scholarly journals A sex-specific evolutionary interaction between ADCY9 and CETP

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Isabel Gamache ◽  
Marc-André Legault ◽  
Jean-Christophe Grenier ◽  
Rocio Sanchez ◽  
Eric Rhéaume ◽  
...  
Keyword(s):  
Epistatic Interaction ◽  
Human Populations ◽  
Uk Biobank ◽  
Rna Seq ◽  
Specific Result ◽  
Transfer Protein ◽  
Clinical Responses ◽  
Males And Females ◽  
The Uk ◽  
Pharmacogenomic Studies

Pharmacogenomic studies have revealed associations between rs1967309 in the adenylyl cyclase type 9 (ADCY9) gene and clinical responses to the cholesteryl ester transfer protein (CETP) modulator dalcetrapib, however, the mechanism behind this interaction is still unknown. Here, we characterized selective signals at the locus associated with the pharmacogenomic response in human populations and we show that rs1967309 region exhibits signatures of positive selection in several human populations. Furthermore, we identified a variant in CETP, rs158477, which is in long-range linkage disequilibrium with rs1967309 in the Peruvian population. The signal is mainly seen in males, a sex-specific result that is replicated in the LIMAA cohort of over 3,400 Peruvians. Analyses of RNA-seq data further suggest an epistatic interaction on CETP expression levels between the two SNPs in multiple tissues, which also differs between males and females. We also detected interaction effects of the two SNPs with sex on cardiovascular phenotypes in the UK Biobank, in line with the sex-specific genotype associations found in Peruvians at these loci. We propose that ADCY9 and CETP coevolved during recent human evolution due to sex-specific selection, which points towards a biological link between dalcetrapib’s pharmacogene ADCY9 and its therapeutic target CETP.

scholarly journals A sex-specific evolutionary interaction between ADCY9 and CETP

2021 ◽  
Author(s):  
Isabel Gamache ◽  
Marc-André Legault ◽  
Jean-Christophe Grenier ◽  
Rocio Sanchez ◽  
Eric Rhéaume ◽  
...  
Keyword(s):  
Linkage Disequilibrium ◽  
Epistatic Interaction ◽  
Human Populations ◽  
Uk Biobank ◽  
Rna Seq ◽  
Specific Result ◽  
Transfer Protein ◽  
Clinical Responses ◽  
The Uk ◽  
Pharmacogenomic Studies

Pharmacogenomic studies have revealed associations between rs1967309 in the adenylyl cyclase type 9 (ADCY9) gene and clinical responses to the cholesteryl ester transfer protein (CETP) modulator dalcetrapib, however, the mechanism behind this interaction is still unknown. Here, we characterized selective signals at the locus associated with the pharmacogenomic response in human populations and we show that rs1967309 region exhibits signatures of natural selection in several human populations. Furthermore, we identified a variant in CETP, rs158477, which is in long-range linkage disequilibrium with rs1967309 in the Peruvian population. The signal is mainly seen in males, a sex-specific result that is replicated in the LIMAA cohort of over 3400 Peruvians. We further detected interaction effects of these two SNPs with sex on cardiovascular phenotypes in the UK Biobank, in line with the sex-specific genotype associations found in Peruvians at these loci. Analyses of RNA-seq data further suggest an epistatic interaction on CETP expression levels between the two SNPs in multiple tissues. We propose that ADCY9 and CETP coevolved during recent human evolution, which points towards a biological link between dalcetrapib's pharmacogene ADCY9 and its therapeutic target CETP.

scholarly journals Inhibition of Cholesteryl Ester Transfer Protein Preserves High-Density Lipoprotein Cholesterol and Improves Survival in Sepsis

Circulation ◽  
2020 ◽  
Author(s):  
Mark Trinder ◽  
Yanan Wang ◽  
Christian M. Madsen ◽  
Tatjana Ponomarev ◽  
Lubos Bohunek ◽  
...  
Keyword(s):  
Confidence Interval ◽  
High Density Lipoprotein ◽  
Cholesteryl Ester Transfer Protein ◽  
Density Lipoprotein ◽  
Hazard Ratio ◽  
Uk Biobank ◽  
Sepsis Mortality ◽  
Genetic Score ◽  
Transfer Protein ◽  
The Uk

