@article {1237, title = {Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Nov}, pages = {937-48}, abstract = {

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

}, keywords = {Body Height, Body Mass Index, Body Size, Body Weight, Chromosome Mapping, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Obesity, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.686}, author = {Speliotes, Elizabeth K and Willer, Cristen J and Berndt, Sonja I and Monda, Keri L and Thorleifsson, Gudmar and Jackson, Anne U and Lango Allen, Hana and Lindgren, Cecilia M and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Randall, Joshua C and Vedantam, Sailaja and Winkler, Thomas W and Qi, Lu and Workalemahu, Tsegaselassie and Heid, Iris M and Steinthorsdottir, Valgerdur and Stringham, Heather M and Weedon, Michael N and Wheeler, Eleanor and Wood, Andrew R and Ferreira, Teresa and Weyant, Robert J and Segr{\`e}, Ayellet V and Estrada, Karol and Liang, Liming and Nemesh, James and Park, Ju-Hyun and Gustafsson, Stefan and Kilpel{\"a}inen, Tuomas O and Yang, Jian and Bouatia-Naji, Nabila and Esko, T{\~o}nu and Feitosa, Mary F and Kutalik, Zolt{\'a}n and Mangino, Massimo and Raychaudhuri, Soumya and Scherag, Andre and Smith, Albert Vernon and Welch, Ryan and Zhao, Jing Hua and Aben, Katja K and Absher, Devin M and Amin, Najaf and Dixon, Anna L and Fisher, Eva and Glazer, Nicole L and Goddard, Michael E and Heard-Costa, Nancy L and Hoesel, Volker and Hottenga, Jouke-Jan and Johansson, Asa and Johnson, Toby and Ketkar, Shamika and Lamina, Claudia and Li, Shengxu and Moffatt, Miriam F and Myers, Richard H and Narisu, Narisu and Perry, John R B and Peters, Marjolein J and Preuss, Michael and Ripatti, Samuli and Rivadeneira, Fernando and Sandholt, Camilla and Scott, Laura J and Timpson, Nicholas J and Tyrer, Jonathan P and van Wingerden, Sophie and Watanabe, Richard M and White, Charles C and Wiklund, Fredrik and Barlassina, Christina and Chasman, Daniel I and Cooper, Matthew N and Jansson, John-Olov and Lawrence, Robert W and Pellikka, Niina and Prokopenko, Inga and Shi, Jianxin and Thiering, Elisabeth and Alavere, Helene and Alibrandi, Maria T S and Almgren, Peter and Arnold, Alice M and Aspelund, Thor and Atwood, Larry D and Balkau, Beverley and Balmforth, Anthony J and Bennett, Amanda J and Ben-Shlomo, Yoav and Bergman, Richard N and Bergmann, Sven and Biebermann, Heike and Blakemore, Alexandra I F and Boes, Tanja and Bonnycastle, Lori L and Bornstein, Stefan R and Brown, Morris J and Buchanan, Thomas A and Busonero, Fabio and Campbell, Harry and Cappuccio, Francesco P and Cavalcanti-Proen{\c c}a, Christine and Chen, Yii-Der Ida and Chen, Chih-Mei and Chines, Peter S and Clarke, Robert and Coin, Lachlan and Connell, John and Day, Ian N M and den Heijer, Martin and Duan, Jubao and Ebrahim, Shah and Elliott, Paul and Elosua, Roberto and Eiriksdottir, Gudny and Erdos, Michael R and Eriksson, Johan G and Facheris, Maurizio F and Felix, Stephan B and Fischer-Posovszky, Pamela and Folsom, Aaron R and Friedrich, Nele and Freimer, Nelson B and Fu, Mao and Gaget, Stefan and Gejman, Pablo V and Geus, Eco J C and Gieger, Christian and Gjesing, Anette P and Goel, Anuj and Goyette, Philippe and Grallert, Harald and Gr{\"a}ssler, J{\"u}rgen and Greenawalt, Danielle M and Groves, Christopher J and Gudnason, Vilmundur and Guiducci, Candace and Hartikainen, Anna-Liisa and Hassanali, Neelam and Hall, Alistair S and Havulinna, Aki S and Hayward, Caroline and Heath, Andrew C and Hengstenberg, Christian and Hicks, Andrew A and Hinney, Anke and Hofman, Albert and Homuth, Georg and Hui, Jennie and Igl, Wilmar and Iribarren, Carlos and Isomaa, Bo and Jacobs, Kevin B and Jarick, Ivonne and Jewell, Elizabeth and John, Ulrich and J{\o}rgensen, Torben and Jousilahti, Pekka and Jula, Antti and Kaakinen, Marika and Kajantie, Eero and Kaplan, Lee M and Kathiresan, Sekar and Kettunen, Johannes and Kinnunen, Leena and Knowles, Joshua W and Kolcic, Ivana and K{\"o}nig, Inke R and Koskinen, Seppo and Kovacs, Peter and Kuusisto, Johanna and Kraft, Peter and Kval{\o}y, Kirsti and Laitinen, Jaana and Lantieri, Olivier and Lanzani, Chiara and Launer, Lenore J and Lecoeur, C{\'e}cile and Lehtim{\"a}ki, Terho and Lettre, Guillaume and Liu, Jianjun and Lokki, Marja-Liisa and Lorentzon, Mattias and Luben, Robert N and Ludwig, Barbara and Manunta, Paolo and Marek, Diana and Marre, Michel and Martin, Nicholas G and McArdle, Wendy L and McCarthy, Anne and McKnight, Barbara and Meitinger, Thomas and Melander, Olle and Meyre, David and Midthjell, Kristian and Montgomery, Grant W and Morken, Mario A and Morris, Andrew P and Mulic, Rosanda and Ngwa, Julius S and Nelis, Mari and Neville, Matt J and Nyholt, Dale R and O{\textquoteright}Donnell, Christopher J and O{\textquoteright}Rahilly, Stephen and Ong, Ken K and Oostra, Ben and Par{\'e}, Guillaume and Parker, Alex N and Perola, Markus and Pichler, Irene and Pietil{\"a}inen, Kirsi H and Platou, Carl G P and Polasek, Ozren and Pouta, Anneli and Rafelt, Suzanne and Raitakari, Olli and Rayner, Nigel W and Ridderstr{\r a}le, Martin and Rief, Winfried and Ruokonen, Aimo and Robertson, Neil R and Rzehak, Peter and Salomaa, Veikko and Sanders, Alan R and Sandhu, Manjinder S and Sanna, Serena and Saramies, Jouko and Savolainen, Markku J and Scherag, Susann and Schipf, Sabine and Schreiber, Stefan and Schunkert, Heribert and Silander, Kaisa and Sinisalo, Juha and Siscovick, David S and Smit, Jan H and Soranzo, Nicole and Sovio, Ulla and Stephens, Jonathan and Surakka, Ida and Swift, Amy J and Tammesoo, Mari-Liis and Tardif, Jean-Claude and Teder-Laving, Maris and Teslovich, Tanya M and Thompson, John R and Thomson, Brian and T{\"o}njes, Anke and Tuomi, Tiinamaija and van Meurs, Joyce B J and van Ommen, Gert-Jan and Vatin, Vincent and Viikari, Jorma and Visvikis-Siest, Sophie and Vitart, Veronique and Vogel, Carla I G and Voight, Benjamin F and Waite, Lindsay L and Wallaschofski, Henri and Walters, G Bragi and Widen, Elisabeth and Wiegand, Susanna and Wild, Sarah H and Willemsen, Gonneke and Witte, Daniel R and Witteman, Jacqueline C and Xu, Jianfeng and Zhang, Qunyuan and Zgaga, Lina and Ziegler, Andreas and Zitting, Paavo and Beilby, John P and Farooqi, I Sadaf and Hebebrand, Johannes and Huikuri, Heikki V and James, Alan L and K{\"a}h{\"o}nen, Mika and Levinson, Douglas F and Macciardi, Fabio and Nieminen, Markku S and Ohlsson, Claes and Palmer, Lyle J and Ridker, Paul M and Stumvoll, Michael and Beckmann, Jacques S and Boeing, Heiner and Boerwinkle, Eric and Boomsma, Dorret I and Caulfield, Mark J and Chanock, Stephen J and Collins, Francis S and Cupples, L Adrienne and Smith, George Davey and Erdmann, Jeanette and Froguel, Philippe and Gr{\"o}nberg, Henrik and Gyllensten, Ulf and Hall, Per and Hansen, Torben and Harris, Tamara B and Hattersley, Andrew T and Hayes, Richard B and Heinrich, Joachim and Hu, Frank B and Hveem, Kristian and Illig, Thomas and Jarvelin, Marjo-Riitta and Kaprio, Jaakko and Karpe, Fredrik and Khaw, Kay-Tee and Kiemeney, Lambertus A and Krude, Heiko and Laakso, Markku and Lawlor, Debbie A and Metspalu, Andres and Munroe, Patricia B and Ouwehand, Willem H and Pedersen, Oluf and Penninx, Brenda W and Peters, Annette and Pramstaller, Peter P and Quertermous, Thomas and Reinehr, Thomas and Rissanen, Aila and Rudan, Igor and Samani, Nilesh J and Schwarz, Peter E H and Shuldiner, Alan R and Spector, Timothy D and Tuomilehto, Jaakko and Uda, Manuela and Uitterlinden, Andre and Valle, Timo T and Wabitsch, Martin and Waeber, G{\'e}rard and Wareham, Nicholas J and Watkins, Hugh and Wilson, James F and Wright, Alan F and Zillikens, M Carola and Chatterjee, Nilanjan and McCarroll, Steven A and Purcell, Shaun and Schadt, Eric E and Visscher, Peter M and Assimes, Themistocles L and Borecki, Ingrid B and Deloukas, Panos and Fox, Caroline S and Groop, Leif C and Haritunians, Talin and Hunter, David J and Kaplan, Robert C and Mohlke, Karen L and O{\textquoteright}Connell, Jeffrey R and Peltonen, Leena and Schlessinger, David and Strachan, David P and van Duijn, Cornelia M and Wichmann, H-Erich and Frayling, Timothy M and Thorsteinsdottir, Unnur and Abecasis, Goncalo R and Barroso, In{\^e}s and Boehnke, Michael and Stefansson, Kari and North, Kari E and McCarthy, Mark I and Hirschhorn, Joel N and Ingelsson, Erik and Loos, Ruth J F} } @article {1204, title = {Common genetic determinants of vitamin D insufficiency: a genome-wide association study.}, journal = {Lancet}, volume = {376}, year = {2010}, month = {2010 Jul 17}, pages = {180-8}, abstract = {

BACKGROUND: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency.

METHODS: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants.

FINDINGS: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95\% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile.

INTERPRETATION: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency.

FUNDING: Full funding sources listed at end of paper (see Acknowledgments).

}, keywords = {Canada, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 4, Cohort Studies, Dietary Supplements, Europe, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Heterozygote, Homozygote, Humans, Immunoassay, International Cooperation, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Seasons, United States, Vitamin D, Vitamin D Deficiency}, issn = {1474-547X}, doi = {10.1016/S0140-6736(10)60588-0}, author = {Wang, Thomas J and Zhang, Feng and Richards, J Brent and Kestenbaum, Bryan and van Meurs, Joyce B and Berry, Diane and Kiel, Douglas P and Streeten, Elizabeth A and Ohlsson, Claes and Koller, Daniel L and Peltonen, Leena and Cooper, Jason D and O{\textquoteright}Reilly, Paul F and Houston, Denise K and Glazer, Nicole L and Vandenput, Liesbeth and Peacock, Munro and Shi, Julia and Rivadeneira, Fernando and McCarthy, Mark I and Anneli, Pouta and de Boer, Ian H and Mangino, Massimo and Kato, Bernet and Smyth, Deborah J and Booth, Sarah L and Jacques, Paul F and Burke, Greg L and Goodarzi, Mark and Cheung, Ching-Lung and Wolf, Myles and Rice, Kenneth and Goltzman, David and Hidiroglou, Nick and Ladouceur, Martin and Wareham, Nicholas J and Hocking, Lynne J and Hart, Deborah and Arden, Nigel K and Cooper, Cyrus and Malik, Suneil and Fraser, William D and Hartikainen, Anna-Liisa and Zhai, Guangju and Macdonald, Helen M and Forouhi, Nita G and Loos, Ruth J F and Reid, David M and Hakim, Alan and Dennison, Elaine and Liu, Yongmei and Power, Chris and Stevens, Helen E and Jaana, Laitinen and Vasan, Ramachandran S and Soranzo, Nicole and Bojunga, J{\"o}rg and Psaty, Bruce M and Lorentzon, Mattias and Foroud, Tatiana and Harris, Tamara B and Hofman, Albert and Jansson, John-Olov and Cauley, Jane A and Uitterlinden, Andr{\'e} G and Gibson, Quince and Jarvelin, Marjo-Riitta and Karasik, David and Siscovick, David S and Econs, Michael J and Kritchevsky, Stephen B and Florez, Jose C and Todd, John A and Dupuis, Jos{\'e}e and Hypp{\"o}nen, Elina and Spector, Timothy D} } @article {1206, title = {Common genetic variants associate with serum phosphorus concentration.}, journal = {J Am Soc Nephrol}, volume = {21}, year = {2010}, month = {2010 Jul}, pages = {1223-32}, abstract = {

Phosphorus is an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorus concentrations, genetic variation may determine interindividual variation in phosphorus metabolism. Here, we report a comprehensive genome-wide association study of serum phosphorus concentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Risk in Communities Study, Framingham Offspring Study, and the Rotterdam Study. We excluded participants with an estimated GFR <45 ml/min per 1.73 m(2) to focus on phosphorus metabolism under normal conditions. We imputed genotypes to approximately 2.5 million single-nucleotide polymorphisms in the HapMap and combined study-specific findings using meta-analysis. We tested top polymorphisms from discovery cohorts in a 5444-person replication sample. Polymorphisms in seven loci with minor allele frequencies 0.08 to 0.49 associate with serum phosphorus concentration (P = 3.5 x 10(-16) to 3.6 x 10(-7)). Three loci were near genes encoding the kidney-specific type IIa sodium phosphate co-transporter (SLC34A1), the calcium-sensing receptor (CASR), and fibroblast growth factor 23 (FGF23), proteins that contribute to phosphorus metabolism. We also identified genes encoding phosphatases, kinases, and phosphodiesterases that have yet-undetermined roles in phosphorus homeostasis. In the replication sample, five of seven top polymorphisms associate with serum phosphorous concentrations (P < 0.05 for each). In conclusion, common genetic variants associate with serum phosphorus in the general population. Further study of the loci identified in this study may help elucidate mechanisms of phosphorus regulation.

}, keywords = {Adult, Aged, European Continental Ancestry Group, Female, Fibroblast Growth Factors, Gene Frequency, Genetic Loci, Genetic Variation, Genome-Wide Association Study, Humans, Kidney, Male, Middle Aged, Phosphorus, Polymorphism, Single Nucleotide, Receptors, Calcium-Sensing, Sex Factors, Sodium-Phosphate Cotransporter Proteins, Type IIa}, issn = {1533-3450}, doi = {10.1681/ASN.2009111104}, author = {Kestenbaum, Bryan and Glazer, Nicole L and K{\"o}ttgen, Anna and Felix, Janine F and Hwang, Shih-Jen and Liu, Yongmei and Lohman, Kurt and Kritchevsky, Stephen B and Hausman, Dorothy B and Petersen, Ann-Kristin and Gieger, Christian and Ried, Janina S and Meitinger, Thomas and Strom, Tim M and Wichmann, H Erich and Campbell, Harry and Hayward, Caroline and Rudan, Igor and de Boer, Ian H and Psaty, Bruce M and Rice, Kenneth M and Chen, Yii-Der Ida and Li, Man and Arking, Dan E and Boerwinkle, Eric and Coresh, Josef and Yang, Qiong and Levy, Daniel and van Rooij, Frank J A and Dehghan, Abbas and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Hofman, Albert and van Duijn, Cornelia M and Shlipak, Michael G and Kao, W H Linda and Witteman, Jacqueline C M and Siscovick, David S and Fox, Caroline S} } @article {1244, title = {Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Dec}, pages = {1068-76}, abstract = {

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

}, keywords = {Animals, Animals, Newborn, Chromosomes, Human, Computational Biology, Electrocardiography, Genetic Loci, Genome-Wide Association Study, Heart Conduction System, Humans, Mice, Mice, Transgenic, Models, Animal, Myocytes, Cardiac, NAV1.8 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Sodium Channels}, issn = {1546-1718}, doi = {10.1038/ng.716}, author = {Sotoodehnia, Nona and Isaacs, Aaron and de Bakker, Paul I W and D{\"o}rr, Marcus and Newton-Cheh, Christopher and Nolte, Ilja M and van der Harst, Pim and M{\"u}ller, Martina and Eijgelsheim, Mark and Alonso, Alvaro and Hicks, Andrew A and Padmanabhan, Sandosh and Hayward, Caroline and Smith, Albert Vernon and Polasek, Ozren and Giovannone, Steven and Fu, Jingyuan and Magnani, Jared W and Marciante, Kristin D and Pfeufer, Arne and Gharib, Sina A and Teumer, Alexander and Li, Man and Bis, Joshua C and Rivadeneira, Fernando and Aspelund, Thor and K{\"o}ttgen, Anna and Johnson, Toby and Rice, Kenneth and Sie, Mark P S and Wang, Ying A and Klopp, Norman and Fuchsberger, Christian and Wild, Sarah H and Mateo Leach, Irene and Estrada, Karol and V{\"o}lker, Uwe and Wright, Alan F and Asselbergs, Folkert W and Qu, Jiaxiang and Chakravarti, Aravinda and Sinner, Moritz F and Kors, Jan A and Petersmann, Astrid and Harris, Tamara B and Soliman, Elsayed Z and Munroe, Patricia B and Psaty, Bruce M and Oostra, Ben A and Cupples, L Adrienne and Perz, Siegfried and de Boer, Rudolf A and Uitterlinden, Andr{\'e} G and V{\"o}lzke, Henry and Spector, Timothy D and Liu, Fang-Yu and Boerwinkle, Eric and Dominiczak, Anna F and Rotter, Jerome I and van Herpen, G{\'e} and Levy, Daniel and Wichmann, H-Erich and van Gilst, Wiek H and Witteman, Jacqueline C M and Kroemer, Heyo K and Kao, W H Linda and Heckbert, Susan R and Meitinger, Thomas and Hofman, Albert and Campbell, Harry and Folsom, Aaron R and van Veldhuisen, Dirk J and Schwienbacher, Christine and O{\textquoteright}Donnell, Christopher J and Volpato, Claudia Beu and Caulfield, Mark J and Connell, John M and Launer, Lenore and Lu, Xiaowen and Franke, Lude and Fehrmann, Rudolf S N and te Meerman, Gerard and Groen, Harry J M and Weersma, Rinse K and van den Berg, Leonard H and Wijmenga, Cisca and Ophoff, Roel A and Navis, Gerjan and Rudan, Igor and Snieder, Harold and Wilson, James F and Pramstaller, Peter P and Siscovick, David S and Wang, Thomas J and Gudnason, Vilmundur and van Duijn, Cornelia M and Felix, Stephan B and Fishman, Glenn I and Jamshidi, Yalda and Stricker, Bruno H Ch and Samani, Nilesh J and K{\"a}{\"a}b, Stefan and Arking, Dan E} } @article {1243, title = {Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo.}, journal = {PLoS Genet}, volume = {6}, year = {2010}, month = {2010 Oct 28}, pages = {e1001184}, abstract = {

