LAUSR

Biomarkers are often used to diagnose and monitor chronic diseases, and greater understanding of how genetic variants associate with biomarker levels has potential to aid risk stratification and identify new therapeutic targets. an analysis of data from the uK Biobank has now provided new insights into the influence of genetic variants on biomarker levels and their relevance to disease phenotype. the analysis involved assessment of 35 biomarkers in 363,228 UK Biobank samples to identify biomarkerassociated loci, followed by phenomewide association analysis to assess whether the variants affect clinically relevant phenotypes. “Our main interest for pursuing this research is that biomarkers are as close as possible to a polygenic set of traits with clear biological connections from genetic association studies,” explains Manuel rivas. “the large number of rare and lowfrequency coding variants within the uK Biobank genotyping array allowed us to identify strong acting coding variants that affect commonly measured biomarker levels in serum and urine.” the researchers identified a number of variants associated with the 12 kidney biomarkers analysed, including a proteintruncating variant in COL4A4 associated with microalbuminuria and kidney disease risk; a frameshift variant in SLC22A2 associated with creatinine levels; rare copy number variants overlapping HNF1B associated with serum urea, creatinine, cystatin C and chronic kidney disease (CKD) in a diabetesdependent manner; and missense alleles in SLC6A19, LRP2, ALDOB and SLC7A9 and two missense variants in SLC25A45, associated with creatininelowering and eGFrraising effects, which provide good therapeutic hypotheses. “Given the size of the uK Biobank we were also able to generate predictive polygenic risk scores (Prs) for the biomarkers using genotypic data alone,” says rivas. “Combining these Prs with diseaseoutcome Prs — an approach we refer to as multiPrs — improved our ability to stratify genetic risk for commonly studied diseases, including CKD.” the researchers intend to follow up on their analyses with exome and wholegenome sequencing data. they are also planning studies to improve biomarker and disease risk prediction in noneuropean populations. Susan J. Allison