | Jarvis, Deborah L. | Spector, Tim D. | Evans, David M. | Lehtimäki, Terho | Vitart, Veronique | Kähönen, Mika | Gyllensten, Ulf | Rudan, Igor | Deary, Ian J. | Karrasch, Stefan | Probst-Hensch, Nicole M. | Heinrich, Joachim | Stubbe, Beate | Wilson, James F. | Wareham, Nicholas J. | James, Alan L. | Morris, Andrew P. | Jarvelin, Marjo-Riitta | Hayward, Caroline | Sayers, Ian | Strachan, David P. | Hall, Ian P. | Tobin, Martin D.
Nature Communications  2015;6:8658.
Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10−8) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.
Genetic and environmental factors impact on lung function, important in the diagnosis of pulmonary diseases. Here the authors use imputation of genotypes to the 1000 Genomes Project reference panel to identify novel, low frequency variants associated with lung function.
doi:10.1038/ncomms9658
PMCID: PMC4686825  PMID: 26635082
Gorski, Mathias | Tin, Adrienne | Garnaas, Maija | McMahon, Gearoid M. | Chu, Audrey Y. | Tayo, Bamidele O. | Pattaro, Cristian | Teumer, Alexander | Chasman, Daniel I. | Chalmers, John | Hamet, Pavel | Tremblay, Johanne | Woodward, Marc | Aspelund, Thor | Eiriksdottir, Gudny | Gudnason, Vilmundur | Harris, Tammara B. | Launer, Lenore J. | Smith, Albert V. | Mitchell, Braxton D. | O'Connell, Jeffrey R. | Shuldiner, Alan R. | Coresh, Josef | Li, Man | Freudenberger, Paul | Hofer, Edith | Schmidt, Helena | Schmidt, Reinhold | Holliday, Elizabeth G. | Mitchell, Paul | Wang, Jie Jin | de Boer, Ian H. | Li, Guo | Siscovick, David S. | Kutalik, Zoltan | Corre, Tanguy | Vollenweider, Peter | Waeber, Gérard | Gupta, Jayanta | Kanetsky, Peter A. | Hwang, Shih-Jen | Olden, Matthias | Yang, Qiong | de Andrade, Mariza | Atkinson, Elizabeth J. | Kardia, Sharon L.R. | Turner, Stephen T. | Stafford, Jeanette M. | Ding, Jingzhong | Liu, Yongmei | Barlassina, Cristina | Cusi, Daniele | Salvi, Erika | Staessen, Jan A | Ridker, Paul M | Grallert, Harald | Meisinger, Christa | Müller-Nurasyid, Martina | Krämer, Bernhard K. | Kramer, Holly | Rosas, Sylvia E. | Nolte, Ilja M. | Penninx, Brenda W. | Snieder, Harold | Del Greco, Fabiola | Franke, Andre | Nöthlings, Ute | Lieb, Wolfgang | Bakker, Stephan J.L. | Gansevoort, Ron T. | van der Harst, Pim | Dehghan, Abbas | Franco, Oscar H. | Hofman, Albert | Rivadeneira, Fernando | Sedaghat, Sanaz | Uitterlinden, André G. | Coassin, Stefan | Haun, Margot | Kollerits, Barbara | Kronenberg, Florian | Paulweber, Bernhard | Aumann, Nicole | Endlich, Karlhans | Pietzner, Mike | Völker, Uwe | Rettig, Rainer | Chouraki, Vincent | Helmer, Catherine | Lambert, Jean-Charles | Metzger, Marie | Stengel, Benedicte | Lehtimäki, Terho | Lyytikäinen, Leo-Pekka | Raitakari, Olli | Johnson, Andrew | Parsa, Afshin | Bochud, Murielle | Heid, Iris M. | Goessling, Wolfram | Köttgen, Anna | Kao, H. Linda | Fox, Caroline S. | Böger, Carsten A.
Kidney international  2014;87(5):1017-1029.
