Shared Genetic Basis and Causal Relationship Between Television Watching, Breakfast Skipping and Type 2 Diabetes: Evidence From a Comprehensive Genetic Analysis

Abstract

Background: Epidemiological investigations have established unhealthy lifestyles, such as excessive leisurely sedentary behavior (especially TV/television watching) and breakfast skipping, increase the risk of type 2 diabetes (T2D), but the causal relationship is unclear. We aimed to understand how single nucleotide variants contribute to the co-occurrence of unhealthy lifestyles and T2D, thereby providing meaningful insights into disease mechanisms.

Methods: Combining summary statistics from genome-wide association studies (GWAS) on TV watching (N = 422218), breakfast skipping (N = 193860) and T2D (N = 159208) in European pedigrees, we conducted comprehensive pairwise genetic analysis, including high-definition likelihood (HDL-method), cross-phenotype association studies (CPASSOC), GWAS-eQTL colocalization analysis and transcriptome-wide association studies (TWAS), to understand the genetic overlap between them. We also performed bidirectional two-sample Mendelian randomization (MR) analysis for causal inference using genetic instrumental variables, and two-step MR mediation analysis was used to assess any effects explained by body mass index, lipid traits and glycemic traits.

Results: HDL-method showed that T2D shared a strong genetic correlation with TV watching (r_g = 0.26; P = 1.63×10^-29) and skipping breakfast (r_g = 0.15; P =2.02×10^-6). CPASSOC identifies eight independent SNPs shared between T2D and TV watching, including one novel shared locus. TWAS and CPASSOC showed that shared genes were enriched in lung, esophageal, adipose, and thyroid tissues and highlighted potential shared regulatory pathways for lipoprotein metabolism, pancreatic β-cell function, cellular senescence and multi-mediator factors. MR showed TV watching had a causal effect on T2D (β_IVW = 0.629, P_IVW = 1.80×10^-10), but no significant results were observed between breakfast skipping and T2D. Mediation analysis provided evidence that body mass index, fasting glucose, hemoglobin A1c and high-density lipoprotein are potential factors that mediate the causal relationship between TV and T2D.

Conclusions: Our findings provide strong evidence of shared genetics and causation between TV watching and T2D and facilitate our identification of common genetic architectures shared between them.

Keywords: Mendelian randomization; TV watching; breakfast skipping; genome genetic correlation; type 2 diabetes.

Figure 1

Conceptual diagram of Mendelian randomization and mediation analysis. (A) Mendelian randomization is based on the following three assumptions. (1) Genetic variants are strongly associated with exposure (p<5×10^-8); (2) instrumental variables can only act on the outcome through exposure, and there is no direct association with the outcome; and (3) instrumental variables are independent of any confounding factors. In this situation, c represents the total effect, SNV: single nucleotide variant. (B) Two-step Mendelian randomization, where a represents the effect of the exposure on the mediator; b represents the effect of mediator on the outcome; c’ represents the direct effect; and a and b are estimated separately using separate genetic instrumental variables for both the exposure and mediator. These estimates are then multiplied together to estimate the indirect effect of the mediator (a * b), and the direct effect c’ = c – a*b.

Figure 2

Numbers of significant genes related to TV watching and breakfast skipping and the number of shared genes with T2D. Significant genes were identified by P _Bonferroni < 0.05. GTEx, genotype-tissue expression project; GWAS, genome-wide association studies; TWAS, transcriptome-wide association study; NSTSG, Number of shared TWAS significant genes between traits; T2D: type 2 diabetes. (A) No. of TWAS Significant Genes for TV watching and No. of Overlapped Genes with T2D. (B) No. of TWAS Significant Genes for breakfast skipping and No. of Overlapped Genes with T2D.

Figure 3

Flowcharts visualizing the process for instrument definition, extraction and harmonization for the two-sample MR analyses conducted in the present study.