scholarly journals Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia

Author(s):  
Antonio F. Pardiñas ◽  
Sophie E. Smart ◽  
Isabella R. Willcocks ◽  
Peter A. Holmans ◽  
Charlotte A. Dennison ◽  
...  
2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1528-1528
Author(s):  
Heena Desai ◽  
Anh Le ◽  
Ryan Hausler ◽  
Shefali Verma ◽  
Anurag Verma ◽  
...  

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]


2020 ◽  
Author(s):  
Craig Smail ◽  
Nicole M. Ferraro ◽  
Matthew G. Durrant ◽  
Abhiram S. Rao ◽  
Matthew Aguirre ◽  
...  

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.


Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Rafik Tadros ◽  
Catherine Francis ◽  
Xiao Xu ◽  
Alexa M Vermeer ◽  
Andrew R Harper ◽  
...  

Introduction: Hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure requiring transplantation in young individuals. While some cases have a monogenic underlying cause, the majority remain unexplained. Objective: To better understand the contribution of common genetic variants in susceptibility and severity of cardiomyopathy. Methods: We conducted three genome-wide association studies (GWAS) and multi-trait analyses in European-ancestry individuals, including a HCM (1,733 cases) and DCM meta-analyses (5,521 cases), and a GWAS of 9 left ventricular (LV) traits in 19,260 healthy participants from the UK Biobank that underwent cardiac magnetic resonance imaging. We investigated genetic correlations between LV traits, HCM and DCM using LD score regression. We used two-sample mendelian randomization (MR) to assess the causal relationship of increased LV contractility with HCM risk. Lastly, we derived a polygenic risk score and assessed whether it modulates maximal LV wall thickness (maxLVWT) and clinical events in 368 sarcomeric mutation carriers, using linear and Cox mixed effects models, respectively. Results: We identified 16 genetic loci (15 novel) associated with HCM, 13 loci (7 novel) associated with DCM, and 23 loci associated with LV traits. We showed strong genetic correlations between LV volumes and contractility traits in the general population and cardiomyopathies, with opposing effects in HCM and DCM. Using MR, we demonstrated a causal association linking increased LV contractility with HCM risk and estimated that each unit (1%) increase in LV ejection fraction increases the risk of HCM by 37% (95% CI 10%-69%, P=0.004). Lastly, a polygenic risk score (PRS HCM ) derived from the HCM GWAS was associated with maxLVWT (P=0.0001) and clinical events (P=0.009) in carriers of HCM-causing rare variants. Conclusion: Our findings highlight the contribution of common genetic variants in susceptibility for HCM and DCM, and in severity in sarcomeric mutation carriers. Our data also point to increased LV contractility as an important mechanism of HCM independently of sarcomere activating rare variants, and highlight the potential clinical relevance of PRS for risk stratification in HCM.


2019 ◽  
Author(s):  
Hilda Bjork Danielsdottir ◽  
Juulia Jylhävä ◽  
Sara Hägg ◽  
Yi Lu ◽  
Lucía Colodro-Conde ◽  
...  

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.


2020 ◽  
pp. 1-16 ◽  
Author(s):  
Jessye M. Maxwell ◽  
Richard A. Russell ◽  
Hei Man Wu ◽  
Natasha Sharapova ◽  
Peter Banthorpe ◽  
...  

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.


2021 ◽  
Vol 12 ◽  
Author(s):  
Stefan Wolking ◽  
Ciarán Campbell ◽  
Caragh Stapleton ◽  
Mark McCormack ◽  
Norman Delanty ◽  
...  

Objective: Resistance to anti-seizure medications (ASMs) presents a significant hurdle in the treatment of people with epilepsy. Genetic markers for resistance to individual ASMs could support clinicians to make better-informed choices for their patients. In this study, we aimed to elucidate whether the response to individual ASMs was associated with common genetic variation.Methods: A cohort of 3,649 individuals of European descent with epilepsy was deeply phenotyped and underwent single nucleotide polymorphism (SNP)-genotyping. We conducted genome-wide association analyses (GWASs) on responders to specific ASMs or groups of functionally related ASMs, using non-responders as controls. We performed a polygenic risk score (PRS) analyses based on risk variants for epilepsy and neuropsychiatric disorders and ASM resistance itself to delineate the polygenic burden of ASM-specific drug resistance.Results: We identified several potential regions of interest but did not detect genome-wide significant loci for ASM-specific response. We did not find polygenic risk for epilepsy, neuropsychiatric disorders, and drug-resistance associated with drug response to specific ASMs or mechanistically related groups of ASMs.Significance: This study could not ascertain the predictive value of common genetic variants for ASM responder status. The identified suggestive loci will need replication in future studies of a larger scale.


2010 ◽  
Vol 80 (45) ◽  
pp. 319-329 ◽  
Author(s):  
Allyson A. West ◽  
Marie A. Caudill

Folate and choline are water-soluble micronutrients that serve as methyl donors in the conversion of homocysteine to methionine. Inadequacy of these nutrients can disturb one-carbon metabolism as evidenced by alterations in circulating folate and/or plasma homocysteine. Among common genetic variants that reside in genes regulating folate absorptive and metabolic processes, homozygosity for the MTHFR 677C > T variant has consistently been shown to have robust effects on status markers. This paper will review the impact of genetic variants in folate-metabolizing genes on folate and choline bioefficacy. Nutrient-gene and gene-gene interactions will be considered along with the need to account for these genetic variants when updating dietary folate and choline recommendations.


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