Polygenic Risk Scores for Psychiatric Disorders Reveal Novel Clues About the Genetics of Disordered Gambling

Background and Aims: Twin studies indicate that disordered gambling (DG) is heritable but are silent with respect to specific genes or pathways involved. Genome-wide association studies of other psychiatric disorders permit calculation of polygenic risk scores (PRS) that reflect the aggregated effects of common genetic variants contributing to risk for the target condition. We investigated whether gambling and DG are associated with PRSs for four psychiatric conditions found to be comorbid with DG in epidemiologic surveys. Design and Setting: Data were drawn from the Wave IV assessment of the National Longitudinal Study of Adolescent to Adult Health, a representative sample of adolescents recruited in 1994-5 and followed into young adulthood. Participants: Analyses were limited to unrelated individuals classified as having European ancestry based on analysis of genetic principal components (N = 5,215). Measurements: Participants were surveyed about lifetime gambling and DG. Genotyping data were used to construct PRSs quantifying participants’ common variant genetic risk for major depression (MDD), attention-deficit hyperactivity disorder (ADHD), bipolar disorder (BD), and schizophrenia (SCZ). Findings: Most participants (78.4%) reported ever having gambled, and 1.3% of those reported lifetime DG. Polygenic risk for BD was associated with decreased odds of lifetime gambling, OR = 0.93 [0.87, 0.99], p = .045, pseudo-R2(%) = 0.12. The SCZ PRS was associated with increased odds of DG, OR = 1.54 [1.07, 2.21], p = .020, pseudo-R2 (%) = 0.85. Polygenic risk for MDD and ADHD were not related to either gambling outcome. Conclusions: Common variant risk for SCZ is associated with DG. Investigating features common to both SCZ and DG might generate valuable clues about the genetically-influenced liabilities to DG.

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Polygenic Risk Scores for Psychiatric Disorders Reveal Novel Clues About the Genetics of Disordered Gambling

Twin Research and Human Genetics ◽

10.1017/thg.2019.90 ◽

2019 ◽

Vol 22 (5) ◽

pp. 283-289

Author(s):

Thomas M. Piasecki ◽

Ian R. Gizer ◽

Wendy S. Slutske

Keyword(s):

Psychiatric Disorders ◽

Association Studies ◽

Twin Studies ◽

European Ancestry ◽

Risk Scores ◽

Adult Health ◽

Disordered Gambling ◽

Polygenic Risk ◽

Common Genetic Variants ◽

Survey Responses

AbstractDisordered gambling (DG) is a rare but serious condition that results in considerable financial and interpersonal harms. Twin studies indicate that DG is heritable but are silent with respect to specific genes or pathways involved. Existing genomewide association studies (GWAS) of DG have been substantially underpowered. Larger GWAS of other psychiatric disorders now permit calculation of polygenic risk scores (PRSs) that reflect the aggregated effects of common genetic variants contributing risk for the target condition. The current study investigated whether gambling and DG are associated with PRSs for four psychiatric conditions found to be comorbid with DG in epidemiologic surveys: major depressive disorder (MDD), attention-deficit hyperactivity disorder (ADHD), bipolar disorder (BD) and schizophrenia (SCZ). Genotype data and survey responses were analyzed from the Wave IV assessment (conducted in 2008) of the National Longitudinal Study of Adolescent to Adult Health, a representative sample of adolescents recruited in 1994–1995 and followed into adulthood. Among participants classified as having European ancestry based on genetic analysis (N = 5215), 78.4% reported ever having gambled, and 1.3% reported lifetime DG. Polygenic risk for BD was associated with decreased odds of lifetime gambling, OR = 0.93 [0.87, 0.99], p = .045, pseudo-R2(%) = .12. The SCZ PRS was associated with increased odds of DG, OR = 1.54 [1.07, 2.21], p = .02, pseudo-R2(%) = .85. Polygenic risk scores for MDD and ADHD were not related to either gambling outcome. Investigating features common to both SCZ and DG might generate valuable clues about the genetically influenced liabilities to DG.

