scholarly journals Genome-wide pleiotropy analysis identifies novel blood pressure variants and improves its polygenic risk scores

Author(s):  
Xiaofeng Zhu ◽  
Luke Zhu ◽  
Heming Wang ◽  
Richard S Cooper ◽  
Aravinda Chakravarti

AbstractSystolic and diastolic blood pressure (S/DBP) are highly correlated modifiable risk factors for cardiovascular disease (CVD). We report here a bidirectional Mendelian Randomization (MR) and pleiotropy analysis of systolic and diastolic blood pressure (BP) summary statistics from the UKB-ICBP BP genome-wide association study (GWAS) and construct a composite genetic risk score (GRS) by including pleiotropic variants. The composite GRS captures greater (1.11-3.26 fold) heritability for BP traits and increases (1.09- and 2.01-fold) Nagelkerke’s R2 for hypertension (HTN) and cardiovascular disease (CVD). We replicated 118 novel BP pleiotropic variants including 18 novel BP loci using summary statistics from the Million Veteran Program (MVP) study. An additional 219 novel BP signals and 40 novel loci were identified after meta-analysis of the UKB-ICBP and MVP summary statistics but without further independent replication. Our study provides further insight into BP regulation and provides a novel way to construct a GRS by including pleiotropic variants for other complex diseases.

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jaakko Laaksonen ◽  
Pashupati P. Mishra ◽  
Ilkka Seppälä ◽  
Leo-Pekka Lyytikäinen ◽  
Emma Raitoharju ◽  
...  

AbstractHigh blood pressure (BP) is a major risk factor for many noncommunicable diseases. The effect of mitochondrial DNA single-nucleotide polymorphisms (mtSNPs) on BP is less known than that of nuclear SNPs. We investigated the mitochondrial genetic determinants of systolic, diastolic, and mean arterial BP. MtSNPs were determined from peripheral blood by sequencing or with genome-wide association study SNP arrays in two independent Finnish cohorts, the Young Finns Study and the Finnish Cardiovascular Study, respectively. In total, over 4200 individuals were included. The effects of individual common mtSNPs, with an additional focus on sex-specificity, and aggregates of rare mtSNPs grouped by mitochondrial genes were evaluated by meta-analysis of linear regression and a sequence kernel association test, respectively. We accounted for the predicted pathogenicity of the rare variants within protein-encoding and the tRNA regions. In the meta-analysis of 87 common mtSNPs, we did not observe significant associations with any of the BP traits. Sex-specific and rare-variant analyses did not pinpoint any significant associations either. Our results are in agreement with several previous studies suggesting that mtDNA variation does not have a significant role in the regulation of BP. Future studies might need to reconsider the mechanisms thought to link mtDNA with hypertension.


2021 ◽  
Vol 7 (1) ◽  
pp. 36-47
Author(s):  
Arditya Damar Kusuma ◽  
Anggoro Budi Hartopo

Abstract Objectives This review has an objective to determine the effectiveness of polyphenol intervention for the primary prevention of cardiovascular disease events and others surrogate endpoint which may correlate with cardiovascular disease events Data Sources These electronic databases were used to search the appropriate trials: MEDLINE (OvidSP, 1946 to March week 2 2020); The Cochrane Central Register of Controlled Trials (CENTRAL,week 2 March 2020). We only used English language trials that were available on these two databases. Review Methods We chose randomized controlled trials both in healthy or having high risk of cardiovascular diseases. Polyphenol as intervention was described as any food or drink that has polyphenol or its derived substance as main content. Placebo or no intervention is the comparison group. Cardiovascular clinical events and surrogate endpoints or cardiovascular disease risk factors are included in the outcome. Revman 5.5 software was used to analyze all the trials and to assess the risk of bias each trial. We selected random or fixed effects depend on the heterogeneity between trials in the meta analysis. Results Seven trials were included with 49200 participants randomized. Heterogeneity was shown between trials regarding the characteristic of participants, types of polyphenol intervention, and follow up periods. Cardiovascular event outcomes are only available in one trial (Howard et al 2006), with the intervention not clearly defined as polyphenol but increasing fruit and grain consumption. This trial shows no evidence was shown on fatal and non-fatal cardiovascular outcome by consuming more fruit and grain with 8 years mean of follow up. By analyzing remaining trials, which provide surrogate endpoints or cardiovascular risk factors, there is no evidence that polyphenol intervention reduce systolic and diastolic blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol level, and triglyceride level. However, reduction total cholesterol level was shown from the baseline (MD -5.41 mg/dl, 95% CI -8.21 to -2.62, P=0.0001). Subgroup analyses were done with dividing the trials that involve women only and both men and women. This analysis shows the reduction of both systolic (MD -2.78 mmHg, 95% CI -5.47 to -0.08, P=0.04) and diastolic blood pressure (MD -2.59 mmHg, 95% CI -4.84 to -0.34, P=0.02) in trials involving both men and women. A sensitivity analysis was done by excluding the trials with risk of bias with no different results effect. Moreover, not any trials reported adverse events of polyphenol. Author’s Conclusion Due to the limitation evidence or trial available, we could not obtain meta analysis on the primary outcome. Nevertheless, this review suggests that polyphenol intervention does show favorable effect on surrogate endpoints which was total cholesterol levels. Besides, systolic blood pressure and diastolic blood pressure in trials which involves both men and women also shown an improvement. The high heterogeneity in this review also suggests that more evidence are needed to assess the effectiveness of polyphenol intervention in reducing cardiovascular event outcomes and risk factors in the future.


