Progranulin is a glycoprotein marking chronic inflammation in obesity and type 2 diabetes. Previous studies suggestedPSRC1(proline and serine rich coiled-coil 1) to be a target of genetic variants associated with serum progranulin levels. We aimed to identify potentially functional variants and characterize their role in regulation ofPSRC1. Phylogenetic module complexity analysis (PMCA) prioritized four polymorphisms (rs12740374, rs629301, rs660240, rs7528419) altering transcription factor binding sites with an overall score for potential regulatory function ofS(all) > 7.0. The effects of these variants on transcriptional activity and binding of transcription factors were tested by luciferase reporter and electrophoretic mobility shift assays (EMSA). In parallel, blood DNA promoter methylation of two regions was tested in subjects with a very high (N = 100) or a very low (N = 100) serum progranulin. Luciferase assays revealed lower activities in vectors carrying the rs629301-A compared with the C allele. Moreover, EMSA indicated a different binding pattern for the two rs629301 alleles, with an additional prominent band for the A allele, which was finally confirmed with the supershift for the Yin Yang 1 transcription factor (YY1). Subjects with high progranulin levels manifested a significantly higher mean DNA methylation (P < 1 x 10(-7)) in one promoter region, which was in line with a significantly lowerPSRC1mRNA expression levels in blood (P = 1 x 10(-3)). Consistently, rs629301-A allele was associated with lowerPSRC1mRNA expression (P < 1 x 10(-7)). Our data suggest that the progranulin-associated variant rs629301 modifies the transcription ofPSRC1through alteration of YY1 binding capacity. DNA methylation studies further support the role ofPSRC1in regulation of progranulin serum levels. Key messages(proline and serine rich coiled-coil 1) SNPs are associated with serum progranulin levels. rs629301 regulates expression by affecting Yin Yang 1 transcription factor (YY1) binding. is also epigenetically regulated in subjects with high progranulin levels.