Genomic approaches for understanding the genetics of complex disease

William L Lowe Jr, Timothy E. Reddy*

*Corresponding author for this work

Research output: Contribution to journalReview article

38 Scopus citations

Abstract

There are thousands of known associations between genetic variants and complex human phenotypes, and the rate of novel discoveries is rapidly increasing. Translating those associations into knowledge of disease mechanisms remains a fundamental challenge because the associated variants are overwhelmingly in noncoding regions of the genome wherewe have fewguiding principles to predict their function. Intersecting the compendium of identified genetic associations with maps of regulatory activity across the human genome has revealed that phenotype-associated variants are highly enriched in candidate regulatory elements. Allele-specific analyses of gene regulation can further prioritize variants that likely have a functional effect on disease mechanisms; and emerging high-throughput assays to quantify the activity of candidate regulatory elements are a promising next step in that direction. Together, these technologies have created the ability to systematically and empirically test hypotheses about the function of noncoding variants and haplotypes at the scale needed for comprehensive and systematic follow-up of genetic association studies. Major coordinated efforts to quantify regulatory mechanisms across genetically diverse populations in increasingly realistic cell models would be highly beneficial to realize that potential.

Original languageEnglish (US)
Pages (from-to)1432-1441
Number of pages10
JournalGenome Research
Volume25
Issue number10
DOIs
StatePublished - Oct 1 2015

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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