%0 Journal Article %J Nat Commun %D 2018 %T GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes. %A Franceschini, Nora %A Giambartolomei, Claudia %A de Vries, Paul S %A Finan, Chris %A Bis, Joshua C %A Huntley, Rachael P %A Lovering, Ruth C %A Tajuddin, Salman M %A Winkler, Thomas W %A Graff, Misa %A Kavousi, Maryam %A Dale, Caroline %A Smith, Albert V %A Hofer, Edith %A van Leeuwen, Elisabeth M %A Nolte, Ilja M %A Lu, Lingyi %A Scholz, Markus %A Sargurupremraj, Muralidharan %A Pitkänen, Niina %A Franzén, Oscar %A Joshi, Peter K %A Noordam, Raymond %A Marioni, Riccardo E %A Hwang, Shih-Jen %A Musani, Solomon K %A Schminke, Ulf %A Palmas, Walter %A Isaacs, Aaron %A Correa, Adolfo %A Zonderman, Alan B %A Hofman, Albert %A Teumer, Alexander %A Cox, Amanda J %A Uitterlinden, André G %A Wong, Andrew %A Smit, Andries J %A Newman, Anne B %A Britton, Annie %A Ruusalepp, Arno %A Sennblad, Bengt %A Hedblad, Bo %A Pasaniuc, Bogdan %A Penninx, Brenda W %A Langefeld, Carl D %A Wassel, Christina L %A Tzourio, Christophe %A Fava, Cristiano %A Baldassarre, Damiano %A O'Leary, Daniel H %A Teupser, Daniel %A Kuh, Diana %A Tremoli, Elena %A Mannarino, Elmo %A Grossi, Enzo %A Eric Boerwinkle %A Schadt, Eric E %A Ingelsson, Erik %A Veglia, Fabrizio %A Rivadeneira, Fernando %A Beutner, Frank %A Chauhan, Ganesh %A Heiss, Gerardo %A Snieder, Harold %A Campbell, Harry %A Völzke, Henry %A Markus, Hugh S %A Deary, Ian J %A Jukema, J Wouter %A de Graaf, Jacqueline %A Price, Jacqueline %A Pott, Janne %A Hopewell, Jemma C %A Liang, Jingjing %A Thiery, Joachim %A Engmann, Jorgen %A Gertow, Karl %A Rice, Kenneth %A Taylor, Kent D %A Dhana, Klodian %A Kiemeney, Lambertus A L M %A Lind, Lars %A Raffield, Laura M %A Launer, Lenore J %A Holdt, Lesca M %A Dörr, Marcus %A Dichgans, Martin %A Traylor, Matthew %A Sitzer, Matthias %A Kumari, Meena %A Kivimaki, Mika %A Nalls, Mike A %A Melander, Olle %A Raitakari, Olli %A Franco, Oscar H %A Rueda-Ochoa, Oscar L %A Roussos, Panos %A Whincup, Peter H %A Amouyel, Philippe %A Giral, Philippe %A Anugu, Pramod %A Wong, Quenna %A Malik, Rainer %A Rauramaa, Rainer %A Burkhardt, Ralph %A Hardy, Rebecca %A Schmidt, Reinhold %A de Mutsert, Renée %A Morris, Richard W %A Strawbridge, Rona J %A Wannamethee, S Goya %A Hägg, Sara %A Shah, Sonia %A McLachlan, Stela %A Trompet, Stella %A Seshadri, Sudha %A Kurl, Sudhir %A Heckbert, Susan R %A Ring, Susan %A Harris, Tamara B %A Lehtimäki, Terho %A Galesloot, Tessel E %A Shah, Tina %A de Faire, Ulf %A Plagnol, Vincent %A Rosamond, Wayne D %A Post, Wendy %A Zhu, Xiaofeng %A Zhang, Xiaoling %A Guo, Xiuqing %A Saba, Yasaman %A Dehghan, Abbas %A Seldenrijk, Adrie %A Morrison, Alanna C %A Hamsten, Anders %A Psaty, Bruce M %A van Duijn, Cornelia M %A Lawlor, Deborah A %A Mook-Kanamori, Dennis O %A Bowden, Donald W %A Schmidt, Helena %A Wilson, James F %A Wilson, James G %A Rotter, Jerome I %A Wardlaw, Joanna M %A Deanfield, John %A Halcox, Julian %A Lyytikäinen, Leo-Pekka %A Loeffler, Markus %A Evans, Michele K %A Debette, Stephanie %A Humphries, Steve E %A Völker, Uwe %A Gudnason, Vilmundur %A Hingorani, Aroon D %A Björkegren, Johan L M %A Casas, Juan P %A O'Donnell, Christopher J %K ADAMTS9 Protein %K Amino Acid Oxidoreductases %K Carotid Intima-Media Thickness %K Coronary Disease %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Lod Score %K Plaque, Atherosclerotic %K Polymorphism, Single Nucleotide %K Protein-Lysine 6-Oxidase %K Quantitative Trait Loci %K Risk Factors %X

