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1.  Genetic fine-mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci 
Gaulton, Kyle J | Ferreira, Teresa | Lee, Yeji | Raimondo, Anne | Mägi, Reedik | Reschen, Michael E | Mahajan, Anubha | Locke, Adam | Rayner, N William | Robertson, Neil | Scott, Robert A | Prokopenko, Inga | Scott, Laura J | Green, Todd | Sparso, Thomas | Thuillier, Dorothee | Yengo, Loic | Grallert, Harald | Wahl, Simone | Frånberg, Mattias | Strawbridge, Rona J | Kestler, Hans | Chheda, Himanshu | Eisele, Lewin | Gustafsson, Stefan | Steinthorsdottir, Valgerdur | Thorleifsson, Gudmar | Qi, Lu | Karssen, Lennart C | van Leeuwen, Elisabeth M | Willems, Sara M | Li, Man | Chen, Han | Fuchsberger, Christian | Kwan, Phoenix | Ma, Clement | Linderman, Michael | Lu, Yingchang | Thomsen, Soren K | Rundle, Jana K | Beer, Nicola L | van de Bunt, Martijn | Chalisey, Anil | Kang, Hyun Min | Voight, Benjamin F | Abecasis, Goncalo R | Almgren, Peter | Baldassarre, Damiano | Balkau, Beverley | Benediktsson, Rafn | Blüher, Matthias | Boeing, Heiner | Bonnycastle, Lori L | Borringer, Erwin P | Burtt, Noël P | Carey, Jason | Charpentier, Guillaume | Chines, Peter S | Cornelis, Marilyn C | Couper, David J | Crenshaw, Andrew T | van Dam, Rob M | Doney, Alex SF | Dorkhan, Mozhgan | Edkins, Sarah | Eriksson, Johan G | Esko, Tonu | Eury, Elodie | Fadista, João | Flannick, Jason | Fontanillas, Pierre | Fox, Caroline | Franks, Paul W | Gertow, Karl | Gieger, Christian | Gigante, Bruna | Gottesman, Omri | Grant, George B | Grarup, Niels | Groves, Christopher J | Hassinen, Maija | Have, Christian T | Herder, Christian | Holmen, Oddgeir L | Hreidarsson, Astradur B | Humphries, Steve E | Hunter, David J | Jackson, Anne U | Jonsson, Anna | Jørgensen, Marit E | Jørgensen, Torben | Kao, Wen-Hong L | Kerrison, Nicola D | Kinnunen, Leena | Klopp, Norman | Kong, Augustine | Kovacs, Peter | Kraft, Peter | Kravic, Jasmina | Langford, Cordelia | Leander, Karin | Liang, Liming | Lichtner, Peter | Lindgren, Cecilia M | Lindholm, Eero | Linneberg, Allan | Liu, Ching-Ti | Lobbens, Stéphane | Luan, Jian’an | Lyssenko, Valeriya | Mӓnnistö, Satu | McLeod, Olga | Meyer, Julia | Mihailov, Evelin | Mirza, Ghazala | Mühleisen, Thomas W | Müller-Nurasyid, Martina | Navarro, Carmen | Nöthen, Markus M | Oskolkov, Nikolay N | Owen, Katharine R | Palli, Domenico | Pechlivanis, Sonali | Peltonen, Leena | Perry, John RB | Platou, Carl GP | Roden, Michael | Ruderfer, Douglas | Rybin, Denis | van der Schouw, Yvonne T | Sennblad, Bengt | Sigurđsson, Gunnar | Stančáková, Alena | Steinbach, Gerald | Storm, Petter | Strauch, Konstantin | Stringham, Heather M | Sun, Qi | Thorand, Barbara | Tikkanen, Emmi | Tonjes, Anke | Trakalo, Joseph | Tremoli, Elena | Tuomi, Tiinamaija | Wennauer, Roman | Wiltshire, Steven | Wood, Andrew R | Zeggini, Eleftheria | Dunham, Ian | Birney, Ewan | Pasquali, Lorenzo | Ferrer, Jorge | Loos, Ruth JF | Dupuis, Josée | Florez, Jose C | Boerwinkle, Eric | Pankow, James S | van Duijn, Cornelia | Sijbrands, Eric | Meigs, James B | Hu, Frank B | Thorsteinsdottir, Unnur | Stefansson, Kari | Lakka, Timo A | Rauramaa, Rainer | Stumvoll, Michael | Pedersen, Nancy L | Lind, Lars | Keinanen-Kiukaanniemi, Sirkka M | Korpi-Hyövӓlti, Eeva | Saaristo, Timo E | Saltevo, Juha | Kuusisto, Johanna | Laakso, Markku | Metspalu, Andres | Erbel, Raimund | Jöckel, Karl-Heinz | Moebus, Susanne | Ripatti, Samuli | Salomaa, Veikko | Ingelsson, Erik | Boehm, Bernhard O | Bergman, Richard N | Collins, Francis S | Mohlke, Karen L | Koistinen, Heikki | Tuomilehto, Jaakko | Hveem, Kristian | Njølstad, Inger | Deloukas, Panagiotis | Donnelly, Peter J | Frayling, Timothy M | Hattersley, Andrew T | de Faire, Ulf | Hamsten, Anders | Illig, Thomas | Peters, Annette | Cauchi, Stephane | Sladek, Rob | Froguel, Philippe | Hansen, Torben | Pedersen, Oluf | Morris, Andrew D | Palmer, Collin NA | Kathiresan, Sekar | Melander, Olle | Nilsson, Peter M | Groop, Leif C | Barroso, Inês | Langenberg, Claudia | Wareham, Nicholas J | O’Callaghan, Christopher A | Gloyn, Anna L | Altshuler, David | Boehnke, Michael | Teslovich, Tanya M | McCarthy, Mark I | Morris, Andrew P
Nature genetics  2015;47(12):1415-1425.
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/near KCNQ1. “Credible sets” of variants most likely to drive each distinct signal mapped predominantly to non-coding sequence, implying that T2D association 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 this T2D-risk allele 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.