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

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Child, Child, Preschool, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 6, Cohort Studies, European Continental Ancestry Group, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Microcirculation, Middle Aged, Polymorphism, Single Nucleotide, Retinal Vessels, Young Adult}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1001184}, author = {Ikram, M Kamran and Sim, Xueling and Xueling, Sim and Jensen, Richard A and Cotch, Mary Frances and Hewitt, Alex W and Ikram, M Arfan and Wang, Jie Jin and Klein, Ronald and Klein, Barbara E K and Breteler, Monique M B and Cheung, Ning and Liew, Gerald and Mitchell, Paul and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Hofman, Albert and de Jong, Paulus T V M and van Duijn, Cornelia M and Kao, Linda and Cheng, Ching-Yu and Smith, Albert Vernon and Glazer, Nicole L and Lumley, Thomas and McKnight, Barbara and Psaty, Bruce M and Jonasson, Fridbert and Eiriksdottir, Gudny and Aspelund, Thor and Harris, Tamara B and Launer, Lenore J and Taylor, Kent D and Li, Xiaohui and Iyengar, Sudha K and Xi, Quansheng and Sivakumaran, Theru A and Mackey, David A and Macgregor, Stuart and Martin, Nicholas G and Young, Terri L and Bis, Josh C and Wiggins, Kerri L and Heckbert, Susan R and Hammond, Christopher J and Andrew, Toby and Fahy, Samantha and Attia, John and Holliday, Elizabeth G and Scott, Rodney J and Islam, F M Amirul and Rotter, Jerome I and McAuley, Annie K and Boerwinkle, Eric and Tai, E Shyong and Gudnason, Vilmundur and Siscovick, David S and Vingerling, Johannes R and Wong, Tien Y} } @article {1217, title = {Genome-wide association analysis identifies multiple loci related to resting heart rate.}, journal = {Hum Mol Genet}, volume = {19}, year = {2010}, month = {2010 Oct 01}, pages = {3885-94}, abstract = {

Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 {\texttimes} 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7\% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6\%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.

}, keywords = {Adult, Aged, Base Pairing, Cohort Studies, Female, Genetic Loci, Genome, Human, Genome-Wide Association Study, Heart Rate, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Rest}, issn = {1460-2083}, doi = {10.1093/hmg/ddq303}, author = {Eijgelsheim, Mark and Newton-Cheh, Christopher and Sotoodehnia, Nona and de Bakker, Paul I W and M{\"u}ller, Martina and Morrison, Alanna C and Smith, Albert V and Isaacs, Aaron and Sanna, Serena and D{\"o}rr, Marcus and Navarro, Pau and Fuchsberger, Christian and Nolte, Ilja M and de Geus, Eco J C and Estrada, Karol and Hwang, Shih-Jen and Bis, Joshua C and R{\"u}ckert, Ina-Maria and Alonso, Alvaro and Launer, Lenore J and Hottenga, Jouke Jan and Rivadeneira, Fernando and Noseworthy, Peter A and Rice, Kenneth M and Perz, Siegfried and Arking, Dan E and Spector, Tim D and Kors, Jan A and Aulchenko, Yurii S and Tarasov, Kirill V and Homuth, Georg and Wild, Sarah H and Marroni, Fabio and Gieger, Christian and Licht, Carmilla M and Prineas, Ronald J and Hofman, Albert and Rotter, Jerome I and Hicks, Andrew A and Ernst, Florian and Najjar, Samer S and Wright, Alan F and Peters, Annette and Fox, Ervin R and Oostra, Ben A and Kroemer, Heyo K and Couper, David and V{\"o}lzke, Henry and Campbell, Harry and Meitinger, Thomas and Uda, Manuela and Witteman, Jacqueline C M and Psaty, Bruce M and Wichmann, H-Erich and Harris, Tamara B and K{\"a}{\"a}b, Stefan and Siscovick, David S and Jamshidi, Yalda and Uitterlinden, Andr{\'e} G and Folsom, Aaron R and Larson, Martin G and Wilson, James F and Penninx, Brenda W and Snieder, Harold and Pramstaller, Peter P and van Duijn, Cornelia M and Lakatta, Edward G and Felix, Stephan B and Gudnason, Vilmundur and Pfeufer, Arne and Heckbert, Susan R and Stricker, Bruno H Ch and Boerwinkle, Eric and O{\textquoteright}Donnell, Christopher J} } @article {1174, title = {Genome-wide association identifies multiple ulcerative colitis susceptibility loci.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Apr}, pages = {332-7}, abstract = {

Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan, comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn{\textquoteright}s disease loci showed that roughly half of the known Crohn{\textquoteright}s disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.

}, keywords = {Colitis, Ulcerative, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Membrane Proteins, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Receptors, IgG}, issn = {1546-1718}, doi = {10.1038/ng.549}, author = {McGovern, Dermot P B and Gardet, Agn{\`e}s and T{\"o}rkvist, Leif and Goyette, Philippe and Essers, Jonah and Taylor, Kent D and Neale, Benjamin M and Ong, Rick T H and Lagac{\'e}, Caroline and Li, Chun and Green, Todd and Stevens, Christine R and Beauchamp, Claudine and Fleshner, Phillip R and Carlson, Marie and D{\textquoteright}Amato, Mauro and Halfvarson, Jonas and Hibberd, Martin L and L{\"o}rdal, Mikael and Padyukov, Leonid and Andriulli, Angelo and Colombo, Elisabetta and Latiano, Anna and Palmieri, Orazio and Bernard, Edmond-Jean and Deslandres, Colette and Hommes, Daan W and de Jong, Dirk J and Stokkers, Pieter C and Weersma, Rinse K and Sharma, Yashoda and Silverberg, Mark S and Cho, Judy H and Wu, Jing and Roeder, Kathryn and Brant, Steven R and Schumm, L Phillip and Duerr, Richard H and Dubinsky, Marla C and Glazer, Nicole L and Haritunians, Talin and Ippoliti, Andy and Melmed, Gil Y and Siscovick, David S and Vasiliauskas, Eric A and Targan, Stephan R and Annese, Vito and Wijmenga, Cisca and Pettersson, Sven and Rotter, Jerome I and Xavier, Ramnik J and Daly, Mark J and Rioux, John D and Seielstad, Mark} } @article {1223, title = {Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels.}, journal = {PLoS Genet}, volume = {6}, year = {2010}, month = {2010 Aug 05}, abstract = {

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

}, keywords = {Adult, Aged, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Magnesium, Male, Middle Aged, Polymorphism, Single Nucleotide, Potassium, Sodium}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1001045}, author = {Meyer, Tamra E and Verwoert, Germaine C and Hwang, Shih-Jen and Glazer, Nicole L and Smith, Albert V and van Rooij, Frank J A and Ehret, Georg B and Boerwinkle, Eric and Felix, Janine F and Leak, Tennille S and Harris, Tamara B and Yang, Qiong and Dehghan, Abbas and Aspelund, Thor and Katz, Ronit and Homuth, Georg and Kocher, Thomas and Rettig, Rainer and Ried, Janina S and Gieger, Christian and Prucha, Hanna and Pfeufer, Arne and Meitinger, Thomas and Coresh, Josef and Hofman, Albert and Sarnak, Mark J and Chen, Yii-Der Ida and Uitterlinden, Andr{\'e} G and Chakravarti, Aravinda and Psaty, Bruce M and van Duijn, Cornelia M and Kao, W H Linda and Witteman, Jacqueline C M and Gudnason, Vilmundur and Siscovick, David S and Fox, Caroline S and K{\"o}ttgen, Anna} } @article {1182, title = {Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest.}, journal = {PLoS One}, volume = {5}, year = {2010}, month = {2010 Mar 25}, pages = {e9879}, abstract = {

BACKGROUND: Existing studies indicate a significant genetic component for sudden cardiac arrest (SCA) and genome-wide association studies (GWAS) provide an unbiased approach for identification of novel genes. We performed a GWAS to identify genetic determinants of SCA.

METHODOLOGY/PRINCIPAL FINDINGS: We used a case-control design within the ongoing Oregon Sudden Unexpected Death Study (Oregon-SUDS). Cases (n = 424) were SCAs with coronary artery disease (CAD) among residents of Portland, OR (2002-07, population approximately 1,000,000) and controls (n = 226) were residents with CAD, but no history of SCA. All subjects were of White-European ancestry and GWAS was performed using Affymetrix 500K/5.0 and 6.0 arrays. High signal markers were genotyped in SCA cases (n = 521) identified from the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) (combined n = 19,611). No SNPs reached genome-wide significance (p<5x10(-8)). SNPs at 6 loci were prioritized for follow-up primarily based on significance of p<10(-4) and proximity to a known gene (CSMD2, GPR37L1, LIN9, B4GALNT3, GPC5, and ZNF592). The minor allele of GPC5 (GLYPICAN 5, rs3864180) was associated with a lower risk of SCA in Oregon-SUDS, an effect that was also observed in ARIC/CHS whites (p<0.05) and blacks (p<0.04). In a combined Cox proportional hazards model analysis that adjusted for race, the minor allele exhibited a hazard ratio of 0.85 (95\% CI 0.74 to 0.98; p<0.01).

CONCLUSIONS/SIGNIFICANCE: A novel genetic locus for SCA, GPC5, was identified from Oregon-SUDS and successfully validated in the ARIC and CHS cohorts. Three other members of the Glypican family have been previously implicated in human disease, including cardiac conditions. The mechanism of this specific association requires further study.

}, keywords = {Aged, Alleles, Case-Control Studies, Cohort Studies, Death, Sudden, Cardiac, Ethnic Groups, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Glypicans, Heart Diseases, Humans, Male, Middle Aged, Models, Genetic, Oligonucleotide Array Sequence Analysis, Oregon, Polymorphism, Single Nucleotide}, issn = {1932-6203}, doi = {10.1371/journal.pone.0009879}, author = {Arking, Dan E and Reinier, Kyndaron and Post, Wendy and Jui, Jonathan and Hilton, Gina and O{\textquoteright}Connor, Ashley and Prineas, Ronald J and Boerwinkle, Eric and Psaty, Bruce M and Tomaselli, Gordon F and Rea, Thomas and Sotoodehnia, Nona and Siscovick, David S and Burke, Gregory L and Marb{\'a}n, Eduardo and Spooner, Peter M and Chakravarti, Aravinda and Chugh, Sumeet S} } @article {1234, title = {Hundreds of variants clustered in genomic loci and biological pathways affect human height.}, journal = {Nature}, volume = {467}, year = {2010}, month = {2010 Oct 14}, pages = {832-8}, abstract = {

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

}, keywords = {Body Height, Chromosomes, Human, Pair 3, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Metabolic Networks and Pathways, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide}, issn = {1476-4687}, doi = {10.1038/nature09410}, author = {Lango Allen, Hana and Estrada, Karol and Lettre, Guillaume and Berndt, Sonja I and Weedon, Michael N and Rivadeneira, Fernando and Willer, Cristen J and Jackson, Anne U and Vedantam, Sailaja and Raychaudhuri, Soumya and Ferreira, Teresa and Wood, Andrew R and Weyant, Robert J and Segr{\`e}, Ayellet V and Speliotes, Elizabeth K and Wheeler, Eleanor and Soranzo, Nicole and Park, Ju-Hyun and Yang, Jian and Gudbjartsson, Daniel and Heard-Costa, Nancy L and Randall, Joshua C and Qi, Lu and Vernon Smith, Albert and M{\"a}gi, Reedik and Pastinen, Tomi and Liang, Liming and Heid, Iris M and Luan, Jian{\textquoteright}an and Thorleifsson, Gudmar and Winkler, Thomas W and Goddard, Michael E and Sin Lo, Ken and Palmer, Cameron and Workalemahu, Tsegaselassie and Aulchenko, Yurii S and Johansson, Asa and Zillikens, M Carola and Feitosa, Mary F and Esko, T{\~o}nu and Johnson, Toby and Ketkar, Shamika and Kraft, Peter and Mangino, Massimo and Prokopenko, Inga and Absher, Devin and Albrecht, Eva and Ernst, Florian and Glazer, Nicole L and Hayward, Caroline and Hottenga, Jouke-Jan and Jacobs, Kevin B and Knowles, Joshua W and Kutalik, Zolt{\'a}n and Monda, Keri L and Polasek, Ozren and Preuss, Michael and Rayner, Nigel W and Robertson, Neil R and Steinthorsdottir, Valgerdur and Tyrer, Jonathan P and Voight, Benjamin F and Wiklund, Fredrik and Xu, Jianfeng and Zhao, Jing Hua and Nyholt, Dale R and Pellikka, Niina and Perola, Markus and Perry, John R B and Surakka, Ida and Tammesoo, Mari-Liis and Altmaier, Elizabeth L and Amin, Najaf and Aspelund, Thor and Bhangale, Tushar and Boucher, Gabrielle and Chasman, Daniel I and Chen, Constance and Coin, Lachlan and Cooper, Matthew N and Dixon, Anna L and Gibson, Quince and Grundberg, Elin and Hao, Ke and Juhani Junttila, M and Kaplan, Lee M and Kettunen, Johannes and K{\"o}nig, Inke R and Kwan, Tony and Lawrence, Robert W and Levinson, Douglas F and Lorentzon, Mattias and McKnight, Barbara and Morris, Andrew P and M{\"u}ller, Martina and Suh Ngwa, Julius and Purcell, Shaun and Rafelt, Suzanne and Salem, Rany M and Salvi, Erika and Sanna, Serena and Shi, Jianxin and Sovio, Ulla and Thompson, John R and Turchin, Michael C and Vandenput, Liesbeth and Verlaan, Dominique J and Vitart, Veronique and White, Charles C and Ziegler, Andreas and Almgren, Peter and Balmforth, Anthony J and Campbell, Harry and Citterio, Lorena and De Grandi, Alessandro and Dominiczak, Anna and Duan, Jubao and Elliott, Paul and Elosua, Roberto and Eriksson, Johan G and Freimer, Nelson B and Geus, Eco J C and Glorioso, Nicola and Haiqing, Shen and Hartikainen, Anna-Liisa and Havulinna, Aki S and Hicks, Andrew A and Hui, Jennie and Igl, Wilmar and Illig, Thomas and Jula, Antti and Kajantie, Eero and Kilpel{\"a}inen, Tuomas O and Koiranen, Markku and Kolcic, Ivana and Koskinen, Seppo and Kovacs, Peter and Laitinen, Jaana and Liu, Jianjun and Lokki, Marja-Liisa and Marusic, Ana and Maschio, Andrea and Meitinger, Thomas and Mulas, Antonella and Par{\'e}, Guillaume and Parker, Alex N and Peden, John F and Petersmann, Astrid and Pichler, Irene and Pietil{\"a}inen, Kirsi H and Pouta, Anneli and Ridderstr{\r a}le, Martin and Rotter, Jerome I and Sambrook, Jennifer G and Sanders, Alan R and Schmidt, Carsten Oliver and Sinisalo, Juha and Smit, Jan H and Stringham, Heather M and Bragi Walters, G and Widen, Elisabeth and Wild, Sarah H and Willemsen, Gonneke and Zagato, Laura and Zgaga, Lina and Zitting, Paavo and Alavere, Helene and Farrall, Martin and McArdle, Wendy L and Nelis, Mari and Peters, Marjolein J and Ripatti, Samuli and van Meurs, Joyce B J and Aben, Katja K and Ardlie, Kristin G and Beckmann, Jacques S and Beilby, John P and Bergman, Richard N and Bergmann, Sven and Collins, Francis S and Cusi, Daniele and den Heijer, Martin and Eiriksdottir, Gudny and Gejman, Pablo V and Hall, Alistair S and Hamsten, Anders and Huikuri, Heikki V and Iribarren, Carlos and K{\"a}h{\"o}nen, Mika and Kaprio, Jaakko and Kathiresan, Sekar and Kiemeney, Lambertus and Kocher, Thomas and Launer, Lenore J and Lehtim{\"a}ki, Terho and Melander, Olle and Mosley, Tom H and Musk, Arthur W and Nieminen, Markku S and O{\textquoteright}Donnell, Christopher J and Ohlsson, Claes and Oostra, Ben and Palmer, Lyle J and Raitakari, Olli and Ridker, Paul M and Rioux, John D and Rissanen, Aila and Rivolta, Carlo and Schunkert, Heribert and Shuldiner, Alan R and Siscovick, David S and Stumvoll, Michael and T{\"o}njes, Anke and Tuomilehto, Jaakko and van Ommen, Gert-Jan and Viikari, Jorma and Heath, Andrew C and Martin, Nicholas G and Montgomery, Grant W and Province, Michael A and Kayser, Manfred and Arnold, Alice M and Atwood, Larry D and Boerwinkle, Eric and Chanock, Stephen J and Deloukas, Panos and Gieger, Christian and Gr{\"o}nberg, Henrik and Hall, Per and Hattersley, Andrew T and Hengstenberg, Christian and Hoffman, Wolfgang and Lathrop, G Mark and Salomaa, Veikko and Schreiber, Stefan and Uda, Manuela and Waterworth, Dawn and Wright, Alan F and Assimes, Themistocles L and Barroso, In{\^e}s and Hofman, Albert and Mohlke, Karen L and Boomsma, Dorret I and Caulfield, Mark J and Cupples, L Adrienne and Erdmann, Jeanette and Fox, Caroline S and Gudnason, Vilmundur and Gyllensten, Ulf and Harris, Tamara B and Hayes, Richard B and Jarvelin, Marjo-Riitta and Mooser, Vincent and Munroe, Patricia B and Ouwehand, Willem H and Penninx, Brenda W and Pramstaller, Peter P and Quertermous, Thomas and Rudan, Igor and Samani, Nilesh J and Spector, Timothy D and V{\"o}lzke, Henry and Watkins, Hugh and Wilson, James F and Groop, Leif C and Haritunians, Talin and Hu, Frank B and Kaplan, Robert C and Metspalu, Andres and North, Kari E and Schlessinger, David and Wareham, Nicholas J and Hunter, David J and O{\textquoteright}Connell, Jeffrey R and Strachan, David P and Wichmann, H-Erich and Borecki, Ingrid B and van Duijn, Cornelia M and Schadt, Eric E and Thorsteinsdottir, Unnur and Peltonen, Leena and Uitterlinden, Andr{\'e} G and Visscher, Peter M and Chatterjee, Nilanjan and Loos, Ruth J F and Boehnke, Michael and McCarthy, Mark I and Ingelsson, Erik and Lindgren, Cecilia M and Abecasis, Goncalo R and Stefansson, Kari and Frayling, Timothy M and Hirschhorn, Joel N} } @article {1222, title = {Interactions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies.}, journal = {Diabetes Care}, volume = {33}, year = {2010}, month = {2010 Dec}, pages = {2684-91}, abstract = {

OBJECTIVE: Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin.

