scholarly journals TU73. GENETIC LIABILITIES OF SCHIZOPHRENIA RISK FACTORS AS POLYGENIC SCORES FOR CASE STATUS PREDICTION: APPLICATION AND BIAS EVALUATION IN A MULTI-ANCESTRY SETTING

2021 ◽  
Vol 51 ◽  
pp. e135
Author(s):  
Umme Habiba ◽  
James T.R. Walters ◽  
Pakeeza A. Shaiq ◽  
Muhammad R. Memon ◽  
Antonio F. Pardinas
Keyword(s):  
Risk Factors ◽  
Polygenic Scores ◽  
Case Status ◽  
Bias Evaluation

scholarly journals Genetic risk for major depressive disorder and loneliness in sex-specific associations with coronary artery disease

2019 ◽  
Author(s):  
Jessica Dennis ◽  
Julia Sealock ◽  
Rebecca T. Levinson ◽  
Eric Farber-Eger ◽  
Jacob Franco ◽  
...  
Keyword(s):  
Risk Factors ◽  
Coronary Artery Disease ◽  
Major Depressive Disorder ◽  
Coronary Artery ◽  
Genetic Risk ◽  
European Ancestry ◽  
Major Depressive ◽  
Polygenic Score ◽  
Polygenic Scores ◽  
Artery Disease

AbstractMajor depressive disorder (MDD) and loneliness are phenotypically and genetically correlated with coronary artery disease (CAD), but whether these associations are explained by pleiotropic genetic variants or shared comorbidities is unclear. To tease apart these scenarios, we first assessed the medical morbidity pattern associated with genetic risk factors for MDD and loneliness by conducting a phenome-wide association study in 18,385 European-ancestry individuals in the Vanderbilt University Medical Center biobank, BioVU. Polygenic scores for MDD and loneliness were developed for each person using previously published meta-GWAS summary statistics, and were tested for association with 882 clinical diagnoses ascertained via billing codes in electronic health records. We discovered strong associations with heart disease diagnoses, and next embarked on targeted analyses of CAD in 3893 cases and 4197 controls. We found odds ratios of 1.11 (95% CI, 1.04–1.18; P 8.43 × 10−4) and 1.13 (95% CI, 1.07–1.20; P 4.51 × 10−6) per 1-SD increase in the polygenic scores for MDD and loneliness, respectively. Results were similar in patients without psychiatric symptoms, and the increased risk persisted in females even after adjusting for multiple conventional risk factors and a polygenic score for CAD. In a final sensitivity analysis, we statistically adjusted for the genetic correlation between MDD and loneliness and re-computed polygenic scores. The polygenic score unique to loneliness remained associated with CAD (OR 1.09, 95% CI 1.03–1.15; P 0.002), while the polygenic score unique to MDD did not (OR 1.00, 95% CI 0.95–1.06; P 0.97). Our replication sample was the Atherosclerosis Risk in Communities (ARIC) cohort of 7197 European-ancestry participants (1598 incident CAD cases). In ARIC, polygenic scores for MDD and loneliness were associated with hazard ratios of 1.07 (95% CI, 0.99–1.14; P = 0.07) and 1.07 (1.01–1.15; P = 0.03), respectively, and we replicated findings from the BioVU sensitivity analyses. We conclude that genetic risk factors for MDD and loneliness act pleiotropically to increase CAD risk in females.

scholarly journals Genetic risk for major depressive disorder and loneliness in gender-specific associations with coronary artery disease

2019 ◽  
Author(s):  
Jessica Dennis ◽  
Julia Sealock ◽  
Rebecca T Levinson ◽  
Eric Farber-Eger ◽  
Jacob Franco ◽  
...  
Keyword(s):  
Risk Factors ◽  
Coronary Artery Disease ◽  
Association Study ◽  
Genetic Risk ◽  
Genetic Risk Factors ◽  
Major Depressive ◽  
Polygenic Score ◽  
Polygenic Scores ◽  
Artery Disease ◽  
Cad Risk

