@article {1098, title = {Genome-wide association study of blood pressure and hypertension.}, journal = {Nat Genet}, volume = {41}, year = {2009}, month = {2009 Jun}, pages = {677-87}, abstract = {

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

}, keywords = {Blood Pressure, Cell Line, Chromosome Mapping, Chromosomes, Human, Diastole, Gene Expression Regulation, Genetic Association Studies, Genome-Wide Association Study, Humans, Hypertension, Liver, Lymphocytes, Meta-Analysis as Topic, Odds Ratio, Phenotype, Prevalence, Risk Assessment, Systole}, issn = {1546-1718}, doi = {10.1038/ng.384}, author = {Levy, Daniel and Ehret, Georg B and Rice, Kenneth and Verwoert, Germaine C and Launer, Lenore J and Dehghan, Abbas and Glazer, Nicole L and Morrison, Alanna C and Johnson, Andrew D and Aspelund, Thor and Aulchenko, Yurii and Lumley, Thomas and K{\"o}ttgen, Anna and Vasan, Ramachandran S and Rivadeneira, Fernando and Eiriksdottir, Gudny and Guo, Xiuqing and Arking, Dan E and Mitchell, Gary F and Mattace-Raso, Francesco U S and Smith, Albert V and Taylor, Kent and Scharpf, Robert B and Hwang, Shih-Jen and Sijbrands, Eric J G and Bis, Joshua and Harris, Tamara B and Ganesh, Santhi K and O{\textquoteright}Donnell, Christopher J and Hofman, Albert and Rotter, Jerome I and Coresh, Josef and Benjamin, Emelia J and Uitterlinden, Andr{\'e} G and Heiss, Gerardo and Fox, Caroline S and Witteman, Jacqueline C M and Boerwinkle, Eric and Wang, Thomas J and Gudnason, Vilmundur and Larson, Martin G and Chakravarti, Aravinda and Psaty, Bruce M and van Duijn, Cornelia M} } @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 {1346, title = {NK-like T cells and plasma cytokines, but not anti-viral serology, define immune fingerprints of resilience and mild disability in exceptional aging.}, journal = {PLoS One}, volume = {6}, year = {2011}, month = {2011}, pages = {e26558}, abstract = {

Exceptional aging has been defined as maintenance of physical and cognitive function beyond the median lifespan despite a history of diseases and/or concurrent subclinical conditions. Since immunity is vital to individual fitness, we examined immunologic fingerprint(s) of highly functional elders. Therefore, survivors of the Cardiovascular Health Study in Pittsburgh, Pennsylvania, USA were recruited (n = 140; mean age = 86 years) and underwent performance testing. Blood samples were collected and examined blindly for humoral factors and T cell phenotypes. Based on results of physical and cognitive performance testing, elders were classified as "impaired" or "unimpaired", accuracy of group assignment was verified by discriminant function analysis. The two groups showed distinct immune profiles as determined by factor analysis. The dominant immune signature of impaired elders consisted of interferon (IFN)-γ, interleukin (IL)-6, tumor necrosis factor-α, and T cells expressing inhibitory natural killer-related receptors (NKR) CD158a, CD158e, and NKG2A. In contrast, the dominant signature of unimpaired elders consisted of IL-5, IL-12p70, and IL-13 with co-expression of IFN-γ, IL-4, and IL-17, and T cells expressing stimulatory NKRs CD56, CD16, and NKG2D. In logistic regression models, unimpaired phenotype was predicted independently by IL-5 and by CD4(+)CD28(null)CD56(+)CD57(+) T cells. All elders had high antibody titers to common viruses including cytomegalovirus. In cellular bioassays, T cell receptor (TCR)-independent ligation of either CD56 or NKG2D elicited activation of T cells. Collectively, these data demonstrate the importance of immunological parameters in distinguishing between health phenotypes of older adults. NKR(+) T cells and cytokine upregulation indicate a unique physiologic environment in old age. Correlation of particular NKR(+) T cell subsets and IL-5 with unimpaired performance, and NKR-driven TCR-independent activation of T cells suggest novel immunopathway(s) that could be exploited to improve immunity in old age.

