FinnGen Study Research Articles

Appraising the Effect of Potential Risk Factors on Thyroid Cancer: A Mendelian Randomization Study

Various risk factors have been associated with the risk of thyroid cancer in observational studies. However, the causality of the risk factors is not clear given the susceptibility of confounding and reverse causation. A 2-sample Mendelian randomization approach was used to estimate the effect of potential risk factors on thyroid cancer risk. Genetic instruments to proxy 55 risk factors were identified by genome-wide association studies (GWAS). Associations of these genetic variants with thyroid cancer risk were estimated in GWAS of the FinnGen Study (989 cases and 217 803 controls). A Bonferroni-corrected threshold of P = 9.09 × 10-4 was considered significant, and P < 0.05 was considered to be suggestive of an association. Telomere length was significantly associated with increased thyroid cancer risk after correction for multiple testing (OR 4.68; 95% CI, 2.35-9.31; P = 1.12 × 10-5). Suggestive associations with increased risk were noted for waist-to-hip ratio (OR 1.85; 95% CI, 1.02-3.35; P = 0.042) and diastolic blood pressure (OR 1.60; 95% CI, 1.08-2.38; P = 0.019). Suggestive associations were noted between hemoglobin A1c (HbA1c) (OR 0.20; 95% CI, 0.05-0.82; P = 0.025) and decreased risk of thyroid cancer. Risk of thyroid cancer was not associated with sex hormones and reproduction, developmental and growth, lipids, diet and lifestyle, or inflammatory factors (All P > 0.05). Our study identified several potential targets for primary prevention of thyroid cancer, including central obesity, diastolic blood pressure, HbA1c, and telomere length, which should inform public health policy.

Mendelian Randomization Analysis Suggests No Associations of Herpes Simplex Virus Infections With Multiple Sclerosis.

Previous studies have suggested an association between infection with herpes simplex virus (HSV) and liability to multiple sclerosis (MS), but it remains largely unknown whether the effect is causal. We performed a two-sample Mendelian randomization (MR) study to explore the relationship between genetically predicted HSV infection and MS risk. Genetic instrumental variables for diagnosed infections with HSV (p < 5 × 10–6) were retrieved from the FinnGen study, and single nucleotide polymorphisms associated with circulating immunoglobulin G (IgG) levels of HSV-1 and HSV-2 and corresponding summary-level statistics of MS were obtained from genome-wide association studies of the European-ancestry. Inverse-variance weighted MR was employed as the primary method and multiple sensitivity analyses were performed. Genetically proxied infection with HSV was not associated with the risk of MS (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.90–1.02; p = 0.22) per one-unit increase in log-OR of herpes viral infections. MR results provided no evidence for the relationship between circulating HSV-1 IgG levels and MS risks (OR = 0.91; 95% CI, 0.81–1.03; p = 0.37), and suggested no causal effect of HSV-2 IgG (OR = 1.04; 95% CI, 0.96–1.13; p = 0.32). Additional sensitivity analyses confirmed the robustness of these null findings. The MR study did not support the causal relationship between genetic susceptibly to HSV and MS in the European population. Further studies are still warranted to provide informative knowledge, and triangulating evidence across multiple lines of evidence are necessary to plan interventions for the treatment and prevention of MS.

Integration of questionnaire-based risk factors improves polygenic risk scores for human coronary heart disease and type 2 diabetes

Large-scale biobank initiatives and commercial repositories store genomic data collected from millions of individuals, and tools to leverage the rapidly growing pool of health and genomic data in disease prevention are needed. Here, we describe the derivation and validation of genomics-enhanced risk tools for two common cardiometabolic diseases, coronary heart disease and type 2 diabetes. Data used for our analyses include the FinnGen study (N = 309,154) and the UK Biobank project (N = 343,672). The risk tools integrate contemporary genome-wide polygenic risk scores with simple questionnaire-based risk factors, including demographic, lifestyle, medication, and comorbidity data, enabling risk calculation across resources where genome data is available. Compared to routinely used clinical risk scores for coronary heart disease and type 2 diabetes prevention, the risk tools show at least equivalent risk discrimination, improved risk reclassification (overall net reclassification improvements ranging from 3.7 [95% CI 2.8–4.6] up to 6.2 [4.6–7.8]), and capacity to be improved even further with standard lipid and blood pressure measurements. Without the need for blood tests or evaluation by a health professional, the risk tools provide a powerful yet simple method for preliminary cardiometabolic risk assessment for individuals with genome data available.