Background: The high-density lipoprotein (HDL) hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors which failed to show significant reductions in cardiovascular events. Plasma levels of HDL-cholesterol (HDL-C) decline drastically during sepsis and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacologic inhibition of CETP would preserve HDL levels and decrease mortality in clinical cohorts and animal models of sepsis. Methods: We examined the effect of a gain-of-function variant in CETP (rs1800777, p.Arg468Gln) and a genetic score for decreased CETP function on 28-day sepsis survival using Cox proportional hazard models adjusted for age and sex in the UK Biobank (n=5,949), Identification of SNPs Predisposing to Altered Acute Lung Injury Risk (iSPAAR; n=882), Copenhagen General Population Study (n=2,068), Copenhagen City Heart Study (n=493), Early Infection (n=200), St. Paul's Intensive Care Unit 2 (n=203), and Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock studies (n=632). We then studied the effect of the CETP inhibitor anacetrapib in adult, female APOE*3-Leiden mice with or with human CETP expression using the cecal-ligation and puncture model of sepsis. Results: A fixed-effect meta-analysis of all 7 cohorts found that the CETP gain-of-function variant was significantly associated with increased risk of acute sepsis mortality (hazard ratio [95% confidence interval]: 1.44 [1.22-1.70], p<0.0001). In addition, a genetic score for decreased CETP function was associated with significantly decreased sepsis mortality in the UK Biobank (hazard ratio [95% confidence interval]: 0.77 [0.59-1.00] per 1 mmol/L increase in HDL-C) and iSPAAR cohorts (hazard ratio [95% confidence interval]: 0.60 [0.37-0.98] per 1 mmol/L increase HDL-C). APOE*3-Leiden.CETP mice treated with anacetrapib had preserved levels of HDL-C and apolipoprotein-AI and increased survival relative to placebo treatment (70.6% vs 35.3%, Log-rank p=0.03), while there was no effect of anacetrapib on the survival of APOE*3-Leiden mice which do not express CETP (50.0% vs 42.9%, Log-rank p=0.87). Conclusions: Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve HDL levels and improve outcomes for individuals with sepsis.

scholarly journals Polygenic Adaptation has Impacted Multiple Anthropometric Traits

2017 ◽  
Author(s):  
Jeremy J. Berg ◽  
Xinjun Zhang ◽  
Graham Coop
Keyword(s):  
Complex Traits ◽  
Association Studies ◽  
Gwas Data ◽  
Human Populations ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Link Type ◽  
Polygenic Scores ◽  
Polygenic Adaptation ◽  
The Uk

AbstractOur understanding of the genetic basis of human adaptation is biased toward loci of large pheno-typic effect. Genome wide association studies (GWAS) now enable the study of genetic adaptation in polygenic phenotypes. We test for polygenic adaptation among 187 world-wide human populations using polygenic scores constructed from GWAS of 34 complex traits. We identify signals of polygenic adaptation for anthropometric traits including height, infant head circumference (IHC), hip circumference and waist-to-hip ratio (WHR). Analysis of ancient DNA samples indicates that a north-south cline of height within Europe and and a west-east cline across Eurasia can be traced to selection for increased height in two late Pleistocene hunter gatherer populations living in western and west-central Eurasia. Our observation that IHC and WHR follow a latitudinal cline in Western Eurasia support the role of natural selection driving Bergmann’s Rule in humans, consistent with thermoregulatory adaptation in response to latitudinal temperature variation.Author’s Note on Failure to ReplicateAfter this preprint was posted, the UK Biobank dataset was released, providing a new and open GWAS resource. When attempting to replicate the height selection results from this preprint using GWAS data from the UK Biobank, we discovered that we could not. In subsequent analyses, we determined that both the GIANT consortium height GWAS data, as well as another dataset that was used for replication, were impacted by stratification issues that created or at a minimum substantially inflated the height selection signals reported here. The results of this second investigation, written together with additional coauthors, have now been published (https://elifesciences.org/articles/39725 along with another paper by a separate group of authors, showing similar issues https://elifesciences.org/articles/39702). A preliminary investigation shows that the other non-height based results may suffer from similar issues. We stand by the theory and statistical methods reported in this paper, and the paper can be cited for these results. However, we have shown that the data on which the major empirical results were based are not sound, and so should be treated with caution until replicated.

scholarly journals Increasing adiposity and metabolic dysfunction prolong QTc interval and increase risk of ventricular arrhythmias: results from the UK Biobank

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
K Patel ◽  
X Li ◽  
X Xu ◽  
L Sun ◽  
M Ardissino ◽  
...  
Keyword(s):  
Ventricular Arrhythmias ◽  
Additive Effect ◽  
Public Institution ◽  
Qtc Interval ◽  
Metabolic Dysfunction ◽  
Uk Biobank ◽  
Qtc Prolongation ◽  
Males And Females ◽  
The Uk ◽  
Genetically Determined