}, keywords = {Adolescent, Adult, Aged, 80 and over, Aging, Cardiovascular Physiological Phenomena, CD56 Antigen, Cognition Disorders, Cytokines, Gene Expression Regulation, Humans, Immunity, Humoral, Killer Cells, Natural, Longevity, Male, NK Cell Lectin-Like Receptor Subfamily K, Phenotype, Physical Fitness, T-Lymphocyte Subsets, Young Adult}, issn = {1932-6203}, doi = {10.1371/journal.pone.0026558}, author = {Vallejo, Abbe N and Hamel, David L and Mueller, Robert G and Ives, Diane G and Michel, Joshua J and Boudreau, Robert M and Newman, Anne B} } @article {6089, title = {Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation.}, journal = {Blood}, volume = {120}, year = {2012}, month = {2012 Dec 06}, pages = {4873-81}, abstract = {

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 {\texttimes} 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 {\texttimes} 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 {\texttimes} 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 {\texttimes} 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.

}, keywords = {Adaptor Proteins, Signal Transducing, ARNTL Transcription Factors, ATPases Associated with Diverse Cellular Activities, Cell Line, Cell Line, Tumor, Cohort Studies, Coronary Artery Disease, Diabetes Mellitus, Type 2, Gene Expression Profiling, Gene Expression Regulation, Gene Frequency, Genome-Wide Association Study, Genotype, Humans, LIM Domain Proteins, Meta-Analysis as Topic, Monocytes, Mucin-3, Plasminogen Activator Inhibitor 1, Polymorphism, Single Nucleotide, PPAR gamma, Proteasome Endopeptidase Complex, RNA Interference, Transcription Factors}, issn = {1528-0020}, doi = {10.1182/blood-2012-06-436188}, author = {Huang, Jie and Sabater-Lleal, Maria and Asselbergs, Folkert W and Tregouet, David and Shin, So-Youn and Ding, Jingzhong and Baumert, Jens and Oudot-Mellakh, Tiphaine and Folkersen, Lasse and Johnson, Andrew D and Smith, Nicholas L and Williams, Scott M and Ikram, Mohammad A and Kleber, Marcus E and Becker, Diane M and Truong, Vinh and Mychaleckyj, Josyf C and Tang, Weihong and Yang, Qiong and Sennblad, Bengt and Moore, Jason H and Williams, Frances M K and Dehghan, Abbas and Silbernagel, G{\"u}nther and Schrijvers, Elisabeth M C and Smith, Shelly and Karakas, Mahir and Tofler, Geoffrey H and Silveira, Angela and Navis, Gerjan J and Lohman, Kurt and Chen, Ming-Huei and Peters, Annette and Goel, Anuj and Hopewell, Jemma C and Chambers, John C and Saleheen, Danish and Lundmark, Per and Psaty, Bruce M and Strawbridge, Rona J and Boehm, Bernhard O and Carter, Angela M and Meisinger, Christa and Peden, John F and Bis, Joshua C and McKnight, Barbara and Ohrvik, John and Taylor, Kent and Franzosi, Maria Grazia and Seedorf, Udo and Collins, Rory and Franco-Cereceda, Anders and Syv{\"a}nen, Ann-Christine and Goodall, Alison H and Yanek, Lisa R and Cushman, Mary and M{\"u}ller-Nurasyid, Martina and Folsom, Aaron R and Basu, Saonli and Matijevic, Nena and van Gilst, Wiek H and Kooner, Jaspal S and Hofman, Albert and Danesh, John and Clarke, Robert and Meigs, James B and Kathiresan, Sekar and Reilly, Muredach P and Klopp, Norman and Harris, Tamara B and Winkelmann, Bernhard R and Grant, Peter J and Hillege, Hans L and Watkins, Hugh and Spector, Timothy D and Becker, Lewis C and Tracy, Russell P and M{\"a}rz, Winfried and Uitterlinden, Andr{\'e} G and Eriksson, Per and Cambien, Francois and Morange, Pierre-Emmanuel and Koenig, Wolfgang and Soranzo, Nicole and van der Harst, Pim and Liu, Yongmei and O{\textquoteright}Donnell, Christopher J and Hamsten, Anders} } @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 {6367, title = {Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {34}, year = {2014}, month = {2014 May}, pages = {1093-101}, abstract = {

OBJECTIVE: Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases. We conducted a meta-analysis of genome-wide association studies to identify novel correlates of circulating levels of tPA.

