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White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials. White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.

Visceral adipose tissue (VAT)—fat stored around the internal organs—has been suggested as an independent risk factor for cardiovascular and metabolic disease1–3, as well as all-cause, cardiovascular-specific and cancer-specific mortality4,5. Yet, the contribution of genetics to VAT, as well as its disease-related effects, are largely unexplored due to the requirement for advanced imaging technologies to accurately measure VAT. Here, we develop sex-stratified, nonlinear prediction models (coefficient of determination = 0.76; typical 95% confidence interval (CI) = 0.74–0.78) for VAT mass using the UK Biobank cohort. We performed a genome-wide association study for predicted VAT mass and identified 102 novel visceral adiposity loci. Predicted VAT mass was associated with increased risk of hypertension, heart attack/angina, type 2 diabetes and hyperlipidemia, and Mendelian randomization analysis showed visceral fat to be a causal risk factor for all four diseases. In particular, a large difference in causal effect between the sexes was found for type 2 diabetes, with an odds ratio of 7.34 (95% CI = 4.48–12.0) in females and an odds ratio of 2.50 (95% CI = 1.98–3.14) in males. Our findings bolster the role of visceral adiposity as a potentially independent risk factor, in particular for type 2 diabetes in Caucasian females. Independent validation in other cohorts is necessary to determine whether the findings can translate to other ethnicities, or outside the UK.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations ( P  < 5 × 10 −8 ), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3 ). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets. Meta-analyses in up to 1.3 million individuals identify 87 rare-variant associations with blood pressure traits. On average, rare variants exhibit effects ~8 times larger than the mean effects of common variants and implicate candidate causal genes at associated regions.

Background Pulmonary arterial hypertension is a life-threatening progressive disorder characterised by high blood pressure (hypertension) in the arteries of the lungs (pulmonary artery). Although treatable, there is no known cure for this rare disorder, and its exact cause is unknown. Mutations in the bone morphogenetic protein receptor type-2 (BMPR2) are the most common genetic cause of familial pulmonary arterial hypertension. This study represents the first-ever trial of treatments aimed at directly rescuing the BMPR2 pathway, repurposing two drugs that have shown promise at restoring levels of BMPR2 signalling: hydroxychloroquine and phenylbutyrate. Methods This three-armed phase II precision medicine study will investigate BMPR2 target engagement and explore the efficacy of two repurposed therapies in pulmonary arterial hypertension patients with BMPR2 mutations. Patients will be stratified based on two BMPR2 mutation classes: missense and haploinsufficient mutations. Eligible subjects will be randomised to one of the three arms (two active therapy arms and a placebo arm, all plus standard of care) following a Bayesian response-adaptive design implemented independently in each stratum and updated in response to a novel panel of primary biomarkers designed to assess biological modification of the disease. Discussion The results of this trial will provide the first randomised evidence of the efficacy of these therapies to rescue BMPR2 function and will efficiently explore the potential for a differential response of these therapies per mutation class to address causes rather than consequences of this rare disease. Trial registration The study has been registered with ISRCTN (ISRCTN10304915, 22/09/2023).

The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension. Gene expression, alternative splicing and DNA methylation profiles from human kidney samples provide insights into the effects of common variants influencing blood pressure. Mendelian randomization uncovers the effects of blood pressure on renal outcomes.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, “Some College” (yes/no) and “Graduated College” (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

Objective This study aims to analyze the genetic characteristics, genotype-phenotype correlation and long-term prognosis of children with idiopathic/hereditary pulmonary arterial hypertension (IPAH/HPAH) in a Chinese tertiary medical center. Methods A retrospective review was conducted for all children with IPAH/HPAH treated at Beijing Anzhen Hospital over the past 15 years. All patients underwent genetic testing. Results In total, 170 children with IPAH/HPAH were included in the study (females n  = 95, 56%), with a median age of diagnosis 6.46 (3.80, 10.70) years. The study population presented with severe conditions at baseline, with 77 patients assessed as clinically high-risk. Genetic testing identified pathogenic variants in 110 patients (64%), with BMPR2 , ACVRL1 , and TBX4 accounted for the main causal genes. Compared to non-carriers, carriers of pathogenic variants had a higher clinical risk at baseline (54% vs. 30%, p  = 0.04). After targeted therapy, carriers experienced greater clinical deterioration ( p  = 0.008). The overall follow-up duration was 2.68 (1.60, 4.98) years, with the survival rate at 1-, 3-, and 5-year was 93.4%, 86.7%, and 68.6%, respectively. The prognosis of carriers was significantly worse than that of non-carriers (Log-rank p  < 0.001). Multivariate Cox regression analysis indicated that pathogenic variants and higher pulmonary vascular resistance index (PVRI) and were associated with a higher risk of death. Conclusion We uncovered a higher rate of pathogenic variants in Chinese pediatric PAH, while targeted therapy improves the overall prognosis of children with PAH, patients with pathogenic variants presented with poorer response to therapy and poorer prognosis.

