Genetic predisposition and alcohol consumption are risk factors for increased blood pressure (BP), but their interactions influencing BP remain understudied. We conducted population-specific and cross-population meta-analyses of genome-wide gene-alcohol (GxAlc) interactions affecting BP in >1.1M individuals from multiple populations. We identified 46 GxAlc interaction loci for BP, including 21 from one-degree-of-freedom interaction tests (PGxAlc<5×10-8; or <0.05/Meff, Meff independent BP associations at P<10-5), and 25 from two-degree-of-freedom tests of main and interaction effects (PGxAlc<0.05/M2df, M2df independent 2df-associations at P2df<5×10-8), including 7 novel and 39 known BP loci. The 12q24 locus highlights the genetic effect of BRAP-rs11066001 on BP, being ~6 times larger in current drinkers than in non-drinkers. Gene prioritization with 46 GxAlc loci identified 15 genes with ≥3 lines of evidence (location, literature, druggability, functional/regulatory annotation, or pathway analyses). Several loci showed sex- and population-specific effects and revealed biological pathways of alcohol's influence on BP, suggesting mechanisms underlying alcohol-induced hypertension.

BACKGROUND:Hypertrophic cardiomyopathy (HCM) is a heritable trait with marked variability in expression and outcomes. Our aims were to discover new genetic loci associated with HCM and to test the effect of a new polygenic risk score (PRS) on incidence, phenotype and outcomes stratified by genotype status. METHODS:A discovery genome-wide association study (GWAS) was performed on 2284 HCM cases and 4525 controls. Two fixed-effects meta-analyses combined our discovery GWAS with single-trait and multi-trait results from a published study. Discovered loci underwent comprehensive bioinformatic analysis including functional and druggability annotations. A PRS using loci from the two meta-analyses was evaluated for association with HCM diagnosis in 411 213 individuals from UK Biobank (UKBB); imaging phenotypes in individuals without HCM; a composite endpoint (including all-cause mortality and transplantation); and sudden cardiac death (SCD) in 1756 HCM cases. PRS analyses were stratified by genotype status. RESULTS:Three loci were found in the discovery GWAS (BAG3, FHOD3 and novel locus PPP1R3A). In the meta-analyses, 70 unique loci were identified, four novel (MYPN, YWHAE, NOS1AP and OBSCN). Bioinformatic analyses identified NOS1AP as a candidate HCM gene. A new PRS was significantly associated with HCM diagnosis (HR=3.19, 95% CI 2.46 to 4.14 for top 5% vs lower 95%; HR=1.88, 95% CI 1.72 to 2.06 per SD increase). Significant associations were found between PRS and greater left ventricular (LV) wall thickness and higher LV ejection fraction in UKBB participants without HCM. Genotype-negative HCM cases in the top 20% of the PRS distribution had an increased risk of SCD (HR=2.72, 95% CI 1.03 to 7.17). CONCLUSIONS:We report novel HCM loci. A new PRS predicted the risk of HCM development and associated imaging characteristics in the UKBB and outcomes in an HCM cohort.

Alcohol misuse is a major global health concern with significant genetic contributions, yet studies in African populations remain limited. We conducted genome-wide association meta-analyses for alcohol drinking initiation and cessation across multiple cohorts comprising individuals from sub-Saharan Africa (N = 20,936) and those with African ancestry from UK Biobank (N = 7,726). Our analyses identified two genome-wide significant loci associated with drinking cessation ( FYB2 and FTO regions) and several suggestive associations overlapping with genes implicated in alcohol metabolism, behavioral traits, and neurodevelopment. These findings provide insights into the genetic architecture of alcohol use behaviors in diverse African populations. By focusing on alcohol drinking initiation and cessation phenotypes, this study complements prior research on alcohol dependence and consumption, highlighting genetic factors influencing vulnerability and resilience. Our results underscore the importance of including diverse ancestries in genetic studies to enhance understanding of alcohol-related behaviors and inform future investigations into prevention and intervention strategies.

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 Müller 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.