2021 ◽  
Author(s):  
Xiaofeng Zhu ◽  
Luke Zhu ◽  
Heming Wang ◽  
Richard Cooper ◽  
Aravinda Chakravarti

Abstract Systolic and diastolic blood pressure (S/DBP) are highly correlated and modifiable risk factors for cardiovascular disease (CVD). We report here a bidirectional Mendelian Randomization (MR) and GWAS pleiotropy analysis of S/DBP summary statistics from large published BP GWAS and construct a composite genetic risk score (GRS), capturing respectively 21%, 11%, and 227% more of SBP, DBP and PP heritability than achieved with the traditional GRS. The composite GRS improves the prediction of hypertension and CVD in persons of European as well as African and Asian descent. We identified and confirmed 120 novel BP pleiotropic variants that are not in linkage disequilibrium with known variants, including 17 novel BP loci. We further observed significant age-modulated genetic effects on BP, hypertension and CVD in both Europeans and Asians. Our study provides further insight into BP regulation and provides a novel way to construct a GRS for correlated traits.


Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Thomas Jaworek ◽  
Steven J Kittner ◽  
Christina Jern ◽  
Frank Erik de Leeuw ◽  
Martin Dichgans ◽  
...  

Introduction: Genetic studies of early-onset disease have been an effective strategy to identify novel pathways and drug targets relevant to later-onset disease. Few studies have investigated the role of common genetic variation in the etiology of early-onset ischemic stroke (IS). Methods: We performed a GWAS meta-analysis of 38 studies from 10 countries, comprised of 5,847 IS cases of European ancestry under age 60 and 32,533 controls. Results: We identified two genome-wide significant (p< 5 x 10 -8 ) loci (see Figure). The ABO locus has previously been associated with venous thrombosis and ischemic stroke in predominantly older adults, but the effect size of our top SNP (OR 1.18; p = 9.1 x 10 -12 ) is larger than the effect size for this same SNP in MEGASTROKE (OR: 1.05; p = 6.5 x 10 -5 ). The lead SNP at the BCL7A/MLXIP locus is a novel GWAS finding for stroke (OR 1.14, 95% CI 1.08-1.19; p = 1.7 x 10 -8 ) and is noteworthy because of prior reports linking SNPs in these genes to BMI and blood pressure. Conclusions: We identified a novel locus that is near variants associated with BMI and blood pressure. Further studies are needed to confirm this locus, examine subtype specificity, and determine its function. The larger effect size observed at the ABO in this early-onset IS sample compared to older-onset IS samples is consistent with a larger role for prothrombotic mechanisms in early-onset IS.


2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Jennifer Kelly ◽  
Hassan Dashti ◽  
Jose M Ordovas ◽  
Gregory Matuszek ◽  
Caren Smith ◽  
...  