RESEARCH DESIGN AND METHODS: Via meta-analysis of data from 14 cohorts comprising \~{} 48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value <0.0028 (0.05 of 18 tests) as statistically significant.

RESULTS: Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95\% CI] per 1-serving-greater whole-grain intake: -0.009 mmol/l glucose [-0.013 to -0.005], P < 0.0001 and -0.011 pmol/l [ln] insulin [-0.015 to -0.007], P = 0.0003). No interactions met our multiple testing-adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele.

CONCLUSIONS: Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.

}, keywords = {Adult, Aged, Blood Glucose, Edible Grain, European Continental Ancestry Group, Fasting, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Insulin, Male, Middle Aged, Polymorphism, Single Nucleotide}, issn = {1935-5548}, doi = {10.2337/dc10-1150}, author = {Nettleton, Jennifer A and McKeown, Nicola M and Kanoni, Stavroula and Lemaitre, Rozenn N and Hivert, Marie-France and Ngwa, Julius and van Rooij, Frank J A and Sonestedt, Emily and Wojczynski, Mary K and Ye, Zheng and Tanaka, Tosh and Garcia, Melissa and Anderson, Jennifer S and Follis, Jack L and Djouss{\'e}, Luc and Mukamal, Kenneth and Papoutsakis, Constantina and Mozaffarian, Dariush and Zillikens, M Carola and Bandinelli, Stefania and Bennett, Amanda J and Borecki, Ingrid B and Feitosa, Mary F and Ferrucci, Luigi and Forouhi, Nita G and Groves, Christopher J and Hallmans, G{\"o}ran and Harris, Tamara and Hofman, Albert and Houston, Denise K and Hu, Frank B and Johansson, Ingegerd and Kritchevsky, Stephen B and Langenberg, Claudia and Launer, Lenore and Liu, Yongmei and Loos, Ruth J and Nalls, Michael and Orho-Melander, Marju and Renstrom, Frida and Rice, Kenneth and Riserus, Ulf and Rolandsson, Olov and Rotter, Jerome I and Saylor, Georgia and Sijbrands, Eric J G and Sjogren, Per and Smith, Albert and Steingr{\'\i}msd{\'o}ttir, Laufey and Uitterlinden, Andr{\'e} G and Wareham, Nicholas J and Prokopenko, Inga and Pankow, James S and van Duijn, Cornelia M and Florez, Jose C and Witteman, Jacqueline C M and Dupuis, Jos{\'e}e and Dedoussis, George V and Ordovas, Jose M and Ingelsson, Erik and Cupples, L Adrienne and Siscovick, David S and Franks, Paul W and Meigs, James B} } @article {1235, title = {Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors.}, journal = {Circ Cardiovasc Genet}, volume = {3}, year = {2010}, month = {2010 Dec}, pages = {523-30}, abstract = {

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

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

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

}, keywords = {Cardiovascular Diseases, Coronary Disease, Female, Genetic Loci, Genome-Wide Association Study, Gout, Humans, Male, Risk Factors, Uric Acid}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.109.934455}, author = {Yang, Qiong and K{\"o}ttgen, Anna and Dehghan, Abbas and Smith, Albert V and Glazer, Nicole L and Chen, Ming-Huei and Chasman, Daniel I and Aspelund, Thor and Eiriksdottir, Gudny and Harris, Tamara B and Launer, Lenore and Nalls, Michael and Hernandez, Dena and Arking, Dan E and Boerwinkle, Eric and Grove, Megan L and Li, Man and Linda Kao, W H and Chonchol, Michel and Haritunians, Talin and Li, Guo and Lumley, Thomas and Psaty, Bruce M and Shlipak, Michael and Hwang, Shih-Jen and Larson, Martin G and O{\textquoteright}Donnell, Christopher J and Upadhyay, Ashish and van Duijn, Cornelia M and Hofman, Albert and Rivadeneira, Fernando and Stricker, Bruno and Uitterlinden, Andr{\'e} G and Par{\'e}, Guillaume and Parker, Alex N and Ridker, Paul M and Siscovick, David S and Gudnason, Vilmundur and Witteman, Jacqueline C and Fox, Caroline S and Coresh, Josef} } @article {1160, title = {New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Feb}, pages = {105-16}, abstract = {

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

}, keywords = {Adolescent, Adult, Alleles, Blood Glucose, Child, Databases, Genetic, Diabetes Mellitus, Type 2, DNA Copy Number Variations, Fasting, Gene Expression Regulation, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeostasis, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, Reproducibility of Results}, issn = {1546-1718}, doi = {10.1038/ng.520}, author = {Dupuis, Jos{\'e}e and Langenberg, Claudia and Prokopenko, Inga and Saxena, Richa and Soranzo, Nicole and Jackson, Anne U and Wheeler, Eleanor and Glazer, Nicole L and Bouatia-Naji, Nabila and Gloyn, Anna L and Lindgren, Cecilia M and M{\"a}gi, Reedik and Morris, Andrew P and Randall, Joshua and Johnson, Toby and Elliott, Paul and Rybin, Denis and Thorleifsson, Gudmar and Steinthorsdottir, Valgerdur and Henneman, Peter and Grallert, Harald and Dehghan, Abbas and Hottenga, Jouke Jan and Franklin, Christopher S and Navarro, Pau and Song, Kijoung and Goel, Anuj and Perry, John R B and Egan, Josephine M and Lajunen, Taina and Grarup, Niels and Spars{\o}, Thomas and Doney, Alex and Voight, Benjamin F and Stringham, Heather M and Li, Man and Kanoni, Stavroula and Shrader, Peter and Cavalcanti-Proen{\c c}a, Christine and Kumari, Meena and Qi, Lu and Timpson, Nicholas J and Gieger, Christian and Zabena, Carina and Rocheleau, Ghislain and Ingelsson, Erik and An, Ping and O{\textquoteright}Connell, Jeffrey and Luan, Jian{\textquoteright}an and Elliott, Amanda and McCarroll, Steven A and Payne, Felicity and Roccasecca, Rosa Maria and Pattou, Fran{\c c}ois and Sethupathy, Praveen and Ardlie, Kristin and Ariyurek, Yavuz and Balkau, Beverley and Barter, Philip and Beilby, John P and Ben-Shlomo, Yoav and Benediktsson, Rafn and Bennett, Amanda J and Bergmann, Sven and Bochud, Murielle and Boerwinkle, Eric and Bonnefond, Am{\'e}lie and Bonnycastle, Lori L and Borch-Johnsen, Knut and B{\"o}ttcher, Yvonne and Brunner, Eric and Bumpstead, Suzannah J and Charpentier, Guillaume and Chen, Yii-Der Ida and Chines, Peter and Clarke, Robert and Coin, Lachlan J M and Cooper, Matthew N and Cornelis, Marilyn and Crawford, Gabe and Crisponi, Laura and Day, Ian N M and de Geus, Eco J C and Delplanque, Jerome and Dina, Christian and Erdos, Michael R and Fedson, Annette C and Fischer-Rosinsky, Antje and Forouhi, Nita G and Fox, Caroline S and Frants, Rune and Franzosi, Maria Grazia and Galan, Pilar and Goodarzi, Mark O and Graessler, J{\"u}rgen and Groves, Christopher J and Grundy, Scott and Gwilliam, Rhian and Gyllensten, Ulf and Hadjadj, Samy and Hallmans, G{\"o}ran and Hammond, Naomi and Han, Xijing and Hartikainen, Anna-Liisa and Hassanali, Neelam and Hayward, Caroline and Heath, Simon C and Hercberg, Serge and Herder, Christian and Hicks, Andrew A and Hillman, David R and Hingorani, Aroon D and Hofman, Albert and Hui, Jennie and Hung, Joe and Isomaa, Bo and Johnson, Paul R V and J{\o}rgensen, Torben and Jula, Antti and Kaakinen, Marika and Kaprio, Jaakko and Kesaniemi, Y Antero and Kivimaki, Mika and Knight, Beatrice and Koskinen, Seppo and Kovacs, Peter and Kyvik, Kirsten Ohm and Lathrop, G Mark and Lawlor, Debbie A and Le Bacquer, Olivier and Lecoeur, C{\'e}cile and Li, Yun and Lyssenko, Valeriya and Mahley, Robert and Mangino, Massimo and Manning, Alisa K and Mart{\'\i}nez-Larrad, Mar{\'\i}a Teresa and McAteer, Jarred B and McCulloch, Laura J and McPherson, Ruth and Meisinger, Christa and Melzer, David and Meyre, David and Mitchell, Braxton D and Morken, Mario A and Mukherjee, Sutapa and Naitza, Silvia and Narisu, Narisu and Neville, Matthew J and Oostra, Ben A and Orr{\`u}, Marco and Pakyz, Ruth and Palmer, Colin N A and Paolisso, Giuseppe and Pattaro, Cristian and Pearson, Daniel and Peden, John F and Pedersen, Nancy L and Perola, Markus and Pfeiffer, Andreas F H and Pichler, Irene and Polasek, Ozren and Posthuma, Danielle and Potter, Simon C and Pouta, Anneli and Province, Michael A and Psaty, Bruce M and Rathmann, Wolfgang and Rayner, Nigel W and Rice, Kenneth and Ripatti, Samuli and Rivadeneira, Fernando and Roden, Michael and Rolandsson, Olov and Sandbaek, Annelli and Sandhu, Manjinder and Sanna, Serena and Sayer, Avan Aihie and Scheet, Paul and Scott, Laura J and Seedorf, Udo and Sharp, Stephen J and Shields, Beverley and Sigurethsson, Gunnar and Sijbrands, Eric J G and Silveira, Angela and Simpson, Laila and Singleton, Andrew and Smith, Nicholas L and Sovio, Ulla and Swift, Amy and Syddall, Holly and Syv{\"a}nen, Ann-Christine and Tanaka, Toshiko and Thorand, Barbara and Tichet, Jean and T{\"o}njes, Anke and Tuomi, Tiinamaija and Uitterlinden, Andr{\'e} G and van Dijk, Ko Willems and van Hoek, Mandy and Varma, Dhiraj and Visvikis-Siest, Sophie and Vitart, Veronique and Vogelzangs, Nicole and Waeber, G{\'e}rard and Wagner, Peter J and Walley, Andrew and Walters, G Bragi and Ward, Kim L and Watkins, Hugh and Weedon, Michael N and Wild, Sarah H and Willemsen, Gonneke and Witteman, Jaqueline C M and Yarnell, John W G and Zeggini, Eleftheria and Zelenika, Diana and Zethelius, Bj{\"o}rn and Zhai, Guangju and Zhao, Jing Hua and Zillikens, M Carola and Borecki, Ingrid B and Loos, Ruth J F and Meneton, Pierre and Magnusson, Patrik K E and Nathan, David M and Williams, Gordon H and Hattersley, Andrew T and Silander, Kaisa and Salomaa, Veikko and Smith, George Davey and Bornstein, Stefan R and Schwarz, Peter and Spranger, Joachim and Karpe, Fredrik and Shuldiner, Alan R and Cooper, Cyrus and Dedoussis, George V and Serrano-R{\'\i}os, Manuel and Morris, Andrew D and Lind, Lars and Palmer, Lyle J and Hu, Frank B and Franks, Paul W and Ebrahim, Shah and Marmot, Michael and Kao, W H Linda and Pankow, James S and Sampson, Michael J and Kuusisto, Johanna and Laakso, Markku and Hansen, Torben and Pedersen, Oluf and Pramstaller, Peter Paul and Wichmann, H Erich and Illig, Thomas and Rudan, Igor and Wright, Alan F and Stumvoll, Michael and Campbell, Harry and Wilson, James F and Bergman, Richard N and Buchanan, Thomas A and Collins, Francis S and Mohlke, Karen L and Tuomilehto, Jaakko and Valle, Timo T and Altshuler, David and Rotter, Jerome I and Siscovick, David S and Penninx, Brenda W J H and Boomsma, Dorret I and Deloukas, Panos and Spector, Timothy D and Frayling, Timothy M and Ferrucci, Luigi and Kong, Augustine and Thorsteinsdottir, Unnur and Stefansson, Kari and van Duijn, Cornelia M and Aulchenko, Yurii S and Cao, Antonio and Scuteri, Angelo and Schlessinger, David and Uda, Manuela and Ruokonen, Aimo and Jarvelin, Marjo-Riitta and Waterworth, Dawn M and Vollenweider, Peter and Peltonen, Leena and Mooser, Vincent and Abecasis, Goncalo R and Wareham, Nicholas J and Sladek, Robert and Froguel, Philippe and Watanabe, Richard M and Meigs, James B and Groop, Leif and Boehnke, Michael and McCarthy, Mark I and Florez, Jose C and Barroso, In{\^e}s} } @article {1567, title = {Candidate gene association study for diabetic retinopathy in persons with type 2 diabetes: the Candidate gene Association Resource (CARe).}, journal = {Invest Ophthalmol Vis Sci}, volume = {52}, year = {2011}, month = {2011 Sep 29}, pages = {7593-602}, abstract = {

PURPOSE: To investigate whether variants in cardiovascular candidate genes, some of which have been previously associated with type 2 diabetes (T2D), diabetic retinopathy (DR), and diabetic nephropathy (DN), are associated with DR in the Candidate gene Association Resource (CARe).

METHODS: Persons with T2D who were enrolled in the study (n = 2691) had fundus photography and genotyping of single nucleotide polymorphisms (SNPs) in 2000 candidate genes. Two case definitions were investigated: Early Treatment Diabetic Retinopathy Study (ETDRS) grades >= 14 and >= 30. The χ{\texttwosuperior} analyses for each CARe cohort were combined by Cochran-Mantel-Haenszel (CMH) pooling of odds ratios (ORs) and corrected for multiple hypothesis testing. Logistic regression was performed with adjustment for other DR risk factors. Results from replication in independent cohorts were analyzed with CMH meta-analysis methods.

RESULTS: Among 39 genes previously associated with DR, DN, or T2D, three SNPs in P-selectin (SELP) were associated with DR. The strongest association was to rs6128 (OR = 0.43, P = 0.0001, after Bonferroni correction). These associations remained significant after adjustment for DR risk factors. Among other genes examined, several variants were associated with DR with significant P values, including rs6856425 tagging α-l-iduronidase (IDUA) (P = 2.1 {\texttimes} 10(-5), after Bonferroni correction). However, replication in independent cohorts did not reveal study-wide significant effects. The P values after replication were 0.55 and 0.10 for rs6128 and rs6856425, respectively.

CONCLUSIONS: Genes associated with DN, T2D, and vascular diseases do not appear to be consistently associated with DR. A few genetic variants associated with DR, particularly those in SELP and near IDUA, should be investigated in additional DR cohorts.

