Polygenic Risk Scores: What Are They Good For?

Zheutlin, Amanda B; Ross, David A.

doi:10.1016/j.biopsych.2018.04.007

Cited by 48 publications

(36 citation statements)

References 10 publications

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“…Clinical implications. It has been stated that "the end game of PGS […] is personalized medicine" [Zheutling & Ross, 2018]. Children and adolescent with high PGS for ASD may be particularly vulnerable and have difficulties with executive function.…”

Section: Discussionmentioning

confidence: 99%

Autism spectrum disorder polygenic scores are associated with every day executive function in children admitted for clinical assessment

et al. 2019

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Autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDs) are behaviorally defined disorders with overlapping clinical features that are often associated with higher‐order cognitive dysfunction, particularly executive dysfunction. Our aim was to determine if the polygenic score (PGS) for ASD is associated with parent‐reported executive dysfunction in everyday life using the Behavior Rating Inventory of Executive Function (BRIEF). Furthermore, we investigated if PGS for general intelligence (INT) and attention deficit/hyperactivity disorder (ADHD) also correlate with BRIEF. We included 176 children, adolescents and young adults aged 5–22 years with full‐scale intelligence quotient (IQ) above 70. All were admitted for clinical assessment of ASD symptoms and 68% obtained an ASD diagnosis. We found a significant difference between low and high ASD PGS groups in the BRIEF behavior regulation index (BRI) (P = 0.015, Cohen's d = 0.69). A linear regression model accounting for age, sex, full‐scale IQ, Social Responsiveness Scale (SRS) total score, ASD, ADHD and INT PGS groups as well as genetic principal components, significantly predicted the BRI score; F(11,130) = 8.142, P < 0.001, R2 = 0.41 (unadjusted). Only SRS total (P < 0.001), ASD PGS 0.1 group (P = 0.018), and sex (P = 0.022) made a significant contribution to the model. This suggests that the common ASD risk gene variants have a stronger association to behavioral regulation aspects of executive dysfunction than ADHD risk or INT variants in a clinical sample with ASD symptoms. Autism Res 2020, 13: 207–220. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary People with autism spectrum disorder (ASD) often have difficulties with higher‐order cognitive processes that regulate thoughts and actions during goal‐directed behavior, also known as executive function (EF). We studied the association between genetics related to ASD and EF and found a relation between high polygenic score (PGS) for ASD and difficulties with behavior regulation aspects of EF in children and adolescents under assessment for ASD. Furthermore, high PGS for general intelligence was related to social problems.

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Section: Discussionmentioning

confidence: 99%

Autism spectrum disorder polygenic scores are associated with every day executive function in children admitted for clinical assessment

et al. 2019

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“…Further elucidation of these associations and incorporation of genetic information may provide important scientific, clinical and public health insights to optimize neonatal health and to curb the trans-generational cycle of obesity. In general, individual SNP effects are small; however, summarizing the effects in GRS has been demonstrated to predict individual’s overall risk to disease and showed promises in the field of cardiac disease to revolutionize medicine on multiple levels ( Torkamani et al, 2018 ; Zheutlin and Ross, 2018 ). Obesity, being a multifactorial hereditary disorder, detailed characterization of interactions between GRS and modifiable environmental factors will facilitate the development of targeted preventative lifestyle, nutritional and clinical interventions.…”

Section: Discussionmentioning

confidence: 99%

Influence of Fetal and Maternal Genetic Susceptibility to Obesity on Birthweight in African Ancestry Populations