APPROACH AND RESULTS: Fourteen cohort studies with tPA measures (N=26 929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P<5.0{\texttimes}10(-8)). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9{\texttimes}10(-14)) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3{\texttimes}10(-9)) is intronic to POLB and <200 kb away from the tPA encoding the gene PLAT. We identified a nonsynonymous SNP (rs2020921) in modest linkage disequilibrium with rs3136739 (r(2)=0.50) within exon 5 of PLAT (P=2.0{\texttimes}10(-8)). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0{\texttimes}10(-9)) within intron 7 of STX2. We further found evidence for the association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased the release of tPA from vascular endothelial cells, whereas silencing STX2 increased the tPA release. Through an in silico lookup, we found no associations of the 3 lead SNPs with coronary artery disease or stroke.

CONCLUSIONS: We identified 3 loci associated with circulating tPA levels, the PLAT region, STXBP5, and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.

}, keywords = {Aged, Cells, Cultured, Coronary Artery Disease, Endothelial Cells, Europe, Female, Gene Expression Regulation, Gene Silencing, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Nerve Tissue Proteins, Phenotype, Polymorphism, Single Nucleotide, R-SNARE Proteins, Risk Factors, Stroke, Syntaxin 1, Tissue Plasminogen Activator, Transfection, United States, Up-Regulation}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.113.302088}, author = {Huang, Jie and Huffman, Jennifer E and Yamakuchi, Munekazu and Yamkauchi, Munekazu and Trompet, Stella and Asselbergs, Folkert W and Sabater-Lleal, Maria and Tr{\'e}gou{\"e}t, David-Alexandre and Chen, Wei-Min and Smith, Nicholas L and Kleber, Marcus E and Shin, So-Youn and Becker, Diane M and Tang, Weihong and Dehghan, Abbas and Johnson, Andrew D and Truong, Vinh and Folkersen, Lasse and Yang, Qiong and Oudot-Mellkah, Tiphaine and Buckley, Brendan M and Moore, Jason H and Williams, Frances M K and Campbell, Harry and Silbernagel, G{\"u}nther and Vitart, Veronique and Rudan, Igor and Tofler, Geoffrey H and Navis, Gerjan J and DeStefano, Anita and Wright, Alan F and Chen, Ming-Huei and de Craen, Anton J M and Worrall, Bradford B and Rudnicka, Alicja R and Rumley, Ann and Bookman, Ebony B and Psaty, Bruce M and Chen, Fang and Keene, Keith L and Franco, Oscar H and B{\"o}hm, Bernhard O and Uitterlinden, Andr{\'e} G and Carter, Angela M and Jukema, J Wouter and Sattar, Naveed and Bis, Joshua C and Ikram, Mohammad A and Sale, Mich{\`e}le M and McKnight, Barbara and Fornage, Myriam and Ford, Ian and Taylor, Kent and Slagboom, P Eline and McArdle, Wendy L and Hsu, Fang-Chi and Franco-Cereceda, Anders and Goodall, Alison H and Yanek, Lisa R and Furie, Karen L and Cushman, Mary and Hofman, Albert and Witteman, Jacqueline C M and Folsom, Aaron R and Basu, Saonli and Matijevic, Nena and van Gilst, Wiek H and Wilson, James F and Westendorp, Rudi G J and Kathiresan, Sekar and Reilly, Muredach P and Tracy, Russell P and Polasek, Ozren and Winkelmann, Bernhard R and Grant, Peter J and Hillege, Hans L and Cambien, Francois and Stott, David J and Lowe, Gordon D and Spector, Timothy D and Meigs, James B and M{\"a}rz, Winfried and Eriksson, Per and Becker, Lewis C and Morange, Pierre-Emmanuel and Soranzo, Nicole and Williams, Scott M and Hayward, Caroline and van der Harst, Pim and Hamsten, Anders and Lowenstein, Charles J and Strachan, David P and O{\textquoteright}Donnell, Christopher J} } @article {6604, title = {Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e100776}, abstract = {