BACKGROUND:Food allergy (FA) arises from a complex interplay between an individual's genetic predisposition and environmental factors, and its prevalence is increasing. Genome-wide association studies to date have been hindered by small sample sizes and varying FA definitions. OBJECTIVE:We sought to identify novel FA risk loci by conducting a genome-wide association study meta-analysis in children and adults by using a multiphenotype approach to ensure a good trade-off between sufficient sample size and valid FA definitions. METHODS:Analyses were conducted separately in children and adults on the basis of the following FA phenotypes: self-report, doctor diagnosis, food-specific sensitization, and doctor diagnosis plus food-specific sensitization. A meta-analysis was performed of genome-wide association studies from up to 16 cohorts of people of European ancestry including 229,426 adults and 14,234 children. Models were adjusted for sex, age, principal components, and, if applicable, further study-specific confounders. Sensitivity models were additionally adjusted for hay fever. Replication was conducted in additional external cohorts and a validation in oral food challenge-defined FA cases. RESULTS:Thirty-seven single nucleotide polymorphisms met suggestive significance (P < 1 × 10-6), with two reaching genome-wide significance: rs116936231 (FGL1) in adult doctor-diagnosed FA plus food-specific sensitization phenotype (stable after additional hay fever adjustment) and rs8022829 (AKAP6-NPAS3), which was significant only in the hay fever-adjusted model in adults. However, neither variant was validated. Further, we identified 3 single nucleotide polymorphisms previously reported for FA and atopic disease. CONCLUSION:This study identified 37 single nucleotide polymorphisms suggestively associated with FA and demonstrated genetic differences across phenotypes. It highlights the need for a unified FA definition and sheds light on FA's shared genetic architecture with allergies.

Purpose:Retinal vascular features provide noninvasive biomarkers of systemic vascular health, and deep learning tools such as AutoMorph now enable their large-scale quantification. However, researchers still lack normative data across diverse ethnic populations. Design:A prospective cohort study. Participants:We analyzed 6843 UK Biobank participants who reported no disease or medical condition according to the World Health Organization's International Classification of Diseases and Related Health Problems. Methods:We analyzed retinal images from the UK Biobank using the AutoMorph deep learning pipeline, which extracted retinal morphometric features such as vessel caliber, fractal dimension, vessel density, and tortuosity. We then used these data to define ethnicity-stratified normative ranges for retinal morphometric features in healthy UK Biobank participants. We examined associations with demographic covariates (age, sex, and ethnicity) using multivariate regression. Main Outcome Measures:We determined normal ranges for retinal morphometric features in the healthy UK Biobank population and assessed associations with age, sex, and ethnicity. Results:The cohort (mean age 53.5 ± 7.9 years; 50.1% male) was predominantly White participants (91.1%). Retinal vascular complexity declined with age, reflected by lower fractal dimension, vessel density, and tortuosity metrics. Zone-specific analyses confirmed age-related reductions in the central retinal artery equivalent and central retinal vein equivalent. Vessel density (0.050 ± 0.005) and fractal dimension (1.052 ± 0.09) were higher among Chinese participants as compared to White participants (P < 0.0001 for both). Across all metrics, ethnicity, followed by sex, exerted the strongest influence on vascular morphometrics. Conclusions:We established the first ethnicity-stratified normative dataset of retinal vascular features derived from the UK Biobank using deep learning. These data provide a reference framework for oculomic biomarkers in multi-ethnic populations and could support precision-medicine approaches to systemic disease risk assessment. Financial Disclosures:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Background:In ∼10% of asthma patients, symptoms remain uncontrolled despite maximal treatment, representing an unmet clinical need. The causal variants, genes and pathways underlying genetic risk factors have not been fully elucidated, and it is unclear whether there are unique genetic risk factors for this asthma subtype. Methods:We used electronic healthcare records linked to UK Biobank to identify asthma patients with high treatment burden and/or worse outcomes. We performed a genome-wide association study (GWAS) with this case population and healthy controls. We sought replication for associated (p≤5×10-6) signals in four independent studies (12 152 cases and 32 316 controls). Replicated signals were fine-mapped and linked to genes and pathways. Results:In total, 7681 participants met our case definition and showed enrichment for adult-onset asthma, female gender and higher body mass index compared to asthma individuals not meeting case criteria. GWAS with 7681 cases and 38 405 controls revealed 21 reproducible association signals that had previously been associated with asthma, but had a larger effect size in our study. Variant-to-gene mapping highlighted 85 candidate genes, five of which were considered high confidence (BACH2, D2HGDH, IL1RL1, RPS26, SMAD3). Conclusion:We present the first use of electronic healthcare records in UK Biobank to identify a subtype of asthma enriched for patients with high treatment burden and/or worse outcomes. Our findings support the role of known asthma genes, highlighting genetic risk variants with stronger effect in these groups of patients. The prioritised genes provide potential therapeutic opportunities for this difficult-to-treat patient population.

