Genetic Association of Lipids and Lipid-Lowering Drug Target Genes With Attention Deficit Hyperactivity Disorder

Lipid metabolism plays an essential role in nervous system development. Cholesterol deficiency leads to a variety of neurodevelopmental disorders, such as autism spectrum disorder and fragile X syndrome. There have been a lot of efforts to search for biological markers associated with and causal to ADHD, among which lipid is one possible etiological factor that is quite widely studied. We aimed to evaluate the causal relationship between lipids traits, lipid-lowering drugs, and attention deficit hyperactivity disorder (ADHD) outcomes using Mendelian randomization (MR) studies.

We used summary data from genome-wide association studies to explore the causal relationships between circulating lipid-related traits and ADHD. Then, quantitative trait loci for the expression of lipid-lowering drug target genes and genetic variants associated with lipid traits were extracted. Summary-data-based MR and inverse-variance-weighted MR (IVW-MR) were used to investigate the correlation between the expression of these drug-target genes and ADHD.

After rigorous screening, 939 instrumental variables were finally included for univariable mendelian randomization analysis. However, there is no correlation between lipid profile and ADHD risk. Drug target analysis by IVW-MR method observed that APOB-mediated low-density lipoprotein cholesterol was associated with lower ADHD risk (odds ratio [OR] = 0.90, 95% confidence interval [CI] [0.84, 0.97]; p = .007), whereas LPL-mediated triglycerides levels were associated with a higher risk of ADHD (OR = 1.13, 95% CI [1.06, 1.21]; p < .001).

Our results suggest that APOB gene and LPL gene may be candidate drug target genes for the treatment of ADHD.