AbstractImportanceEpidemiological evidence indicates that major depressive disorder (MDD) and loneliness both reduce life expectancies, but mechanisms underlying the excess morbidity are unclear. Electronic health records (EHRs) linked to genetic data offer new opportunities to address this knowledge gap.ObjectiveTo determine the medical morbidity pattern associated with genetic risk factors for MDD and loneliness, two common psychological traits with adverse health outcomes.DesignPhenome-wide association study using EHRs spanning 1990 to 2017 from the Vanderbilt University Medical Center biobank, BioVU. Top associations with coronary artery disease (CAD) were replicated in the Atherosclerosis Risk in Communities (ARIC) cohort.SettingHospital-based EHR study, with replication in a population-based cohort study.Participants18,385 genotyped adult patients in BioVU. Replication in ARIC included 7,197 genotyped participants. All participants were of European ancestry.ExposuresPolygenic scores for MDD and loneliness were developed for each individual using previously published meta-GWAS summary statistics.Main Outcomes and MeasuresThe phenome-wide association study included 882 clinical diagnoses ascertained via billing codes in the EHR. ARIC included 1598 incident CAD cases.ResultsBioVU patients had a median EHR length of 9.91 years. In the phenome-wide association study, polygenic scores for MDD and loneliness were significantly associated with psychiatric and cardiac phenotypes. Targeted analyses of CAD in 3,893 cases and 4,197 controls in BioVU found odds ratios of 1.11 (95% CI, 1.04-1.18; P=8.43×10−4) and 1.13 (95% CI, 1.07-1.20; P=4.51×10−6) per 1-SD increase in the polygenic scores for MDD and loneliness, respectively. Comparable hazard ratios in ARIC were 1.07 (95% CI, 0.99-1.14; P=0.07) and 1.07 (1.01-1.15; P=0.03). Across both studies, the increased risk persisted in women after adjusting for multiple conventional risk factors, a polygenic score for CAD, and psychiatric symptoms (available in BioVU). Controlling for genetic risk factors shared between MDD and loneliness, the polygenic score for loneliness conditioned on MDD remained associated with CAD risk, but the polygenic score for MDD conditioned on loneliness did not.Conclusions and RelevanceGenetic risk factors for MDD and loneliness act pleiotropically to increase CAD risk in women. Continued research into the biological and clinical connections between the heart and mind is warranted.

scholarly journals Identifying intergenerational risk factors for ADHD symptoms using polygenic scores in the Norwegian Mother, Father and Child Cohort

2021 ◽  
Author(s):  
Jean-Baptiste Pingault ◽  
Wikus Barkhuizen ◽  
Biyao Wang ◽  
Laurie J. Hannigan ◽  
Espen Moen Eilertsen ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cohort Study ◽  
Educational Attainment ◽  
Intergenerational Transmission ◽  
Rating Scale ◽  
Autism Spectrum ◽  
Intellectual Ability ◽  
Adhd Symptoms ◽  
Genetic Transmission ◽  
Polygenic Scores

