The potential of current polygenic risk scores to predict high myopia and myopic macular degeneration in multi-ethnic Singapore adults

Purpose: To evaluate the trans-ancestry portability of current myopia polygenic risk scores (PRS) to predict high myopia (HM) and myopic macular degeneration (MMD) in an Asian population. Design: Population-based study. Subjects: A total of 5,894 (2,141 Chinese, 1,913 Indians, and 1,840 Malays) adults from the Singapore Epidemiology of Eye Diseases (SEED) study were included in the analysis. The mean age was 57.0 (standard deviation, SD = 9.31) years. A total of 361 adults had HM (spherical equivalent, SE -0.5D). Methods: The PRS, derived from 687,289 HapMap3 SNPs from the largest genome-wide association study of myopia in Europeans to date (n = 260,974), was assessed on its ability to predict HM and MMD versus controls. Main outcome measures: The primary outcomes were the area under the receiver operating characteristic curve (AUROC) to predict HM and MMD. Results: The PRS had an AUROC of 0.73 (95% CI: 0.70, 0.75) for HM and 0.66 (95% CI: 0.63, 0.70) for MMD versus no myopia controls. The inclusion of the PRS with other predictors (age, sex, educational attainment (EA), and ancestry; age-by-ancestry; sex-by-ancestry and EA-by-ancestry interactions; and 20 genotypic principal components) increased the AUROC to 0.84 (95% CI: 0.82, 0.86) for HM and 0.79 (95% CI: 0.76, 0.82) for MMD. Individuals with a PRS in the top 5% had 4.66 (95% CI: 3.34, 6.42) times higher risk for HM and 3.43 (95% CI: 2.27, 5.05) times higher risk for MMD compared to the remaining 95% of individuals. Conclusion: The PRS is a good predictor for HM and will facilitate the identification of high-risk children to prevent myopia progression to HM. In addition, the PRS also predicts MMD and will help to identify high-risk myopic adults who require closer monitoring for myopia-related complications.info:eu-repo/semantics/publishedVersio

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Funding The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)

Tissue-specific sex-differences in human gene expression

Despite extensive sex-differences in human complex traits and disease, the male and female genomes differ only in the sex chromosomes. This implies that most sex-differentiated traits are the result of differences in the expression of genes that are common to both sexes. While sex-differences in gene expression have been observed in a range of different tissues, the biological mechanisms for tissue-specific sex-differences (TSSD) in gene expression are not well understood. A total of 30 640 autosomal and 1021 X-linked transcripts were tested for heterogeneity in sex-difference effect sizes in n = 617 individuals across 40 tissue-types in GTEx. This identified 65 autosomal and 66 X-linked TSSD transcripts (corresponding to unique genes) at a stringent significance threshold. Results for X-linked TSSD transcripts showed mainly concordant direction of sex-differences across tissues and replicate previous findings. Autosomal TSSD transcripts had mainly discordant direction of sex-differences across tissues. The top cis-eQTLs across tissues for autosomal TSSD transcripts are located a similar distance away from the nearest androgen and estrogen binding motifs and the nearest enhancer, as compared to cis-eQTLs for transcripts with stable sex-differences in gene expression across tissue-types. Enhancer regions that overlap top cis-eQTLs for TSSD transcripts, however, were found to be more dispersed across tissues. These observations suggest that androgen and estrogen regulatory elements in a cis region may play a common role in sex-differences in gene expression, but TSSD in gene expression may additionally be due to causal variants located in tissue-specific enhancer regions

Genetic determinants of tissue factor pathway inhibitor plasma levels

International audienceTissue factor pathway inhibitor (TFPI) impedes early stages of the blood coagulation response, and low TFPI plasma levels increase the risk of thrombosis. TFPI plasma levels are heritable, but specific genetic determinants are unclear. We conducted a comprehensive review of genetic risk factors for TFPI plasma levels and identified 26 studies. We included 16 studies, as well as results from two unpublished genome-wide studies, in random effects meta-analyses of four commonly reported genetic variants in TFPI and its promoter (rs5940, rs7586970/rs8176592, rs10931292, and rs10153820) and 10 studies were summarised narratively. rs5940 was associated with all measures of TFPI (free, total, and activity), and rs7586970 was associated with total TFPI. Neither rs10931292 nor rs10153820 showed evidence of association. The narrative summary included 6 genes and genetic variants (P151L mutation in TFPI, PROS1, F5, APOE, GLA, and V617F mutation in JAK2) as well as a genome-wide linkage study, and suggested future research directions. A limitation of the systematic review was the heterogeneous measurement of TFPI. Nonetheless, our review found robust evidence that rs5940 and rs7586970 moderate TFPI plasma levels and are candidate risk factors for thrombosis, and that the regulation of TFPI plasma levels involves genetic factors beyond the TFPI gene

Sex-specific effect of CPB2 Ala147Thr but not Thr325Ile variants on the risk of venous thrombosis: A comprehensive meta-analysis

International audienceBackground: Thrombin activatable fibrinolysis inhibitor (TAFI), encoded by the Carboxypeptidase B2 gene (CPB2), is an inhibitor of fibrinolysis and plays a role in the pathogenesis of venous thrombosis. Experimental findings support a functional role of genetic variants in CPB2, while epidemiological studies have been unable to confirm associations with risk of venous thrombosis. Sex-specific effects could underlie the observed inconsistent associations between CPB2 genetic variants and venous thrombosis.Methods: A comprehensive literature search was conducted for associations between Ala147Thr and Thr325Ile variants with venous thrombosis. Authors were contacted to provide sex-specific genotype counts from their studies. Combined and sex-specific random effects meta-analyses were used to estimate a pooled effect estimate for primary and secondary genetic models.Results: A total of 17 studies met the inclusion criteria. A sex-specific meta-analysis applying a dominant model supported a protective effect of Ala147Thr on venous thrombosis in females (OR = 0.81, 95%CI: 0.68,0.97; p = 0.018), but not in males (OR = 1.06, 95%CI:0.96–1.16; p = 0.263). The Thr325Ile did not show a sex-specific effect but showed variation in allele frequencies by geographic region. A subgroup analysis of studies in European countries showed decreased risk, with a recessive model (OR = 0.83, 95%CI:0.71–0.97, p = 0.021) for venous thrombosis.Conclusions: A comprehensive literature review, including unpublished data, provided greater statistical power for the analyses and decreased the likelihood of publication bias influencing the results. Sex-specific analyses explained apparent discrepancies across genetic studies of Ala147Thr and venous thrombosis. While, careful selection of genetic models based on population genetics, evolutionary and biological knowledge can increase power by decreasing the need to adjust for testing multiple models

Autosomal genetic control of human gene expression does not differ across the sexes

Background: Despite their nearly identical genomes, males and females differ in risk, incidence, prevalence, severity and age-at-onset of many diseases. Sexual dimorphism is also seen in human autosomal gene expression, and has largely been explored by examining the contribution of genotype-by-sex interactions to variation in gene expression