Polygenic Risk Score, Parental Socioeconomic Status, Family History of Psychiatric Disorders, and the Risk for Schizophrenia

AbstractObjectiveTo systematically investigate the association of environmental risk factors and prodromal features with incident Parkinson’s disease (PD) diagnosis and the interaction of genetic risk with these factors. To evaluate existing risk prediction algorithms and the impact of including addition genetic risk on the performance of prediction.MethodsWe identified individuals with incident PD diagnoses (n=1276) and unmatched controls (n=500,406) in UK Biobank. We determined the association of risk factors with incident PD using adjusted logistic regression models. A polygenic risk score (PRS) was constructed and used to examine gene-environment interactions. The PRS was also incorporated into a previously-developed prediction algorithm for finding incident cases.ResultsStrong evidence of association (Pcorr<0.05) was found between PD and a positive family history of PD, a positive family history of dementia, non-smoking, low alcohol consumption, depression, and daytime somnolence, and novel associations with epilepsy and earlier menarche. Individuals with the highest 10% of PRS scores had increased risk of PD (OR=3.30, 95% CI 2.57-4.24) compared to the lowest risk decile. Higher PRS scores were associated with earlier age at PD diagnosis and inclusion of the PRS in the PREDICT-PD algorithm improved model performance (Nagelkerke pseudo-R2 0.0053, p=6.87×10−14). We found evidence of interaction between the PRS and diabetes.InterpretationHere we used UK Biobank data to reproduce several well-known associations with PD, to demonstrate the validity and predictive power of a polygenic risk score, and to demonstrate a novel gene-environment interaction, whereby the effect of diabetes on PD risk appears to depend on prior genetic risk for PD.

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Relative contributions of family history and a polygenic risk score on COPD and related outcomes: COPDGene and ECLIPSE studies

BMJ Open Respiratory Research ◽

10.1136/bmjresp-2020-000755 ◽

2020 ◽

Vol 7 (1) ◽

pp. e000755

Author(s):

Matthew Moll ◽

Sharon M. Lutz ◽

Auyon J. Ghosh ◽

Phuwanat Sakornsakolpat ◽

Craig P. Hersh ◽

...

Keyword(s):

Family History ◽

Risk Score ◽

Characteristic Curve ◽

Significant Proportion ◽

Chronic Obstructive ◽

Polygenic Risk Score ◽

Positive Interaction ◽

Polygenic Risk ◽

Mediation Analyses ◽

The Impact

IntroductionFamily history is a risk factor for chronic obstructive pulmonary disease (COPD). We previously developed a COPD risk score from genome-wide genetic markers (Polygenic Risk Score, PRS). Whether the PRS and family history provide complementary or redundant information for predicting COPD and related outcomes is unknown.MethodsWe assessed the predictive capacity of family history and PRS on COPD and COPD-related outcomes in non-Hispanic white (NHW) and African American (AA) subjects from COPDGene and ECLIPSE studies. We also performed interaction and mediation analyses.ResultsIn COPDGene, family history and PRS were significantly associated with COPD in a single model (PFamHx <0.0001; PPRS<0.0001). Similar trends were seen in ECLIPSE. The area under the receiver operator characteristic curve for a model containing family history and PRS was significantly higher than a model with PRS (p=0.00035) in NHWs and a model with family history (p<0.0001) alone in NHWs and AAs. Both family history and PRS were significantly associated with measures of quantitative emphysema and airway thickness. There was a weakly positive interaction between family history and the PRS under the additive, but not multiplicative scale in NHWs (relative excess risk due to interaction=0.48, p=0.04). Mediation analyses found that a significant proportion of the effect of family history on COPD was mediated through PRS in NHWs (16.5%, 95% CI 9.4% to 24.3%), but not AAs.ConclusionFamily history and the PRS provide complementary information for predicting COPD and related outcomes. Future studies can address the impact of obtaining both measures in clinical practice.

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Polygenic Risk Score is a Predictor of Adenomatous Polyps at Screening Colonoscopy

10.21203/rs.3.rs-62371/v2 ◽

2020 ◽

Author(s):

Michael Northcutt ◽

Zhuqing Shi ◽

Michael Zijlstra ◽

Ayush Shah ◽

Siqun Zheng ◽

...

Keyword(s):