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): National Institute for Health Research Background/purpose: Small-scale studies have associated obesity and metabolic ill-health with QTc interval prolongation. Whether these associations are modulated by an underlying genetic predilection and translate into higher risks of ventricular arrhythmias (VA) is unknown. Methods  Using the UK Biobank and adjusted multivariate regression analysis, we studied the associations between QTc and clinical measures of adiposity and metabolic ill-health. A polygenic risk score was used to determine whether these associations are modulated by a genetic predilection for QTc prolongation. We compared QTc between four clinical phenotypes defined according to presence (+) or absence (-) of obesity (Ob), and metabolic ill-health (MU). Logistic regression was used to calculate odds ratios (OR) for VA amongst these groups. Results  23,683 individuals (11,563 male, mean age 61.0 + 7.5years) had ECG and clinical data available. QTc prolongs with increasing body mass index (0.76ms/kg/m2, 95%CI: 0.68-0.83ms/kg/m2), body fat (0.45ms/%, 95%CI:0.39-0.50ms/%), hip girth (0.35ms/cm, 95%CI:0.31-0.39ms/cm) and waist girth (0.32ms/cm, 95%CI:0.29-0.35ms/cm); all p &lt; 0.001. Genetically determined repolarisation reserve has no significant modulatory effect on the QTc-prolonging effects of increasing adiposity. Referenced to Ob-MU-, Ob + MU- and Ob-MU+ independently prolong QTc to a comparable extent, and Ob + MU+ has an additive effect on QTc prolongation. With reference to Ob-MU-, OR for VA in Ob-MU+ males and females were 5.96 (95%CI:4.70-7.55) and 5.10 (95%CI:3.34-7.80), respectively. OR for Ob + MU+ were 6.99 (95%CI:5.72-8.54) and 3.56 (95%CI:2.66-4.77) in males and females, respectively, (all p &lt; 0.001, see Table). Conclusion  Adiposity and metabolic perturbation prolong QTc to a similar extent, and their co-existence exerts an additive effect. These effects are independent of genetically determined repolarisation reserve. Despite their comparable QTc prolonging effects, metabolic ill-health is associated with higher OR for VA than obesity. VA in obesity and metabolic dysfunctionReference phenotypeOb + MU-Ob-MU+Ob + MU+Ob-MU+male1.10(0.87-1.39)ns5.96 (4.70-7.55)***6.99(5.72-8.54)***female0.87(0.64-1.18)ns5.10(3.34-7.80)***3.56(2.66-4.77)***Ob + MU-male--6.01(4.98-7.26)***female--5.61(4.18-7.52)***Ob + MU+male--1.25(1.05-1.49)*female--1.16(0.80-1.68)nsOb, obese; MU, metabolically unhealthy; +, presence; -, absence; ns, non-significant; *p &lt; 0.05; ***p &lt; 0.001. Abstract Figure. QTc in obesity and metabolic dysfunction

scholarly journals Inferring population structure in biobank-scale genomic data

2021 ◽  
Author(s):  
Alec M Chiu ◽  
Erin K Molloy ◽  
Zilong Tan ◽  
Ameet Talwalkar ◽  
Sriram Sankararaman
Keyword(s):  
Population Structure ◽  
Genetic Variants ◽  
Genomic Data ◽  
Human Populations ◽  
Uk Biobank ◽  
Medical Genomic ◽  
Variation Data ◽  
Genomic Studies ◽  
Comparable Accuracy ◽  
The Uk

Inferring the structure of human populations from genetic variation data is a key task in population and medical genomic studies. While a number of methods for population structure inference have been proposed, current methods are impractical to run on biobank-scale genomic datasets containing millions of individuals and genetic variants. We introduce SCOPE, a method for population structure inference that is orders of magnitude faster than existing methods while achieving comparable accuracy. SCOPE infers population structure in about a day on a dataset containing one million individuals and variants as well as on the UK Biobank dataset containing 488,363 individuals and 569,346 variants. Furthermore, SCOPE can leverage allele frequencies from previous studies to improve the interpretability of population structure estimates.

Low birthweight is associated with poorer limb muscle mass and grip strength in middle age: findings from the UK Biobank Imaging Enhancement

2019 ◽  
Author(s):  
Elizabeth Curtis ◽  
Justin Liu ◽  
Kate Ward ◽  
Karen Jameson ◽  
Zahra Raisi-Estabragh ◽  
...  
Keyword(s):  
Grip Strength ◽  
Muscle Mass ◽  
Low Birthweight ◽  
Middle Age ◽  
Limb Muscle ◽  
Uk Biobank ◽  
The Uk

Contrasting Broad- and Clinically- defined Polygenic Indicators of Depression and Depression-related Phenotypes in Adults and Children

2020 ◽  
Author(s):  
John E. McGeary ◽  
Chelsie Benca-Bachman ◽  
Victoria Risner ◽  
Christopher G Beevers ◽  
Brandon Gibb ◽  
...  
Keyword(s):  
Suicidal Ideation ◽  
Cognitive Reappraisal ◽  
Twin Studies ◽  
European Ancestry ◽  
Summary Statistics ◽  
Depression Severity ◽  
Uk Biobank ◽  
Polygenic Scores ◽  
Adults And Children ◽  
The Uk

Twin studies indicate that 30-40% of the disease liability for depression can be attributed to genetic differences. Here, we assess the explanatory ability of polygenic scores (PGS) based on broad- (PGSBD) and clinical- (PGSMDD) depression summary statistics from the UK Biobank using independent cohorts of adults (N=210; 100% European Ancestry) and children (N=728; 70% European Ancestry) who have been extensively phenotyped for depression and related neurocognitive phenotypes. PGS associations with depression severity and diagnosis were generally modest, and larger in adults than children. Polygenic prediction of depression-related phenotypes was mixed and varied by PGS. Higher PGSBD, in adults, was associated with a higher likelihood of having suicidal ideation, increased brooding and anhedonia, and lower levels of cognitive reappraisal; PGSMDD was positively associated with brooding and negatively related to cognitive reappraisal. Overall, PGS based on both broad and clinical depression phenotypes have modest utility in adult and child samples of depression.

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