AbstractImportanceKnowledge of the mechanisms underlying the intergenerational transmission of risk for attention-deficit/hyperactivity disorder (ADHD) symptoms can inform psychosocial interventions.ObjectiveTo investigate whether parental genetic risk factors associate with their children’s ADHD symptoms due to genetic transmission of risk or due to parental genetic liability that influences offspring ADHD via parenting environments (genetic nurture).Design and participantsThis study is based on the Norwegian Mother, Father and Child Cohort Study and uses data from the Medical Birth Registry of Norway. This prospective cohort study consisted of 5,405 mother-father-offspring trios recruited between 1999 – 2008.ExposuresWe calculated polygenic scores for parental traits previously associated with ADHD, including psychopathology, substance use, neuroticism, educational attainment and intellectual ability.Main outcomes and measuresMothers reported on their 8-year-old children’s ADHD symptoms using the Parent/Teacher Rating Scale for Disruptive Behavior Disorders.ResultsMaternal polygenic scores for ADHD, autism spectrum disorder (ASD), neuroticism and smoking predicted child ADHD symptoms in bivariate analyses. After jointly modelling maternal, paternal and child polygenic scores, ADHD symptoms were predicted by children’s polygenic scores for ADHD (β = 0.10; 95% CI 0.07 to 0.14), smoking (β = 0.07; 95% CI 0.03 to 0.10) and educational attainment (β = −0.09; 95% CI −0.13 to −0.05), indicating direct genetic transmission of risk. Mothers’ polygenic scores for ASD (β = 0.05; 95% CI 0.02 to 0.08) and neuroticism (β = 0.05; 95% CI 0.01 to 0.08) predicted children’s ADHD symptoms conditional on fathers’ and children’s scores, implicating genetic nurture, or effects due to population stratification or assortative mating.ConclusionsThese results suggest that associations between some parental traits and offspring ADHD symptoms likely reflect a nuanced mix of direct genetic transmission (ADHD, smoking and educational attainment) and genetic nurture (ASD and neuroticism). If confirmed, these findings support previous evidence that maternal ASD or neuroticism may be possible targets for intervention to help break the chain of the intergenerational transmission of ADHD risk.

scholarly journals Genetic sensitivity analysis: adjusting for genetic confounding in epidemiological associations

2019 ◽  
Author(s):  
Jean-Baptiste Pingault ◽  
Frühling Rijsdijk ◽  
Tabea Schoeler ◽  
Shing Wan Choi ◽  
Saskia Selzam ◽  
...  
Keyword(s):  
Risk Factors ◽  
Body Mass Index ◽  
Attention Deficit Hyperactivity Disorder ◽  
Sensitivity Analysis ◽  
Risk Factor ◽  
Attention Deficit ◽  
Maternal Education ◽  
Educational Achievement ◽  
Hyperactivity Disorder ◽  
Polygenic Scores

AbstractAssociations between exposures and outcomes reported in epidemiological studies are typically unadjusted for genetic confounding. We propose a two-stage approach for estimating the degree to which such observed associations can be explained by genetic confounding. First, we assess attenuation of exposure effects in regressions controlling for increasingly powerful polygenic scores. Second, we use structural equation models to estimate genetic confounding using heritability estimates derived from both SNP-based and twin-based studies. We examine associations between maternal education and three developmental outcomes – child educational achievement, Body Mass Index, and Attention Deficit Hyperactivity Disorder. Polygenic scores explain between 14.3% and 23.0% of the original associations, while analyses under SNP- and twin-based heritability scenarios indicate that observed associations could be almost entirely explained by genetic confounding. Thus, caution is needed when interpreting associations from non-genetically informed epidemiology studies. Our approach, akin to a genetically informed sensitivity analysis can be applied widely.Author summaryAn objective shared across the life, behavioural, and social sciences is to identify factors that increase risk for a particular disease or trait. However, identifying true risk factors is challenging. Often, a risk factor is statistically associated with a disease even if it is not really relevant, meaning that even successfully improving the risk factor will not impact the disease. One reason for the existence of such misleading associations stems from genetic confounding. This is when genetic factors influence both the risk factor and the disease, which generates a statistical association even in the absence of a true effect of the risk factor. Here, we propose a method to estimate genetic confounding and quantify its effect on observed associations. We show that a large part of the associations between maternal education and three child outcomes - educational achievement, body mass index and Attention-Deficit Hyperactivity Disorder-is explained by genetic confounding. Our findings can be applied to better understand the role of genetics in explaining associations of key risk factors with diseases and traits.

