Clinical implementation of polygenic risk scores.

Challenges With Colorectal Cancer Family History Assessment—Motivation to Translate Polygenic Risk Scores Into Practice

A Blueprint for Genetic Determinism

Background:Postoperative nausea and vomiting (PONV) is a key driver of unplanned admission and patient satisfaction after surgery. Because traditional risk factors do not completely explain variability in risk, this study hypothesized that genetics may contribute to the overall risk for this complication. The objective of this research is to perform a genome-wide association study of PONV, derive a polygenic risk score for PONV, assess associations between the risk score and PONV in a validation cohort, and compare any genetic contributions to known clinical risks for PONV.Methods:Surgeries with integrated genetic and perioperative data performed under general anesthesia at Michigan Medicine (Ann Arbor, Michigan) and Vanderbilt University Medical Center (Nashville, Tennessee) were studied. PONV was defined as nausea or emesis occurring and documented in the postanesthesia care unit. In the discovery phase, genome-wide association studies were performed on each genetic cohort, and the results were meta-analyzed. Next, the polygenic phase assessed whether a polygenic score, derived from genome-wide association study in a derivation cohort from Vanderbilt University Medical Center, improved prediction within a validation cohort from Michigan Medicine, as quantified by discrimination (c-statistic) and net reclassification index.Results:Of 64,523 total patients, 5,703 developed PONV (8.8%). The study identified 46 genetic variants exceeding the threshold of P < 1 × 10−5, occurring with minor allele frequency greater than 1%, and demonstrating concordant effects in both cohorts. Standardized polygenic score was associated with PONV in a basic model, controlling for age and sex (adjusted odds ratio, 1.027 per SD increase in overall genetic risk; 95% CI, 1.001 to 1.053; P = 0.044), a model based on known clinical risks (adjusted odds ratio, 1.029; 95% CI, 1.003 to 1.055; P = 0.030), and a full clinical regression, controlling for 21 demographic, surgical, and anesthetic factors, (adjusted odds ratio, 1.029; 95% CI, 1.002 to 1.056; P = 0.033). The addition of polygenic score improved overall discrimination in models based on known clinical risk factors (c-statistic, 0.616 compared to 0.613; P = 0.028) and improved net reclassification of 4.6% of cases.Conclusions:Standardized polygenic risk was associated with PONV in all three of the study’s models, but the genetic influence was smaller than exerted by clinical risk factors. Specifically, a patient with a polygenic risk score greater than 1 SD above the mean has 2 to 3% greater odds of developing PONV when compared to the baseline population, which is at least an order of magnitude smaller than the increase associated with having prior PONV or motion sickness (55%), having a history of migraines (17%), or being female (83%) and is not clinically significant. Furthermore, the use of a polygenic risk score does not meaningfully improve discrimination compared to clinical risk factors and is not clinically useful.

Polygenic Risk Scores for Follow Up After Colonoscopy and Polypectomy: Another Tool for Risk Stratification and Planning Surveillance?

Pleural mesothelioma (PM) is a lethal cancer primarily caused by asbestos exposure. Not all exposed individuals develop PM, suggesting the involvement of additional factors. This underscores the need for robust predictive models integrating biomarkers from multi-omic domains to improve risk stratification and early detection. We developed and evaluated polygenic risk scores (PRS) and methylation risk scores (MRS) using a retrospective case-control study (749 participants: 387 PM cases, 362 controls) and a nested case-control European Prospective Investigation into Cancer and Nutrition (EPIC)-Meso study (268 participants: 134 preclinical PM cases, 134 matched controls) within the EPIC cohort. Genome-wide association analyses in the retrospective case-control study identified PM-associated variants. The PRS (1123 SNPs with p < 0.001) in the retrospective training subset stratified disease risk in the test set (ORs 3.46-9.54 across top percentiles) and improved model discrimination (AUC = 0.75 vs. 0.71 in baseline model, p = 0.04). In EPIC-Meso, PRS performance was limited (AUC = 0.52). External validation in the UK-Biobank (UKBB) confirmed a modest but consistent association with PM-risk. A Meta-PRS derived from the UKBB-FinnGen meta-analysis replicated this trend in the full retrospective dataset, showing higher OR across top percentiles (2.5-12.3) and improved discrimination (AUC 0.74 vs. 0.72, p = 0.016). MRS, with 68 differentially methylated CpGs (effect-size >|0.10|, FDR p < 0.05) in the retrospective training set, increased the AUC from 0.66 to 0.85 (p < 0.001) in the test set and from 0.51 to 0.62 in EPIC-Meso. PRS was most predictive in low-exposure groups, while MRS remained robust across exposure levels. Combined PRS-MRS models improved discrimination. Integrating multi-omic biomarkers can enhance PM-risk stratification and support earlier, targeted interventions in high-risk asbestos-exposed groups.