}, keywords = {Cardiovascular Diseases, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Diabetic Retinopathy, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Iduronidase, Odds Ratio, P-Selectin, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1552-5783}, doi = {10.1167/iovs.11-7510}, author = {Sobrin, Lucia and Green, Todd and Sim, Xueling and Jensen, Richard A and Tai, E Shyong and Tay, Wan Ting and Wang, Jie Jin and Mitchell, Paul and Sandholm, Niina and Liu, Yiyuan and Hietala, Kustaa and Iyengar, Sudha K and Brooks, Matthew and Buraczynska, Monika and Van Zuydam, Natalie and Smith, Albert V and Gudnason, Vilmundur and Doney, Alex S F and Morris, Andrew D and Leese, Graham P and Palmer, Colin N A and Swaroop, Anand and Taylor, Herman A and Wilson, James G and Penman, Alan and Chen, Ching J and Groop, Per-Henrik and Saw, Seang-Mei and Aung, Tin and Klein, Barbara E and Rotter, Jerome I and Siscovick, David S and Cotch, Mary Frances and Klein, Ronald and Daly, Mark J and Wong, Tien Y} } @article {1288, title = {Enhanced statistical tests for GWAS in admixed populations: assessment using African Americans from CARe and a Breast Cancer Consortium.}, journal = {PLoS Genet}, volume = {7}, year = {2011}, month = {2011 Apr}, pages = {e1001371}, abstract = {

While genome-wide association studies (GWAS) have primarily examined populations of European ancestry, more recent studies often involve additional populations, including admixed populations such as African Americans and Latinos. In admixed populations, linkage disequilibrium (LD) exists both at a fine scale in ancestral populations and at a coarse scale (admixture-LD) due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered SNP association (LD mapping) or admixture association (mapping by admixture-LD), but not both. Here, we introduce a new statistical framework for combining SNP and admixture association in case-control studies, as well as methods for local ancestry-aware imputation. We illustrate the gain in statistical power achieved by these methods by analyzing data of 6,209 unrelated African Americans from the CARe project genotyped on the Affymetrix 6.0 chip, in conjunction with both simulated and real phenotypes, as well as by analyzing the FGFR2 locus using breast cancer GWAS data from 5,761 African-American women. We show that, at typed SNPs, our method yields an 8\% increase in statistical power for finding disease risk loci compared to the power achieved by standard methods in case-control studies. At imputed SNPs, we observe an 11\% increase in statistical power for mapping disease loci when our local ancestry-aware imputation framework and the new scoring statistic are jointly employed. Finally, we show that our method increases statistical power in regions harboring the causal SNP in the case when the causal SNP is untyped and cannot be imputed. Our methods and our publicly available software are broadly applicable to GWAS in admixed populations.

}, keywords = {African Americans, Algorithms, Breast Neoplasms, Chromosome Mapping, Coronary Disease, Diabetes Mellitus, Type 2, Female, Gene Frequency, Genetic Variation, Genetics, Population, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Linkage Disequilibrium, Male, Odds Ratio, Phenotype, Polymorphism, Single Nucleotide, Principal Component Analysis, Receptor, Fibroblast Growth Factor, Type 2, Software}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1001371}, author = {Pasaniuc, Bogdan and Zaitlen, Noah and Lettre, Guillaume and Chen, Gary K and Tandon, Arti and Kao, W H Linda and Ruczinski, Ingo and Fornage, Myriam and Siscovick, David S and Zhu, Xiaofeng and Larkin, Emma and Lange, Leslie A and Cupples, L Adrienne and Yang, Qiong and Akylbekova, Ermeg L and Musani, Solomon K and Divers, Jasmin and Mychaleckyj, Joe and Li, Mingyao and Papanicolaou, George J and Millikan, Robert C and Ambrosone, Christine B and John, Esther M and Bernstein, Leslie and Zheng, Wei and Hu, Jennifer J and Ziegler, Regina G and Nyante, Sarah J and Bandera, Elisa V and Ingles, Sue A and Press, Michael F and Chanock, Stephen J and Deming, Sandra L and Rodriguez-Gil, Jorge L and Palmer, Cameron D and Buxbaum, Sarah and Ekunwe, Lynette and Hirschhorn, Joel N and Henderson, Brian E and Myers, Simon and Haiman, Christopher A and Reich, David and Patterson, Nick and Wilson, James G and Price, Alkes L} } @article {1311, title = {Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium.}, journal = {PLoS Genet}, volume = {7}, year = {2011}, month = {2011 Jul}, pages = {e1002193}, abstract = {

Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p = 3 x 10$^{-}$$^{6}$$^{4}$) and lower levels of eicosapentaenoic acid (EPA, p = 5 x 10$^{-}$$^{5}$$^{8}$) and docosapentaenoic acid (DPA, p = 4 x 10$^{-}${\textonesuperior}$^{5}$$^{4}$). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p = 2 x 10$^{-}${\textonesuperior}{\texttwosuperior}) and DPA (p = 1 x 10$^{-}$$^{4}${\textthreesuperior}) and lower docosahexaenoic acid (DHA, p = 1 x 10$^{-}${\textonesuperior}$^{5}$). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1 x 10$^{-}$$^{8}$). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.

}, keywords = {Alleles, Continental Population Groups, Fatty Acids, Omega-3, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002193}, author = {Lemaitre, Rozenn N and Tanaka, Toshiko and Tang, Weihong and Manichaikul, Ani and Foy, Millennia and Kabagambe, Edmond K and Nettleton, Jennifer A and King, Irena B and Weng, Lu-Chen and Bhattacharya, Sayanti and Bandinelli, Stefania and Bis, Joshua C and Rich, Stephen S and Jacobs, David R and Cherubini, Antonio and McKnight, Barbara and Liang, Shuang and Gu, Xiangjun and Rice, Kenneth and Laurie, Cathy C and Lumley, Thomas and Browning, Brian L and Psaty, Bruce M and Chen, Yii-der I and Friedlander, Yechiel and Djouss{\'e}, Luc and Wu, Jason H Y and Siscovick, David S and Uitterlinden, Andr{\'e} G and Arnett, Donna K and Ferrucci, Luigi and Fornage, Myriam and Tsai, Michael Y and Mozaffarian, Dariush and Steffen, Lyn M} } @article {1304, title = {Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals.}, journal = {PLoS Genet}, volume = {7}, year = {2011}, month = {2011 Jun}, pages = {e1002158}, abstract = {

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8{\texttimes}10(-10)). The risk allele, while ancestral, has a frequency of ~1.4\%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95\% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

}, keywords = {Adult, Aged, Alleles, Chromosomes, Human, Pair 2, Death, Sudden, Cardiac, European Continental Ancestry Group, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Myocardial Contraction, Polymorphism, Single Nucleotide}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002158}, author = {Arking, Dan E and Junttila, M Juhani and Goyette, Philippe and Huertas-Vazquez, Adriana and Eijgelsheim, Mark and Blom, Marieke T and Newton-Cheh, Christopher and Reinier, Kyndaron and Teodorescu, Carmen and Uy-Evanado, Audrey and Carter-Monroe, Naima and Kaikkonen, Kari S and Kortelainen, Marja-Leena and Boucher, Gabrielle and Lagac{\'e}, Caroline and Moes, Anna and Zhao, XiaoQing and Kolodgie, Frank and Rivadeneira, Fernando and Hofman, Albert and Witteman, Jacqueline C M and Uitterlinden, Andr{\'e} G and Marsman, Roos F and Pazoki, Raha and Bardai, Abdennasser and Koster, Rudolph W and Dehghan, Abbas and Hwang, Shih-Jen and Bhatnagar, Pallav and Post, Wendy and Hilton, Gina and Prineas, Ronald J and Li, Man and K{\"o}ttgen, Anna and Ehret, Georg and Boerwinkle, Eric and Coresh, Josef and Kao, W H Linda and Psaty, Bruce M and Tomaselli, Gordon F and Sotoodehnia, Nona and Siscovick, David S and Burke, Greg L and Marb{\'a}n, Eduardo and Spooner, Peter M and Cupples, L Adrienne and Jui, Jonathan and Gunson, Karen and Kesaniemi, Y Antero and Wilde, Arthur A M and Tardif, Jean-Claude and O{\textquoteright}Donnell, Christopher J and Bezzina, Connie R and Virmani, Renu and Stricker, Bruno H C H and Tan, Hanno L and Albert, Christine M and Chakravarti, Aravinda and Rioux, John D and Huikuri, Heikki V and Chugh, Sumeet S} } @article {1267, title = {Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels.}, journal = {Circulation}, volume = {123}, year = {2011}, month = {2011 Feb 22}, pages = {731-8}, abstract = {

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

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

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

}, keywords = {Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Risk Factors, Vasculitis}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.110.948570}, author = {Dehghan, Abbas and Dupuis, Jos{\'e}e and Barbalic, Maja and Bis, Joshua C and Eiriksdottir, Gudny and Lu, Chen and Pellikka, Niina and Wallaschofski, Henri and Kettunen, Johannes and Henneman, Peter and Baumert, Jens and Strachan, David P and Fuchsberger, Christian and Vitart, Veronique and Wilson, James F and Par{\'e}, Guillaume and Naitza, Silvia and Rudock, Megan E and Surakka, Ida and de Geus, Eco J C and Alizadeh, Behrooz Z and Guralnik, Jack and Shuldiner, Alan and Tanaka, Toshiko and Zee, Robert Y L and Schnabel, Renate B and Nambi, Vijay and Kavousi, Maryam and Ripatti, Samuli and Nauck, Matthias and Smith, Nicholas L and Smith, Albert V and Sundvall, Jouko and Scheet, Paul and Liu, Yongmei and Ruokonen, Aimo and Rose, Lynda M and Larson, Martin G and Hoogeveen, Ron C and Freimer, Nelson B and Teumer, Alexander and Tracy, Russell P and Launer, Lenore J and Buring, Julie E and Yamamoto, Jennifer F and Folsom, Aaron R and Sijbrands, Eric J G and Pankow, James and Elliott, Paul and Keaney, John F and Sun, Wei and Sarin, Antti-Pekka and Fontes, Jo{\~a}o D and Badola, Sunita and Astor, Brad C and Hofman, Albert and Pouta, Anneli and Werdan, Karl and Greiser, Karin H and Kuss, Oliver and Meyer zu Schwabedissen, Henriette E and Thiery, Joachim and Jamshidi, Yalda and Nolte, Ilja M and Soranzo, Nicole and Spector, Timothy D and V{\"o}lzke, Henry and Parker, Alexander N and Aspelund, Thor and Bates, David and Young, Lauren and Tsui, Kim and Siscovick, David S and Guo, Xiuqing and Rotter, Jerome I and Uda, Manuela and Schlessinger, David and Rudan, Igor and Hicks, Andrew A and Penninx, Brenda W and Thorand, Barbara and Gieger, Christian and Coresh, Joe and Willemsen, Gonneke and Harris, Tamara B and Uitterlinden, Andr{\'e} G and Jarvelin, Marjo-Riitta and Rice, Kenneth and Radke, D{\"o}rte and Salomaa, Veikko and Willems van Dijk, Ko and Boerwinkle, Eric and Vasan, Ramachandran S and Ferrucci, Luigi and Gibson, Quince D and Bandinelli, Stefania and Snieder, Harold and Boomsma, Dorret I and Xiao, Xiangjun and Campbell, Harry and Hayward, Caroline and Pramstaller, Peter P and van Duijn, Cornelia M and Peltonen, Leena and Psaty, Bruce M and Gudnason, Vilmundur and Ridker, Paul M and Homuth, Georg and Koenig, Wolfgang and Ballantyne, Christie M and Witteman, Jacqueline C M and Benjamin, Emelia J and Perola, Markus and Chasman, Daniel I} } @article {1377, title = {Genome-wide association and functional follow-up reveals new loci for kidney function.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1002584}, abstract = {

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

}, keywords = {African Americans, Aged, Animals, Caspase 9, Cyclin-Dependent Kinases, DEAD-box RNA Helicases, DNA Helicases, European Continental Ancestry Group, Female, Follow-Up Studies, Gene Knockdown Techniques, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Kidney, Kidney Failure, Chronic, Male, Middle Aged, Phosphoric Diester Hydrolases, Zebrafish}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002584}, author = {Pattaro, Cristian and K{\"o}ttgen, Anna and Teumer, Alexander and Garnaas, Maija and B{\"o}ger, Carsten A and Fuchsberger, Christian and Olden, Matthias and Chen, Ming-Huei and Tin, Adrienne and Taliun, Daniel and Li, Man and Gao, Xiaoyi and Gorski, Mathias and Yang, Qiong and Hundertmark, Claudia and Foster, Meredith C and O{\textquoteright}Seaghdha, Conall M and Glazer, Nicole and Isaacs, Aaron and Liu, Ching-Ti and Smith, Albert V and O{\textquoteright}Connell, Jeffrey R and Struchalin, Maksim and Tanaka, Toshiko and Li, Guo and Johnson, Andrew D and Gierman, Hinco J and Feitosa, Mary and Hwang, Shih-Jen and Atkinson, Elizabeth J and Lohman, Kurt and Cornelis, Marilyn C and Johansson, Asa and T{\"o}njes, Anke and Dehghan, Abbas and Chouraki, Vincent and Holliday, Elizabeth G and Sorice, Rossella and Kutalik, Zolt{\'a}n and Lehtim{\"a}ki, Terho and Esko, T{\~o}nu and Deshmukh, Harshal and Ulivi, Sheila and Chu, Audrey Y and Murgia, Federico and Trompet, Stella and Imboden, Medea and Kollerits, Barbara and Pistis, Giorgio and Harris, Tamara B and Launer, Lenore J and Aspelund, Thor and Eiriksdottir, Gudny and Mitchell, Braxton D and Boerwinkle, Eric and Schmidt, Helena and Cavalieri, Margherita and Rao, Madhumathi and Hu, Frank B and Demirkan, Ayse and Oostra, Ben A and de Andrade, Mariza and Turner, Stephen T and Ding, Jingzhong and Andrews, Jeanette S and Freedman, Barry I and Koenig, Wolfgang and Illig, Thomas and D{\"o}ring, Angela and Wichmann, H-Erich and Kolcic, Ivana and Zemunik, Tatijana and Boban, Mladen and Minelli, Cosetta and Wheeler, Heather E and Igl, Wilmar and Zaboli, Ghazal and Wild, Sarah H and Wright, Alan F and Campbell, Harry and Ellinghaus, David and N{\"o}thlings, Ute and Jacobs, Gunnar and Biffar, Reiner and Endlich, Karlhans and Ernst, Florian and Homuth, Georg and Kroemer, Heyo K and Nauck, Matthias and Stracke, Sylvia and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Kovacs, Peter and Stumvoll, Michael and M{\"a}gi, Reedik and Hofman, Albert and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Aulchenko, Yurii S and Polasek, Ozren and Hastie, Nick and Vitart, Veronique and Helmer, Catherine and Wang, Jie Jin and Ruggiero, Daniela and Bergmann, Sven and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Nikopensius, Tiit and Province, Michael and Ketkar, Shamika and Colhoun, Helen and Doney, Alex and Robino, Antonietta and Giulianini, Franco and Kr{\"a}mer, Bernhard K and Portas, Laura and Ford, Ian and Buckley, Brendan M and Adam, Martin and Thun, Gian-Andri and Paulweber, Bernhard and Haun, Margot and Sala, Cinzia and Metzger, Marie and Mitchell, Paul and Ciullo, Marina and Kim, Stuart K and Vollenweider, Peter and Raitakari, Olli and Metspalu, Andres and Palmer, Colin and Gasparini, Paolo and Pirastu, Mario and Jukema, J Wouter and Probst-Hensch, Nicole M and Kronenberg, Florian and Toniolo, Daniela and Gudnason, Vilmundur and Shuldiner, Alan R and Coresh, Josef and Schmidt, Reinhold and Ferrucci, Luigi and Siscovick, David S and van Duijn, Cornelia M and Borecki, Ingrid and Kardia, Sharon L R and Liu, Yongmei and Curhan, Gary C and Rudan, Igor and Gyllensten, Ulf and Wilson, James F and Franke, Andre and Pramstaller, Peter P and Rettig, Rainer and Prokopenko, Inga and Witteman, Jacqueline C M and Hayward, Caroline and Ridker, Paul and Parsa, Afshin and Bochud, Murielle and Heid, Iris M and Goessling, Wolfram and Chasman, Daniel I and Kao, W H Linda and Fox, Caroline S} } @article {1378, title = {Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1002607}, abstract = {

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5{\texttimes}10(-8)-1.2{\texttimes}10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3{\texttimes}10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3{\texttimes}10(-3), n = 22,044), increased triglycerides (p = 2.6{\texttimes}10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8{\texttimes}10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4{\texttimes}10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5{\texttimes}10(-13), n = 96,748) and decreased BMI (p = 1.4{\texttimes}10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