doi:10.1038/ng.3437
PMCID: PMC4666734  PMID: 26551672
2.  Genetic fine-mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci 
Gaulton, Kyle J | Ferreira, Teresa | Lee, Yeji | Raimondo, Anne | Mägi, Reedik | Reschen, Michael E | Mahajan, Anubha | Locke, Adam | Rayner, N William | Robertson, Neil | Scott, Robert A | Prokopenko, Inga | Scott, Laura J | Green, Todd | Sparso, Thomas | Thuillier, Dorothee | Yengo, Loic | Grallert, Harald | Wahl, Simone | Frånberg, Mattias | Strawbridge, Rona J | Kestler, Hans | Chheda, Himanshu | Eisele, Lewin | Gustafsson, Stefan | Steinthorsdottir, Valgerdur | Thorleifsson, Gudmar | Qi, Lu | Karssen, Lennart C | van Leeuwen, Elisabeth M | Willems, Sara M | Li, Man | Chen, Han | Fuchsberger, Christian | Kwan, Phoenix | Ma, Clement | Linderman, Michael | Lu, Yingchang | Thomsen, Soren K | Rundle, Jana K | Beer, Nicola L | van de Bunt, Martijn | Chalisey, Anil | Kang, Hyun Min | Voight, Benjamin F | Abecasis, Goncalo R | Almgren, Peter | Baldassarre, Damiano | Balkau, Beverley | Benediktsson, Rafn | Blüher, Matthias | Boeing, Heiner | Bonnycastle, Lori L | Borringer, Erwin P | Burtt, Noël P | Carey, Jason | Charpentier, Guillaume | Chines, Peter S | Cornelis, Marilyn C | Couper, David J | Crenshaw, Andrew T | van Dam, Rob M | Doney, Alex SF | Dorkhan, Mozhgan | Edkins, Sarah | Eriksson, Johan G | Esko, Tonu | Eury, Elodie | Fadista, João | Flannick, Jason | Fontanillas, Pierre | Fox, Caroline | Franks, Paul W | Gertow, Karl | Gieger, Christian | Gigante, Bruna | Gottesman, Omri | Grant, George B | Grarup, Niels | Groves, Christopher J | Hassinen, Maija | Have, Christian T | Herder, Christian | Holmen, Oddgeir L | Hreidarsson, Astradur B | Humphries, Steve E | Hunter, David J | Jackson, Anne U | Jonsson, Anna | Jørgensen, Marit E | Jørgensen, Torben | Kao, Wen-Hong L | Kerrison, Nicola D | Kinnunen, Leena | Klopp, Norman | Kong, Augustine | Kovacs, Peter | Kraft, Peter | Kravic, Jasmina | Langford, Cordelia | Leander, Karin | Liang, Liming | Lichtner, Peter | Lindgren, Cecilia M | Lindholm, Eero | Linneberg, Allan | Liu, Ching-Ti | Lobbens, Stéphane | Luan, Jian’an | Lyssenko, Valeriya | Männistö, Satu | McLeod, Olga | Meyer, Julia | Mihailov, Evelin | Mirza, Ghazala | Mühleisen, Thomas W | Müller-Nurasyid, Martina | Navarro, Carmen | Nöthen, Markus M | Oskolkov, Nikolay N | Owen, Katharine R | Palli, Domenico | Pechlivanis, Sonali | Peltonen, Leena | Perry, John RB | Platou, Carl GP | Roden, Michael | Ruderfer, Douglas | Rybin, Denis | van der Schouw, Yvonne T | Sennblad, Bengt | Sigurðsson, Gunnar | Stančáková, Alena | Steinbach, Gerald | Storm, Petter | Strauch, Konstantin | Stringham, Heather M | Sun, Qi | Thorand, Barbara | Tikkanen, Emmi | Tonjes, Anke | Trakalo, Joseph | Tremoli, Elena | Tuomi, Tiinamaija | Wennauer, Roman | Wiltshire, Steven | Wood, Andrew R | Zeggini, Eleftheria | Dunham, Ian | Birney, Ewan | Pasquali, Lorenzo | Ferrer, Jorge | Loos, Ruth JF | Dupuis, Josée | Florez, Jose C | Boerwinkle, Eric | Pankow, James S | van Duijn, Cornelia | Sijbrands, Eric | Meigs, James B | Hu, Frank B | Thorsteinsdottir, Unnur | Stefansson, Kari | Lakka, Timo A | Rauramaa, Rainer | Stumvoll, Michael | Pedersen, Nancy L | Lind, Lars | Keinanen-Kiukaanniemi, Sirkka M | Korpi-Hyövälti, Eeva | Saaristo, Timo E | Saltevo, Juha | Kuusisto, Johanna | Laakso, Markku | Metspalu, Andres | Erbel, Raimund | Jöckel, Karl-Heinz | Moebus, Susanne | Ripatti, Samuli | Salomaa, Veikko | Ingelsson, Erik | Boehm, Bernhard O | Bergman, Richard N | Collins, Francis S | Mohlke, Karen L | Koistinen, Heikki | Tuomilehto, Jaakko | Hveem, Kristian | Njølstad, Inger | Deloukas, Panagiotis | Donnelly, Peter J | Frayling, Timothy M | Hattersley, Andrew T | de Faire, Ulf | Hamsten, Anders | Illig, Thomas | Peters, Annette | Cauchi, Stephane | Sladek, Rob | Froguel, Philippe | Hansen, Torben | Pedersen, Oluf | Morris, Andrew D | Palmer, Collin NA | Kathiresan, Sekar | Melander, Olle | Nilsson, Peter M | Groop, Leif C | Barroso, Inês | Langenberg, Claudia | Wareham, Nicholas J | O’Callaghan, Christopher A | Gloyn, Anna L | Altshuler, David | Boehnke, Michael | Teslovich, Tanya M | McCarthy, Mark I | Morris, Andrew P
Nature genetics  2015;47(12):1415-1425.
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/near KCNQ1. “Credible sets” of variants most likely to drive each distinct signal mapped predominantly to non-coding sequence, implying that T2D association 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 this T2D-risk allele 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.
doi:10.1038/ng.3437
PMCID: PMC4666734  PMID: 26551672
3.  Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis 
Human Molecular Genetics  2013;22(25):5107-5120.
Smooth muscle cell (SMC) proliferation is a hallmark of vascular injury and disease. Global hypomethylation occurs during SMC proliferation in culture and in vivo during neointimal formation. Regardless of the programmed or stochastic nature of hypomethylation, identifying these changes is important in understanding vascular disease, as maintenance of a cells' epigenetic profile is essential for maintaining cellular phenotype. Global hypomethylation of proliferating aortic SMCs and concomitant decrease of DNMT1 expression were identified in culture during passage. An epigenome screen identified regions of the genome that were hypomethylated during proliferation and a region containing Collagen, type XV, alpha 1 (COL15A1) was selected by ‘genomic convergence’ for characterization. COL15A1 transcript and protein levels increased with passage-dependent decreases in DNA methylation and the transcript was sensitive to treatment with 5-Aza-2′-deoxycytidine, suggesting DNA methylation-mediated gene expression. Phenotypically, knockdown of COL15A1 increased SMC migration and decreased proliferation and Col15a1 expression was induced in an atherosclerotic lesion and localized to the atherosclerotic cap. A sequence variant in COL15A1 that is significantly associated with atherosclerosis (rs4142986, P = 0.017, OR = 1.434) was methylated and methylation of the risk allele correlated with decreased gene expression and increased atherosclerosis in human aorta. In summary, hypomethylation of COL15A1 occurs during SMC proliferation and the consequent increased gene expression may impact SMC phenotype and atherosclerosis formation. Hypomethylated genes, such as COL15A1, provide evidence for concomitant epigenetic regulation and genetic susceptibility, and define a class of causal targets that sit at the intersection of genetic and epigenetic predisposition in the etiology of complex disease.
doi:10.1093/hmg/ddt365
PMCID: PMC3842173  PMID: 23912340
4.  CARM1 is Required in Embryonic Stem Cells to Maintain Pluripotency and Resist Differentiation 
Stem cells (Dayton, Ohio)  2009;27(11):2637-2645.
Histone H3 methylation at R17 and R26 recently emerged as a novel epigenetic mechanism regulating pluripotency in mouse embryos. Blastomeres of four-cell embryos with high H3 methylation at these sites show unrestricted potential, whereas those with lower levels cannot support development when aggregated in chimeras of like cells. Increasing histone H3 methylation, through expression of coactivator-associated-protein-arginine-methyltransferase 1 (CARM1) in embryos, elevates expression of key pluripotency genes and directs cells to the pluripotent inner cell mass. We demonstrate CARM1 is also required for the self-renewal and pluripotency of embryonic stem (ES) cells. In ES cells, CARM1 depletion downregulates pluripotency genes leading to their differentiation. CARM1 associates with Oct4/Pou5f1 and Sox2 promoters that display detectable levels of R17/26 histone H3 methylation. In CARM1 overexpressing ES cells, histone H3 arginine methylation is also at the Nanog promoter to which CARM1 now associates. Such cells express Nanog at elevated levels and delay their response to differentiation signals. Thus, like in four-cell embryo blastomeres, histone H3 arginine methylation by CARM1 in ES cells allows epigenetic modulation of pluripotency.
doi:10.1002/stem.131
PMCID: PMC4135545  PMID: 19544422
CARM1; ES cells; pluripotency; differentiation; chromatin; arginine histone methylation
5.  5′ isomiR variation is of functional and evolutionary importance 
Nucleic Acids Research  2014;42(14):9424-9435.
We have sequenced miRNA libraries from human embryonic, neural and foetal mesenchymal stem cells. We report that the majority of miRNA genes encode mature isomers that vary in size by one or more bases at the 3′ and/or 5′ end of the miRNA. Northern blotting for individual miRNAs showed that the proportions of isomiRs expressed by a single miRNA gene often differ between cell and tissue types. IsomiRs were readily co-immunoprecipitated with Argonaute proteins in vivo and were active in luciferase assays, indicating that they are functional. Bioinformatics analysis predicts substantial differences in targeting between miRNAs with minor 5′ differences and in support of this we report that a 5′ isomiR-9–1 gained the ability to inhibit the expression of DNMT3B and NCAM2 but lost the ability to inhibit CDH1 in vitro. This result was confirmed by the use of isomiR-specific sponges. Our analysis of the miRGator database indicates that a small percentage of human miRNA genes express isomiRs as the dominant transcript in certain cell types and analysis of miRBase shows that 5′ isomiRs have replaced canonical miRNAs many times during evolution. This strongly indicates that isomiRs are of functional importance and have contributed to the evolution of miRNA genes.
doi:10.1093/nar/gku656
PMCID: PMC4132760  PMID: 25056318
6.  The correlation between reading and mathematics ability at age twelve has a substantial genetic component 
Nature Communications  2014;5:4204.
