Multi-ancestry genome-wide association study of neutrophil-lymphocyte ratio and polygenic risk score development to explore causal association with diabetic retinopathy

BackgroundNeutrophil-lymphocyte Ratio (NLR) is a biomarker of inflammation and was associated with diabetic retinopathy (DR) in earlier studies. ObjectiveTo investigate the genetic loci influencing NLR and to estimate the heritability and causality of DR with the NLR polygenic risk score (PRS). DesignGenome-wide association study, conditional analysis, Fine and Gray model (FGR), Mendelian Randomization (MR) SettingScottish and South Indian populations drawn from population cohorts and electronic medical records. Participants29,317 individuals, with a considerable proportion diagnosed with diabetes. MeasurementsEffect estimates from GWAS to compute PRS and causal association with DR. ResultsHeritability estimates for the Scottish and Indian cohorts were 35.3% and 8.7% respectively. The top Single Nucleotide Polymorphisms (SNPs) in the multi-ancestry analysis (n=29,317) were intergenic: rs1825819 (Chr4:T/C) (Beta=-0.05, p=2.00x10-9), rs2980871 (Chr8:A/G) (Beta=0.04, p=4.64x10-8), rs2227322 (Chr17:C/G) (Beta=0.07, p=4.12x10-20) and rs4808047 (Chr19:T/C) (Beta= - 0.07, p=5.93x10-12). For the construction of best-fit PRS, we used 74,377 of 55,333,12 variants. There was a dose-response relationship between the PRS and NLR. The subhazard ratio (sHR) for NLR PRS association with DR was not statistically significant sHR=1.01 (95% CI: 0.97, 1.06, p=0.48). Null associations were observed in both cross-sectional and time-based MR analyses for PRS with DR. LimitationsA substantial proportion of the dataset was used for training the PRS algorithm. Due to trans-ancestry differences, PRS and subsequent analysis were conducted only in the Scottish cohorts. ConclusionsMultiple novel intergenic SNP associations were discovered, complementing those previously identified. Of these, some SNPs were also associated with genes known to regulate white blood cells, but not specifically NLR. More studies are required to confirm the causality between systemic inflammation and DR. Primary Funding SourceNational Institute for Health Research, Pioneer and Leading Goose R&D Program of Zhejiang 2023, and the Ningbo International Collaboration Program 2023.