et al. 2018

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Fetal and maternal genetic propensity to obesity can influence birthweight. We investigated the effects of fetal and maternal genetic risk of obesity on birthweight and evaluated whether these genetic influences modify the well-known association between maternal pre-pregnancy body mass index (BMI) and birthweight. In 950 mother-baby pairs of African ancestry, a genetic risk score for adulthood obesity was generated for mothers (mGRS) and their babies (bGRS) as the weighted sum of BMI-increasing alleles of 97 single nucleotide polymorphisms known to be associated with BMI. The median GRS value was used as a cut-off to define high or low bGRS and mGRS. High bGRS was significantly associated with 70 g lower birthweight (95% Confidence Interval [CI] = −127.4 to −12.4) compared to low bGRS. mGRS was positively correlated with birthweight but the association was not significant. mGRS modified the significant birthweight-increasing effect of maternal pre-pregnancy BMI (P-for-interaction = 0.03); among mothers with low mGRS, those who were overweight or obese had 127.7 g heavier babies (95% CI = 27.1 to 228.2) compared to those who had normal weight. In summary, fetal obesity genetic risk loci exert direct influence on birthweight, and maternal loci modify the effect of pre-pregnancy BMI on birthweight.

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“…These findings support the use of newer risk scoring methods that can incorporate more genetic variants by directly modeling LD structure. Precision of PRSs may also increase through larger discovery sample sizes 12 and with refinement of EHR-based case definitions. Nonetheless, it remains to be seen whether combining PRS risk estimates with other clinical predictors can meaningfully contribute to individualized risk assessment in psychiatry.…”

Section: Discussionmentioning

confidence: 99%

“…Given the substantial heritability of many psychiatric disorders 9 and their polygenic architecture 10 , there is increasing interest in using quantitative measures of genetic risk for risk stratification 11 . Polygenic risk scores (PRSs), in particular, are easy and inexpensive to generate and can be applied well before illness onset, making them a promising candidate for clinical integration 12 . In fact, a recent study investigating the clinical utility of PRSs for several common, non-psychiatric diseases found that PRS can identify a larger fraction of high risk individuals than are identified by clinically-validated monogenic mutations, and called explicitly for evaluations of these scores in clinical settings 13 .…”

Section: Introductionmentioning

confidence: 99%

Penetrance and pleiotropy of polygenic risk scores for schizophrenia in 106,160 patients across four healthcare systems

Zheutlin

Dennis

Restrepo³

et al. 2018

Preprint

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OBJECTIVE: Individuals at high risk for schizophrenia may benefit from early intervention but few validated risk predictors are available. Genetic profiling is one approach to risk stratification that has been extensively validated in research cohorts, but its utility in clinical settings remains largely unexplored. Moreover, the broad health consequences of a high genetic risk of schizophrenia are poorly understood, despite being relevant to treatment decisions. METHOD:We used electronic health records for 106,160 patients from four healthcare systems to evaluate the penetrance and pleiotropy of genetic risk for schizophrenia. Polygenic risk scores (PRSs) for schizophrenia were calculated from summary statistics and tested for association with 1359 disease categories, including schizophrenia and psychosis, in phenome-wide association studies. Effects were combined through meta-analysis across sites.RESULTS: PRSs were robustly associated with schizophrenia (odds ratio per standard deviation increase in PRS=1.55 [95% confidence interval (CI), 1.4-1.7], p=4.48 x 10 -16 ) and patients in the highest risk decile of the PRS distribution had up to 4.6-fold increased odds of schizophrenia compared to those in the bottom decile (95% CI, 2.9-7.3, p=1.37 x 10 -10 ). PRSs were also positively associated with a range of other phenotypes, including anxiety, mood, substance use, neurological, and personality disorders, as well as suicidal behavior, memory loss, and urinary syndromes; they were inversely related to obesity. CONCLUSIONS:We demonstrate that an available measure of genetic risk for schizophrenia is robustly associated with schizophrenia in healthcare settings and has pleiotropic effects on related psychiatric disorders as well as other medical syndromes. Our results provide an initial indication of the opportunities and limitations that may arise with the future application of PRS testing in healthcare systems.

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Polygenic Risk Scores: What Are They Good For?

Cited by 48 publications

References 10 publications

Autism spectrum disorder polygenic scores are associated with every day executive function in children admitted for clinical assessment

Autism spectrum disorder polygenic scores are associated with every day executive function in children admitted for clinical assessment

Influence of Fetal and Maternal Genetic Susceptibility to Obesity on Birthweight in African Ancestry Populations

Penetrance and pleiotropy of polygenic risk scores for schizophrenia in 106,160 patients across four healthcare systems

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