Dissecting how genetic and environmental influences impact on learning is helpful for maximizing numeracy and literacy. Here we show, using twin and genome-wide analysis, that there is a substantial genetic component to children’s ability in reading and mathematics, and estimate that around one half of the observed correlation in these traits is due to shared genetic effects (so-called Generalist Genes). Thus, our results highlight the potential role of the learning environment in contributing to differences in a child’s cognitive abilities at age twelve.
Understanding the genetic basis of cognitive traits could aid the development of numeracy and literacy skills in children. Here the authors show that reading and mathematics have a large overlapping genetic component and suggest that a child's learning environment has a key role in creating differences between them.
doi:10.1038/ncomms5204
PMCID: PMC4102107  PMID: 25003214
7.  Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis 
Beecham, Ashley H | Patsopoulos, Nikolaos A | Xifara, Dionysia K | Davis, Mary F | Kemppinen, Anu | Cotsapas, Chris | Shahi, Tejas S | Spencer, Chris | Booth, David | Goris, An | Oturai, Annette | Saarela, Janna | Fontaine, Bertrand | Hemmer, Bernhard | Martin, Claes | Zipp, Frauke | D’alfonso, Sandra | Martinelli-Boneschi, Filippo | Taylor, Bruce | Harbo, Hanne F | Kockum, Ingrid | Hillert, Jan | Olsson, Tomas | Ban, Maria | Oksenberg, Jorge R | Hintzen, Rogier | Barcellos, Lisa F | Agliardi, Cristina | Alfredsson, Lars | Alizadeh, Mehdi | Anderson, Carl | Andrews, Robert | Søndergaard, Helle Bach | Baker, Amie | Band, Gavin | Baranzini, Sergio E | Barizzone, Nadia | Barrett, Jeffrey | Bellenguez, Céline | Bergamaschi, Laura | Bernardinelli, Luisa | Berthele, Achim | Biberacher, Viola | Binder, Thomas M C | Blackburn, Hannah | Bomfim, Izaura L | Brambilla, Paola | Broadley, Simon | Brochet, Bruno | Brundin, Lou | Buck, Dorothea | Butzkueven, Helmut | Caillier, Stacy J | Camu, William | Carpentier, Wassila | Cavalla, Paola | Celius, Elisabeth G | Coman, Irène | Comi, Giancarlo | Corrado, Lucia | Cosemans, Leentje | Cournu-Rebeix, Isabelle | Cree, Bruce A C | Cusi, Daniele | Damotte, Vincent | Defer, Gilles | Delgado, Silvia R | Deloukas, Panos | di Sapio, Alessia | Dilthey, Alexander T | Donnelly, Peter | Dubois, Bénédicte | Duddy, Martin | Edkins, Sarah | Elovaara, Irina | Esposito, Federica | Evangelou, Nikos | Fiddes, Barnaby | Field, Judith | Franke, Andre | Freeman, Colin | Frohlich, Irene Y | Galimberti, Daniela | Gieger, Christian | Gourraud, Pierre-Antoine | Graetz, Christiane | Graham, Andrew | Grummel, Verena | Guaschino, Clara | Hadjixenofontos, Athena | Hakonarson, Hakon | Halfpenny, Christopher | Hall, Gillian | Hall, Per | Hamsten, Anders | Harley, James | Harrower, Timothy | Hawkins, Clive | Hellenthal, Garrett | Hillier, Charles | Hobart, Jeremy | Hoshi, Muni | Hunt, Sarah E | Jagodic, Maja | Jelčić, Ilijas | Jochim, Angela | Kendall, Brian | Kermode, Allan | Kilpatrick, Trevor | Koivisto, Keijo | Konidari, Ioanna | Korn, Thomas | Kronsbein, Helena | Langford, Cordelia | Larsson, Malin | Lathrop, Mark | Lebrun-Frenay, Christine | Lechner-Scott, Jeannette | Lee, Michelle H | Leone, Maurizio A | Leppä, Virpi | Liberatore, Giuseppe | Lie, Benedicte A | Lill, Christina M | Lindén, Magdalena | Link, Jenny | Luessi, Felix | Lycke, Jan | Macciardi, Fabio | Männistö, Satu | Manrique, Clara P | Martin, Roland | Martinelli, Vittorio | Mason, Deborah | Mazibrada, Gordon | McCabe, Cristin | Mero, Inger-Lise | Mescheriakova, Julia | Moutsianas, Loukas | Myhr, Kjell-Morten | Nagels, Guy | Nicholas, Richard | Nilsson, Petra | Piehl, Fredrik | Pirinen, Matti | Price, Siân E | Quach, Hong | Reunanen, Mauri | Robberecht, Wim | Robertson, Neil P | Rodegher, Mariaemma | Rog, David | Salvetti, Marco | Schnetz-Boutaud, Nathalie C | Sellebjerg, Finn | Selter, Rebecca C | Schaefer, Catherine | Shaunak, Sandip | Shen, Ling | Shields, Simon | Siffrin, Volker | Slee, Mark | Sorensen, Per Soelberg | Sorosina, Melissa | Sospedra, Mireia | Spurkland, Anne | Strange, Amy | Sundqvist, Emilie | Thijs, Vincent | Thorpe, John | Ticca, Anna | Tienari, Pentti | van Duijn, Cornelia | Visser, Elizabeth M | Vucic, Steve | Westerlind, Helga | Wiley, James S | Wilkins, Alastair | Wilson, James F | Winkelmann, Juliane | Zajicek, John | Zindler, Eva | Haines, Jonathan L | Pericak-Vance, Margaret A | Ivinson, Adrian J | Stewart, Graeme | Hafler, David | Hauser, Stephen L | Compston, Alastair | McVean, Gil | De Jager, Philip | Sawcer, Stephen | McCauley, Jacob L
Nature genetics  2013;45(11):1353-1360.
Using the ImmunoChip custom genotyping array, we analysed 14,498 multiple sclerosis subjects and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (p-value < 1.0 × 10-4). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 multiple sclerosis subjects and 26,703 healthy controls. In these 80,094 individuals of European ancestry we identified 48 new susceptibility variants (p-value < 5.0 × 10-8); three found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants in 103 discrete loci outside of the Major Histocompatibility Complex. With high resolution Bayesian fine-mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalogue of multiple sclerosis risk variants and illustrates the value of fine-mapping in the resolution of GWAS signals.
