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author:("semi, joan")
1.  The South Asian Genome 
PLoS ONE  2014;9(8):e102645.
The genetic sequence variation of people from the Indian subcontinent who comprise one-quarter of the world's population, is not well described. We carried out whole genome sequencing of 168 South Asians, along with whole-exome sequencing of 147 South Asians to provide deeper characterisation of coding regions. We identify 12,962,155 autosomal sequence variants, including 2,946,861 new SNPs and 312,738 novel indels. This catalogue of SNPs and indels amongst South Asians provides the first comprehensive map of genetic variation in this major human population, and reveals evidence for selective pressures on genes involved in skin biology, metabolism, infection and immunity. Our results will accelerate the search for the genetic variants underlying susceptibility to disorders such as type-2 diabetes and cardiovascular disease which are highly prevalent amongst South Asians.
doi:10.1371/journal.pone.0102645
PMCID: PMC4130493  PMID: 25115870
2.  Coronary heart disease in Indian Asians 
The Indian Asian population accounts for a fifth of all global deaths from coronary heart disease (CHD). CHD deaths on the Indian subcontinent have doubled since 1990, and are predicted to rise a further 50% by 2030. Reasons underlying the increased CHD mortality among Indian Asians remain unknown. Although conventional cardiovascular risk factors contribute to CHD in Indian Asians as in other populations, these do not account for their increased risk. Type-2 diabetes, insulin resistance and related metabolic disturbances are more prevalent amongst Indian Asians than Europeans, and have been proposed as major determinants of higher CHD risk among Indian Asians. However, this view is not supported by prospective data. Genome-wide association studies have not identified differences in allele frequencies or effect sizes in known loci to explain the increased CHD risk in Indian Asians. Limited knowledge of mechanisms underlying higher CHD risk amongst Indian Asians presents a major obstacle to reducing the burden of CHD in this population. Systems biology approaches such as genomics, epigenomics, metabolomics and transcriptomics, provide a non-biased approach for discovery of novel biomarkers and disease pathways underlying CHD. Incorporation of these ‘omic’ approaches in prospective Indian Asian cohorts such as the London Life Sciences Population Study (LOLIPOP) provide an exciting opportunity for the identification of new risk factors underlying CHD in this high risk population.
doi:10.5339/gcsp.2014.4
PMCID: PMC4104373  PMID: 25054115
Coronary heart disease; Indian Asian; LOLIPOP; genome; epigenome; metabolome; GWAS
3.  Genome-wide association study in people of South Asian ancestry identifies six novel susceptibility loci for type 2 diabetes 
Nature genetics  2011;43(10):984-989.
We carried out a genome wide association study of type-2 diabetes (T2D) amongst 20,119 people of South Asian ancestry (5,561 with T2D); we identified 20 independent SNPs associated with T2D at P<10−4 for testing amongst a further 38,568 South Asians (13,170 with T2D). In combined analysis, common genetic variants at six novel loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) were associated with T2D (P=4.1×10−8 to P=1.9×10−11); SNPs at GRB14 were also associated with insulin sensitivity, and at ST6GAL1 and HNF4A with pancreatic beta-cell function respectively. Our findings provide additional insight into mechanisms underlying T2D, and demonstrate the potential for new discovery from genetic association studies in South Asians who have increased susceptibility to T2D.
