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bioRxiv · 10.1101/315259

Genetic analyses in UK Biobank identifies 78 novel loci associated with urinary biomarkers providing new insights into the biology of kidney function and chronic disease

Zanetti, D.·Rao, A.·Gustafsson, S.·Assimes, T.·Montgomery, S. B.·Ingelsson, E.
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Abstract

BackgroundUrine biomarkers, such as creatinine, microalbumin, potassium and sodium are strongly associated with several common diseases including chronic kidney disease, cardiovascular disease and diabetes mellitus. Knowledge about the genetic determinants of the levels of these biomarker may shed light on pathophysiological mechanisms underlying the development of these diseases.\n\nMethodsWe performed genome-wide association studies of urinary levels of creatinine, microalbumin, potassium, and sodium in up to 326,441 unrelated individuals of European ancestry from the UK Biobank, a large population-based cohort study of over 500,000 individuals recruited across the United Kingdom in 2006-2010. Further, we explored genetic correlations, tissue-specific gene expression and possible causal genes related to these biomarkers.\n\nResultsWe identified 23 genome-wide significant independent loci associated with creatinine, 20 for microalbumin, 12 for potassium, and 38 for sodium. We confirmed several established associations including between the CUBN locus and microalbumin (rs141640975, p=3.11e-68). Variants associated with the levels of urinary creatinine, potassium, and sodium mapped to loci previously associated with obesity (GIPR, rs1800437, p=9.81e-10), caffeine metabolism (CYP1A1, rs2472297, p=1.61e-8) and triglycerides (GCKR, rs1260326, p=4.37e-16), respectively. We detected high pairwise genetic correlation between the levels of four urinary biomarkers, and significant genetic correlation between their levels and several anthropometric, cardiovascular, glycemic, lipid and kidney traits. We highlight GATM as causally implicated in the genetic control of urine creatinine, and GIPR, a potential diabetes drug target, as a plausible causal gene involved in regulation of urine creatinine and sodium.\n\nConclusionWe report 78 novel genome-wide significant associations with urinary levels of creatinine, microalbumin, potassium and sodium in the UK Biobank, confirming several previously established associations and providing new insights into the genetic basis of these traits and their connection to chronic diseases.\n\nAuthor SummaryUrine biomarkers, such as creatinine, microalbumin, potassium and sodium are strongly associated with several common diseases including chronic kidney disease, cardiovascular disease and diabetes mellitus. Knowledge about the genetic determinants of the levels of these biomarker may shed light on pathophysiological mechanisms underlying the development of these diseases. Here, we performed genome-wide association studies of urinary levels of creatinine, microalbumin, potassium and sodium in up to 326,441 unrelated individuals of European ancestry from the UK Biobank. Further, we explored genetic correlations, tissue-specific gene expression and possible causal genes related to these biomarkers. We identified 78 novel genome-wide significant associations with urinary biomarkers, confirming several previously established associations and providing new insights into the genetic basis of these traits and their connection to chronic diseases. Further, we highlight GATM as causally implicated in the genetic control of urine creatinine, and GIPR, a potential diabetes drug target, as a plausible causal gene involved in regulation of urine creatinine and sodium. The knowledge arising from our work may improve the predictive utility of the respective biomarker and point to new therapeutic strategies to prevent common diseases.

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Zanetti, D., Rao, A., Gustafsson, S., Assimes, T., Montgomery, S. B., Ingelsson, E.. 2018-05-05. Genetic analyses in UK Biobank identifies 78 novel loci associated with urinary biomarkers providing new insights into the biology of kidney function and chronic disease. https://doi.org/10.1101/315259

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