Retinal arteriolar tortuosity as a candidate genetic window to inner-ear microvasculature: distributed sharing with blood pressure at CSK and PAWR and a roadmap for larger hearing GWAS

Background: The inner ear is supplied by the labyrinthine artery, which is functionally close to an end artery with limited collateral reserve. Microvascular abnormalities have been implicated in sudden sensorineural hearing loss (SSNHL) and age-related hearing loss, yet inner-ear microvasculature cannot be assessed in vivo and current hearing genome-wide association studies (GWAS) are underpowered. We evaluated the shared genetic architecture of retinal arteriolar tortuosity (retina_AT) with blood pressure, cerebral small vessel disease (cSVD) and hearing phenotypes, and examined whether retinal microvasculature could serve as a candidate genetic window to inner-ear microvasculature. Methods: We used linkage-disequilibrium score regression (LDSC) to estimate SNP heritability for 19 phenotypes and genome-wide genetic correlations (rg) for 11 prespecified pairs. We ran approximate Bayes-factor colocalization (coloc.abf) between 19 independent retinal loci and systolic blood pressure (SBP), together with 95% credible-set fine-mapping, UCSC gene annotation, colocalization with GTEx aortic and tibial-artery expression QTL (eQTL) data and with white-matter hyperintensities (WMH), hearing-GWAS power calculations, and univariable and multivariable Mendelian randomization (MR) of blood pressure and heart rate on hearing. Results: Only retina_AT with SBP was significant genome-wide (rg = 0.10, P = 4.2x10, FDR q = 0.00042). The strongest retinal locus, 13q34, did not colocalize (PP.H3 = 0.996; peaks about 267 kb apart; allelic heterogeneity), whereas two secondary loci colocalized strongly--CSK at 15q24 (PP.H4 = 0.98; 3/3 credible variants within CSK) and PAWR at 12q21 (PP.H4 = 0.99; 3/5 within PAWR)--supported by tissue-matched, moderate eQTL evidence (PP.H4 = 0.71-0.75). At 13q34, retina_AT with WMH was an adequately powered null (PP.H4 = 0.019; only this region and phenotype were tested). On the hearing side, sharing of the blood-pressure magnitude (rg {approx} 0.10) was a near-powered null (about 1.5-fold larger sample needed for 80% power under that assumption, versus about 15-fold for weak rg {approx} 0.03 sharing), and rg [≥] 0.12 was excluded; MR found no robust causal effect. Conclusions: Retinal arteriolar tortuosity shows limited, distributed genetic sharing with blood pressure at the vascular-tone genes CSK and PAWR; no sharing with WMH was observed at 13q34 (only this region was tested). Retinal microvasculature may serve as a candidate genetic window to inner-ear microvasculature, but this analogy awaits direct testing by larger, vessel-oriented hearing GWAS and inner-ear tissue functional studies.