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.

Keywords: Adolescence; epistasis; genetics; obesity.

Figure 1

Effect of interaction¹ between PRKD1 and FTO² on BMI-for-age Z-score in adolescence. Footnote: ¹Mixed effects model, BMI = β + βSNP1xSNP2 + βSNP1 + βSNP2 + βage + βsex + f + s + ε ²PRKD1 (rs11847697) risk allele (T), FTO (rs9939609) risk allele (A) – Dashed grey line: Main effect of FTO risk allele on Z-BMI with no influence from PRKD1 risk allele. Dotted dark grey line: Effect of 1 PRKD1 risk allele on the relationship between FTO and Z-BMI. Solid black line: Effect of 2 PRKD1 risk alleles on the FTO/Z-BMI association.