Genome wide association studies (GWAS) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, SNPs at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1 and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFRdecline of 3ml/min/1.73m2 or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11 and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 hours after gentamicin treatment compared to controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.
doi:10.1038/ki.2014.361
PMCID: PMC4425568  PMID: 25493955
chronic kidney disease; kidney development
Moayyeri, Alireza | Hsu, Yi-Hsiang | Karasik, David | Estrada, Karol | Xiao, Su-Mei | Nielson, Carrie | Srikanth, Priya | Giroux, Sylvie | Wilson, Scott G. | Zheng, Hou-Feng | Smith, Albert V. | Pye, Stephen R. | Leo, Paul J. | Teumer, Alexander | Hwang, Joo-Yeon | Ohlsson, Claes | McGuigan, Fiona | Minster, Ryan L. | Hayward, Caroline | Olmos, José M. | Lyytikäinen, Leo-Pekka | Lewis, Joshua R. | Swart, Karin M.A. | Masi, Laura | Oldmeadow, Chris | Holliday, Elizabeth G. | Cheng, Sulin | van Schoor, Natasja M. | Harvey, Nicholas C. | Kruk, Marcin | del Greco M, Fabiola | Igl, Wilmar | Trummer, Olivia | Grigoriou, Efi | Luben, Robert | Liu, Ching-Ti | Zhou, Yanhua | Oei, Ling | Medina-Gomez, Carolina | Zmuda, Joseph | Tranah, Greg | Brown, Suzanne J. | Williams, Frances M. | Soranzo, Nicole | Jakobsdottir, Johanna | Siggeirsdottir, Kristin | Holliday, Kate L. | Hannemann, Anke | Go, Min Jin | Garcia, Melissa | Polasek, Ozren | Laaksonen, Marika | Zhu, Kun | Enneman, Anke W. | McEvoy, Mark | Peel, Roseanne | Sham, Pak Chung | Jaworski, Maciej | Johansson, Åsa | Hicks, Andrew A. | Pludowski, Pawel | Scott, Rodney | Dhonukshe-Rutten, Rosalie A.M. | van der Velde, Nathalie | Kähönen, Mika | Viikari, Jorma S. | Sievänen, Harri | Raitakari, Olli T. | González-Macías, Jesús | Hernández, Jose L. | Mellström, Dan | Ljunggren, Östen | Cho, Yoon Shin | Völker, Uwe | Nauck, Matthias | Homuth, Georg | Völzke, Henry | Haring, Robin | Brown, Matthew A. | McCloskey, Eugene | Nicholson, Geoffrey C. | Eastell, Richard | Eisman, John A. | Jones, Graeme | Reid, Ian R. | Dennison, Elaine M. | Wark, John | Boonen, Steven | Vanderschueren, Dirk | Wu, Frederick C.W. | Aspelund, Thor | Richards, J. Brent | Bauer, Doug | Hofman, Albert | Khaw, Kay-Tee | Dedoussis, George | Obermayer-Pietsch, Barbara | Gyllensten, Ulf | Pramstaller, Peter P. | Lorenc, Roman S. | Cooper, Cyrus | Kung, Annie Wai Chee | Lips, Paul | Alen, Markku | Attia, John | Brandi, Maria Luisa | de Groot, Lisette C.P.G.M. | Lehtimäki, Terho | Riancho, José A. | Campbell, Harry | Liu, Yongmei | Harris, Tamara B. | Akesson, Kristina | Karlsson, Magnus | Lee, Jong-Young | Wallaschofski, Henri | Duncan, Emma L. | O'Neill, Terence W. | Gudnason, Vilmundur | Spector, Timothy D. | Rousseau, François | Orwoll, Eric | Cummings, Steven R. | Wareham, Nick J. | Rivadeneira, Fernando | Uitterlinden, Andre G. | Prince, Richard L. | Kiel, Douglas P. | Reeve, Jonathan | Kaptoge, Stephen K.
