scholarly journals PCSK9 genetic variants, life-long lowering of LDL-cholesterol and cognition: a large-scale Mendelian randomization study

2018 ◽  
Author(s):  
Donald M. Lyall ◽  
Joey Ward ◽  
Maciej Banach ◽  
George Davey Smith ◽  
Jason G. Gill ◽  
...  
Keyword(s):  
Reaction Time ◽  
Cognitive Ability ◽  
Genetic Variants ◽  
Large Scale ◽  
Ldl Cholesterol ◽  
Smoking Status ◽  
Time Trial ◽  
Uk Biobank ◽  
Pcsk9 Inhibitors ◽  
The Individual

AbstractAimsPCSK9 inhibitors lower LDL cholesterol and are efficacious at reducing risk of vascular disease, however questions remain about potential adverse effects on cognitive function. We examined the association of LDL cholesterol-lowering genetic variants in PCSK9 with continuous measures of cognitive abilityMethods and ResultsSix independent SNPs in PCSK9 were used in up to 337,348 individuals from the UK Biobank who underwent measures of cognitive ability (fluid reasoning, reaction time, trial making test and digit symbol coding. Scaled to a 50mg/dL lower LDL cholesterol, the PCSK9 allele score was associated with a lower risk of CHD (odds ratio 0.73; 95% CI: 0.60 to 0.90, P = 0.003). The scaled PCSK9 allele score nominally associated with worse log reaction time (0.04 standard deviations; 95%CI: 0.00, 0.08; P=0.038). Although no strong associations of the PCSK9 allele score were identified with any cognitive trait, the imprecision around the estimates meant that we could not exclude a similar magnitude of effect of genetic inhibition of PCSK9 to that seen with established risk factors, including APOEe4 or smoking status for any of the individual cognition traits. Point estimates for the PCSK9 allele score and cognition traits were all on the harmful side of unity.ConclusionsUsing currently available data in UK Biobank, we are not able to rule out meaningful associations of PCSK9 genetic variants with cognition traits. These data highlight the need for further large-scale genetic analyses and, in parallel, continued pharmacovigilance for patients currently treated with PCSK9 inhibitors.

scholarly journals PCSK9 genetic variants and cognitive abilities: a large-scale Mendelian randomization study

2021 ◽  
Vol 17 (1) ◽  
pp. 241-244
Author(s):  
Donald Lyall ◽  
Joey Ward ◽  
Maciej Banach ◽  
George Smith ◽  
Jason Gill ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Cognitive Abilities ◽  
Large Scale ◽  
Ldl Cholesterol ◽  
Mendelian Randomization ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Pcsk9 Inhibitors ◽  
Continuous Measures ◽  
Rule Out

IntroductionPCSK9 inhibitors lower low-density lipoprotein (LDL) cholesterol and are efficacious at reducing vascular disease, however questions remain about potential effects on cognitive function.MethodsWe examined the association of genetic variants in PCSK9 with continuous measures of cognitive ability in UK Biobank. Six independent polymorphisms in PCSK9 were used in up to 337,348 individuals.ResultsThe PCSK9 allele score was associated with a lower risk of CHD, and weakly with worse log reaction time.ConclusionsWe are unable to rule out meaningful associations of PCSK9 genetic variants with cognition, emphasising the potential need for continued pharmacovigilance for patients currently treated with PCSK9 inhibitors.

scholarly journals Predicting the effect of statins on cancer risk using genetic variants from a Mendelian randomization study in the UK Biobank

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Paul Carter ◽  
Mathew Vithayathil ◽  
Siddhartha Kar ◽  
Rahul Potluri ◽  
Amy M Mason ◽  
...  
Keyword(s):  
Standard Deviation ◽  
Cancer Risk ◽  
Genetic Variants ◽  
Ldl Cholesterol ◽  
Human Genetics ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Uk Biobank ◽  
Standard Deviation Increase ◽  
The Uk

Laboratory studies have suggested oncogenic roles of lipids, as well as anticarcinogenic effects of statins. Here we assess the potential effect of statin therapy on cancer risk using evidence from human genetics. We obtained associations of lipid-related genetic variants with the risk of overall and 22 site-specific cancers for 367,703 individuals in the UK Biobank. In total, 75,037 individuals had a cancer event. Variants in the HMGCR gene region, which represent proxies for statin treatment, were associated with overall cancer risk (odds ratio [OR] per one standard deviation decrease in low-density lipoprotein [LDL] cholesterol 0.76, 95% confidence interval [CI] 0.65–0.88, p=0.0003) but variants in gene regions representing alternative lipid-lowering treatment targets (PCSK9, LDLR, NPC1L1, APOC3, LPL) were not. Genetically predicted LDL-cholesterol was not associated with overall cancer risk (OR per standard deviation increase 1.01, 95% CI 0.98–1.05, p=0.50). Our results predict that statins reduce cancer risk but other lipid-lowering treatments do not. This suggests that statins reduce cancer risk through a cholesterol independent pathway.