Purpose:To define the genetic architecture of foveal morphology and explore its relevance to foveal hypoplasia (FH), a hallmark of developmental macular disorders. Methods:We applied deep-learning algorithms to quantify foveal pit depth from central optical coherence tomography (OCT) B-scans in 61,269 UK Biobank participants. A genome-wide association study (GWAS) was conducted using REGENIE, adjusting for age, sex, height, and ancestry. Rare coding variants (frequency <1%) were analyzed in an exome-wide rare-variant association study (RVAS). Candidate genes were prioritized using integrative mapping; pathway, cross-ancestry, and genetic-correlation analyses were exploratory. Results:GWAS identified 126 sentinel variants, including 47 novel associations. Integrative mapping prioritized 129 putative causal genes, with 64 not previously implicated in foveal biology. Enriched pathways included retinoic acid metabolism (e.g., CYP26A1), photoreceptor differentiation (e.g., VSX2), extracellular matrix organization, and pigmentation. RVAS identified missense variants in ACTN3 and ESYT3 (P < 5 × 10-⁹) associated with FH features. Polygenic scores were predictive across African and South Asian ancestries. Overlap was observed with monogenic FH genes (TYR, OCA2, PAX6, AHR) and with genes underlying systemic diseases (COL11A1, KIF11, TUBB4B, PHYH). Re-examination of OCTs in affected individuals confirmed FH in select cases, including those with recurrent TUBB4B p.(Arg390Trp) variants. Conclusions:This is the first GWAS of human foveal morphology. Our findings redefine the genetic and biological framework underlying normal foveal development and foveal hypoplasia (FH). By linking common variation to rare monogenic disease, we establish a continuum model of FH with implications for future mechanistic and clinical investigation.

Background Exposure to fine particulate matter (PM2.5) is linked to many adverse outcomes, including respiratory and cardiovascular diseases. South Africa's reliance on coal combustion has led to poor air quality. Indoor air pollution exacerbates health risks in low-income households, necessitating thorough assessment. In this study, a human health risk assessment (HHRA) provided an understanding of health risks posed by indoor and outdoor PM2.5 concentrations in rural and urban settings. Methods During two campaigns, PM2.5 concentrations were monitored indoors (low-cost sensors in households) and outdoors (Zephyr sensors). We employed the method of the US Environmental Protection Agency in 22 urban households and 22 rural households. Results During a cooler period, indoor PM2.5 concentrations in all households exceeded the World Health Organization (WHO) Air Quality Guidelines. In Soweto, the winter 24-h PM2.5 concentrations reached as high as 491.4 mu g/m(3) (Household 19), surpassing all the WHO guideline targets, with the highest at 75 mu g/m(3). Even with conditions of higher atmospheric dispersion and less solid fuel burning, almost half of rural households had Hazard Quotients (HQs) > 1. In both seasons in urban areas and winter in rural areas, HQ values consistently remained >1, signalling greater health risks. Indoor PM2.5 concentrations almost consistently exceeded outdoor reference limits in both rural and urban locations throughout the year, underscoring the additional pollution burden due to indoor solid fuel burning and personal smoking habits. One Agincourt household recorded a warm period 24-h peak PM2.5 concentration of 1054 mu g/m(3) indoors, far higher than any corresponding outdoor values. Conclusions There is an urgent need for interventions to mitigate indoor air pollution that presents significant health risks to household occupants. Reducing health risks associated with high PM2.5 concentrations require interventions to mitigate outdoor PM2.5 levels and solid fuel use indoors. (347 words)

