scholarly journals Polygenic risk scores for schizophrenia are associated with oculomotor endophenotypes

2021 ◽  
pp. 1-9
Author(s):  
Annabell Coors ◽  
Mohammed-Aslam Imtiaz ◽  
Meta M. Boenniger ◽  
N. Ahmad Aziz ◽  
Monique M. B. Breteler ◽  
...  
Keyword(s):  
General Population ◽  
Smooth Pursuit ◽  
Association Studies ◽  
Meta Analysis ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Pursuit Velocity ◽  
Oculomotor Function ◽  
Multivariable Regression Models

Abstract Background Schizophrenia is a heterogeneous disorder with substantial heritability. The use of endophenotypes may help clarify its aetiology. Measures from the smooth pursuit and antisaccade eye movement tasks have been identified as endophenotypes for schizophrenia in twin and family studies. However, the genetic basis of the overlap between schizophrenia and these oculomotor markers is largely unknown. Here, we tested whether schizophrenia polygenic risk scores (PRS) were associated with oculomotor performance in the general population. Methods Analyses were based on the data of 2956 participants (aged 30–95) of the Rhineland Study, a community-based cohort study in Bonn, Germany. Genotyping was performed on Omni-2.5 exome arrays. Using summary statistics from a recent meta-analysis based on the two largest schizophrenia genome-wide association studies to date, we quantified genetic risk for schizophrenia by creating PRS at different p value thresholds for genetic markers. We examined associations between PRS and oculomotor performance using multivariable regression models. Results Higher PRS were associated with higher antisaccade error rate and latency, and lower antisaccade amplitude gain. PRS showed inconsistent patterns of association with smooth pursuit velocity gain and were not associated with saccade rate during smooth pursuit or performance on a prosaccade control task. Conclusions There is an overlap between genetic determinants of schizophrenia and oculomotor endophenotypes. Our findings suggest that the mechanisms that underlie schizophrenia also affect oculomotor function in the general population.

scholarly journals Distribution of 54 polygenic risk scores for common diseases in long lived individuals and their offspring

2021 ◽  
Author(s):  
Sophia Gunn ◽  
Michael Wainberg ◽  
Zeyuan Song ◽  
Stacy Andersen ◽  
Robert Boudreau ◽  
...  
Keyword(s):  
General Population ◽  
Genetic Risk ◽  
Disease Risk ◽  
Association Studies ◽  
Risk Scores ◽  
Human Longevity ◽  
Genome Wide Association Studies ◽  
Predictive Values ◽  
Polygenic Risk ◽  
Polygenic Scores

Background: A surprising and well-replicated result in genetic studies of human longevity is that centenarians appear to carry disease-associated variants in numbers similar to the general population. With the proliferation of large genome-wide association studies (GWAS) in recent years, investigators have turned to polygenic scores to leverage GWAS results into a measure of genetic risk that can better predict risk of disease than individual significant variants alone. Methods: We selected 54 polygenic risk scores (PRSs) developed for a variety of outcomes and we calculated their values in individuals from the New England Centenarian Study (NECS, N = 4886) and the Long Life Family Study (LLFS, N = 4577). We compared the distribution of these PRSs among exceptionally long-lived individuals (ELLI), their offspring and controls and we also examined their predictive values, using t-tests and regression models adjusting for sex and principal components reflecting ancestral background of the individuals (PCs). In our analyses we controlled for multiple testing using a Bonferroni-adjusted threshold for 54 traits. Results: We found that only 4 of the 54 PRSs differed between ELLIs and controls in both cohorts. ELLIs had significantly lower mean PRSs for Alzheimer's disease (AD), coronary artery disease (CAD) and systemic lupus than controls, suggesting genetic predisposition to extreme longevity may be mediated by reduced susceptibility to these traits. ELLIs also had significantly higher mean PRSs for improved cognitive function. In addition, the PRS for AD was associated with higher risk of dementia among controls but not ELLIs (p = 0.0004, 0.3 in NECS, p = 0.03, 0.93 in LLFS respectively). Interestingly, ELLIs did not have a larger number of homozygous risk genotypes for AD (TNECS = -1.72, TLLFs = 0.83) and CAD (TNECS = -5.08, TLLFs = -0.31) in both cohorts, but did have significantly larger number of homozygous protective genotypes than controls for the two traits (AD: TNECS =3.10, TLLFs = 2.2, CAD: TNECS = 6.57, TLLFs =2.36, respectively). Conclusions: ELLIs have a similar burden of genetic disease risk as the general population for most traits, but have significantly lower genetic risk of AD, CAD, and lupus. The lack of association between AD PRS and dementia among ELLIs suggests that their genetic risk for AD is somehow buffered by protective genetic or environmental factors.

