title: Common genetic variation in and near the melanocortin 4 receptor gene (MC4R) is associated with body mass index in American Indian adults and children.
abstract: Six rare functional coding mutations were previously identified in melanocortin 4 receptor (MC4R) in 6,760 American Indians. Individuals heterozygous for one of these mutations become obese while young. We now investigate whether common non-coding variation near MC4R also contributes to obesity. Fifty-six tag single-nucleotide polymorphisms (SNPs) were genotyped in 3,229 full-heritage Pima Indians, and nine of these SNPs which showed evidence for association were genotyped in additional 3,852 mixed-heritage American Indians. Associations of SNPs with maximum body mass index (BMI) in adulthood (n = 5,918), BMI z score in childhood (n = 5,350), percent body fat (n = 864), energy expenditure (n = 358) and ad libitum food intake (n = 178) were assessed. Conditional analyses demonstrated that SNPs, rs74861148 and rs483125, were independently associated with BMI in adulthood (β = 0.68 kg/m(2) per risk allele, p = 5 × 10(-5); β = 0.58 kg/m(2), p = 0.002, respectively) and BMI z score in childhood (β = 0.05, p = 0.02; β = 0.07, p = 0.01, respectively). One haplotype (frequency = 0.35) of the G allele at rs74861148 and the A allele at rs483125 provided the strongest evidence for association with adult BMI (β = 0.89 kg/m(2), p = 5.5 × 10(-7)), and was also associated with childhood BMI z score (β = 0.08, p = 0.001). In addition, a promoter SNP rs11872992 was nominally associated with adult BMI (β = 0.61 kg/m(2), p = 0.05) and childhood BMI z score (β = 0.11, p = 0.01), where the risk allele also modestly decreased transcription in vitro by 12 % (p = 0.005). This risk allele was further associated with increased percent body fat (β = 2.2 %, p = 0.002), increased food intake (β = 676 kcal/day, p = 0.007) and decreased energy expenditure (β = -53.4 kcal/day, p = 0.054). Common and rare variation in MC4R contributes to obesity in American Indians.
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 445 North 5th street, Phoenix, AZ, 85004, USA, ymuller@mail.nih.gov.
authors.forename: Yunhua L
authors.initials: YL
authors.lastname: Muller
authors.forename: Marie S
authors.initials: MS
authors.lastname: Thearle
authors.forename: Paolo
authors.initials: P
authors.lastname: Piaggi
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hanson
authors.forename: Duncan
authors.initials: D
authors.lastname: Hoffman
authors.forename: Brittany
authors.initials: B
authors.lastname: Gene
authors.forename: Darin
authors.initials: D
authors.lastname: Mahkee
authors.forename: Ke
authors.initials: K
authors.lastname: Huang
authors.forename: Sayuko
authors.initials: S
authors.lastname: Kobes
authors.forename: Susanne
authors.initials: S
authors.lastname: Votruba
authors.forename: William C
authors.initials: WC
authors.lastname: Knowler
authors.forename: Clifton
authors.initials: C
authors.lastname: Bogardus
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Baier
mesh_terms: D000293:Adolescent; D000328:Adult; D001130:Arizona; D001823:Body Composition / Q000235:genetics; D015992:Body Mass Index; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D008137:Longitudinal Studies; D008297:Male; D009154:Mutation; D009765:Obesity / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*; D012306:Risk; D055815:Young Adult
chemical_list: C470072:MC4R protein, human; D044105:Receptor, Melanocortin, Type 4
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