Human Molecular Genetics  2014;23(11):3054-3068.
Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10−8) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10−14). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10−6 also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.
doi:10.1093/hmg/ddt675
PMCID: PMC4038791  PMID: 24430505
Background
There is limited information on genetic factors associated with sudden cardiac arrest (SCA).
Objective
To assess the association of common variation in genes in fatty acid pathways with SCA risk.
Methods
We selected 85 candidate genes and 1155 single nucleotide polymorphisms (SNPs) tagging common variation in each gene. We investigated the SNP associations with SCA in a population-based case-control study. Cases (n=2160) were from a repository of SCA in the greater Seattle area. Controls (n=2615), frequency-matched on age and sex, were from the same area. We used linear logistic regression to examine SNP associations with SCA. We performed p-min permutation tests to account for multiple comparisons within each gene. The SNP associations with corrected p-value < 0.05 were then examined in a meta-analysis of these SNP associations in nine replication studies totaling 2129 SCA cases and 23833 non-cases.
Results
Eight SNPs in or near 8 genes were associated with SCA risk in the discovery study, one of which was nominally significant in the replication phase (rs7737692, minor allele frequency 36%, near the LPCAT1 gene). For each copy of the minor allele, rs7737692 was associated with 13% lower SCA risk (−21% to −5%) in the discovery phase and 9% lower risk (95% CI −16% to - 1%) in the replication phase.
Conclusions
While none of the associations reached significance with Bonferroni correction, a common genetic variant near LPCAT1, a gene involved in the remodeling of phospholipids, was nominally associated with incident SCA risk. Further study is needed to validate this observation.
doi:10.1016/j.hrthm.2014.01.008
PMCID: PMC3966996  PMID: 24418166
death; sudden; genetic epidemiology
Arking, Dan E. | Pulit, Sara L. | Crotti, Lia | van der Harst, Pim | Munroe, Patricia B. | Koopmann, Tamara T. | Sotoodehnia, Nona | Rossin, Elizabeth J. | Morley, Michael | Wang, Xinchen | Johnson, Andrew D. | Lundby, Alicia | Gudbjartsson, Daníel F. | Noseworthy, Peter A. | Eijgelsheim, Mark | Bradford, Yuki | Tarasov, Kirill V. | Dörr, Marcus | Müller-Nurasyid, Martina | Lahtinen, Annukka M. | Nolte, Ilja M. | Smith, Albert Vernon | Bis, Joshua C. | Isaacs, Aaron | Newhouse, Stephen J. | Evans, Daniel S. | Post, Wendy S. | Waggott, Daryl | Lyytikäinen, Leo-Pekka | Hicks, Andrew A. | Eisele, Lewin | Ellinghaus, David | Hayward, Caroline | Navarro, Pau | Ulivi, Sheila | Tanaka, Toshiko | Tester, David J. | Chatel, Stéphanie | Gustafsson, Stefan | Kumari, Meena | Morris, Richard W. | Naluai, Åsa T. | Padmanabhan, Sandosh | Kluttig, Alexander | Strohmer, Bernhard | Panayiotou, Andrie G. | Torres, Maria | Knoflach, Michael | Hubacek, Jaroslav A. | Slowikowski, Kamil | Raychaudhuri, Soumya | Kumar, Runjun D. | Harris, Tamara B. | Launer, Lenore J. | Shuldiner, Alan R. | Alonso, Alvaro | Bader, Joel S. | Ehret, Georg | Huang, Hailiang | Kao, W.H. Linda | Strait, James B. | Macfarlane, Peter W. | Brown, Morris | Caulfield, Mark