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

%B Nat Commun %V 9 %P 5141 %8 2018 Dec 03 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/30510157?dopt=Abstract %R 10.1038/s41467-018-07340-5 %0 Journal Article %J Diabetes %D 2017 %T An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans. %A Scott, Robert A %A Scott, Laura J %A Mägi, Reedik %A Marullo, Letizia %A Gaulton, Kyle J %A Kaakinen, Marika %A Pervjakova, Natalia %A Pers, Tune H %A Johnson, Andrew D %A Eicher, John D %A Jackson, Anne U %A Ferreira, Teresa %A Lee, Yeji %A Ma, Clement %A Steinthorsdottir, Valgerdur %A Thorleifsson, Gudmar %A Qi, Lu %A Van Zuydam, Natalie R %A Mahajan, Anubha %A Chen, Han %A Almgren, Peter %A Voight, Ben F %A Grallert, Harald %A Müller-Nurasyid, Martina %A Ried, Janina S %A Rayner, Nigel W %A Robertson, Neil %A Karssen, Lennart C %A van Leeuwen, Elisabeth M %A Willems, Sara M %A Fuchsberger, Christian %A Kwan, Phoenix %A Teslovich, Tanya M %A Chanda, Pritam %A Li, Man %A Lu, Yingchang %A Dina, Christian %A Thuillier, Dorothee %A Yengo, Loic %A Jiang, Longda %A Sparso, Thomas %A Kestler, Hans A %A Chheda, Himanshu %A Eisele, Lewin %A Gustafsson, Stefan %A Frånberg, Mattias %A Strawbridge, Rona J %A Benediktsson, Rafn %A Hreidarsson, Astradur B %A Kong, Augustine %A Sigurðsson, Gunnar %A Kerrison, Nicola D %A Luan, Jian'an %A Liang, Liming %A Meitinger, Thomas %A Roden, Michael %A Thorand, Barbara %A Esko, Tõnu %A Mihailov, Evelin %A Fox, Caroline %A Liu, Ching-Ti %A Rybin, Denis %A Isomaa, Bo %A Lyssenko, Valeriya %A Tuomi, Tiinamaija %A Couper, David J %A Pankow, James S %A Grarup, Niels %A Have, Christian T %A Jørgensen, Marit E %A Jørgensen, Torben %A Linneberg, Allan %A Cornelis, Marilyn C %A van Dam, Rob M %A Hunter, David J %A Kraft, Peter %A Sun, Qi %A Edkins, Sarah %A Owen, Katharine R %A Perry, John R B %A Wood, Andrew R %A Zeggini, Eleftheria %A Tajes-Fernandes, Juan %A Abecasis, Gonçalo R %A Bonnycastle, Lori L %A Chines, Peter S %A Stringham, Heather M %A Koistinen, Heikki A %A Kinnunen, Leena %A Sennblad, Bengt %A Mühleisen, Thomas W %A Nöthen, Markus M %A Pechlivanis, Sonali %A Baldassarre, Damiano %A Gertow, Karl %A Humphries, Steve E %A Tremoli, Elena %A Klopp, Norman %A Meyer, Julia %A Steinbach, Gerald %A Wennauer, Roman %A Eriksson, Johan G %A Mӓnnistö, Satu %A Peltonen, Leena %A Tikkanen, Emmi %A Charpentier, Guillaume %A Eury, Elodie %A Lobbens, Stéphane %A Gigante, Bruna %A Leander, Karin %A McLeod, Olga %A Bottinger, Erwin P %A Gottesman, Omri %A Ruderfer, Douglas %A Blüher, Matthias %A Kovacs, Peter %A Tonjes, Anke %A Maruthur, Nisa M %A Scapoli, Chiara %A Erbel, Raimund %A Jöckel, Karl-Heinz %A Moebus, Susanne %A de Faire, Ulf %A Hamsten, Anders %A Stumvoll, Michael %A Deloukas, Panagiotis %A Donnelly, Peter J %A Frayling, Timothy M %A Hattersley, Andrew T %A Ripatti, Samuli %A Salomaa, Veikko %A Pedersen, Nancy L %A Boehm, Bernhard O %A Bergman, Richard N %A Collins, Francis S %A Mohlke, Karen L %A Tuomilehto, Jaakko %A Hansen, Torben %A Pedersen, Oluf %A Barroso, Inês %A Lannfelt, Lars %A Ingelsson, Erik %A Lind, Lars %A Lindgren, Cecilia M %A Cauchi, Stephane %A Froguel, Philippe %A Loos, Ruth J F %A Balkau, Beverley %A Boeing, Heiner %A Franks, Paul W %A Barricarte Gurrea, Aurelio %A Palli, Domenico %A van der Schouw, Yvonne T %A Altshuler, David %A Groop, Leif C %A Langenberg, Claudia %A Wareham, Nicholas J %A Sijbrands, Eric %A van Duijn, Cornelia M %A Florez, Jose C %A Meigs, James B %A Eric Boerwinkle %A Gieger, Christian %A Strauch, Konstantin %A Metspalu, Andres %A Morris, Andrew D %A Palmer, Colin N A %A Hu, Frank B %A Thorsteinsdottir, Unnur %A Stefansson, Kari %A Dupuis, Josée %A Morris, Andrew P %A Boehnke, Michael %A McCarthy, Mark I %A Prokopenko, Inga %K Diabetes Mellitus, Type 2 %K Gene Expression Regulation %K Genetic Variation %K Genome-Wide Association Study %K Humans %K White People %X

