Perspective: Quality Versus Quantity; Is It Important to Assess the Role of Enhancers in Complex Disease from an In Vivo Perspective?

Andrew R McEwan, Alasdair MacKenzie* (Corresponding Author)

*Corresponding author for this work

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Sequencing of the human genome has permitted the development of genome-wide association studies (GWAS) to analyze the genetics of a number of complex disorders such as depression, anxiety and substance abuse. Thanks to their ability to analyze huge cohort sizes, these studies have successfully identified thousands of loci associated with a broad spectrum of complex diseases. Disconcertingly, the majority of these GWAS hits occur in non-coding regions of the genome, much of which controls the cell-type-specific expression of genes essential to health. In contrast to gene coding sequences, it is a challenge to understand the function of this non-coding regulatory genome using conventional biochemical techniques in cell lines. The current commentary scrutinizes the field of complex genetics from the standpoint of the large-scale whole-genome functional analysis of the promoters and cis-regulatory elements using chromatin markers. We contrast these large scale quantitative techniques against comparative genomics and in vivo analyses including CRISPR/CAS9 genome editing to determine the functional characteristics of these elements and to understand how polymorphic variation and epigenetic changes within these elements might contribute to complex disease and drug response. Most importantly, we suggest that, although the role of chromatin markers will continue to be important in identifying and characterizing enhancers, more emphasis must be placed on their analysis in relevant in-vivo models that take account of the appropriate cell-type-specific roles of these elements. It is hoped that offering these insights might refocus progress in analyzing the data tsunami of non-coding GWAS and whole-genome sequencing “hits” that threatens to overwhelm progress in the field.
Original languageEnglish
Article number7856
Number of pages12
Journal International Journal of Molecular Sciences
Issue number21
Publication statusPublished - 23 Oct 2020


  • complex disease
  • gene regulation
  • chromatin modification
  • comparative genomics
  • CRISPR genome editing
  • promoter
  • enhancer
  • polymorphisms
  • mental health
  • alcohol abuse
  • pharmacogenomics
  • anxiety
  • Alcohol abuse
  • Enhancer
  • Gene regulation
  • Mental health
  • Comparative genomics
  • Complex disease
  • Polymorphisms
  • Promoter
  • Anxiety
  • Chromatin modification
  • Pharmacogenomics


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