Polygenic Risk Scores and C4 Expression

Polygenic risk scores (PRS) were calculated for EUR subjects. Genotype imputation was performed on the Michigan Imputation Server [69 (link)] using the TOPMed reference panel. Quality control included filtering for genotyping rate > 0.99, sample missingness < 0.01, Hardy-Weinberg Equilibrium P > 1 × 10⁻⁶, minor allele frequency > 1%, and imputation score > 0.8. GCTA v1.93.31 [70 (link)] was used to compute the genetic relationship matrix; a relatedness cutoff of 0.05 was applied. Genetic variants in the major histocompatibility complex (MHC) locus were excluded prior to PRS calculation. PRS were generated using summary statistics from the largest available genome-wide association study of schizophrenia [10 (link)] (40,675 cases, 64,643 controls) and adult brain surface area [71 ] (33,992 subjects) in PRS-CS [72 ], applying the LD reference panel from the 1000 Genomes Project phase 3 samples and the recommended global shrinkage parameter for highly polygenic traits (phi = 1e−2). Analyses assessing the interaction between C4 expression and PRS were restricted to youth with common C4 structural haplotypes (AL, AL-AL, AL-BL, AL-BS, BS), resulting in a final sample of 3730 EUR youth (female N = 1737; male N = 1993) and 7,715,663 genetic variants.