Low Intelligence Predicts Higher Risks of Coronary Artery Disease and Myocardial Infarction: Evidence From Mendelian Randomization Study.

Background: Low intelligence has been shown to be associated with a high risk of cardiovascular disease in observational studies. It remains unclear whether the association is causal. This study aimed to explore the causal association of intelligence with coronary artery disease (CAD) and myocardial infarction (MI). Methods: A two-sample Mendelian randomization study was designed to infer the causality. A total of 121 single nucleotide polymorphisms were selected as a genetic instrumental variable for intelligence. Summary data on CAD (n = 184,305) and MI (n = 171,875) were obtained from the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis (CARDIoGRAM) plus The Coronary Artery Disease (C4D) Genetics (CARDIoGRAMplusC4D) consortium and the FinnGen study. Inverse variance weighting method was used to calculate the effect estimates. Sensitivity analyses including other statistical models and leave-one-out analysis were conducted to verify the robustness of results. MR-Egger test was performed to assess the pleiotropy. Results: Genetically predicted higher intelligence was significantly associated with lower risk of CAD (OR, .76; 95%CI, .69–.85; p = 1.5 × 10–7) and MI (OR, .78; 95%CI, .70–.87; p = 7.9 × 10–6). The results remained consistent in the majority of the sensitivity analyses and were repeated in the FinnGen datasets. MR-Egger test suggested no evidence of directional pleiotropy for the association with coronary artery disease (intercept = −.01, p = .19) and myocardial infarction (intercept = −.01, p = .06). Conclusion: This Mendelian randomization analysis provided genetic evidence for the causal association between low intelligence and increased risks of CAD and MI.

Associations of Visceral Adipose Tissue, Circulating Protein Biomarkers, and Risk of Cardiovascular Diseases: A Mendelian Randomization Analysis.

Aim: To evaluate the genetic associations of visceral adipose tissue (VAT) mass with metabolic risk factors and cardiovascular disease (CVD) endpoints and to construct a network analysis about the underlying mechanism using Mendelian randomization (MR) analysis. Methods and Results: Using summary statistics from genome-wide association studies (GWAS), we conducted the two-sample MR to assess the effects of VAT mass on 10 metabolic risk factors and 53 CVD endpoints. Genetically predicted VAT mass was associated with metabolic risk factors, including triglyceride (odds ratio, OR, 1.263 [95% confidence interval, CI, 1.203–1.326]), high-density lipoprotein cholesterol (OR, 0.719 [95% CI, 0.678–0.763]), type 2 diabetes (OR, 2.397 [95% CI, 1.965–2.923]), fasting glucose (OR, 1.079 [95% CI, 1.046–1.113]), fasting insulin (OR, 1.194 [95% CI, 1.16–1.229]), and insulin resistance (OR, 1.204 [95% CI, 1.16–1.25]). Genetically predicted VAT mass was associated with CVD endpoints, including atrial fibrillation (OR, 1.414 [95% CI, 1.332 = 1.5]), coronary artery disease (OR, 1.573 [95% CI, 1.439 = 1.72]), myocardial infarction (OR, 1.633 [95% CI, 1.484 =1.796]), heart failure (OR, 1.711 [95% CI, 1.599–1.832]), any stroke (OR, 1.29 [1.193–1.394]), ischemic stroke (OR, 1.292 [1.189–1.404]), large artery stroke (OR, 1.483 [1.206–1.823]), cardioembolic stroke (OR, 1.261 [1.096–1.452]), and intracranial aneurysm (OR, 1.475 [1.235–1.762]). In the FinnGen study, the relevance of VAT mass to coronary heart disease, stroke, cardiac arrhythmia, vascular diseases, hypertensive heart disease, and cardiac death was found. In network analysis to identify the underlying mechanism between VAT and CVDs, VAT mass was positively associated with 23 cardiovascular-related proteins (e.g., Leptin, Hepatocyte growth factor, interleukin-16), and inversely with 6 proteins (e.g., Galanin peptides, Endothelial cell-specific molecule 1). These proteins were further associated with 32 CVD outcomes. Conclusion: Mendelian randomization analysis has shown that VAT mass was associated with a wide range of CVD outcomes including coronary heart disease, cardiac arrhythmia, vascular diseases, and stroke. A few circulating proteins may be the mediators between VAT and CVDs.

