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Genome-wide association and multi-omics functional screens reveal the genetic architecture of foveal development

Foveal hypoplasia causes visual impairment across congenital eye disorders, yet the genetic programmes governing foveal development remain poorly characterised and no tractable model exists for foveal disease. In the first genome-wide association study of foveal hypoplasia, we identified 42 sentinel variants mapping to 54 effector genes supported by >= 2 criteria from a variant-to-gene framework incorporating developmental multi-omics. Disruption of six effector genes using mutant lines and CRISPR knockouts in the zebrafish high acuity zone recapitulates structural, functional, and ultrastructural hallmarks of foveal hypoplasia, establishing the first vertebrate disease model. Integration with human foetal single-cell and spatial transcriptomics reveals two temporal waves of effector gene expression and identifies Muller glia as critical mediators of foveal patterning. Phenome-wide analyses reveal foveal variants are pleiotropic with refractive, lenticular, and metabolic traits, connecting foveal development to anterior segment and systemic disease biology. These findings should inform mechanistic studies of macular disease.

Age as a moderator of a brief alcohol intervention among injury patients in Northern Tanzania

Background: Alcohol use is a leading modifiable risk factor for injury in sub-Saharan Africa. In Tanzania, young people ([≤]24 years) experience greater alcohol-related harm despite drinking less frequently than adults. Punguza Pombe kwa Afya Yako (PPKAY) is a culturally adapted, brief intervention for injury patients in Tanzania. This study examined whether age moderates its effectiveness. Methods: We conducted an exploratory secondary analysis of baseline and 3-month data from the PPKAY randomized trial among injury patients aged [≥]18 years at Kilimanjaro Christian Medical Centre, Tanzania. Eligible participants reporting alcohol use before injury, AUDIT [≥]8, or positive breathalyzer were randomized to usual care or PPKAY with SMS boosters. The primary outcome was binge drinking days. Count outcomes were analyzed using negative binomial regression with robust SEs and continuous outcomes using mixed-effects models. Effect modification was assessed using a three-way interaction (Time x intervention x Age). Results: Among 543 participants (mean age 36.8 years; 16.2% aged 18–24), age moderated the intervention effect for drinking days (IRR = 0.27, 95% CI 0.07 – 0.98; p = 0.046) and drinks consumed (IRR = 0.17, 95% CI 0.04 – 0.77; p = 0.021). The intervention reduced 4 drinking days (95% CI -7.1 to -0.8) and 27.5 drinks (95% CI -42.8 to -12.2) among young people, while adults showed reductions in both arms, without intervention-specific effect. Conclusion: The effects of ED-based brief alcohol interventions are not uniform, varying across both age groups and alcohol-related outcomes. We found a greater responsiveness in drinking frequency and quantity reported among young people.