J. | Samani, Nilesh J. | Kronenberg, Florian | Willeit, Johann | Smith, J. Gustav | Greiser, Karin H. | zu Schwabedissen, Henriette Meyer | Werdan, Karl | Carella, Massimo | Zelante, Leopoldo | Heckbert, Susan R. | Psaty, Bruce M. | Rotter, Jerome I. | Kolcic, Ivana | Polašek, Ozren | Wright, Alan F. | Griffin, Maura | Daly, Mark J. | Arnar, David O. | Hólm, Hilma | Thorsteinsdottir, Unnur | Denny, Joshua C. | Roden, Dan M. | Zuvich, Rebecca L. | Emilsson, Valur | Plump, Andrew S. | Larson, Martin G. | O'Donnell, Christopher J. | Yin, Xiaoyan | Bobbo, Marco | D'Adamo, Adamo P. | Iorio, Annamaria | Sinagra, Gianfranco | Carracedo, Angel | Cummings, Steven R. | Nalls, Michael A. | Jula, Antti | Kontula, Kimmo K. | Marjamaa, Annukka | Oikarinen, Lasse | Perola, Markus | Porthan, Kimmo | Erbel, Raimund | Hoffmann, Per | Jöckel, Karl-Heinz | Kälsch, Hagen | Nöthen, Markus M. | consortium, HRGEN | den Hoed, Marcel | Loos, Ruth J.F. | Thelle, Dag S. | Gieger, Christian | Meitinger, Thomas | Perz, Siegfried | Peters, Annette | Prucha, Hanna | Sinner, Moritz F. | Waldenberger, Melanie | de Boer, Rudolf A. | Franke, Lude | van der Vleuten, Pieter A. | Beckmann, Britt Maria | Martens, Eimo | Bardai, Abdennasser | Hofman, Nynke | Wilde, Arthur A.M. | Behr, Elijah R. | Dalageorgou, Chrysoula | Giudicessi, John R. | Medeiros-Domingo, Argelia | Barc, Julien | Kyndt, Florence | Probst, Vincent | Ghidoni, Alice | Insolia, Roberto | Hamilton, Robert M. | Scherer, Stephen W. | Brandimarto, Jeffrey | Margulies, Kenneth | Moravec, Christine E. | Fabiola Del, Greco M. | Fuchsberger, Christian | O'Connell, Jeffrey R. | Lee, Wai K. | Watt, Graham C.M. | Campbell, Harry | Wild, Sarah H. | El Mokhtari, Nour E. | Frey, Norbert | Asselbergs, Folkert W. | Leach, Irene Mateo | Navis, Gerjan | van den Berg, Maarten P. | van Veldhuisen, Dirk J. | Kellis, Manolis | Krijthe, Bouwe P. | Franco, Oscar H. | Hofman, Albert | Kors, Jan A. | Uitterlinden, André G. | Witteman, Jacqueline C.M. | Kedenko, Lyudmyla | Lamina, Claudia | Oostra, Ben A. | Abecasis, Gonçalo R. | Lakatta, Edward G. | Mulas, Antonella | Orrú, Marco | Schlessinger, David | Uda, Manuela | Markus, Marcello R.P. | Völker, Uwe | Snieder, Harold | Spector, Timothy D. | Ärnlöv, Johan | Lind, Lars | Sundström, Johan | Syvänen, Ann-Christine | Kivimaki, Mika | Kähönen, Mika | Mononen, Nina | Raitakari, Olli T. | Viikari, Jorma S. | Adamkova, Vera | Kiechl, Stefan | Brion, Maria | Nicolaides, Andrew N. | Paulweber, Bernhard | Haerting, Johannes | Dominiczak, Anna F. | Nyberg, Fredrik | Whincup, Peter H. | Hingorani, Aroon | Schott, Jean-Jacques | Bezzina, Connie R. | Ingelsson, Erik | Ferrucci, Luigi | Gasparini, Paolo | Wilson, James F. | Rudan, Igor | Franke, Andre | Mühleisen, Thomas W. | Pramstaller, Peter P. | Lehtimäki, Terho J. | Paterson, Andrew D. | Parsa, Afshin | Liu, Yongmei | van Duijn, Cornelia | Siscovick, David S. | Gudnason, Vilmundur | Jamshidi, Yalda | Salomaa, Veikko | Felix, Stephan B. | Sanna, Serena | Ritchie, Marylyn D. | Stricker, Bruno H. | Stefansson, Kari | Boyer, Laurie A. | Cappola, Thomas P. | Olsen, Jesper V. | Lage, Kasper | Schwartz, Peter J. | Kääb, Stefan | Chakravarti, Aravinda | Ackerman, Michael J. | Pfeufer, Arne | de Bakker, Paul I.W. | Newton-Cheh, Christopher
Nature genetics  2014;46(8):826-836.