Genome-wide analysis identifies SORCS3 as a novel susceptibility locus for panic disorder in the FinnGen study

Genome-wide analysis identifies SORCS3 as a novel susceptibility locus for panic disorder in the FinnGen study

Diet-Derived Antioxidants and Risk of Kidney Stone Disease: Results From the NHANES 2007-2018 and Mendelian Randomization Study.

We aimed to explore the associations between diet-derived antioxidants and kidney stone disease (KSD) risk in this study. We performed weighted multivariable-adjusted logistic regression to assess the associations between the six main diet-derived antioxidants and the risk of KSD by using data from the National Health and Nutrition Examination Survey (NHANES) 2007–2018. Then, we used the Mendelian randomization (MR) approach to verify the causal relationships between circulating antioxidants levels and KSD risk. Genetic tools were extracted from published genome-wide association studies (GWAS). Summary data for KSD was from the FinnGen study and UK biobank. Inverse variance weighted (IVW) was the primary analysis. The 26,438 participants, including 2,543 stone formers, were included for analyses. There were no significant associations between retinol, vitamin B6, vitamin C, vitamin E, and lycopene intake with the risk of KSD across all the quartile categories. Similarly, pooled odds ratio (OR) for KSD risk in genetically predicted per unit change were 1.25 (95% CI: 0.39, 4.02; p = 0.712), 1.14 (95% CI: 0.84, 1.53; p = 0.400), 0.75 (95% CI: 0.52, 1.10; p = 0.141), 1.66 (95% CI: 0.80, 3.46; p = 0.178), 1.27 (95% CI: 0.29, 5.62; p = 0.756), and 0.92 (95% CI: 0.76, 1.12; p = 0.417) for retinol, β-carotene, vitamin B6, vitamin C, α-tocopherol, and lycopene, respectively. The above estimates were replicated in the secondary analyses using UK biobank data. Our study did not support a causal association between circulating antioxidants levels and KSD risk. However, these findings should be verified in larger sample-size MR due to the pleiotropy and other limitations.

Commonly occurring genetic polymorphisms with a major impact on the risk of nonsyndromic strabismus: replication in a sample from Finland

To replicate associations between polymorphisms in the WRB and TSPAN10 genes and strabismus in an independent Finnish cohort and to calculate their population attributable risk. Polymorphisms in the WRB (rs2244352) and TSPAN10 (rs6420484) genes were investigated in individuals from the FinnGen study group who had one of three categories of strabismus, with clinical diagnoses of (1) "strabismus-all subtypes" (3,515 cases and 173,384 controls), (2) "convergent concomitant strabismus" (ICD-10 code H50.0; 737 cases and 170,976 controls), and (3) "divergent concomitant strabismus" (ICD-10 code H50.1; 1,059 cases and 170,976 controls). The WRB polymorphism was associated with "all subtypes" of strabismus (OR = 1.08; P = 0.008) and divergent strabismus (OR = 1.11; P = 0.046) but not with convergent strabismus (P = 0.41). The WRB polymorphism had a population attributable risk of 3.4% for all strabismus subtypes and 4.7% for divergent strabismus. The TSPAN10 polymorphism was associated with all three strabismus phenotypes: "all subtypes" (OR = 1.08; P = 0.002), convergent strabismus (OR = 1.19; P = 0.001) and divergent strabismus (OR = 1.20; P =7.21E-05). The population attributable risk for the TSPAN10 polymorphism was 6.0% for any strabismus, 13.3% for convergent strabismus, and 13.9% for divergent strabismus. Genetic association with strabismus was replicated in a Finnish cohort for two common polymorphisms. Under the assumption that these polymorphisms are independent of other risk factors, they are responsible for up to 20% of isolated cases of strabismus in Finland, similar to estimates in other European populations.

