The use of polygenic risk scores to identify phenotypes associated with genetic risk of schizophrenia: Systematic review

Mistry, Sumit; Harrison, Jamie; Smith, Daniel J.; Escott‐Price, Valentina; Zammit, Stanley

doi:10.1016/j.schres.2017.10.037

Cited by 130 publications

(106 citation statements)

References 63 publications

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“…We then permuted the SZ and PRS column vector, respectively, and recalculated the mean and dispersion effects. For cortical thickness the true test statistics and the permuted statistical maps where then submitted to PALM 43 to correct for multiple comparisons using threshold-free cluster enhancement (TFCE) and tail approximation 47 (600 permutations: eMethods: Permutation). Maps were thresholded at a significance level of p<.05.…”

Section: Methodsmentioning

confidence: 99%

The dark side of the mean: brain structural heterogeneity in schizophrenia and its polygenic risk

Alnæs

Kaufmann

Meer

et al. 2018

Preprint

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Telephone: +47 23 02 73 50, Fax: +47 23 02 73 33 32 33 34 3 Key Points 35Question: Is schizophrenia and its polygenic risk associated with brain structural 36 heterogeneity in addition to mean changes? 37Findings: In a sample of 1151 patients and 2010 controls, schizophrenia was associated with 38 increased heterogeneity in fronto-temporal thickness, cortical, ventricle, and hippocampal 39 volumes, besides robust reductions in mean estimates. In an independent sample of 12,490 40 controls, polygenic risk for schizophrenia was associated with thinner fronto-temporal 41 cortices and smaller CA2/3 of the left hippocampus, but not with heterogeneity. 42Meaning: Schizophrenia is associated with increased inter-individual differences in brain 43 structure, possibly reflecting clinical heterogeneity, gene-environment interactions, or 44 secondary disease factors. 45 46 4 Abstract 47 Importance: Between-subject variability in brain structure is determined by gene-48 environment interactions, possibly reflecting differential sensitivity to environmental and 49 genetic perturbations. Magnetic resonance imaging (MRI) studies have revealed thinner 50 cortices and smaller subcortical volumes in patients. However, such group-level comparisons 51 may mask considerable within-group heterogeneity, which has largely remained unnoticed in 52 the literature 53Objective: To compare brain structural variability between individuals with SZ and healthy 54 controls (HC) and to test if respective variability reflects the polygenic risk for SZ (PRS) in 55 HC. 56Design, Setting, and Participants: We compared MRI derived cortical thickness and 57 subcortical volumes between 2,010 healthy controls and 1,151 patients with SZ across 16 58cohorts. Secondly, we tested for associations between PRS and MRI features in 12,490 59 participants from UK Biobank. 60 Main Outcomes and Measures:We modeled mean and dispersion effects of SZ and PRS 61 using double generalized linear models. We performed vertex-wise analyses for thickness, 62 and region-of-interest analysis for cortical, subcortical and hippocampal subfield volumes. 63Follow-up analyses included within-sample analysis, controlling for intracranial volume and 64 population covariates, test of robustness of PRS threshold, and outlier removal. 65Results: Compared to controls, patients with SZ showed higher heterogeneity in cortical 66 thickness, cortical and ventricle volumes, and hippocampal subfields. Higher PRS was 67 associated with thinner frontal and temporal cortices, as well as smaller left CA2/3, but was 68 not significantly associated with dispersion. 69Conclusion and relevance: SZ is associated with substantial brain structural heterogeneity 70 beyond the mean differences. These findings possibly reflect higher differential sensitivity to 71 5 environmental and genetic perturbations in patients, supporting the heterogeneous nature of 72 SZ. Higher PRS for SZ was associated with thinner fronto-temporal cortices and smaller 73 subcortical volumes, but there were no significant associati...

