Systematic Localization of Common Disease-Associated Variation in Regulatory DNA

Predictions of Genetic Disease Many genome-wide association studies (GWAS) have identified loci and variants associated with disease, but the ability to predict disease on the basis of these genetic variants remains small. Maurano et al. (p. 1190; see the Perspective by Schadt and Chang; see the cover) characterize the location of GWAS variants in the genome with respect to their proximity to regulatory DNA [marked by deoxyribonuclease I (DNase I) hypersensitive sites] by tissue type, disease, and enrichments in physiologically relevant transcription factor binding sites and networks. They found many noncoding disease associations in regulatory DNA, indicating tissue and developmental-specific regulatory roles for many common genetic variants and thus enabling links to be made between gene regulation and adult-onset disease. Genetic variants that have been associated with diseases are concentrated in regulatory regions of the genome. Genome-wide association studies have identified many noncoding variants associated with common diseases and traits. We show that these variants are concentrated in regulatory DNA marked by deoxyribonuclease I (DNase I) hypersensitive sites (DHSs). Eighty-eight percent of such DHSs are active during fetal development and are enriched in variants associated with gestational exposure–related phenotypes. We identified distant gene targets for hundreds of variant-containing DHSs that may explain phenotype associations. Disease-associated variants systematically perturb transcription factor recognition sequences, frequently alter allelic chromatin states, and form regulatory networks. We also demonstrated tissue-selective enrichment of more weakly disease-associated variants within DHSs and the de novo identification of pathogenic cell types for Crohn’s disease, multiple sclerosis, and an electrocardiogram trait, without prior knowledge of physiological mechanisms. Our results suggest pervasive involvement of regulatory DNA variation in common human disease and provide pathogenic insights into diverse disorders.

[1]  M. King,et al.  Evolution at two levels in humans and chimpanzees. , 1975, Science.

[2]  F. Collins,et al.  A point mutation in the Aγ-globin gene promoter in Greek hereditary persistence of fetal haemoglobin , 1985, Nature.

[3]  D. S. Gross,et al.  Nuclease hypersensitive sites in chromatin. , 1988, Annual review of biochemistry.

[4]  P. Gluckman,et al.  Fetal nutrition and cardiovascular disease in adult life , 1993, The Lancet.

[5]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[6]  G I Bell,et al.  Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. , 2001, The New England journal of medicine.

[7]  G. Wray,et al.  Abundant raw material for cis-regulatory evolution in humans. , 2002, Molecular biology and evolution.

[8]  Naoto Endo,et al.  Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Dominic P. Kwiatkowski,et al.  In vivo characterization of regulatory polymorphisms by allele-specific quantification of RNA polymerase loading , 2003, Nature Genetics.

[10]  John D. Storey,et al.  Statistical significance for genomewide studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Michael R. Green,et al.  Transcriptional regulatory elements in the human genome. , 2006, Annual review of genomics and human genetics.

[12]  Alexander E. Kel,et al.  TRANSFAC® and its module TRANSCompel®: transcriptional gene regulation in eukaryotes , 2005, Nucleic Acids Res..

[13]  T. Taniguchi,et al.  The IRF family transcription factors in immunity and oncogenesis. , 2008, Annual review of immunology.

[14]  Cole Trapnell,et al.  Ultrafast and memory-efficient alignment of short DNA sequences to the human genome , 2009, Genome Biology.

[15]  L. Liang,et al.  Mapping complex disease traits with global gene expression , 2009, Nature Reviews Genetics.

[16]  Christian Gieger,et al.  A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium , 2009, Nature Genetics.

[17]  Christopher A. Haiman,et al.  The 8q24 cancer risk variant rs6983267 demonstrates long-range interaction with MYC in colorectal cancer , 2009, Nature Genetics.

[18]  P. Visscher,et al.  Common polygenic variation contributes to risk of schizophrenia and bipolar disorder , 2009, Nature.

[19]  Jonathan M. Mudge,et al.  The consensus coding sequence (CCDS) project: Identifying a common protein-coding gene set for the human and mouse genomes. , 2009, Genome research.

[20]  S. Sebert,et al.  Nutritional programming of the metabolic syndrome , 2009, Nature Reviews Endocrinology.

[21]  Martha L. Bulyk,et al.  UniPROBE: an online database of protein binding microarray data on protein–DNA interactions , 2008, Nucleic Acids Res..

[22]  Gonçalo R. Abecasis,et al.  The Sequence Alignment/Map format and SAMtools , 2009, Bioinform..

[23]  S. Brand.  Crohn’s disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn’s disease , 2009, Gut.

[24]  Olle Melander,et al.  From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus , 2010, Nature.

[25]  N. Cox,et al.  Trait-Associated SNPs Are More Likely to Be eQTLs: Annotation to Enhance Discovery from GWAS , 2010, PLoS genetics.

[26]  Tariq Ahmad,et al.  Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci , 2010, Nature Genetics.

[27]  D. Altshuler,et al.  A map of human genome variation from population-scale sequencing , 2010, Nature.

[28]  L. Peltonen,et al.  Lack of support for association between the KIF1B rs10492972[C] variant and multiple sclerosis , 2010, Nature Genetics.

[29]  Jingyuan Fu,et al.  Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction , 2010, Nature Genetics.

[30]  T. Mikkelsen,et al.  The NIH Roadmap Epigenomics Mapping Consortium , 2010, Nature Biotechnology.

[31]  Sharon R Grossman,et al.  Integrating common and rare genetic variation in diverse human populations , 2010, Nature.

[32]  David J. Arenillas,et al.  JASPAR 2010: the greatly expanded open-access database of transcription factor binding profiles , 2009, Nucleic Acids Res..

[33]  J. Stamatoyannopoulos,et al.  Chromatin accessibility pre-determines glucocorticoid receptor binding patterns , 2011, Nature Genetics.

[34]  Nathaniel D. Heintzman,et al.  9p21 DNA variants associated with Coronary Artery Disease impair IFNγ signaling response , 2011, Nature.

[35]  Kasper Lage,et al.  Pervasive Sharing of Genetic Effects in Autoimmune Disease , 2011, PLoS genetics.

[36]  A. Bar-Or,et al.  B cells in multiple sclerosis: connecting the dots. , 2011, Current opinion in immunology.

[37]  B. Stranger,et al.  Progress and Promise of Genome-Wide Association Studies for Human Complex Trait Genetics , 2011, Genetics.

[38]  William Stafford Noble,et al.  FIMO: scanning for occurrences of a given motif , 2011, Bioinform..

[39]  P. D. de Bakker,et al.  Genome‐wide meta‐analysis identifies novel multiple sclerosis susceptibility loci , 2011, Annals of neurology.

[40]  Joseph K. Pickrell,et al.  DNaseI sensitivity QTLs are a major determinant of human expression variation , 2011, Nature.

[41]  Matthew T. Maurano,et al.  Widespread Site-Dependent Buffering of Human Regulatory Polymorphism , 2012, PLoS genetics.

[42]  Nathan C. Sheffield,et al.  The accessible chromatin landscape of the human genome , 2012, Nature.

[43]  Richard S. Sandstrom,et al.  BEDOPS: high-performance genomic feature operations , 2012, Bioinform..

[44]  I. Grosse,et al.  A transcriptomic hourglass in plant embryogenesis , 2012, Nature.

[45]  Raymond K. Auerbach,et al.  Extensive Promoter-Centered Chromatin Interactions Provide a Topological Basis for Transcription Regulation , 2012, Cell.

[46]  Greg Gibson,et al.  Rare and common variants: twenty arguments , 2012, Nature Reviews Genetics.