Diet-Derived Antioxidants Do Not Decrease Risk of Ischemic Stroke: A Mendelian Randomization Study in 1Million People.

BackgroundDietary intake and blood concentrations of vitamins E and C, lycopene, and carotenoids have been associated with a lower risk of incident (ischemic) stroke. However, causality cannot be inferred from these associations. Here, we investigated causality by analyzing the associations between genetically influenced antioxidant levels in blood and ischemic stroke using Mendelian randomization.Methods and ResultsFor each circulating antioxidant (vitamins E and C, lycopene, β‐carotene, and retinol), which were assessed as either absolute blood levels and/or high‐throughput metabolite levels, independent genetic instrumental variables were selected from earlier genome‐wide association studies (P<5×10−8). We used summary statistics for single‐nucleotide polymorphisms–stroke associations from 3 European‐ancestry cohorts (cases/controls): MEGASTROKE (60 341/454 450), UK Biobank (2404/368 771), and the FinnGen study (8046/164 286). Mendelian randomization analyses were performed on each exposure per outcome cohort using inverse variance–weighted analyses and subsequently meta‐analyzed. In a combined sample of 1 058 298 individuals (70 791 cases), none of the genetically influenced absolute antioxidants or antioxidant metabolite concentrations were causally associated with a lower risk of ischemic stroke. For absolute antioxidants levels, the odds ratios (ORs) ranged between 0.94 (95% CI, 0.85–1.05) for vitamin C and 1.04 (95% CI, 0.99–1.08) for lycopene. For metabolites, ORs ranged between 1.01 (95% CI, 0.98–1.03) for retinol and 1.12 (95% CI, 0.88–1.42) for vitamin E.ConclusionsThis study did not provide evidence for a causal association between dietary‐derived antioxidant levels and ischemic stroke. Therefore, antioxidant supplements to increase circulating levels are unlikely to be of clinical benefit to prevent ischemic stroke.

Abstract 10301: Polygenic Risk Scores for Prediction of Atrial Fibrillation and Other Adverse Outcomes After Coronary Revascularization

Introduction: Both coronary heart disease and coronary procedures predispose patients to adverse events. To improve our understanding of the genetic factors underlying postoperative prognosis, we studied the association between polygenic risk scores (PRSs) and postprocedural complications in coronary revascularization patients. Hypothesis: We hypothesized that PRSs could improve risk prediction of postprocedural complications. Methods: The study sample comprised 8296, 6132, and 13082 participants of the FinnGen study who underwent percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), or any revascularization, respectively. We genotyped the participants and identified adverse events during follow up of up to 30 years by record linkage with nationwide healthcare registers. We computed PRSs for each postoperative adverse outcome (atrial fibrillation [AF], myocardial infarction, stroke and bleeding complications) for all participants based on UK Biobank study GWAS summary statistics. We used multivariable-adjusted Cox proportional hazards models and c-statistics to examine the association between PRSs and outcomes. Results: A 1-SD increase in AF-PRS was associated with greater risk of postoperative AF with HRs of 1.22 (95% CI, 1.16-1.28), 1.15 (95% CI, 1.10-1.20) and 1.18 (95% CI, 1.14-1.22) after PCI, CABG, and any revascularization, respectively (Figure). In contrast, the association of the PRSs with other postoperative complications was non-existent to marginal. Inclusion of the AF-PRS in a model with a clinical risk score resulted in significant model fit improvement (increase in model c-statistic 0.0059-0.0098, depending on procedure type; P&lt;0.0002 for all). Conclusions: The AF-PRS could be potentially used to improve AF prevention and clinical outcomes in revascularization patients.

Leveraging Northern European population history: novel low-frequency variants for polycystic ovary syndrome.