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

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

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

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

}, keywords = {Adult, Chromosomes, Human, Pair 11, Female, Gene Expression Regulation, Genetic Loci, Genome-Wide Association Study, Humans, Longitudinal Studies, Male, Respiration}, issn = {1932-6203}, doi = {10.1371/journal.pone.0100776}, author = {Tang, Wenbo and Kowgier, Matthew and Loth, Daan W and Soler Artigas, Maria and Joubert, Bonnie R and Hodge, Emily and Gharib, Sina A and Smith, Albert V and Ruczinski, Ingo and Gudnason, Vilmundur and Mathias, Rasika A and Harris, Tamara B and Hansel, Nadia N and Launer, Lenore J and Barnes, Kathleen C and Hansen, Joyanna G and Albrecht, Eva and Aldrich, Melinda C and Allerhand, Michael and Barr, R Graham and Brusselle, Guy G and Couper, David J and Curjuric, Ivan and Davies, Gail and Deary, Ian J and Dupuis, Jos{\'e}e and Fall, Tove and Foy, Millennia and Franceschini, Nora and Gao, Wei and Gl{\"a}ser, Sven and Gu, Xiangjun and Hancock, Dana B and Heinrich, Joachim and Hofman, Albert and Imboden, Medea and Ingelsson, Erik and James, Alan and Karrasch, Stefan and Koch, Beate and Kritchevsky, Stephen B and Kumar, Ashish and Lahousse, Lies and Li, Guo and Lind, Lars and Lindgren, Cecilia and Liu, Yongmei and Lohman, Kurt and Lumley, Thomas and McArdle, Wendy L and Meibohm, Bernd and Morris, Andrew P and Morrison, Alanna C and Musk, Bill and North, Kari E and Palmer, Lyle J and Probst-Hensch, Nicole M and Psaty, Bruce M and Rivadeneira, Fernando and Rotter, Jerome I and Schulz, Holger and Smith, Lewis J and Sood, Akshay and Starr, John M and Strachan, David P and Teumer, Alexander and Uitterlinden, Andr{\'e} G and V{\"o}lzke, Henry and Voorman, Arend and Wain, Louise V and Wells, Martin T and Wilk, Jemma B and Williams, O Dale and Heckbert, Susan R and Stricker, Bruno H and London, Stephanie J and Fornage, Myriam and Tobin, Martin D and O{\textquoteright}Connor, George T and Hall, Ian P and Cassano, Patricia A} } @article {6817, title = {DCAF4, a novel gene associated with leucocyte telomere length.}, journal = {J Med Genet}, volume = {52}, year = {2015}, month = {2015 Mar}, pages = {157-62}, abstract = {

BACKGROUND: Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR).

RESULTS: Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4{\texttimes}10(-10)) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1{\texttimes}10(-3) and 2{\texttimes}10(-3), respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97{\texttimes}10(-169) to 3.42{\texttimes}10(-24).

CONCLUSIONS: We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.

}, keywords = {Alleles, Carrier Proteins, Gene Expression Regulation, Genome-Wide Association Study, Humans, Leukocytes, Melanoma, Risk Factors, Telomere, Telomere Homeostasis}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2014-102681}, author = {Mangino, Massimo and Christiansen, Lene and Stone, Rivka and Hunt, Steven C and Horvath, Kent and Eisenberg, Dan T A and Kimura, Masayuki and Petersen, Inge and Kark, Jeremy D and Herbig, Utz and Reiner, Alex P and Benetos, Athanase and Codd, Veryan and Nyholt, Dale R and Sinnreich, Ronit and Christensen, Kaare and Nassar, Hisham and Hwang, Shih-Jen and Levy, Daniel and Bataille, Veronique and Fitzpatrick, Annette L and Chen, Wei and Berenson, Gerald S and Samani, Nilesh J and Martin, Nicholas G and Tishkoff, Sarah and Schork, Nicholas J and Kyvik, Kirsten Ohm and Dalg{\r a}rd, Christine and Spector, Timothy D and Aviv, Abraham} } @article {6951, title = {Interaction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies and methylation analysis of 3 studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.}, journal = {Am J Clin Nutr}, volume = {103}, year = {2016}, month = {2016 Feb}, pages = {567-78}, abstract = {

