scholarly journals Neuroticism as a predictor of frailty in old age: a genetically informative approach

2019 ◽  
Author(s):  
Hilda Bjork Danielsdottir ◽  
Juulia Jylhävä ◽  
Sara Hägg ◽  
Yi Lu ◽  
Lucía Colodro-Conde ◽  
...  
Keyword(s):  
Old Age ◽  
Genetic Variants ◽  
Control Method ◽  
Frailty Index ◽  
Genetic Influences ◽  
Risk Scores ◽  
Polygenic Risk ◽  
Common Genetic Variants ◽  
Shared Genetic

ABSTRACTObjectiveNeuroticism is associated with poor health outcomes, but its contribution to the accumulation of health deficits in old age, i.e. frailty, is largely unknown. We aimed to explore associations between neuroticism and frailty cross-sectionally and over up to 29 years, and to investigate the contribution of shared genetic influences.MethodData were derived from the UK Biobank (UKB, n=502,631), the Australian Over 50’s Study (AO50, n=3,011) and the Swedish Twin Registry (SALT n=23,744, SATSA n=1,637). Associations between neuroticism and the Frailty Index were investigated using regression analysis cross-sectionally in UKB, AO50 and SATSA, and longitudinally in SALT (25-29y follow-up) and SATSA (6 and 23y follow-up). The co-twin control method was applied to explore the contribution of underlying shared familial factors (SALT, SATSA, AO50). Genome-wide polygenic risk scores for neuroticism in all samples were used to further assess whether common genetic variants associated with neuroticism predict frailty.ResultsHigh neuroticism was consistently associated with greater frailty cross-sectionally (adjusted β, 95% confidence intervals in UKB= 0.32, 0.32-0.33; AO50= 0.35, 0.31-0.39; SATSA= 0.33, 0.27-0.39) and longitudinally up to 29 years (SALT= 0.24; 0.22-0.25; SATSA 6y= 0.31, 0.24-0.38; SATSA 23y= 0.16, 0.07-0.25). When controlling for underlying shared genetic and environmental factors the neuroticism-frailty association remained significant, although decreased. Polygenic risk scores for neuroticism significantly predicted frailty in the two larger samples (meta-analyzed total β= 0.06, 0.05-0.06).ConclusionHigh neuroticism is associated with the development and course of frailty. Both environmental and genetic influences, including neuroticism-associated genetic variants, contribute to this relationship.

Performance of polygenic risk scores for cancer prediction in an academic biobank.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1528-1528
Author(s):  
Heena Desai ◽  
Anh Le ◽  
Ryan Hausler ◽  
Shefali Verma ◽  
Anurag Verma ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Variants ◽  
Association Studies ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
European Americans ◽  
Genome Wide ◽  
Common Genetic Variants

1528 Background: The discovery of rare genetic variants associated with cancer have a tremendous impact on reducing cancer morbidity and mortality when identified; however, rare variants are found in less than 5% of cancer patients. Genome wide association studies (GWAS) have identified hundreds of common genetic variants significantly associated with a number of cancers, but the clinical utility of individual variants or a polygenic risk score (PRS) derived from multiple variants is still unclear. Methods: We tested the ability of polygenic risk score (PRS) models developed from genome-wide significant variants to differentiate cases versus controls in the Penn Medicine Biobank. Cases for 15 different cancers and cancer-free controls were identified using electronic health record billing codes for 11,524 European American and 5,994 African American individuals from the Penn Medicine Biobank. Results: The discriminatory ability of the 15 PRS models to distinguish their respective cancer cases versus controls ranged from 0.68-0.79 in European Americans and 0.74-0.93 in African Americans. Seven of the 15 cancer PRS trended towards an association with their cancer at a p<0.05 (Table), and PRS for prostate, thyroid and melanoma were significantly associated with their cancers at a bonferroni corrected p<0.003 with OR 1.3-1.6 in European Americans. Conclusions: Our data demonstrate that common variants with significant associations from GWAS studies can distinguish cancer cases versus controls for some cancers in an unselected biobank population. Given the small effects, future studies are needed to determine how best to incorporate PRS with other risk factors in the precision prediction of cancer risk. [Table: see text]

scholarly journals Integration of rare large-effect expression variants improves polygenic risk prediction