STUDY QUESTIONCan we identify novel variants associated with polycystic ovary syndrome (PCOS) by leveraging the unique population history of Northern Europe?SUMMARY ANSWERWe identified three novel genome-wide significant associations with PCOS, with two putative independent causal variants in the checkpoint kinase 2 (CHEK2) gene and a third in myosin X (MYO10).WHAT IS KNOWN ALREADYPCOS is a common, complex disorder with unknown aetiology. While previous genome-wide association studies (GWAS) have mapped several loci associated with PCOS, the analysis of populations with unique population history and genetic makeup has the potential to uncover new low-frequency variants with larger effects.STUDY DESIGN, SIZE, DURATIONA population-based case–control GWAS was carried out.PARTICIPANTS/MATERIALS, SETTING, METHODSWe identified PCOS cases from national registers by ICD codes (ICD-10 E28.2, ICD-9 256.4, or ICD-8 256.90), and all remaining women were considered controls. We then conducted a three-stage case–control GWAS: in the discovery phase, we had a total of 797 cases and 140 558 controls from the FinnGen study. For validation, we used an independent dataset from the Estonian Biobank, including 2812 cases and 89 230 controls. Finally, we performed a joint meta-analysis of 3609 cases and 229 788 controls from both cohorts. Additionally, we reran the association analyses including BMI as a covariate, with 2169 cases and 160 321 controls from both cohorts.MAIN RESULTS AND THE ROLE OF CHANCETwo out of the three novel genome-wide significant variants associating with PCOS, rs145598156 (P = 3.6×10−8, odds ratio (OR) = 3.01 [2.02–4.50] minor allele frequency (MAF) = 0.005) and rs182075939 (P = 1.9×10−16, OR = 1.69 [1.49–1.91], MAF = 0.04), were found to be enriched in the Finnish and Estonian populations and are tightly linked to a deletion c.1100delC (r2 = 0.95) and a missense I157T (r2 = 0.83) in CHEK2. The third novel association is a common variant near MYO10 (rs9312937, P = 1.7 × 10−8, OR = 1.16 [1.10–1.23], MAF = 0.44). We also replicated four previous reported associations near the genes Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4), DENN Domain Containing 1A (DENND1A), FSH Subunit Beta (FSHB) and Zinc Finger And BTB Domain Containing 16 (ZBTB16). When adding BMI as a covariate only one of the novel variants remained genome-wide significant in the meta-analysis (the EstBB lead signal in CHEK2 rs182075939, P = 1.9×10−16, OR = 1.74 [1.5–2.01]) possibly owing to reduced sample size.LARGE SCALE DATAThe age- and BMI-adjusted GWAS meta-analysis summary statistics are available for download from the GWAS Catalog with accession numbers GCST90044902 and GCST90044903.LIMITATIONS, REASONS FOR CAUTIONThe main limitation was the low prevalence of PCOS in registers; however, the ones with the diagnosis most likely represent the most severe cases. Also, BMI data were not available for all (63% for FinnGen, 76% for EstBB), and the biobank setting limited the accessibility of PCOS phenotypes and laboratory values.WIDER IMPLICATIONS OF THE FINDINGSThis study encourages the use of isolated populations to perform genetic association studies for the identification of rare variants contributing to the genetic landscape of complex diseases such as PCOS.STUDY FUNDING/COMPETING INTEREST(S)This work has received funding from the European Union’s Horizon 2020 research and innovation programme under the MATER Marie Skłodowska-Curie grant agreement No. 813707 (N.P.-G., T.L., T.P.), the Estonian Research Council grant (PRG687, T.L.), the Academy of Finland grants 315921 (T.P.), 321763 (T.P.), 297338 (J.K.), 307247 (J.K.), 344695 (H.L.), Novo Nordisk Foundation grant NNF17OC0026062 (J.K.), the Sigrid Juselius Foundation project grants (T.L., J.K., T.P.), Finska Läkaresällskapet (H.L.) and Jane and Aatos Erkko Foundation (H.L.). The funders had no role in study design, data collection and analysis, publishing or preparation of the manuscript. The authors declare no conflicts of interest.

Polygenic Score for Physical Activity Is Associated with Multiple Common Diseases.