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD.
doi:10.1038/ng.3014
PMCID: PMC4124521  PMID: 24952745
genome-wide association study; QT interval; Long QT Syndrome; sudden cardiac death; myocardial repolarization; arrhythmias
van der Valk, Ralf J.P. | Kreiner-Møller, Eskil | Kooijman, Marjolein N. | Guxens, Mònica | Stergiakouli, Evangelia | Sääf, Annika | Bradfield, Jonathan P. | Geller, Frank | Hayes, M. Geoffrey | Cousminer, Diana L. | Körner, Antje | Thiering, Elisabeth | Curtin, John A. | Myhre, Ronny | Huikari, Ville | Joro, Raimo | Kerkhof, Marjan | Warrington, Nicole M. | Pitkänen, Niina | Ntalla, Ioanna | Horikoshi, Momoko | Veijola, Riitta | Freathy, Rachel M. | Teo, Yik-Ying | Barton, Sheila J. | Evans, David M. | Kemp, John P. | St Pourcain, Beate | Ring, Susan M. | Davey Smith, George | Bergström, Anna | Kull, Inger | Hakonarson, Hakon | Mentch, Frank D. | Bisgaard, Hans | Chawes, Bo | Stokholm, Jakob | Waage, Johannes | Eriksen, Patrick | Sevelsted, Astrid | Melbye, Mads | van Duijn, Cornelia M. | Medina-Gomez, Carolina | Hofman, Albert | de Jongste, Johan C. | Taal, H. Rob | Uitterlinden, André G. | Armstrong, Loren L. | Eriksson, Johan | Palotie, Aarno | Bustamante, Mariona | Estivill, Xavier | Gonzalez, Juan R. | Llop, Sabrina | Kiess, Wieland | Mahajan, Anubha | Flexeder, Claudia | Tiesler, Carla M.T. | Murray, Clare S. | Simpson, Angela | Magnus, Per | Sengpiel, Verena | Hartikainen, Anna-Liisa | Keinanen-Kiukaanniemi, Sirkka | Lewin, Alexandra | Da Silva Couto Alves, Alexessander | Blakemore, Alexandra I. | Buxton, Jessica L. | Kaakinen, Marika | Rodriguez, Alina | Sebert, Sylvain | Vaarasmaki, Marja | Lakka, Timo | Lindi, Virpi | Gehring, Ulrike | Postma, Dirkje S. | Ang, Wei | Newnham, John P. | Lyytikäinen, Leo-Pekka | Pahkala, Katja | Raitakari, Olli T. | Panoutsopoulou, Kalliope | Zeggini, Eleftheria | Boomsma, Dorret I. | Groen-Blokhuis, Maria | Ilonen, Jorma | Franke, Lude | Hirschhorn, Joel N. | Pers, Tune H. | Liang, Liming | Huang, Jinyan | Hocher, Berthold | Knip, Mikael | Saw, Seang-Mei | Holloway, John W. | Melén, Erik | Grant, Struan F.A. | Feenstra, Bjarke | Lowe, William L. | Widén, Elisabeth | Sergeyev, Elena | Grallert, Harald | Custovic, Adnan | Jacobsson, Bo | Jarvelin, Marjo-Riitta | Atalay, Mustafa | Koppelman, Gerard H. | Pennell, Craig E. | Niinikoski, Harri | Dedoussis, George V. | Mccarthy, Mark I. | Frayling, Timothy M. | Sunyer, Jordi | Timpson, Nicholas J. | Rivadeneira, Fernando | Bønnelykke, Klaus | Jaddoe, Vincent W.V.