Family History ◽

Risk Score ◽

Genetic Risk Score ◽

Positive Family History ◽

Snp Array ◽

Adenomatous Polyps ◽

Screening Colonoscopy ◽

Polygenic Risk Score ◽

Average Risk ◽

Polygenic Risk

Abstract Background: Single nucleotide polymorphism (SNP)-based polygenic risk scoring is predictive of colorectal cancer (CRC) risk. However, few studies have investigated the association of genetic risk score (GRS) with detection of adenomatous polyps at screening colonoscopy. Methods: We randomly selected 1,769 Caucasian subjects who underwent screening colonoscopy from the Genomic Health Initiative (GHI), a biobank of NorthShore University HealthSystem. Outcomes from initial screening colonoscopy were recorded. Twenty-two CRC risk-associated SNPs were obtained from the Affymetrix™ SNP array and used to calculate an odds ratio (OR)-weighted and population-standardized GRS. Subjects with GRS of <0.5, 0.5-1.5, and >1.5 were categorized as low, average and elevated risk.Results: Among 1,769 subjects, 520 (29%) had 1 or more adenomatous polyps. GRS was significantly higher in subjects with adenomatous polyps than those without; mean (95% confidence interval) was 1.02 (1.00-1.05) and 0.97 (0.95-0.99), respectively, p<0.001. The association remained significant after adjusting for age, gender, body mass index, and family history, p<0.001. The detection rate of adenomatous polyps was 10.8%, 29.0% and 39.7% in subjects with low, average and elevated GRS, respectively, p-trend <0.001. Higher GRS was also associated with early age diagnosis of adenomatous polyps, p<0.001. In contrast, positive family history was not associated with risk and age of adenomatous polyps.Conclusions: GRS was significantly associated with adenomatous polyps in subjects undergoing screening colonoscopy. This result may help in stratifying average risk patients and facilitating personalized colonoscopy screening strategies.

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Delineating genetic and familial risk for psychopathology in the ABCD study

10.1101/2020.09.08.20186908 ◽

2020 ◽

Author(s):

Clare E Palmer ◽

Robert John Loughnan ◽

Carolina Makowski ◽

Wesley Thompson ◽

Deanna Barch ◽

...

Keyword(s):

Family History ◽

Psychiatric Disorders ◽

Genetic Risk ◽

Familial Risk ◽

Risk Scores ◽

Typically Developing ◽

Polygenic Risk ◽

Hyperactivity Disorder ◽

History Of ◽

Risk Predictors

Psychiatric disorders place a huge burden on those affected and their families, as well as society. Nearly all psychiatric disorders have a heritable component and lifetime prevalence rates of several disorders are higher among first degree biological relatives of individuals with a diagnosis. Given that many psychiatric disorders have their onset in adolescence, estimating genetic risk during childhood may identify at-risk individuals for early intervention that can reduce this burden. Here we measured genetic risk for psychopathology using both polygenic risk scores (PRS) and family history in a large typically developing sample of 9-10 year old children from the Adolescent Brain and Cognitive Development (ABCD) StudySM and determined associations with a large battery of behavioural phenotypes. By including all genetic risk predictors in the same model, we were able to delineate unique behavioral associations across these measures. Polygenic risk for Attention Deficit Hyperactivity Disorder (ADHD) and depression (DEP) was associated with unique patterns of both externalizing and internalizing behaviors. Family history of conduct problems, depression and anxiety/stress additionally predicted unique behavioral variance across similar measures. These findings provide important insight into the potential predictive utility of PRS and family history in early adolescence and suggest that they may be signaling differential, additive information that could be useful for quantifying risk during development.

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Capturing additional genetic risk from family history for improved polygenic risk prediction

10.1101/2022.01.06.22268853 ◽

2022 ◽

Author(s):

Tianyuan Lu ◽

Vincenzo Forgetta ◽

J Brent Richards ◽

Celia MT Greenwood

Keyword(s):

Family History ◽

Risk Prediction ◽

Risk Score ◽

Genetic Risk ◽

Adult Height ◽

Prediction Models ◽

European Ancestry ◽

Polygenic Risk Score ◽

Parental History ◽

Polygenic Risk

Family history of complex traits may reflect transmitted rare pathogenic variants, intrafamilial shared exposures to environmental and lifestyle factors, as well as a common genetic predisposition. We developed a latent factor model to quantify trait heritability in excess of that captured by a common variant-based polygenic risk score, but inferable from family history. We applied our model to predict adult height for 941 children in the Avon Longitudinal Study of Parents and Children cohort as well as 11 complex diseases for ~400,000 European ancestry participants in the UK Biobank. Parental history brought consistent significant improvements in the predictive power of polygenic risk prediction. For instance, a joint predictor was able to explain ~55% of the total variance in sex-adjusted adult height z-scores, close to the estimated heritability. Our work showcases an innovative paradigm for risk calculation, and supports incorporation of family history into polygenic risk score-based genetic risk prediction models.

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Abstract 2567: Genetic risk stratification for breast cancer based on a polygenic risk score and family history.

10.1158/1538-7445.am2013-2567 ◽

2013 ◽

Author(s):

Nasim Mavaddat ◽

Paul Pharoah ◽

Per Hall ◽

Douglas Easton ◽

Montserrat Garcia-Closas

Keyword(s):

Breast Cancer ◽

Family History ◽

Risk Stratification ◽

Risk Score ◽

Genetic Risk ◽

Polygenic Risk Score ◽

Polygenic Risk

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37ASSOCIATION OF THE POLYGENIC RISK SCORE FOR MAJOR PSYCHIATRIC DISORDERS WITH CLINICAL FEATURES IN BIPOLAR DISORDER AND CONTROLS

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2018.08.044 ◽

2019 ◽

Vol 29 ◽

pp. S1088

Author(s):

Jie Song ◽

Lu Yi ◽

Sarah Bergen ◽

Erik Smedler ◽

Mikael Landen

Keyword(s):

Bipolar Disorder ◽

Psychiatric Disorders ◽

Clinical Features ◽

Risk Score ◽

Polygenic Risk Score ◽

Polygenic Risk

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Prognostic Value of a Polygenic Risk Score for Coronary Heart Disease in Individuals Aged 70 Years and Older

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.121.003429 ◽

2021 ◽

Author(s):

Johannes T. Neumann ◽

Moeen Riaz ◽

Andrew Bakshi ◽

Galina Polekhina ◽

Le T.P. Thao ◽

...