Genetic pleiotropy, in which the same genes affect two or more traits, may partially explain the frequently observed associations between high physical activity (PA) and later reduced morbidity or mortality. This study investigated associations between PA polygenic risk scores (PRS) and cardiometabolic diseases among the Finnish population. PRS for device-measured overall PA were adapted to a FinnGen study cohort of 218,792 individuals with genomewide genotyping and extensive digital longitudinal health register data. Associations between PA PRS and body mass index, diseases, and mortality were analyzed with linear and logistic regression models. A high PA PRS predicted a lower body mass index (β = -0.025 kg·m-2 per one SD change in PA PRS, SE = 0.013, P = 1.87 × 10-80). The PA PRS also predicted a lower risk for diseases that typically develop later in life or not at all among highly active individuals. A lower disease risk was systematically observed for cardiovascular diseases (odds ratio [OR] per 1 SD change in PA PRS = 0.95, P = 9.5 × 10-19) and, for example, hypertension [OR = 0.93, P = 2.7 × 10-44), type 2 diabetes (OR = 0.91, P = 4.1 × 10-42), and coronary heart disease (OR = 0.95, P = 1.2 × 10-9). Participants with high PA PRS had also lower mortality risk (OR = 0.97, P = 0.0003). Genetically less active persons are at a higher risk of developing cardiometabolic diseases, which may partly explain the previously observed associations between low PA and higher disease and mortality risk. The same inherited physical fitness and metabolism-related mechanisms may be associated both with PA levels and with cardiometabolic disease risk.

Uniting biobank resources reveals novel genetic pathways modulating susceptibility for atopic dermatitis

Atopic dermatitis (AD) is a common chronic inflammatory skin disease with high heritability. Previous genome-wide association studies have identified several loci predisposing to AD. These findings explain approximately 30% of the variance in AD susceptibility, suggesting that further work is required to fully understand the genetic underpinnings. We sought to gain additional understanding of the genetic contribution to AD risk by using biobank resources. We completed a genome-wide meta-analysis of AD in 796,661 individuals (Ncases= 22,474) from the FinnGen study, the Estonian Biobank, and the UK Biobank. We further performed downstream in silico analyses to characterize the risk variants at the novel loci. We report 30 loci associating with AD (P< 5×10-8), 5 of which are novel. In 2 of the novel loci, we identified missense mutations with deleterious predictions in desmocollin 1 and serpin family B member 7, genes encoding proteins crucial to epidermal strength and integrity. These findings elucidate novel genetic pathways involved in AD pathophysiology. The likely involvement of desmocollin 1 and serpin family B member 7 in AD pathogenesis may offer opportunities for the development of novel treatment strategies for AD in the future.

ANGPTL8 protein-truncating variant associated with lower serum triglycerides and risk of coronary disease.

Protein-truncating variants (PTVs) affecting dyslipidemia risk may point to therapeutic targets for cardiometabolic disease. Our objective was to identify PTVs that were associated with both lipid levels and the risk of coronary artery disease (CAD) or type 2 diabetes (T2D) and assess their possible associations with risks of other diseases. To achieve this aim, we leveraged the enrichment of PTVs in the Finnish population and tested the association of low-frequency PTVs in 1,209 genes with serum lipid levels in the Finrisk Study (n = 23,435). We then tested which of the lipid-associated PTVs were also associated with the risks of T2D or CAD, as well as 2,683 disease endpoints curated in the FinnGen Study (n = 218,792). Two PTVs were associated with both lipid levels and the risk of CAD or T2D: triglyceride-lowering variants in ANGPTL8 (-24.0[-30.4 to -16.9] mg/dL per rs760351239-T allele, P = 3.4 × 10−9) and ANGPTL4 (-14.4[-18.6 to -9.8] mg/dL per rs746226153-G allele, P = 4.3 × 10−9). The risk of T2D was lower in carriers of the ANGPTL4 PTV (OR = 0.70[0.60–0.81], P = 2.2 × 10−6) than noncarriers. The odds of CAD were 47% lower in carriers of a PTV in ANGPTL8 (OR = 0.53[0.37–0.76], P = 4.5 × 10−4) than noncarriers. Finally, the phenome-wide scan of the ANGPTL8 PTV showed that the ANGPTL8 PTV carriers were less likely to use statin therapy (68,782 cases, OR = 0.52[0.40–0.68], P = 1.7 × 10−6) compared to noncarriers. Our findings provide genetic evidence of potential long-term efficacy and safety of therapeutic targeting of dyslipidemias.