Introduction: Varenicline is an alpha(4)beta(2) nicotinic acetylcholine receptor partial agonist with the highest therapeutic efficacy of any pharmacological smoking cessation aid and a 12-month cessation rate of 26%. Genetic variation may be associated with varenicline response, but to date, no genome-wide association studies of varenicline response have been published. Methods: In this study, we investigated the genetic contribution to varenicline effectiveness using two electronic health record-derived phenotypes. We defined short-term varenicline effectiveness (SVE) and long-term varenicline effectiveness (LVE) by assessing smoking status at 3 and 12 months, respectively, after initiating varenicline treatment. In Stage 1, comprising five European cohort studies, we tested genome-wide associations with SVE (1405 cases, 2074 controls) and LVE (1576 cases, 2555 controls), defining sentinel variants (the most strongly associated variant within 1 Mb) with p-value < 5 x 10(-6) to follow up in Stage 2. In Stage 2, we tested association between sentinel variants and comparable smoking cessation endpoints in varenicline randomized controlled trials. We subsequently meta-analyzed Stages 1 and 2. Results: No variants reached genome-wide significance in the meta-analysis. In Stage 1, 10 sentinel variants were associated with SVE and five with LVE at a suggestive significance threshold (p-value < 5 x 10(-6)); none of these sentinels were previously implicated in varenicline-aided smoking cessation or in genetic studies of smoking behavior. Conclusions: We provide initial insights into the biological underpinnings of varenicline-aided smoking cessation, through implicating genes involved in various processes, including gene expression, cilium assembly, and early-stage development.

BACKGROUND:Glycated hemoglobin (HbA1c) measures the average blood sugar level over the past three months. As a vital biomarker of blood glucose levels, it is used to diagnose Type-2 diabetes mellitus (T2D) and monitor glycemic control. A heritability estimate of 47% to 59% suggests that about half of the variation in HbA1c levels can be attributed to genetic factors. Despite African populations being the most genetically diverse and unique for fine-mapping, there is a paucity of data on the genetic drivers of HbA1c in African individuals. In this study, we performed functional annotation and a Phenome-Wide Association Study (PheWAS) of HbA1c-associated variants in two African populations. METHOD:In this study, we utilized summary statistics of the HbA1c GWAS meta-analysis of 7,526 individuals from South Africa and Uganda to conduct a PheWAS using GWASATLAS. We also performed a functional analysis using the functional mapping and annotation (FUMA) tool. Single nucleotide polymorphisms (SNPs) were prioritized using the SNP2GENE function, while the gene expression patterns and shared molecular functions were explored in the GENE2FUNC. RESULT:Three genome-wide significant loci were identified with the lead SNPs: rs6724428, rs148228241, and rs8045544 - mapped to GULP1, HBA1, and ITFG3 genes, respectively. The minor allele frequencies of rs148228241 (0.07) and rs8045544 (0.19) are rare or non-existent in non-African populations. Both rs8045544 and rs148228241 are significantly associated with the mean corpuscular hemoglobin concentration (MCHC). A lower MCHC is associated with alpha thalassaemia, resulting from deletions in HBA1 and HBA2 genes. Such deletions are prevalent in malaria-endemic regions of Africa due to their selective survival advantage. The rs6724428 variant is associated with skeletal functions, reflecting the link between glucose metabolism and bone mineral density. DISCUSSION:Our findings highlight the interplay between glucose metabolism, erythropoiesis, and skeletal health. The significant associations of HbA1c-variants with both skeletal function and MCHC underscore the potential of these variants to impact broader physiological processes. A large-scale study of African individuals will be essential to unravel genetic variants influencing HbA1c.

