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Investigation of a genome wide association signal for obesity: synthetic association and haplotype analyses at the melanocortin 4 receptor gene locus.
PLoS One 2010; 5(11):e13967Plos

Abstract

BACKGROUND

Independent genome-wide association studies (GWAS) showed an obesogenic effect of two single nucleotide polymorphisms (SNP; rs12970134 and rs17782313) more than 150 kb downstream of the melanocortin 4 receptor gene (MC4R). It is unclear if the SNPs directly influence MC4R function or expression, or if the SNPs are on a haplotype that predisposes to obesity or includes functionally relevant genetic variation (synthetic association). As both exist, functionally relevant mutations and polymorphisms in the MC4R coding region and a robust association downstream of the gene, MC4R is an ideal model to explore synthetic association.

METHODOLOGY/PRINCIPAL FINDINGS

We analyzed a genomic region (364.9 kb) encompassing the MC4R in GWAS data of 424 obesity trios (extremely obese child/adolescent and both parents). SNP rs12970134 showed the lowest p-value (p = 0.004; relative risk for the obesity effect allele: 1.37); conditional analyses on this SNP revealed that 7 of 78 analyzed SNPs provided independent signals (p≤0.05). These 8 SNPs were used to derive two-marker haplotypes. The three best (according to p-value) haplotype combinations were chosen for confirmation in 363 independent obesity trios. The confirmed obesity effect haplotype includes SNPs 3' and 5' of the MC4R. Including MC4R coding variants in a joint model had almost no impact on the effect size estimators expected under synthetic association.

CONCLUSIONS/SIGNIFICANCE

A haplotype reaching from a region 5' of the MC4R to a region at least 150 kb from the 3' end of the gene showed a stronger association to obesity than single SNPs. Synthetic association analyses revealed that MC4R coding variants had almost no impact on the association signal. Carriers of the haplotype should be enriched for relevant mutations outside the MC4R coding region and could thus be used for re-sequencing approaches. Our data also underscore the problems underlying the identification of relevant mutations depicted by GWAS derived SNPs.

Authors+Show Affiliations

Institute of Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Essen, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21085626

Citation

Scherag, André, et al. "Investigation of a Genome Wide Association Signal for Obesity: Synthetic Association and Haplotype Analyses at the Melanocortin 4 Receptor Gene Locus." PloS One, vol. 5, no. 11, 2010, pp. e13967.
Scherag A, Jarick I, Grothe J, et al. Investigation of a genome wide association signal for obesity: synthetic association and haplotype analyses at the melanocortin 4 receptor gene locus. PLoS ONE. 2010;5(11):e13967.
Scherag, A., Jarick, I., Grothe, J., Biebermann, H., Scherag, S., Volckmar, A. L., ... Hinney, A. (2010). Investigation of a genome wide association signal for obesity: synthetic association and haplotype analyses at the melanocortin 4 receptor gene locus. PloS One, 5(11), pp. e13967. doi:10.1371/journal.pone.0013967.
Scherag A, et al. Investigation of a Genome Wide Association Signal for Obesity: Synthetic Association and Haplotype Analyses at the Melanocortin 4 Receptor Gene Locus. PLoS ONE. 2010 Nov 15;5(11):e13967. PubMed PMID: 21085626.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Investigation of a genome wide association signal for obesity: synthetic association and haplotype analyses at the melanocortin 4 receptor gene locus. AU - Scherag,André, AU - Jarick,Ivonne, AU - Grothe,Jessica, AU - Biebermann,Heike, AU - Scherag,Susann, AU - Volckmar,Anna-Lena, AU - Vogel,Carla Ivane Ganz, AU - Greene,Brandon, AU - Hebebrand,Johannes, AU - Hinney,Anke, Y1 - 2010/11/15/ PY - 2010/07/16/received PY - 2010/10/24/accepted PY - 2010/11/19/entrez PY - 2010/11/19/pubmed PY - 2011/4/28/medline SP - e13967 EP - e13967 JF - PloS one JO - PLoS ONE VL - 5 IS - 11 N2 - BACKGROUND: Independent genome-wide association studies (GWAS) showed an obesogenic effect of two single nucleotide polymorphisms (SNP; rs12970134 and rs17782313) more than 150 kb downstream of the melanocortin 4 receptor gene (MC4R). It is unclear if the SNPs directly influence MC4R function or expression, or if the SNPs are on a haplotype that predisposes to obesity or includes functionally relevant genetic variation (synthetic association). As both exist, functionally relevant mutations and polymorphisms in the MC4R coding region and a robust association downstream of the gene, MC4R is an ideal model to explore synthetic association. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed a genomic region (364.9 kb) encompassing the MC4R in GWAS data of 424 obesity trios (extremely obese child/adolescent and both parents). SNP rs12970134 showed the lowest p-value (p = 0.004; relative risk for the obesity effect allele: 1.37); conditional analyses on this SNP revealed that 7 of 78 analyzed SNPs provided independent signals (p≤0.05). These 8 SNPs were used to derive two-marker haplotypes. The three best (according to p-value) haplotype combinations were chosen for confirmation in 363 independent obesity trios. The confirmed obesity effect haplotype includes SNPs 3' and 5' of the MC4R. Including MC4R coding variants in a joint model had almost no impact on the effect size estimators expected under synthetic association. CONCLUSIONS/SIGNIFICANCE: A haplotype reaching from a region 5' of the MC4R to a region at least 150 kb from the 3' end of the gene showed a stronger association to obesity than single SNPs. Synthetic association analyses revealed that MC4R coding variants had almost no impact on the association signal. Carriers of the haplotype should be enriched for relevant mutations outside the MC4R coding region and could thus be used for re-sequencing approaches. Our data also underscore the problems underlying the identification of relevant mutations depicted by GWAS derived SNPs. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/21085626/Investigation_of_a_genome_wide_association_signal_for_obesity:_synthetic_association_and_haplotype_analyses_at_the_melanocortin_4_receptor_gene_locus_ L2 - http://dx.plos.org/10.1371/journal.pone.0013967 DB - PRIME DP - Unbound Medicine ER -