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We present a genome-wide association study of a general happiness measure in 118,851 participants from the UK Biobank. Using BOLT-LMM, we identify 3 significant loci with a heritability estimate of 0.8%. Linkage disequilibrium score regression was performed on the ‘big five’ personality traits finding significant associations with lower neuroticism and higher extraversion and conscientiousness. Using a novel approach, we construct LDpred-inf polygenic risk scores in the Adolescent Brain Cognitive Development (ABCD) cohort and the Add Health cohort. We detected nominally significant associations with several well-being measures in ABCD and significant correlations with a happiness measure in Add Health. Additionally, we tested for associations with several brain regions in a white British subsample of UK Biobank finding significant associations with several brain structure and integrity phenotypes.We demonstrated a genetic basis for general happiness level and brain structure that appears to remain consistent throughout the lifespan and across multiple ancestral backgrounds.Author summaryAt the genetic level, there has been little investigation into whether people may have a baseline happiness level which varies from person to person. Here we perform a genetic analysis in the UK Biobank to identify three genetic loci that associate with general happiness level and preform genetic correlations of our results with the ‘Big Five’ personality traits, identifying significant correlations with neuroticism, conscientiousness and extraversion.We use the resulting summary statistics to create LDpred-inf polygenic risk scores in UK biobank identifying several brain metrics and regions associate with genetic loading for general happiness level. We also use a novel method to create LDpred-inf polygenic risk scores in two other cohorts, ABCD and Add Health. We found significant correlations with an independent happiness measure in Add Health and nominally significant correlations with several well-being measures in ABCD in both those of European Ancestry and all other ancestries found in these cohorts. We also attempted to replicate our UK Biobank MRi finding in ABCD.We conclude there is evidence that individuals have a general happiness level that is in part genetic which spans across age and ancestry.

Interindividual differences in generation of new fat cells determine body fat and type 2 diabetes risk. We utilized the GENiAL cohort, which consists of participants who have undergone abdominal adipose biopsy, to perform a genome-wide association study (GWAS) of fat cell number (n=896). Candidate genes from the genetic study were knocked down by siRNA in human adipose derived stem cells. We report 318 SNPs and 17 genetic loci displaying suggestive (p-5) association with fat cell number. Two loci pass threshold for GWAS-significance, on chromosome 2 (lead SNP rs149660479-G) and 7 (rs147389390-deletion). We filtered for fat cell number-associated SNPs (p-5) using evidence of genotype-specific expression. Where this was observed we selected genes for follow-up investigation and hereby identified SPATS2L and KCTD18 as regulators of cell proliferation consistent with the genetic data. Furthermore, 30 reported type 2 diabetes-associated SNPs displayed nominal and consistent associations with fat cell number. Functional follow up of candidate genes identified RPL8, HSD17B12 and PEPD displaying effects on cell proliferation consistent with genetic association and gene expression findings. In conclusion findings presented herein identify SPATS2L, KCTD18, RPL8, HSD17B12, and PEPD of potential importance in controlling fat cell numbers (plasticity), the size of body fat and diabetes risk.

BACKGROUND Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) near the uromodulin gene (UMOD) affecting uromodulin excretion and blood pressure (BP). Uromodulin is almost exclusively expressed in the thick ascending limb (TAL) of the loop of Henle and its effect on BP appears to be mediated via the TAL sodium transporter, NKCC2. Loop-diuretics block NKCC2 but are not commonly used in hypertension management. Volume overload is one of the primary drivers for uncontrolled hypertension, so targeting loop-diuretics to individuals who are more likely to respond to this drug class, using the UMOD genotype, could be an efficient precision medicine strategy. METHODS The BHF UMOD Trial is a genotype-blinded, multicenter trial comparing BP response to torasemide between individuals possessing the AA genotype of the SNP rs13333226 and those possessing the G allele. 240 participants (≥18 years) with uncontrolled BP, on ≥1 antihypertensive agent for ≥3 months, will receive treatment with Torasemide, 5 mg daily for 16 weeks. Uncontrolled BP is average home systolic BP (SBP) >135 mmHg and/or diastolic BP >85 mmHg. The primary outcome is the change in 24-hour ambulatory SBP area under the curve between baseline and end of treatment. Sample size was calculated to detect a 4 mmHg difference between groups at 90% power. Approval by West of Scotland Research Ethics Committee 5 (16/WS/0160). RESULTS The study should conclude August 2021. CONCLUSIONS If our hypothesis is confirmed, a genotype-based treatment strategy for loop diuretics would help reduce the burden of uncontrolled hypertension. CLINICAL TRIALS REGISTRATION https://clinicaltrials.gov/ct2/show/NCT03354897., Graphical Abstract Graphical Abstract