Background Beta-blocker (BB) and calcium channel blocker (CCB) antihypertensive drugs are commonly used in pregnancy. However, data on their relative impact on maternal and foetal outcomes are limited. We leveraged genetic variants mimicking BB and CCB antihypertensive drugs to investigate their effects on risk of pre-eclampsia, gestational diabetes and birthweight using the Mendelian randomization paradigm. Methods Genetic association estimates for systolic blood pressure (SBP) were extracted from summary data of a genome-wide association study (GWAS) on 757,601 participants. Uncorrelated single-nucleotide polymorphisms (SNPs) associated with SBP ( p  < 5 × 10 −8 ) in BB and CCB drug target gene regions were selected as proxies for drug target perturbation. Genetic association estimates for the outcomes were extracted from GWASs on 4743 cases and 136,325 controls (women without a hypertensive disorder in pregnancy) for pre-eclampsia or eclampsia, 7676 cases and 130,424 controls (women without any pregnancy-related morbidity) for gestational diabetes, and 155,202 women (who have given birth at least once) for birthweight of the first child. All studies were in European ancestry populations. Mendelian randomization estimates were generated using the two-sample inverse-variance weighted model. Results Although not reaching the conventional threshold for statistical significance, genetically-proxied BB was associated with reduced risk of pre-eclampsia (OR per 10 mmHg SBP reduction 0.27, 95%CI 0.06–1.19, p  = 0.08) and increased risk of gestational diabetes (OR per 10 mmHg SBP reduction 2.01, 95%CI 0.91–4.42, p  = 0.08), and significantly associated with lower birthweight of first child (beta per 10 mmHg SBP reduction − 0.27, 95%CI − 0.39 to − 0.15, p  = 1.90 × 10 −5 ). Genetically-proxied CCB was associated with reduced risk of pre-eclampsia and eclampsia (OR 0.62, 95%CI 0.43–0.89, p  = 9.33 × 10 −3 ), and was not associated with gestational diabetes (OR 1.05, 95% CI 0.76–1.45, p  = 0.76) or changes in birthweight of first child (beta per 10 mmHg SBP reduction 0.02, 95%CI − 0.04–0.07, p  = 0.54). Conclusions While BB and CCB antihypertensive drugs may both be efficacious for lowering blood pressure in pregnancy, this genetic evidence suggests that BB use may lower birthweight. Conversely, CCB use may reduce risk of pre-eclampsia and eclampsia without impacting gestational diabetes risk or birthweight. These data support further study on the effects of BBs on birthweight.

Our goal was to identify new environmental or genetic causes in heritable pulmonary arterial hypertension (HPAH) families outside the 18 known diagnostics PAH genes. PAH gene panel sequencing was performed for 47 HPAH families which revealed pathogenic variants in 39 families. Five of the remaining families agreed to whole exome sequencing and to fill in a drug and toxin exposure questionnaire. In Family 1 and 2, mother and daughter with HPAH carried a likely pathogenic variant in the CYBA gene and a variant of uncertain significance in the FKBP1A gene, respectively, following ACMG guidelines. In Family 3, we detected a likely pathogenic variant in the PTGR2 gene. These genes could play part in PAH pathogenesis but further functional analyses are required to corroborate these findings. In the remaining two families, we could not identify any plausible genetic cause. However, a father and son with PAH reported exposure to trichloroethylene, asbestos and tramadol in Family 4. In Family 5, two brothers with pulmonary veno-occlusive disease showed occupational toxin exposure. Thus, our findings indicate that not only a genetic predisposition but also environmental triggers should be investigated for HPAH patients.

Background Genome-wide and clinical studies have linked the 677C→T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) with hypertension, whilst limited evidence shows that intervention with riboflavin (i.e. the MTHFR co-factor) can lower blood pressure (BP) in hypertensive patients with the variant MTHFR 677TT genotype. We investigated the impact of this common polymorphism on BP throughout adulthood and hypothesised that riboflavin status would modulate the genetic risk of hypertension. Methods Observational data on 6076 adults of 18–102 years were drawn from the Joint Irish Nutrigenomics Organisation project, comprising the Trinity-Ulster Department of Agriculture (TUDA; volunteer sample) and the National Adult Nutrition Survey (NANS; population-based sample) cohorts. Participants were recruited from the Republic of Ireland and Northern Ireland (UK) in 2008–2012 using standardised methods. Results The variant MTHFR 677TT genotype was identified in 12% of adults. From 18 to 70 years, this genotype was associated with an increased risk of hypertension (i.e. systolic BP ≥ 140 and/or a diastolic BP ≥ 90 mmHg): odds ratio (OR) 1.42, 95% confidence interval (CI) 1.07 to 1.90; P  = 0.016, after adjustment for antihypertensive drug use and other significant factors, namely, age, male sex, BMI, alcohol and total cholesterol. Low or deficient biomarker status of riboflavin (observed in 30.2% and 30.0% of participants, respectively) exacerbated the genetic risk of hypertension, with a 3-fold increased risk for the TT genotype in combination with deficient riboflavin status (OR 3.00, 95% CI, 1.34–6.68; P  = 0.007) relative to the CC genotype combined with normal riboflavin status. Up to 65 years, we observed poorer BP control rates on antihypertensive treatment in participants with the TT genotype (30%) compared to those without this variant, CT (37%) and CC (45%) genotypes ( P  < 0.027). Conclusions The MTHFR 677TT genotype is associated with higher BP independently of homocysteine and predisposes adults to an increased risk of hypertension and poorer BP control with antihypertensive treatment, whilst better riboflavin status is associated with a reduced genetic risk. Riboflavin intervention may thus offer a personalised approach to prevent the onset of hypertension in adults with the TT genotype; however, this requires confirmation in a randomised trial in non-hypertensive adults.