Neuropathic pain is a common and debilitating symptom with limited treatment options. Genetic studies, which can provide vital evidence for drug development, have identified only 3 genome-wide significant signals for neuropathic pain traits. To address this, we performed the largest genome-wide association study (GWAS) to date of all-cause neuropathic pain and neuropathic pain subtypes. We defined all-cause neuropathic pain and 33 neuropathic pain subtypes using DeepPheWAS software in the UK Biobank, taking advantage of the longitudinal drug prescription data alongside clinical and self-reported records. We performed a GWAS of all-cause neuropathic pain (33,278 cases, 140,134 controls) as our primary analysis and GWASs of neuropathic pain subtypes as secondary analyses. We used 8 variant-to-gene criteria to identify putative causal genes. We identified 7 independent novel genome-wide associations for neuropathic pain phenotypes, which mapped to 22 novel putative causal genes. NCAM1 was the only gene identified from the primary analysis of all-cause neuropathic pain and met the most variant-to-gene criteria (4) of any identified gene. Of the 21 other genes, ASCC1, CHST3, C4A/C4B, and KCNN2 had the most compelling evidence for mechanistic involvement in neuropathic pain. We have performed the largest GWAS to date of all-cause neuropathic pain and more than doubled the number of genome-wide significant associations for neuropathic pain traits, identifying putative causal genes. There is strong evidence for the involvement of NCAM1 in neuropathic pain, which merits for further study for drug development.

Cigarette smoking influences blood pressure (BP) levels. Studying and accounting for potential gene-smoking interactions can help discover novel loci and provide insights into biological pathways for smoking-associated BP regulation. We conducted a genome-wide association meta-analysis involving 1,188,241 individuals from 66 studies in five ancestry groups, analyzing systolic BP, diastolic BP, and pulse pressure while considering interactions between genetic variants and three smoking exposures: smoking status, cigarettes per day, and pack years. These analyses identified twelve novel loci for BP at genome-wide significance ( P < 5 × 10 - 9 ), and highlighted biological processes including tight junction integrity, mitochondrial health, vascular relaxation, and endothelial function. In smoking status-stratified analyses, smoking modifies the genetic effect of six variants on BP. To prioritize likely causal, we developed and applied SuSiEgxe, a fine-mapping method based on a two-degree-of-freedom joint test using gene-environment interaction summary statistics. Fine-mapped loci uncovered immune-related pathway for smoking-associated BP regulation.

Infections can lead to persistent symptoms and diseases such as shingles after varicella zoster or rheumatic fever after streptococcal infections. Similarly, severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection can result in long coronavirus disease (COVID), typically manifesting as fatigue, pulmonary symptoms and cognitive dysfunction. The biological mechanisms behind long COVID remain unclear. We performed a genome-wide association study for long COVID including up to 6,450 long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We discovered an association of FOXP4 with long COVID, independent of its previously identified association with severe COVID-19. The signal was replicated in 9,500 long COVID cases and 798,835 population controls. Given the transcription factor FOXP4's role in lung physiology and pathology, our findings highlight the importance of lung function in the pathophysiology of long COVID.

IntroductionObservational studies have identified associations between hematological traits and type-2 diabetes mellitus (T2D). However, it is difficult to infer causal effects due to the potential of confounding. Our study utilizes the Mendelian randomization (MR) approach to address the above limitation and investigate the causal effect of hematological traits such as white blood cell (WBC), platelets (PLT), and red blood cell (RBC) on T2D in individuals of African ancestry.MethodsThe participating cohorts included participants of African ancestry in the Blood Cell consortium and the Million Veteran Program dataset. Using GWAS summary statistics, we applied a univariable and multivariable Two-sample MR to estimate the causal relationship between hematological traits and T2D.ResultsIn the main IVW MR estimates, genetically predicted levels of mean corpuscular hemoglobin concentration (MCHC), mean corpuscular hemoglobin (MCH), and mean corpuscular volume (MCV) were associated with decreased risk of T2D. We also observed a decreased risk of T2D with genetically predicted total WBC count and neutrophil count (NEU), for the WBC traits. The multivariable analysis further supported the direct associations of genetically predicted MCH, MCHC, and MCV levels with a decreased risk of T2D. For the European ancestry, a similar pattern of association was observed for MCH and MCV.DiscussionThese findings indicate that hematological traits may differentially play a role in the development of T2D and be affected by T2D. However, further research is needed to validate and explore the biological pathways and mechanisms involved in these associations.

