The Impact of ACEs on BMI: An Investigation of the Genotype-Environment Effects of BMI

Abstract

Adverse Childhood Experiences are stressful and traumatic events occurring before the age of eighteen shown to cause mental and physical health problems, including increased risk of obesity. Obesity remains an ongoing national challenge with no predicted solution. We examine a subset of the Healthy Nevada Project, focusing on a multi-ethnic cohort of 15,886 sequenced participants with recalled adverse childhood events, to study how ACEs and their genotype-environment interactions affect BMI. Specifically, the Healthy Nevada Project participants sequenced by the Helix Exome+ platform were cross-referenced to their electronic medical records and social health determinants questionnaire to identify: 1) the effect of ACEs on BMI in the absence of genetics; 2) the effect of genotype-environment interactions on BMI; 3) how these gene-environment interactions differ from standard genetic associations of BMI. The study found very strong significant associations between the number of adverse childhood experiences and adult obesity. Additionally, we identified fifty-five common and rare variants that exhibited gene-interaction effects including three variants in the CAMK1D gene and four variants in LHPP; both genes are linked to schizophrenia. Surprisingly, none of the variants identified with interactive effects were in canonical obesity-related genes. Here we show the delicate balance between genes and environment, and how the two strongly influence each other.

Keywords: BMI; GWEIS; adverse child experiences; gene-environment interactions; schizophrenia.

FIGURE 1

ACE Relationship vs. BMI. This figure shows the relationship between the number of ACEs experienced and average BMI in each ACEs group, irrespective of age, sex, or ethnicity. The black line depicts the simple linear regression with slope 0.36 (p << 2 × 10⁻¹⁶) and y-intercept 28.03. Additionally, a simply one-way ANOVA shows a statistically significant difference in the BMI index between the ACE groups (p < 2 × 10⁻¹⁶).

FIGURE 2

Manhattan plot of significant GWEIS results. Each point in this figure represents a result of a single variant’s genotype-environment analysis. The x-axis represents the genomic position of each of 4,876,698 variants. The y-axis represents −log₁₀-transformed raw p-values of each genotypic association. For ease of viewing, only variants in genes above the horizontal line α = 1 × 10⁻⁵ are annotated.

FIGURE 3

GWEIS identification of rs12777434 interaction with ACEs. This figure shows the interactive effect of variant rs12777434 in CAMK1D. Homozygotes in the reference allele show a substantial increase in BMI for each number of ACEs encountered (0.24 kg/m ² ). However, with each copy of the minor allele, participants show much greater changes: 0.48 kg/m ² and 0.57 kg/m ² , respectively. Differences in BMI between the three genotypes are shown to be statistically significant at ACEs N = 0, 5, 9 at significance level α = 0.05, and at N = 6 and 7 ACEs at significance level α = 0.10, using simple one-way ANOVA analysis.