Evolving epidemiology of reported cryptosporidiosis cases in the United States, 1995–2012

2015 ◽  
Vol 144 (8) ◽  
pp. 1792-1802 ◽  
Author(s):  
J. E. PAINTER ◽  
J. W. GARGANO ◽  
J. S. YODER ◽  
S. A. COLLIER ◽  
M. C. HLAVSA
Keyword(s):  
United States ◽  
Risk Factors ◽  
Race And Ethnicity ◽  
Negative Binomial ◽  
Disease Outbreaks ◽  
Negative Binomial Regression ◽  
The United States ◽  
Case Status ◽  
Estimate Rate ◽  
Rate Ratios

SUMMARYCryptosporidiumis the leading aetiology of waterborne disease outbreaks in the United States. This report briefly describes the temporal and geographical distribution of US cryptosporidiosis cases and presents analyses of cryptosporidiosis case data reported in the United States for 1995–2012. The Cochran–Armitage test was used to assess changes in the proportions of cases by case status (confirmedvs.non-confirmed), sex, race, and ethnicity over the study period. Negative binomial regression models were used to estimate rate ratios (RR) and 95% confidence intervals (CI) for comparing rates across three time periods (1995–2004, 2005–2008, 2009–2012). The proportion of confirmed cases significantly decreased (P< 0·0001), and a crossover from male to female predominance in case-patients occurred (P< 0·0001). Overall, compared to 1995–2004, rates were higher in 2005–2008 (RR 2·92, 95% CI 2·08–4·09) and 2009–2012 (RR 2·66, 95% CI 1·90–3·73). However, rate changes from 2005–2008 to 2009–2012 varied by age group (Pinteraction< 0·0001): 0–14 years (RR 0·55, 95% CI 0·42–0·71), 15–44 years (RR 0·99, 95% CI 0·82–1·19), 45–64 years (RR 1·47, 95% CI 1·21–1·79) and ⩾65 years (RR 2·18, 95% CI 1·46–3·25). The evolving epidemiology of cryptosporidiosis necessitates further identification of risk factors in population subgroups. Adding systematic molecular typing ofCryptosporidiumspecimens to US national cryptosporidiosis surveillance would help further identify risk factors and markedly expand understanding of cryptosporidiosis epidemiology in the United States.

scholarly journals 2203. Patient-Specific Risk Stratification to Identify Patients at High and Low Risk for P. aeruginosa in Community-Acquired Pneumonia

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S751-S751
Author(s):  
William Justin Moore ◽  
Caroline Cruce ◽  
Karolina Harkabuz ◽  
Shereen Salama ◽  
Sarah Sutton ◽  
...  
Keyword(s):  
Risk Factors ◽  
Logistic Regression ◽  
Risk Stratification ◽  
Antibiotic Use ◽  
Community Acquired Pneumonia ◽  
Low Risk ◽  
Patient Specific ◽  
Stepwise Logistic Regression ◽  
Case Status ◽  
The Impact

Abstract Background Pseudomonas aeruginosa (PsA) is an infrequent pathogen associated with poor outcomes in community-acquired pneumonia (CAP). Identifying patients at high and low-risk for PsA in CAP is necessary to reduce inappropriate and overly broad-spectrum antibiotic use. We evaluated the distribution of risk-factors in hospitalized CAP patients with and without PsA infection. Methods Design: retrospective, single-center, case–control study. Inclusion: hospitalized CAP patients admitted to the general medicine wards between January 1, 2014 and May 29, 2018. Exclusion: cystic fibrosis, ≥ 3 admissions within 30 days, CAP requiring ICU admission, and death within 48 hours of admission. Case patients had PsA in respiratory or blood cultures during the index CAP admission. Controls were randomly selected targeting a 3:1 ratio. Comorbidities, pneumonia severity index, and m-APACHE II were assessed. Gram-negative risk factors defined by Shindo et al. 2013 (PMID: 23855620) and validated by Kobayashi et al. (2018; PMID: 30349327) were scored for each patient. Stepwise logistic regression was used to identify covariates that distinguished cases from controls at a P < 0.2; these were then used to generate propensity weights (i.e., inverse-probability conditioned on covariates). Unadjusted and adjusted odds ratios for case status were estimated using logistic regression according to: the total number of risk factors present and threshold values, respectively. All analyses were conducted using IC Stata (v.14.2). Results 54 cases and 152 controls were included. The distribution of the patient-specific sum of risk factors for PsA is shown in Figure 1. The univariate OR for case status was 4.29 (95% CI:1.55–11.9) at n = 3 risk factors, which was similar after propensity weight adjustment [aOR = 4.64 (95% CI: 1.32–16.3)]. The univariate OR of case status was 2.98 among patients with ≥ 3 risk factors (95% CI: 1.34–6.62), which was similar after propensity weight adjustment [aOR = 2.8 (95% CI: 1.02–7.72)], and correct classification was 73.8%. Conclusion At a threshold of ≥ 3 PsA risk factors, cases and controls were well classified, even after adjusting for propensity weights. The impact of patient-specific PsA risk-stratification on CAP outcomes and appropriate antibiotic use should be evaluated. Disclosures All authors: No reported disclosures.