Background:Specialist intervention in COPD is often reactive, resulting in inequalities in the provision of care. A proactive approach, in which individuals with modifiable disease are identified from primary care records, may help to tackle this inequality in access. Aim:To estimate the prevalence of "treatable traits" in COPD in a primary care research database and to assess health service usage. Methods:We performed a secondary analysis of individuals with either 1) a primary care diagnosis of COPD or 2) obstructive spirometry and history of ever smoking in a large observational study recruiting individuals aged 40-69 years old in Leicestershire, UK. Spirometry, height, weight and smoking history were collected prospectively and linked to individuals' primary care records. "Treatable traits" were identified from primary care records (frequent exacerbations, current smoking, low body mass index, respiratory failure, severe breathlessness, potential suitability for lung volume reduction or psychological comorbidity). Differences in demographics and health usage between those with and without "treatable traits" were assessed. Results:In total, of the 347 individuals with COPD, 186 had at least one "treatable trait". Compared to those without treatable traits, individuals with treatable traits were younger (61 vs 64 years, p<0.001), had more severe airflow obstruction (FEV1 86% vs 94% predicted, p=0.002), higher eosinophil count (0.32 vs 0.27 cells/μL, p=0.04) and were more socioeconomically deprived (UK Indices of Multiple Deprivation decile 4.3 vs 5.8, p<0.001). Individuals with treatable traits had a higher annual primary care health usage (47 vs 30 visits per year, p=0.001). Referrals rates to specialist respiratory services were low in both groups. Conclusion:Treatable traits are common in COPD and can be identified from routinely collected primary care data. Treatable traits are associated with younger age and greater deprivation. These individuals pose a significant burden to primary care yet are rarely referred to specialist respiratory services.

BACKGROUND:Chronic dry cough is a symptom of common lung conditions, can occur as a side-effect of angiotensin-converting enzyme inhibitors (ACEis), or may be unexplained. Despite the substantial health burden presented by chronic dry cough, its biological mechanisms remain unclear. We hypothesised shared genetic architecture between chronic dry cough and ACEi-induced cough and aimed to identify causal genes underlying both phenotypes. METHODS:We performed multi-ancestry genome-wide association studies (GWAS) of chronic dry cough and ACEi-induced cough, and a multi-trait GWAS of both phenotypes, utilising data from five cohort studies. Chronic dry cough was defined by questionnaire responses, and ACEi-induced cough by treatment switches or clinical diagnosis in electronic health records. We mapped putative causal genes and performed phenome-wide association studies (PheWAS) of associated variants, and polygenic scores for ACEi-induced cough, to identify pleiotropic effects. RESULTS:We found seven novel genetic association signals reaching p<5×10-8 in the multi-trait or single-trait analyses of chronic dry cough and ACEi-induced cough. The novel variants mapped to 10 novel genes, and we mapped an additional three novel genes to known risk variants, many of which implicate neurological functions (CTNNA1, KCNA10, MAPKAP1, OR4C12, OR4C13, SIL1). The polygenic-score-based PheWAS highlighted associations with an elevated risk of several clinical conditions including asthma, diabetes and multi-site chronic pain. CONCLUSION:Our findings provide support for neuronal dysfunction underlying cough hypersensitivity in chronic dry cough and ACEi-induced cough, and identify diseases and traits associated with genetic predisposition to cough that could inform drug target discovery.

Here we report the first genome-wide association study of foveal pit depth. In a cohort of 61,269 individuals, we identified 123 genome-wide significant loci associated with pit depth, including 47 novel associations not previously linked to macular traits. Using 12 complementary variant-to-gene mapping strategies, we prioritised 128 putative causal genes, 64 of which have not previously been implicated in foveal development. Our findings reveal previously unrecognised biological influences on foveal morphogenesis, including retinoic acid metabolism (implicating CYP26A1 for the first time in human foveal development), extracellular matrix and cytoskeletal dynamics, and retinal cell fate determination. In addition, rare-variant analysis uncovered two further gene associations, including ESYT3, a gene not previously linked to foveal structure. Together, these results provide new insights into the genetic architecture and molecular pathways underlying human foveal development, and offer a foundation for future functional studies aimed at characterising foveal development and disease.