}, keywords = {Adiponectin, African Americans, Asian Continental Ancestry Group, Cholesterol, HDL, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose Tolerance Test, Humans, Insulin Resistance, Male, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Waist-Hip Ratio}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002607}, author = {Dastani, Zari and Hivert, Marie-France and Timpson, Nicholas and Perry, John R B and Yuan, Xin and Scott, Robert A and Henneman, Peter and Heid, Iris M and Kizer, Jorge R and Lyytik{\"a}inen, Leo-Pekka and Fuchsberger, Christian and Tanaka, Toshiko and Morris, Andrew P and Small, Kerrin and Isaacs, Aaron and Beekman, Marian and Coassin, Stefan and Lohman, Kurt and Qi, Lu and Kanoni, Stavroula and Pankow, James S and Uh, Hae-Won and Wu, Ying and Bidulescu, Aurelian and Rasmussen-Torvik, Laura J and Greenwood, Celia M T and Ladouceur, Martin and Grimsby, Jonna and Manning, Alisa K and Liu, Ching-Ti and Kooner, Jaspal and Mooser, Vincent E and Vollenweider, Peter and Kapur, Karen A and Chambers, John and Wareham, Nicholas J and Langenberg, Claudia and Frants, Rune and Willems-Vandijk, Ko and Oostra, Ben A and Willems, Sara M and Lamina, Claudia and Winkler, Thomas W and Psaty, Bruce M and Tracy, Russell P and Brody, Jennifer and Chen, Ida and Viikari, Jorma and K{\"a}h{\"o}nen, Mika and Pramstaller, Peter P and Evans, David M and St Pourcain, Beate and Sattar, Naveed and Wood, Andrew R and Bandinelli, Stefania and Carlson, Olga D and Egan, Josephine M and B{\"o}hringer, Stefan and van Heemst, Diana and Kedenko, Lyudmyla and Kristiansson, Kati and Nuotio, Marja-Liisa and Loo, Britt-Marie and Harris, Tamara and Garcia, Melissa and Kanaya, Alka and Haun, Margot and Klopp, Norman and Wichmann, H-Erich and Deloukas, Panos and Katsareli, Efi and Couper, David J and Duncan, Bruce B and Kloppenburg, Margreet and Adair, Linda S and Borja, Judith B and Wilson, James G and Musani, Solomon and Guo, Xiuqing and Johnson, Toby and Semple, Robert and Teslovich, Tanya M and Allison, Matthew A and Redline, Susan and Buxbaum, Sarah G and Mohlke, Karen L and Meulenbelt, Ingrid and Ballantyne, Christie M and Dedoussis, George V and Hu, Frank B and Liu, Yongmei and Paulweber, Bernhard and Spector, Timothy D and Slagboom, P Eline and Ferrucci, Luigi and Jula, Antti and Perola, Markus and Raitakari, Olli and Florez, Jose C and Salomaa, Veikko and Eriksson, Johan G and Frayling, Timothy M and Hicks, Andrew A and Lehtim{\"a}ki, Terho and Smith, George Davey and Siscovick, David S and Kronenberg, Florian and van Duijn, Cornelia and Loos, Ruth J F and Waterworth, Dawn M and Meigs, James B and Dupuis, Jos{\'e}e and Richards, J Brent and Voight, Benjamin F and Scott, Laura J and Steinthorsdottir, Valgerdur and Dina, Christian and Welch, Ryan P and Zeggini, Eleftheria and Huth, Cornelia and Aulchenko, Yurii S and Thorleifsson, Gudmar and McCulloch, Laura J and Ferreira, Teresa and Grallert, Harald and Amin, Najaf and Wu, Guanming and Willer, Cristen J and Raychaudhuri, Soumya and McCarroll, Steve A and Hofmann, Oliver M and Segr{\`e}, Ayellet V and van Hoek, Mandy and Navarro, Pau and Ardlie, Kristin and Balkau, Beverley and Benediktsson, Rafn and Bennett, Amanda J and Blagieva, Roza and Boerwinkle, Eric and Bonnycastle, Lori L and Bostr{\"o}m, Kristina Bengtsson and Bravenboer, Bert and Bumpstead, Suzannah and Burtt, Noel P and Charpentier, Guillaume and Chines, Peter S and Cornelis, Marilyn and Crawford, Gabe and Doney, Alex S F and Elliott, Katherine S and Elliott, Amanda L and Erdos, Michael R and Fox, Caroline S and Franklin, Christopher S and Ganser, Martha and Gieger, Christian and Grarup, Niels and Green, Todd and Griffin, Simon and Groves, Christopher J and Guiducci, Candace and Hadjadj, Samy and Hassanali, Neelam and Herder, Christian and Isomaa, Bo and Jackson, Anne U and Johnson, Paul R V and J{\o}rgensen, Torben and Kao, Wen H L and Kong, Augustine and Kraft, Peter and Kuusisto, Johanna and Lauritzen, Torsten and Li, Man and Lieverse, Aloysius and Lindgren, Cecilia M and Lyssenko, Valeriya and Marre, Michel and Meitinger, Thomas and Midthjell, Kristian and Morken, Mario A and Narisu, Narisu and Nilsson, Peter and Owen, Katharine R and Payne, Felicity and Petersen, Ann-Kristin and Platou, Carl and Proen{\c c}a, Christine and Prokopenko, Inga and Rathmann, Wolfgang and Rayner, N William and Robertson, Neil R and Rocheleau, Ghislain and Roden, Michael and Sampson, Michael J and Saxena, Richa and Shields, Beverley M and Shrader, Peter and Sigurdsson, Gunnar and Spars{\o}, Thomas and Strassburger, Klaus and Stringham, Heather M and Sun, Qi and Swift, Amy J and Thorand, Barbara and Tichet, Jean and Tuomi, Tiinamaija and van Dam, Rob M and van Haeften, Timon W and van Herpt, Thijs and van Vliet-Ostaptchouk, Jana V and Walters, G Bragi and Weedon, Michael N and Wijmenga, Cisca and Witteman, Jacqueline and Bergman, Richard N and Cauchi, Stephane and Collins, Francis S and Gloyn, Anna L and Gyllensten, Ulf and Hansen, Torben and Hide, Winston A and Hitman, Graham A and Hofman, Albert and Hunter, David J and Hveem, Kristian and Laakso, Markku and Morris, Andrew D and Palmer, Colin N A and Rudan, Igor and Sijbrands, Eric and Stein, Lincoln D and Tuomilehto, Jaakko and Uitterlinden, Andre and Walker, Mark and Watanabe, Richard M and Abecasis, Goncalo R and Boehm, Bernhard O and Campbell, Harry and Daly, Mark J and Hattersley, Andrew T and Pedersen, Oluf and Barroso, In{\^e}s and Groop, Leif and Sladek, Rob and Thorsteinsdottir, Unnur and Wilson, James F and Illig, Thomas and Froguel, Philippe and van Duijn, Cornelia M and Stefansson, Kari and Altshuler, David and Boehnke, Michael and McCarthy, Mark I and Soranzo, Nicole and Wheeler, Eleanor and Glazer, Nicole L and Bouatia-Naji, Nabila and M{\"a}gi, Reedik and Randall, Joshua and Elliott, Paul and Rybin, Denis and Dehghan, Abbas and Hottenga, Jouke Jan and Song, Kijoung and Goel, Anuj and Lajunen, Taina and Doney, Alex and Cavalcanti-Proen{\c c}a, Christine and Kumari, Meena and Timpson, Nicholas J and Zabena, Carina and Ingelsson, Erik and An, Ping and O{\textquoteright}Connell, Jeffrey and Luan, Jian{\textquoteright}an and Elliott, Amanda and McCarroll, Steven A and Roccasecca, Rosa Maria and Pattou, Fran{\c c}ois and Sethupathy, Praveen and Ariyurek, Yavuz and Barter, Philip and Beilby, John P and Ben-Shlomo, Yoav and Bergmann, Sven and Bochud, Murielle and Bonnefond, Am{\'e}lie and Borch-Johnsen, Knut and B{\"o}ttcher, Yvonne and Brunner, Eric and Bumpstead, Suzannah J and Chen, Yii-Der Ida and Chines, Peter and Clarke, Robert and Coin, Lachlan J M and Cooper, Matthew N and Crisponi, Laura and Day, Ian N M and de Geus, Eco J C and Delplanque, Jerome and Fedson, Annette C and Fischer-Rosinsky, Antje and Forouhi, Nita G and Franzosi, Maria Grazia and Galan, Pilar and Goodarzi, Mark O and Graessler, J{\"u}rgen and Grundy, Scott and Gwilliam, Rhian and Hallmans, G{\"o}ran and Hammond, Naomi and Han, Xijing and Hartikainen, Anna-Liisa and Hayward, Caroline and Heath, Simon C and Hercberg, Serge and Hillman, David R and Hingorani, Aroon D and Hui, Jennie and Hung, Joe and Kaakinen, Marika and Kaprio, Jaakko and Kesaniemi, Y Antero and Kivimaki, Mika and Knight, Beatrice and Koskinen, Seppo and Kovacs, Peter and Kyvik, Kirsten Ohm and Lathrop, G Mark and Lawlor, Debbie A and Le Bacquer, Olivier and Lecoeur, C{\'e}cile and Li, Yun and Mahley, Robert and Mangino, Massimo and Mart{\'\i}nez-Larrad, Mar{\'\i}a Teresa and McAteer, Jarred B and McPherson, Ruth and Meisinger, Christa and Melzer, David and Meyre, David and Mitchell, Braxton D and Mukherjee, Sutapa and Naitza, Silvia and Neville, Matthew J and Orr{\`u}, Marco and Pakyz, Ruth and Paolisso, Giuseppe and Pattaro, Cristian and Pearson, Daniel and Peden, John F and Pedersen, Nancy L and Pfeiffer, Andreas F H and Pichler, Irene and Polasek, Ozren and Posthuma, Danielle and Potter, Simon C and Pouta, Anneli and Province, Michael A and Rayner, Nigel W and Rice, Kenneth and Ripatti, Samuli and Rivadeneira, Fernando and Rolandsson, Olov and Sandbaek, Annelli and Sandhu, Manjinder and Sanna, Serena and Sayer, Avan Aihie and Scheet, Paul and Seedorf, Udo and Sharp, Stephen J and Shields, Beverley and Sigur{\dh}sson, Gunnar and Sijbrands, Eric J G and Silveira, Angela and Simpson, Laila and Singleton, Andrew and Smith, Nicholas L and Sovio, Ulla and Swift, Amy and Syddall, Holly and Syv{\"a}nen, Ann-Christine and T{\"o}njes, Anke and Uitterlinden, Andr{\'e} G and van Dijk, Ko Willems and Varma, Dhiraj and Visvikis-Siest, Sophie and Vitart, Veronique and Vogelzangs, Nicole and Waeber, G{\'e}rard and Wagner, Peter J and Walley, Andrew and Ward, Kim L and Watkins, Hugh and Wild, Sarah H and Willemsen, Gonneke and Witteman, Jaqueline C M and Yarnell, John W G and Zelenika, Diana and Zethelius, Bj{\"o}rn and Zhai, Guangju and Zhao, Jing Hua and Zillikens, M Carola and Borecki, Ingrid B and Meneton, Pierre and Magnusson, Patrik K E and Nathan, David M and Williams, Gordon H and Silander, Kaisa and Bornstein, Stefan R and Schwarz, Peter and Spranger, Joachim and Karpe, Fredrik and Shuldiner, Alan R and Cooper, Cyrus and Serrano-R{\'\i}os, Manuel and Lind, Lars and Palmer, Lyle J and Hu, Frank B and Franks, Paul W and Ebrahim, Shah and Marmot, Michael and Kao, W H Linda and Pramstaller, Peter Paul and Wright, Alan F and Stumvoll, Michael and Hamsten, Anders and Buchanan, Thomas A and Valle, Timo T and Rotter, Jerome I and Penninx, Brenda W J H and Boomsma, Dorret I and Cao, Antonio and Scuteri, Angelo and Schlessinger, David and Uda, Manuela and Ruokonen, Aimo and Jarvelin, Marjo-Riitta and Peltonen, Leena and Mooser, Vincent and Sladek, Robert and Musunuru, Kiran and Smith, Albert V and Edmondson, Andrew C and Stylianou, Ioannis M and Koseki, Masahiro and Pirruccello, James P and Chasman, Daniel I and Johansen, Christopher T and Fouchier, Sigrid W and Peloso, Gina M and Barbalic, Maja and Ricketts, Sally L and Bis, Joshua C and Feitosa, Mary F and Orho-Melander, Marju and Melander, Olle and Li, Xiaohui and Li, Mingyao and Cho, Yoon Shin and Go, Min Jin and Kim, Young Jin and Lee, Jong-Young and Park, Taesung and Kim, Kyunga and Sim, Xueling and Ong, Rick Twee-Hee and Croteau-Chonka, Damien C and Lange, Leslie A and Smith, Joshua D and Ziegler, Andreas and Zhang, Weihua and Zee, Robert Y L and Whitfield, John B and Thompson, John R and Surakka, Ida and Spector, Tim D and Smit, Johannes H and Sinisalo, Juha and Scott, James and Saharinen, Juha and Sabatti, Chiara and Rose, Lynda M and Roberts, Robert and Rieder, Mark and Parker, Alex N and Par{\'e}, Guillaume and O{\textquoteright}Donnell, Christopher J and Nieminen, Markku S and Nickerson, Deborah A and Montgomery, Grant W and McArdle, Wendy and Masson, David and Martin, Nicholas G and Marroni, Fabio and Lucas, Gavin and Luben, Robert and Lokki, Marja-Liisa and Lettre, Guillaume and Launer, Lenore J and Lakatta, Edward G and Laaksonen, Reijo and Kyvik, Kirsten O and K{\"o}nig, Inke R and Khaw, Kay-Tee and Kaplan, Lee M and Johansson, Asa and Janssens, A Cecile J W and Igl, Wilmar and Hovingh, G Kees and Hengstenberg, Christian and Havulinna, Aki S and Hastie, Nicholas D and Harris, Tamara B and Haritunians, Talin and Hall, Alistair S and Groop, Leif C and Gonzalez, Elena and Freimer, Nelson B and Erdmann, Jeanette and Ejebe, Kenechi G and D{\"o}ring, Angela and Dominiczak, Anna F and Demissie, Serkalem and Deloukas, Panagiotis and de Faire, Ulf and Crawford, Gabriel and Chen, Yii-der I and Caulfield, Mark J and Boekholdt, S Matthijs and Assimes, Themistocles L and Quertermous, Thomas and Seielstad, Mark and Wong, Tien Y and Tai, E-Shyong and Feranil, Alan B and Kuzawa, Christopher W and Taylor, Herman A and Gabriel, Stacey B and Holm, Hilma and Gudnason, Vilmundur and Krauss, Ronald M and Ordovas, Jose M and Munroe, Patricia B and Kooner, Jaspal S and Tall, Alan R and Hegele, Robert A and Kastelein, John J P and Schadt, Eric E and Strachan, David P and Reilly, Muredach P and Samani, Nilesh J and Schunkert, Heribert and Cupples, L Adrienne and Sandhu, Manjinder S and Ridker, Paul M and Rader, Daniel J and Kathiresan, Sekar} } @article {6288, title = {Common variants in Mendelian kidney disease genes and their association with renal function.}, journal = {J Am Soc Nephrol}, volume = {24}, year = {2013}, month = {2013 Dec}, pages = {2105-17}, abstract = {

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

}, keywords = {Databases, Genetic, European Continental Ancestry Group, Gene Frequency, Genetic Variation, Genome-Wide Association Study, Humans, Kidney, Mendelian Randomization Analysis, Phenotype, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic}, issn = {1533-3450}, doi = {10.1681/ASN.2012100983}, author = {Parsa, Afshin and Fuchsberger, Christian and K{\"o}ttgen, Anna and O{\textquoteright}Seaghdha, Conall M and Pattaro, Cristian and de Andrade, Mariza and Chasman, Daniel I and Teumer, Alexander and Endlich, Karlhans and Olden, Matthias and Chen, Ming-Huei and Tin, Adrienne and Kim, Young J and Taliun, Daniel and Li, Man and Feitosa, Mary and Gorski, Mathias and Yang, Qiong and Hundertmark, Claudia and Foster, Meredith C and Glazer, Nicole and Isaacs, Aaron and Rao, Madhumathi and Smith, Albert V and O{\textquoteright}Connell, Jeffrey R and Struchalin, Maksim and Tanaka, Toshiko and Li, Guo and Hwang, Shih-Jen and Atkinson, Elizabeth J and Lohman, Kurt and Cornelis, Marilyn C and Johansson, Asa and T{\"o}njes, Anke and Dehghan, Abbas and Couraki, Vincent and Holliday, Elizabeth G and Sorice, Rossella and Kutalik, Zolt{\'a}n and Lehtim{\"a}ki, Terho and Esko, T{\~o}nu and Deshmukh, Harshal and Ulivi, Sheila and Chu, Audrey Y and Murgia, Federico and Trompet, Stella and Imboden, Medea and Kollerits, Barbara and Pistis, Giorgio and Harris, Tamara B and Launer, Lenore J and Aspelund, Thor and Eiriksdottir, Gudny and Mitchell, Braxton D and Boerwinkle, Eric and Schmidt, Helena and Hofer, Edith and Hu, Frank and Demirkan, Ayse and Oostra, Ben A and Turner, Stephen T and Ding, Jingzhong and Andrews, Jeanette S and Freedman, Barry I and Giulianini, Franco and Koenig, Wolfgang and Illig, Thomas and D{\"o}ring, Angela and Wichmann, H-Erich and Zgaga, Lina and Zemunik, Tatijana and Boban, Mladen and Minelli, Cosetta and Wheeler, Heather E and Igl, Wilmar and Zaboli, Ghazal and Wild, Sarah H and Wright, Alan F and Campbell, Harry and Ellinghaus, David and N{\"o}thlings, Ute and Jacobs, Gunnar and Biffar, Reiner and Ernst, Florian and Homuth, Georg and Kroemer, Heyo K and Nauck, Matthias and Stracke, Sylvia and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Kovacs, Peter and Stumvoll, Michael and M{\"a}gi, Reedik and Hofman, Albert and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Aulchenko, Yurii S and Polasek, Ozren and Hastie, Nick and Vitart, Veronique and Helmer, Catherine and Wang, Jie Jin and Stengel, B{\'e}n{\'e}dicte and Ruggiero, Daniela and Bergmann, Sven and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Nikopensius, Tiit and Province, Michael and Colhoun, Helen and Doney, Alex and Robino, Antonietta and Kr{\"a}mer, Bernhard K and Portas, Laura and Ford, Ian and Buckley, Brendan M and Adam, Martin and Thun, Gian-Andri and Paulweber, Bernhard and Haun, Margot and Sala, Cinzia and Mitchell, Paul and Ciullo, Marina and Vollenweider, Peter and Raitakari, Olli and Metspalu, Andres and Palmer, Colin and Gasparini, Paolo and Pirastu, Mario and Jukema, J Wouter and Probst-Hensch, Nicole M and Kronenberg, Florian and Toniolo, Daniela and Gudnason, Vilmundur and Shuldiner, Alan R and Coresh, Josef and Schmidt, Reinhold and Ferrucci, Luigi and van Duijn, Cornelia M and Borecki, Ingrid and Kardia, Sharon L R and Liu, Yongmei and Curhan, Gary C and Rudan, Igor and Gyllensten, Ulf and Wilson, James F and Franke, Andre and Pramstaller, Peter P and Rettig, Rainer and Prokopenko, Inga and Witteman, Jacqueline and Hayward, Caroline and Ridker, Paul M and Bochud, Murielle and Heid, Iris M and Siscovick, David S and Fox, Caroline S and Kao, W Linda and B{\"o}ger, Carsten A} } @article {6027, title = {Genetic loci for retinal arteriolar microcirculation.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e65804}, abstract = {