2020 ◽  
Author(s):  
Craig Smail ◽  
Nicole M. Ferraro ◽  
Matthew G. Durrant ◽  
Abhiram S. Rao ◽  
Matthew Aguirre ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Rare Variants ◽  
Complex Trait ◽  
Risk Scores ◽  
Multiple Traits ◽  
Polygenic Risk ◽  
Common Genetic Variants ◽  
Using Data ◽  
The Uk ◽  
The Impact

SummaryPolygenic risk scores (PRS) aim to quantify the contribution of multiple genetic loci to an individual’s likelihood of a complex trait or disease. However, existing PRS estimate genetic liability using common genetic variants, excluding the impact of rare variants. We identified rare, large-effect variants in individuals with outlier gene expression from the GTEx project and then assessed their impact on PRS predictions in the UK Biobank (UKB). We observed large deviations from the PRS-predicted phenotypes for carriers of multiple outlier rare variants; for example, individuals classified as “low-risk” but in the top 1% of outlier rare variant burden had a 6-fold higher rate of severe obesity. We replicated these findings using data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) biobank and the Million Veteran Program, and demonstrated that PRS across multiple traits will significantly benefit from the inclusion of rare genetic variants.

Multifactorial disorders and polygenic risk scores: predicting common diseases and the possibility of adverse selection in life and protection insurance

2020 ◽  
pp. 1-16 ◽  
Author(s):  
Jessye M. Maxwell ◽  
Richard A. Russell ◽  
Hei Man Wu ◽  
Natasha Sharapova ◽  
Peter Banthorpe ◽  
...  
Keyword(s):  
Risk Factors ◽  
Adverse Selection ◽  
Genetic Variants ◽  
Risk Information ◽  
Risk Scores ◽  
Uk Biobank ◽  
Polygenic Risk ◽  
Common Genetic Variants ◽  
Multifactorial Disorders ◽  
The Uk

Abstract During the past decade, genetics research has allowed scientists and clinicians to explore the human genome in detail and reveal many thousands of common genetic variants associated with disease. Genetic risk scores, known as polygenic risk scores (PRSs), aggregate risk information from the most important genetic variants into a single score that describes an individual’s genetic predisposition to a given disease. This article reviews recent developments in the predictive utility of PRSs in relation to a person’s susceptibility to breast cancer and coronary artery disease. Prognostic models for these disorders are built using data from the UK Biobank, controlling for typical clinical and underwriting risk factors. Furthermore, we explore the possibility of adverse selection where genetic information about multifactorial disorders is available for insurance purchasers but not for underwriters. We demonstrate that prediction of multifactorial diseases, using PRSs, provides population risk information additional to that captured by normal underwriting risk factors. This research using the UK Biobank is in the public interest as it contributes to our understanding of predicting risk of disease in the population. Further research is imperative to understand how PRSs could cause adverse selection if consumers use this information to alter their insurance purchasing behaviour.

scholarly journals Use of schizophrenia and bipolar disorder polygenic risk scores to identify psychotic disorders

2018 ◽  
Vol 213 (3) ◽  
pp. 535-541 ◽  
Author(s):  
Maria Stella Calafato ◽  
Johan H. Thygesen ◽  
Siri Ranlund ◽  
Eirini Zartaloudi ◽  
Wiepke Cahn ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Predictive Models ◽  
Genetic Variants ◽  
Psychotic Disorders ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
Early Interventions ◽  
Polygenic Risk ◽  
Increases In Risk ◽  
Shared Genetic

BackgroundThere is increasing evidence for shared genetic susceptibility between schizophrenia and bipolar disorder. Although genetic variants only convey subtle increases in risk individually, their combination into a polygenic risk score constitutes a strong disease predictor.AimsTo investigate whether schizophrenia and bipolar disorder polygenic risk scores can distinguish people with broadly defined psychosis and their unaffected relatives from controls.MethodUsing the latest Psychiatric Genomics Consortium data, we calculated schizophrenia and bipolar disorder polygenic risk scores for 1168 people with psychosis, 552 unaffected relatives and 1472 controls.ResultsPatients with broadly defined psychosis had dramatic increases in schizophrenia and bipolar polygenic risk scores, as did their relatives, albeit to a lesser degree. However, the accuracy of predictive models was modest.ConclusionsAlthough polygenic risk scores are not ready for clinical use, it is hoped that as they are refined they could help towards risk reduction advice and early interventions for psychosis.Declaration of interestR.M.M. has received honoraria for lectures from Janssen, Lundbeck, Lilly, Otsuka and Sunovian.