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci ( < 5 × 10), including variants near the , , and genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

%B Diabetes %V 66 %P 2888-2902 %8 2017 Nov %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/28566273?dopt=Abstract %R 10.2337/db16-1253 %0 Journal Article %J J Med Genet %D 2016 %T Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels. %A van Leeuwen, Elisabeth M %A Aniko Sabo %A Bis, Joshua C %A Huffman, Jennifer E %A Manichaikul, Ani %A Smith, Albert V %A Feitosa, Mary F %A Demissie, Serkalem %A Joshi, Peter K %A Duan, Qing %A Marten, Jonathan %A van Klinken, Jan B %A Surakka, Ida %A Nolte, Ilja M %A Zhang, Weihua %A Mbarek, Hamdi %A Li-Gao, Ruifang %A Trompet, Stella %A Verweij, Niek %A Evangelou, Evangelos %A Lyytikäinen, Leo-Pekka %A Tayo, Bamidele O %A Deelen, Joris %A van der Most, Peter J %A van der Laan, Sander W %A Arking, Dan E %A Morrison, Alanna %A Dehghan, Abbas %A Franco, Oscar H %A Hofman, Albert %A Rivadeneira, Fernando %A Sijbrands, Eric J %A Uitterlinden, André G %A Mychaleckyj, Josyf C %A Campbell, Archie %A Hocking, Lynne J %A Padmanabhan, Sandosh %A Brody, Jennifer A %A Rice, Kenneth M %A White, Charles C %A Harris, Tamara %A Isaacs, Aaron %A Campbell, Harry %A Lange, Leslie A %A Rudan, Igor %A Kolcic, Ivana %A Navarro, Pau %A Zemunik, Tatijana %A Salomaa, Veikko %A Kooner, Angad S %A Kooner, Jaspal S %A Lehne, Benjamin %A Scott, William R %A Tan, Sian-Tsung %A de Geus, Eco J %A Milaneschi, Yuri %A Penninx, Brenda W J H %A Willemsen, Gonneke %A de Mutsert, Renée %A Ford, Ian %A Gansevoort, Ron T %A Segura-Lepe, Marcelo P %A Raitakari, Olli T %A Viikari, Jorma S %A Nikus, Kjell %A Forrester, Terrence %A McKenzie, Colin A %A de Craen, Anton J M %A de Ruijter, Hester M %A Pasterkamp, Gerard %A Snieder, Harold %A Oldehinkel, Albertine J %A Slagboom, P Eline %A Cooper, Richard S %A Kähönen, Mika %A Lehtimäki, Terho %A Elliott, Paul %A van der Harst, Pim %A Jukema, J Wouter %A Mook-Kanamori, Dennis O %A Boomsma, Dorret I %A Chambers, John C %A Swertz, Morris %A Ripatti, Samuli %A Willems van Dijk, Ko %A Vitart, Veronique %A Polasek, Ozren %A Hayward, Caroline %A Wilson, James G %A Wilson, James F %A Gudnason, Vilmundur %A Rich, Stephen S %A Psaty, Bruce M %A Borecki, Ingrid B %A Eric Boerwinkle %A Rotter, Jerome I %A Cupples, L Adrienne %A van Duijn, Cornelia M %K Angiopoietin-Like Protein 4 %K Angiopoietins %K Exons %K Fasting %K Female %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

