title: Abundant local interactions in the 4p16.1 region suggest functional mechanisms underlying SLC2A9 associations with human serum uric acid.
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.
authors.affiliation: 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.
authors.forename: Wen-Hua
authors.initials: WH
authors.lastname: Wei
authors.affiliation: Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, USA.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Guo
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
authors.forename: Alida S D
authors.initials: AS
authors.lastname: Kindt
authors.affiliation: Department of Biochemistry, University of Otago, PO Box 56, Dunedin, New Zealand.
authors.forename: Tony R
authors.initials: TR
authors.lastname: Merriman
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Semple
authors.affiliation: Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
authors.forename: Chris S
authors.initials: CS
authors.lastname: Haley
mesh_terms: D002460:Cell Line; D002894:Chromosomes, Human, Pair 4; D019295:Computational Biology; D004742:Enhancer Elements, Genetic; D004843:Epistasis, Genetic; D005260:Female; D055106:Genome-Wide Association Study; D023281:Genomics; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008957:Models, Genetic; D015233:Models, Statistical; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable; D014527:Uric Acid / Q000097:blood*
chemical_list: D051246:Glucose Transport Proteins, Facilitative; C411811:SLC2A9 protein, human; D014527:Uric Acid