Genomic control for association studies.
Bernie Devlin,Kathryn Roeder +1 more
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The performance of the genomic control method is quite good for plausible effects of liability genes, which bodes well for future genetic analyses of complex disorders.Abstract:
A dense set of single nucleotide polymorphisms (SNP) covering the genome and an efficient method to assess SNP genotypes are expected to be available in the near future. An outstanding question is how to use these technologies efficiently to identify genes affecting liability to complex disorders. To achieve this goal, we propose a statistical method that has several optimal properties: It can be used with case control data and yet, like family-based designs, controls for population heterogeneity; it is insensitive to the usual violations of model assumptions, such as cases failing to be strictly independent; and, by using Bayesian outlier methods, it circumvents the need for Bonferroni correction for multiple tests, leading to better performance in many settings while still constraining risk for false positives. The performance of our genomic control method is quite good for plausible effects of liability genes, which bodes well for future genetic analyses of complex disorders.read more
Citations
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A mixture model approach for the analysis of microarray gene expression data
David B. Allison,Gary L. Gadbury,Moonseong Heo,Jose R. Fernandez,Cheol Koo Lee,Thomas A. Prolla,Richard Weindruch +6 more
TL;DR: A sequence of procedures involving finite mixture modeling and bootstrap inference is developed to address issues in studies involving many thousands of genes, including calorically restricted mice.
Journal ArticleDOI
FTO genotype is associated with phenotypic variability of body mass index
Jian Yang,Jian Yang,Ruth J. F. Loos,Ruth J. F. Loos,Joseph E. Powell,Joseph E. Powell,Sarah E. Medland,Elizabeth K. Speliotes,Daniel I. Chasman,Lynda M. Rose,Gudmar Thorleifsson,Valgerdur Steinthorsdottir,Reedik Mägi,Reedik Mägi,Lindsay L. Waite,Albert V. Smith,Laura M. Yerges-Armstrong,Keri L. Monda,David Hadley,Anubha Mahajan,Guo Li,Karen Kapur,Karen Kapur,Veronique Vitart,Jennifer E. Huffman,Sophie R. Wang,Sophie R. Wang,Cameron D. Palmer,Cameron D. Palmer,Tõnu Esko,Krista Fischer,Jing Hua Zhao,Ayse Demirkan,Aaron Isaacs,Mary F. Feitosa,Jian'an Luan,Nancy L. Heard-Costa,Charles S. White,Anne U. Jackson,Michael Preuss,Andreas Ziegler,Joel Eriksson,Zoltán Kutalik,Francesca Frau,Ilja M. Nolte,Jana V. van Vliet-Ostaptchouk,Jouke-Jan Hottenga,Kevin B. Jacobs,Niek Verweij,Anuj Goel,Carolina Medina-Gomez,Karol Estrada,Jennifer L. Bragg-Gresham,Serena Sanna,Carlo Sidore,Carlo Sidore,Jonathan Tyrer,Alexander Teumer,Inga Prokopenko,Massimo Mangino,Cecilia M. Lindgren,Themistocles L. Assimes,Alan R. Shuldiner,Alan