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Section: Methodsmentioning

confidence: 99%

The dark side of the mean: brain structural heterogeneity in schizophrenia and its polygenic risk

Alnæs

Kaufmann

Meer

et al. 2018

Preprint

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“…As the reference GWAS and the target samples become larger, PRSs will gain power that may allow us to understand how behavioral and other phenotypes relate to each other at the level of the gene. For a recent review of the application of PRS on schizophrenia-related phenotypes, see Mistry et al [102]. …”

Section: Common Low-penetrance Variants and Gwasmentioning

confidence: 99%

Recent Advances in the Genetics of Schizophrenia

Avramopoulos

2018

Complex Psychiatry

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The last decade brought tremendous progress in the field of schizophrenia genetics. As a result of extensive collaborations and multiple technological advances, we now recognize many types of genetic variants that increase the risk. These include large copy number variants, rare coding inherited and de novο variants, and over 100 loci harboring common risk variants. While the type and contribution to the risk vary among genetic variants, there is concordance in the functions of genes they implicate, such as those whose RNA binds the fragile X-related protein FMRP and members of the activity-regulated cytoskeletal complex involved in learning and memory. Gene expression studies add important information on the biology of the disease and recapitulate the same functional gene groups. Studies of alternative phenotypes help us widen our understanding of the genetic architecture of mental function and dysfunction, how diseases overlap not only with each other but also with non-disease phenotypes. The challenge is to apply this new knowledge to prevention and treatment and help patients. The data generated so far and emerging technologies, including new methods in cell engineering, offer significant promise that in the next decade we will unlock the translational potential of these significant discoveries.

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“…GWAS studies have found a significant genetic overlap between cognition and schizophrenia [18][19][20] , and a recent study by Toulopoulou et al 21 showed that the variance in schizophrenia liability explained by PRS was partially mediated through cognitive deficit.…”

Section: Introductionmentioning

confidence: 99%

Jumping To Conclusions, General Intelligence, And Psychosis Liability: Findings From The Multi-Centre EU-GEI Case-Control Study

Tripoli

Quattrone

Ferraro³

et al. 2019

Preprint

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AbstractBackgroundThe “jumping to conclusions” (JTC) bias is associated with both psychosis and general cognition but their relationship is unclear. In this study, we set out to clarify the relationship between the JTC bias, IQ, psychosis and polygenic liability to schizophrenia and IQ.Methods817 FEP patients and 1294 population-based controls completed assessments of general intelligence (IQ), and JTC (assessed by the number of beads drawn on the probabilistic reasoning “beads” task) and provided blood or saliva samples from which we extracted DNA and computed polygenic risk scores for IQ and schizophrenia.ResultsThe estimated proportion of the total effect of case/control differences on JTC mediated by IQ was 79%. Schizophrenia Polygenic Risk Score (SZ PRS) was non-significantly associated with a higher number of beads drawn (B= 0.47, 95% CI −0.21 to 1.16, p=0.17); whereas IQ PRS (B=0.51, 95% CI 0.25 to 0.76, p<0.001) significantly predicted the number of beads drawn, and was thus associated with reduced JTC bias. The JTC was more strongly associated with higher level of psychotic-like experiences (PLE) in controls, including after controlling for IQ (B= −1.7, 95% CI −2.8 to −0.5, p=0.006), but did not relate to delusions in patients.Conclusionsthe JTC reasoning bias in psychosis is not a specific cognitive deficit but is rather a manifestation or consequence, of general cognitive impairment. Whereas, in the general population, the JTC bias is related to psychotic-like experiences, independent of IQ. The work has potential to inform interventions targeting cognitive biases in early psychosis.

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The use of polygenic risk scores to identify phenotypes associated with genetic risk of schizophrenia: Systematic review

Cited by 130 publications

References 63 publications

The dark side of the mean: brain structural heterogeneity in schizophrenia and its polygenic risk

The dark side of the mean: brain structural heterogeneity in schizophrenia and its polygenic risk

Recent Advances in the Genetics of Schizophrenia

Jumping To Conclusions, General Intelligence, And Psychosis Liability: Findings From The Multi-Centre EU-GEI Case-Control Study

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