scholarly journals Polygenic Risk Scores Shed Light on the Relationship between Schizophrenia and Cognitive Functioning: Review and Meta-Analysis

2020 ◽  
Vol 9 (2) ◽  
pp. 341 ◽  
Author(s):  
Jasmina Mallet ◽  
Yann Le Strat ◽  
Caroline Dubertret ◽  
Philip Gorwood
Keyword(s):  
Association Studies ◽  
Meta Analysis ◽  
Treatment Strategies ◽  
Population Based ◽  
Current Treatment ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Efficient Treatment ◽  
Polygenic Risk ◽  
Complex Human Traits

Schizophrenia is a multifactorial disease associated with widespread cognitive impairment. Although cognitive deficits are one of the factors most strongly associated with functional impairment in schizophrenia (SZ), current treatment strategies hardly tackle these impairments. To develop more efficient treatment strategies in patients, a better understanding of their pathogenesis is needed. Recent progress in genetics, driven by large genome-wide association studies (GWAS) and the use of polygenic risk scores (PRS), has provided new insights about the genetic architecture of complex human traits, including cognition and SZ. Here, we review the recent findings examining the genetic links between SZ and cognitive functions in population-based samples as well as in participants with SZ. The performed meta-analysis showed a negative correlation between the polygenetic risk score of schizophrenia and global cognition (p < 0.001) when the samples rely on general and healthy participants, while no significant correlation was detected when the three studies devoted to schizophrenia patients were meta-analysed (p > 0.05). Our review and meta-analysis therefore argues against universal pleiotropy for schizophrenia alleles and cognition, since cognition in SZ patients would be underpinned by the same genetic factors than in the general population, and substantially independent of common variant liability to the disorder.

scholarly journals S173. GENOME-WIDE ASSOCIATION STUDIES OF SCHIZOPHRENIA AND BIPOLAR DISORDER IN A DIVERSE COHORT OF US VETERANS

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S103-S103
Author(s):  
Tim Bigdeli ◽  
Ayman Fanous ◽  
Nallakkandi Rajeevan ◽  
Frederick Sayward ◽  
Yuli Li ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Summary Statistics ◽  
Polygenic Risk ◽  
Genome Wide ◽  
Us Veterans

Abstract Background Schizophrenia and bipolar disorder are debilitating neuropsychiatric illnesses collectively affecting 2% of the world’s population, and which cause tremendous human suffering that impacts patients, their families and their communities. Recognizing the major impact of these disorders on the psychosocial function of more than 200,000 US Veterans, the Department of Veterans Affairs (VA) recently genotyping of nearly 9,000 veterans with schizophrenia or bipolar I disorder in Cooperative Studies Program (CSP) #572: “Genetics of Functional Disability in Schizophrenia and Bipolar Illness”, all of whom were extensively assessed for neurocognitive function and disability, and genotyped using a custom Affymetrix Axiom Biobank array. Methods Primary genome-wide association studies (GWAS) of schizophrenia and bipolar disorder were performed across and within ancestry goups, with attempted replication in matched subjects from the PGC and Genomic Psychiatry Cohort (GPC). We combined results for CSP#572 with available summary statistics from the PGC, Indonesia Schizophrenia Consortium and Genetic REsearch on schizophreniA neTwork-China and Netherland (GREAT-CN) study, and multi-ethnic GPC cohorts, achieving among the largest and most diverse studies of these disorders to date. Results Polygenic risk scores based on published PGC summary statistics for schizophrenia or bipolar disorder were significantly associated with case status among EA (P&lt;10–30) and AA (P&lt;0.0005) participants in CSP#572. Our primary analyses of schizophrenia yielded a single genome-wide significant association with variants in CHD7 at 8q12.2 for European-American (EA) participants, which remained significant in a joint analysis of EA and African-American (AA) subjects (P=4.62e-08). While no genome-wide significant associations were detected by our within-ancestry analyses of bipolar disorder, a cross-ancestry meta-analysis of CSP#572 participants yielded a significant finding at 10q25 with variants in SORCS3 (P=2.62e-08). Among loci attaining P&lt;0.0001 in our within-ancestry analyses, 4 and 8 subsequently achieved genome-wide significance, respectively, when jointly analyzed with matched subjects from the PGC and GPC. Combining our results with published summary statistics, we performed a cross-ancestry GWAS meta-analysis of 69,280 schizophrenia cases and 138,379 controls, identifying 200 genome-wide significant loci of which 76 are newly reported here. Cross-ancestry analysis of 28,326 bipolar cases and 90,570 controls identified 24 genome-wide significant loci, including novel associations with common variants in PAX5, DOCK2, MACROD2, BRE, KCNG1, and LINC01378. Discussion We newly describe genome-wide analyses in a diverse cohort of US Veterans with schizophrenia or bipolar disorder, benchmarking the predictive value of polygenic risk scores based on published GWAS findings. Leveraging available summary statistics from studies of global populations, we add to burgeoning lists of genomic loci implicated in the etiologies of these disorders.