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

}, keywords = {Aged, Aged, 80 and over, Arterioles, Chromosomes, Human, Pair 5, European Continental Ancestry Group, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Male, MEF2 Transcription Factors, Microcirculation, Middle Aged, Models, Genetic, Retinal Vessels}, issn = {1932-6203}, doi = {10.1371/journal.pone.0065804}, author = {Sim, Xueling and Jensen, Richard A and Ikram, M Kamran and Cotch, Mary Frances and Li, Xiaohui and Macgregor, Stuart and Xie, Jing and Smith, Albert Vernon and Boerwinkle, Eric and Mitchell, Paul and Klein, Ronald and Klein, Barbara E K and Glazer, Nicole L and Lumley, Thomas and McKnight, Barbara and Psaty, Bruce M and de Jong, Paulus T V M and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Aspelund, Thor and Eiriksdottir, Gudny and Harris, Tamara B and Jonasson, Fridbert and Launer, Lenore J and Attia, John and Baird, Paul N and Harrap, Stephen and Holliday, Elizabeth G and Inouye, Michael and Rochtchina, Elena and Scott, Rodney J and Viswanathan, Ananth and Li, Guo and Smith, Nicholas L and Wiggins, Kerri L and Kuo, Jane Z and Taylor, Kent D and Hewitt, Alex W and Martin, Nicholas G and Montgomery, Grant W and Sun, Cong and Young, Terri L and Mackey, David A and van Zuydam, Natalie R and Doney, Alex S F and Palmer, Colin N A and Morris, Andrew D and Rotter, Jerome I and Tai, E Shyong and Gudnason, Vilmundur and Vingerling, Johannes R and Siscovick, David S and Wang, Jie Jin and Wong, Tien Y} } @article {6075, title = {Genome-wide association analyses identify 18 new loci associated with serum urate concentrations.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Feb}, pages = {145-54}, abstract = {

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

}, keywords = {Analysis of Variance, European Continental Ancestry Group, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Glucose, Gout, Humans, Inhibins, Polymorphism, Single Nucleotide, Signal Transduction, Uric Acid}, issn = {1546-1718}, doi = {10.1038/ng.2500}, author = {K{\"o}ttgen, Anna and Albrecht, Eva and Teumer, Alexander and Vitart, Veronique and Krumsiek, Jan and Hundertmark, Claudia and Pistis, Giorgio and Ruggiero, Daniela and O{\textquoteright}Seaghdha, Conall M and Haller, Toomas and Yang, Qiong and Tanaka, Toshiko and Johnson, Andrew D and Kutalik, Zolt{\'a}n and Smith, Albert V and Shi, Julia and Struchalin, Maksim and Middelberg, Rita P S and Brown, Morris J and Gaffo, Angelo L and Pirastu, Nicola and Li, Guo and Hayward, Caroline and Zemunik, Tatijana and Huffman, Jennifer and Yengo, Loic and Zhao, Jing Hua and Demirkan, Ayse and Feitosa, Mary F and Liu, Xuan and Malerba, Giovanni and Lopez, Lorna M and van der Harst, Pim and Li, Xinzhong and Kleber, Marcus E and Hicks, Andrew A and Nolte, Ilja M and Johansson, Asa and Murgia, Federico and Wild, Sarah H and Bakker, Stephan J L and Peden, John F and Dehghan, Abbas and Steri, Maristella and Tenesa, Albert and Lagou, Vasiliki and Salo, Perttu and Mangino, Massimo and Rose, Lynda M and Lehtim{\"a}ki, Terho and Woodward, Owen M and Okada, Yukinori and Tin, Adrienne and M{\"u}ller, Christian and Oldmeadow, Christopher and Putku, Margus and Czamara, Darina and Kraft, Peter and Frogheri, Laura and Thun, Gian Andri and Grotevendt, Anne and Gislason, Gauti Kjartan and Harris, Tamara B and Launer, Lenore J and McArdle, Patrick and Shuldiner, Alan R and Boerwinkle, Eric and Coresh, Josef and Schmidt, Helena and Schallert, Michael and Martin, Nicholas G and Montgomery, Grant W and Kubo, Michiaki and Nakamura, Yusuke and Tanaka, Toshihiro and Munroe, Patricia B and Samani, Nilesh J and Jacobs, David R and Liu, Kiang and D{\textquoteright}Adamo, Pio and Ulivi, Sheila and Rotter, Jerome I and Psaty, Bruce M and Vollenweider, Peter and Waeber, G{\'e}rard and Campbell, Susan and Devuyst, Olivier and Navarro, Pau and Kolcic, Ivana and Hastie, Nicholas and Balkau, Beverley and Froguel, Philippe and Esko, T{\~o}nu and Salumets, Andres and Khaw, Kay Tee and Langenberg, Claudia and Wareham, Nicholas J and Isaacs, Aaron and Kraja, Aldi and Zhang, Qunyuan and Wild, Philipp S and Scott, Rodney J and Holliday, Elizabeth G and Org, Elin and Viigimaa, Margus and Bandinelli, Stefania and Metter, Jeffrey E and Lupo, Antonio and Trabetti, Elisabetta and Sorice, Rossella and D{\"o}ring, Angela and Lattka, Eva and Strauch, Konstantin and Theis, Fabian and Waldenberger, Melanie and Wichmann, H-Erich and Davies, Gail and Gow, Alan J and Bruinenberg, Marcel and Stolk, Ronald P and Kooner, Jaspal S and Zhang, Weihua and Winkelmann, Bernhard R and Boehm, Bernhard O and Lucae, Susanne and Penninx, Brenda W and Smit, Johannes H and Curhan, Gary and Mudgal, Poorva and Plenge, Robert M and Portas, Laura and Persico, Ivana and Kirin, Mirna and Wilson, James F and Mateo Leach, Irene and van Gilst, Wiek H and Goel, Anuj and Ongen, Halit and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Imboden, Medea and von Eckardstein, Arnold and Cucca, Francesco and Nagaraja, Ramaiah and Piras, Maria Grazia and Nauck, Matthias and Schurmann, Claudia and Budde, Kathrin and Ernst, Florian and Farrington, Susan M and Theodoratou, Evropi and Prokopenko, Inga and Stumvoll, Michael and Jula, Antti and Perola, Markus and Salomaa, Veikko and Shin, So-Youn and Spector, Tim D and Sala, Cinzia and Ridker, Paul M and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Hengstenberg, Christian and Nelson, Christopher P and Meschia, James F and Nalls, Michael A and Sharma, Pankaj and Singleton, Andrew B and Kamatani, Naoyuki and Zeller, Tanja and Burnier, Michel and Attia, John and Laan, Maris and Klopp, Norman and Hillege, Hans L and Kloiber, Stefan and Choi, Hyon and Pirastu, Mario and Tore, Silvia and Probst-Hensch, Nicole M and V{\"o}lzke, Henry and Gudnason, Vilmundur and Parsa, Afshin and Schmidt, Reinhold and Whitfield, John B and Fornage, Myriam and Gasparini, Paolo and Siscovick, David S and Polasek, Ozren and Campbell, Harry and Rudan, Igor and Bouatia-Naji, Nabila and Metspalu, Andres and Loos, Ruth J F and van Duijn, Cornelia M and Borecki, Ingrid B and Ferrucci, Luigi and Gambaro, Giovanni and Deary, Ian J and Wolffenbuttel, Bruce H R and Chambers, John C and M{\"a}rz, Winfried and Pramstaller, Peter P and Snieder, Harold and Gyllensten, Ulf and Wright, Alan F and Navis, Gerjan and Watkins, Hugh and Witteman, Jacqueline C M and Sanna, Serena and Schipf, Sabine and Dunlop, Malcolm G and T{\"o}njes, Anke and Ripatti, Samuli and Soranzo, Nicole and Toniolo, Daniela and Chasman, Daniel I and Raitakari, Olli and Kao, W H Linda and Ciullo, Marina and Fox, Caroline S and Caulfield, Mark and Bochud, Murielle and Gieger, Christian} } @article {6072, title = {Genome-wide association study of retinopathy in individuals without diabetes.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e54232}, abstract = {

BACKGROUND: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes.

METHODS: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy.

RESULTS: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3{\textpm}0.23 (beta {\textpm} standard error), p = 6.6{\texttimes}10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (\~{}2\%), the quality of the imputation was moderate (r(2) \~{}0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension.

CONCLUSIONS: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.

}, keywords = {Aged, Aged, 80 and over, Female, Genome-Wide Association Study, Genotype, Histone Deacetylases, Humans, Hypertension, Male, Polymorphism, Single Nucleotide, Repressor Proteins, Retinal Diseases}, issn = {1932-6203}, doi = {10.1371/journal.pone.0054232}, author = {Jensen, Richard A and Sim, Xueling and Li, Xiaohui and Cotch, Mary Frances and Ikram, M Kamran and Holliday, Elizabeth G and Eiriksdottir, Gudny and Harris, Tamara B and Jonasson, Fridbert and Klein, Barbara E K and Launer, Lenore J and Smith, Albert Vernon and Boerwinkle, Eric and Cheung, Ning and Hewitt, Alex W and Liew, Gerald and Mitchell, Paul and Wang, Jie Jin and Attia, John and Scott, Rodney and Glazer, Nicole L and Lumley, Thomas and McKnight, Barbara and Psaty, Bruce M and Taylor, Kent and Hofman, Albert and de Jong, Paulus T V M and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Tay, Wan-Ting and Teo, Yik Ying and Seielstad, Mark and Liu, Jianjun and Cheng, Ching-Yu and Saw, Seang-Mei and Aung, Tin and Ganesh, Santhi K and O{\textquoteright}Donnell, Christopher J and Nalls, Mike A and Wiggins, Kerri L and Kuo, Jane Z and van Duijn, Cornelia M and Gudnason, Vilmundur and Klein, Ronald and Siscovick, David S and Rotter, Jerome I and Tai, E Shong and Vingerling, Johannes and Wong, Tien Y} } @article {6163, title = {Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake.}, journal = {Am J Clin Nutr}, volume = {97}, year = {2013}, month = {2013 Jun}, pages = {1395-402}, abstract = {

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 {\texttimes} 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 {\textpm} SE: 0.25 {\textpm} 0.04\%; P = 1.68 {\texttimes} 10(-8)) and lower fat (β {\textpm} SE: -0.21 {\textpm} 0.04\%; P = 1.57 {\texttimes} 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 {\textpm} SE: 0.10 {\textpm} 0.02\%; P = 9.96 {\texttimes} 10(-10)), independent of BMI (after adjustment for BMI, β {\textpm} SE: 0.08 {\textpm} 0.02\%; P = 3.15 {\texttimes} 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).

}, keywords = {Alleles, Atherosclerosis, Body Mass Index, Dietary Carbohydrates, Dietary Fats, Dietary Proteins, Energy Intake, European Continental Ancestry Group, Fibroblast Growth Factors, Follow-Up Studies, Gene-Environment Interaction, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Life Style, Obesity, Polymorphism, Single Nucleotide, Prospective Studies, Quantitative Trait Loci, Surveys and Questionnaires}, issn = {1938-3207}, doi = {10.3945/ajcn.112.052183}, author = {Tanaka, Toshiko and Ngwa, Julius S and van Rooij, Frank J A and Zillikens, M Carola and Wojczynski, Mary K and Frazier-Wood, Alexis C and Houston, Denise K and Kanoni, Stavroula and Lemaitre, Rozenn N and Luan, Jian{\textquoteright}an and Mikkil{\"a}, Vera and Renstrom, Frida and Sonestedt, Emily and Zhao, Jing Hua and Chu, Audrey Y and Qi, Lu and Chasman, Daniel I and de Oliveira Otto, Marcia C and Dhurandhar, Emily J and Feitosa, Mary F and Johansson, Ingegerd and Khaw, Kay-Tee and Lohman, Kurt K and Manichaikul, Ani and McKeown, Nicola M and Mozaffarian, Dariush and Singleton, Andrew and Stirrups, Kathleen and Viikari, Jorma and Ye, Zheng and Bandinelli, Stefania and Barroso, In{\^e}s and Deloukas, Panos and Forouhi, Nita G and Hofman, Albert and Liu, Yongmei and Lyytik{\"a}inen, Leo-Pekka and North, Kari E and Dimitriou, Maria and Hallmans, G{\"o}ran and K{\"a}h{\"o}nen, Mika and Langenberg, Claudia and Ordovas, Jose M and Uitterlinden, Andr{\'e} G and Hu, Frank B and Kalafati, Ioanna-Panagiota and Raitakari, Olli and Franco, Oscar H and Johnson, Andrew and Emilsson, Valur and Schrack, Jennifer A and Semba, Richard D and Siscovick, David S and Arnett, Donna K and Borecki, Ingrid B and Franks, Paul W and Kritchevsky, Stephen B and Lehtim{\"a}ki, Terho and Loos, Ruth J F and Orho-Melander, Marju and Rotter, Jerome I and Wareham, Nicholas J and Witteman, Jacqueline C M and Ferrucci, Luigi and Dedoussis, George and Cupples, L Adrienne and Nettleton, Jennifer A} } @article {6291, title = {Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations.}, journal = {PLoS Genet}, volume = {9}, year = {2013}, month = {2013}, pages = {e1003796}, abstract = {

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

}, keywords = {Animals, Bone and Bones, Bone Density, Calcium, European Continental Ancestry Group, Gene Expression Regulation, Genome-Wide Association Study, Homeostasis, Humans, Kidney, Mice, Polymorphism, Single Nucleotide}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003796}, author = {O{\textquoteright}Seaghdha, Conall M and Wu, Hongsheng and Yang, Qiong and Kapur, Karen and Guessous, Idris and Zuber, Annie Mercier and K{\"o}ttgen, Anna and Stoudmann, Candice and Teumer, Alexander and Kutalik, Zolt{\'a}n and Mangino, Massimo and Dehghan, Abbas and Zhang, Weihua and Eiriksdottir, Gudny and Li, Guo and Tanaka, Toshiko and Portas, Laura and Lopez, Lorna M and Hayward, Caroline and Lohman, Kurt and Matsuda, Koichi and Padmanabhan, Sandosh and Firsov, Dmitri and Sorice, Rossella and Ulivi, Sheila and Brockhaus, A Catharina and Kleber, Marcus E and Mahajan, Anubha and Ernst, Florian D and Gudnason, Vilmundur and Launer, Lenore J and Mace, Aurelien and Boerwinckle, Eric and Arking, Dan E and Tanikawa, Chizu and Nakamura, Yusuke and Brown, Morris J and Gaspoz, Jean-Michel and Theler, Jean-Marc and Siscovick, David S and Psaty, Bruce M and Bergmann, Sven and Vollenweider, Peter and Vitart, Veronique and Wright, Alan F and Zemunik, Tatijana and Boban, Mladen and Kolcic, Ivana and Navarro, Pau and Brown, Edward M and Estrada, Karol and Ding, Jingzhong and Harris, Tamara B and Bandinelli, Stefania and Hernandez, Dena and Singleton, Andrew B and Girotto, Giorgia and Ruggiero, Daniela and d{\textquoteright}Adamo, Adamo Pio and Robino, Antonietta and Meitinger, Thomas and Meisinger, Christa and Davies, Gail and Starr, John M and Chambers, John C and Boehm, Bernhard O and Winkelmann, Bernhard R and Huang, Jie and Murgia, Federico and Wild, Sarah H and Campbell, Harry and Morris, Andrew P and Franco, Oscar H and Hofman, Albert and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and V{\"o}lker, Uwe and Hannemann, Anke and Biffar, Reiner and Hoffmann, Wolfgang and Shin, So-Youn and Lescuyer, Pierre and Henry, Hughes and Schurmann, Claudia and Munroe, Patricia B and Gasparini, Paolo and Pirastu, Nicola and Ciullo, Marina and Gieger, Christian and M{\"a}rz, Winfried and Lind, Lars and Spector, Tim D and Smith, Albert V and Rudan, Igor and Wilson, James F and Polasek, Ozren and Deary, Ian J and Pirastu, Mario and Ferrucci, Luigi and Liu, Yongmei and Kestenbaum, Bryan and Kooner, Jaspal S and Witteman, Jacqueline C M and Nauck, Matthias and Kao, W H Linda and Wallaschofski, Henri and Bonny, Olivier and Fox, Caroline S and Bochud, Murielle} } @article {6555, title = {Association of levels of fasting glucose and insulin with rare variants at the chromosome 11p11.2-MADD locus: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.}, journal = {Circ Cardiovasc Genet}, volume = {7}, year = {2014}, month = {2014 Jun}, pages = {374-382}, abstract = {

BACKGROUND: Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels.

METHODS AND RESULTS: Sequencing (mean depth, 38{\texttimes}) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9\% of which were rare (minor allele frequency <1\%) and novel. We analyzed rare variants in 5 gene regions with FI or fasting glucose using the sequence kernel association test. At NR1H3, 53 rare variants were jointly associated with FI (P=2.73{\texttimes}10(-3)); of these, 7 were predicted to have regulatory function and showed association with FI (P=1.28{\texttimes}10(-3)). Conditioning on 2 previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are >2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6\% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity.

CONCLUSIONS: Sequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity.

}, keywords = {Aged, Aged, 80 and over, Aging, Blood Glucose, Chromosomes, Human, Pair 11, Cohort Studies, Death Domain Receptor Signaling Adaptor Proteins, Diabetes Mellitus, Type 2, Fasting, Female, Gene Frequency, Genetic Variation, Genome-Wide Association Study, Genomics, Guanine Nucleotide Exchange Factors, Heart Diseases, Humans, Insulin, Male, Middle Aged, Polymorphism, Single Nucleotide, Sequence Analysis, DNA}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.113.000169}, author = {Cornes, Belinda K and Brody, Jennifer A and Nikpoor, Naghmeh and Morrison, Alanna C and Chu, Huan and Ahn, Byung Soo and Wang, Shuai and Dauriz, Marco and Barzilay, Joshua I and Dupuis, Jos{\'e}e and Florez, Jose C and Coresh, Josef and Gibbs, Richard A and Kao, W H Linda and Liu, Ching-Ti and McKnight, Barbara and Muzny, Donna and Pankow, James S and Reid, Jeffrey G and White, Charles C and Johnson, Andrew D and Wong, Tien Y and Psaty, Bruce M and Boerwinkle, Eric and Rotter, Jerome I and Siscovick, David S and Sladek, Robert and Meigs, James B} } @article {6563, title = {Effects of long-term averaging of quantitative blood pressure traits on the detection of genetic associations.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Jul 03}, pages = {49-65}, abstract = {

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 {\texttimes} 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.