Association between Polygenic Risk Scores for ADHD and Asthma: A Birth Cohort Investigation

2021 ◽  
pp. 108705472110201
Author(s):  
Douglas Teixeira Leffa ◽  
Bernardo Horta ◽  
Fernando C. Barros ◽  
Ana M. B. Menezes ◽  
Thais Martins-Silva ◽  
...  
Keyword(s):  
Birth Cohort ◽  
Genetic Background ◽  
Adult Adhd ◽  
Risk Scores ◽  
Asthma Diagnosis ◽  
Polygenic Risk ◽  
Increased Risk ◽  
Genetic Overlap ◽  
Genetic Mechanisms ◽  
Shared Genetic

Objective: Shared genetic mechanisms have been hypothesized to explain the comorbidity between ADHD and asthma. To evaluate their genetic overlap, we relied on data from the 1982 Pelotas birth cohort to test the association between polygenic risk scores (PRSs) for ADHD (ADHD-PRSs) and asthma, and PRSs for asthma (asthma-PRSs) and ADHD. Method: We analyzed data collected at birth, 2, 22, and 30 years from 3,574 individuals. Results: Subjects with ADHD had increased risk of having asthma (OR 1.92, 95% CI 1.01–3.66). The association was stronger for females. Our results showed no evidence of association between ADHD-PRSs and asthma or asthma-PRSs and ADHD. However, an exploratory analysis suggested that adult ADHD might be genetically associated with asthma. Conclusion: Our results do not support a shared genetic background between both conditions. Findings should be viewed in light of important limitations, particularly the sample size and the self-reported asthma diagnosis. Studies in larger datasets are required to better explore the genetic overlap between adult ADHD and asthma.

scholarly journals Age-related late-onset disease heritability patterns and implications for genome-wide association studies

2018 ◽  
Author(s):  
Roman Teo Oliynyk
Keyword(s):  
Old Age ◽  
Cumulative Incidence ◽  
Late Onset ◽  
Association Studies ◽  
Genome Wide Association ◽  
Risk Scores ◽  
Cerebral Stroke ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Genome Wide

AbstractBackgroundGenome-wide association studies and other computational biology techniques are gradually discovering the causal gene variants that contribute to late-onset human diseases. After more than a decade of genome-wide association study efforts, these can account for only a fraction of the heritability implied by familial studies, the so-called “missing heritability” problem.MethodsComputer simulations of polygenic late-onset diseases in an aging population have quantified the risk allele frequency decrease at older ages caused by individuals with higher polygenic risk scores becoming ill proportionately earlier. This effect is most prominent for diseases characterized by high cumulative incidence and high heritability, examples of which include Alzheimer’s disease, coronary artery disease, cerebral stroke, and type 2 diabetes.ResultsThe incidence rate for late-onset diseases grows exponentially for decades after early onset ages, guaranteeing that the cohorts used for genome-wide association studies overrepresent older individuals with lower polygenic risk scores, whose disease cases are disproportionately due to environmental causes such as old age itself. This mechanism explains the decline in clinical predictive power with age and the lower discovery power of familial studies of heritability and genome-wide association studies. It also explains the relatively constant-with-age heritability found for late-onset diseases of lower prevalence, exemplified by cancers.ConclusionsFor late-onset polygenic diseases showing high cumulative incidence together with high initial heritability, rather than using relatively old age-matched cohorts, study cohorts combining the youngest possible cases with the oldest possible controls may significantly improve the discovery power of genome-wide association studies.

scholarly journals Shared genetic background between children and adults with attention deficit/hyperactivity disorder

2019 ◽  
Author(s):  
Paula Rovira ◽  
Ditte Demontis ◽  
Cristina Sánchez-Mora ◽  
Tetyana Zayats ◽  
Marieke Klein ◽  
...  
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Attention Deficit ◽  
Genetic Variants ◽  
Genetic Background ◽  
Genetic Architecture ◽  
Neurodevelopmental Disorder ◽  
Genome Wide Association Studies ◽  
Hyperactivity Disorder ◽  
Common Genetic Variants ◽  
Shared Genetic

