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Systematic localization of common disease-associated variation in regulatory DNA.

ABSTRACT: 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.

SUBMITTER: Maurano MT

PROVIDER: S-EPMC3771521 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Systematic localization of common disease-associated variation in regulatory DNA.

Maurano Matthew T MT Humbert Richard R Rynes Eric E Thurman Robert E RE Haugen Eric E Wang Hao H Reynolds Alex P AP Sandstrom Richard R Qu Hongzhu H Brody Jennifer J Shafer Anthony A Neri Fidencio F Lee Kristen K Kutyavin Tanya T Stehling-Sun Sandra S Johnson Audra K AK Canfield Theresa K TK Giste Erika E Diegel Morgan M Bates Daniel D Hansen R Scott RS Neph Shane S Sabo Peter J PJ Heimfeld Shelly S Raubitschek Antony A Ziegler Steven S Cotsapas Chris C Sotoodehnia Nona N Glass Ian I Sunyaev Shamil R SR Kaul Rajinder R Stamatoyannopoulos John A JA

Science (New York, N.Y.) 20120905 6099

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 phen ...[more]

PMID: 22955828

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Project description:Genome-wide association studies (GWAS) have successfully identified 145 genomic regions that contribute to schizophrenia risk, but linkage disequilibrium (LD) makes it challenging to discern causal variants. Computational finemapping prioritized thousands of credible variants, ~98% of which lie within poorly characterized non-coding regions. To functionally validate their regulatory effects, we performed a massively parallel reporter assay (MPRA) on 5,173 finemapped schizophrenia GWAS variants in primary human neural progenitors (HNPs). We identified 440 variants with allelic regulatory effects (MPRA-positive variants), with 72% of GWAS loci containing at least one MPRA-positive variant. Transcription factor binding had modest predictive power for predicting the allelic activity of MPRA-positive variants, while GWAS association, finemap posterior probability, enhancer overlap, and evolutionary conservation failed to predict MPRA-positive variants. Furthermore, 64% of MPRA-positive variants did not exhibit eQTL signature, suggesting that MPRA could identify yet unexplored variants with regulatory potentials. MPRA-positive variants differed from eQTLs, as they were more frequently located in distal neuronal enhancers. Therefore, we leveraged neuronal 3D chromatin architecture to identify 273 genes that physically interact with MPRA-positive variants. These genes annotated by chromatin interactome displayed higher mutational constraints and regulatory complexity than genes annotated by eQTLs, recapitulating a recent finding that eQTL- and GWAS-detected variants map to genes with different properties. Finally, we propose a model in which allelic activity of multiple variants within a GWAS locus can be aggregated to predict gene expression by taking chromatin contact frequency and accessibility into account. In conclusion, we demonstrate that MPRA can effectively identify functional regulatory variants and delineate previously unknown regulatory principles of schizophrenia.

Dataset Information

Systematic localization of common disease-associated variation in regulatory DNA.

Publications

Systematic localization of common disease-associated variation in regulatory DNA.

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