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

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.1528 ◽

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]

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Sleep Deficits and Cannabis Use Behaviors: An Analysis of Shared Genetics Using Linkage Disequilibrium Score Regression and Polygenic Risk Prediction

10.1101/2020.05.02.053983 ◽

2020 ◽

Author(s):

Evan A. Winiger ◽

Jarrod M. Ellingson ◽

Claire L. Morrison ◽

Robin P. Corley ◽

Joëlle A. Pasman ◽

...

Keyword(s):

Linkage Disequilibrium ◽

Sleep Duration ◽

Association Studies ◽

Genetic Correlations ◽

Cannabis Use ◽

European Ancestry ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Short Sleep Duration ◽

Polygenic Risk

AbstractStudy ObjectivesEstimate the genetic relationship of cannabis use with sleep deficits and eveningness chronotype.MethodsWe used linkage disequilibrium score regression (LDSC) to analyze genetic correlations between sleep deficits and cannabis use behaviors. Secondly, we generated sleep deficit polygenic risk scores (PRSs) and estimated their ability to predict cannabis use behaviors using logistic regression. Summary statistics came from existing genome wide association studies (GWASs) of European ancestry that were focused on sleep duration, insomnia, chronotype, lifetime cannabis use, and cannabis use disorder (CUD). A target sample for PRS prediction consisted of high-risk participants and participants from twin/family community-based studies (n = 796, male = 66%; mean age = 26.81). Target data consisted of self-reported sleep (sleep duration, feeling tired, and taking naps) and cannabis use behaviors (lifetime use, number of lifetime uses, past 180-day use, age of first use, and lifetime CUD symptoms).ResultsSignificant genetic correlation between lifetime cannabis use and eveningness chronotype (rG = 0.24, p < 0.01), as well as between CUD and both short sleep duration (<7 h) (rG = 0.23, p = 0.02) and insomnia (rG = 0.20, p = 0.02). Insomnia PRS predicted earlier age of first cannabis use (β = −0.09, p = 0.02) and increased lifetime CUD symptom count use (β = 0.07, p = 0.03).ConclusionCannabis use is genetically associated with both sleep deficits and an eveningness chronotype, suggesting that there are genes that predispose individuals to both cannabis use and sleep deficits.

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Polygenic transcriptome risk scores (PTRS) can improve portability of polygenic risk scores across ancestries

Genome Biology ◽

10.1186/s13059-021-02591-w ◽

2022 ◽

Vol 23 (1) ◽

Author(s):

Yanyu Liang ◽

Milton Pividori ◽

Ani Manichaikul ◽

Abraham A. Palmer ◽

Nancy J. Cox ◽

...

Keyword(s):

Association Studies ◽

Poor Performance ◽

Genome Wide Association ◽

European Ancestry ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Transcript Levels ◽

Polygenic Risk ◽

Genome Wide

Abstract Background Polygenic risk scores (PRS) are valuable to translate the results of genome-wide association studies (GWAS) into clinical practice. To date, most GWAS have been based on individuals of European-ancestry leading to poor performance in populations of non-European ancestry. Results We introduce the polygenic transcriptome risk score (PTRS), which is based on predicted transcript levels (rather than SNPs), and explore the portability of PTRS across populations using UK Biobank data. Conclusions We show that PTRS has a significantly higher portability (Wilcoxon p=0.013) in the African-descent samples where the loss of performance is most acute with better performance than PRS when used in combination.

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Assessment of Polygenic Architecture and Risk Prediction based on Common Variants Across Fourteen Cancers

10.1101/723825 ◽

2019 ◽

Cited By ~ 1

Author(s):

Yan Zhang ◽

Amber N. Wilcox ◽

Haoyu Zhang ◽

Parichoy Pal Choudhury ◽

Douglas F. Easton ◽

...

