Polygenic Scores in Epidemiology: Risk Prediction, Etiology, and Clinical Utility

Maher, Brion S.

doi:10.1007/s40471-015-0055-3

Cited by 57 publications

(40 citation statements)

References 39 publications

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“…The use of PRS for risk stratification and prediction is well established . The utility of a predictor is evaluated by estimating the area under the receiver‐operating characteristic (ROC) curve (AUC), which graphically displays the true‐positive rate (sensitivity) against the false‐positive rate (1 – specificity) for all possible cutpoints of a continuous predictor (Fig.…”

Section: Genetic Association Studiesmentioning

confidence: 99%

Genome‐wide association studies and polygenic risk scores for skin cancer: clinically useful yet?

Roberts

Asgari

Toland³

2019

Br J Dermatol

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Summary Background Genome‐wide association studies (GWAS) have identified thousands of susceptibility variants, although most have been associated with small individual risk estimates that offer little predictive value. However, combining multiple variants into polygenic risk scores (PRS) may be more informative. Multiple studies have developed PRS composed of GWAS‐identified variants for cutaneous cancers. This review highlights data from these studies. Objectives To review published GWAS and PRS studies for melanoma, cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC), and discuss their potential clinical utility. Methods We searched PubMed and the National Human Genome Research Institute–European Bioinformatics Institute GWAS catalogue to identify relevant studies. Results Results from 21 GWAS (11 melanoma, 3 cSCC, 7 BCC) and 11 PRS studies are summarized. Six loci in pigmentation genes overlap between these three cancers (ASIP/RALY, IRF4, MC1R, OCA2, SLC45A2 and TYR). Additional loci overlap for cSCC/BCC and BCC/melanoma, but no other loci are shared between cSCC and melanoma. PRS for melanoma show roughly two‐to‐threefold increases in risk and modest improvements in risk prediction (2–7% increases). PRS are associated with twofold and threefold increases in risk of cSCC and BCC, respectively, with small improvements (2% increase) in predictive ability. Conclusions Existing data indicate that PRS may offer small, but potentially meaningful, improvements to risk prediction. Additional research is needed to clarify the potential utility of PRS in cutaneous carcinomas. Clinical translation will require well‐powered validation studies incorporating known risk factors to evaluate PRS as tools for screening. What's already known about this topic? Over 50 susceptibility loci for melanoma, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) have been identified in genome‐wide association studies (GWAS). Polygenic risk scores (PRS) using variants identified from GWAS have also been developed for melanoma, BCC and cSCC, and investigated with respect to clinical risk prediction. What does this study add? This review provides an overview of GWAS findings and the potential clinical utility of PRS for melanoma, BCC and cSCC.

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Section: Genetic Association Studiesmentioning

confidence: 99%

Genome‐wide association studies and polygenic risk scores for skin cancer: clinically useful yet?

Roberts

Asgari

Toland³

2019

Br J Dermatol

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“…Then, based on the genotypes of the individuals in the target data set at these loci, it calculates a PRS for each individual. While most of the selected loci are not genome-wide significant, and many are false positives, those will have random effect size and direction; so, final score is mostly driven by true risk loci (for a review on PRSs, see Maher [94]). In the original paper, the author used this method to formally demonstrate a long-suspected genetic overlap between schizophrenia and BD that is also supported by CNV and rare variant data.…”

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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“…However, there are several limits with the use of PRS to disentangle the links between SZ and cognition. Some are dependent of the caveats of the PRS technic (for review, see [77]). Some are more specific to this review.…”

Section: Discussionmentioning

confidence: 99%

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

Mallet

Strat

Dubertret

et al. 2020

JCM

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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.

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Polygenic Scores in Epidemiology: Risk Prediction, Etiology, and Clinical Utility

Cited by 57 publications

References 39 publications

Genome‐wide association studies and polygenic risk scores for skin cancer: clinically useful yet?

Genome‐wide association studies and polygenic risk scores for skin cancer: clinically useful yet?

Recent Advances in the Genetics of Schizophrenia

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

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