MeQTL analysis of childhood obesity links epigenetics with a risk SNP rs17782313 near MC4R from meta-analysis

Abstract

Earlier GWAS has identified that rs17782313 near MC4R was associated with obesity. However, subsequent studies showed conflicting results, especially among childhood. Besides, the mechanisms underlying the association between rs17782313 and childhood obesity remain largely unexplored, and genetic and epigenetic may interact and together affect the development of childhood obesity. We conducted a comprehensive meta-analysis to assess the association between rs17782313 and childhood obesity. MeQTL and eQTL analysis was applied to explore the effect of rs17782313 on DNA methylation and MC4R expression. We found that rs17782313 near MC4R was associated with increased childhood obesity risk and BMI z-score in several inheritable models (P < 0.05). Additionally, the similar trend was observed among subgroups of Asians, Caucasian. Furthermore, meQTL and eQTL analysis indicated that individuals carrying rs17782313 TT genotype were significantly associated with increased methylation level of cg10097150 located in MC4R promoter and decreased expression of MC4R than those with CT/CC genotype (P = 1.7 × 10−4 and P = 1.9 × 10−3 respectively). Our results strongly confirmed that rs17782313 was associated with increased risk of childhood obesity. Furthermore, rs17782313 T allele was correlated with promoter hypermethylation and decreased expression of MC4R, thus involved in the development of childhood obesity.

Evaluation of the MC4R gene across eMERGE network identifies many unreported obesity-associated variants

“…Interestingly we noted negative eQTL of the BMI-increasing risk alleles for MC4R expression in brain tissue which could functionally explain a milder form of MC4R deficiency for these common variants, consistent with monogenic mutation effects. To our knowledge, the only functional study for MC4R upstream variants was performed in nonbrain tissue (intestinal tissue) showing increased eQTL expression of MC4R for BMI-risk allele (rs17782313-C) [ 41 ].…”

Prospective Study of Epigenetic Age Acceleration and Incidence of Cardiovascular Disease Outcomes in the ARIC Study (Atherosclerosis Risk in Communities)

“…DNA methylation patterns change over the life course in response to genetic and environmental stimuli, including diet, smoking, alcohol, physical activity, obesity, and stress. 1–8 Methylation at specific CpG sites may reflect cumulative exposure to major risk factors involved in the pathogenesis of complex, aging-related conditions such as cardiovascular disease (CVD).…”

Polimorfismos de los genes del sistema leptina-melanocortina asociados con la obesidad en la población adulta de Barranquilla

“…Lo mismo sucede con el polimorfismo rs17782313 del gen MC4R , el cual se ha asociado con un elevado IMC ( 8 , 28 , ( 29 ) y con la aparición temprana de obesidad grave 9 . Se ha sugerido que los portadores del genotipo TT de este polimorfismo tienen un nivel notablemente mayor de hipermetilación en el promotor de MC4R en comparación con los portadores de los genotipos CT y CC, lo que puede contribuir a regular la expresión de MC4R y, por consiguiente, al desarrollo de la obesidad 30 . Sin embargo, en otros estudios no se ha podido demostrar la asociación de este polimorfismo con la obesidad, como es el caso de las investigaciones en población polaca y africana 8 , 31 .…”