Human Molecular Genetics  2014;24(4):1155-1168.
Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10−6) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10−8, explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10−4) and adult height (N = 127 513; P = 1.45 × 10−5). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.
doi:10.1093/hmg/ddu510
PMCID: PMC4447786  PMID: 25281659
Yaghootkar, Hanieh | Lamina, Claudia | Scott, Robert A. | Dastani, Zari | Hivert, Marie-France | Warren, Liling L. | Stancáková, Alena | Buxbaum, Sarah G. | Lyytikäinen, Leo-Pekka | Henneman, Peter | Wu, Ying | Cheung, Chloe Y.Y. | Pankow, James S. | Jackson, Anne U. | Gustafsson, Stefan | Zhao, Jing Hua | Ballantyne, Christie M. | Xie, Weijia | Bergman, Richard N. | Boehnke, Michael | el Bouazzaoui, Fatiha | Collins, Francis S. | Dunn, Sandra H. | Dupuis, Josee | Forouhi, Nita G. | Gillson, Christopher | Hattersley, Andrew T. | Hong, Jaeyoung | Kähönen, Mika | Kuusisto, Johanna | Kedenko, Lyudmyla | Kronenberg, Florian | Doria, Alessandro | Assimes, Themistocles L. | Ferrannini, Ele | Hansen, Torben | Hao, Ke | Häring, Hans | Knowles, Joshua W. | Lindgren, Cecilia M. | Nolan, John J. | Paananen, Jussi | Pedersen, Oluf | Quertermous, Thomas | Smith, Ulf | Lehtimäki, Terho | Liu, Ching-Ti | Loos, Ruth J.F. | McCarthy, Mark I. | Morris, Andrew D. | Vasan, Ramachandran S. | Spector, Tim D. | Teslovich, Tanya M. | Tuomilehto, Jaakko | van Dijk, Ko Willems | Viikari, Jorma S. | Zhu, Na | Langenberg, Claudia | Ingelsson, Erik | Semple, Robert K. | Sinaiko, Alan R. | Palmer, Colin N.A. | Walker, Mark | Lam, Karen S.L. | Paulweber, Bernhard | Mohlke, Karen L. | van Duijn, Cornelia | Raitakari, Olli T. | Bidulescu, Aurelian | Wareham, Nick J. | Laakso, Markku | Waterworth, Dawn M. | Lawlor, Debbie A. | Meigs, James B. | Richards, J. Brent | Frayling, Timothy M.
Diabetes  2013;62(10):3589-3598.
Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics–based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26–0.35) increase in fasting insulin, a 0.34-SD (0.30–0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47–2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI −0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (−0.20 SD; 95% CI −0.38 to −0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75–1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: −0.03 SD; 95% CI −0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95–1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.
doi:10.2337/db13-0128
PMCID: PMC3781444  PMID: 23835345
Journal of Bone and Mineral Research  2014;29(4):1015-1024.
