Purpose: Randomised controlled trials ( RCT s) allow reliable causal inferences to be drawn regarding the effectiveness of specific interventions. However, they are expensive to carry out, and not all exposure‐outcome relationships can be tested in an RCT framework: for example, it would be unethical to deliberately expose participants to a putative risk factor, or the time‐scale involved may be prohibitive. Mendelian randomisation ( MR ) has been proposed as an alternative approach for drawing causal inferences, with the major advantage that the method can often be applied to existing, cross‐sectional study datasets. Therefore, results from an MR study can be obtained much more quickly and cheaply than through an RCT . Recent findings: The validity of causal inferences from an MR study are dependent on two key assumptions, neither of which can be tested fully. Nevertheless, several approaches have been proposed in the last 3 years that either highlight questionable results, or provide valid causal inference if the necessary assumptions are met only in part. Compared to certain other areas of clinical practice, the ophthalmic research community has been slow to adopt MR . Summary: An MR study cannot match an RCT in its strength of evidence for a claim of causality. However, MR still has much to offer. In some circumstances, an MR study can provide causal insight into research questions that cannot be addressed by an RCT , while more generally, an MR study can be used to evaluate the supporting evidence before deciding to embark on a lengthy and costly RCT .

Purpose: The purpose of this study was to investigate if education contributes to the risk of myopia because educational activities typically occur indoors or because of other factors, such as prolonged near viewing. Methods: This was a two-sample Mendelian randomization study. Participants were from the UK Biobank, Avon Longitudinal Study of Parents and Children, and Generation R. Genetic variants associated with years spent in education or time spent outdoors were used as instrumental variables. The main outcome measures were: (1) spherical equivalent refractive error attained by adulthood, and (2) risk of an early age-of-onset of spectacle wear (EAOSW), defined as an age-of-onset of 15 years or below. Results: Time spent outdoors was found to have a small genetic component (heritability 9.8%) that tracked from childhood to adulthood. A polygenic score for time outdoors was associated with children's time outdoors; a polygenic score for years spent in education was inversely associated with children's time outdoors. Accounting for the relationship between time spent outdoors and myopia in a multivariable Mendelian randomization analysis reduced the size of the causal effect of more years in education on myopia to −0.17 diopters (D) per additional year of formal education (95% confidence interval [CI] = −0.32 to −0.01) compared with the estimate from a univariable Mendelian randomization analysis of −0.27 D per year (95% CI = −0.41 to −0.13). Comparable results were obtained for the outcome EAOSW. Conclusions: Accounting for the effects of time outdoors reduced the estimated causal effect of education on myopia by 40%. These results suggest about half of the relationship between education and myopia may be mediated by children not being outdoors during schooling.

The aim of the study was directed at studying the sex-specific features of the correlation between genome-wide association studies (GWAS)-noticeable polymorphisms and hypertension (HTN). In two groups of European subjects of Russia (n = 1405 in total), such as men (n = 821 in total: n = 564 HTN, n = 257 control) and women (n = 584 in total: n = 375 HTN, n = 209 control), the distribution of ten specially selected polymorphisms (they have confirmed associations of GWAS level with blood pressure (BP) parameters and/or HTN in Europeans) has been considered. The list of studied loci was as follows: (PLCE1) rs932764 A > G, (AC026703.1) rs1173771 G > A, (CERS5) rs7302981 G > A, (HFE) rs1799945 C > G, (OBFC1) rs4387287 C > A, (BAG6) rs805303 G > A, (RGL3) rs167479 T > G, (ARHGAP42) rs633185 C > G, (TBX2) rs8068318 T > C, and (ATP2B1) rs2681472 A > G. The contribution of individual loci and their inter-locus interactions to the HTN susceptibility with bioinformatic interpretation of associative links was evaluated separately in men’s and women’s cohorts. The men–women differences in involvement in the disease of the BP/HTN-associated GWAS SNPs were detected. Among women, the HTN risk has been associated with HFE rs1799945 C > G (genotype GG was risky; OR_GG = 11.15 p_permGG = 0.014) and inter-locus interactions of all 10 examined SNPs as part of 26 intergenic interactions models. In men, the polymorphism BAG6 rs805303 G > A (genotype AA was protective; OR_AA = 0.30 p_permAA = 0.0008) and inter-SNPs interactions of eight loci in only seven models have been founded as HTN-correlated. HTN-linked loci and strongly linked SNPs were characterized by pronounced polyvector functionality in both men and women, but at the same time, signaling pathways of HTN-linked genes/SNPs in women and men were similar and were represented mainly by immune mechanisms. As a result, the present study has demonstrated a more pronounced contribution of BP/HTN-associated GWAS SNPs to the HTN susceptibility (due to weightier intergenic interactions) in European women than in men.

Strabismus is a common pediatric eye misalignment and has complex genetic and environmental causes. Previous genome-wide association studies (GWAS) encountered difficulties in identifying strabismus risk variants due to heterogeneity and small samples. We performed large meta-analyses of 11 European-ancestry GWAS (7 sources), analysing broad strabismus (20,464 cases, 954,921 controls) and subtypes (esotropia/exotropia). We discovered 4 loci (e.g., NPLOC4-TSPAN10-PDE6G-FAAP100, COL6A1) for strabismus and 5 additional loci (e.g., CHRNA4, MAD1L1) for strabismus subtypes and we successfully replicated the previously reported strabismus variant near NPLOC4-TSPAN10-PDE6G-FAAP100. Using mendelian randomisation, we found genetic evidence supporting maternal smoking as a causal risk factor for strabismus in offspring.

In this study we searched for correlations between polymorphic variants that determine sex hormone-binding globulin concentration (SHBG_con) and uterine fibroids (UFs). The work was performed on a sample of 1542 women (569 with UFs and 973 without UFs [control]), from whom we obtained experimental data on the distribution of nine single-nucleotide polymorphisms (SNPs) affecting the SHBG_con (data confirmed in genome-wide association studies [GWASs]). When searching for associations with UFs, both the independent effects of SNPs and the effects of their SNP–SNP interactions (SNP-SNP_ints) were taken into account during the “deep study” of the functionality of seven important UF loci and 115 strongly linked [r² ≥ 0.80] variants (an in silico methodology was used). As the results show, two SHBG_con-related SNPs correlated with UF risk: rs3779195 [T/A] BAIAP2L1 (OR_AA = 0.38; 95%CI_AA = 0.20–0.91; p_perm(AA) = 0.023) and rs440837 [A/G] ZBTB10 (OR_GG = 1.93; 95%CI_GG = 1.17–3.14; p_perm(GG) = 0.010). At the same time, seven SHBG_con-related SNPs interacting with each other (four models of such SNP-SNP_ints [p_perm ≤ 0.01)] were found to influence UF risk. These SHBG_con-related SNPs, determining susceptibility to UF, showed strong functional relevance and were involved in pathways of gene transcription regulation, interactions with hormone ligand-binding receptors, the content control of SHBG, testosterone, liver enzymes, lipids, etc. This study’s results demonstrate the effect of significant SHBG_con-related genetic determinants of UF risk.