Identification of Novel Noncoding Genetic Variants of Serum Urate Using Whole-Genome Sequencing in 7,339 Chinese...

To investigate the genetic architecture of low-frequency and rare variants of serum urate (SU) in East Asian populations, and to clarify its role as a heritable and modifiable risk factor for gout and cardiometabolic diseases.

We conducted the largest two-stage, whole-genome sequencing-based, genome-wide scan for SU levels in East Asians, analyzing 9.1 million variants across 7,339 Han Chinese participants from the Healthy Zhejiang One Million People (HOPE) cohort.

We verified associations at common and low-frequency loci and identified a novel, replicable male-specific locus at MAN1A2, along with a candidate low-frequency male-specific locus at CPE. Furthermore, using the STAARpipeline framework, we probed rare missense and putative loss-of-function variant aggregates in genes such as SLC22A12, SLC2A9, and G6PC2, which were validated in our replication data set or the UK Biobank. Moreover, we identified and replicated novel associations with rare promoter variants near HDC and SLC22A12, highlighting their potential role in the context of noncoding regulation. Additionally, deep learning-based fine-mapping revealed transcription factors such as HNF1A, RUNX1, and SRF as potential up-regulators of SU-associated genes.

By resolving East Asian-specific allelic architecture and revealing ancestral diversity in SU genetics, this study advanced translational opportunities for precision urate-lowering therapies and prioritized novel candidates for future research.