scholarly journals Septic Shock: A Genomewide Association Study and Polygenic Risk Score Analysis

2020 ◽  
Vol 23 (4) ◽  
pp. 204-213
Author(s):  
Shannon D’Urso ◽  
Dorrilyn Rajbhandari ◽  
Elizabeth Peach ◽  
Erika de Guzman ◽  
Qiang Li ◽  
...  
Keyword(s):  
Septic Shock ◽  
Genetic Association ◽  
Risk Score ◽  
Noncoding Rna ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Score Analysis ◽  
Genomewide Association

AbstractPrevious genetic association studies have failed to identify loci robustly associated with sepsis, and there have been no published genetic association studies or polygenic risk score analyses of patients with septic shock, despite evidence suggesting genetic factors may be involved. We systematically collected genotype and clinical outcome data in the context of a randomized controlled trial from patients with septic shock to enrich the presence of disease-associated genetic variants. We performed genomewide association studies of susceptibility and mortality in septic shock using 493 patients with septic shock and 2442 population controls, and polygenic risk score analysis to assess genetic overlap between septic shock risk/mortality with clinically relevant traits. One variant, rs9489328, located in AL589740.1 noncoding RNA, was significantly associated with septic shock (p = 1.05 × 10–10); however, it is likely a false-positive. We were unable to replicate variants previously reported to be associated (p < 1.00 × 10–6 in previous scans) with susceptibility to and mortality from sepsis. Polygenic risk scores for hematocrit and granulocyte count were negatively associated with 28-day mortality (p = 3.04 × 10–3; p = 2.29 × 10–3), and scores for C-reactive protein levels were positively associated with susceptibility to septic shock (p = 1.44 × 10–3). Results suggest that common variants of large effect do not influence septic shock susceptibility, mortality and resolution; however, genetic predispositions to clinically relevant traits are significantly associated with increased susceptibility and mortality in septic individuals.

scholarly journals Investigation of the Genetic Association between Quantitative Measures of Psychosis and Schizophrenia: A Polygenic Risk Score Analysis

PLoS ONE ◽  
2012 ◽  
Vol 7 (6) ◽  
pp. e37852 ◽  
Author(s):  
Eske M. Derks ◽  
Jacob A. S. Vorstman ◽  
Stephan Ripke ◽  
Rene S. Kahn ◽  
Roel A. Ophoff ◽  
...  
Keyword(s):  
Genetic Association ◽  
Risk Score ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Score Analysis

scholarly journals Pharmacogenetic Polygenic Risk Score for Bronchodilator Response in Children and Adolescents with Asthma: Proof-of-Concept

2021 ◽  
Vol 11 (4) ◽  
pp. 319
Author(s):  
Joanne E. Sordillo ◽  
Sharon M. Lutz ◽  
Michael J. McGeachie ◽  
Jessica Lasky-Su ◽  
Scott T. Weiss ◽  
...  
Keyword(s):  
Standard Deviation ◽  
Risk Score ◽  
Association Studies ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Linear Regression Models ◽  
Standard Deviation Increase ◽  
Polygenic Risk ◽  
Bronchodilator Response ◽  
Children With Asthma

Genome-wide association studies (GWAS) of response to asthma medications have primarily focused on Caucasian populations, with findings that may not be generalizable to minority populations. We derived a polygenic risk score (PRS) for response to albuterol as measured by bronchodilator response (BDR), and examined the PRS in a cohort of Hispanic school-aged children with asthma. We leveraged a published GWAS of BDR to identify relevant genetic variants, and ranked the top variants according to their Combined Annotation Dependent Depletion (CADD) scores. Variants with CADD scores greater than 10 were used to compute the PRS. Once we derived the PRS, we determined the association of the PRS with BDR in a cohort of Hispanic children with asthma (the Genetics of Asthma in Costa Rica Study (GACRS)) in adjusted linear regression models. Mean BDR in GACRS participants was5.6% with a standard deviation of 10.2%. We observed a 0.63% decrease in BDR in response to albuterol for a standard deviation increase in the PRS (p = 0.05). We also observed decreased odds of a BDR response at or above the 12% threshold for a one standard deviation increase in the PRS (OR = 0.80 (95% CI 0.67 to 0.95)). Our findings show that combining variants from a pharmacogenetic GWAS into a PRS may be useful for predicting medication response in asthma.

scholarly journals Polygenic risk for schizophrenia, transition and cortical gyrification: a high-risk study

2017 ◽  
Vol 48 (9) ◽  
pp. 1532-1539 ◽  
Author(s):  
E. Neilson ◽  
C. Bois ◽  
T.-K. Clarke ◽  
L. Hall ◽  
E. C. Johnstone ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Score ◽  
Familial Risk ◽  
Positive Association ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Score Analysis ◽  
Increased Risk ◽  
Heritable Disorder ◽  
Diagnostic Symptoms

AbstractBackgroundSchizophrenia is a highly heritable disorder, linked to several structural abnormalities of the brain. More specifically, previous findings have suggested that increased gyrification in frontal and temporal regions are implicated in the pathogenesis of schizophrenia.MethodsThe current study included participants at high familial risk of schizophrenia who remained well (n= 31), who developed sub-diagnostic symptoms (n= 28) and who developed schizophrenia (n= 9) as well as healthy controls (HC) (n= 16). We first tested whether individuals at high familial risk of schizophrenia carried an increased burden of trait-associated alleles using polygenic risk score analysis. We then assessed the extent to which polygenic risk was associated with gyral folding in the frontal and temporal lobes.ResultsWe found that individuals at high familial risk of schizophrenia who developed schizophrenia carried a significantly greater burden of risk-conferring variants for the disorder compared to those at high risk (HR) who developed sub-diagnostic symptoms or remained well and HC. Furthermore, within the HR cohort, there was a significant and positive association between schizophrenia polygenic risk score and bilateral frontal gyrification.ConclusionsThese results suggest that polygenic risk for schizophrenia impacts upon early neurodevelopment to confer greater gyral folding in adulthood and an increased risk of developing the disorder.

