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Genetic association study of adiposity and melanocortin-4 receptor (MC4R) common variants: Replication and functional characterization of non-coding regions

Evans, DS and Calton, MA and Kim, MJ and Kwok, PY and Miljkovic, I and Harris, T and Koster, A and Liu, Y and Tranah, GJ and Ahituv, N and Hsueh, WC and Vaisse, C (2014) Genetic association study of adiposity and melanocortin-4 receptor (MC4R) common variants: Replication and functional characterization of non-coding regions. PLoS ONE, 9 (5).

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Abstract

Common genetic variants 3′ of MC4R within two large linkage disequilibrium (LD) blocks spanning 288 kb have been associated with common and rare forms of obesity. This large association region has not been refined and the relevant DNA segments within the association region have not been identified. In this study, we investigated whether common variants in the MC4R gene region were associated with adiposity-related traits in a biracial population-based study. Single nucleotide polymorphisms (SNPs) in the MC4R region were genotyped with a custom array and a genome-wide array and associations between SNPs and five adiposity-related traits were determined using race-stratified linear regression. Previously reported associations between lower BMI and the minor alleles of rs2229616/Val103Ile and rs52820871/Ile251Leu were replicated in white female participants. Among white participants, rs11152221 in a proximal 3′ LD block (closer to MC4R) was significantly associated with multiple adiposity traits, but SNPs in a distal 309 LD block (farther from MC4R ) were not. In a case-control study of severe obesity, rs11152221 was significantly associated. The association results directed our follow-up studies to the proximal LD block downstream of MC4R. By considering nucleotide conservation, the significance of association, and proximity to the MC4R gene, we identified a candidate MC4R regulatory region. This candidate region was sequenced in 20 individuals from a study of severe obesity in an attempt to identify additional variants, and the candidate region was tested for enhancer activity using in vivo enhancer assays in zebrafish and mice. Novel variants were not identified by sequencing and the candidate region did not drive reporter gene expression in zebrafish or mice. The identification of a putative insulator in this region could help to explain the challenges faced in this study and others to link SNPs associated with adiposity to altered MC4R expression. © 2014 Evans et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Evans, DS
Calton, MA
Kim, MJ
Kwok, PY
Miljkovic, IMiljkovicI@edc.pitt.eduIVM1
Harris, T
Koster, A
Liu, Y
Tranah, GJ
Ahituv, N
Hsueh, WC
Vaisse, C
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorHribal, Marta LetiziaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 12 May 2014
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 9
Number: 5
DOI or Unique Handle: 10.1371/journal.pone.0096805
Schools and Programs: Graduate School of Public Health > Epidemiology
Refereed: Yes
Date Deposited: 30 Jun 2014 15:07
Last Modified: 05 Feb 2019 11:55
URI: http://d-scholarship.pitt.edu/id/eprint/22009

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