Journal ArticleDOI
Parameters for reliable results in genetic association studies in common disease.
Ingrid Dahlman,Iain A. Eaves,Roman Kosoy,V. Anne Morrison,Joanne M. Heward,Stephen C. L. Gough,Amit Allahabadia,Jayne A. Franklyn,Jaakko Tuomilehto,Eva Tuomilehto-Wolf,Francesco Cucca,Cristian Guja,Constantin Ionescu-Tirgoviste,Helen Stevens,Philippa Carr,Sarah Nutland,Patricia McKinney,Julian P.H. Shield,William Y.S. Wang,Heather J. Cordell,Neil Walker,John A. Todd,Patrick Concannon +22 more
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TLDR
Using 2,873 families, a recently published association of the interleukin 12B gene in 422 type I diabetic families was unable to confirm, emphasizing the need for large datasets, small P values and independent replication if results are to be reliable.Abstract:
It is increasingly apparent that the identification of true genetic associations in common multifactorial disease will require studies comprising thousands rather than the hundreds of individuals employed to date. Using 2,873 families, we were unable to confirm a recently published association of the interleukin 12B gene in 422 type I diabetic families. These results emphasize the need for large datasets, small P values and independent replication if results are to be reliable.read more
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Journal ArticleDOI
Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease
H Ueda,Howson Jmm.,Laura Esposito,Joanne M. Heward,Hywel Snook,Giselle Chamberlain,Dan Rainbow,Hunter Kmd.,Anne Smith,G Di Genova,G Di Genova,Mathias H. Herr,Mathias H. Herr,Ingrid Dahlman,Ingrid Dahlman,F Payne,Deborah J. Smyth,Christopher E. Lowe,Twells Rcj.,Sarah Howlett,Barry C. Healy,Sarah Nutland,Helen E. Rance,Vincent H. Everett,Luc J. Smink,A C Lam,Heather J. Cordell,Neil Walker,C Bordin,John S. Hulme,Costantino Motzo,Francesco Cucca,J F Hess,Michael L. Metzker,Michael L. Metzker,Jane Rogers,Simon G. Gregory,Amit Allahabadia,Amit Allahabadia,R Nithiyananthan,Eva Tuomilehto-Wolf,Jaakko Tuomilehto,Polly J. Bingley,Kathleen M Gillespie,Dag E. Undlien,Kjersti S. Rønningen,Cristian Guja,Constantin Ionescu-Tirgoviste,David A. Savage,Alexander P. Maxwell,Dennis Carson,Christopher Patterson,Jayne A. Franklyn,David Clayton,Laurence B. Peterson,Linda S. Wicker,John A. Todd,Gough Scl. +57 more
TL;DR: In this article, the authors identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4) as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes.
Journal ArticleDOI
Problems of reporting genetic associations with complex outcomes.
TL;DR: It is suggested that the most important factors underlying inability to replicate these associations are publication bias, failure to attribute results to chance, and inadequate sample sizes, problems that are all rectifiable.
Journal ArticleDOI
Genome-wide association studies: theoretical and practical concerns
TL;DR: The main factors — including models of the allelic architecture of common diseases, sample size, map density and sample-collection biases — that need to be taken into account in order to optimize the cost efficiency of identifying genuine disease-susceptibility loci are outlined.
Journal ArticleDOI
Finding Genes That Underlie Complex Traits
TL;DR: This work proposes standards for proof of gene discovery in complex traits and evaluates the nature of the genes identified to date, and demonstrates the insights that can be expected from the accelerating pace of geneiscovery in this field.
Journal ArticleDOI
The Genetic Association Database
TL;DR: The development of a genetic association database (GAD) that aims to collect, standardize and archive genetic association study data and to make it easily accessible to the scientific community is described.
References
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Journal ArticleDOI
The Future of Genetic Studies of Complex Human Diseases
TL;DR: The identification of the genetic basis of complex human diseases such as schizophrenia and diabetes has proven difficult as mentioned in this paper, and Risch and Merikangas proposed that they can best accomplish this goal by combining the power of the human genome project with association studies.
Journal Article
Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM).
TL;DR: The statistical basis for this "transmission test for linkage disequilibrium" (transmission/disequilibrium test] is described and the relationship of this test to tests of cosegregation that are based on the proportion of haplotypes or genes identical by descent in affected sibs is shown.
Journal ArticleDOI
Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus
Simon T. Bennett,Anneke Lucassen,S C Gough,Elizabeth E. Powell,Dag E. Undlien,L E Pritchard,Marilyn E. Merriman,Y Kawaguchi,M J Dronsfield,M J Dronsfield,Flemming Pociot +10 more
TL;DR: Although it is shown that the insulin gene is expressed biallelically in the adult pancreas, it is presented preliminary evidence that the level of transcription in vivo is correlated with allelic variation within the VNTR.
Journal ArticleDOI
Large upward bias in estimation of locus-specific effects from genomewide scans
TL;DR: It is argued that attempts at bias correction give unsatisfactory results, and that pointwise estimation in an independent data set may be the only way of obtaining reliable estimates of locus-specific effect-and then only if one does not condition on statistical significance being obtained.
Journal ArticleDOI
Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele
Grant Morahan,Dexing Huang,Susie I. Ymer,Michael Cancilla,Katrina Stephen,Preeti Dabadghao,George A. Werther,Brian D. Tait,Leonard C. Harrison,Peter G. Colman +9 more
TL;DR: A new susceptibility locus, IDDM18, is reported, located near the interleukin-12 (IL-12)p40 gene, IL12B, which may influence T-cell responses crucial for either mediating or protecting against this and other autoimmune diseases.
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Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease
H Ueda,Howson Jmm.,Laura Esposito,Joanne M. Heward,Hywel Snook,Giselle Chamberlain,Dan Rainbow,Hunter Kmd.,Anne Smith,G Di Genova,G Di Genova,Mathias H. Herr,Mathias H. Herr,Ingrid Dahlman,Ingrid Dahlman,F Payne,Deborah J. Smyth,Christopher E. Lowe,Twells Rcj.,Sarah Howlett,Barry C. Healy,Sarah Nutland,Helen E. Rance,Vincent H. Everett,Luc J. Smink,A C Lam,Heather J. Cordell,Neil Walker,C Bordin,John S. Hulme,Costantino Motzo,Francesco Cucca,J F Hess,Michael L. Metzker,Michael L. Metzker,Jane Rogers,Simon G. Gregory,Amit Allahabadia,Amit Allahabadia,R Nithiyananthan,Eva Tuomilehto-Wolf,Jaakko Tuomilehto,Polly J. Bingley,Kathleen M Gillespie,Dag E. Undlien,Kjersti S. Rønningen,Cristian Guja,Constantin Ionescu-Tirgoviste,David A. Savage,Alexander P. Maxwell,Dennis Carson,Christopher Patterson,Jayne A. Franklyn,David Clayton,Laurence B. Peterson,Linda S. Wicker,John A. Todd,Gough Scl. +57 more