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Hum Mol Genet. 2014 Oct 1;23(19):5061-8. doi: 10.1093/hmg/ddu227. Epub 2014 May 12.

Abundant local interactions in the 4p16.1 region suggest functional mechanisms underlying SLC2A9 associations with human serum uric acid.

Author information

1
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK, Arthritis Research UK Centre for Genetics and Genomics, Institute of Inflammation and Repair, Faculty of Medical and Human Sciences, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester M13 9PT, UK, wenhua.wei@manchester.ac.uk.
2
Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, USA.
3
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
4
Department of Biochemistry, University of Otago, PO Box 56, Dunedin, New Zealand.

Abstract

Human serum uric acid concentration (SUA) is a complex trait. A recent meta-analysis of multiple genome-wide association studies (GWAS) identified 28 loci associated with SUA jointly explaining only 7.7% of the SUA variance, with 3.4% explained by two major loci (SLC2A9 and ABCG2). Here we examined whether gene-gene interactions had any roles in regulating SUA using two large GWAS cohorts included in the meta-analysis [the Atherosclerosis Risk in Communities study cohort (ARIC) and the Framingham Heart Study cohort (FHS)]. We found abundant genome-wide significant local interactions in ARIC in the 4p16.1 region located mostly in an intergenic area near SLC2A9 that were not driven by linkage disequilibrium and were replicated in FHS. Taking the forward selection approach, we constructed a model of five SNPs with marginal effects and three epistatic SNP pairs in ARIC-three marginal SNPs were located within SLC2A9 and the remaining SNPs were all located in the nearby intergenic area. The full model explained 1.5% more SUA variance than that explained by the lead SNP alone, but only 0.3% was contributed by the marginal and epistatic effects of the SNPs in the intergenic area. Functional analysis revealed strong evidence that the epistatically interacting SNPs in the intergenic area were unusually enriched at enhancers active in ENCODE hepatic (HepG2, P = 4.7E-05) and precursor red blood (K562, P = 5.0E-06) cells, putatively regulating transcription of WDR1 and SLC2A9. These results suggest that exploring epistatic interactions is valuable in uncovering the complex functional mechanisms underlying the 4p16.1 region.

PMID:
24821702
PMCID:
PMC4159153
DOI:
10.1093/hmg/ddu227
[Indexed for MEDLINE]
Free PMC Article

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