scholarly journals A meta-analysis of polygenic risk scores for mood disorders, neuroticism, and schizophrenia in antidepressant response

2021 ◽  
Author(s):  
Giuseppe Fanelli ◽  
Katharina Domschke ◽  
Alessandra Minelli ◽  
Massimo Gennarelli ◽  
Paolo Martini ◽  
...  
Keyword(s):  
Antidepressant Treatment ◽  
Association Studies ◽  
Meta Analysis ◽  
Predictive Performance ◽  
Risk Scores ◽  
Clinical Samples ◽  
Genome Wide Association Studies ◽  
Bonferroni Correction ◽  
Polygenic Risk ◽  
Genome Wide

About two-thirds of patients with major depressive disorder (MDD) fail to achieve symptom remission after the initial antidepressant treatment. Despite a role of genetic factors was proven, the specific underpinnings are not fully understood yet. Polygenic risk scores (PRSs), which summarise the additive effect of multiple risk variants across the genome, might provide insights into the underlying genetics. This study aims to investigate the possible association of PRSs for bipolar disorder, MDD, neuroticism, and schizophrenia (SCZ) with antidepressant non-response or non-remission in patients with MDD. PRSs were calculated at eight genome-wide P-thresholds based on publicly available summary statistics of the largest genome-wide association studies. Logistic regressions were performed between PRSs and non-response or non-remission in six European clinical samples, adjusting for age, sex, baseline symptom severity, recruitment sites, and population stratification. Results were meta-analysed across samples, including up to 3,637 individuals. Bonferroni correction was applied. In the meta-analysis, no result was significant after Bonferroni correction. The top result was found for MDD-PRS and non-remission (p=0.004), with patients in the highest vs. lowest PRS quintile being more likely not to achieve remission (OR=1.5, 95% CI=1.11-1.98, p=0.007). Nominal associations were also found between MDD-PRS and non-response (p=0.013), as well as between SCZ-PRS and non-remission (p=0.035). Although PRSs are still not able to predict non-response or non-remission, our results are in line with previous works; methodological improvements in PRSs calculation may improve their predictive performance and have a meaningful role in precision psychiatry.

scholarly journals Polygenic Risk Score of Longevity Predicts Longer Survival Across an Age Continuum

2020 ◽  
Author(s):  
Niccolo’ Tesi ◽  
Sven J van der Lee ◽  
Marc Hulsman ◽  
Iris E Jansen ◽  
Najada Stringa ◽  
...  
Keyword(s):  
Older Adults ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Risk Scores ◽  
Human Longevity ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Age Related

Abstract Studying the genome of centenarians may give insights into the molecular mechanisms underlying extreme human longevity and the escape of age-related diseases. Here, we set out to construct polygenic risk scores (PRSs) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with maintained cognitive health (N = 343), a population-matched cohort of older adults from 5 cohorts (N = 2905), and summary statistics data from genome-wide association studies on parental longevity, we constructed a PRS including 330 variants that significantly discriminated between centenarians and older adults. This PRS was also associated with longer survival in an independent sample of younger individuals (p = .02), leading up to a 4-year difference in survival based on common genetic factors only. We show that this PRS was, in part, able to compensate for the deleterious effect of the APOE-ε4 allele. Using an integrative framework, we annotated the 330 variants included in this PRS by the genes they associate with. We find that they are enriched with genes associated with cellular differentiation, developmental processes, and cellular response to stress. Together, our results indicate that an extended human life span is, in part, the result of a constellation of variants each exerting small advantageous effects on aging-related biological mechanisms that maintain overall health and decrease the risk of age-related diseases.

scholarly journals An atlas of polygenic risk score associations to highlight putative causal relationships across the human phenome

2018 ◽  
Author(s):  
Tom G. Richardson ◽  
Sean Harrison ◽  
Gibran Hemani ◽  
George Davey Smith
Keyword(s):  
Web Application ◽  
Large Scale ◽  
Complex Disease ◽  
Association Studies ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Genetic Liability ◽  
Polygenic Risk ◽  
The Uk

AbstractThe age of large-scale genome-wide association studies (GWAS) has provided us with an unprecedented opportunity to evaluate the genetic liability of complex disease using polygenic risk scores (PRS). In this study, we have analysed 162 PRS (P<5×l0 05) derived from GWAS and 551 heritable traits from the UK Biobank study (N=334,398). Findings can be investigated using a web application (http://mrcieu.mrsoftware.org/PRS_atlas/), which we envisage will help uncover both known and novel mechanisms which contribute towards disease susceptibility.To demonstrate this, we have investigated the results from a phenome-wide evaluation of schizophrenia genetic liability. Amongst findings were inverse associations with measures of cognitive function which extensive follow-up analyses using Mendelian randomization (MR) provided evidence of a causal relationship. We have also investigated the effect of multiple risk factors on disease using mediation and multivariable MR frameworks. Our atlas provides a resource for future endeavours seeking to unravel the causal determinants of complex disease.