doi:10.1038/ng.921
PMCID: PMC3773920  PMID: 21874001
4.  Genetic loci influencing kidney function and chronic kidney disease in man 
Chambers, John C | Zhang, Weihua | Lord, Graham M | van der Harst, Pim | Lawlor, Debbie A | Sehmi, Joban S | Gale, Daniel P | Wass, Mark N | Ahmadi, Kourosh R | Bakker, Stephan JL | Beckmann, Jacqui | Bilo, Henk JG | Bochud, Murielle | Brown, Morris J | Caulfield, Mark J | Connell, John M C | Cook, Terence | Cotlarciuc, Ioana | Smith, George Davey | de Silva, Ranil | Deng, Guohong | Devuyst, Olivier | Dikkeschei, Lambert D. | Dimkovic, Nada | Dockrell, Mark | Dominiczak, Anna | Ebrahim, Shah | Eggermann, Thomas | Farrall, Martin | Ferrucci, Luigi | Floege, Jurgen | Forouhi, Nita G | Gansevoort, Ron T | Han, Xijin | Hedblad, Bo | van der Heide, Jaap J Homan | Hepkema, Bouke G | Hernandez-Fuentes, Maria | Hypponen, Elina | Johnson, Toby | de Jong, Paul E | Kleefstra, Nanne | Lagou, Vasiliki | Lapsley, Marta | Li, Yun | Loos, Ruth J F | Luan, Jian'an | Luttropp, Karin | Maréchal, Céline | Melander, Olle | Munroe, Patricia B | Nordfors, Louise | Parsa, Afshin | Penninx, Brenda W. | Perucha, Esperanza | Pouta, Anneli | Prokopenko, Inga | Roderick, Paul J | Ruokonen, Aimo | Samani, Nilesh | Sanna, Serena | Schalling, Martin | Schlessinger, David | Schlieper, Georg | Seelen, Marc AJ | Shuldiner, Alan R | Sjögren, Marketa | Smit, Johannes H. | Snieder, Harold | Soranzo, Nicole | Spector, Timothy D | Stenvinkel, Peter | Sternberg, Michael JE | Swaminathan, Ramasamyiyer | Tanaka, Toshiko | Ubink-Veltmaat, Lielith J. | Uda, Manuela | Vollenweider, Peter | Wallace, Chris | Waterworth, Dawn | Zerres, Klaus | Waeber, Gerard | Wareham, Nicholas J | Maxwell, Patrick H | McCarthy, Mark I | Jarvelin, Marjo-Riitta | Mooser, Vincent | Abecasis, Goncalo R | Lightstone, Liz | Scott, James | Navis, Gerjan | Elliott, Paul | Kooner., Jaspal S
Nature genetics  2010;42(5):373-375.
Chronic kidney disease (CKD), the result of permanent loss of kidney function, is a major global problem. We identify common genetic variants at chr2p12-p13, chr6q26, chr17q23 and chr19q13 associated with serum creatinine, a marker of kidney function (P=10−10 to 10−15). SNPs rs10206899 (near NAT8, chr2p12-p13) and rs4805834 (near SLC7A9, chr19q13) were also associated with CKD. Our findings provide new insight into metabolic, solute and drug-transport pathways underlying susceptibility to CKD.
doi:10.1038/ng.566
PMCID: PMC3748585  PMID: 20383145
5.  Seventy-five genetic loci influencing the human red blood cell 
van der Harst, Pim | Zhang, Weihua | Leach, Irene Mateo | Rendon, Augusto | Verweij, Niek | Sehmi, Joban | Paul, Dirk S. | Elling, Ulrich | Allayee, Hooman | Li, Xinzhong | Radhakrishnan, Aparna | Tan, Sian-Tsung | Voss, Katrin | Weichenberger, Christian X. | Albers, Cornelis A. | Al-Hussani, Abtehale | Asselbergs, Folkert W. | Ciullo, Marina | Danjou, Fabrice | Dina, Christian | Esko, Tõnu | Evans, David M. | Franke, Lude | Gögele, Martin | Hartiala, Jaana | Hersch, Micha | Holm, Hilma | Hottenga, Jouke-Jan | Kanoni, Stavroula | Kleber, Marcus E. | Lagou, Vasiliki | Langenberg, Claudia | Lopez, Lorna M. | Lyytikäinen, Leo-Pekka | Melander, Olle | Murgia, Federico | Nolte, Ilja M. | O’Reilly, Paul F. | Padmanabhan, Sandosh | Parsa, Afshin | Pirastu, Nicola | Porcu, Eleonora | Portas, Laura | Prokopenko, Inga | Ried, Janina S. | Shin, So-Youn | Tang, Clara S. | Teumer, Alexander | Traglia, Michela | Ulivi, Sheila | Westra, Harm-Jan | Yang, Jian | Zhao, Jing Hua | Anni, Franco | Abdellaoui, Abdel | Attwood, Antony | Balkau, Beverley | Bandinelli, Stefania | Bastardot, François | Benyamin, Beben | Boehm, Bernhard O. | Cookson, William O. | Das, Debashish | de Bakker, Paul I. W. | de Boer, Rudolf A. | de Geus, Eco J. C. | de Moor, Marleen H. | Dimitriou, Maria | Domingues, Francisco S. | Döring, Angela | Engström, Gunnar | Eyjolfsson, Gudmundur Ingi | Ferrucci, Luigi | Fischer, Krista | Galanello, Renzo | Garner, Stephen F. | Genser, Bernd | Gibson, Quince D. | Girotto, Giorgia | Gudbjartsson, Daniel Fannar | Harris, Sarah E. | Hartikainen, Anna-Liisa | Hastie, Claire E. | Hedblad, Bo | Illig, Thomas | Jolley, Jennifer | Kähönen, Mika | Kema, Ido P. | Kemp, John P. | Liang, Liming | Lloyd-Jones, Heather | Loos, Ruth J. F. | Meacham, Stuart | Medland, Sarah E. | Meisinger, Christa | Memari, Yasin | Mihailov, Evelin | Miller, Kathy | Moffatt, Miriam F. | Nauck, Matthias | Novatchkova, Maria | Nutile, Teresa | Olafsson, Isleifur | Onundarson, Pall T. | Parracciani, Debora | Penninx, Brenda W. | Perseu, Lucia | Piga, Antonio | Pistis, Giorgio | Pouta, Anneli | Puc, Ursula | Raitakari, Olli | Ring, Susan M. | Robino, Antonietta | Ruggiero, Daniela | Ruokonen, Aimo | Saint-Pierre, Aude | Sala, Cinzia | Salumets, Andres | Sambrook, Jennifer | Schepers, Hein | Schmidt, Carsten Oliver | Silljé, Herman H. W. | Sladek, Rob | Smit, Johannes H. | Starr, John M. | Stephens, Jonathan | Sulem, Patrick | Tanaka, Toshiko | Thorsteinsdottir, Unnur | Tragante, Vinicius | van Gilst, Wiek H. | van Pelt, L. Joost | van Veldhuisen, Dirk J. | Völker, Uwe | Whitfield, John B. | Willemsen, Gonneke | Winkelmann, Bernhard R. | Wirnsberger, Gerald | Algra, Ale | Cucca, Francesco | d’Adamo, Adamo Pio | Danesh, John | Deary, Ian J. | Dominiczak, Anna F. | Elliott, Paul | Fortina, Paolo | Froguel, Philippe | Gasparini, Paolo | Greinacher, Andreas | Hazen, Stanley L. | Jarvelin, Marjo-Riitta | Khaw, Kay Tee | Lehtimäki, Terho | Maerz, Winfried | Martin, Nicholas G. | Metspalu, Andres | Mitchell, Braxton D. | Montgomery, Grant W. | Moore, Carmel | Navis, Gerjan | Pirastu, Mario | Pramstaller, Peter P. | Ramirez-Solis, Ramiro | Schadt, Eric | Scott, James | Shuldiner, Alan R. | Smith, George Davey | Smith, J. Gustav | Snieder, Harold | Sorice, Rossella | Spector, Tim D. | Stefansson, Kari | Stumvoll, Michael | Wilson Tang, W. H. | Toniolo, Daniela | Tönjes, Anke | Visscher, Peter M. | Vollenweider, Peter | Wareham, Nicholas J. | Wolffenbuttel, Bruce H. R. | Boomsma, Dorret I. | Beckmann, Jacques S. | Dedoussis, George V. | Deloukas, Panos | Ferreira, Manuel A. | Sanna, Serena | Uda, Manuela | Hicks, Andrew A. | Penninger, Josef Martin | Gieger, Christian | Kooner, Jaspal S. | Ouwehand, Willem H. | Soranzo, Nicole | Chambers, John C
Nature  2012;492(7429):369-375.