}, keywords = {Blood Pressure, Genome-Wide Association Study, Humans, Longitudinal Studies, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.06.002}, author = {Ganesh, Santhi K and Chasman, Daniel I and Larson, Martin G and Guo, Xiuqing and Verwoert, Germain and Bis, Joshua C and Gu, Xiangjun and Smith, Albert V and Yang, Min-Lee and Zhang, Yan and Ehret, Georg and Rose, Lynda M and Hwang, Shih-Jen and Papanicolau, George J and Sijbrands, Eric J and Rice, Kenneth and Eiriksdottir, Gudny and Pihur, Vasyl and Ridker, Paul M and Vasan, Ramachandran S and Newton-Cheh, Christopher and Raffel, Leslie J and Amin, Najaf and Rotter, Jerome I and Liu, Kiang and Launer, Lenore J and Xu, Ming and Caulfield, Mark and Morrison, Alanna C and Johnson, Andrew D and Vaidya, Dhananjay and Dehghan, Abbas and Li, Guo and Bouchard, Claude and Harris, Tamara B and Zhang, He and Boerwinkle, Eric and Siscovick, David S and Gao, Wei and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Hofman, Albert and Willer, Cristen J and Franco, Oscar H and Huo, Yong and Witteman, Jacqueline C M and Munroe, Patricia B and Gudnason, Vilmundur and Palmas, Walter and van Duijn, Cornelia and Fornage, Myriam and Levy, Daniel and Psaty, Bruce M and Chakravarti, Aravinda} } @article {6544, title = {Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Aug}, pages = {826-36}, abstract = {

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 loci associated with QT interval that collectively explain \~{}8-10\% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode 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 new candidate genes for ventricular arrhythmias, LQTS and SCD.

}, keywords = {Adult, Aged, Arrhythmias, Cardiac, Calcium Signaling, Death, Sudden, Cardiac, Electrocardiography, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Long QT Syndrome, Male, Middle Aged, Myocardium, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.3014}, author = {Arking, Dan E and Pulit, Sara L and Crotti, Lia and van der Harst, Pim and Munroe, Patricia B and Koopmann, Tamara T and Sotoodehnia, Nona and Rossin, Elizabeth J and Morley, Michael and Wang, Xinchen and Johnson, Andrew D and Lundby, Alicia and Gudbjartsson, Daniel F and Noseworthy, Peter A and Eijgelsheim, Mark and Bradford, Yuki and Tarasov, Kirill V and D{\"o}rr, Marcus and M{\"u}ller-Nurasyid, Martina and Lahtinen, Annukka M and Nolte, Ilja M and Smith, Albert Vernon and Bis, Joshua C and Isaacs, Aaron and Newhouse, Stephen J and Evans, Daniel S and Post, Wendy S and Waggott, Daryl and Lyytik{\"a}inen, Leo-Pekka and Hicks, Andrew A and Eisele, Lewin and Ellinghaus, David and Hayward, Caroline and Navarro, Pau and Ulivi, Sheila and Tanaka, Toshiko and Tester, David J and Chatel, St{\'e}phanie and Gustafsson, Stefan and Kumari, Meena and Morris, Richard W and Naluai, {\r A}sa T and Padmanabhan, Sandosh and Kluttig, Alexander and Strohmer, Bernhard and Panayiotou, Andrie G and Torres, Maria and Knoflach, Michael and Hubacek, Jaroslav A and Slowikowski, Kamil and Raychaudhuri, Soumya and Kumar, Runjun D and Harris, Tamara B and Launer, Lenore J and Shuldiner, Alan R and Alonso, Alvaro and Bader, Joel S and Ehret, Georg and Huang, Hailiang and Kao, W H Linda and Strait, James B and Macfarlane, Peter W and Brown, Morris and Caulfield, Mark J and Samani, Nilesh J and Kronenberg, Florian and Willeit, Johann and Smith, J Gustav and Greiser, Karin H and Meyer Zu Schwabedissen, Henriette and Werdan, Karl and Carella, Massimo and Zelante, Leopoldo and Heckbert, Susan R and Psaty, Bruce M and Rotter, Jerome I and Kolcic, Ivana and Polasek, Ozren and Wright, Alan F and Griffin, Maura and Daly, Mark J and Arnar, David O and Holm, Hilma and Thorsteinsdottir, Unnur and Denny, Joshua C and Roden, Dan M and Zuvich, Rebecca L and Emilsson, Valur and Plump, Andrew S and Larson, Martin G and O{\textquoteright}Donnell, Christopher J and Yin, Xiaoyan and Bobbo, Marco and D{\textquoteright}Adamo, Adamo P and Iorio, Annamaria and Sinagra, Gianfranco and Carracedo, Angel and Cummings, Steven R and Nalls, Michael A and Jula, Antti and Kontula, Kimmo K and Marjamaa, Annukka and Oikarinen, Lasse and Perola, Markus and Porthan, Kimmo and Erbel, Raimund and Hoffmann, Per and J{\"o}ckel, Karl-Heinz and K{\"a}lsch, Hagen and N{\"o}then, Markus M and den Hoed, Marcel and Loos, Ruth J F and Thelle, Dag S and Gieger, Christian and Meitinger, Thomas and Perz, Siegfried and Peters, Annette and Prucha, Hanna and Sinner, Moritz F and Waldenberger, Melanie and de Boer, Rudolf A and Franke, Lude and van der Vleuten, Pieter A and Beckmann, Britt Maria and Martens, Eimo and Bardai, Abdennasser and Hofman, Nynke and Wilde, Arthur A M and Behr, Elijah R and Dalageorgou, Chrysoula and Giudicessi, John R and Medeiros-Domingo, Argelia and Barc, Julien and Kyndt, Florence and Probst, Vincent and Ghidoni, Alice and Insolia, Roberto and Hamilton, Robert M and Scherer, Stephen W and Brandimarto, Jeffrey and Margulies, Kenneth and Moravec, Christine E and del Greco M, Fabiola and Fuchsberger, Christian and O{\textquoteright}Connell, Jeffrey R and Lee, Wai K and Watt, Graham C M and Campbell, Harry and Wild, Sarah H and El Mokhtari, Nour E and Frey, Norbert and Asselbergs, Folkert W and Mateo Leach, Irene and Navis, Gerjan and van den Berg, Maarten P and van Veldhuisen, Dirk J and Kellis, Manolis and Krijthe, Bouwe P and Franco, Oscar H and Hofman, Albert and Kors, Jan A and Uitterlinden, Andr{\'e} G and Witteman, Jacqueline C M and Kedenko, Lyudmyla and Lamina, Claudia and Oostra, Ben A and Abecasis, Goncalo R and Lakatta, Edward G and Mulas, Antonella and Orr{\`u}, Marco and Schlessinger, David and Uda, Manuela and Markus, Marcello R P and V{\"o}lker, Uwe and Snieder, Harold and Spector, Timothy D and Arnl{\"o}v, Johan and Lind, Lars and Sundstr{\"o}m, Johan and Syv{\"a}nen, Ann-Christine and Kivimaki, Mika and K{\"a}h{\"o}nen, Mika and Mononen, Nina and Raitakari, Olli T and Viikari, Jorma S and Adamkova, Vera and Kiechl, Stefan and Brion, Maria and Nicolaides, Andrew N and Paulweber, Bernhard and Haerting, Johannes and Dominiczak, Anna F and Nyberg, Fredrik and Whincup, Peter H and Hingorani, Aroon D and Schott, Jean-Jacques and Bezzina, Connie R and Ingelsson, Erik and Ferrucci, Luigi and Gasparini, Paolo and Wilson, James F and Rudan, Igor and Franke, Andre and M{\"u}hleisen, Thomas W and Pramstaller, Peter P and Lehtim{\"a}ki, Terho J and Paterson, Andrew D and Parsa, Afshin and Liu, Yongmei and van Duijn, Cornelia M and Siscovick, David S and Gudnason, Vilmundur and Jamshidi, Yalda and Salomaa, Veikko and Felix, Stephan B and Sanna, Serena and Ritchie, Marylyn D and Stricker, Bruno H and Stefansson, Kari and Boyer, Laurie A and Cappola, Thomas P and Olsen, Jesper V and Lage, Kasper and Schwartz, Peter J and K{\"a}{\"a}b, Stefan and Chakravarti, Aravinda and Ackerman, Michael J and Pfeufer, Arne and de Bakker, Paul I W and Newton-Cheh, Christopher} } @article {6585, title = {Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes.}, journal = {PLoS Genet}, volume = {10}, year = {2014}, month = {2014 Aug}, pages = {e1004517}, abstract = {

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 {\texttimes} 10(-94)}, keywords = {African Americans, Diabetes Mellitus, Type 2, Genome-Wide Association Study, HLA-B27 Antigen, HMGA2 Protein, Humans, KCNQ1 Potassium Channel, Mutant Chimeric Proteins, Polymorphism, Single Nucleotide, Transcription Factor 7-Like 2 Protein}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1004517}, author = {Ng, Maggie C Y and Shriner, Daniel and Chen, Brian H and Li, Jiang and Chen, Wei-Min and Guo, Xiuqing and Liu, Jiankang and Bielinski, Suzette J and Yanek, Lisa R and Nalls, Michael A and Comeau, Mary E and Rasmussen-Torvik, Laura J and Jensen, Richard A and Evans, Daniel S and Sun, Yan V and An, Ping and Patel, Sanjay R and Lu, Yingchang and Long, Jirong and Armstrong, Loren L and Wagenknecht, Lynne and Yang, Lingyao and Snively, Beverly M and Palmer, Nicholette D and Mudgal, Poorva and Langefeld, Carl D and Keene, Keith L and Freedman, Barry I and Mychaleckyj, Josyf C and Nayak, Uma and Raffel, Leslie J and Goodarzi, Mark O and Chen, Y-D Ida and Taylor, Herman A and Correa, Adolfo and Sims, Mario and Couper, David and Pankow, James S and Boerwinkle, Eric and Adeyemo, Adebowale and Doumatey, Ayo and Chen, Guanjie and Mathias, Rasika A and Vaidya, Dhananjay and Singleton, Andrew B and Zonderman, Alan B and Igo, Robert P and Sedor, John R and Kabagambe, Edmond K and Siscovick, David S and McKnight, Barbara and Rice, Kenneth and Liu, Yongmei and Hsueh, Wen-Chi and Zhao, Wei and Bielak, Lawrence F and Kraja, Aldi and Province, Michael A and Bottinger, Erwin P and Gottesman, Omri and Cai, Qiuyin and Zheng, Wei and Blot, William J and Lowe, William L and Pacheco, Jennifer A and Crawford, Dana C and Grundberg, Elin and Rich, Stephen S and Hayes, M Geoffrey and Shu, Xiao-Ou and Loos, Ruth J F and Borecki, Ingrid B and Peyser, Patricia A and Cummings, Steven R and Psaty, Bruce M and Fornage, Myriam and Iyengar, Sudha K and Evans, Michele K and Becker, Diane M and Kao, W H Linda and Wilson, James G and Rotter, Jerome I and Sale, Mich{\`e}le M and Liu, Simin and Rotimi, Charles N and Bowden, Donald W} } @article {6577, title = {Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Feb 06}, pages = {233-45}, abstract = {

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.

}, keywords = {Adult, Aged, Apolipoproteins E, Cholesterol, LDL, Cohort Studies, Dyslipidemias, Exome, Female, Follow-Up Studies, Gene Frequency, Genetic Code, Genome-Wide Association Study, Genotype, Humans, Lipase, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Proprotein Convertase 9, Proprotein Convertases, Receptors, LDL, Sequence Analysis, DNA, Serine Endopeptidases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.01.010}, author = {Lange, Leslie A and Hu, Youna and Zhang, He and Xue, Chenyi and Schmidt, Ellen M and Tang, Zheng-Zheng and Bizon, Chris and Lange, Ethan M and Smith, Joshua D and Turner, Emily H and Jun, Goo and Kang, Hyun Min and Peloso, Gina and Auer, Paul and Li, Kuo-Ping and Flannick, Jason and Zhang, Ji and Fuchsberger, Christian and Gaulton, Kyle and Lindgren, Cecilia and Locke, Adam and Manning, Alisa and Sim, Xueling and Rivas, Manuel A and Holmen, Oddgeir L and Gottesman, Omri and Lu, Yingchang and Ruderfer, Douglas and Stahl, Eli A and Duan, Qing and Li, Yun and Durda, Peter and Jiao, Shuo and Isaacs, Aaron and Hofman, Albert and Bis, Joshua C and Correa, Adolfo and Griswold, Michael E and Jakobsdottir, Johanna and Smith, Albert V and Schreiner, Pamela J and Feitosa, Mary F and Zhang, Qunyuan and Huffman, Jennifer E and Crosby, Jacy and Wassel, Christina L and Do, Ron and Franceschini, Nora and Martin, Lisa W and Robinson, Jennifer G and Assimes, Themistocles L and Crosslin, David R and Rosenthal, Elisabeth A and Tsai, Michael and Rieder, Mark J and Farlow, Deborah N and Folsom, Aaron R and Lumley, Thomas and Fox, Ervin R and Carlson, Christopher S and Peters, Ulrike and Jackson, Rebecca D and van Duijn, Cornelia M and Uitterlinden, Andr{\'e} G and Levy, Daniel and Rotter, Jerome I and Taylor, Herman A and Gudnason, Vilmundur and Siscovick, David S and Fornage, Myriam and Borecki, Ingrid B and Hayward, Caroline and Rudan, Igor and Chen, Y Eugene and Bottinger, Erwin P and Loos, Ruth J F and S{\ae}trom, P{\r a}l and Hveem, Kristian and Boehnke, Michael and Groop, Leif and McCarthy, Mark and Meitinger, Thomas and Ballantyne, Christie M and Gabriel, Stacey B and O{\textquoteright}Donnell, Christopher J and Post, Wendy S and North, Kari E and Reiner, Alexander P and Boerwinkle, Eric and Psaty, Bruce M and Altshuler, David and Kathiresan, Sekar and Lin, Dan-Yu and Jarvik, Gail P and Cupples, L Adrienne and Kooperberg, Charles and Wilson, James G and Nickerson, Deborah A and Abecasis, Goncalo R and Rich, Stephen S and Tracy, Russell P and Willer, Cristen J} } @article {6844, title = {Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians.}, journal = {Am J Clin Nutr}, volume = {102}, year = {2015}, month = {2015 Nov}, pages = {1266-78}, abstract = {

BACKGROUND: Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown.

OBJECTIVE: We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus.

DESIGN: Fourteen studies that are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium participated in the analysis. Data were provided for up to 50,345 participants. Using linear regression within studies and a fixed-effects meta-analysis across studies, we examined 1) the associations of processed meat and unprocessed red meat intake with fasting glucose and insulin concentrations; and 2) the interactions of processed meat and unprocessed red meat with genetic risk score related to fasting glucose or insulin resistance on fasting glucose and insulin concentrations.

RESULTS: Processed meat was associated with higher fasting glucose, and unprocessed red meat was associated with both higher fasting glucose and fasting insulin concentrations after adjustment for potential confounders [not including body mass index (BMI)]. For every additional 50-g serving of processed meat per day, fasting glucose was 0.021 mmol/L (95\% CI: 0.011, 0.030 mmol/L) higher. Every additional 100-g serving of unprocessed red meat per day was associated with a 0.037-mmol/L (95\% CI: 0.023, 0.051-mmol/L) higher fasting glucose concentration and a 0.049-ln-pmol/L (95\% CI: 0.035, 0.063-ln-pmol/L) higher fasting insulin concentration. After additional adjustment for BMI, observed associations were attenuated and no longer statistically significant. The association of processed meat and fasting insulin did not reach statistical significance after correction for multiple comparisons. Observed associations were not modified by genetic loci known to influence fasting glucose or insulin resistance.

CONCLUSION: The association of higher fasting glucose and insulin concentrations with meat consumption was not modified by an index of glucose- and insulin-related single-nucleotide polymorphisms. Six of the participating studies are registered at clinicaltrials.gov as NCT0000513 (Atherosclerosis Risk in Communities), NCT00149435 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetics of Lipid Lowering Drugs and Diet Network), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

}, keywords = {Blood Glucose, Cohort Studies, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hyperglycemia, Hyperinsulinism, Insulin, Insulin Resistance, Insulin-Secreting Cells, Meat, Meat Products, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1938-3207}, doi = {10.3945/ajcn.114.101238}, author = {Fretts, Amanda M and Follis, Jack L and Nettleton, Jennifer A and Lemaitre, Rozenn N and Ngwa, Julius S and Wojczynski, Mary K and Kalafati, Ioanna Panagiota and Varga, Tibor V and Frazier-Wood, Alexis C and Houston, Denise K and Lahti, Jari and Ericson, Ulrika and van den Hooven, Edith H and Mikkil{\"a}, Vera and Kiefte-de Jong, Jessica C and Mozaffarian, Dariush and Rice, Kenneth and Renstrom, Frida and North, Kari E and McKeown, Nicola M and Feitosa, Mary F and Kanoni, Stavroula and Smith, Caren E and Garcia, Melissa E and Tiainen, Anna-Maija and Sonestedt, Emily and Manichaikul, Ani and van Rooij, Frank J A and Dimitriou, Maria and Raitakari, Olli and Pankow, James S and Djouss{\'e}, Luc and Province, Michael A and Hu, Frank B and Lai, Chao-Qiang and Keller, Margaux F and Per{\"a}l{\"a}, Mia-Maria and Rotter, Jerome I and Hofman, Albert and Graff, Misa and K{\"a}h{\"o}nen, Mika and Mukamal, Kenneth and Johansson, Ingegerd and Ordovas, Jose M and Liu, Yongmei and M{\"a}nnist{\"o}, Satu and Uitterlinden, Andr{\'e} G and Deloukas, Panos and Sepp{\"a}l{\"a}, Ilkka and Psaty, Bruce M and Cupples, L Adrienne and Borecki, Ingrid B and Franks, Paul W and Arnett, Donna K and Nalls, Mike A and Eriksson, Johan G and Orho-Melander, Marju and Franco, Oscar H and Lehtim{\"a}ki, Terho and Dedoussis, George V and Meigs, James B and Siscovick, David S} } @article {6802, title = {Gene {\texttimes} dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry.}, journal = {Hum Mol Genet}, volume = {24}, year = {2015}, month = {2015 Aug 15}, pages = {4728-38}, abstract = {

Obesity is highly heritable. Genetic variants showing robust associations with obesity traits have been identified through genome-wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphisms were genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjusted WHR~and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006-0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjusted WHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.