Distinct Genetic Profiles in Postpartum Depression With Different Trajectory of Illness

2020 ◽  
Author(s):  
Nagahide Takahashi ◽  
Hanae Tainaka ◽  
Tomoko Nishimura ◽  
Taeko Harada ◽  
Akemi Okumura ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Postpartum Depression ◽  
Risk Score ◽  
Association Studies ◽  
Depression Scale ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Gene Set Enrichment ◽  
Polygenic Risk ◽  
Gene Set

Abstract BackgroundPostpartum depression (PPD) is a common and highly heritabledisorder in the postnatal period of new mothers. The development of PPD is shown to affectneurodevelopment in children and recent evidence suggests thatthe trajectory of PPDisalso associated with children’s neurodevelopment and mental conditions. Thus, early identification and intervention for individuals at high risk of PPD are urgently needed.Additionally, it is not clear whether genetic factors affect thetrajectory of PPD. Therefore, using a polygenic risk score (PRS) approach, we investigated if PRS for depression (Depression-PRS) and bipolar disorder (Bipolar-PRS) are associated with the development and clinical course of PPD.Methods Usingrecent large genome-wide association studies(GWAS) of depression and bipolar disorder as discovery cohorts, we calculatedDepression-PRS and Bipolar-PRS in each individual. Then, we investigated the possible association between Depression-PRS and Bipolar-PRS with the development andtrajectory of PPD insubjects from the Hamamatsu Birth Cohort for mothers and children (n = 136). Depressive symptoms were assessed using the Edinburgh Postpartum Depression Scale. Gene-set enrichment analyses were used to identify pathways underlying these conditions. ResultsDepression-PRS was significantly higher in subjects with PPD than in those without PPD(t = -3.283, P = 0.002)and logistic analysis showed that Depression-PRS significantly increases therisk of developing PPD(OR [SE] = 2.274 [0.585], P = 0.002). Furthermore, Depression-PRS was positively associated with continuity of PPD (β [SE]=1.621 [0.672]; P = 0.032).Gene-set enrichment analyses revealed that pathways such as“response to hormone”(β[SE] -2.285[1.002], P < 0.001) and “epigenetic regulation”(β[SE] 2.831 [1.317], P < 0.001) were involved in the continuity of PPD. ConclusionThese preliminary findings indicate that the genetic component plays an important role not only in the development but also inthe continuity of PPD. A polygenic risk score approach could be useful to identify subjects at risk for PPD, especially for persistent PPD,who needcareful monitoring and intervention after delivery.

scholarly journals POLYGENIC RISK SCORE ANALYSIS OF ALZHEIMER’S DISEASE IN CASES WITHOUT APOE4 OR APOE2 ALLELES

2018 ◽  
pp. 1-4
Author(s):  
V. Escott-Price ◽  
A. Myers ◽  
M. Huentelman ◽  
M. Shoai ◽  
J. Hardy
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Score ◽  
Clinical Trial Design ◽  
Polygenic Risk Score ◽  
Carrier Status ◽  
Predictive Utility ◽  
Polygenic Risk ◽  
Score Analysis ◽  
E4 Allele

The We and others have previously shown that polygenic risk score analysis (PRS) has considerable predictive utility for identifying those at high risk of developing Alzheimer’s disease (AD) with an area under the curve (AUC) of >0.8. However, by far the greatest determinant of this risk is the apolipoprotein E locus with the E4 allele alone giving an AUC of ~0.68 and the inclusion of the protective E2 allele increasing this to ~0.69 in a clinical cohort. An important question is to determine how good PRS is at predicting risk in those who do not carry the E4 allele (E3 homozygotes, E3E2 and E2E2) and in those who carry neither the E4 or E2 allele (i.e. E3 homozygotes). Previous studies have shown that PRS remains a significant predictor of AD risk in clinical cohorts after controlling for APOE ε4 carrier status. In this study we assess the accuracy of PRS prediction in a cohort of pathologically confirmed AD cases and controls. The exclusion of APOE4 carriers has surprisingly little effect on the PRS prediction accuracy (AUC ~0.83 [95% CI: 0.80-0.86]), and the accuracy remained higher than that in clinical cohorts with APOE included as a predictor. From a practical perspective this suggests that PRS analysis will have predictive utility even in E4 negative individuals and may be useful in clinical trial design.

scholarly journals A polygenic risk score analysis of psychosis endophenotypes across brain functional, structural, and cognitive domains

2017 ◽  
Vol 177 (1) ◽  
pp. 21-34 ◽  
Author(s):  
Siri Ranlund ◽  
Stella Calafato ◽  
Johan H. Thygesen ◽  
Kuang Lin ◽  
Wiepke Cahn ◽  
...  
Keyword(s):  
Risk Score ◽  
Polygenic Risk Score ◽  
Cognitive Domains ◽  
Polygenic Risk ◽  
Score Analysis

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]

Sign in / Sign up

Export Citation Format

Share Document