An Exploratory Study of the Association Between UGT1A1*28 Polymorphism and Polygenic Scores for General Intelligence in a High-Coverage Whole Genome Sequencing Cohort

Unconjugated bilirubin (UCB), traditionally regarded as a metabolic waste product or a marker of hepatic dysfunction, is increasingly recognized as a potent endogenous antioxidant with neuroprotective properties. Individuals with Gilbert’s Syndrome, characterized by the homozygous UGT1A1*28 polymorphism (rs3064158), maintain mildly elevated UCB levels throughout their lives. This study investigates the hypothesis that this specific metabolic phenotype correlates with a higher polygenic predisposition for general cognitive ability (IQ). Utilizing raw, high-coverage (30x) Whole Genome Sequencing (WGS) data from the 1000 Genomes Project (NYGC, N=2503), we constructed Polygenic Risk Scores (PRS) for intelligence based on the most recent large-scale GWAS summary statistics (Okbay et al., 2022). We implemented a rigorous bioinformatic pipeline to resolve the complex indel structure of the UGT1A1 promoter, which is frequently misclassified in standard array-based studies. After controlling for population stratification via Principal Component Analysis (PC1-PC5) and excluding physical Linkage Disequilibrium by removing the entire Chromosome 2 from the model, we observed a significant positive correlation (r=0.11, p=0.0105) between the UGT1A1*28 genotype and polygenic cognitive potential in the European cohort (N=586). The analysis revealed an overdominance effect (heterozygote advantage), where carriers of a single allele (genotype TA6/TA7) exhibited PRS results on average 20.28% higher than the group with a normal genotype. These findings, confirmed by a 1,000,000-iteration Monte Carlo permutation test (empirical p=0.0103), suggest the existence of an optimal metabolic window for cognitive potential expression and indicate the relevance of incorporating metabolic markers in psychiatric differential diagnosis.