AbstractAttention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.

scholarly journals Alzheimer’s disease genetic risk and sleep phenotypes: association with more slow-waves and daytime sleepiness

2020 ◽  
Author(s):  
Vincenzo Muto ◽  
Ekaterina Koshmanova ◽  
Pouya Ghaemmaghami ◽  
Mathieu Jaspar ◽  
Christelle Meyer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Young Adults ◽  
Genetic Variants ◽  
Daytime Sleepiness ◽  
Sleep Disturbances ◽  
Cognitive Disorders ◽  
Risk Scores ◽  
Polygenic Risk ◽  
Genome Wide

AbstractSleep disturbances and genetic variants have been identified as risk factors for Alzheimer’s disease. Whether genome-wide polygenic risk scores (PRS) for AD associate with sleep phenotypes in young adults, decades before typical AD symptom onset, is currently not known. We extensively phenotyped sleep under different sleep conditions and compute whole-genome Polygenic Risk Scores (PRS) for AD in a carefully selected homogenous sample of healthy 363 young men (22.1 y ± 2.7) devoid of sleep and cognitive disorders. AD PRS was associated with more slow wave energy, i.e. the cumulated power in the 0.5-4 Hz EEG band, a marker of sleep need, during habitual sleep and following sleep loss. Furthermore higher AD PRS was correlated with higher habitual daytime sleepiness. These results imply that sleep features may be associated with AD liability in young adults, when current AD biomarkers are typically negative, and reinforce the idea that sleep may be an efficient intervention target for AD.

scholarly journals Do we measure or compute polygenic risk scores? Why language matters

2020 ◽  
Author(s):  
Bart Penders ◽  
A. Cecile J.W. Janssens
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Genetic Variants ◽  
Sodium Level ◽  
Risk Scores ◽  
Polygenic Risk ◽  
Stark Contrast ◽  
Epistemic Objects ◽  
Knowledge Claims

Here, we argue that polygenic risk scores (PRSs) are different epistemic objects as compared to other biomarkers such as blood pressure or sodium level. While the latter two may be subject to variation, measured inaccurately or interpreted in various ways, blood flow has a pressure and sodium is available in a concentration that can be quantified and visualised. In stark contrast, PRSs are calculated, compiled or constructed through the statistical assemblage of genetic variants. How researchers frame and name PRSs has consequences for how we interpret and value their results. We distinguish between the tangible and inferential understanding of PRS and the corresponding languages of measurement and computation, respectively. The conflation of these frames obscures important questions we need to ask: what PRS seeks to represent, whether current ways of ‘doing PRS’ are optimal and responsible, and upon what we base the credibility of PRS-based knowledge claims.

scholarly journals Risk Prediction Using Polygenic Risk Scores for Prevention of Stroke and Other Cardiovascular Diseases

Stroke ◽  
2021 ◽  
Author(s):  
Gad Abraham ◽  
Loes Rutten-Jacobs ◽  
Michael Inouye
Keyword(s):  
Risk Prediction ◽  
Risk Scores ◽  
Future Research ◽  
Cvd Risk ◽  
Polygenic Risk ◽  
Monogenic Disorders ◽  
Current State ◽  
Common Genetic Variants ◽  
Artery Disease

Early prediction of risk of cardiovascular disease (CVD), including stroke, is a cornerstone of disease prevention. Clinical risk scores have been widely used for predicting CVD risk from known risk factors. Most CVDs have a substantial genetic component, which also has been confirmed for stroke in recent gene discovery efforts. However, the role of genetics in prediction of risk of CVD, including stroke, has been limited to testing for highly penetrant monogenic disorders. In contrast, the importance of polygenic variation, the aggregated effect of many common genetic variants across the genome with individually small effects, has become more apparent in the last 5 to 10 years, and powerful polygenic risk scores for CVD have been developed. Here we review the current state of the field of polygenic risk scores for CVD including stroke, and their potential to improve CVD risk prediction. We present findings and lessons from diseases such as coronary artery disease as these will likely be useful to inform future research in stroke polygenic risk prediction.

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