BACKGROUND: So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.

METHODS: We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage.

RESULTS: Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.

CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.

%B J Med Genet %V 53 %P 441-9 %8 2016 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/27036123?dopt=Abstract %R 10.1136/jmedgenet-2015-103439 %0 Journal Article %J NPJ Aging Mech Dis %D 2015 %T Fine mapping the region reveals a common intronic insertion associated to HDL-C. %A van Leeuwen, Elisabeth M %A Huffman, Jennifer E %A Bis, Joshua C %A Isaacs, Aaron %A Mulder, Monique %A Aniko Sabo %A Smith, Albert V %A Demissie, Serkalem %A Manichaikul, Ani %A Brody, Jennifer A %A Feitosa, Mary F %A Duan, Qing %A Schraut, Katharina E %A Navarro, Pau %A Van Vliet-Ostaptchouk, Jana V %A Zhu, Gu %A Mbarek, Hamdi %A Trompet, Stella %A Verweij, Niek %A Lyytikäinen, Leo-Pekka %A Deelen, Joris %A Nolte, Ilja M %A van der Laan, Sander W %A Davies, Gail %A Vermeij-Verdoold, Andrea Jm %A van Oosterhout, Andy Alj %A Vergeer-Drop, Jeannette M %A Arking, Dan E %A Trochet, Holly %A Medina-Gomez, Carolina %A Rivadeneira, Fernando %A Uitterlinden, André G %A Dehghan, Abbas %A Franco, Oscar H %A Sijbrands, Eric J %A Hofman, Albert %A White, Charles C %A Mychaleckyj, Josyf C %A Peloso, Gina M %A Swertz, Morris A %A Willemsen, Gonneke %A de Geus, Eco J %A Milaneschi, Yuri %A Penninx, Brenda Wjh %A Ford, Ian %A Buckley, Brendan M %A de Craen, Anton Jm %A Starr, John M %A Deary, Ian J %A Pasterkamp, Gerard %A Oldehinkel, Albertine J %A Snieder, Harold %A Slagboom, P Eline %A Nikus, Kjell %A Kähönen, Mika %A Lehtimäki, Terho %A Viikari, Jorma S %A Raitakari, Olli T %A van der Harst, Pim %A Jukema, J Wouter %A Hottenga, Jouke-Jan %A Boomsma, Dorret I %A Whitfield, John B %A Montgomery, Grant %A Martin, Nicholas G %A Polasek, Ozren %A Vitart, Veronique %A Hayward, Caroline %A Kolcic, Ivana %A Wright, Alan F %A Rudan, Igor %A Joshi, Peter K %A Wilson, James F %A Lange, Leslie A %A Wilson, James G %A Gudnason, Vilmundur %A Harris, Tamar B %A Morrison, Alanna C %A Borecki, Ingrid B %A Rich, Stephen S %A Padmanabhan, Sandosh %A Psaty, Bruce M %A Rotter, Jerome I %A Smith, Blair H %A Eric Boerwinkle %A Cupples, L Adrienne %A van Duijn, Cornelia %X