SEX DIFFERENCES IN THE GENETIC RISK FOR HYPERTENSION

Abstract Objective: The development of hypertension differs markedly between men and women. The genetic drivers of this difference have not been fully studied. Genome-wide polygenic risk scores (PRSs), consisting of data from up to 6 M single nucleotide polymorphisms have been shown to considerably improve hypertension risk prediction, particularly in early-onset disease. However, the sex differences in the ability of PRSs to predict hypertension has not been studied previously. Figure Survival curves from Cox proportional hazards models illustrate the cumulative risk of hypertension by systolic blood pressure PRS categories in FinnGen for women and men. We observed 123 579 women and 95 213 men with 27 804 and 28 113 cases of incident hypertension, respectively. Design and method: Our study sample comprised 218792 FinnGen Study participants with lifetime register-based follow-up for incident hypertension (56% women, mean age 58 years). We used publicly available genome-wide association results from UK Biobank to compute sex-specific PRSs for systolic blood pressure. We categorized SBP PRS into five bins according to percentiles (&lt;2.5, 2.5–20, 20–80, 80–97.5, &gt; 97.5) and used middle bin as the reference. We used multivariable-adjusted Cox proportional hazards models to measure the association between the PRSs and incident hypertension. Results: The PRS was more strongly associated with incident hypertension in women than in men (Figure). The hazard ratios (HR) per 1 SD increase in PRSs were 1.42 (95% CI, 1.40–1.44) for women and 1.27 (95% CI, 1.26–1.29) with an interaction P-value of 4x10–29. The difference between women (HR, 1.56; 95% CI, 1.53–1.58) and men (HR, 1.35; 95% CI, 1.32–1.37) was even greater for early-onset hypertension (onset at age &lt; 55 years). Men and women in the top 2.5 PRS percentile had 2.1-fold (95% CI, 2.0–2.3) and 1.8-fold (95% CI, 1.7–1.9) greater risks of developing hypertension than the reference group. Conclusions: The genetic risk of hypertension appears to be more distinctive in women than in men, which may reflect physiological differences starting already at an early age. These results emphasize the use of sex-specific PRSs in clinical prediction of hypertension.

POLYGENIC RISK SCORES PREDICT HYPERTENSION ONSET AND CARDIOVASCULAR RISK

Abstract Objective: We aimed to quantify the predictive ability of polygenic risk scores in hypertension and demonstrate that they improve a gold standard clinical risk score of hypertension in the general population. Design and method: Our study sample comprised N = 218,792 FinnGen Study participants with lifetime follow-up (mean age 58 years, 56% women). We used recently developed Bayesian methodology and publicly available genome-wide association data to compute polygenic risk scores (PRS) for systolic (SBP) and diastolic blood pressure (DBP). Next, in a well-phenotyped subset of 22,624 FINRISK study participants, we calculated the 4-year clinical risk of hypertension and 10-year clinical risk of cardiovascular disease (CVD) using gold standard risk scores. Using time-to-event analysis, we then assessed (1) the association of blood pressure PRSs with hypertension, age of hypertension onset, and CVD in all FinnGen participants, and (2) the incremental improvement in model discrimination when combining blood pressure PRSs with the 4-year and 10-year clinical risk predictions of hypertension and CVD in the FINRISK cohorts. Results: Compared to having an average PRS, elevated PRS was associated with up to 2.3-fold risk of hypertension and an 11-year earlier disease onset (Figure). In subgroup analyses, the risk was only 1.6-fold for late-onset hypertension (age &gt; = 55 years), whereas it was 2.8-fold for early-onset hypertension (age &lt; 55 years). Elevated SBP PRS was also associated with up to 1.3-fold risk of CVD and a 4-year earlier disease onset. SBP and DBP PRSs improved clinical risk prediction for hypertension, increasing the C-statistic by 0.7% (0.3–1.1; P = 0.0017) and generating a category-free Net Reclassification Improvement of 9.3% (1.9–16.8; P = 0.014). Inclusion of blood pressure PRSs did not improve the clinical CVD risk score. Conclusions: We demonstrated that genetic information improves clinical risk prediction of hypertension. Blood pressure PRSs could be used together with traditional risk factors to improve prediction of hypertension and particularly early-onset hypertension, which confers substantially increased CVD risk. When used independently, PRSs offer a simple and increasingly affordable way to measure genetic predisposition to hypertension at any point in life. Individuals with elevated blood pressure PRSs could benefit from genetic counseling and intensive early intervention.