doi:10.1038/ng.2770
PMCID: PMC3832895  PMID: 24076602
8.  The zebrafish reference genome sequence and its relationship to the human genome 
Howe, Kerstin | Clark, Matthew D. | Torroja, Carlos F. | Torrance, James | Berthelot, Camille | Muffato, Matthieu | Collins, John E. | Humphray, Sean | McLaren, Karen | Matthews, Lucy | McLaren, Stuart | Sealy, Ian | Caccamo, Mario | Churcher, Carol | Scott, Carol | Barrett, Jeffrey C. | Koch, Romke | Rauch, Gerd-Jörg | White, Simon | Chow, William | Kilian, Britt | Quintais, Leonor T. | Guerra-Assunção, José A. | Zhou, Yi | Gu, Yong | Yen, Jennifer | Vogel, Jan-Hinnerk | Eyre, Tina | Redmond, Seth | Banerjee, Ruby | Chi, Jianxiang | Fu, Beiyuan | Langley, Elizabeth | Maguire, Sean F. | Laird, Gavin K. | Lloyd, David | Kenyon, Emma | Donaldson, Sarah | Sehra, Harminder | Almeida-King, Jeff | Loveland, Jane | Trevanion, Stephen | Jones, Matt | Quail, Mike | Willey, Dave | Hunt, Adrienne | Burton, John | Sims, Sarah | McLay, Kirsten | Plumb, Bob | Davis, Joy | Clee, Chris | Oliver, Karen | Clark, Richard | Riddle, Clare | Eliott, David | Threadgold, Glen | Harden, Glenn | Ware, Darren | Mortimer, Beverly | Kerry, Giselle | Heath, Paul | Phillimore, Benjamin | Tracey, Alan | Corby, Nicole | Dunn, Matthew | Johnson, Christopher | Wood, Jonathan | Clark, Susan | Pelan, Sarah | Griffiths, Guy | Smith, Michelle | Glithero, Rebecca | Howden, Philip | Barker, Nicholas | Stevens, Christopher | Harley, Joanna | Holt, Karen | Panagiotidis, Georgios | Lovell, Jamieson | Beasley, Helen | Henderson, Carl | Gordon, Daria | Auger, Katherine | Wright, Deborah | Collins, Joanna | Raisen, Claire | Dyer, Lauren | Leung, Kenric | Robertson, Lauren | Ambridge, Kirsty | Leongamornlert, Daniel | McGuire, Sarah | Gilderthorp, Ruth | Griffiths, Coline | Manthravadi, Deepa | Nichol, Sarah | Barker, Gary | Whitehead, Siobhan | Kay, Michael | Brown, Jacqueline | Murnane, Clare | Gray, Emma | Humphries, Matthew | Sycamore, Neil | Barker, Darren | Saunders, David | Wallis, Justene | Babbage, Anne | Hammond, Sian | Mashreghi-Mohammadi, Maryam | Barr, Lucy | Martin, Sancha | Wray, Paul | Ellington, Andrew | Matthews, Nicholas | Ellwood, Matthew | Woodmansey, Rebecca | Clark, Graham | Cooper, James | Tromans, Anthony | Grafham, Darren | Skuce, Carl | Pandian, Richard | Andrews, Robert | Harrison, Elliot | Kimberley, Andrew | Garnett, Jane | Fosker, Nigel | Hall, Rebekah | Garner, Patrick | Kelly, Daniel | Bird, Christine | Palmer, Sophie | Gehring, Ines | Berger, Andrea | Dooley, Christopher M. | Ersan-Ürün, Zübeyde | Eser, Cigdem | Geiger, Horst | Geisler, Maria | Karotki, Lena | Kirn, Anette | Konantz, Judith | Konantz, Martina | Oberländer, Martina | Rudolph-Geiger, Silke | Teucke, Mathias | Osoegawa, Kazutoyo | Zhu, Baoli | Rapp, Amanda | Widaa, Sara | Langford, Cordelia | Yang, Fengtang | Carter, Nigel P. | Harrow, Jennifer | Ning, Zemin | Herrero, Javier | Searle, Steve M. J. | Enright, Anton | Geisler, Robert | Plasterk, Ronald H. A. | Lee, Charles | Westerfield, Monte | de Jong, Pieter J. | Zon, Leonard I. | Postlethwait, John H. | Nüsslein-Volhard, Christiane | Hubbard, Tim J. P. | Crollius, Hugues Roest | Rogers, Jane | Stemple, Derek L.
Nature  2013;496(7446):498-503.
Zebrafish have become a popular organism for the study of vertebrate gene function1,2. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease3–5. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes6, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.
doi:10.1038/nature12111
PMCID: PMC3703927  PMID: 23594743
9.  A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease 
Holmans, Peter | Moskvina, Valentina | Jones, Lesley | Sharma, Manu | Vedernikov, Alexey | Buchel, Finja | Sadd, Mohamad | Bras, Jose M. | Bettella, Francesco | Nicolaou, Nayia | Simón-Sánchez, Javier | Mittag, Florian | Gibbs, J. Raphael | Schulte, Claudia | Durr, Alexandra | Guerreiro, Rita | Hernandez, Dena | Brice, Alexis | Stefánsson, Hreinn | Majamaa, Kari | Gasser, Thomas | Heutink, Peter | Wood, Nicholas W. | Martinez, Maria | Singleton, Andrew B. | Nalls, Michael A. | Hardy, John | Morris, Huw R. | Williams, Nigel M. | Arepalli, Sampath | Barker, Roger | Barrett, Jeffrey | Ben-Shlomo, Yoav | Berendse, Henk W. | Berg, Daniela | Bhatia, Kailash | de Bie, Rob M.A. | Biffi, Alessandro | Bloem, Bas | Brice, Alexis | Bochdanovits, Zoltan | Bonin, Michael | Bras, Jose M. | Brockmann, Kathrin | Brooks, Janet | Burn, David J. | Charlesworth, Gavin | Chen, Honglei | Chinnery, Patrick F. | Chong, Sean | Clarke, Carl E. | Cookson, Mark R. | Cooper, Jonathan M. | Corvol, Jen-Christophe | Counsell, Carl | Damier, Philippe | Dartigues, Jean Francois | Deloukas, Panagiotis | Deuschl, Günther | Dexter, David T. | van Dijk, Karin D. | Dillman, Allissa | Durif, Frank | Durr, Alexandra | Edkins, Sarah | Evans, Jonathan R. | Foltynie, Thomas | Gao, Jianjun | Gardner, Michelle | Gasser, Thomas | Gibbs, J. Raphael | Goate, Alison | Gray, Emma | Guerreiro, Rita | Gústafsson, Ómar | Hardy, John | Harris, Clare | Hernandez, Dena G. | Heutink, Peter | van Hilten, Jacobus J. | Hofman, Albert | Hollenbeck, Albert | Holmans, Peter | Holton, Janice | Hu, Michele | Huber, Heiko | Hudson, Gavin | Hunt, Sarah E. | Huttenlocher, Johanna | Illig, Thomas | Langford, Cordelia | Lees, Andrew | Lesage, Suzanne | Lichtner, Peter | Limousin, Patricia | Lopez, Grisel | Lorenz, Delia | Martinez, Maria | McNeill, Alisdair | Moorby, Catriona | Moore, Matthew | Morris, Huw | Morrison, Karen E. | Moskvina, Valentina | Mudanohwo, Ese | Nalls, Michael A. | Pearson, Justin | Perlmutter, Joel S. | Pétursson, Hjörvar | Plagnol, Vincent | Pollak, Pierre | Post, Bart | Potter, Simon | Ravina, Bernard | Revesz, Tamas | Riess, Olaf | Rivadeneira, Fernando | Rizzu, Patrizia | Ryten, Mina | Saad, Mohamad | Sawcer, Stephen | Schapira, Anthony | Scheffer, Hans | Sharma, Manu | Shaw, Karen | Sheerin, Una-Marie | Shoulson, Ira | Schulte, Claudia | Sidransky, Ellen | Simón-Sánchez, Javier | Singleton, Andrew B. | Smith, Colin | Stefánsson, Hreinn | Stefánsson, Kári | Steinberg, Stacy | Stockton, Joanna D. | Sveinbjornsdottir, Sigurlaug | Talbot, Kevin | Tanner, Carlie M. | Tashakkori-Ghanbaria, Avazeh | Tison, François | Trabzuni, Daniah | Traynor, Bryan J. | Uitterlinden, André G. | Velseboer, Daan | Vidailhet, Marie | Walker, Robert | van de Warrenburg, Bart | Wickremaratchi, Mirdhu | Williams, Nigel | Williams-Gray, Caroline H. | Winder-Rhodes, Sophie | Wood, Nicholas
Human Molecular Genetics  2012;22(5):1039-1049.
Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1–2% in people >60 and 3–4% in people >80. Genome-wide association (GWA) studies have now implicated significant evidence for association in at least 18 genomic regions. We have studied a large PD-meta analysis and identified a significant excess of SNPs (P < 1 × 10−16) that are associated with PD but fall short of the genome-wide significance threshold. This result was independent of variants at the 18 previously implicated regions and implies the presence of additional polygenic risk alleles. To understand how these loci increase risk of PD, we applied a pathway-based analysis, testing for biological functions that were significantly enriched for genes containing variants associated with PD. Analysing two independent GWA studies, we identified that both had a significant excess in the number of functional categories enriched for PD-associated genes (minimum P = 0.014 and P = 0.006, respectively). Moreover, 58 categories were significantly enriched for associated genes in both GWA studies (P < 0.001), implicating genes involved in the ‘regulation of leucocyte/lymphocyte activity’ and also ‘cytokine-mediated signalling’ as conferring an increased susceptibility to PD. These results were unaltered by the exclusion of all 178 genes that were present at the 18 genomic regions previously reported to be strongly associated with PD (including the HLA locus). Our findings, therefore, provide independent support to the strong association signal at the HLA locus and imply that the immune-related genetic susceptibility to PD is likely to be more widespread in the genome than previously appreciated.
doi:10.1093/hmg/dds492
PMCID: PMC3561909  PMID: 23223016
11.  Selective nuclear export of specific classes of mRNA from mammalian nuclei is promoted by GANP 
Nucleic Acids Research  2014;42(8):5059-5071.
The nuclear phase of the gene expression pathway culminates in the export of mature messenger RNAs (mRNAs) to the cytoplasm through nuclear pore complexes. GANP (germinal- centre associated nuclear protein) promotes the transfer of mRNAs bound to the transport factor NXF1 to nuclear pore complexes. Here, we demonstrate that GANP, subunit of the TRanscription-EXport-2 (TREX-2) mRNA export complex, promotes selective nuclear export of a specific subset of mRNAs whose transport depends on NXF1. Genome-wide gene expression profiling showed that half of the transcripts whose nuclear export was impaired following NXF1 depletion also showed reduced export when GANP was depleted. GANP-dependent transcripts were highly expressed, yet short-lived, and were highly enriched in those encoding central components of the gene expression machinery such as RNA synthesis and processing factors. After injection into Xenopus oocyte nuclei, representative GANP-dependent transcripts showed faster nuclear export kinetics than representative transcripts that were not influenced by GANP depletion. We propose that GANP promotes the nuclear export of specific classes of mRNAs that may facilitate rapid changes in gene expression.
doi:10.1093/nar/gku095
PMCID: PMC4005691  PMID: 24510098
12.  Influence of genetic background on tumor karyotypes: evidence for breed-associated cytogenetic aberrations in canine appendicular osteosarcoma 
Recurrent chromosomal aberrations in solid tumors can reveal the genetic pathways involved in the evolution of a malignancy and in some cases predict biological behavior. However, the role of individual genetic backgrounds in shaping karyotypes of sporadic tumors is unknown. The genetic structure of purebred dog breeds coupled with their susceptibility to spontaneous cancers provides a robust model with which to address this question. We tested the hypothesis that there is an association between breed and the distribution of genomic copy number imbalances in naturally-occurring canine tumors through assessment of a cohort of Golden Retrievers and Rottweilers diagnosed with spontaneous appendicular osteosarcoma. Our findings reveal significant correlations between breed and tumor karyotypes that are independent from gender, age at diagnosis and histological classification. These data indicate for the first time that individual genetic backgrounds, as defined by breed in dogs, influence tumor karyotypes in a cancer with extensive genomic instability.
doi:10.1007/s10577-009-9028-z
PMCID: PMC3758998  PMID: 19337847
microarray; comparative genomic hybridization (CGH); canine; osteosarcoma; chromosome
13.  Genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1 
Strange, Amy | Capon, Francesca | Spencer, Chris CA | Knight, Jo | Weale, Michael E | Allen, Michael H | Barton, Anne | Band, Gavin | Bellenguez, Céline | Bergboer, Judith GM | Blackwell, Jenefer M | Bramon, Elvira | Bumpstead, Suzannah J | Casas, Juan P | Cork, Michael J | Corvin, Aiden | Deloukas, Panos | Dilthey, Alexander | Duncanson, Audrey | Edkins, Sarah | Estivill, Xavier | Fitzgerald, Oliver | Freeman, Colin | Giardina, Emiliano | Gray, Emma | Hofer, Angelika | Hüffmeier, Ulrike | Hunt, Sarah E | Irvine, Alan D | Jankowski, Janusz | Kirby, Brian | Langford, Cordelia | Lascorz, Jesús | Leman, Joyce | Leslie, Stephen | Mallbris, Lotus | Markus, Hugh S | Mathew, Christopher G | McLean, WH Irwin | McManus, Ross | Mössner, Rotraut | Moutsianas, Loukas | Naluai, Åsa T | Nestle, Frank O | Novelli, Giuseppe | Onoufriadis, Alexandros | Palmer, Colin NA | Perricone, Carlo | Pirinen, Matti | Plomin, Robert | Potter, Simon C | Pujol, Ramon M | Rautanen, Anna | Riveira-Munoz, Eva | Ryan, Anthony W | Salmhofer, Wolfgang | Samuelsson, Lena | Sawcer, Stephen J | Schalkwijk, Joost | Smith, Catherine H | Ståhle, Mona | Su, Zhan | Tazi-Ahnini, Rachid | Traupe, Heiko | Viswanathan, Ananth C | Warren, Richard B | Weger, Wolfgang | Wolk, Katarina | Wood, Nicholas | Worthington, Jane | Young, Helen S | Zeeuwen, Patrick LJM | Hayday, Adrian | Burden, A David | Griffiths, Christopher EM | Kere, Juha | Reis, André | McVean, Gilean | Evans, David M | Brown, Matthew A | Barker, Jonathan N | Peltonen, Leena | Donnelly, Peter | Trembath, Richard C
Nature genetics  2010;42(11):985-990.
doi:10.1038/ng.694
PMCID: PMC3749730  PMID: 20953190
14.  Common variants in the HLA-DRB1-HLA-DQA1 Class II region are associated with susceptibility to visceral leishmaniasis 
Nature genetics  2013;45(2):208-213.
To identify susceptibility loci for visceral leishmaniasis we undertook genome-wide association studies in two populations; 989 cases and 1089 controls from India, and 357 cases in 308 Brazilian families (1970 individuals). The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, resulting in Pcombined=2.76×10−17 and OR(95%CI)=1.41(1.30-1.52) across the three cohorts at rs9271858. A conditional analysis provided evidence for multiple associations within the HLA-DRB1-HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion the HLA-DRB1-HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species.
doi:10.1038/ng.2518
PMCID: PMC3664012  PMID: 23291585
15.  Genome-wide association study of intraocular pressure identifies the GLCCI1/ICA1 region as a glaucoma susceptibility locus 
Human Molecular Genetics  2013;22(22):4653-4660.
To discover quantitative trait loci for intraocular pressure, a major risk factor for glaucoma and the only modifiable one, we performed a genome-wide association study on a discovery cohort of 2175 individuals from Sydney, Australia. We found a novel association between intraocular pressure and a common variant at 7p21 near to GLCCI1 and ICA1. The findings in this region were confirmed through two UK replication cohorts totalling 4866 individuals (rs59072263, Pcombined = 1.10 × 10−8). A copy of the G allele at this SNP is associated with an increase in mean IOP of 0.45 mmHg (95%CI = 0.30–0.61 mmHg). These results lend support to the implication of vesicle trafficking and glucocorticoid inducibility pathways in the determination of intraocular pressure and in the pathogenesis of primary open-angle glaucoma.
doi:10.1093/hmg/ddt293
PMCID: PMC3904806  PMID: 23836780
16.  Identification of fifteen new psoriasis susceptibility loci highlights the role of innate immunity 
Nature genetics  2012;44(12):1341-1348.
Summary
To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of three genome-wide association studies (GWAS) and two independent datasets genotyped on the Immunochip, involving 10,588 cases and 22,806 controls in total. We identified 15 new disease susceptibility regions, increasing the number of psoriasis-associated loci to 36 for Caucasians. Conditional analyses identified five independent signals within previously known loci. The newly identified shared disease regions encompassed a number of genes whose products regulate T-cell function (e.g. RUNX3, TAGAP and STAT3). The new psoriasis-specific regions were notable for candidate genes whose products are involved in innate host defense, encoding proteins with roles in interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C), and NF-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.
doi:10.1038/ng.2467
PMCID: PMC3510312  PMID: 23143594
17.  High density genetic mapping identifies new susceptibility loci for rheumatoid arthritis 
Nature genetics  2012;44(12):1336-1340.