R. Shuldiner,Jennie Hui,John Beilby,Wendy L. McArdle,Per Hall,Talin Haritunians,Lina Zgaga,Lina Zgaga,Ivana Kolcic,Ozren Polasek,Tatijana Zemunik,Ben A. Oostra,M. Juhani Junttila,Henrik Grönberg,Stefan Schreiber,Annette Peters,Andrew A. Hicks,Jonathan Stephens,Jonathan Stephens,Nicola S. Foad,Nicola S. Foad,Jaana Laitinen,Anneli Pouta,Anneli Pouta,Marika Kaakinen,Gonneke Willemsen,Jacqueline M. Vink,Sarah H Wild,Gerjan Navis,Folkert W. Asselbergs,Georg Homuth,Ulrich John,Carlos Iribarren,Tamara B. Harris,Lenore J. Launer,Vilmundur Gudnason,Jeffrey R. O'Connell,Eric Boerwinkle,Gemma Cadby,Lyle J. Palmer,Alan James,Arthur W. Musk,Erik Ingelsson,Bruce M. Psaty,Bruce M. Psaty,Jacques S. Beckmann,Gerard Waeber,Peter Vollenweider,Caroline Hayward,Alan F. Wright,Igor Rudan,Igor Rudan,Leif Groop,Andres Metspalu,Kay-Tee Khaw,Cornelia M. van Duijn,Ingrid B. Borecki,Michael A. Province,Nicholas J. Wareham,Jean-Claude Tardif,Heikki V. Huikuri,L. Adrienne Cupples,Larry D. Atwood,Caroline S. Fox,Michael Boehnke,Francis S. Collins,Karen L. Mohlke,Jeanette Erdmann,Heribert Schunkert,Christian Hengstenberg,Klaus Stark,Mattias Lorentzon,Claes Ohlsson,Daniele Cusi,Jan A. Staessen,Jan A. Staessen,Melanie M. van der Klauw,Peter P. Pramstaller,Sekar Kathiresan,Sekar Kathiresan,Sekar Kathiresan,Jennifer Jolley,Jennifer Jolley,Samuli Ripatti,Samuli Ripatti,Samuli Ripatti,Marjo-Riitta Järvelin,Marjo-Riitta Järvelin,Marjo-Riitta Järvelin,Eco J. C. de Geus,Dorret I. Boomsma,Brenda W. J. H. Penninx,James F. Wilson,Harry Campbell,Stephen J. Chanock,Pim van der Harst,Anders Hamsten,Hugh Watkins,Albert Hofman,Jacqueline C. M. Witteman,M. Carola Zillikens,André G. Uitterlinden,Fernando Rivadeneira,Lambertus A. Kiemeney,Sita H. Vermeulen,Gonçalo R. Abecasis,David Schlessinger,Sabine Schipf,Michael Stumvoll,Anke Tönjes,Tim D. Spector,Kari E. North,Guillaume Lettre,Mark I. McCarthy,Sonja I. Berndt,Andrew C. Heath,Pamela A. F. Madden,Dale R. Nyholt,Grant W. Montgomery,Nicholas G. Martin,Barbara McKnight,David P. Strachan,William G. Hill,Harold Snieder,Paul M. Ridker,Unnur Thorsteinsdottir,Unnur Thorsteinsdottir,Kari Stefansson,Kari Stefansson,Timothy M. Frayling,Joel N. Hirschhorn,Joel N. Hirschhorn,Michael E. Goddard,Michael E. Goddard,Peter M. Visscher,Peter M. Visscher +198 more
TL;DR: The authors performed a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations.
Journal ArticleDOI
Common Variants at 10 Genomic Loci Influence Hemoglobin A1C Levels via Glycemic and Nonglycemic Pathways
Nicole Soranzo,Serena Sanna,Eleanor Wheeler,Christian Gieger,Dörte Radke,Josée Dupuis,Nabila Bouatia-Naji,Claudia Langenberg,Inga Prokopenko,Elliot S. Stolerman,Manjinder S. Sandhu,Matthew M. Heeney,Joseph M. Devaney,Muredach P. Reilly,Sally L. Ricketts +14 more
TL;DR: In this article, the authors investigated the extent to which genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA 1c.
Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps
Anubha Mahajan,Daniel Taliun,Matthias Thurner,Neil R. Robertson,Jason M. Torres,N. William Rayner,Anthony Payne,Valgerdur Steinthorsdottir,Robert A. Scott,Niels Grarup,James P. Cook,Ellen M. Schmidt,Matthias Wuttke,Chloé Sarnowski,Reedik Magill,Jana Nano,Christian Gieger,Stella Trompet,Cécile Lecoeur,Michael Preuss,Bram P. Prins,Xiuqing Guo,Lawrence F. Bielak,Jennifer E. Below,Donald W. Bowden,John C. Chambers,Young-Jin Kim,Maggie C.Y. Ng,Lauren E. Petty,Xueling Sim,Weihua Zhang,Amanda J. Bennett,Jette Bork-Jensen,Chad M. Brummett,Mickaël Canouil,Kai-Uwe Ec Kardt,Krista Fischer,Sharon L.R. Kardia,Florian Kronenberg,Kristi Läll,Ching-Ti Liu,Adam E. Locke,Jian'an Luan,Loanna Ntalla,Vibe Nylander,Sebastian Schoenherr,Claudia Schurmann,Loic Yengo,Erwin P. Bottinger,Ivan Brandslund,Cramer Christensen,George Dedoussis,Jose C. Florez,Ian Ford,Timothy M. Frayling,Vilmantas Giedraitis,Sophie Hackinger,Andrew T. Hattersley,Christian Herder,M. Arfan Ikram,Martin Ingelsson,Marit E. Jørgensen,Torben Jørgensen,Jennifer Kriebel,Johanna Kuusisto,Symen Ligthart,Cecilia M. Lindgren,Allan Linneberg,Valeriya Lyssenko,Vasiliki Mamakou,Thomas Meitinger,Karen L. Mohlke,Andrew D. Morris,Girish N. Nadkarni,James S. Pankow,Annette Peters,Naveed Sattar,Alena Stančáková,Konstantin Strauch,Kent D. Taylor,Barbara Thorand,Gudmar Thorleifsson,Unnur Thorsteinsdottir,Jaakko Tuomilehto,Daniel R. Witte,Josée Dupuis,Patricia A. Peyser,Eleftheria Zeggini,Ruth J. F. Loos,Philippe Froguel,Erik Ingelsson,Lars Lind,Leif Groop,Markku Laakso,Francis S. Collins,J. Wouter Jukema,Colin N. A. Palmer,Harald Grallert,Andres Metspalu,Abbas Dehghan,Anna Koettgen,Gonçalo R. Abecasis,James B. Meigs,Rotter, Jerome, I,Jonathan Marchini,Oluf Pedersen,Torben Hansen,Claudia Langenberg,Nicholas J. Wareham,Kari Stefansson,Anna L. Gloyn,Andrew P. Morris,Michael Boehnke,McCarthy, Mark, I +113 more
Abstract: We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%, 14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).Combining 32 genome-wide association studies with high-density imputation provides a comprehensive view of the genetic contribution to type 2 diabetes in individuals of European ancestry with respect to locus discovery, causal-variant resolution, and mechanistic insight.
Journal ArticleDOI
Genome-Wide Association Study of Blood Pressure Extremes Identifies Variant near UMOD Associated with Hypertension
Sandosh Padmanabhan,Olle Melander,Toby Johnson,Anna Maria Di Blasio,Wai K. Lee,Davide Gentilini,Claire E. Hastie,Cristina Menni,Cristina Menni,Maria Cristina Monti,Christian Delles,Stewart Laing,Barbara Corso,Gerjan Navis,Arjan J. Kwakernaak,Pim van der Harst,Murielle Bochud,Marc Maillard,Michel Burnier,Thomas Hedner,Sverre E. Kjeldsen,Björn Wahlstrand,Marketa Sjögren,Cristiano Fava,Cristiano Fava,Martina Montagnana,Martina Montagnana,Elisa Danese,Elisa Danese,Ole Torffvit,Bo Hedblad,Harold Snieder,John M. C. Connell,Morris Brown,Nilesh J. Samani,Martin Farrall,Giancarlo Cesana,Giuseppe Mancia,Stefano Signorini,Guido Grassi,Susana Eyheramendy,H.-Erich Wichmann,Maris Laan,David P. Strachan,Peter S. Sever,Denis C. Shields,Alice Stanton,Peter Vollenweider,Alexander Teumer,Henry Völzke,Rainer Rettig,Christopher Newton-Cheh,Christopher Newton-Cheh,Pankaj Arora,Pankaj Arora,Feng Zhang,Nicole Soranzo,Nicole Soranzo,Tim D. Spector,Gavin Lucas,Sekar Kathiresan,Sekar Kathiresan,David S. Siscovick,Jian'an Luan,Ruth J. F. Loos,Nicholas J. Wareham,Brenda W.J.H. Penninx,Brenda W.J.H. Penninx,Brenda W.J.H. Penninx,Ilja M. Nolte,Martin W. McBride,William H. Miller,Stuart A. Nicklin,Andrew H. Baker,Delyth Graham,Robert A. McDonald,Jill P. Pell,Naveed Sattar,Paul Welsh,Patricia B. Munroe,Mark J. Caulfield,Alberto Zanchetti,Anna F. Dominiczak +82 more
TL;DR: The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.
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