scholarly journals Educational attainment as a modifier of the effect of polygenic scores for cardiovascular risk factors: cross-sectional and prospective analysis of UK Biobank

2021 ◽  
Author(s):  
Alice R Carter ◽  
Sean Harrison ◽  
Dipender Gill ◽  
George Davey Smith ◽  
Amy E Taylor ◽  
...  
Keyword(s):  
Risk Factors ◽  
Atrial Fibrillation ◽  
Type 2 Diabetes ◽  
Cardiovascular Risk ◽  
Educational Attainment ◽  
Cardiovascular Risk Factors ◽  
Genetic Susceptibility ◽  
Effect Modification ◽  
Polygenic Scores

AbstractBackgroundUnderstanding the interplay between educational attainment and genetic predictors of cardiovascular risk may improve our understanding of mechanisms relating educational attainment to cardiovascular disease.MethodsIn up to 320 120 UK Biobank participants of White British ancestry (mean age = 57, female 54%), we created polygenic scores for nine cardiovascular risk factors or diseases: alcohol consumption, body mass index, low-density lipoprotein cholesterol, lifetime smoking behaviour, systolic blood pressure, atrial fibrillation, coronary heart disease, type 2 diabetes and stroke. We estimated whether educational attainment modified genetic susceptibility to these risk factors and diseases.ResultsOn the additive scale, higher educational attainment reduced genetic susceptibility to higher BMI, smoking, atrial fibrillation and type 2 diabetes, but increased genetic susceptibility to higher LDL-C and higher systolic blood pressure.On the multiplicative scale, there was evidence that higher educational attainment increased genetic susceptibility to atrial fibrillation and coronary heart disease, but no evidence of effect modification was found for all other considered traits.ConclusionsEducational attainment modifies the genetic susceptibility to some cardiovascular risk factors and diseases. The direction of this effect was mixed across traits considered and differences in associations between the effect of the polygenic score across strata of educational attainment was uniformly small. Therefore, any effect modification by education of genetic susceptibility to cardiovascular risk factors or diseases is unlikely to contribute substantially to the mechanisms driving inequalities in cardiovascular risk.Key MessagesThe role of educational attainment in modifying the effect of polygenic scores for a wide range of cardiovascular risk factors or diseases has not previously been studiedWe explore whether educational attainment modifies the effects of polygenic susceptibility to alcohol consumption, body mass index, low-density lipoprotein cholesterol, lifetime smoking behaviour, systolic blood pressure, atrial fibrillation, coronary heart disease, type 2 diabetes and strokeEffect modification by education was observed for some cardiovascular polygenic scores, but not all.Effects were not always in the hypothesised direction and were dependent on the scale of analysis.Modification of the effect of genetic susceptibility to cardiovascular risk factors or cardiovascular disease by educational attainment is unlikely to contribute substantially to the mechanisms driving inequalities in cardiovascular risk.

scholarly journals Transferability of genetic loci and polygenic scores for cardiometabolic traits in British Pakistanis and Bangladeshis

