title: Influence of SNP*SNP interaction on BMI in European American adolescents: findings from the National Longitudinal Study of Adolescent Health.
abstract: BACKGROUND
  Adolescent obesity is predictive of future weight gain, obesity and adult onset severe obesity (body mass index [BMI] ≥40 kg m(-2) ). Despite successful efforts to identify Single Nucleotide Polymorphisms (SNPs) influencing BMI, <5% of the 40-80% heritability of the phenotype has been explained. Identification of gene-gene (G-G) interactions between known variants can help explain this hidden heritability as well as identify potential biological mechanisms affecting weight gain during this critical developmental period.
  
  
  OBJECTIVE
  We have recently shown distinct genetic effects on BMI across the life course, and thus it is important to examine the evidence for epistasis in adolescence.
  
  
  METHODS
  In adolescent participants of European descent from wave II of the National Longitudinal Study of Adolescent Health (Add Health, n = 5072, ages 12-21, 52.5% female), we tested 34 established BMI-related SNPs for G-G interaction effects on BMI z-score. We used mixed-effects regression, assuming multiplicative interaction models adjusting for age, sex and geographic region, with random effects for family and school.
  
  
  RESULTS
  For 28 G-G interactions that were nominally significant (P < 0.05), we attempted to replicate our results in an adolescent sample from the Childhood European American Cohort from Philadelphia. In the replication study, one interaction (PRKD1-FTO) was significant after correction for multiple testing.
  
  
  CONCLUSIONS
  Our results are suggestive of epistatic effects on BMI during adolescence and point to potentially interactive effects between genes in biological pathways important in obesity.
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.|Carolina Population Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: K L
authors.identifier: http://orcid.org/0000-0003-0070-6145
authors.initials: KL
authors.lastname: Young
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.|Carolina Population Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: M
authors.initials: M
authors.lastname: Graff
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.|Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: North
authors.affiliation: Carolina Population Center, University of North Carolina, Chapel Hill, NC, USA.|Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Richardson
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Bradfield
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia, Research Institute, Philadelphia, PA, USA.
authors.forename: S F A
authors.initials: SF
authors.lastname: Grant
authors.affiliation: Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC, USA.|Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Lange
authors.affiliation: Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC, USA.|Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Lange
authors.affiliation: Carolina Population Center, University of North Carolina, Chapel Hill, NC, USA.|Department of Sociology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Harris
authors.affiliation: Carolina Population Center, University of North Carolina, Chapel Hill, NC, USA.|Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: P
authors.initials: P
authors.lastname: Gordon-Larsen
mesh_terms: D000293:Adolescent; D000067697:Adolescent Health; D015992:Body Mass Index; D004843:Epistasis, Genetic / Q000235:genetics*; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D063766:Pediatric Obesity / Q000453:epidemiology* / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D014481:United States / Q000453:epidemiology; D015430:Weight Gain / Q000235:genetics*; D044465:White People; D055815:Young Adult
keywords: Adolescence; epistasis; genetics; obesity