The European Union, the UK National Institute for Health Research, the Wellcome Trust, the UK Medical Research Council, Action on Hearing Loss, the UK Biotechnology and Biological Sciences Research Council, the Oak Foundation, the Economic and Social Research Council, Helmholtz Zentrum Munchen, the German Research Center for Environmental Health, the German Federal Ministry of Education and Research, the German Center for Diabetes Research, the Munich Center for Health Sciences, the Ministry of Science and Research of the State of North Rhine-Westphalia, and the German Federal Ministry of Health.

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

No abstract

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

No abstract

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10 −6 ) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10 −8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models. alcohol consumption; cholesterol; gene-environment interactions; gene-lifestyle interactions; genome-wide association studies; lipids; triglycerides Abbreviations: A1CF, APOBEC1 complementation factor gene; APOBEC1, apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1; APOBEC1, apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 gene; CHARGE, Cohorts for Heart and Aging Research in Genomic Epidemiology; DEPICT, Data-driven Expression Prioritized Integration for Complex Traits; df, degrees of freedom; FDR, false discovery rate; GWAS, genome-wide association study(ies); HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PCSK5, proprotein convertase subtilisin/kexin type 5; PCSK5, proprotein convertase subtilisin/kexin type 5 gene; PCSK9, proprotein convertase subtilisin/kexin type 9 gene; TG, triglycerides; VEGF-B, vascular endothelial growth factor B; VEGFB, vascular endothelial growth factor B gene.

Hypertension is the leading risk factor for cardiovascular disease and leading cause of premature death globally. In 2008, approximately 40% of adults were diagnosed with hypertension, with more than 1.5 billion people estimated to be affected globally by 2025. Hypertension disproportionally affects low- and middle-income countries, where the prevalence is higher and where the health systems are more fragile. This qualitative study explored patients’ experiences on the management and control of hypertension in rural Bangladesh, Sri Lanka and Pakistan. We conducted sixty semi-structured interviews, with 20 participants in each country. Hypertensive individuals were recruited based on age, gender and hypertensive status. Overall, patients’ reported symptoms across the three countries were quite similar, although perceptions of hypertension were mixed. The majority of patients reported low knowledge on how to prevent or treat hypertension. The main barriers to accessing health services, as reported by participants, were inadequate services and poor quality of existing facilities, shortage of medicine supplies, busyness of doctors due to high patient load, long travel distance to facilities, and long waiting times once facilities were reached. Patients also mentioned that cost was a barrier to accessing services and adhering to medication. Many patients, when asked for areas of improvement, reported on the importance of the provider-patient relationship and mentioned valuing doctors who spent time with them, provided advice, and could be trusted. However, most patients reported that, especially at primary health care level and in government hospitals, the experience with their doctor did not meet their expectations. Patients in the three countries reported desire for good quality local medical services, the need for access to doctors, medicine and diagnostics and decreased cost for medication and medical services. Patients also described welcoming health care outreach activities near their homes. Areas of improvement could focus on reorienting community health workers’ activities; involving family members in comprehensive counseling for medication adherence; providing appropriate training for health care staff to deliver effective information and services for controlling hypertension to patients; enhancing primary health care and specialist services; improving supplies of hypertensive medication in public facilities; taking into account patients’ cultural and social background when providing services; and facilitating access and treatment to those who are most vulnerable.