2021 ◽  
Author(s):  
Qin Qin Huang ◽  
Neneh Sallah ◽  
Diana Dunca ◽  
Bhavi Trivedi ◽  
Karen A Hunt ◽  
...  
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Risk Prediction ◽  
European Ancestry ◽  
Mendelian Randomisation ◽  
Genetic Loci ◽  
Clinical Risk ◽  
Polygenic Scores ◽  
British Pakistanis ◽  
Cardiometabolic Traits

Background: Individuals with South Asian ancestry have higher risk of heart disease than other groups in Western countries; however, most genetic research has focused on European-ancestry (EUR) individuals. It is unknown whether reported genetic loci and polygenic scores (PGSs) for cardiometabolic traits are transferable to South Asians, and whether PGSs have utility in clinical settings. Methods: Using data from 22,000 British Pakistani and Bangladeshi individuals with linked electronic health records from the Genes & Health cohort (G&H), we conducted genome-wide association studies (GWAS) and characterised the genetic architecture of coronary artery disease (CAD), body mass index (BMI), lipid biomarkers and blood pressure. We applied a new technique to assess the extent to which loci from GWAS in EUR samples were transferable. We tested how well existing findings from EUR studies performed in genetic risk prediction and Mendelian randomisation in G&H. Results: Trans-ancestry genetic correlations between G&H and EUR samples for the tested traits were not significantly lower than 1, except for BMI (rg=0.85, p=0.02). We found evidence for transferability for the vast majority of loci from EUR discovery studies that were sufficiently powered to replicate in G&H. PGSs showed variable transferability in G&H, with the relative accuracy compared to EUR (ratio of incremental r2/AUC) ≥0.95 for HDL-C, triglycerides, and blood pressure, but lower for BMI (0.78) and CAD (0.42). We observed significant improvement in categorical net reclassification in G&H (NRI=3.9%; 95% CI 0.9-7.0) when adding a previously developed CAD PGS to clinical risk factors (QRISK3). We used transferable loci as genetic instruments in trans-ancestry Mendelian randomisation and found evidence of an increased CAD risk for higher LDL-C and BMI, and for lower HDL-C in G&H, consistent with our findings for EUR samples. Conclusions: The genetic loci for CAD and its risk factors are largely transferable from EUR studies to British Pakistanis and Bangladeshis, whereas the transferability of PGSs varies greatly between traits. Our analyses suggest clinical utility for addition of PGS to existing clinical risk prediction tools for this population.

Human Toxocara infection of the central nervous system and neurological disorders: a case-control study

Parasitology ◽  
1997 ◽  
Vol 115 (5) ◽  
pp. 537-543 ◽  
Author(s):  
J.-F. MAGNAVAL ◽  
V. GALINDO ◽  
L. T. GLICKMAN ◽  
M. CLANET
Keyword(s):  
Risk Factors ◽  
Central Nervous System ◽  
Nervous System ◽  
Case Control Study ◽  
Neurological Diseases ◽  
Clinical Signs ◽  
Multivariate Logistic Regression Analysis ◽  
Case Control ◽  
Case Status ◽  
Control Study

Infection with Toxocara canis is a common world-wide human helminthiasis, which rarely elicits central nervous system (CNS) impairment. A case-control study to investigate this discrepancy was carried out, in which the cases were 27 adult neurological inpatients for whom a definite aetiological diagnosis was lacking, and for whom positive immunodiagnosis of toxocariasis had been obtained, both in cerebrospinal fluid (CSF) and in serum. Two control groups were used. Controls were adult inpatients with other neurological diseases who had no evidence of T. canis infection of the CNS. Multivariate logistic regression analysis did not reveal any positive relation between case status and clinical signs. A significant association was observed between case status and an elevated CSF cell count. Rural residence, ownership of dogs, and dementia were shown to be risk factors for toxocaral infection of CNS. These results suggest that migration of T. canis larvae in the human brain does not frequently induce a recognizable neurological syndrome but is correlated with the association of several risk factors including exposure to dogs, a status possibly responsible for repeated low-dose infections.

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