}, keywords = {Adult, Body Mass Index, Case-Control Studies, Diet, Western, Epistasis, Genetic, European Continental Ancestry Group, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Obesity, Polymorphism, Single Nucleotide}, issn = {1460-2083}, doi = {10.1093/hmg/ddv186}, author = {Nettleton, Jennifer A and Follis, Jack L and Ngwa, Julius S and Smith, Caren E and Ahmad, Shafqat and Tanaka, Toshiko and Wojczynski, Mary K and Voortman, Trudy and Lemaitre, Rozenn N and Kristiansson, Kati and Nuotio, Marja-Liisa and Houston, Denise K and Per{\"a}l{\"a}, Mia-Maria and Qi, Qibin and Sonestedt, Emily and Manichaikul, Ani and Kanoni, Stavroula and Ganna, Andrea and Mikkil{\"a}, Vera and North, Kari E and Siscovick, David S and Harald, Kennet and McKeown, Nicola M and Johansson, Ingegerd and Rissanen, Harri and Liu, Yongmei and Lahti, Jari and Hu, Frank B and Bandinelli, Stefania and Rukh, Gull and Rich, Stephen and Booij, Lisanne and Dmitriou, Maria and Ax, Erika and Raitakari, Olli and Mukamal, Kenneth and M{\"a}nnist{\"o}, Satu and Hallmans, G{\"o}ran and Jula, Antti and Ericson, Ulrika and Jacobs, David R and van Rooij, Frank J A and Deloukas, Panos and Sjogren, Per and K{\"a}h{\"o}nen, Mika and Djouss{\'e}, Luc and Perola, Markus and Barroso, In{\^e}s and Hofman, Albert and Stirrups, Kathleen and Viikari, Jorma and Uitterlinden, Andr{\'e} G and Kalafati, Ioanna P and Franco, Oscar H and Mozaffarian, Dariush and Salomaa, Veikko and Borecki, Ingrid B and Knekt, Paul and Kritchevsky, Stephen B and Eriksson, Johan G and Dedoussis, George V and Qi, Lu and Ferrucci, Luigi and Orho-Melander, Marju and Zillikens, M Carola and Ingelsson, Erik and Lehtim{\"a}ki, Terho and Renstrom, Frida and Cupples, L Adrienne and Loos, Ruth J F and Franks, Paul W} } @article {6615, title = {Genetic loci associated with circulating levels of very long-chain saturated fatty acids.}, journal = {J Lipid Res}, volume = {56}, year = {2015}, month = {2015 Jan}, pages = {176-84}, abstract = {

Very long-chain saturated fatty acids (VLSFAs) are saturated fatty acids with 20 or more carbons. In contrast to the more abundant saturated fatty acids, such as palmitic acid, there is growing evidence that circulating VLSFAs may have beneficial biological properties. Whether genetic factors influence circulating levels of VLSFAs is not known. We investigated the association of common genetic variation with plasma phospholipid/erythrocyte levels of three VLSFAs by performing genome-wide association studies in seven population-based cohorts comprising 10,129 subjects of European ancestry. We observed associations of circulating VLSFA concentrations with common variants in two genes, serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3), a gene involved in the rate-limiting step of de novo sphingolipid synthesis, and ceramide synthase 4 (CERS4). The SPTLC3 variant at rs680379 was associated with higher arachidic acid (20:0 , P = 5.81 {\texttimes} 10(-13)). The CERS4 variant at rs2100944 was associated with higher levels of 20:0 (P = 2.65 {\texttimes} 10(-40)) and in analyses that adjusted for 20:0, with lower levels of behenic acid (P = 4.22 {\texttimes} 10(-26)) and lignoceric acid (P = 3.20 {\texttimes} 10(-21)). These novel associations suggest an inter-relationship of circulating VLSFAs and sphingolipid synthesis.

}, keywords = {Cohort Studies, Fatty Acids, Genetic Loci, Genetic Variation, Genome-Wide Association Study, Humans}, issn = {1539-7262}, doi = {10.1194/jlr.M052456}, author = {Lemaitre, Rozenn N and King, Irena B and Kabagambe, Edmond K and Wu, Jason H Y and McKnight, Barbara and Manichaikul, Ani and Guan, Weihua and Sun, Qi and Chasman, Daniel I and Foy, Millennia and Wang, Lu and Zhu, Jingwen and Siscovick, David S and Tsai, Michael Y and Arnett, Donna K and Psaty, Bruce M and Djouss{\'e}, Luc and Chen, Yii-der I and Tang, Weihong and Weng, Lu-Chen and Wu, Hongyu and Jensen, Majken K and Chu, Audrey Y and Jacobs, David R and Rich, Stephen S and Mozaffarian, Dariush and Steffen, Lyn and Rimm, Eric B and Hu, Frank B and Ridker, Paul M and Fornage, Myriam and Friedlander, Yechiel} } @article {7004, title = {Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium.}, journal = {PLoS One}, volume = {11}, year = {2016}, month = {2016}, pages = {e0144997}, abstract = {

BACKGROUND: Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.

METHODS: We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5{\texttimes}10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.

RESULTS: In Stage I 15 loci passed the threshold of 5{\texttimes}10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8{\texttimes}10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2{\texttimes}10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2{\texttimes}10-3).

CONCLUSIONS: QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.

}, keywords = {Aged, Cohort Studies, Cooperative Behavior, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Myocardial Infarction, Polymorphism, Single Nucleotide, Prospective Studies}, issn = {1932-6203}, doi = {10.1371/journal.pone.0144997}, author = {Dehghan, Abbas and Bis, Joshua C and White, Charles C and Smith, Albert Vernon and Morrison, Alanna C and Cupples, L Adrienne and Trompet, Stella and Chasman, Daniel I and Lumley, Thomas and V{\"o}lker, Uwe and Buckley, Brendan M and Ding, Jingzhong and Jensen, Majken K and Folsom, Aaron R and Kritchevsky, Stephen B and Girman, Cynthia J and Ford, Ian and D{\"o}rr, Marcus and Salomaa, Veikko and Uitterlinden, Andr{\'e} G and Eiriksdottir, Gudny and Vasan, Ramachandran S and Franceschini, Nora and Carty, Cara L and Virtamo, Jarmo and Demissie, Serkalem and Amouyel, Philippe and Arveiler, Dominique and Heckbert, Susan R and Ferrieres, Jean and Ducimetiere, Pierre and Smith, Nicholas L and Wang, Ying A and Siscovick, David S and Rice, Kenneth M and Wiklund, Per-Gunnar and Taylor, Kent D and Evans, Alun and Kee, Frank and Rotter, Jerome I and Karvanen, Juha and Kuulasmaa, Kari and Heiss, Gerardo and Kraft, Peter and Launer, Lenore J and Hofman, Albert and Markus, Marcello R P and Rose, Lynda M and Silander, Kaisa and Wagner, Peter and Benjamin, Emelia J and Lohman, Kurt and Stott, David J and Rivadeneira, Fernando and Harris, Tamara B and Levy, Daniel and Liu, Yongmei and Rimm, Eric B and Jukema, J Wouter and V{\"o}lzke, Henry and Ridker, Paul M and Blankenberg, Stefan and Franco, Oscar H and Gudnason, Vilmundur and Psaty, Bruce M and Boerwinkle, Eric and O{\textquoteright}Donnell, Christopher J} } @article {7596, title = {Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.}, journal = {PLoS Med}, volume = {14}, year = {2017}, month = {2017 Sep}, pages = {e1002383}, abstract = {

BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.

METHODS \& FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95\% CI 1.04-1.06, per HbA1c-raising allele, p = 3 {\texttimes} 10-29); whereas GS-E was not (OR = 1.00, 95\% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11\%) was associated with an absolute decrease in HbA1c of 0.81\%-units (95\% CI 0.66-0.96) per allele in hemizygous men, and 0.68\%-units (95\% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2\% (N = 0.65 million, 95\% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.

CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

}, keywords = {Diabetes Mellitus, Type 2, Genetic Variation, Genome-Wide Association Study, Glycated Hemoglobin A, Humans, Phenotype, Risk}, issn = {1549-1676}, doi = {10.1371/journal.pmed.1002383}, author = {Wheeler, Eleanor and Leong, Aaron and Liu, Ching-Ti and Hivert, Marie-France and Strawbridge, Rona J and Podmore, Clara and Li, Man and Yao, Jie and Sim, Xueling and Hong, Jaeyoung and Chu, Audrey Y and Zhang, Weihua and Wang, Xu and Chen, Peng and Maruthur, Nisa M and Porneala, Bianca C and Sharp, Stephen J and Jia, Yucheng and Kabagambe, Edmond K and Chang, Li-Ching and Chen, Wei-Min and Elks, Cathy E and Evans, Daniel S and Fan, Qiao and Giulianini, Franco and Go, Min Jin and Hottenga, Jouke-Jan and Hu, Yao and Jackson, Anne U and Kanoni, Stavroula and Kim, Young Jin and Kleber, Marcus E and Ladenvall, Claes and Lecoeur, C{\'e}cile and Lim, Sing-Hui and Lu, Yingchang and Mahajan, Anubha and Marzi, Carola and Nalls, Mike A and Navarro, Pau and Nolte, Ilja M and Rose, Lynda M and Rybin, Denis V and Sanna, Serena and Shi, Yuan and Stram, Daniel O and Takeuchi, Fumihiko and Tan, Shu Pei and van der Most, Peter J and van Vliet-Ostaptchouk, Jana V and Wong, Andrew and Yengo, Loic and Zhao, Wanting and Goel, Anuj and Martinez Larrad, Maria Teresa and Radke, D{\"o}rte and Salo, Perttu and Tanaka, Toshiko and van Iperen, Erik P A and Abecasis, Goncalo and Afaq, Saima and Alizadeh, Behrooz Z and Bertoni, Alain G and Bonnefond, Am{\'e}lie and B{\"o}ttcher, Yvonne and Bottinger, Erwin P and Campbell, Harry and Carlson, Olga D and Chen, Chien-Hsiun and Cho, Yoon Shin and Garvey, W Timothy and Gieger, Christian and Goodarzi, Mark O and Grallert, Harald and Hamsten, Anders and Hartman, Catharina A and Herder, Christian and Hsiung, Chao Agnes and Huang, Jie and Igase, Michiya and Isono, Masato and Katsuya, Tomohiro and Khor, Chiea-Chuen and Kiess, Wieland and Kohara, Katsuhiko and Kovacs, Peter and Lee, Juyoung and Lee, Wen-Jane and Lehne, Benjamin and Li, Huaixing and Liu, Jianjun and Lobbens, Stephane and Luan, Jian{\textquoteright}an and Lyssenko, Valeriya and Meitinger, Thomas and Miki, Tetsuro and Miljkovic, Iva and Moon, Sanghoon and Mulas, Antonella and M{\"u}ller, Gabriele and M{\"u}ller-Nurasyid, Martina and Nagaraja, Ramaiah and Nauck, Matthias and Pankow, James S and Polasek, Ozren and Prokopenko, Inga and Ramos, Paula S and Rasmussen-Torvik, Laura and Rathmann, Wolfgang and Rich, Stephen S and Robertson, Neil R and Roden, Michael and Roussel, Ronan and Rudan, Igor and Scott, Robert A and Scott, William R and Sennblad, Bengt and Siscovick, David S and Strauch, Konstantin and Sun, Liang and Swertz, Morris and Tajuddin, Salman M and Taylor, Kent D and Teo, Yik-Ying and Tham, Yih Chung and T{\"o}njes, Anke and Wareham, Nicholas J and Willemsen, Gonneke and Wilsgaard, Tom and Hingorani, Aroon D and Egan, Josephine and Ferrucci, Luigi and Hovingh, G Kees and Jula, Antti and Kivimaki, Mika and Kumari, Meena and Nj{\o}lstad, Inger and Palmer, Colin N A and Serrano R{\'\i}os, Manuel and Stumvoll, Michael and Watkins, Hugh and Aung, Tin and Bl{\"u}her, Matthias and Boehnke, Michael and Boomsma, Dorret I and Bornstein, Stefan R and Chambers, John C and Chasman, Daniel I and Chen, Yii-Der Ida and Chen, Yduan-Tsong and Cheng, Ching-Yu and Cucca, Francesco and de Geus, Eco J C and Deloukas, Panos and Evans, Michele K and Fornage, Myriam and Friedlander, Yechiel and Froguel, Philippe and Groop, Leif and Gross, Myron D and Harris, Tamara B and Hayward, Caroline and Heng, Chew-Kiat and Ingelsson, Erik and Kato, Norihiro and Kim, Bong-Jo and Koh, Woon-Puay and Kooner, Jaspal S and K{\"o}rner, Antje and Kuh, Diana and Kuusisto, Johanna and Laakso, Markku and Lin, Xu and Liu, Yongmei and Loos, Ruth J F and Magnusson, Patrik K E and M{\"a}rz, Winfried and McCarthy, Mark I and Oldehinkel, Albertine J and Ong, Ken K and Pedersen, Nancy L and Pereira, Mark A and Peters, Annette and Ridker, Paul M and Sabanayagam, Charumathi and Sale, Michele and Saleheen, Danish and Saltevo, Juha and Schwarz, Peter Eh and Sheu, Wayne H H and Snieder, Harold and Spector, Timothy D and Tabara, Yasuharu and Tuomilehto, Jaakko and van Dam, Rob M and Wilson, James G and Wilson, James F and Wolffenbuttel, Bruce H R and Wong, Tien Yin and Wu, Jer-Yuarn and Yuan, Jian-Min and Zonderman, Alan B and Soranzo, Nicole and Guo, Xiuqing and Roberts, David J and Florez, Jose C and Sladek, Robert and Dupuis, Jos{\'e}e and Morris, Andrew P and Tai, E-Shyong and Selvin, Elizabeth and Rotter, Jerome I and Langenberg, Claudia and Barroso, In{\^e}s and Meigs, James B} } @article {7791, title = {Genome-wide association meta-analysis of circulating odd-numbered chain saturated fatty acids: Results from the CHARGE Consortium.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0196951}, abstract = {

BACKGROUND: Odd-numbered chain saturated fatty acids (OCSFA) have been associated with potential health benefits. Although some OCSFA (e.g., C15:0 and C17:0) are found in meats and dairy products, sources and metabolism of C19:0 and C23:0 are relatively unknown, and the influence of non-dietary determinants, including genetic factors, on circulating levels of OCSFA is not established.

OBJECTIVE: To elucidate the biological processes that influence circulating levels of OCSFA by investigating associations between genetic variation and OCSFA.

DESIGN: We performed a meta-analysis of genome-wide association studies (GWAS) of plasma phospholipid/erythrocyte levels of C15:0, C17:0, C19:0, and C23:0 among 11,494 individuals of European descent. We also investigated relationships between specific single nucleotide polymorphisms (SNPs) in the lactase (LCT) gene, associated with adult-onset lactase intolerance, with circulating levels of dairy-derived OCSFA, and evaluated associations of candidate sphingolipid genes with C23:0 levels.

RESULTS: We found no genome-wide significant evidence that common genetic variation is associated with circulating levels of C15:0 or C23:0. In two cohorts with available data, we identified one intronic SNP (rs13361131) in myosin X gene (MYO10) associated with C17:0 level (P = 1.37{\texttimes}10-8), and two intronic SNP (rs12874278 and rs17363566) in deleted in lymphocytic leukemia 1 (DLEU1) region associated with C19:0 level (P = 7.07{\texttimes}10-9). In contrast, when using a candidate-gene approach, we found evidence that three SNPs in LCT (rs11884924, rs16832067, and rs3816088) are associated with circulating C17:0 level (adjusted P = 4{\texttimes}10-2). In addition, nine SNPs in the ceramide synthase 4 (CERS4) region were associated with circulating C23:0 levels (adjusted P<5{\texttimes}10-2).

CONCLUSIONS: Our findings suggest that circulating levels of OCSFA may be predominantly influenced by non-genetic factors. SNPs associated with C17:0 level in the LCT gene may reflect genetic influence in dairy consumption or in metabolism of dairy foods. SNPs associated with C23:0 may reflect a role of genetic factors in the synthesis of sphingomyelin.

}, keywords = {Fatty Acids, Genome-Wide Association Study, Humans, Introns, Lactase, Myosins, Polymorphism, Single Nucleotide, Sphingomyelins, Sphingosine N-Acyltransferase, Tumor Suppressor Proteins}, issn = {1932-6203}, doi = {10.1371/journal.pone.0196951}, author = {de Oliveira Otto, Marcia C and Lemaitre, Rozenn N and Sun, Qi and King, Irena B and Wu, Jason H Y and Manichaikul, Ani and Rich, Stephen S and Tsai, Michael Y and Chen, Y D and Fornage, Myriam and Weihua, Guan and Aslibekyan, Stella and Irvin, Marguerite R and Kabagambe, Edmond K and Arnett, Donna K and Jensen, Majken K and McKnight, Barbara and Psaty, Bruce M and Steffen, Lyn M and Smith, Caren E and Riserus, Ulf and Lind, Lars and Hu, Frank B and Rimm, Eric B and Siscovick, David S and Mozaffarian, Dariush} }