Recently, we reported a method to estimate the proportion of phenotypic variance explained by all SNPs from genome-wide association studies, and estimated that half of the heritability for human height was captured by common SNPs. Here we partition genetic variation for height, body mass index (BMI), von Willebrand factor (vWF) and QT interval (QTi) onto chromosomes and chromosome segments, using 586,898 SNPs genotyped on 11,586 unrelated individuals. We estimate that ~45%, ~17%, ~25% and ~21% of variance in height, BMI, vWF and QTi, respectively, can be explained by considering all autosomal SNPs simultaneously, and a further ~0.5–1% by X-chromosome SNPs for height, BMI and vWF. We show that variance explained by each chromosome for height and QTi is proportional to the total gene length on that chromosome. In genome-wide analyses, common SNPs in or near genes explain more variation than SNPs between genes. We propose a novel approach to estimate variation due to cryptic relatedness and population stratification. Our results provide further evidence that a substantial proportion of heritability is accounted for by causal variants in linkage disequilibrium with common SNPs; that height, BMI and QTi are highly polygenic traits; and that the additive variation explained by a part of the genome is approximately proportional to the total length of DNA contained within genes therein.

Clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) was detected using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells (>5–10%) with the same abnormal karyotype (presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rises rapidly to 2–3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions that pinpoint the locations of genes previously associated with hematological cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer prior to DNA sampling, those without a prior diagnosis have an estimated 10-fold higher risk of a subsequent hematological cancer (95% confidence interval = 6–18).

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Artificial intelligence (AI) based on deep learning (DL) has sparked tremendous global interest in recent years. DL has been widely adopted in image recognition, speech recognition and natural language processing, but is only beginning to impact on healthcare. In ophthalmology, DL has been applied to fundus photographs, optical coherence tomography and visual fields, achieving robust classification performance in the detection of diabetic retinopathy and retinopathy of prematurity, the glaucoma-like disc, macular oedema and age-related macular degeneration. DL in ocular imaging may be used in conjunction with telemedicine as a possible solution to screen, diagnose and monitor major eye diseases for patients in primary care and community settings. Nonetheless, there are also potential challenges with DL application in ophthalmology, including clinical and technical challenges, explainability of the algorithm results, medicolegal issues, and physician and patient acceptance of the AI ‘black-box’ algorithms. DL could potentially revolutionise how ophthalmology is practised in the future. This review provides a summary of the state-of-the-art DL systems described for ophthalmic applications, potential challenges in clinical deployment and the path forward.

BACKGROUND Temporal increases in the consumption of sugar-sweetened beverages have paralleled the rise in obesity prevalence, but whether the intake of such beverages interacts with the genetic predisposition to adiposity is unknown. METHODS We analyzed the interaction between genetic predisposition and the intake of sugar-sweetened beverages in relation to body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) and obesity risk in 6934 women from the Nurses’ Health Study (NHS) and in 4423 men from the Health Professionals Follow-up Study (HPFS) and also in a replication cohort of 21,740 women from the Women’s Genome Health Study (WGHS). The genetic-predisposition score was calculated on the basis of 32 BMI-associated loci. The intake of sugar-sweetened beverages was examined prospectively in relation to BMI. RESULTS In the NHS and HPFS cohorts, the genetic association with BMI was stronger among participants with higher intake of sugar-sweetened beverages than among those with lower intake. In the combined cohorts, the increases in BMI per increment of 10 risk alleles were 1.00 for an intake of less than one serving per month, 1.12 for one to four servings per month, 1.38 for two to six servings per week, and 1.78 for one or more servings per day (P<0.001 for interaction). For the same categories of intake, the relative risks of incident obesity per increment of 10 risk alleles were 1.19 (95% confidence interval [CI], 0.90 to 1.59), 1.67 (95% CI, 1.28 to 2.16), 1.58 (95% CI, 1.01 to 2.47), and 5.06 (95% CI, 1.66 to 15.5) (P = 0.02 for interaction). In the WGHS cohort, the increases in BMI per increment of 10 risk alleles were 1.39, 1.64, 1.90, and 2.53 across the four categories of intake (P = 0.001 for interaction); the relative risks for incident obesity were 1.40 (95% CI, 1.19 to 1.64), 1.50 (95% CI, 1.16 to 1.93), 1.54 (95% CI, 1.21 to 1.94), and 3.16 (95% CI, 2.03 to 4.92), respectively (P = 0.007 for interaction). CONCLUSIONS The genetic association with adiposity appeared to be more pronounced with greater intake of sugar-sweetened beverages.

Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10−8). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4–1.88, P = 2.7 × 10−10, and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29–1.68, P = 4.9 × 10−9). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10−4; tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63–0.75], p = 1.86×10−18), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21–1.43], p = 3.87×10−11). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50–0.67], p = 1.17×10−12) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53–0.72], p = 8.88×10−10). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41–0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54–1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.

Glaucoma is the leading cause of irreversible blindness globally.1 Despite its gravity, the disease is frequently undiagnosed in the community.2 Raised intraocular pressure (IOP) is the most important risk factor for primary open-angle glaucoma (POAG).3,4 Here we present a meta-analysis of 139,555 European participants that identified 112 genomic loci associated with IOP, 68 of which are novel. These loci suggest a strong role for angiopoietin-receptor tyrosine kinase signaling, lipid metabolism, mitochondrial function and developmental processes underlying risk for elevated IOP. In addition, 48 of these loci were associated with glaucoma in an independent cohort, 14 of which at a Bonferroni-corrected threshold. Regression-based glaucoma prediction models had an area under Receiving Operator Characteristic curve (AUROC) of 0.76 in USA NEIGHBORHOOD study participants and 0.74 in independent glaucoma cases from UK Biobank. Genetic prediction models for POAG offer an opportunity to target screening and timely therapy to individuals most at risk.