Abstract Objectives Phylloquinone is transported on triglyceride-rich lipoproteins. Preliminary evidence from a genome-wide association meta-analysis suggests that genetic variants that influence triglycerides (TGs), such as rs964184 at the APOA1/C3/A4/A5 gene cluster, also influence circulating phylloquinone. To further evaluate this overlap, we examined the linear relationship between a weighted TG genetic risk score (wTG-GRS) with circulating phylloquinone. Methods We constructed a wTG-GRS comprised of 20 SNPs that were previously associated with TGs in a genome-wide association meta-analysis for blood lipids (n > 188,000 individuals of European ancestry). The assigned weights corresponded to the effect-sizes (β) reported for each SNP's association with TGs. With meta-analytic summary statistic data from a separate genome-wide association meta-analysis of circulating phylloquinone (n = 2138 individuals of European ancestry), a statistical technique was used to approximate the linear association of the wTG-GRS with circulating phylloquinone. A p-value of 0.05 for the estimate was considered statistically significant. First, the estimate was calculated without adjustment for TGs using Model 1 summary statistics, then calculated with adjustment for TGs using Model 2 summary statistics. Results The estimate for the linear association of the wTG-GRS with circulating phylloquinone was significant without and with adjustment for TGs (Model 1: β = 0.052, P = < 0.0001, Model 2: β = 0.027, P = 0.0001, respectively). The goodness-of-fit of the model was improved from Model 1 (p-het = 0.022) to Model 2 (p-het = 0.054). Conclusions The associations of TG-related SNPs with circulating phylloquinone were proportional to their associations with TGs. This provides further evidence of the shared genetic links between TGs and phylloquinone and suggests genetic studies of vitamin K should consider TGs. Funding Sources Study supported by the USDA Agricultural Research Service under Cooperative Agreement No. 58-1950-7-707 and NHLBI T32HL069772.


2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Peng Wu ◽  
Lin Ding ◽  
Xiaodong Li ◽  
Siyang Liu ◽  
Fanjun Cheng ◽  
...  

AbstractCOVID-19 has caused numerous infections with diverse clinical symptoms. To identify human genetic variants contributing to the clinical development of COVID-19, we genotyped 1457 (598/859 with severe/mild symptoms) and sequenced 1141 (severe/mild: 474/667) patients of Chinese ancestry. We further incorporated 1401 genotyped and 948 sequenced ancestry-matched population controls, and tested genome-wide association on 1072 severe cases versus 3875 mild or population controls, followed by trans-ethnic meta-analysis with summary statistics of 3199 hospitalized cases and 897,488 population controls from the COVID-19 Host Genetics Initiative. We identified three significant signals outside the well-established 3p21.31 locus: an intronic variant in FOXP4-AS1 (rs1853837, odds ratio OR = 1.28, P = 2.51 × 10−10, allele frequencies in Chinese/European AF = 0.345/0.105), a frameshift insertion in ABO (rs8176719, OR = 1.19, P = 8.98 × 10−9, AF = 0.422/0.395) and a Chinese-specific intronic variant in MEF2B (rs74490654, OR = 8.73, P = 1.22 × 10−8, AF = 0.004/0). These findings highlight an important role of the adaptive immunity and the ABO blood-group system in protection from developing severe COVID-19.


Gut ◽  
2021 ◽  
pp. gutjnl-2020-323868
Author(s):  
Tenghao Zheng ◽  
David Ellinghaus ◽  
Simonas Juzenas ◽  
François Cossais ◽  
Greta Burmeister ◽  
...  

ObjectiveHaemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date.DesignWe conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry.ResultsWe demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix.ConclusionHEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.


2020 ◽  
Author(s):  
Adrian I Campos ◽  
Nathan Ingold ◽  
Yunru Huang ◽  
Pik Fang Kho ◽  
Xikun Han ◽  
...  