Summary
Using the Immunochip custom single nucleotide polymorphism (SNP) array, designed for dense genotyping of 186 genome wide association study (GWAS) confirmed loci we analysed 11,475 rheumatoid arthritis cases of European ancestry and 15,870 controls for 129,464 markers. The data were combined in meta-analysis with GWAS data from additional independent cases (n=2,363) and controls (n=17,872). We identified fourteen novel loci; nine were associated with rheumatoid arthritis overall and 5 specifically in anti-citrillunated peptide antibody positive disease, bringing the number of confirmed European ancestry rheumatoid arthritis loci to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at six loci and association to low frequency variants (minor allele frequency <0.05) at 4 loci. Bioinformatic analysis of the data generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.
doi:10.1038/ng.2462
PMCID: PMC3605761  PMID: 23143596
18.  Genome-wide association study identifies five new breast cancer susceptibility loci 
Nature genetics  2010;42(6):504-507.
Breast cancer is the most common cancer in women in developed countries. To identify common breast cancer susceptibility alleles, we conducted a genome-wide association study in which 582,886 SNPs were genotyped in 3,659 cases with a family history of the disease and 4,897 controls. Promising associations were evaluated in a second stage, comprising 12,576 cases and 12,223 controls. We identified five new susceptibility loci, on chromosomes 9, 10 and 11 (P = 4.6 × 10−7 to P = 3.2 × 10−15). We also identified SNPs in the 6q25.1 (rs3757318, P = 2.9 × 10−6), 8q24 (rs1562430, P = 5.8 × 10−7) and LSP1 (rs909116, P = 7.3 × 10−7) regions that showed more significant association with risk than those reported previously. Previously identified breast cancer susceptibility loci were also found to show larger effect sizes in this study of familial breast cancer cases than in previous population-based studies, consistent with polygenic susceptibility to the disease.
doi:10.1038/ng.586
PMCID: PMC3632836  PMID: 20453838
19.  Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes 
Morris, Andrew P | Voight, Benjamin F | Teslovich, Tanya M | Ferreira, Teresa | Segrè, Ayellet V | Steinthorsdottir, Valgerdur | Strawbridge, Rona J | Khan, Hassan | Grallert, Harald | Mahajan, Anubha | Prokopenko, Inga | Kang, Hyun Min | Dina, Christian | Esko, Tonu | Fraser, Ross M | Kanoni, Stavroula | Kumar, Ashish | Lagou, Vasiliki | Langenberg, Claudia | Luan, Jian'an | Lindgren, Cecilia M | Müller-Nurasyid, Martina | Pechlivanis, Sonali | Rayner, N William | Scott, Laura J | Wiltshire, Steven | Yengo, Loic | Kinnunen, Leena | Rossin, Elizabeth J | Raychaudhuri, Soumya | Johnson, Andrew D | Dimas, Antigone S | Loos, Ruth J F | Vedantam, Sailaja | Chen, Han | Florez, Jose C | Fox, Caroline | Liu, Ching-Ti | Rybin, Denis | Couper, David J | Kao, Wen Hong L | Li, Man | Cornelis, Marilyn C | Kraft, Peter | Sun, Qi | van Dam, Rob M | Stringham, Heather M | Chines, Peter S | Fischer, Krista | Fontanillas, Pierre | Holmen, Oddgeir L | Hunt, Sarah E | Jackson, Anne U | Kong, Augustine | Lawrence, Robert | Meyer, Julia | Perry, John RB | Platou, Carl GP | Potter, Simon | Rehnberg, Emil | Robertson, Neil | Sivapalaratnam, Suthesh | Stančáková, Alena | Stirrups, Kathleen | Thorleifsson, Gudmar | Tikkanen, Emmi | Wood, Andrew R | Almgren, Peter | Atalay, Mustafa | Benediktsson, Rafn | Bonnycastle, Lori L | Burtt, Noël | Carey, Jason | Charpentier, Guillaume | Crenshaw, Andrew T | Doney, Alex S F | Dorkhan, Mozhgan | Edkins, Sarah | Emilsson, Valur | Eury, Elodie | Forsen, Tom | Gertow, Karl | Gigante, Bruna | Grant, George B | Groves, Christopher J | Guiducci, Candace | Herder, Christian | Hreidarsson, Astradur B | Hui, Jennie | James, Alan | Jonsson, Anna | Rathmann, Wolfgang | Klopp, Norman | Kravic, Jasmina | Krjutškov, Kaarel | Langford, Cordelia | Leander, Karin | Lindholm, Eero | Lobbens, Stéphane | Männistö, Satu | Mirza, Ghazala | Mühleisen, Thomas W | Musk, Bill | Parkin, Melissa | Rallidis, Loukianos | Saramies, Jouko | Sennblad, Bengt | Shah, Sonia | Sigurðsson, Gunnar | Silveira, Angela | Steinbach, Gerald | Thorand, Barbara | Trakalo, Joseph | Veglia, Fabrizio | Wennauer, Roman | Winckler, Wendy | Zabaneh, Delilah | Campbell, Harry | van Duijn, Cornelia | Uitterlinden89-, Andre G | Hofman, Albert | Sijbrands, Eric | Abecasis, Goncalo R | Owen, Katharine R | Zeggini, Eleftheria | Trip, Mieke D | Forouhi, Nita G | Syvänen, Ann-Christine | Eriksson, Johan G | Peltonen, Leena | Nöthen, Markus M | Balkau, Beverley | Palmer, Colin N A | Lyssenko, Valeriya | Tuomi, Tiinamaija | Isomaa, Bo | Hunter, David J | Qi, Lu | Shuldiner, Alan R | Roden, Michael | Barroso, Ines | Wilsgaard, Tom | Beilby, John | Hovingh, Kees | Price, Jackie F | Wilson, James F | Rauramaa, Rainer | Lakka, Timo A | Lind, Lars | Dedoussis, George | Njølstad, Inger | Pedersen, Nancy L | Khaw, Kay-Tee | Wareham, Nicholas J | Keinanen-Kiukaanniemi, Sirkka M | Saaristo, Timo E | Korpi-Hyövälti, Eeva | Saltevo, Juha | Laakso, Markku | Kuusisto, Johanna | Metspalu, Andres | Collins, Francis S | Mohlke, Karen L | Bergman, Richard N | Tuomilehto, Jaakko | Boehm, Bernhard O | Gieger, Christian | Hveem, Kristian | Cauchi, Stephane | Froguel, Philippe | Baldassarre, Damiano | Tremoli, Elena | Humphries, Steve E | Saleheen, Danish | Danesh, John | Ingelsson, Erik | Ripatti, Samuli | Salomaa, Veikko | Erbel, Raimund | Jöckel, Karl-Heinz | Moebus, Susanne | Peters, Annette | Illig, Thomas | de Faire, Ulf | Hamsten, Anders | Morris, Andrew D | Donnelly, Peter J | Frayling, Timothy M | Hattersley, Andrew T | Boerwinkle, Eric | Melander, Olle | Kathiresan, Sekar | Nilsson, Peter M | Deloukas, Panos | Thorsteinsdottir, Unnur | Groop, Leif C | Stefansson, Kari | Hu, Frank | Pankow, James S | Dupuis, Josée | Meigs, James B | Altshuler, David | Boehnke, Michael | McCarthy, Mark I
Nature genetics  2012;44(9):981-990.