Aims Endothelin-1 (ET-1) is a potent vasoconstrictor peptide linked to vascular diseases through a common intronic gene enhancer [(rs9349379-G allele), chromosome 6 (PHACTR1/EDN1)]. We performed a multimodality investigation into the role of ET-1 and this gene variant in the pathogenesis of coronary microvascular dysfunction (CMD) in patients with symptoms and/or signs of ischaemia but no obstructive coronary artery disease (CAD). Methods and results Three hundred and ninety-one patients with angina were enrolled. Of these, 206 (53%) with obstructive CAD were excluded leaving 185 (47%) eligible. One hundred and nine (72%) of 151 subjects who underwent invasive testing had objective evidence of CMD (COVADIS criteria). rs9349379-G allele frequency was greater than in contemporary reference genome bank control subjects [allele frequency 46% (129/280 alleles) vs. 39% (5551/14380); P = 0.013]. The G allele was associated with higher plasma serum ET-1 [least squares mean 1.59 pg/mL vs. 1.28 pg/mL; 95% confidence interval (CI) 0.10–0.53; P = 0.005]. Patients with rs9349379-G allele had over double the odds of CMD [odds ratio (OR) 2.33, 95% CI 1.10–4.96; P = 0.027]. Multimodality non-invasive testing confirmed the G allele was associated with linked impairments in myocardial perfusion on stress cardiac magnetic resonance imaging at 1.5 T (N = 107; GG 56%, AG 43%, AA 31%, P = 0.042) and exercise testing (N = 87; −3.0 units in Duke Exercise Treadmill Score; −5.8 to −0.1; P = 0.045). Endothelin-1 related vascular mechanisms were assessed ex vivo using wire myography with endothelin A receptor (ETA) antagonists including zibotentan. Subjects with rs9349379-G allele had preserved peripheral small vessel reactivity to ET-1 with high affinity of ETA antagonists. Zibotentan reversed ET-1-induced vasoconstriction independently of G allele status. Conclusion We identify a novel genetic risk locus for CMD. These findings implicate ET-1 dysregulation and support the possibility of precision medicine using genetics to target oral ETA antagonist therapy in patients with microvascular angina. Trial registration ClinicalTrials.gov: NCT03193294.

Mutations in the collagen genes COL4A1 and COL4A2 cause Mendelian eye, kidney and cerebrovascular disease including intracerebral haemorrhage, and common collagen IV variants are a risk factor for sporadic intracerebral haemorrhage. COL4A1 and COL4A2 mutations cause endoplasmic reticulum (ER) stress and basement membrane (BM) defects, and recent data suggest an association of ER stress with intracerebral haemorrhage due to a COL4A2 mutation. However, the potential of ER-stress as a therapeutic target for the multi-systemic COL4A1 pathologies remains unclear. We performed a preventative oral treatment of Col4a1 mutant mice with the chemical chaperone phenyl butyric acid (PBA), which reduced adult intracerebral haemorrhage. Importantly, treatment of adult mice with established disease also reduced intracerebral haemorrhage. However, PBA treatment did not alter eye and kidney defects, establishing tissue specific outcomes of targeting Col4a1-derived ER stress, and therefore this treatment may not be applicable for patients with eye and renal disease. While PBA treatment reduced ER-stress and increased collagen IV incorporation into BMs, the persistence of defects in BM structure and reduced ability of the BM to withstand mechanical stress indicate PBA may be counter-indicative for pathologies caused by matrix defects. These data establish that treatment for COL4A1 disease requires a multi-pronged treatment approach that restores both ER homeostasis and matrix defects. Alleviating ER-stress is a valid therapeutic target for preventing and treating established adult intracerebral haemorrhage, but collagen IV patients will require stratification based on their clinical presentation and mechanism of their mutations.

A complex network of interacting pathways involving renal, neural, endocrine, vascular and other mechanisms controls the main determinants of blood pressure - cardiac output and total peripheral resistance. Multiple genes within each of these systems contribute to the specialized functions regulating blood pressure. The monogenic forms of blood pressure dysregulation have provided valuable insights into blood pressure regulation and expanded our understanding of both the mechanisms and the treatment of hypertension. Genome wide association studies have identified over 100 single nucleotide polymorphisms associated with blood pressure phenotypes and have identified plausible novel pathways of BP regulation and putative drug targets.