Anaemia is a chief determinant of globalill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P <10−8, which together explain 4–9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
doi:10.1038/nature11677
PMCID: PMC3623669  PMID: 23222517
6.  Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma 
Chambers, John C | Zhang, Weihua | Sehmi, Joban | Li, Xinzhong | Wass, Mark N | Van der Harst, Pim | Holm, Hilma | Sanna, Serena | Kavousi, Maryam | Baumeister, Sebastian E | Coin, Lachlan J | Deng, Guohong | Gieger, Christian | Heard-Costa, Nancy L | Hottenga, Jouke-Jan | Kühnel, Brigitte | Kumar, Vinod | Lagou, Vasiliki | Liang, Liming | Luan, Jian’an | Vidal, Pedro Marques | Leach, Irene Mateo | O’Reilly, Paul F | Peden, John F | Rahmioglu, Nilufer | Soininen, Pasi | Speliotes, Elizabeth K | Yuan, Xin | Thorleifsson, Gudmar | Alizadeh, Behrooz Z | Atwood, Larry D | Borecki, Ingrid B | Brown, Morris J | Charoen, Pimphen | Cucca, Francesco | Das, Debashish | de Geus, Eco J C | Dixon, Anna L | Döring, Angela | Ehret, Georg | Eyjolfsson, Gudmundur I | Farrall, Martin | Forouhi, Nita G | Friedrich, Nele | Goessling, Wolfram | Gudbjartsson, Daniel F | Harris, Tamara B | Hartikainen, Anna-Liisa | Heath, Simon | Hirschfield, Gideon M | Hofman, Albert | Homuth, Georg | Hyppönen, Elina | Janssen, Harry L A | Johnson, Toby | Kangas, Antti J | Kema, Ido P | Kühn, Jens P | Lai, Sandra | Lathrop, Mark | Lerch, Markus M | Li, Yun | Liang, T Jake | Lin, Jing-Ping | Loos, Ruth J F | Martin, Nicholas G | Moffatt, Miriam F | Montgomery, Grant W | Munroe, Patricia B | Musunuru, Kiran | Nakamura, Yusuke | O’Donnell, Christopher J | Olafsson, Isleifur | Penninx, Brenda W | Pouta, Anneli | Prins, Bram P | Prokopenko, Inga | Puls, Ralf | Ruokonen, Aimo | Savolainen, Markku J | Schlessinger, David | Schouten, Jeoffrey N L | Seedorf, Udo | Sen-Chowdhry, Srijita | Siminovitch, Katherine A | Smit, Johannes H | Spector, Timothy D | Tan, Wenting | Teslovich, Tanya M | Tukiainen, Taru | Uitterlinden, Andre G | Van der Klauw, Melanie M | Vasan, Ramachandran S | Wallace, Chris | Wallaschofski, Henri | Wichmann, H-Erich | Willemsen, Gonneke | Würtz, Peter | Xu, Chun | Yerges-Armstrong, Laura M | Abecasis, Goncalo R | Ahmadi, Kourosh R | Boomsma, Dorret I | Caulfield, Mark | Cookson, William O | van Duijn, Cornelia M | Froguel, Philippe | Matsuda, Koichi | McCarthy, Mark I | Meisinger, Christa | Mooser, Vincent | Pietiläinen, Kirsi H | Schumann, Gunter | Snieder, Harold | Sternberg, Michael J E | Stolk, Ronald P | Thomas, Howard C | Thorsteinsdottir, Unnur | Uda, Manuela | Waeber, Gérard | Wareham, Nicholas J | Waterworth, Dawn M | Watkins, Hugh | Whitfield, John B | Witteman, Jacqueline C M | Wolffenbuttel, Bruce H R | Fox, Caroline S | Ala-Korpela, Mika | Stefansson, Kari | Vollenweider, Peter | Völzke, Henry | Schadt, Eric E | Scott, James | Järvelin, Marjo-Riitta | Elliott, Paul | Kooner, Jaspal S
Nature genetics  2011;43(11):1131-1138.
Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10−8 to P = 10−190). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.
doi:10.1038/ng.970
PMCID: PMC3482372  PMID: 22001757
7.  Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels 
Nature genetics  2009;41(11):1170-1172.
We carried out a genome-wide association study of hemoglobin levels in 16,001 individuals of European and Indian Asian ancestry. The most closely associated SNP (rs855791) results in nonsynonymous (V736A) change in the serine protease domain of TMPRSS6 and a blood hemoglobin concentration 0.13 (95% CI 0.09–0.17) g/dl lower per copy of allele A (P = 1.6 × 10−13). Our findings suggest that TMPRSS6, a regulator of hepcidin synthesis and iron handling, is crucial in hemoglobin level maintenance.
doi:10.1038/ng.462
PMCID: PMC3178047  PMID: 19820698
8.  Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study 
Fox, Ervin R. | Young, J. Hunter | Li, Yali | Dreisbach, Albert W. | Keating, Brendan J. | Musani, Solomon K. | Liu, Kiang | Morrison, Alanna C. | Ganesh, Santhi | Kutlar, Abdullah | Ramachandran, Vasan S. | Polak, Josef F. | Fabsitz, Richard R. | Dries, Daniel L. | Farlow, Deborah N. | Redline, Susan | Adeyemo, Adebowale | Hirschorn, Joel N. | Sun, Yan V. | Wyatt, Sharon B. | Penman, Alan D. | Palmas, Walter | Rotter, Jerome I. | Townsend, Raymond R. | Doumatey, Ayo P. | Tayo, Bamidele O. | Mosley, Thomas H. | Lyon, Helen N. | Kang, Sun J. | Rotimi, Charles N. | Cooper, Richard S. | Franceschini, Nora | Curb, J. David | Martin, Lisa W. | Eaton, Charles B. | Kardia, Sharon L.R. | Taylor, Herman A. | Caulfield, Mark J. | Ehret, Georg B. | Johnson, Toby | Chakravarti, Aravinda | Zhu, Xiaofeng | Levy, Daniel | Munroe, Patricia B. | Rice, Kenneth M. | Bochud, Murielle | Johnson, Andrew D. | Chasman, Daniel I. | Smith, Albert V. | Tobin, Martin D. | Verwoert, Germaine C. | Hwang, Shih-Jen | Pihur, Vasyl | Vollenweider, Peter | O'Reilly, Paul F. | Amin, Najaf | Bragg-Gresham, Jennifer L. | Teumer, Alexander | Glazer, Nicole L. | Launer, Lenore | Zhao, Jing Hua | Aulchenko, Yurii | Heath, Simon | Sõber, Siim | Parsa, Afshin | Luan, Jian'an | Arora, Pankaj | Dehghan, Abbas | Zhang, Feng | Lucas, Gavin | Hicks, Andrew A. | Jackson, Anne U. | Peden, John F. | Tanaka, Toshiko | Wild, Sarah H. | Rudan, Igor | Igl, Wilmar | Milaneschi, Yuri | Parker, Alex N. | Fava, Cristiano | Chambers, John C. | Kumari, Meena | JinGo, Min | van der Harst, Pim | Kao, Wen Hong Linda | Sjögren, Marketa | Vinay, D.G. | Alexander, Myriam | Tabara, Yasuharu | Shaw-Hawkins, Sue | Whincup, Peter H. | Liu, Yongmei | Shi, Gang | Kuusisto, Johanna | Seielstad, Mark | Sim, Xueling | Nguyen, Khanh-Dung Hoang | Lehtimäki, Terho | Matullo, Giuseppe | Wu, Ying | Gaunt, Tom R. | Charlotte Onland-Moret, N. | Cooper, Matthew N. | Platou, Carl G.P. | Org, Elin | Hardy, Rebecca | Dahgam, Santosh | Palmen, Jutta | Vitart, Veronique | Braund, Peter S. | Kuznetsova, Tatiana | Uiterwaal, Cuno S.P.M. | Campbell, Harry | Ludwig, Barbara | Tomaszewski, Maciej | Tzoulaki, Ioanna | Palmer, Nicholette D. | Aspelund, Thor | Garcia, Melissa | Chang, Yen-Pei C. | O'Connell, Jeffrey R. | Steinle, Nanette I. | Grobbee, Diederick E. | Arking, Dan E. | Hernandez, Dena | Najjar, Samer | McArdle, Wendy L. | Hadley, David | Brown, Morris J. | Connell, John M. | Hingorani, Aroon D. | Day, Ian N.M. | Lawlor, Debbie A. | Beilby, John P. | Lawrence, Robert W. | Clarke, Robert | Collins, Rory | Hopewell, Jemma C. | Ongen, Halit | Bis, Joshua C. | Kähönen, Mika | Viikari, Jorma | Adair, Linda S. | Lee, Nanette R. | Chen, Ming-Huei | Olden, Matthias | Pattaro, Cristian | Hoffman Bolton, Judith A. | Köttgen, Anna | Bergmann, Sven | Mooser, Vincent | Chaturvedi, Nish | Frayling, Timothy M. | Islam, Muhammad | Jafar, Tazeen H. | Erdmann, Jeanette | Kulkarni, Smita R. | Bornstein, Stefan R. | Grässler, Jürgen | Groop, Leif | Voight, Benjamin F. | Kettunen, Johannes | Howard, Philip | Taylor, Andrew | Guarrera, Simonetta | Ricceri, Fulvio | Emilsson, Valur | Plump, Andrew | Barroso, Inês | Khaw, Kay-Tee | Weder, Alan B. | Hunt, Steven C. | Bergman, Richard N. | Collins, Francis S. | Bonnycastle, Lori L. | Scott, Laura J. | Stringham, Heather M. | Peltonen, Leena | Perola, Markus | Vartiainen, Erkki | Brand, Stefan-Martin | Staessen, Jan A. | Wang, Thomas J. | Burton, Paul R. | SolerArtigas, Maria | Dong, Yanbin | Snieder, Harold | Wang, Xiaoling | Zhu, Haidong | Lohman, Kurt K. | Rudock, Megan E. | Heckbert, Susan R. | Smith, Nicholas L. | Wiggins, Kerri L. | Shriner, Daniel | Veldre, Gudrun | Viigimaa, Margus | Kinra, Sanjay | Prabhakaran, Dorairajan | Tripathy, Vikal | Langefeld, Carl D. | Rosengren, Annika | Thelle, Dag S. | MariaCorsi, Anna | Singleton, Andrew | Forrester, Terrence | Hilton, Gina | McKenzie, Colin A. | Salako, Tunde | Iwai, Naoharu | Kita, Yoshikuni | Ogihara, Toshio | Ohkubo, Takayoshi | Okamura, Tomonori | Ueshima, Hirotsugu | Umemura, Satoshi | Eyheramendy, Susana | Meitinger, Thomas | Wichmann, H.-Erich | Cho, Yoon Shin | Kim, Hyung-Lae | Lee, Jong-Young | Scott, James | Sehmi, Joban S. | Zhang, Weihua | Hedblad, Bo | Nilsson, Peter | Smith, George Davey | Wong, Andrew | Narisu, Narisu | Stančáková, Alena | Raffel, Leslie J. | Yao, Jie | Kathiresan, Sekar | O'Donnell, Chris | Schwartz, Steven M. | Arfan Ikram, M. | Longstreth, Will T. | Seshadri, Sudha | Shrine, Nick R.G. | Wain, Louise V. | Morken, Mario A. | Swift, Amy J. | Laitinen, Jaana | Prokopenko, Inga | Zitting, Paavo | Cooper, Jackie A. | Humphries, Steve E. | Danesh, John | Rasheed, Asif | Goel, Anuj | Hamsten, Anders | Watkins, Hugh | Bakker, Stephan J.L. | van Gilst, Wiek H. | Janipalli, Charles S. | Radha Mani, K. | Yajnik, Chittaranjan S. | Hofman, Albert | Mattace-Raso, Francesco U.S. | Oostra, Ben