title: Extensive Association of Common Disease Variants with Regulatory Sequence.
abstract: Overlap between non-coding DNA regulatory sequences and common variant associations can help to identify specific cell and tissue types that are relevant for particular diseases. In a systematic manner, we analyzed variants from 94 genome-wide association studies (reporting at least 12 loci at p<5x10-8) by projecting them onto 466 epigenetic datasets (characterizing DNase I hypersensitive sites; DHSs) derived from various adult and fetal tissue samples and cell lines including many biological replicates. We were able to confirm many expected associations, such as the involvement of specific immune cell types in immune-related diseases and tissue types in diseases that affect specific organs, for example, inflammatory bowel disease and coronary artery disease. Other notable associations include adrenal glands in coronary artery disease, the immune system in Alzheimer's disease, and the kidney for bone marrow density. The association signals for some GWAS (for example, myopia or age at menarche) did not show a clear pattern with any of the cell or tissue types studied. In general, the identified variants from GWAS tend to be located outside coding regions. Altogether, we have performed an extensive characterization of GWAS signals in relation to cell and tissue-specific DHSs, demonstrating a key role for regulatory mechanisms in common diseases and complex traits.
authors.affiliation: Division of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, 3584 EA, The Netherlands.
authors.forename: Michal
authors.initials: M
authors.lastname: Mokry
authors.affiliation: Department of Cardiology, Division Heart and Lungs, University Medical Centre Utrecht, Utrecht, 3508 GA, The Netherlands.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Harakalova
authors.affiliation: Department of Cardiology, Division Heart and Lungs, University Medical Centre Utrecht, Utrecht, 3508 GA, The Netherlands.|Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, 3501 DG, The Netherlands.|Institute of Cardiovascular Science, faculty of Population Health Sciences, University College London, London, WC1E 6BT, United Kingdom.
authors.forename: Folkert W
authors.initials: FW
authors.lastname: Asselbergs
authors.affiliation: Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, 3508 GA, The Netherlands.|Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, 3508 GA, The Netherlands.
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.affiliation: Division of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, 3584 EA, The Netherlands.
authors.forename: Edward E S
authors.initials: EE
authors.lastname: Nieuwenhuis
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000235:genetics*; D003324:Coronary Artery Disease / Q000235:genetics*; D030561:Databases, Nucleic Acid; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007154:Immune System Diseases / Q000235:genetics*; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D008297:Male; D012045:Regulatory Sequences, Nucleic Acid