ABSTRACT
We hypothesized that bone resorption acts to increase bone strength through stimulation of periosteal expansion. Hence, we examined whether bone resorption, as reflected by serum β‐C‐telopeptides of type I collagen (CTX), is positively associated with periosteal circumference (PC), in contrast to inverse associations with parameters related to bone remodeling such as cortical bone mineral density (BMDC). CTX and mid‐tibial peripheral quantitative computed tomography (pQCT) scans were available in 1130 adolescents (mean age 15.5 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC). Analyses were adjusted for age, gender, time of sampling, tanner stage, lean mass, fat mass, and height. CTX was positively related to PC (β = 0.19 [0.13, 0.24]) (coefficient = SD change per SD increase in CTX, 95% confidence interval)] but inversely associated with BMDC (β = –0.46 [–0.52,–0.40]) and cortical thickness [β = –0.11 (–0.18, –0.03)]. CTX was positively related to bone strength as reflected by the strength‐strain index (SSI) (β = 0.09 [0.03, 0.14]). To examine the causal nature of this relationship, we then analyzed whether single‐nucleotide polymorphisms (SNPs) within key osteoclast regulatory genes, known to reduce areal/cortical BMD, conversely increase PC. Fifteen such genetic variants within or proximal to genes encoding receptor activator of NF‐κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) were identified by literature search. Six of the 15 alleles that were inversely related to BMD were positively related to CTX (p < 0.05 cut‐off) (n = 2379). Subsequently, we performed a meta‐analysis of associations between these SNPs and PC in ALSPAC (n = 3382), Gothenburg Osteoporosis and Obesity Determinants (GOOD) (n = 938), and the Young Finns Study (YFS) (n = 1558). Five of the 15 alleles that were inversely related to BMD were positively related to PC (p < 0.05 cut‐off). We conclude that despite having lower BMD, individuals with a genetic predisposition to higher bone resorption have greater bone size, suggesting that higher bone resorption is permissive for greater periosteal expansion. © 2014 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
doi:10.1002/jbmr.2093
PMCID: PMC4138988  PMID: 24014423
CTX; BONE RESORPTION; PERIOSTEAL EXPANSION; pQCT
Background: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants.
Objective: The objective of the study was to identify common genetic variants that are associated with macronutrient intake.
Design: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10−6 were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data.
Results: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10−8) and lower fat (β ± SE: −0.21 ± 0.04%; P = 1.57 × 10−9) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)–increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10−10), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10−7).
Conclusion: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).
doi:10.3945/ajcn.112.052183
PMCID: PMC3652928  PMID: 23636237
Willer, Cristen J. | Schmidt, Ellen M. | Sengupta, Sebanti | Peloso, Gina M. | Gustafsson, Stefan | Kanoni, Stavroula | Ganna, Andrea | Chen, Jin | Buchkovich, Martin L. | Mora, Samia | Beckmann, Jacques S. | Bragg-Gresham, Jennifer L. | Chang, Hsing-Yi | Demirkan, Ayşe | Den Hertog, Heleen M. | Do, Ron | Donnelly, Louise A. | Ehret, Georg B. | Esko, Tõnu | Feitosa, Mary F. | Ferreira, Teresa | Fischer, Krista | Fontanillas, Pierre | Fraser, Ross M. | Freitag, Daniel F. | Gurdasani, Deepti | Heikkilä, Kauko | Hyppönen, Elina | Isaacs, Aaron | Jackson, Anne U. | Johansson, Åsa | Johnson, Toby | Kaakinen, Marika | Kettunen, Johannes | Kleber, Marcus E. | Li, Xiaohui | Luan, Jian’an | Lyytikäinen, Leo-Pekka | Magnusson, Patrik K.E. | Mangino, Massimo | Mihailov, Evelin | Montasser, May E. | Müller-Nurasyid, Martina | Nolte, Ilja M. | O’Connell, Jeffrey R. | Palmer, Cameron D. | Perola, Markus | Petersen, Ann-Kristin | Sanna, Serena | Saxena, Richa | Service, Susan K. | Shah, Sonia | Shungin, Dmitry | Sidore, Carlo | Song, Ci | Strawbridge, Rona J. | Surakka, Ida | Tanaka, Toshiko | Teslovich, Tanya M. | Thorleifsson, Gudmar | Van den Herik, Evita G. | Voight, Benjamin F. | Volcik, Kelly A. | Waite, Lindsay L. | Wong, Andrew | Wu, Ying | Zhang, Weihua | Absher, Devin | Asiki, Gershim | Barroso, Inês | Been, Latonya F. | Bolton, Jennifer L. | Bonnycastle, Lori L | Brambilla, Paolo | Burnett, Mary S. | Cesana, Giancarlo | Dimitriou, Maria | Doney, Alex S.F. | Döring, Angela | Elliott, Paul | Epstein, Stephen E. | Ingi Eyjolfsson, Gudmundur | Gigante, Bruna | Goodarzi, Mark O. | Grallert, Harald | Gravito, Martha L. | Groves, Christopher J. | Hallmans, Göran | Hartikainen, Anna-Liisa | Hayward, Caroline | Hernandez, Dena | Hicks, Andrew A. | Holm, Hilma | Hung, Yi-Jen | Illig, Thomas | Jones, Michelle R. | Kaleebu, Pontiano | Kastelein, John J.P. | Khaw, Kay-Tee | Kim, Eric | Klopp, Norman | Komulainen, Pirjo | Kumari, Meena | Langenberg, Claudia | Lehtimäki, Terho | Lin, Shih-Yi | Lindström, Jaana | Loos, Ruth J.F. | Mach, François | McArdle, Wendy L | Meisinger, Christa | Mitchell, Braxton D. | Müller, Gabrielle | Nagaraja, Ramaiah | Narisu, Narisu | Nieminen, Tuomo V.M. | Nsubuga, Rebecca N. | Olafsson, Isleifur | Ong, Ken K. | Palotie, Aarno | Papamarkou, Theodore | Pomilla, Cristina | Pouta, Anneli | Rader, Daniel J. | Reilly, Muredach P. | Ridker, Paul M. | Rivadeneira, Fernando | Rudan, Igor | Ruokonen, Aimo | Samani, Nilesh | Scharnagl, Hubert | Seeley, Janet | Silander, Kaisa | Stančáková, Alena | Stirrups, Kathleen | Swift, Amy J. | Tiret, Laurence | Uitterlinden, Andre G. | van Pelt, L. Joost | Vedantam, Sailaja | Wainwright, Nicholas | Wijmenga, Cisca | Wild, Sarah H. | Willemsen, Gonneke | Wilsgaard, Tom | Wilson, James F. | Young, Elizabeth H. | Zhao, Jing Hua | Adair, Linda S. | Arveiler, Dominique | Assimes, Themistocles L. | Bandinelli, Stefania | Bennett, Franklyn | Bochud, Murielle | Boehm, Bernhard O. | Boomsma, Dorret I. | Borecki, Ingrid B. | Bornstein, Stefan R. | Bovet, Pascal | Burnier, Michel | Campbell, Harry | Chakravarti, Aravinda | Chambers, John C. | Chen, Yii-Der Ida | Collins, Francis S. | Cooper, Richard S. | Danesh, John | Dedoussis, George | de Faire, Ulf | Feranil, Alan B. | Ferrières, Jean | Ferrucci, Luigi | Freimer, Nelson B. | Gieger, Christian | Groop, Leif C. | Gudnason, Vilmundur | Gyllensten, Ulf | Hamsten, Anders | Harris, Tamara B. | Hingorani, Aroon | Hirschhorn, Joel N. | Hofman, Albert | Hovingh, G. 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Adrienne | Sandhu, Manjinder S. | Rich, Stephen S. | Boehnke, Michael | Deloukas, Panos | Kathiresan, Sekar | Mohlke, Karen L. | Ingelsson, Erik | Abecasis, Gonçalo R.
Nature genetics  2013;45(11):1274-1283.
Low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and total cholesterol are heritable, modifiable, risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,578 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5×10−8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian, and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipids are often associated with cardiovascular and metabolic traits including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio, and body mass index. Our results illustrate the value of genetic data from individuals of diverse ancestries and provide insights into biological mechanisms regulating blood lipids to guide future genetic, biological, and therapeutic research.
doi:10.1038/ng.2797
PMCID: PMC3838666  PMID: 24097068

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