Keyword(s):

Association Studies ◽

Disease Incidence ◽

Effect Sizes ◽

European Ancestry ◽

Risk Scores ◽

Average Risk ◽

Genome Wide Association Studies ◽

Lymphoid Leukemia ◽

Polygenic Risk ◽

Wide Range

AbstractWe analyzed summary-level data from genome-wide association studies (GWAS) of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) contributing to risk, as well as the distribution of their associated effect sizes. All cancers evaluated showed polygenicity, involving at a minimum thousands of independent susceptibility variants. For some malignancies, particularly chronic lymphoid leukemia (CLL) and testicular cancer, there are a larger proportion of variants with larger effect sizes than those for other cancers. In contrast, most variants for lung and breast cancers have very small associated effect sizes. For different cancer sites, we estimate a wide range of GWAS sample sizes, required to explain 80% of GWAS heritability, varying from 60,000 cases for CLL to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores, compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that polygenic risk scores have substantial potential for risk stratification for relatively common cancers such as breast, prostate and colon, but limited potential for other cancer sites because of modest heritability and lower disease incidence.

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On cross-ancestry cancer polygenic risk scores

PLoS Genetics ◽

10.1371/journal.pgen.1009670 ◽

2021 ◽

Vol 17 (9) ◽

pp. e1009670

Author(s):

Lars G. Fritsche ◽

Ying Ma ◽

Daiwei Zhang ◽

Maxwell Salvatore ◽

Seunggeun Lee ◽

...

Keyword(s):

Breast Cancer ◽

South Asian ◽

Disease Risk ◽

Association Studies ◽

East Asian ◽

European Ancestry ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Polygenic Risk ◽

Target Sample

Polygenic risk scores (PRS) can provide useful information for personalized risk stratification and disease risk assessment, especially when combined with non-genetic risk factors. However, their construction depends on the availability of summary statistics from genome-wide association studies (GWAS) independent from the target sample. For best compatibility, it was reported that GWAS and the target sample should match in terms of ancestries. Yet, GWAS, especially in the field of cancer, often lack diversity and are predominated by European ancestry. This bias is a limiting factor in PRS research. By using electronic health records and genetic data from the UK Biobank, we contrast the utility of breast and prostate cancer PRS derived from external European-ancestry-based GWAS across African, East Asian, European, and South Asian ancestry groups. We highlight differences in the PRS distributions of these groups that are amplified when PRS methods condense hundreds of thousands of variants into a single score. While European-GWAS-derived PRS were not directly transferrable across ancestries on an absolute scale, we establish their predictive potential when considering them separately within each group. For example, the top 10% of the breast cancer PRS distributions within each ancestry group each revealed significant enrichments of breast cancer cases compared to the bottom 90% (odds ratio of 2.81 [95%CI: 2.69,2.93] in European, 2.88 [1.85, 4.48] in African, 2.60 [1.25, 5.40] in East Asian, and 2.33 [1.55, 3.51] in South Asian individuals). Our findings highlight a compromise solution for PRS research to compensate for the lack of diversity in well-powered European GWAS efforts while recruitment of diverse participants in the field catches up.

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Performance of polygenic risk scores for cancer prediction in a racially diverse academic biobank

10.1101/2021.05.13.21256833 ◽

2021 ◽

Author(s):

Louise Wang ◽

Heena Desai ◽

Shefali S. Verma ◽

Anh Le ◽

Ryan Hausler ◽

...