scholarly journals Fine-tuning Polygenic Risk Scores with GWAS Summary Statistics

2019 ◽  
Author(s):  
Zijie Zhao ◽  
Yanyao Yi ◽  
Yuchang Wu ◽  
Xiaoyuan Zhong ◽  
Yupei Lin ◽  
...  
Keyword(s):  
Association Studies ◽  
Fine Tuning ◽  
Risk Scores ◽  
Training Dataset ◽  
Validation Dataset ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Summary Statistics ◽  
Polygenic Risk ◽  
Model Tuning

AbstractPolygenic risk scores (PRSs) have wide applications in human genetics research. Notably, most PRS models include tuning parameters which improve predictive performance when properly selected. However, existing model-tuning methods require individual-level genetic data as the training dataset or as a validation dataset independent from both training and testing samples. These data rarely exist in practice, creating a significant gap between PRS methodology and applications. Here, we introduce PUMAS (Parameter-tuning Using Marginal Association Statistics), a novel method to fine-tune PRS models using summary statistics from genome-wide association studies (GWASs). Through extensive simulations, external validations, and analysis of 65 traits, we demonstrate that PUMAS can perform a variety of model-tuning procedures (e.g. cross-validation) using GWAS summary statistics and can effectively benchmark and optimize PRS models under diverse genetic architecture. On average, PUMAS improves the predictive R2 by 205.6% and 62.5% compared to PRSs with arbitrary p-value cutoffs of 0.01 and 1, respectively. Applied to 211 neuroimaging traits and Alzheimer’s disease, we show that fine-tuned PRSs will significantly improve statistical power in downstream association analysis. We believe our method resolves a fundamental problem without a current solution and will greatly benefit genetic prediction applications.

scholarly journals Age-related late-onset disease heritability patterns and implications for genome-wide association studies

2018 ◽  
Author(s):  
Roman Teo Oliynyk
Keyword(s):  
Old Age ◽  
Cumulative Incidence ◽  
Late Onset ◽  
Association Studies ◽  
Genome Wide Association ◽  
Risk Scores ◽  
Cerebral Stroke ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Genome Wide

AbstractBackgroundGenome-wide association studies and other computational biology techniques are gradually discovering the causal gene variants that contribute to late-onset human diseases. After more than a decade of genome-wide association study efforts, these can account for only a fraction of the heritability implied by familial studies, the so-called “missing heritability” problem.MethodsComputer simulations of polygenic late-onset diseases in an aging population have quantified the risk allele frequency decrease at older ages caused by individuals with higher polygenic risk scores becoming ill proportionately earlier. This effect is most prominent for diseases characterized by high cumulative incidence and high heritability, examples of which include Alzheimer’s disease, coronary artery disease, cerebral stroke, and type 2 diabetes.ResultsThe incidence rate for late-onset diseases grows exponentially for decades after early onset ages, guaranteeing that the cohorts used for genome-wide association studies overrepresent older individuals with lower polygenic risk scores, whose disease cases are disproportionately due to environmental causes such as old age itself. This mechanism explains the decline in clinical predictive power with age and the lower discovery power of familial studies of heritability and genome-wide association studies. It also explains the relatively constant-with-age heritability found for late-onset diseases of lower prevalence, exemplified by cancers.ConclusionsFor late-onset polygenic diseases showing high cumulative incidence together with high initial heritability, rather than using relatively old age-matched cohorts, study cohorts combining the youngest possible cases with the oldest possible controls may significantly improve the discovery power of genome-wide association studies.

Risk of Breast Cancer Among Carriers of Pathogenic Variants in Breast Cancer Predisposition Genes Varies by Polygenic Risk Score

2021 ◽  
pp. JCO.20.01992
Author(s):  
Chi Gao ◽  
Eric C. Polley ◽  
Steven N. Hart ◽  
Hongyan Huang ◽  
Chunling Hu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
General Population ◽  
Association Studies ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
First Degree Relatives ◽  
Pathogenic Variants ◽  
Predisposition Genes ◽  
Brca1 Brca2

PURPOSE This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population. METHODS A total of 26,798 non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, BRIP1, CDH1, and NF1. PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor–specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC. RESULTS The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of BRCA1, BRCA2, and PALB2 carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of ATM and CHEK2 carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk. CONCLUSION PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of CHEK2 and nearly half of ATM carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.

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