Importance Polygenic risk scores (PRS) are predictors of the genetic susceptibility to diseases, calculated for individuals as weighted counts of thousands of risk variants in which the risk variants and their weights have been identified in genome-wide association studies. Polygenic risk scores show promise in aiding clinical decision-making in many areas of medical practice. This review evaluates the potential use of PRS in psychiatry. Observations On their own, PRS will never be able to establish or definitively predict a diagnosis of common complex conditions (eg, mental health disorders), because genetic factors only contribute part of the risk and PRS will only ever capture part of the genetic contribution. Combining PRS with other risk factors has potential to improve outcome prediction and aid clinical decision-making (eg, determining follow-up options for individuals seeking help who are at clinical risk of future illness). Prognostication of adverse physical health outcomes or response to treatment in clinical populations are of great interest for psychiatric practice, but data from larger samples are needed to develop and evaluate PRS. Conclusions and Relevance Polygenic risk scores will contribute to risk assessment in clinical psychiatry as it evolves to combine information from molecular, clinical, and lifestyle metrics. The genome-wide genotype data needed to calculate PRS are inexpensive to generate and could become available to psychiatrists as a by-product of practices in other medical specialties. The utility of PRS in clinical psychiatry, as well as ethical issues associated with their use, should be evaluated in the context of realistic expectations of what PRS can and cannot deliver. Clinical psychiatry has lagged behind other fields of health care in its use of new technologies and routine clinical data for research. Now is the time to catch up.

Could Polygenic Risk Scores Be Useful in Psychiatry?: A Review.

The predictive utility of polygenic scores is increasing, and many polygenic scoring methods are available, but it is unclear which method performs best. This study evaluates the predictive utility of polygenic scoring methods within a reference-standardized framework, which uses a common set of variants and reference-based estimates of linkage disequilibrium and allele frequencies to construct scores. Eight polygenic score methods were tested: p-value thresholding and clumping (pT+clump), SBLUP, lassosum, LDpred1, LDpred2, PRScs, DBSLMM and SBayesR, evaluating their performance to predict outcomes in UK Biobank and the Twins Early Development Study (TEDS). Strategies to identify optimal p-value thresholds and shrinkage parameters were compared, including 10-fold cross validation, pseudovalidation and infinitesimal models (with no validation sample), and multi-polygenic score elastic net models. LDpred2, lassosum and PRScs performed strongly using 10-fold cross-validation to identify the most predictive p-value threshold or shrinkage parameter, giving a relative improvement of 16-18% over pT+clump in the correlation between observed and predicted outcome values. Using pseudovalidation, the best methods were PRScs, DBSLMM and SBayesR. PRScs pseudovalidation was only 3% worse than the best polygenic score identified by 10-fold cross validation. Elastic net models containing polygenic scores based on a range of parameters consistently improved prediction over any single polygenic score. Within a reference-standardized framework, the best polygenic prediction was achieved using LDpred2, lassosum and PRScs, modeling multiple polygenic scores derived using multiple parameters. This study will help researchers performing polygenic score studies to select the most powerful and predictive analysis methods.

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Evaluation of polygenic prediction methodology within a reference-standardized framework

Compared with linear mixed model-based genome-wide association (GWA) methods, generalized linear mixed model (GLMM)-based methods have better statistical properties when applied to binary traits but are computationally much slower. In the present study, leveraging efficient sparse matrix-based algorithms, we developed a GLMM-based GWA tool, fastGWA-GLMM, that is severalfold to orders of magnitude faster than the state-of-the-art tools when applied to the UK Biobank (UKB) data and scalable to cohorts with millions of individuals. We show by simulation that the fastGWA-GLMM test statistics of both common and rare variants are well calibrated under the null, even for traits with extreme case-control ratios. We applied fastGWA-GLMM to the UKB data of 456,348 individuals, 11,842,647 variants and 2,989 binary traits (full summary statistics available at http://fastgwa.info/ukbimpbin ), and identified 259 rare variants associated with 75 traits, demonstrating the use of imputed genotype data in a large cohort to discover rare variants for binary complex traits.

A generalized linear mixed model association tool for biobank-scale data.

Background The predictive utility of polygenic scores is increasing, and many polygenic scoring methods are available, but it is unclear which method performs best. This study evaluates the predictive utility of polygenic scoring methods within a reference-standardized framework, which uses a common set of variants and reference-based estimates of linkage disequilibrium and allele frequencies to construct scores. Methods Six polygenic score methods were tested: p-value thresholding and clumping (pT+clump), SBLUP, lassosum, LDPred, PRScs and SBayesR, evaluating their performance to predict outcomes in UK Biobank and the Twins Early Development Study (TEDS). Strategies to identify optimal p-value threshold and shrinkage parameters were compared, including 10-fold cross validation, pseudovalidation (with no validation sample), and multi-polygenic score elastic net models. Results lassosum, PRScs and LDPred performed strongly using 10-fold cross-validation to identify the most predictive p-value threshold or shrinkage parameter, giving a relative improvement of 14-17% over pT+clump in the correlation between observed and predicted outcome values. Using pseudovalidation, the best method was PRScs, with a relative improvement of >11% over other pseudovalidation methods (lassosum, SBLUP, SBayesR, LDPred), and only 1% less than the best polygenic score identified by 10-fold cross validation. Elastic net models containing polygenic scores based on a range of parameters consistently improved prediction over any single polygenic score. Conclusion Within a reference-standardized framework, the best polygenic prediction was achieved using lassosum and PRScs, modeling multiple polygenic scores derived using multiple parameters. This study will help researchers performing polygenic score studies to select the most powerful and predictive analysis methods.