BACKGROUND: Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein ( gene. In this study, we investigate the association of and HDL-C further to identify novel, independent variants associated with HDL-C in humans.

METHODS: We performed a meta-analysis of HDL-C within the region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing.

RESULTS: The meta-analysis of HDL-C within the region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (=3.179 mg/dl ( value=5.25×10), =0.859 mg/dl ( value=9.51×10)), and this finding suggests that these five novel variants may partly explain the association of with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261.

CONCLUSIONS: The causal variants in that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C.

%B NPJ Aging Mech Dis %V 1 %P 15011 %8 2015 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/28721259?dopt=Abstract %R 10.1038/npjamd.2015.11 %0 Journal Article %J Nat Genet %D 2015 %T Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. %A Gaulton, Kyle J %A Ferreira, Teresa %A Lee, Yeji %A Raimondo, Anne %A Mägi, Reedik %A Reschen, Michael E %A Mahajan, Anubha %A Locke, Adam %A Rayner, N William %A Robertson, Neil %A Scott, Robert A %A Prokopenko, Inga %A Scott, Laura J %A Green, Todd %A Sparso, Thomas %A Thuillier, Dorothee %A Yengo, Loic %A Grallert, Harald %A Wahl, Simone %A Frånberg, Mattias %A Strawbridge, Rona J %A Kestler, Hans %A Chheda, Himanshu %A Eisele, Lewin %A Gustafsson, Stefan %A Steinthorsdottir, Valgerdur %A Thorleifsson, Gudmar %A Qi, Lu %A Karssen, Lennart C %A van Leeuwen, Elisabeth M %A Willems, Sara M %A Li, Man %A Chen, Han %A Fuchsberger, Christian %A Kwan, Phoenix %A Ma, Clement %A Linderman, Michael %A Lu, Yingchang %A Thomsen, Soren K %A Rundle, Jana K %A Beer, Nicola L %A van de Bunt, Martijn %A Chalisey, Anil %A Kang, Hyun Min %A Voight, Benjamin F %A Abecasis, Gonçalo R %A Almgren, Peter %A Baldassarre, Damiano %A Balkau, Beverley %A Benediktsson, Rafn %A Blüher, Matthias %A Boeing, Heiner %A Bonnycastle, Lori L %A Bottinger, Erwin P %A Burtt, Noël P %A Carey, Jason %A Charpentier, Guillaume %A Chines, Peter S %A Cornelis, Marilyn C %A Couper, David J %A Crenshaw, Andrew T %A van Dam, Rob M %A Doney, Alex S F %A Dorkhan, Mozhgan %A Edkins, Sarah %A Eriksson, Johan G %A Esko, Tõnu %A Eury, Elodie %A Fadista, João %A Flannick, Jason %A Fontanillas, Pierre %A Fox, Caroline %A Franks, Paul W %A Gertow, Karl %A Gieger, Christian %A Gigante, Bruna %A Gottesman, Omri %A Grant, George B %A Grarup, Niels %A Groves, Christopher J %A Hassinen, Maija %A Have, Christian T %A Herder, Christian %A Holmen, Oddgeir L %A Hreidarsson, Astradur B %A Humphries, Steve E %A Hunter, David J %A Jackson, Anne U %A Jonsson, Anna %A Jørgensen, Marit E %A Jørgensen, Torben %A Kao, Wen-Hong L %A Kerrison, Nicola D %A Kinnunen, Leena %A Klopp, Norman %A Kong, Augustine %A Kovacs, Peter %A Kraft, Peter %A Kravic, Jasmina %A