BackgroundBreast cancer patients from the indigenous Arab population present much earlier than patients from Western countries and have traditionally been underrepresented in cancer genomics studies. The contribution of polygenic and Mendelian risk toward the earlier onset of breast cancer in the population remains elusive.MethodsWe performed low-pass whole genome sequencing (lpWGS) and whole-exome sequencing (WES) from 220 female breast cancer patients unselected for positive family history from the indigenous Arab population. Using publicly available resources, we imputed population-specific variants and calculated breast cancer burden-sensitive polygenic risk scores (PRS). Variant pathogenicity was also evaluated on exome variants with high coverage.ResultsVariants imputed from lpWGS showed high concordance with paired exome (median dosage correlation: 0.9459, Interquartile range: 0.9410–0.9490). After adjusting the PRS to the Arab population, we found significant associations between PRS performance in risk prediction and first-degree relative breast cancer history prediction (Spearman rho=0.43, p = 0.03), where breast cancer patients in the top PRS decile are 5.53 (95% CI 1.76–17.97, p = 0.003) times more likely also to have a first-degree relative diagnosed with breast cancer compared to those in the middle deciles. In addition, we found evidence for the genetic liability threshold model of breast cancer where among patients with a family history of breast cancer, pathogenic rare variant carriers had significantly lower PRS than non-carriers (p = 0.0205, Mann-Whitney U test) while for non-carriers every standard deviation increase in PRS corresponded to 4.52 years (95% CI 8.88–0.17, p = 0.042) earlier age of presentation.ConclusionsOverall, our study provides a framework to assess polygenic risk in an understudied population using lpWGS and identifies common variant risk as a factor independent of pathogenic variant carrier status for earlier age of onset of breast cancer among indigenous Arab breast cancer patients.

Genetic substudies of randomized controlled trials demonstrate that high coronary heart disease (CHD) polygenic risk score modifies statin CHD relative risk reduction; it is unknown if the association extends to statin users undergoing routine care. We sought to determine how statin effectiveness is modified by CHD polygenic risk score in a real-world cohort of participants without previous myocardial infarction. We determined CHD polygenic risk scores in participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. Covariate-adjusted Cox regression models were used to compare the risk of cardiovascular outcomes between statin users and matched nonusers. Statin effectiveness on incident myocardial infarction showed no gradient with increasing 10-year Pooled Cohort Equations atherosclerotic cardiovascular disease (ASCVD) risk across low, borderline, intermediate, and high ASCVD risk score groups. In contrast, statin effectiveness by polygenic risk was largest in the high polygenic risk score group (hazard ratio (HR) 0.41, 95% confidence interval (CI), 0.31-0.53; P=1.5E-11), intermediate in the intermediate polygenic risk score group (HR 0.56, 95% CI, 0.47-0.66; P=8.4E-12), and smallest in the low polygenic risk score group (HR 0.67, 95% CI, 0.47-0.97; P=0.03; P for high vs. low=0.01). ASCVD risk and statin low-density lipoprotein cholesterol (LDL-C) lowering did not differ across polygenic risk score groups. In patients undergoing routine care, CHD polygenic risk modified statin relative risk reduction of incident myocardial infarction independent of LDL-C lowering. Our findings extend prior work by identifying a subset (i.e., self-identified White individuals with low CHD polygenic risk scores) with attenuated clinical benefit from statins.

Rare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequence data enables examination of the joint contribution of rare and common variations to the QT interval in the population. We performed a genome-wide association study of the QTc in 84 630 UK Biobank participants and created a polygenic risk score (PRS). Among 26 976 participants with whole-genome sequencing and ECG data in the TOPMed (Trans-Omics for Precision Medicine) program, we identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. We examined QTc associations with the PRS and with rare variants in TOPMed. Fifty-four independent loci were identified by genome-wide association study in the UK Biobank. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS composed of 1 110 494 common variants was significantly associated with the QTc in TOPMed (ΔQTc/decile of PRS=1.4 ms [95% CI, 1.3 to 1.5]; P=1.1×10-196). Carriers of putative pathogenic rare variants had longer QTc than noncarriers (ΔQTc=10.9 ms [95% CI, 7.4 to 14.4]). Of individuals with QTc>480 ms, 23.7% carried either a monogenic rare variant or had a PRS in the top decile (3.4% monogenic, 21% top decile of PRS). QTc duration in the population is influenced by both rare variants in genes underlying cardiac repolarization and polygenic risk, with a sizeable contribution from polygenic risk. Comprehensive assessment of the genetic determinants of QTc prolongation includes incorporation of both polygenic and monogenic risk.

PurposeLupus nephritis (LN) is a major clinical challenge and cause of significant morbidity and mortality in systemic lupus erythematosus (SLE). Today >180 SLE risk loci at Genome-wide significance (GWS, p...