/pdf/evaluation-of-polygenic-prediction-methodology-within-a-27wxl1yo2u.pdf

Evaluation of Polygenic Prediction Methodology within a Reference-Standardized Framework

Genetic prediction of complex traits with polygenic scores: a statistical review.

A Comparison of Ten Polygenic Score Methods for Psychiatric Disorders Applied Across Multiple Cohorts

Polygenic scores (PGSs), which assess the genetic risk of individuals for a disease, are calculated as a weighted count of risk alleles identified in genome-wide association studies (GWASs). PGS methods differ in terms of which DNA variants are included in the score and the weights assigned to them. PGSs are evaluated in independent target samples of individuals with known disease status. Evaluation of new PGS methods are made using simulated data or single target cohort, however, in real data sets there can be heterogeneity between target sample cohorts, which could reflect a number of real or artefactual factors. The Psychiatric Genomics Consortium working groups for schizophrenia (SCZ) and major depressive disorder (MDD) bring together many independently collected case-control cohorts for GWAS meta-analysis. These resources are used here in repeated application of leave-one-cohort-out GWAS analyses, generating robust conclusions for PGS prediction applied across multiple target (left-out) cohorts. Eight PGS methods (P+T, SBLUP, LDpred-Inf, LDpred-funct, LDpred, PRS-CS, PRS-CS-auto, SBayesR) are compared. We found that SBayesR had the highest prediction evaluation statistics in most comparisons. For SCZ across 30 target cohorts, the SBayesR PGS achieved a mean area under the receiver operator characteristic curve (AUC) of 0.733, and explained 9.9% of variance on the liability scale. For MDD across 26 target cohorts, the AUC and variance explained were 0.601 and 4.0%, respectively. The variance explained by the SBayesR PGS was 46% and 43% higher for SCZ and MDD, respectively, compared to the basic p-value thresholding P+T method.

https://www.medrxiv.org/content/medrxiv/early/2020/09/11/2020.09.10.20192310.full.pdf

A comprehensive evaluation of polygenic score methods across cohorts in psychiatric disorders

Distinctions between major depressive disorder (MDD) and perinatal depression (PND) reflect varying views of PND, from a unique etiological subtype of MDD to an MDD episode that happens to coincide with childbirth. This case–control study investigated genetic differences between PND and MDD outside the perinatal period (non‐perinatal depression or NPD).

Perinatal depression is associated with a higher polygenic risk for major depressive disorder than non‐perinatal depression

Objectives This study sought to evaluate the prevalence, timing of onset and duration of symptoms of depression in the perinatal period (PND) in women with depression, according to whether they had a history of depression prior to their first perinatal period. We further sought to identify biopsychosocial correlates of perinatal symptoms in women with depression. Design and setting The Australian Genetics of Depression Study is an online case cohort study of the aetiology of depression. For a range of variables, women with depression who report significant perinatal depressive symptoms were compared with women with lifetime depression who did not experience perinatal symptoms. Participants In a large sample of parous women with major depressive disorder (n=7182), we identified two subgroups of PND cases with and without prior depression history (n=2261; n=878, respectively). Primary and secondary outcome measures The primary outcome measure was a positive screen for PND on the lifetime version of the Edinburgh Postnatal Depression Scale. Descriptive measures reported lifetime prevalence, timing of onset and duration of PND symptoms. There were no secondary outcome measures. Results The prevalence of PND among parous women was 70%. The majority of women reported at least one perinatal episode with symptoms both antenatally and postnatally. Of women who experienced depression prior to first pregnancy, PND cases were significantly more likely to report more episodes of depression (OR=1.15 per additional depression episode, 95% CI 1.13 to 1.17, p<0.001), non-European ancestry (OR 1.5, 95% CI 1.0 to 2.1, p=0.03), severe nausea during pregnancy (OR 1.3, 95% CI 1.1 to 1.6, p=0.006) and emotional abuse (OR 1.4, 95% CI 1.1 to 1.7, p=0.005). Conclusions The majority of parous women with lifetime depression in this study experienced PND, associated with more complex, severe depression. Results highlight the importance of perinatal assessments of depressive symptoms, particularly for women with a history of depression or childhood adverse experiences.

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Jacqueline Kiewa

Papers

A Comparison of Ten Polygenic Score Methods for Psychiatric Disorders Applied Across Multiple Cohorts

A comprehensive evaluation of polygenic score methods across cohorts in psychiatric disorders

Perinatal depression is associated with a higher polygenic risk for major depressive disorder than non‐perinatal depression

Lifetime prevalence and correlates of perinatal depression in a case-cohort study of depression