Pervasive sharing of genetic effects in autoimmune disease.
Chris Cotsapas,Benjamin F. Voight,Benjamin F. Voight,Elizabeth J. Rossin,Kasper Lage,Kasper Lage,Kasper Lage,Benjamin M. Neale,Chris Wallace,Gonçalo R. Abecasis,Jeffrey C. Barrett,Timothy W. Behrens,Judy H. Cho,Philip L. De Jager,Philip L. De Jager,James T. Elder,Robert R. Graham,Peter K. Gregersen,Lars Klareskog,Katherine A. Siminovitch,David A. van Heel,Cisca Wijmenga,Jane Worthington,John A. Todd,David A. Hafler,Stephen S. Rich,Mark J. Daly +26 more
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In this article, the authors evaluated the extent of this sharing for 107 immune disease-risk SNPs in seven diseases: celiac disease, Crohn's disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes.Abstract:
Genome-wide association (GWA) studies have identified numerous, replicable, genetic associations between common single nucleotide polymorphisms (SNPs) and risk of common autoimmune and inflammatory (immune-mediated) diseases, some of which are shared between two diseases. Along with epidemiological and clinical evidence, this suggests that some genetic risk factors may be shared across diseases-as is the case with alleles in the Major Histocompatibility Locus. In this work we evaluate the extent of this sharing for 107 immune disease-risk SNPs in seven diseases: celiac disease, Crohn's disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes. We have developed a novel statistic for Cross Phenotype Meta-Analysis (CPMA) which detects association of a SNP to multiple, but not necessarily all, phenotypes. With it, we find evidence that 47/107 (44%) immune-mediated disease risk SNPs are associated to multiple-but not all-immune-mediated diseases (SNP-wise P(CPMA)<0.01). We also show that distinct groups of interacting proteins are encoded near SNPs which predispose to the same subsets of diseases; we propose these as the mechanistic basis of shared disease risk. We are thus able to leverage genetic data across diseases to construct biological hypotheses about the underlying mechanism of pathogenesis.read more
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Systematic localization of common disease-associated variation in regulatory DNA.
Matthew T. Maurano,Richard Humbert,Eric Rynes,Robert E. Thurman,Eric Haugen,Hao Wang,Alex Reynolds,Richard Sandstrom,Hongzhu Qu,Hongzhu Qu,Jennifer A. Brody,Anthony Shafer,Fidencio Neri,Kristen Lee,Tanya Kutyavin,Sandra Stehling-Sun,Audra K. Johnson,Theresa K. Canfield,Erika Giste,Morgan Diegel,Daniel Bates,R. Scott Hansen,Shane Neph,Peter J. Sabo,Shelly Heimfeld,Antony Raubitschek,Steven F. Ziegler,Chris Cotsapas,Nona Sotoodehnia,Ian A. Glass,Shamil R. Sunyaev,Rajinder Kaul,John A. Stamatoyannopoulos +32 more
TL;DR: P pervasive involvement of regulatory DNA variation in common human disease and provide pathogenic insights into diverse disorders are suggested.
Journal ArticleDOI
An atlas of genetic correlations across human diseases and traits.
Brendan Bulik-Sullivan,Brendan Bulik-Sullivan,Hilary K. Finucane,Verneri Anttila,Verneri Anttila,Alexander Gusev,Felix R. Day,Po-Ru Loh,Po-Ru Loh,Laramie E. Duncan,Laramie E. Duncan,John R. B. Perry,Nick Patterson,Elise B. Robinson,Elise B. Robinson,Mark J. Daly,Mark J. Daly,Alkes L. Price,Alkes L. Price,Benjamin M. Neale,Benjamin M. Neale +20 more
TL;DR: This work introduces a technique—cross-trait LD Score regression—for estimating genetic correlation that requires only GWAS summary statistics and is not biased by sample overlap, and uses this method to estimate 276 genetic correlations among 24 traits.
Journal ArticleDOI
Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis
Jordan W. Smoller,Kenneth S. Kendler,Nicholas John Craddock,Phil Lee,Benjamin M. Neale,John I. Nurnberger,Stephan Ripke,Susan L. Santangelo,Patrick F. Sullivan,Shaun Purcell,Richard Anney,Jan K. Buitelaar,Ayman H. Fanous,Stephen V. Faraone,Witte J.G. Hoogendijk,Klaus-Peter Lesch,Douglas F. Levinson,Roy H. Perlis,Marcella Rietschel,Brien P. Riley,Edmund J.S. Sonuga-Barke,Russell Schachar,Thomas G. Schulze,Anita Thapar,Michael C. Neale,Patrick Bender,Sven Cichon,Mark J. Daly,John R. Kelsoe,Thomas Lehner,Michael Conlon O'Donovan,Pablo V. Gejman,Jonathan Sebat,Pamela Sklar +33 more
TL;DR: The findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset, and variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology.
Journal ArticleDOI
Five years of GWAS discovery
Peter M. Visscher,Peter M. Visscher,Matthew A. Brown,Mark I. McCarthy,Mark I. McCarthy,Jian Yang +5 more
TL;DR: The past five years have seen many scientific and biological discoveries made through the experimental design of genome-wide association studies (GWASs), which were aimed at detecting variants at genomic loci that are associated with complex traits in the population and, in particular, at detecting associations between common single-nucleotide polymorphisms (SNPs) and common diseases such as heart disease, diabetes, auto-immune diseases, and psychiatric disorders.
Journal ArticleDOI
An Expanded View of Complex Traits: From Polygenic to Omnigenic
TL;DR: It is proposed that gene regulatory networks are sufficiently interconnected such that all genes expressed in disease-relevant cells are liable to affect the functions of core disease-related genes and that most heritability can be explained by effects on genes outside core pathways.
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TL;DR: The many new candidate genes suggested by these results include IL10, IL19, IL20, GLIS3, CD69 and IL27.
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