Electrolytes have a crucial role in maintaining health and their serum levels are homeostatically maintained within a narrow range by multiple pathways involving the kidneys. Here we use metabolomics profiling (592 fasting serum metabolites) to identify molecular markers and pathways associated with serum electrolyte levels in two independent population-based cohorts. We included 1523 adults from TwinsUK not on blood pressure-lowering therapy and without renal impairment to look for metabolites associated with chloride, sodium, potassium and bicarbonate by running linear mixed models adjusting for covariates and multiple comparisons. For each electrolyte, we further performed pathway enrichment analysis (PAGE algorithm). Results were replicated in an independent cohort. Chloride, potassium, bicarbonate and sodium associated with 10, 58, 36 and 17 metabolites respectively (each P −5), mainly lipids. Of all the electrolytes, serum potassium showed the most significant associations with individual fatty acid metabolites and specific enrichment of fatty acid pathways. In contrast, serum sodium and bicarbonate showed associations predominantly with amino-acid related species. In the first study to examine systematically associations between serum electrolytes and small circulating molecules, we identified novel metabolites and metabolic pathways associated with serum electrolyte levels. The role of these metabolic pathways on electrolyte homeostasis merits further studies.

Hypertension and heart failure are leading causes of death and disability worldwide. Both are complex multifactorial conditions with hypertension and heart failure at either ends of the cardiovascular continuum. Rare mutations resulting in monogenic forms of hypertension, hypotension and cardiomyopathies highlight the importance of genetics in disease causation and consequent implications for disease prediction and treatment. Advances in genomics have accelerated over the last decade leading to an unparalleled leap in our understanding of the genetic architecture of both hypertension and heart failure. In this chapter, we describe the current state of the art in the genetics of both conditions, hypertension and heart failure, focussing on biologic pathways that are perturbed and opportunities for early detection and treatment.

Previously, our comprehensive cardiovascular characterization study validated Uromodulin as a blood pressure gene. Uromodulin is a glycoprotein exclusively synthesized at the thick ascending limb of the loop of Henle and is encoded by the Umod gene. Umod−/− mice have significantly lower blood pressure than Umod+/+ mice, are resistant to salt-induced changes in blood pressure, and show a leftward shift in pressure-natriuresis curves reflecting changes of sodium reabsorption. Salt stress triggers transcription factors and genes that alter renal sodium reabsorption. To date there are no studies on renal transcriptome responses to salt stress. Here we aimed use RNA-Seq to delineate salt stress pathways in tubules isolated from Umod+/+ mice (a model of sodium retention) and Umod−/− mice (a model of sodium depletion) ± 300 mosmol sodium chloride (n = 3 per group). In response to salt stress, the tubules of Umod+/+ mice displayed an upregulation of heat shock transcripts. The greatest changes occurred in the expression of: Hspa1a (Log2 fold change 4.35, P = 2.48 e−12) and Hspa1b (Log2 fold change 4.05, P = 2.48 e−12). This response was absent in tubules of Umod−/− mice. Interestingly, seven of the genes discordantly expressed in the Umod−/− tubules were electrolyte transporters. Our results are the first to show that salt stress in renal tubules alters the transcriptome, increasing the expression of heat shock genes. This direction of effect in Umod+/+ tubules suggest the difference is due to the presence of Umod facilitating greater sodium entry into the tubule cell reflecting a specific response to salt stress.

Background: In the SPRINT trial,In SPRINT, achievement of target BP in the intensive arm required a higher number of drugs. Whilst intensive treatment of SBP was associated with an increased incidence of adverse events, it is unclear whether the use of multiple drug classes would result in adverse outcomes. Methods: The number of drug classes prescribed at randomisation and at 1,2,3,6,9,12 months were used to identify distinct trajectory groups in the standard and intensive arm using Latent Class Mixed Modelling. Data were available in 8,449 participants. Cox-PH models, adjusted for age, sex, SBP, prevalent CVD, prevalent CKD and number of drug classes at randomisation, were used to assess the association between drug class trajectories and pre-specified outcomes from SPRINT. Results: The SPRINT population classified into 6 groups (3 standard, 3 intensive) based on the trajectories of drug classes prescribed over the first year are shown in Panel A with corresponding SBP by drug class groups in Panel B. Cox-PH model (reference group 4) showed group 5 (SBP 125 mmHg on >4 drug classes) had significantly higher risk of the primary outcome (HR 1.62 95% CI [1.12-2.04]; p 0.011), heart failure (HR 3.68 [1.95-6.94]; p Conclusions: In SPRINT, treatment with >4 antihypertensive drug classes was associated with poor outcomes, specifically increased risk of death and heart failure, independent of blood pressure achieved in the first year, possibly related to the period of drug exposure. These results caution clinicians to assess need for multiple drugs and tighter blood pressure control.