Keyword(s):

Cancer Risk ◽

Genetic Factors ◽

Association Studies ◽

European Ancestry ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Discriminatory Ability ◽

Polygenic Risk ◽

Genome Wide ◽

European Populations

Purpose: Genome-wide association studies (GWAS) have identified hundreds of single nucleotide polymorphisms (SNPs) significantly associated with several cancers, but the predictive ability of polygenic risk scores (PRS) derived from multiple variants is unclear for many cancers, especially among non-European populations. Methods: Genome wide genotype data was available for 20,079 individuals enrolled in an academic biobank. PRS were derived from significant DNA variants for 15 cancers. Logistic regression was used to determine the discriminatory accuracy of each cancer-specific PRS in patients of genetically determined African and European ancestry separately. Results: Among European individuals, four PRS were significantly associated with their respective cancers (breast, colon, melanoma, and prostate), with an OR ranging from 1.25-1.47. Among African individuals, PRS for breast, colon, and prostate were significantly associated with their respective cancers. The discriminatory ability of a model comprised of age, sex, and principal components was 0.617–0.709, and the AUC increased by 1-4% with the addition of the PRS in Europeans. AUC was overall higher in the full model including PRS (AUC 0.742-0.818) in African individuals, but the PRS increased the AUC by less than 1% in the majority of cancers in African individuals. Conclusion: PRS constructed from SNPs moderately increased discriminatory ability for cancer status over age, sex, and nonspecific genetic factors in individuals of European but not African ancestry. Further large-scale studies are needed to identify ancestry-specific genetic factors for cancer risk in non-European populations to incorporate PRS into cancer risk assessment.

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Polygenic risk scores across the extended psychosis spectrum

Translational Psychiatry ◽

10.1038/s41398-021-01720-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lukasz Smigielski ◽

Sergi Papiol ◽

Anastasia Theodoridou ◽

Karsten Heekeren ◽

Miriam Gerstenberg ◽

...

Keyword(s):

At Risk ◽

Association Studies ◽

Bayesian Regression ◽

Mitigation Measures ◽

Risk Scores ◽

Type I ◽

Genome Wide Association Studies ◽

Type Ii ◽

Polygenic Risk ◽

Common Genetic Variants

AbstractAs early detection of symptoms in the subclinical to clinical psychosis spectrum may improve health outcomes, knowing the probabilistic susceptibility of developing a disorder could guide mitigation measures and clinical intervention. In this context, polygenic risk scores (PRSs) quantifying the additive effects of multiple common genetic variants hold the potential to predict complex diseases and index severity gradients. PRSs for schizophrenia (SZ) and bipolar disorder (BD) were computed using Bayesian regression and continuous shrinkage priors based on the latest SZ and BD genome-wide association studies (Psychiatric Genomics Consortium, third release). Eight well-phenotyped groups (n = 1580; 56% males) were assessed: control (n = 305), lower (n = 117) and higher (n = 113) schizotypy (both groups of healthy individuals), at-risk for psychosis (n = 120), BD type-I (n = 359), BD type-II (n = 96), schizoaffective disorder (n = 86), and SZ groups (n = 384). PRS differences were investigated for binary traits and the quantitative Positive and Negative Syndrome Scale. Both BD-PRS and SZ-PRS significantly differentiated controls from at-risk and clinical groups (Nagelkerke’s pseudo-R2: 1.3–7.7%), except for BD type-II for SZ-PRS. Out of 28 pairwise comparisons for SZ-PRS and BD-PRS, 9 and 12, respectively, reached the Bonferroni-corrected significance. BD-PRS differed between control and at-risk groups, but not between at-risk and BD type-I groups. There was no difference between controls and schizotypy. SZ-PRSs, but not BD-PRSs, were positively associated with transdiagnostic symptomology. Overall, PRSs support the continuum model across the psychosis spectrum at the genomic level with possible irregularities for schizotypy. The at-risk state demands heightened clinical attention and research addressing symptom course specifiers. Continued efforts are needed to refine the diagnostic and prognostic accuracy of PRSs in mental healthcare.

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Polygenic Risk Scores for Cardio-renal-metabolic Diseases in the Penn Medicine Biobank

10.1101/759381 ◽

2019 ◽

Author(s):

R.L. Kember ◽

A. Verma ◽

S. Verma ◽

A. Lucas ◽

R. Judy ◽

...