scholarly journals The associations between self-reported depression, self-reported chronic inflammatory conditions and cognitive abilities in UK Biobank

2019 ◽  
Vol 60 ◽  
pp. 63-70 ◽  
Author(s):  
Laura M. Lyall ◽  
Breda Cullen ◽  
Donald M. Lyall ◽  
Samuel P. Leighton ◽  
Stefan Siebert ◽  
...  
Keyword(s):  
Reaction Time ◽  
Cognitive Ability ◽  
Cognitive Performance ◽  
Cognitive Abilities ◽  
Inflammatory Diseases ◽  
Large Population ◽  
Cognitive Test ◽  
Digit Symbol Substitution Test ◽  
Uk Biobank ◽  
Inflammatory Conditions

AbstractBackground:Depression and chronic inflammatory medical conditions have been linked to impaired cognitive ability. However despite frequent comorbidity, their combined association with cognitive ability has rarely been examined.Methods:This study examined associations between self-reported depression and chronic inflammatory diseases and their interaction with cognitive performance in 456,748 participants of the UK Biobank, adjusting for sociodemographic and lifestyle factors. Numbers with available data ranged from 94,899 to 453,208 depending on the cognitive test.Results:Self-reported depression was associated with poorer performance compared to controls in several cognitive tests (fully adjusted models, reaction time: B = 6.08, 95% CI = 5.09, 7.07; pairs matching: incidence rate ratio = 1.02, 95% CI = 1.02, 1.03; Trail Making Test B: B = 1.37, 95% CI = 0.88, 1.87; Digit Symbol Substitution Test (DSST): B = −0.35, 95% CI = −0.44, −0.27). Self-reported chronic inflammatory conditions were associated with slower reaction time (B = 3.79, 95% CI = 2.81, 4.78) and lower DSST scores (B = −0.21, 95% CI = −0.30, −0.13). No interaction effects were observed.Discussion:In this large, population-based study we provide evidence of lower cognitive performance in both depression and a comprehensive category of chronic inflammatory conditions. Results are consistent with additive effects of both types of disorder on cognitive ability. Clinicians should be aware of such effects, particularly as cognitive impairment is linked to poorer disease outcomes and quality of life.

scholarly journals Smoking and COVID-19 outcomes: an observational and Mendelian randomisation study using the UK Biobank cohort

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2021-217080
Author(s):  
Ashley K Clift ◽  
Adam von Ende ◽  
Pui San Tan ◽  
Hannah M Sallis ◽  
Nicola Lindson ◽  
...  
Keyword(s):  
Large Scale ◽  
Hospital Admissions ◽  
Causal Effect ◽  
Smoking Status ◽  
Smoking Initiation ◽  
Mendelian Randomisation ◽  
Uk Biobank ◽  
Never Smokers ◽  
The Uk ◽  
Analytical Approaches

BackgroundConflicting evidence has emerged regarding the relevance of smoking on risk of COVID-19 and its severity.MethodsWe undertook large-scale observational and Mendelian randomisation (MR) analyses using UK Biobank. Most recent smoking status was determined from primary care records (70.8%) and UK Biobank questionnaire data (29.2%). COVID-19 outcomes were derived from Public Health England SARS-CoV-2 testing data, hospital admissions data, and death certificates (until 18 August 2020). Logistic regression was used to estimate associations between smoking status and confirmed SARS-CoV-2 infection, COVID-19-related hospitalisation, and COVID-19-related death. Inverse variance-weighted MR analyses using established genetic instruments for smoking initiation and smoking heaviness were undertaken (reported per SD increase).ResultsThere were 421 469 eligible participants, 1649 confirmed infections, 968 COVID-19-related hospitalisations and 444 COVID-19-related deaths. Compared with never-smokers, current smokers had higher risks of hospitalisation (OR 1.80, 95% CI 1.26 to 2.29) and mortality (smoking 1–9/day: OR 2.14, 95% CI 0.87 to 5.24; 10–19/day: OR 5.91, 95% CI 3.66 to 9.54; 20+/day: OR 6.11, 95% CI 3.59 to 10.42). In MR analyses of 281 105 White British participants, genetically predicted propensity to initiate smoking was associated with higher risks of infection (OR 1.45, 95% CI 1.10 to 1.91) and hospitalisation (OR 1.60, 95% CI 1.13 to 2.27). Genetically predicted higher number of cigarettes smoked per day was associated with higher risks of all outcomes (infection OR 2.51, 95% CI 1.20 to 5.24; hospitalisation OR 5.08, 95% CI 2.04 to 12.66; and death OR 10.02, 95% CI 2.53 to 39.72).InterpretationCongruent results from two analytical approaches support a causal effect of smoking on risk of severe COVID-19.

