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Arthritis Res Ther. 2018 Sep 29;20(1):216. doi: 10.1186/s13075-018-1721-x.

From association to mechanism in complex disease genetics: the role of the 3D genome.

Author information

1
Division of Genomics and Data Sciences, Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, OK, 73104, USA.
2
School of Electrical and Computer Engineering, University of Oklahoma, Devan Energy Hall 150, 110 West Boyd Street, Norman, OK, 73019, USA.
3
Division of Genomics and Data Sciences, Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, OK, 73104, USA. gaffneyp@omrf.org.

Abstract

Genome-wide association studies (GWAS) and fine mapping studies in autoimmune diseases have identified thousands of genetic variants, the majority of which are located in non-protein-coding enhancer regions. Enhancers function within the context of the three-dimensional (3D) genome to form long-range DNA looping events with target gene promoters that spatially and temporally regulate gene expression. Investigating the functional significance of GWAS variants in the context of the 3D genome is essential for mechanistic understanding of these variants and how they influence disease pathology by altering DNA looping between enhancers and the target gene promoters they regulate. In this review, we discuss the functional complexity of the 3D genome and the technological approaches used to characterize DNA looping events. We then highlight examples from the literature that illustrate how functional mapping of the 3D genome can assist in defining mechanisms that influence pathogenic gene expression. We conclude by highlighting future advances necessary to fully integrate 3D genome analyses into the functional workup of GWAS variants in the continuing effort to improve the health of patients with autoimmune diseases.

KEYWORDS:

3D genome; Autoimmune disease; Chromatin conformation; Complex genetic disease; DNA looping; Enhancer; Functional genomics; GWAS; Promoter

PMID:
30268153
PMCID:
PMC6162955
DOI:
10.1186/s13075-018-1721-x
[Indexed for MEDLINE]
Free PMC Article

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