Keyword(s):

Genetic Risk ◽

Metabolic Diseases ◽

Association Studies ◽

African Ancestry ◽

Treatment Strategies ◽

European Ancestry ◽

Risk Scores ◽

Future Research ◽

Genome Wide Association Studies ◽

Polygenic Risk

AbstractCardio-renal-metabolic (CaReMe) conditions are common and the leading cause of mortality around the world. Genome-wide association studies have shown that these diseases are polygenic and share many genetic risk factors. Identifying individuals at high genetic risk will allow us to target prevention and treatment strategies. Polygenic risk scores (PRS) are aggregate weighted counts that can demonstrate an individual’s genetic liability for disease. However, current PRS are often based on European ancestry individuals, limiting the implementation of precision medicine efforts in diverse populations. In this study, we develop PRS for six diseases and traits related to cardio-renal-metabolic disease in the Penn Medicine Biobank. We investigate their performance in both European and African ancestry individuals, and identify genetic and phenotypic overlap within these conditions. We find that genetic risk is associated with the primary phenotype in both ancestries, but this does not translate into a model of predictive value in African ancestry individuals. We conclude that future research should prioritize genetic studies in diverse ancestries in order to address this disparity.

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Polygenic risk prediction and SNCA haplotype analysis in a Latino Parkinson's disease cohort

10.1101/2021.11.09.21265082 ◽

2021 ◽

Author(s):

Douglas P. Loesch ◽

Andrea RVR Horimoto ◽

Irem Sarihan ◽

Miguel Inca-Martinez ◽

Emily Mason ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Risk Prediction ◽

Association Studies ◽

Gwas Data ◽

European Ancestry ◽

Risk Scores ◽

Phenotypic Variance ◽

Genome Wide Association Studies ◽

Polygenic Risk

Background: Large-scale Parkinson's disease (PD) genome-wide association studies (GWAS) and meta-analyses have, until recently, only been conducted on subjects with European-ancestry. Consequently, polygenic risk scores (PRS) constructed using PD GWAS data are likely to be less predictive when applied to non-European cohorts. Methods: Using GWAS data from Nalls et al. 2019, we constructed a PD PRS for a Latino PD cohort (LARGE-PD) and tested it for association with PD status. We validated the PRS performance through testing the PD PRS in an independent cohort of Latino PD patients and by repeating the PRS analysis in LARGE-PD with the addition of 440 external Peruvian controls. To explore the global distribution of PD PRS, we utilized 1000 Genomes Project (1KGP) and Peruvian Genome Project (PGP) data to estimate PD risk allele frequencies. We also tested SNCA haplotypes for association with PD risk using logistic regression in LARGE-PD and a European-ancestry PD cohort from the International Parkinson Disease Genomics Consortium (IPDGC). Results: The GWAS-significant PD PRS had an area under the receiver-operator curve (AUC) of 0.668 (95% CI: 0.640-0.695) and explained 2.8% of the phenotypic variance in LARGE-PD as determined via pseudo R2. The inclusion of external Peruvian data as controls mitigated this result, dropping the AUC 0.632 (95% CI: 0.607-0.657). In 1KGP Latinos, we found the PD PRS to exhibit a bias by ancestry. At the SNCA locus, haplotypes differ by ancestry. Ancestry-specific SNCA haplotypes are significantly associated with PD status in both LARGE-PD and the IPDGC cohort (p-value < 0.05). Apart from rs356182, these haplotypes share as little as 14% of their variants. Conclusion: The PD PRS has potential for PD risk prediction in Latinos, but variability caused by admixture patterns and bias in the PD PRS calculated using only European-ancestry data limits its utility. The inclusion of diverse subjects can help elucidate PD risk loci and improve risk prediction in non-European cohorts. In the case of the SNCA locus, by leveraging a Latino cohort, we provide orthogonal evidence for rs356182 causality.

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