To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis.
doi:10.1038/ng.2383
PMCID: PMC3442244  PMID: 22885922
20.  Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes 
Morris, Andrew P | Voight, Benjamin F | Teslovich, Tanya M | Ferreira, Teresa | Segré, Ayellet V | Steinthorsdottir, Valgerdur | Strawbridge, Rona J | Khan, Hassan | Grallert, Harald | Mahajan, Anubha | Prokopenko, Inga | Kang, Hyun Min | Dina, Christian | Esko, Tonu | Fraser, Ross M | Kanoni, Stavroula | Kumar, Ashish | Lagou, Vasiliki | Langenberg, Claudia | Luan, Jian’an | Lindgren, Cecilia M | Müller-Nurasyid, Martina | Pechlivanis, Sonali | Rayner, N William | Scott, Laura J | Wiltshire, Steven | Yengo, Loic | Kinnunen, Leena | Rossin, Elizabeth J | Raychaudhuri, Soumya | Johnson, Andrew D | Dimas, Antigone S | Loos, Ruth J F | Vedantam, Sailaja | Chen, Han | Florez, Jose C | Fox, Caroline | Liu, Ching-Ti | Rybin, Denis | Couper, David J | Kao, Wen Hong L | Li, Man | Cornelis, Marilyn C | Kraft, Peter | Sun, Qi | van Dam, Rob M | Stringham, Heather M | Chines, Peter S | Fischer, Krista | Fontanillas, Pierre | Holmen, Oddgeir L | Hunt, Sarah E | Jackson, Anne U | Kong, Augustine | Lawrence, Robert | Meyer, Julia | Perry, John R B | Platou, Carl G P | Potter, Simon | Rehnberg, Emil | Robertson, Neil | Sivapalaratnam, Suthesh | Stančáková, Alena | Stirrups, Kathleen | Thorleifsson, Gudmar | Tikkanen, Emmi | Wood, Andrew R | Almgren, Peter | Atalay, Mustafa | Benediktsson, Rafn | Bonnycastle, Lori L | Burtt, Noël | Carey, Jason | Charpentier, Guillaume | Crenshaw, Andrew T | Doney, Alex S F | Dorkhan, Mozhgan | Edkins, Sarah | Emilsson, Valur | Eury, Elodie | Forsen, Tom | Gertow, Karl | Gigante, Bruna | Grant, George B | Groves, Christopher J | Guiducci, Candace | Herder, Christian | Hreidarsson, Astradur B | Hui, Jennie | James, Alan | Jonsson, Anna | Rathmann, Wolfgang | Klopp, Norman | Kravic, Jasmina | Krjutškov, Kaarel | Langford, Cordelia | Leander, Karin | Lindholm, Eero | Lobbens, Stéphane | Männistö, Satu | Mirza, Ghazala | Mühleisen, Thomas W | Musk, Bill | Parkin, Melissa | Rallidis, Loukianos | Saramies, Jouko | Sennblad, Bengt | Shah, Sonia | Sigurðsson, Gunnar | Silveira, Angela | Steinbach, Gerald | Thorand, Barbara | Trakalo, Joseph | Veglia, Fabrizio | Wennauer, Roman | Winckler, Wendy | Zabaneh, Delilah | Campbell, Harry | van Duijn, Cornelia | Uitterlinden, Andre G | Hofman, Albert | Sijbrands, Eric | Abecasis, Goncalo R | Owen, Katharine R | Zeggini, Eleftheria | Trip, Mieke D | Forouhi, Nita G | Syvänen, Ann-Christine | Eriksson, Johan G | Peltonen, Leena | Nöthen, Markus M | Balkau, Beverley | Palmer, Colin N A | Lyssenko, Valeriya | Tuomi, Tiinamaija | Isomaa, Bo | Hunter, David J | Qi, Lu | Shuldiner, Alan R | Roden, Michael | Barroso, Ines | Wilsgaard, Tom | Beilby, John | Hovingh, Kees | Price, Jackie F | Wilson, James F | Rauramaa, Rainer | Lakka, Timo A | Lind, Lars | Dedoussis, George | Njølstad, Inger | Pedersen, Nancy L | Khaw, Kay-Tee | Wareham, Nicholas J | Keinanen-Kiukaanniemi, Sirkka M | Saaristo, Timo E | Korpi-Hyövälti, Eeva | Saltevo, Juha | Laakso, Markku | Kuusisto, Johanna | Metspalu, Andres | Collins, Francis S | Mohlke, Karen L | Bergman, Richard N | Tuomilehto, Jaakko | Boehm, Bernhard O | Gieger, Christian | Hveem, Kristian | Cauchi, Stephane | Froguel, Philippe | Baldassarre, Damiano | Tremoli, Elena | Humphries, Steve E | Saleheen, Danish | Danesh, John | Ingelsson, Erik | Ripatti, Samuli | Salomaa, Veikko | Erbel, Raimund | Jöckel, Karl-Heinz | Moebus, Susanne | Peters, Annette | Illig, Thomas | de Faire, Ulf | Hamsten, Anders | Morris, Andrew D | Donnelly, Peter J | Frayling, Timothy M | Hattersley, Andrew T | Boerwinkle, Eric | Melander, Olle | Kathiresan, Sekar | Nilsson, Peter M | Deloukas, Panos | Thorsteinsdottir, Unnur | Groop, Leif C | Stefansson, Kari | Hu, Frank | Pankow, James S | Dupuis, Josée | Meigs, James B | Altshuler, David | Boehnke, Michael | McCarthy, Mark I
Nature genetics  2012;44(9):981-990.
To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis.
doi:10.1038/ng.2383
PMCID: PMC3442244  PMID: 22885922
21.  GENETICS OF GENE EXPRESSION IN PRIMARY IMMUNE CELLS IDENTIFIES CELL-SPECIFIC MASTER REGULATORS AND ROLES OF HLA ALLELES 
Nature genetics  2012;44(5):502-510.
Trans-acting genetic variants play a substantial, albeit poorly characterized, role in the heritable determination of gene expression. Using paired purified primary monocytes and B-cells we identify novel, predominantly cell-specific, cis- and trans-eQTL (expression quantitative trait loci). These include multi-locus trans-associations to LYZ in monocytes and to KLF4 in B-cells. Additionally, we observe B-cell specific trans-association of rs11171739 at 12q13.2, a known autoimmune disease locus, to IP6K2 (pB-cell=5.8×10−15), PRIC285 (pB-cell=3.0×10−10) and an upstream region of CDKN1A (pB-cell=2×10−52; pmonocyte=1.8×10−4), suggesting roles for cell cycle regulation and PPARγ signaling in disease pathogenesis. We also find specific HLA alleles forming trans-association with the expression of AOAH and ARHGAP24 in monocytes but not in B-cells. In summary, we demonstrate that mapping gene expression in defined primary cell populations identifies new cell-specific trans-regulated networks and provides insights into the genetic basis of disease susceptibility.
doi:10.1038/ng.2205
PMCID: PMC3437404  PMID: 22446964
22.  Rare and functional SIAE variants are not associated with autoimmune disease risk in up to 66,924 individuals of European ancestry 
Nature genetics  2011;44(1):3-5.
doi:10.1038/ng.1037
PMCID: PMC3287292  PMID: 22200769
23.  Genome-Wide Screening for Genetic Alterations in Esophageal Cancer by aCGH Identifies 11q13 Amplification Oncogenes Associated with Nodal Metastasis 
PLoS ONE  2012;7(6):e39797.
Background
Esophageal squamous cell carcinoma (ESCC) is highly prevalent in China and other Asian countries, as a major cause of cancer-related mortality. ESCC displays complex chromosomal abnormalities, including multiple structural and numerical aberrations. Chromosomal abnormalities, such as recurrent amplifications and homozygous deletions, directly contribute to tumorigenesis through altering the expression of key oncogenes and tumor suppressor genes.
Methodology/Principle Findings
To understand the role of genetic alterations in ESCC pathogenesis and identify critical amplification/deletion targets, we performed genome-wide 1-Mb array comparative genomic hybridization (aCGH) analysis for 10 commonly used ESCC cell lines. Recurrent chromosomal gains were frequently detected on 3q26-27, 5p15-14, 8p12, 8p22-24, 11q13, 13q21-31, 18p11 and 20q11-13, with frequent losses also found on 8p23-22, 11q22, 14q32 and 18q11-23. Gain of 11q13.3-13.4 was the most frequent alteration in ESCC. Within this region, CCND1 oncogene was identified with high level of amplification and overexpression in ESCC, while FGF19 and SHANK2 was also remarkably over-expressed. Moreover, a high concordance (91.5%) of gene amplification and protein overexpression of CCND1 was observed in primary ESCC tumors. CCND1 amplification/overexpression was also significantly correlated with the lymph node metastasis of ESCC.
Conclusion
These findings suggest that genomic gain of 11q13 is the major mechanism contributing to the amplification. Novel oncogenes identified within the 11q13 amplicon including FGF19 and SHANK2 may play important roles in ESCC tumorigenesis.
doi:10.1371/journal.pone.0039797
PMCID: PMC3382571  PMID: 22761904
24.  Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease 
Nature genetics  2011;43(12):1193-1201.
