Genomic regions associated with alpha-fetoproteins identified through a population-scale study in the Taiwan biobank

Alpha-fetoprotein (AFP), a fetal plasma protein, serves as a diagnostic marker for hepatocellular carcinoma (HCC) and germ cell tumors, with prior genome-wide association studies (GWAS) identifying AFP and PPIP5K1 as associated with its levels. The aim of this study was to identify novel genetic loci associated with serum AFP levels in the Taiwanese population and to elucidate their potential regulatory mechanisms, particularly in liver tissue, by integrating GWAS with expression quantitative trait loci (eQTL) analyses. We conducted a two-stage GWAS of serum AFP levels using participants from the Taiwan Biobank. The discovery cohort included 18 267 individuals, and findings were replicated in an independent sample of 21 994 individuals. Linear mixed models were used to assess genome-wide associations, adjusting for age, sex, and population structure via principal components. Quality control measures were applied to both genotyped and imputed SNPs. To explore functional implications, eQTL analyses were performed using publicly available liver tissue data, focusing on liver-specific regulatory effects. We identified 57 candidate genes across 10 genomic regions on chromosomes 2, 3, 4, 15, 17, and 22. For instance, SNPs in genes like SMC6, SENP7, and TP53BP1 demonstrated significant associations with AFP levels, contributing previously unreported genetic variations. eQTL analysis linked 55 of these genes in regulatory functions, especially within liver tissues, supporting their involvement in AFP expression. Our findings, integrating GWAS and eQTL approaches, enhance understanding of AFP heritability and suggest diagnostic and therapeutic potential for HCC, pending further validation in personalized medicine contexts.