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. 2013 Sep 16;8(9):e74362.
doi: 10.1371/journal.pone.0074362. eCollection 2013.

Common Genetic Variation Near MC4R Has a Sex-Specific Impact on Human Brain Structure and Eating Behavior

Free PMC article

Common Genetic Variation Near MC4R Has a Sex-Specific Impact on Human Brain Structure and Eating Behavior

Annette Horstmann et al. PLoS One. .
Free PMC article


Obesity is associated with genetic and environmental factors but the underlying mechanisms remain poorly understood. Recent genome-wide association studies (GWAS) identified obesity- and type 2 diabetes-associated genetic variants located within or near genes that modulate brain activity and development. Among the top hits is rs17782313 near MC4R, encoding for the melanocortin-4-receptor, which is expressed in brain regions that regulate eating. Here, we hypothesized rs17782313-associated changes in human brain regions that regulate eating behavior. Therefore, we examined effects of common variants at rs17782313 near MC4R on brain structure and eating behavior. Only in female homozygous carriers of the risk allele we found significant increases of gray matter volume (GMV) in the right amygdala, a region known to influence eating behavior, and the right hippocampus, a structure crucial for memory formation and learning. Further, we found bilateral increases in medial orbitofrontal cortex, a multimodal brain structure encoding the subjective value of reinforcers, and bilateral prefrontal cortex, a higher order regulation area. There was no association between rs17782313 and brain structure in men. Moreover, among female subjects only, we observed a significant increase of 'disinhibition', and, more specifically, on 'emotional eating' scores of the Three Factor Eating Questionnaire in carriers of the variant rs17782313's risk allele. These findings suggest that rs17782313's effect on eating behavior is mediated by central mechanisms and that these effects are sex-specific.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.


Figure 1
Figure 1. Sex-specific effect of rs17782313 near MC4R on ‘disinhibition’ scores (interaction F2,177 = 4.7, p = .01).
Female homozygous carriers of the minor allele (CC) had significantly higher scores than both female heterozygous subjects (AC; difference in means 3.42, standard error 1.25, p = .024) and female subjects carrying no minor allele (AA; difference in means 4.93, standard error 1.22, p<.001). No significant difference was found for men (F2,107<1.5).
Figure 2
Figure 2. Sex-specific association between rs17782313 and gray matter volume (GMV).
Sex-specific effects of genotype at rs17782313 on GMV in the right amygdala/hippocampus (z-value 3.97, x = 14, y = −6, z = −22) and bilateral medial orbitofrontal cortex (OFC; left OFC: z-value 3.95, x = −12, y = 24, z = −22; right OFC: z-value 3.76, x = 12, y = 20, z = −20), adjusted for participant’s BMI, age, global gray and white matter volume (interaction between gender and genotype, voxel-wise threshold p<.005, cluster threshold p<.05, corrected for non-isotropic smoothness, indicated by red color). Female homozygous carriers of the minor allele (CC) had higher values than heterozygous subjects (AC) or non-carriers (AA, voxel-wise threshold p<.001, cluster threshold p<.05, corrected for non-isotropic smoothness). No significant difference was found for men.
Figure 3
Figure 3. Distribution of gray matter volume and ‘disinhibition’ scores for brain areas showing a significant interaction between gender and genotype.
Gray matter volume (GMV) in right amygdala (upper row), left orbitofrontal cortex (second row), left dorsolateral prefrontal cortex (third row) and right prefrontal cortex (bottom row) plotted against values on the ‘disinhibition’ subscale of the Three Factor Eating Questionnaire (TFEQ 51) for women (middle column) and men (right column) separately. Left column indicates the brain region where gray matter volume was extracted. Filled dark circles indicate homozygous carriers of the risk allele (CC) at rs17782313, filled gray circles indicate heterozygous subjects (AC) and open circles indicate homozygous carriers of the wildtype allele (AA). pr = partial correlation coefficient controlling for BMI, p = p-value of partial correlation analysis.

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    1. Thorleifsson G, Walters GB, Gudbjartsson DF, Steinthorsdottir V, Sulem P, et al. (2009) Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nature genetics 41: 18–24 doi: 10.1038/ng.274 - DOI - PubMed
    1. Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nature Neuroscience 8: 571–578 doi: 10.1038/nn1455 - DOI - PubMed
    1. Beckman TR, Shi Q, Levine AS, Billington CJ (2009) Amygdalar opioids modulate hypothalamic melanocortin-induced anorexia. Physiology & behavior 96: 568–573 doi: 10.1016/j.physbeh.2008.12.007 - DOI - PMC - PubMed
    1. Farooqi IS, Keogh JM, Yeo GSH, Lank EJ, Cheetham T (2003) Clinical Spectrum of Obesity and Mutations in the Melanocortin 4 Receptor Gene. The New England journal of medicine 348: 1085–1095. - PubMed
    1. Gelez H, Poirier S, Facchinetti P, Allers K a, Wayman C, et al. (2010) Neuroanatomical distribution of the melanocortin-4 receptors in male and female rodent brain. Journal of chemical neuroanatomy 40: 310–324 doi: 10.1016/j.jchemneu.2010.09.002 - DOI - PubMed

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Grant support

The work of AH, BP, MS, AV and YB is supported by the IFB Adiposity Diseases, Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01E01001 ( The work of AH, BP, MS and AV is funded by the German Research Foundation (DFG) (, within the framework of the CRC 1052 'Obesity Mechanisms'. PK is funded by a research grant from the Boehringer Ingelheim Foundation ( The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.