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Trends Genet. 2014 Apr;30(4):140-9. doi: 10.1016/j.tig.2014.02.006. Epub 2014 Mar 22.

Laying a solid foundation for Manhattan--'setting the functional basis for the post-GWAS era'.

Author information

1
Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH, USA.
2
The Princess Margaret Cancer Centre - University Health Network, Toronto, ON, M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
3
The Princess Margaret Cancer Centre - University Health Network, Toronto, ON, M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Ontario Institute for Cancer Research, Toronto, ON, Canada. Electronic address: mlupien@uhnres.utoronto.ca.

Abstract

Genome-wide association studies (GWAS) have identified more than 8900 genetic variants, mainly single-nucleotide polymorphisms (SNPs), associated with hundreds of human traits and diseases, which define risk-associated loci. Variants that map to coding regions can affect protein sequence, translation rate, and alternative splicing, all of which influence protein function. However, the vast majority of sequence variants map to non-coding intergenic and intronic regions, and it has been much more challenging to assess the functional nature of these variants. Recent work annotating the non-coding regions of the genome has contributed to post-GWAS studies by facilitating the identification of the functional targets of risk-associated loci. Many non-coding genetic variants within risk-associated loci alter gene expression by modulating the activity of cis-regulatory elements. We review here these recent findings, discuss their implication for the post-GWAS era, and relate their importance to the interpretation of disease-associated mutations identified through whole-genome sequencing.

KEYWORDS:

GWAS; causal variant; functional genomic; genetic risk variant; missing heritability; non-coding

PMID:
24661571
PMCID:
PMC4026049
DOI:
10.1016/j.tig.2014.02.006
[Indexed for MEDLINE]
Free PMC Article

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