Keyword(s):

Risk Score ◽

Cardiovascular Events ◽

Prognostic Value ◽

Clinical Utility ◽

Polygenic Risk Score ◽

Older Individuals ◽

Conventional Model ◽

Polygenic Risk ◽

History Of ◽

Genomic Risk

Background: The use of a polygenic risk score (PRS) to improve risk prediction of coronary heart disease (CHD) events has been demonstrated to have clinical utility in the general adult population. However, the prognostic value of a PRS for CHD has not been examined specifically in older populations of individuals aged ≥70 years, who comprise a distinct high-risk subgroup. The objective of this study was to evaluate the predictive value of a PRS for incident CHD events in a prospective cohort of older individuals without a history of cardiovascular events. Methods: We used data from 12 792 genotyped, healthy older individuals enrolled into the ASPREE trial (Aspirin in Reducing Events in the Elderly), a randomized double-blind placebo-controlled clinical trial investigating the effect of daily 100 mg aspirin on disability-free survival. Participants had no previous history of diagnosed atherothrombotic cardiovascular events, dementia, or persistent physical disability at enrollment. We calculated a PRS (meta-genomic risk score) consisting of 1.7 million genetic variants. The primary outcome was a composite of incident myocardial infarction or CHD death over 5 years. Results: At baseline, the median population age was 73.9 years, and 54.9% were female. In total, 254 incident CHD events occurred. When the PRS was added to conventional risk factors, it was independently associated with CHD (hazard ratio, 1.24 [95% CI, 1.08–1.42], P =0.002). The area under the curve of the conventional model was 70.53 (95% CI, 67.00–74.06), and after inclusion of the PRS increased to 71.78 (95% CI, 68.32–75.24, P =0.019), demonstrating improved prediction. Reclassification was also improved, as the continuous net reclassification index after adding PRS to the conventional model was 0.25 (95% CI, 0.15–0.28). Conclusion: A PRS for CHD performs well in older people and improves prediction over conventional cardiovascular risk factors. Our study provides evidence that genomic risk prediction for CHD has clinical utility in individuals aged 70 years and older. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01038583

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Polygenic risk score is a predictor of adenomatous polyps at screening colonoscopy

BMC Gastroenterology ◽

10.1186/s12876-021-01645-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Michael J. Northcutt ◽

Zhuqing Shi ◽

Michael Zijlstra ◽

Ayush Shah ◽

Siqun Zheng ◽

...

Keyword(s):

Family History ◽

Risk Score ◽

Genetic Risk Score ◽

Positive Family History ◽

Snp Array ◽

Adenomatous Polyps ◽

Screening Colonoscopy ◽

Polygenic Risk Score ◽

Average Risk ◽

Polygenic Risk

Abstract Background Single nucleotide polymorphism (SNP)-based polygenic risk scoring is predictive of colorectal cancer (CRC) risk. However, few studies have investigated the association of genetic risk score (GRS) with detection of adenomatous polyps at screening colonoscopy. Methods We randomly selected 1769 Caucasian subjects who underwent screening colonoscopy from the Genomic Health Initiative (GHI), a biobank of NorthShore University HealthSystem. Outcomes from initial screening colonoscopy were recorded. Twenty-two CRC risk-associated SNPs were obtained from the Affymetrix™ SNP array and used to calculate an odds ratio (OR)-weighted and population-standardized GRS. Subjects with GRS of < 0.5, 0.5–1.5, and > 1.5 were categorized as low, average and elevated risk. Results Among 1,769 subjects, 520 (29%) had 1 or more adenomatous polyps. GRS was significantly higher in subjects with adenomatous polyps than those without; mean (95% confidence interval) was 1.02 (1.00–1.05) and 0.97 (0.95–0.99), respectively, p < 0.001. The association remained significant after adjusting for age, gender, body mass index, and family history, p < 0.001. The detection rate of adenomatous polyps was 10.8%, 29.0% and 39.7% in subjects with low, average and elevated GRS, respectively, p-trend < 0.001. Higher GRS was also associated with early age diagnosis of adenomatous polyps, p < 0.001. In contrast, positive family history was not associated with risk and age of adenomatous polyps. Conclusions GRS was significantly associated with adenomatous polyps in subjects undergoing screening colonoscopy. This result may help in stratifying average risk patients and facilitating personalized colonoscopy screening strategies.

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