title: The missense variation landscape of FTO, MC4R, and TMEM18 in obese children of African Ancestry.
abstract: OBJECTIVE
  Common variation at the loci harboring fat mass and obesity (FTO), melanocortin receptor 4 (MC4R), and transmembrane protein 18 (TMEM18) is consistently reported as being statistically most strongly associated with obesity. Investigations if these loci also harbor rarer missense variants that confer substantially higher risk of common childhood obesity in African American (AA) children were conducted.
  
  
  METHODS
  The exons of FTO, MC4R, and TMEM18 in an initial subset of our cohort were sequenced, that is, 200 obese (BMI ≥ 95 th percentile) and 200 lean AA children (BMI ≤ 5 th percentile). Any missense exonic variants that were uncovered went on to be further genotyped in a further 768 obese and 768 lean (BMI≤50th percentile) children of the same ethnicity.
  
  
  RESULTS
  A number of exonic variants were observed from our sequencing effort: seven in FTO, of which four were non-synonymous (A163T, G182A, M400V, and A405V), thirteen in MC4R, of which six were non-synonymous (V103I, N123S, S136A, F202L, N240S, and I251L), and four in TMEM18, of which two were non-synonymous (P2S and V113L). Follow-up genotyping of these missense variants revealed only one significant difference in allele frequency between cases and controls, namely with N240S in MC4R (Fisher's exact P = 0.0001).
  
  
  CONCLUSIONS
  In summary, moderately rare missense variants within the FTO, MC4R, and TMEM18 genes observed in our study did not confer risk of common childhood obesity in African Americans except for a degree of evidence for one known loss-of-function variant in MC4R.
authors.affiliation: Division of Human Genetics, Research Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Deliard
authors.forename: Saarene
authors.initials: S
authors.lastname: Panossian
authors.forename: Frank D
authors.initials: FD
authors.lastname: Mentch
authors.forename: Cecilia E
authors.initials: CE
authors.lastname: Kim
authors.forename: Cuiping
authors.initials: C
authors.lastname: Hou
authors.forename: Edward C
authors.initials: EC
authors.lastname: Frackelton
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Bradfield
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Glessner
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhang
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Patrick M A
authors.initials: PM
authors.lastname: Sleiman
authors.forename: Rosetta M
authors.initials: RM
authors.lastname: Chiavacci
authors.forename: Robert I
authors.initials: RI
authors.lastname: Berkowitz
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhao
authors.forename: Struan F A
authors.initials: SF
authors.lastname: Grant
mesh_terms: D000293:Adolescent; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D044383:Black People / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005091:Exons; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D020125:Mutation, Missense; D009765:Obesity / Q000208:ethnology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*; D001741:Black or African American
chemical_list: D008565:Membrane Proteins; D011506:Proteins; D044105:Receptor, Melanocortin, Type 4; C530715:TMEM18 protein, human; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human