We densely genotyped, using 1000 Genomes Project pilot CEU and additional re-sequencing study variants, 183 reported immune-mediated disease non-HLA risk loci in 12,041 celiac disease cases and 12,228 controls. We identified 13 new celiac disease risk loci at genome wide significance, bringing the total number of known loci (including HLA) to 40. Multiple independent association signals are found at over a third of these loci, attributable to a combination of common, low frequency, and rare genetic variants. In comparison with previously available data such as HapMap3, our dense genotyping in a large sample size provided increased resolution of the pattern of linkage disequilibrium, and suggested localization of many signals to finer scale regions. In particular, 29 of 54 fine-mapped signals appeared localized to specific single genes - and in some instances to gene regulatory elements. We define a complex genetic architecture of risk regions, and refine risk signals, providing a next step towards elucidating causal disease mechanisms.
doi:10.1038/ng.998
PMCID: PMC3242065  PMID: 22057235
25.  Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis 
Sawcer, Stephen | Hellenthal, Garrett | Pirinen, Matti | Spencer, Chris C.A. | Patsopoulos, Nikolaos A. | Moutsianas, Loukas | Dilthey, Alexander | Su, Zhan | Freeman, Colin | Hunt, Sarah E. | Edkins, Sarah | Gray, Emma | Booth, David R. | Potter, Simon C. | Goris, An | Band, Gavin | Oturai, Annette Bang | Strange, Amy | Saarela, Janna | Bellenguez, Céline | Fontaine, Bertrand | Gillman, Matthew | Hemmer, Bernhard | Gwilliam, Rhian | Zipp, Frauke | Jayakumar, Alagurevathi | Martin, Roland | Leslie, Stephen | Hawkins, Stanley | Giannoulatou, Eleni | D’alfonso, Sandra | Blackburn, Hannah | Boneschi, Filippo Martinelli | Liddle, Jennifer | Harbo, Hanne F. | Perez, Marc L. | Spurkland, Anne | Waller, Matthew J | Mycko, Marcin P. | Ricketts, Michelle | Comabella, Manuel | Hammond, Naomi | Kockum, Ingrid | McCann, Owen T. | Ban, Maria | Whittaker, Pamela | Kemppinen, Anu | Weston, Paul | Hawkins, Clive | Widaa, Sara | Zajicek, John | Dronov, Serge | Robertson, Neil | Bumpstead, Suzannah J. | Barcellos, Lisa F. | Ravindrarajah, Rathi | Abraham, Roby | Alfredsson, Lars | Ardlie, Kristin | Aubin, Cristin | Baker, Amie | Baker, Katharine | Baranzini, Sergio E. | Bergamaschi, Laura | Bergamaschi, Roberto | Bernstein, Allan | Berthele, Achim | Boggild, Mike | Bradfield, Jonathan P. | Brassat, David | Broadley, Simon A. | Buck, Dorothea | Butzkueven, Helmut | Capra, Ruggero | Carroll, William M. | Cavalla, Paola | Celius, Elisabeth G. | Cepok, Sabine | Chiavacci, Rosetta | Clerget-Darpoux, Françoise | Clysters, Katleen | Comi, Giancarlo | Cossburn, Mark | Cournu-Rebeix, Isabelle | Cox, Mathew B. | Cozen, Wendy | Cree, Bruce A.C. | Cross, Anne H. | Cusi, Daniele | Daly, Mark J. | Davis, Emma | de Bakker, Paul I.W. | Debouverie, Marc | D’hooghe, Marie Beatrice | Dixon, Katherine | Dobosi, Rita | Dubois, Bénédicte | Ellinghaus, David | Elovaara, Irina | Esposito, Federica | Fontenille, Claire | Foote, Simon | Franke, Andre | Galimberti, Daniela | Ghezzi, Angelo | Glessner, Joseph | Gomez, Refujia | Gout, Olivier | Graham, Colin | Grant, Struan F.A. | Guerini, Franca Rosa | Hakonarson, Hakon | Hall, Per | Hamsten, Anders | Hartung, Hans-Peter | Heard, Rob N. | Heath, Simon | Hobart, Jeremy | Hoshi, Muna | Infante-Duarte, Carmen | Ingram, Gillian | Ingram, Wendy | Islam, Talat | Jagodic, Maja | Kabesch, Michael | Kermode, Allan G. | Kilpatrick, Trevor J. | Kim, Cecilia | Klopp, Norman | Koivisto, Keijo | Larsson, Malin | Lathrop, Mark | Lechner-Scott, Jeannette S. | Leone, Maurizio A. | Leppä, Virpi | Liljedahl, Ulrika | Bomfim, Izaura Lima | Lincoln, Robin R. | Link, Jenny | Liu, Jianjun | Lorentzen, Åslaug R. | Lupoli, Sara | Macciardi, Fabio | Mack, Thomas | Marriott, Mark | Martinelli, Vittorio | Mason, Deborah | McCauley, Jacob L. | Mentch, Frank | Mero, Inger-Lise | Mihalova, Tania | Montalban, Xavier | Mottershead, John | Myhr, Kjell-Morten | Naldi, Paola | Ollier, William | Page, Alison | Palotie, Aarno | Pelletier, Jean | Piccio, Laura | Pickersgill, Trevor | Piehl, Fredrik | Pobywajlo, Susan | Quach, Hong L. | Ramsay, Patricia P. | Reunanen, Mauri | Reynolds, Richard | Rioux, John D. | Rodegher, Mariaemma | Roesner, Sabine | Rubio, Justin P. | Rückert, Ina-Maria | Salvetti, Marco | Salvi, Erika | Santaniello, Adam | Schaefer, Catherine A. | Schreiber, Stefan | Schulze, Christian | Scott, Rodney J. | Sellebjerg, Finn | Selmaj, Krzysztof W. | Sexton, David | Shen, Ling | Simms-Acuna, Brigid | Skidmore, Sheila | Sleiman, Patrick M.A. | Smestad, Cathrine | Sørensen, Per Soelberg | Søndergaard, Helle Bach | Stankovich, Jim | Strange, Richard C. | Sulonen, Anna-Maija | Sundqvist, Emilie | Syvänen, Ann-Christine | Taddeo, Francesca | Taylor, Bruce | Blackwell, Jenefer M. | Tienari, Pentti | Bramon, Elvira | Tourbah, Ayman | Brown, Matthew A. | Tronczynska, Ewa | Casas, Juan P. | Tubridy, Niall | Corvin, Aiden | Vickery, Jane | Jankowski, Janusz | Villoslada, Pablo | Markus, Hugh S. | Wang, Kai | Mathew, Christopher G. | Wason, James | Palmer, Colin N.A. | Wichmann, H-Erich | Plomin, Robert | Willoughby, Ernest | Rautanen, Anna | Winkelmann, Juliane | Wittig, Michael | Trembath, Richard C. | Yaouanq, Jacqueline | Viswanathan, Ananth C. | Zhang, Haitao | Wood, Nicholas W. | Zuvich, Rebecca | Deloukas, Panos | Langford, Cordelia | Duncanson, Audrey | Oksenberg, Jorge R. | Pericak-Vance, Margaret A. | Haines, Jonathan L. | Olsson, Tomas | Hillert, Jan | Ivinson, Adrian J. | De Jager, Philip L. | Peltonen, Leena | Stewart, Graeme J. | Hafler, David A. | Hauser, Stephen L. | McVean, Gil | Donnelly, Peter | Compston, Alastair
Nature  2011;476(7359):214-219.
Multiple sclerosis (OMIM 126200) is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability.1 Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals;2,3 and systematic attempts to identify linkage in multiplex families have confirmed that variation within the Major Histocompatibility Complex (MHC) exerts the greatest individual effect on risk.4 Modestly powered Genome-Wide Association Studies (GWAS)5-10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects play a key role in disease susceptibility.11 Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the Class I region. Immunologically relevant genes are significantly over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis.
doi:10.1038/nature10251
PMCID: PMC3182531  PMID: 21833088
multiple sclerosis; GWAS; genetics

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