BACKGROUND: DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression.

OBJECTIVE: We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation.

DESIGN: We selected 7 SNPs on the basis of predicted relations in fatty acids, methylation, and lipids. We conducted a meta-analysis and a methylation and mediation analysis with the use of data from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium and the ENCODE (Encyclopedia of DNA Elements) consortium.

RESULTS: On the basis of the meta-analysis of 7 cohorts in the CHARGE consortium, higher plasma HDL cholesterol was associated with fewer C alleles at ATP-binding cassette subfamily A member 1 (ABCA1) rs2246293 (β = -0.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (β = 3.87 mg/dL, P = 5.62 {\texttimes} 10(21)). The difference in HDL cholesterol associated with higher circulating EPA was dependent on genotypes at rs2246293, and it was greater for each additional C allele (β = 1.69 mg/dL, P = 0.006). In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study, higher ABCA1 promoter cg14019050 methylation was associated with more C alleles at rs2246293 (β = 8.84\%, P = 3.51 {\texttimes} 10(18)) and lower circulating EPA (β = -1.46\%, P = 0.009), and the mean difference in methylation of cg14019050 that was associated with higher EPA was smaller with each additional C allele of rs2246293 (β = -2.83\%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r = -0.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r = -0.12, P = 0.0002). An additional mediation analysis was meta-analyzed across the GOLDN study, Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Compared with the model without the adjustment of cg14019050 methylation, the model with such adjustment provided smaller estimates of the mean plasma HDL cholesterol concentration in association with both the rs2246293 C allele and EPA and a smaller difference by rs2246293 genotypes in the EPA-associated HDL cholesterol. However, the differences between 2 nested models were NS (P > 0.05).

CONCLUSION: We obtained little evidence that the gene-by-fatty acid interactions on blood lipids act through DNA methylation.

}, keywords = {Apolipoproteins E, ATP Binding Cassette Transporter 1, Cholesterol, HDL, Cohort Studies, Diet, DNA Methylation, Eicosapentaenoic Acid, Epigenesis, Genetic, Fatty Acids, Gene Expression Regulation, Humans, Lipids, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Triglycerides}, issn = {1938-3207}, doi = {10.3945/ajcn.115.112987}, author = {Ma, Yiyi and Follis, Jack L and Smith, Caren E and Tanaka, Toshiko and Manichaikul, Ani W and Chu, Audrey Y and Samieri, Cecilia and Zhou, Xia and Guan, Weihua and Wang, Lu and Biggs, Mary L and Chen, Yii-der I and Hernandez, Dena G and Borecki, Ingrid and Chasman, Daniel I and Rich, Stephen S and Ferrucci, Luigi and Irvin, Marguerite Ryan and Aslibekyan, Stella and Zhi, Degui and Tiwari, Hemant K and Claas, Steven A and Sha, Jin and Kabagambe, Edmond K and Lai, Chao-Qiang and Parnell, Laurence D and Lee, Yu-Chi and Amouyel, Philippe and Lambert, Jean-Charles and Psaty, Bruce M and King, Irena B and Mozaffarian, Dariush and McKnight, Barbara and Bandinelli, Stefania and Tsai, Michael Y and Ridker, Paul M and Ding, Jingzhong and Mstat, Kurt Lohmant and Liu, Yongmei and Sotoodehnia, Nona and Barberger-Gateau, Pascale and Steffen, Lyn M and Siscovick, David S and Absher, Devin and Arnett, Donna K and Ordovas, Jose M and Lemaitre, Rozenn N} } @article {8558, title = {Systems biology approach to late-onset Alzheimer{\textquoteright}s disease genome-wide association study identifies novel candidate genes validated using brain expression data and Caenorhabditis elegans experiments.}, journal = {Alzheimers Dement}, volume = {13}, year = {2017}, month = {2017 Oct}, pages = {1133-1142}, abstract = {

INTRODUCTION: We sought to determine whether a systems biology approach may identify novel late-onset Alzheimer{\textquoteright}s disease (LOAD) loci.