Rationale: Sleep apnoea is a complex disorder characterised by periods of halted breathing during sleep. Despite its association with serious health conditions such as cardiovascular disease, the aetiology of sleep apnoea remains understudied, and previous genetic studies have failed to identify replicable genetic risk factors. Objective: To advance our understanding of factors that increase susceptibility to sleep apnoea by identifying novel genetic associations. Methods: We conducted a genome-wide association study (GWAS) meta-analysis of sleep apnoea across five cohorts, and a previously published GWAS of apnoea-hypopnea index (N Total =510,484). Further, we used multi-trait analysis of GWAS (MTAG) to boost statistical power, leveraging the high genetic correlations between apnoea, snoring and body mass index. Replication was performed in an independent sample from 23andMe, Inc (N Total =1,477,352; N cases =175,522). Results: Our results revealed 39 independent genomic loci robustly associated with sleep apnoea risk, and significant genetic correlations with multisite chronic pain, sleep disorders, diabetes, high blood pressure, osteoarthritis, asthma and BMI-related traits. We also derived polygenic risk scores for sleep apnoea in a leave-one-out independent cohort and predicted probable sleep apnoea in participants (OR=1.15 to 1.22; variance explained = 0.4 to 0.9%). Conclusions: We report novel genetic markers robustly associated with sleep apnoea risk and substantial molecular overlap with other complex traits, thus advancing our understanding of the underlying biological mechanisms of susceptibility to sleep apnoea.


Author(s):  
Kristin Tsuo ◽  
Wei Zhou ◽  
Ying Wang ◽  
Masahiro Kanai ◽  
Shinichi Namba ◽  
...  

Asthma is a complex disease that affects millions of people and varies in prevalence by an order of magnitude across geographic regions and populations. However, the extent to which genetic variation contributes to these disparities is unclear, as studies probing the genetics of asthma have been primarily limited to populations of European (EUR) descent. As part of the Global Biobank Meta-analysis Initiative (GBMI), we conducted the largest genome-wide association study of asthma to date (153,763 cases and 1,647,022 controls) via meta-analysis across 18 biobanks spanning multiple countries and ancestries. Altogether, we discovered 180 genome-wide significant loci (p < 5x10-8) associated with asthma, 49 of which are not previously reported. We replicate well-known associations such as IL1RL1 and STAT6, and find that overall the novel associations have smaller effects than previously-discovered loci, highlighting our substantial increase in statistical power. Despite the considerable range in prevalence among biobanks, from 3% to 24%, the genetic effects of associated loci are largely consistent across the biobanks and ancestries. To further investigate the polygenic architecture of asthma, we construct polygenic risk scores (PRS) using a multi-ancestry approach, which yields higher predictive power for asthma in non-EUR populations compared to PRS derived from previous asthma meta-analyses and using other methods. Additionally, we find considerable genetic overlap between asthma and chronic obstructive pulmonary disease (COPD) across ancestries but minimal overlap in enriched biological pathways. Our work underscores the multifactorial nature of asthma development and offers insight into the shared genetic architecture of asthma that may be differentially perturbed by environmental factors and contribute to variation in prevalence.


2018 ◽  
Author(s):  
Niamh Mullins ◽  
Tim B. Bigdeli ◽  
Anders D Børglum ◽  
Jonathan R I Coleman ◽  
Ditte Demontis ◽  
...  

AbstractObjectiveOver 90% of suicide attempters have a psychiatric diagnosis, however twin and family studies suggest that the genetic etiology of suicide attempt (SA) is partially distinct from that of the psychiatric disorders themselves. Here, we present the largest genome-wide association study (GWAS) on suicide attempt using major depressive disorder (MDD), bipolar disorder (BIP) and schizophrenia (SCZ) cohorts from the Psychiatric Genomics Consortium.MethodSamples comprise 1622 suicide attempters and 8786 non-attempters with MDD, 3264 attempters and 5500 non-attempters with BIP and 1683 attempters and 2946 non-attempters with SCZ. SA GWAS were performed comparing attempters to non-attempters in each disorder followed by meta-analysis across disorders. Polygenic risk scoring investigated the genetic relationship between SA and the psychiatric disorders.ResultsThree genome-wide significant loci for SA were found: one associated with SA in MDD, one in BIP, and one in the meta-analysis of SA in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. Polygenic risk scores for major depression were significantly associated with SA in MDD (P=0.0002), BIP (P=0.0006) and SCZ (P=0.0006).ConclusionsThis study provides new information on genetic associations and the genetic etiology of SA across psychiatric disorders. The finding that polygenic risk scores for major depression predict suicide attempt across disorders provides a possible starting point for predictive modelling and preventative strategies. Further collaborative efforts to increase sample size hold potential to robustly identify genetic associations and gain biological insights into the etiology of suicide attempt.


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