A. | Demirkan, Ayse | Isaacs, Aaron | Rivadeneira, Fernando | Lakatta, Edward G. | Orru, Marco | Scuteri, Angelo | Ala-Korpela, Mika | Kangas, Antti J. | Lyytikäinen, Leo-Pekka | Soininen, Pasi | Tukiainen, Taru | Würz, Peter | Twee-Hee Ong, Rick | Dörr, Marcus | Kroemer, Heyo K. | Völker, Uwe | Völzke, Henry | Galan, Pilar | Hercberg, Serge | Lathrop, Mark | Zelenika, Diana | Deloukas, Panos | Mangino, Massimo | Spector, Tim D. | Zhai, Guangju | Meschia, James F. | Nalls, Michael A. | Sharma, Pankaj | Terzic, Janos | Kranthi Kumar, M.J. | Denniff, Matthew | Zukowska-Szczechowska, Ewa | Wagenknecht, Lynne E. | Fowkes, Gerald R. | Charchar, Fadi J. | Schwarz, Peter E.H. | Hayward, Caroline | Guo, Xiuqing | Bots, Michiel L. | Brand, Eva | Samani, Nilesh J. | Polasek, Ozren | Talmud, Philippa J. | Nyberg, Fredrik | Kuh, Diana | Laan, Maris | Hveem, Kristian | Palmer, Lyle J. | van der Schouw, Yvonne T. | Casas, Juan P. | Mohlke, Karen L. | Vineis, Paolo | Raitakari, Olli | Wong, Tien Y. | Shyong Tai, E. | Laakso, Markku | Rao, Dabeeru C. | Harris, Tamara B. | Morris, Richard W. | Dominiczak, Anna F. | Kivimaki, Mika | Marmot, Michael G. | Miki, Tetsuro | Saleheen, Danish | Chandak, Giriraj R. | Coresh, Josef | Navis, Gerjan | Salomaa, Veikko | Han, Bok-Ghee | Kooner, Jaspal S. | Melander, Olle | Ridker, Paul M. | Bandinelli, Stefania | Gyllensten, Ulf B. | Wright, Alan F. | Wilson, James F. | Ferrucci, Luigi | Farrall, Martin | Tuomilehto, Jaakko | Pramstaller, Peter P. | Elosua, Roberto | Soranzo, Nicole | Sijbrands, Eric J.G. | Altshuler, David | Loos, Ruth J.F. | Shuldiner, Alan R. | Gieger, Christian | Meneton, Pierre | Uitterlinden, Andre G. | Wareham, Nicholas J. | Gudnason, Vilmundur | Rettig, Rainer | Uda, Manuela | Strachan, David P. | Witteman, Jacqueline C.M. | Hartikainen, Anna-Liisa | Beckmann, Jacques S. | Boerwinkle, Eric | Boehnke, Michael | Larson, Martin G. | Järvelin, Marjo-Riitta | Psaty, Bruce M. | Abecasis, Gonçalo R. | Elliott, Paul | van Duijn , Cornelia M. | Newton-Cheh, Christopher
Human Molecular Genetics  2011;20(11):2273-2284.
The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10−8) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10−8). The top IBC association for SBP was rs2012318 (P= 6.4 × 10−6) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10−6) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.
doi:10.1093/hmg/ddr092
PMCID: PMC3090190  PMID: 21378095
9.  Common Genetic Variation Near Melatonin Receptor MTNR1B Contributes to Raised Plasma Glucose and Increased Risk of Type 2 Diabetes Among Indian Asians and European Caucasians 
Diabetes  2009;58(11):2703-2708.
OBJECTIVE
Fasting plasma glucose and risk of type 2 diabetes are higher among Indian Asians than among European and North American Caucasians. Few studies have investigated genetic factors influencing glucose metabolism among Indian Asians.