Langford, Cordelia %A Leander, Karin %A Liang, Liming %A Lichtner, Peter %A Lindgren, Cecilia M %A Lindholm, Eero %A Linneberg, Allan %A Liu, Ching-Ti %A Lobbens, Stéphane %A Luan, Jian'an %A Lyssenko, Valeriya %A Männistö, Satu %A McLeod, Olga %A Meyer, Julia %A Mihailov, Evelin %A Mirza, Ghazala %A Mühleisen, Thomas W %A Müller-Nurasyid, Martina %A Navarro, Carmen %A Nöthen, Markus M %A Oskolkov, Nikolay N %A Owen, Katharine R %A Palli, Domenico %A Pechlivanis, Sonali %A Peltonen, Leena %A Perry, John R B %A Platou, Carl G P %A Roden, Michael %A Ruderfer, Douglas %A Rybin, Denis %A van der Schouw, Yvonne T %A Sennblad, Bengt %A Sigurðsson, Gunnar %A Stančáková, Alena %A Steinbach, Gerald %A Storm, Petter %A Strauch, Konstantin %A Stringham, Heather M %A Sun, Qi %A Thorand, Barbara %A Tikkanen, Emmi %A Tonjes, Anke %A Trakalo, Joseph %A Tremoli, Elena %A Tuomi, Tiinamaija %A Wennauer, Roman %A Wiltshire, Steven %A Wood, Andrew R %A Zeggini, Eleftheria %A Dunham, Ian %A Birney, Ewan %A Pasquali, Lorenzo %A Ferrer, Jorge %A Loos, Ruth J F %A Dupuis, Josée %A Florez, Jose C %A Eric Boerwinkle %A Pankow, James S %A van Duijn, Cornelia %A Sijbrands, Eric %A Meigs, James B %A Hu, Frank B %A Thorsteinsdottir, Unnur %A Stefansson, Kari %A Lakka, Timo A %A Rauramaa, Rainer %A Stumvoll, Michael %A Pedersen, Nancy L %A Lind, Lars %A Keinanen-Kiukaanniemi, Sirkka M %A Korpi-Hyövälti, Eeva %A Saaristo, Timo E %A Saltevo, Juha %A Kuusisto, Johanna %A Laakso, Markku %A Metspalu, Andres %A Erbel, Raimund %A Jöcke, Karl-Heinz %A Moebus, Susanne %A Ripatti, Samuli %A Salomaa, Veikko %A Ingelsson, Erik %A Boehm, Bernhard O %A Bergman, Richard N %A Collins, Francis S %A Mohlke, Karen L %A Koistinen, Heikki %A Tuomilehto, Jaakko %A Hveem, Kristian %A Njølstad, Inger %A Deloukas, Panagiotis %A Donnelly, Peter J %A Frayling, Timothy M %A Hattersley, Andrew T %A de Faire, Ulf %A Hamsten, Anders %A Illig, Thomas %A Peters, Annette %A Cauchi, Stephane %A Sladek, Rob %A Froguel, Philippe %A Hansen, Torben %A Pedersen, Oluf %A Morris, Andrew D %A Palmer, Collin N A %A Kathiresan, Sekar %A Melander, Olle %A Nilsson, Peter M %A Groop, Leif C %A Barroso, Inês %A Langenberg, Claudia %A Wareham, Nicholas J %A O'Callaghan, Christopher A %A Gloyn, Anna L %A Altshuler, David %A Boehnke, Michael %A Teslovich, Tanya M %A McCarthy, Mark I %A Morris, Andrew P %K Binding Sites %K Case-Control Studies %K Chromatin Immunoprecipitation %K Chromosome Mapping %K Diabetes Mellitus, Type 2 %K Gene Expression Regulation %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genomics %K Hepatocyte Nuclear Factor 3-beta %K Humans %K Islets of Langerhans %K Liver %K Molecular Sequence Annotation %K Polymorphism, Single Nucleotide %K Receptor, Melatonin, MT2 %X

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

%B Nat Genet %V 47 %P 1415-25 %8 2015 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/26551672?dopt=Abstract %R 10.1038/ng.3437