Ewan Birney

The fovea is the small depression at the neurosensory retina that underlies high-resolution central vision. It is vulnerable to disease and disruption of its architecture can lead to visual disability. Foveal morphology varies substantially across individuals but the molecular causes and functional consequences of this variation remain incompletely understood. Here, we analyse six foveal morphological parameters derived from optical coherence tomography (OCT) images of 39,521 UK Biobank participants. We find marked variation in foveal morphology and identify significant associations with sex and genetic ancestry. Genome-wide association studies identify 162 lead loci across the six foveal morphological parameters, implicating genes involved in pigmentation (including TYR , TSPAN10 and GPR143 ) and developmental patterning (including FGFR2 , CYP26C1 and CYP1A1 ). Heritability estimates range from 29 to 43%. Foveal pit volume is associated with future risk of age-related macular degeneration (AMD) (hazard ratio 1.09, p = 0.026), a finding supported by Mendelian randomisation. Given the strong correlations among foveal traits, the specificify of this association to pit volume remains unclear. These results establish foveal morphology as a highly heritable trait that is biologically linked to AMD.

Studying the genetics of intelligence provides insight into the neurobiology of cognitive function and rare neurodevelopmental conditions. Here we integrated fluid intelligence (FI) tests across different UK Biobank measures and imputed FI for unmeasured individuals, increasing the sample size from ~270,000 to >455,000. We show through extensive validation that the imputed phenotype genetically resembles measured FI, although some noncognitive signal likely remains. Combining measured and imputed FI increases the number of independent significant common SNP associations from 390 to 550 and reduces the ascertainment bias introduced by FI test participants being, on average, more educated. Rare variant analyses identify 26 significantly associated genes (false discovery rate < 1%), including 8 without strong prior evidence of involvement in intelligence or neurodevelopmental conditions, which replicate in aggregate in external cohorts. Our results demonstrate that imputed intelligence can boost power for genetic discovery and support its use to help discover new neurodevelopmental condition-associated genes.

BioStudies – one package for all the data supporting a study

BioStudies – one package for all the data supporting a study

The genetic program of animal development is conserved, but its rate of execution varies across species. Heterochrony, shifts in the relative timing of developmental events, generates phenotypic variation, but its prevalence and origin are unclear. Here, we compare two vertebrates with a 3-fold difference in developmental rate, zebrafish ( Danio rerio ) and medaka ( Oryzias latipes ) and characterize heterochrony with embryo-scale single-cell genomics. We generated an atlas of >1.2M single-cell transcriptomes of medaka from blastula to hatch and developed a new approach to represent medaka development in "zebrafish time", uncovering many cryptic, cell-level timing shifts not predicted by medaka's slower development. We confirm a divergent heterochrony in the medaka notochord using in vivo imaging, revealing that coupled acceleration and delay of sister cell types shapes the species-specific morphology of this tissue. Our results point to cell type-specific timing deviations as a reservoir of phenotypic variation and we propose that species-specific developmental rate can emerge from these cell-level differences.

The eye is a recognized source of biomarkers for cardiovascular and neurodegenerative disease risk. Here we characterize the breadth of these associations and identify biological axes that may mediate them. Using UK Biobank data, we developed a multi-omic analysis pipeline integrating physiological, radiomic, metabolomic and genomic information. We trained retinal adversarial autoencoders to represent optical coherence tomography images and color fundus photographs as 256-dimensional embeddings. Retinal adversarial autoencoder-derived embeddings were associated with a range of cardiovascular and neurodegenerative diseases, including ischemic heart disease, cerebrovascular disease, Parkinson’s disease and dementia. Examining associations across diverse omics datasets, we provide evidence linking ophthalmic imaging features to neurological and cardiovascular anatomy and function, lipid metabolism and gene sets associated with neurodegenerative pathology. Collectively, our findings show that ophthalmic features reflect complex, multisystem biological processes and reinforce the role of the eye as a composite indicator of systemic health.

Genetic support for drug targets substantially increases clinical success rates, establishing genome-wide association studies (GWAS) as central to therapeutic hypothesis generation. However, the same genetic evidence that reveals causal gene–disease relationships simultaneously exposes organism-level safety liabilities—a dimension requiring principled, genome-wide quantification. Here we systematically analyse 100,526 GWAS to yield 789,453 credible sets and gene prioritisations for 15,641 genes, with discovery showing no saturation as GWAS expand and increase diversity. We find that 64% of GWAS-implicated genes are pleiotropic, associated with traits across multiple diseases and showing a non-linear relationship between the degree of pleiotropy and clinical success. Highly pleiotropic genes—concentrated in immune, inflammatory, and oncogenic signalling programmes—are enriched in safety-terminated clinical programmes, mouse lethal knockouts, and cancer driver genes, establishing gene-level pleiotropy as a potential measure of genetically-informed organism-level safety liability. Protein-altering variant (PAV) support amplifies therapeutic signal (OR = 6.0), yet PAV targets show higher average pleiotropy, introducing a competing safety liability. Combining PAV support with intermediate pleiotropy (2–5 therapeutic areas) resolves this tension, yielding OR = 10.3 and relative success = 4.8—a profile already satisfied by 52 approved therapies. As GWAS continue to expand in scale and resolution, these findings lay the groundwork for increasingly sophisticated target discovery strategies that yield safer and more effective therapeutic hypotheses.

The optomotor response (OMR) provides a robust readout assay for evaluating visually guided locomotion and has been widely applied to various animal models. We present a scalable, high-throughput OMR platform with tuneable and moving stripe patterns simultaneously projected to the side of 50 petri dishes. The setup is optimized for hatchling-stage medaka ( Oryzias latipes and Oryzias sakaizumii ) and larval stage zebrafish ( Danio rerio ) and integrates custom software for automated generation of visual stimuli and specimen detection, enabling precise and automated quantification of optomotor behaviour across thousands of individuals. Using this platform, we systematically assess the visual performance of zebrafish and five medaka strains. By varying stripe width, direction, speed, contrast, and colour, we address spatial resolution, contrast, and colour sensitivity. Albino mutant medaka exhibited the highest sensitivity, responding at lower stripe widths and across a broader range of contrasts and chromatic conditions. Interestingly, some Cab and HO5 hatchlings displayed uni-directional response, revealing strain-specific visuomotor differences. Our platform enables reliable detection of OMR behaviour already at hatching and supports robust analysis of visuomotor function. The modular design, automated detection, analysis pipeline, and capacity for large sample numbers make it a powerful tool for comparative vision research, high-throughput genetic screening, and systematic behavioural profiling.