scholarly journals Heritability of Regional Brain Volumes in Large-Scale Neuroimaging and Genetic Studies

2018 ◽  
Vol 29 (7) ◽  
pp. 2904-2914 ◽  
Author(s):  
Bingxin Zhao ◽  
Joseph G Ibrahim ◽  
Yun Li ◽  
Tengfei Li ◽  
Yue Wang ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Large Scale ◽  
Research Area ◽  
Nucleotide Polymorphisms ◽  
Uk Biobank ◽  
Volume Data ◽  
Brain Volumes ◽  
Symmetric Pattern ◽  
Regional Brain ◽  
Common Genetic Variants

Abstract Brain genetics is an active research area. The degree to which genetic variants impact variations in brain structure and function remains largely unknown. We examined the heritability of regional brain volumes (P ~ 100) captured by single-nucleotide polymorphisms (SNPs) in UK Biobank (n ~ 9000). We found that regional brain volumes are highly heritable in this study population and common genetic variants can explain up to 80% of their variabilities (median heritability 34.8%). We observed omnigenic impact across the genome and examined the enrichment of SNPs in active chromatin regions. Principal components derived from regional volume data are also highly heritable, but the amount of variance in brain volume explained by the component did not seem to be related to its heritability. Heritability estimates vary substantially across large-scale functional networks, exhibit a symmetric pattern across left and right hemispheres, and are consistent in females and males (correlation = 0.638). We repeated the main analysis in Alzheimer’s Disease Neuroimaging Initiative (n ~ 1100), Philadelphia Neurodevelopmental Cohort (n ~ 600), and Pediatric Imaging, Neurocognition, and Genetics (n ~ 500) datasets, which demonstrated that more stable estimates can be obtained from the UK Biobank.

scholarly journals Common genetic variants and health outcomes appear geographically structured in the UK Biobank sample: Old concerns returning and their implications

2018 ◽  
Author(s):  
Simon Haworth ◽  
Ruth Mitchell ◽  
Laura Corbin ◽  
Kaitlin H Wade ◽  
Tom Dudding ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Complex Traits ◽  
Large Scale ◽  
Genetic Data ◽  
Population Based ◽  
Risk Scores ◽  
Phenotypic Variance ◽  
Uk Biobank ◽  
Common Genetic Variants ◽  
The Uk

Introductory paragraphThe inclusion of genetic data in large studies has enabled the discovery of genetic contributions to complex traits and their application in applied analyses including those using genetic risk scores (GRS) for the prediction of phenotypic variance. If genotypes show structure by location and coincident structure exists for the trait of interest, analyses can be biased. Having illustrated structure in an apparently homogeneous collection, we aimed to a) test for geographical stratification of genotypes in UK Biobank and b) assess whether stratification might induce bias in genetic association analysis.We found that single genetic variants are associated with birth location within UK Biobank and that geographic structure in genetic data could not be accounted for using routine adjustment for study centre and principal components (PCs) derived from genotype data. We found that GRS for complex traits do appear geographically structured and analysis using GRS can yield biased associations. We discuss the likely origins of these observations and potential implications for analysis within large-scale population based genetic studies.

scholarly journals Age-varying genetic associations and implications for bias in Mendelian randomization analyses

2021 ◽  
Author(s):  
Jeremy A Labrecque ◽  
Sonja A Swanson
Keyword(s):  
Body Mass Index ◽  
Alcohol Consumption ◽  
Body Mass ◽  
Genetic Variants ◽  
Ldl Cholesterol ◽  
Mendelian Randomization ◽  
Uk Biobank ◽  
Genetic Associations ◽  
C Reactive Protein ◽  
Reactive Protein

Estimates from conventional Mendelian randomization (MR) analyses can be biased when the genetic variants proposed as instruments vary over age in their relationship with the exposure. For four exposures commonly studied using MR, we assessed the degree to which their relationship with genetic variants commonly used as instruments varies by age using flexible, spline-based models in UK Biobank data. Using these models, we then estimated how biased MR estimates would be due to age-varying relationships using plasmode simulations. We found that most genetic variants had age-varying relationships with the exposure for which they are a proposed instrument. Body mass index and LDL cholesterol had the most variation while alcohol consumption had very little. This variation over age led to small potential biases in some cases (e.g. alcohol consumption and C-reactive protein) and large potential biases for many proposed instruments for BMI and LDL.