METHODS: We performed gene-wide association analyses and integrated results with human protein-protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aβ proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions.

RESULTS: We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1, and ATP5H were associated with Aβ toxicity, and NDUFS3, SLC25A11, ATP5H, and APP were differentially expressed in the temporal cortex.

DISCUSSION: Network analyses identified novel LOAD candidate genes. We demonstrated a functional role for four of these in a C. elegans model and found enrichment of differentially expressed genes in the temporal cortex.

}, keywords = {Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Animals, Genetically Modified, Antigens, Neoplasm, Caenorhabditis elegans, Disease Models, Animal, Early Growth Response Protein 1, Female, Gene Expression Regulation, Genome-Wide Association Study, Heparin-binding EGF-like Growth Factor, Humans, Male, Membrane Transport Proteins, Mitochondrial ADP, ATP Translocases, NADH Dehydrogenase, Polymorphism, Single Nucleotide, Protein Interaction Maps, RNA Interference, Systems Biology, Temporal Lobe}, issn = {1552-5279}, doi = {10.1016/j.jalz.2017.01.016}, author = {Mukherjee, Shubhabrata and Russell, Joshua C and Carr, Daniel T and Burgess, Jeremy D and Allen, Mariet and Serie, Daniel J and Boehme, Kevin L and Kauwe, John S K and Naj, Adam C and Fardo, David W and Dickson, Dennis W and Montine, Thomas J and Ertekin-Taner, Nilufer and Kaeberlein, Matt R and Crane, Paul K} } @article {8257, title = {Strong impact of natural-selection-free heterogeneity in genetics of age-related phenotypes.}, journal = {Aging (Albany NY)}, volume = {10}, year = {2018}, month = {2018 03 29}, pages = {492-514}, abstract = {

A conceptual difficulty in genetics of age-related phenotypes that make individuals vulnerable to disease in post-reproductive life is genetic heterogeneity attributed to an undefined role of evolution in establishing their molecular mechanisms. Here, we performed univariate and pleiotropic genome-wide meta-analyses of 20 age-related phenotypes leveraging longitudinal information in a sample of 33,431 individuals and dealing with the natural-selection-free genetic heterogeneity. We identified 142 non-proxy single nucleotide polymorphisms (SNPs) with phenotype-specific (18 SNPs) and pleiotropic (124 SNPs) associations at genome-wide level. Univariate meta-analysis identified two novel (11.1\%) and replicated 16 SNPs whereas pleiotropic meta-analysis identified 115 novel (92.7\%) and nine replicated SNPs. Pleiotropic associations for most novel (93.9\%) and all replicated SNPs were strongly impacted by the natural-selection-free genetic heterogeneity in its unconventional form of antagonistic heterogeneity, implying antagonistic directions of genetic effects for directly correlated phenotypes. Our results show that the common genome-wide approach is well adapted to handle homogeneous univariate associations within Mendelian framework whereas most associations with age-related phenotypes are more complex and well beyond that framework. Dissecting the natural-selection-free genetic heterogeneity is critical for gaining insights into genetics of age-related phenotypes and has substantial and unexplored yet potential for improving efficiency of genome-wide analysis.

}, keywords = {Aging, Computational Biology, Gene Expression Regulation, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide}, issn = {1945-4589}, doi = {10.18632/aging.101407}, author = {Kulminski, Alexander M and Huang, Jian and Loika, Yury and Arbeev, Konstantin G and Bagley, Olivia and Yashkin, Arseniy and Duan, Matt and Culminskaya, Irina} }