RESEARCH DESIGN AND METHODS
We carried out genome-wide association studies for fasting glucose in 5,089 nondiabetic Indian Asians genotyped with the Illumina Hap610 BeadChip and 2,385 Indian Asians (698 with type 2 diabetes) genotyped with the Illumina 300 BeadChip. Results were compared with findings in 4,462 European Caucasians.
RESULTS
We identified three single nucleotide polymorphisms (SNPs) associated with glucose among Indian Asians at P < 5 × 10−8, all near melatonin receptor MTNR1B. The most closely associated was rs2166706 (combined P = 2.1 × 10−9), which is in moderate linkage disequilibrium with rs1387153 (r2 = 0.60) and rs10830963 (r2 = 0.45), both previously associated with glucose in European Caucasians. Risk allele frequency and effect sizes for rs2166706 were similar among Indian Asians and European Caucasians: frequency 46.2 versus 45.0%, respectively (P = 0.44); effect 0.05 (95% CI 0.01–0.08) versus 0.05 (0.03–0.07 mmol/l), respectively, higher glucose per allele copy (P = 0.84). SNP rs2166706 was associated with type 2 diabetes in Indian Asians (odds ratio 1.21 [95% CI 1.06–1.38] per copy of risk allele; P = 0.006). SNPs at the GCK, GCKR, and G6PC2 loci were also associated with glucose among Indian Asians. Risk allele frequencies of rs1260326 (GCKR) and rs560887 (G6PC2) were higher among Indian Asians compared with European Caucasians.
CONCLUSIONS
Common genetic variation near MTNR1B influences blood glucose and risk of type 2 diabetes in Indian Asians. Genetic variation at the MTNR1B, GCK, GCKR, and G6PC2 loci may contribute to abnormal glucose metabolism and related metabolic disturbances among Indian Asians.
doi:10.2337/db08-1805
PMCID: PMC2768158  PMID: 19651812
10.  Genome-Wide Meta-Analysis for Serum Calcium Identifies Significantly Associated SNPs near the Calcium-Sensing Receptor (CASR) Gene 
PLoS Genetics  2010;6(7):e1001035.
Calcium has a pivotal role in biological functions, and serum calcium levels have been associated with numerous disorders of bone and mineral metabolism, as well as with cardiovascular mortality. Here we report results from a genome-wide association study of serum calcium, integrating data from four independent cohorts including a total of 12,865 individuals of European and Indian Asian descent. Our meta-analysis shows that serum calcium is associated with SNPs in or near the calcium-sensing receptor (CASR) gene on 3q13. The top hit with a p-value of 6.3×10-37 is rs1801725, a missense variant, explaining 1.26% of the variance in serum calcium. This SNP had the strongest association in individuals of European descent, while for individuals of Indian Asian descent the top hit was rs17251221 (p = 1.1×10-21), a SNP in strong linkage disequilibrium with rs1801725. The strongest locus in CASR was shown to replicate in an independent Icelandic cohort of 4,126 individuals (p = 1.02×10-4). This genome-wide meta-analysis shows that common CASR variants modulate serum calcium levels in the adult general population, which confirms previous results in some candidate gene studies of the CASR locus. This study highlights the key role of CASR in calcium regulation.
Author Summary
Calcium levels in blood serum play an important role in many biological processes. The regulation of serum calcium is under strong genetic control. This study describes the first meta-analysis of a genome-wide association study from four cohorts totaling 12,865 participants of European and Indian Asian descent. Confirming previous results in some candidate gene studies, we find that common polymorphisms at the calcium-sensing receptor (CASR) gene locus are associated with serum calcium concentrations. We show that CASR variants give rise to the strongest signals associated with serum calcium levels in both European and Indian Asian populations, while no other locus reaches genome-wide significance. Our results show that CASR is a key player in genetic regulation of serum calcium in the adult general population.
doi:10.1371/journal.pgen.1001035
PMCID: PMC2908705  PMID: 20661308

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