RESUMO
The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.
Assuntos
Epigênese Genética/genética , Epigenômica , Genoma Humano/genética , Sequência de Bases , Linhagem da Célula/genética , Células Cultivadas , Cromatina/química , Cromatina/genética , Cromatina/metabolismo , Cromossomos Humanos/química , Cromossomos Humanos/genética , Cromossomos Humanos/metabolismo , DNA/química , DNA/genética , DNA/metabolismo , Metilação de DNA , Conjuntos de Dados como Assunto , Elementos Facilitadores Genéticos/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Histonas/metabolismo , Humanos , Especificidade de Órgãos/genética , RNA/genética , Valores de ReferênciaRESUMO
Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10(-8)) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.