Genome-wide association studies reconstructing chronic kidney disease

ABSTRACT Chronic kidney disease (CKD) is a major health problem with an increasing epidemiological burden, and is the 16th leading cause of years of life lost worldwide. It is estimated that more than 10% of the population have a variable stage of CKD, while about 850 million people worldwide are affected. Nevertheless, public awareness remains low, clinical access is inappropriate in many circumstances and medication is still ineffective due to the lack of clear therapeutic targets. One of the main issues that drives these problems is the fact that CKD remains a clinical entity with significant causal ambiguity. Beyond diabetes mellitus and hypertension, which are the two major causes of kidney disease, there are still many gray areas in the diagnostic context of CKD. Genetics nowadays emerges as a promising field in nephrology. The role of genetic factors in CKD’s causes and predisposition is well documented and thousands of genetic variants are well established to contribute to the high burden of disease. Next-generation sequencing is increasingly revealing old and new rare variants that cause Mendelian forms of chronic nephropathy while genome-wide association studies (GWAS) uncover common variants associated with CKD-defining traits in the general population. In this article we review how GWAS has revolutionized—and continues to revolutionize—the old concept of CKD. Furthermore, we present how the investigation of common genetic variants with previously unknown kidney significance has begun to expand our knowledge on disease understanding, providing valuable insights into disease mechanisms and perhaps paving the way for novel therapeutic targets.