Loss-of-Function Variants in the SYNPO2L Gene Are Associated With Atrial Fibrillation.

Multiple genome-wide association studies (GWAS) have identified numerous loci associated with atrial fibrillation (AF). However, the genes driving these associations and how they contribute to the AF pathogenesis remains poorly understood. To identify genes likely to be driving the observed association, we searched the FinnGen study consisting of 12,859 AF cases and 73,341 controls for rare genetic variants predicted to cause loss-of-function. A specific splice site variant was found in the SYNPO2L gene, located in an AF associated locus on chromosome 10. This variant was associated with an increased risk of AF with a relatively high odds ratio of 3.5 (p = 9.9 × 10−8). SYNPO2L is an important gene involved in the structural development and function of the cardiac myocyte and our findings thus support the recent suggestions that AF can present as atrial cardiomyopathy.

The rs738409 G Allele in PNPLA3 Is Associated With a Reduced Risk of COVID-19 Mortality and Hospitalization

The rs738409 G Allele in PNPLA3 Is Associated With a Reduced Risk of COVID-19 Mortality and Hospitalization

Sleep apnoea is a risk factor for severe COVID-19

BackgroundObstructive sleep apnoea (OSA) is associated with higher body mass index (BMI), diabetes, older age and male gender, which are all risk factors for severe COVID-19.We aimed to study if...

Diet-Derived Circulating Antioxidants and Risk of Coronary Heart Disease: A Mendelian Randomization Study

BackgroundPreviously, observational studies have identified associations between higher levels of dietary-derived antioxidants and lower risk of coronary heart disease (CHD), whereas randomized clinical trials showed no reduction in CHD risk following antioxidant supplementation. ObjectivesThe purpose of this study was to investigate possible causal associations between dietary-derived circulating antioxidants and primary CHD risk using 2-sample Mendelian randomization (MR). MethodsSingle-nucleotide polymorphisms for circulating antioxidants (vitamins E and C, retinol, β-carotene, and lycopene), assessed as absolute levels and metabolites, were retrieved from the published data and were used as genetic instrumental variables. Summary statistics for gene-CHD associations were obtained from 3 databases: the CARDIoGRAMplusC4D consortium (60,801 cases; 123,504 control subjects), UK Biobank (25,306 cases; 462,011 control subjects), and FinnGen study (7,123 cases; 89,376 control subjects). For each exposure, MR analyses were performed per outcome database and were subsequently meta-analyzed. ResultsAmong an analytic sample of 768,121 individuals (93,230 cases), genetically predicted circulating antioxidants were not causally associated with CHD risk. For absolute antioxidants, the odds ratio for CHD ranged between 0.94 (95% confidence interval [CI]: 0.63 to 1.41) for retinol and 1.03 (95% CI: 0.97 to 1.10) for β-carotene per unit increase in ln-transformed antioxidant values. For metabolites, the odds ratio ranged between 0.93 (95% CI: 0.82 to 1.06) for γ-tocopherol and 1.01 (95% CI: 0.95 to 1.08) for ascorbate per 10-fold increase in metabolite levels. ConclusionsEvidence from our study did not support a protective effect of genetic predisposition to high dietary-derived antioxidant levels on CHD risk. Therefore, it is unlikely that taking antioxidants to increase blood antioxidants levels will have a clinical benefit for the prevention of primary CHD.