Granularity of SERPINA1 alleles by DNA sequencing in CanCOLD

2020 ◽  
Vol 56 (4) ◽  
pp. 2000958 ◽  
Author(s):  
Nisha Gupta ◽  
Nathalie Gaudreault ◽  
Sébastien Thériault ◽  
Pei Zhi Li ◽  
Cyndi Henry ◽  
...  
Keyword(s):  
Dna Sequencing ◽  
Genetic Variants ◽  
Smoking Status ◽  
Serum Levels ◽  
Population Based ◽  
Missense Mutations ◽  
Cumulative Impact ◽  
Diffusion Capacity ◽  
Severe Deficiency ◽  
The Individual

DNA sequencing of the SERPINA1 gene to detect α1-antitrypsin (AAT) deficiency (AATD) may provide a better appreciation of the individual and cumulative impact of genetic variants on AAT serum levels and COPD phenotypes.AAT serum level and DNA sequencing of the coding regions of SERPINA1 were performed in 1359 participants of the Canadian Cohort Obstructive Lung Disease (CanCOLD) study. Clinical assessment for COPD included questionnaires, pulmonary function testing and computed tomography (CT) imaging. Phenotypes were tested for association with SERPINA1 genotypes collated into four groups: normal (MM), mild (MS and MI), intermediate (heterozygote MZ, non-S/non-Z/non-I, compound IS, and homozygote SS) and severe (ZZ and SZ) deficiency. Smoking strata and MZ-only analyses were also performed.34 genetic variants were identified including 25 missense mutations. Overall, 8.1% of alleles in this Canadian cohort were deficient and 15.5% of 1359 individuals were carriers of at least one deficient allele. Four AATD subjects were identified and had statistically lower diffusion capacity and greater CT-based emphysema. No COPD phenotypes were associated with mild and intermediate AATD in the overall cohort or stratified by smoking status. MZ heterozygotes had similar CT-based emphysema, but lowered diffusion capacity compared with normal and mild deficiency.In this Canadian population-based cohort, comprehensive genetic testing for AATD reveals a variety of deficient alleles affecting 15.5% of subjects. COPD phenotype was demonstrated in severe deficiency and MZ heterozygotes. This study shows the feasibility of implementing a diagnostic test for AATD using DNA sequencing in a large cohort.

scholarly journals Risk, Prediction and Prevention of Hereditary Breast Cancer – Large-Scale Genomic Studies in Times of Big and Smart Data

2018 ◽  
Vol 78 (05) ◽  
pp. 481-492 ◽  
Author(s):  
Marius Wunderle ◽  
Gregor Olmes ◽  
Naiba Nabieva ◽  
Lothar Häberle ◽  
Sebastian Jud ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Practice ◽  
Genetic Testing ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Risk Prediction ◽  
Genetic Variants ◽  
Large Scale ◽  
Risk Genes ◽  
The Individual

AbstractOver the last two decades genetic testing for mutations in BRCA1 and BRCA2 has become standard of care for women and men who are at familial risk for breast or ovarian cancer. Currently, genetic testing more often also includes so-called panel genes, which are assumed to be moderate-risk genes for breast cancer. Recently, new large-scale studies provided more information about the risk estimation of those genes. The utilization of information on panel genes with regard to their association with the individual breast cancer risk might become part of future clinical practice. Furthermore, large efforts have been made to understand the influence of common genetic variants with a low impact on breast cancer risk. For this purpose, almost 450 000 individuals have been genotyped for almost 500 000 genetic variants in the OncoArray project. Based on first results it can be assumed that – together with previously identified common variants – more than 170 breast cancer risk single nucleotide polymorphisms can explain up to 18% of familial breast cancer risk. The knowledge about genetic and non-genetic risk factors and its implementation in clinical practice could especially be of use for individualized prevention. This includes an individualized risk prediction as well as the individualized selection of screening methods regarding imaging and possible lifestyle interventions. The aim of this review is to summarize the most recent developments in this area and to provide an overview on breast cancer risk genes, risk prediction models and their utilization for the individual patient.

A Different Kind of Animal

2019 ◽  
Author(s):  
Robert Boyd
Keyword(s):  
Cognitive Ability ◽  
Cultural Adaptation ◽  
Dominant Species ◽  
Large Scale ◽  
Human Beings ◽  
Unique Combination ◽  
Essential Ingredient ◽  
Princeton University

Human beings have evolved to become the most dominant species on Earth. This astonishing transformation is usually explained in terms of cognitive ability—people are just smarter than all the rest. But this book argues that culture—our ability to learn from each other—has been the essential ingredient of our remarkable success. The book shows how a unique combination of cultural adaptation and large-scale cooperation has transformed our species and assured our survival—making us the different kind of animal we are today. The book is based on the Tanner Lectures delivered at Princeton University, featuring challenging responses across the chapters.

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