Common Genetic Variants Associate with Serum Phosphorus Concentration

Phosphorusis an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorusconcentrations, genetic variation may determine interindividual variation in phosphorusmetabolism. Here, we report a comprehensive genome-wide association study of serum phosphorusconcentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Riskin Communities Study, Framingham Offspring Study, and the Rotterdam Study. We excluded participants with an estimated GFR 45 ml/min per 1.73 m 2 to focus on phosphorusmetabolism under normal conditions. We imputed genotypes to approximately 2.5 million single-nucleotide polymorphisms in the HapMap and combined study-specific findings using meta-analysis. We tested top polymorphisms from discovery cohorts in a 5444-person replication sample. Polymorphisms in seven loci with minor allele frequencies0.08 to 0.49 associate with serum phosphorusconcentration (P 3.5 10 16 to 3.6 10 7 ). Three loci were near genes encoding the kidney-specific type IIa sodium phosphateco-transporter (SLC34A1), the calcium-sensing receptor(CASR), and fibroblast growth factor 23(FGF23), proteins that contribute to phosphorusmetabolism. We also identified genes encoding phosphatases, kinases, and phosphodiesterases that have yetundetermined roles in phosphorushomeostasis. In the replication sample, five of seven top polymorphisms associatewith serum phosphorous concentrations (P 0.05 for each). In conclusion, common genetic variants associate with serum phosphorusin the general population. Further study of the loci identified in this study may help elucidate mechanisms of phosphorusregulation.