Breast cancer has been associated with monogenic, polygenic, and epidemiologic (clinical, reproductive, and lifestyle) risk factors, but studies evaluating the combined effects of these factors have been limited. We extended previous work in breast cancer risk modeling, incorporating pathogenic variants (PV) in six breast cancer predisposition genes and a 105-SNP polygenic risk score (PRS), to include an epidemiologic risk score (ERS) in a sample of non-Hispanic White women drawn from prospective cohorts and population-based case-control studies, with 23,518 cases and 22,832 controls, from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium. The model predicts 4.4-fold higher risk of breast cancer for postmenopausal women with no predisposition PV and median PRS, but with the highest versus lowest ERS. Overall, women with CHEK2 PVs had >20% lifetime risk of breast cancer. However, 15.6% of women with CHEK2 PVs and a family history of breast cancer, and 45.1% of women with CHEK2 PVs but without a family history of breast cancer, had low (<20%) predicted lifetime risk and thus were below the threshold for MRI screening. CHEK2 PV carriers at the 10th percentile of the joint distribution of ERS and PRS, without a family history of breast cancer, had a predicted lifetime risk similar to the general population. These results illustrate that an ERS, alone and combined with the PRS, can contribute to clinically relevant risk stratification. Integrating monogenic, polygenic, and epidemiologic risk factors in breast cancer risk prediction models may inform personalized screening and prevention efforts.

MP69-12 ADDED VALUE OF GENETIC RISK SCORE TO THE PROSTATE CANCER PREVENTION TRIAL (PCPT) RISK CALCULATOR: FINDINGS FROM THE PCPT STUDY

Introduction: Genetic predisposition for CAD is well established. Polygenic risk scores are emerging as tools to quantify the genomic component of an individual’s risk for CAD. However, their clinical utility for individual risk stratification is unclear. Hypothesis: 180 SNPs previously identified in Caucasian Genome Wide-Association Studies for CAD were used to construct a weighted restricted polygenic risk score (PRS; normalized range 11.18 -17.58). This study hypothesizes that a low PRS (&lt;85th percentile) is associated with coronary calcium score (CAC) of zero. Methods: Between January 2018 &amp; March 2020, 21,784 patients underwent CAC screening and/or PRS testing. Caucasian patients with both PRS and CAC scores were identified. Fisher’s exact test was utilized to test the association between low PRS and CAC score of zero. Results: 3,197 Caucasian patients had both PRS and CAC calculated, 1597 (49.9%) of whom had CAC greater than zero. Characteristics are summarized in table 1. Odds ratio of low PRS associated with CAC zero was 1.34 (95% CI 1.08 - 1.67; p=0.0079). Conclusions: In our Caucasian cohort, there is a statistically significant correlation between a low PRS and absence of coronary artery calcium. This is a real-world analysis incorporating genomic data for individual CAD risk stratification. Further studies on a larger, ethnically diverse cohort are needed.

46 - THE POLYGENIC EPISTASIS RISK SCORE DEMONSTRATES SIGNIFICANT ROLE OF GENE INTERACTION IN BIPOLAR DISORDER

BACKGROUNDSchizotypy (ST) and psychotic-like experiences and negative symptoms (PENS) are commonly used phenotypes in high-risk and early intervention research for schizophrenia and other non-affective psychoses. However, the origin of these phenotypes in the general population is poorly understood and their association with the genetic predisposition to psychoses has not yet been proven.AIMThe aim of this study is to answer the question of whether data on the relations of ST and PENS with polygenic risk scores for schizophrenia (SZ-PRS) support the hypothesis that these phenotypes are subclinical manifestations of genetic liability for schizophrenia.METHODSLiterature describing these relations in the general population was analyzed. The literature search was performed in the PubMed database using the following keywords in English: ((“schizotyp*” OR “psychotic-like experiences” OR “psychosis proneness” OR “psychotic experiences”) AND (”polygenic risk” OR “genetic liability” OR “polygenic score”)); the search in eLIBRARY.RU was conducted using the Russian words for “schizotypy”, “schizotypal features”, “psychotic experiences”, “psychotic experience”, “psychotic symptoms”, and “polygenic risk”, covering publications from 2009 to 2024.RESULTSOf the identified records, 45 publications were found eligible. No expected positive correlations of SZ-PRS with common ST measures have been observed. For PENS, the results are inconsistent. Overall, SZ-PRS correlate more often with the PENS general factor and negative symptoms than with psychotic experiences per se.CONCLUSIONThe literature does not provide convincing evidence of the association between SZ-PRS and ST/PENS. The search for the substantive psychological meaning of polygenic vulnerability to psychosis captured by SZ-PRS should be expanded to other personality processes and traits.

Article 1: Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here, we report a screen for de novo mutations in patients with 2 classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in 4 patients, and ALG13, with the same de novo mutation in 2 patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR, and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders. Article 2: Identifying genetic risk factors for highly heterogeneous disorders such as epilepsy remains challenging. Here, we present, to our knowledge, the largest whole-exome sequencing study of epilepsy to date, with more than 54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate 7 individual genes, 3 gene sets and 4 copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies and generalized and focal epilepsies, whereas most other gene discoveries are subtype specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single-nucleotide/short insertion and deletion variants, copy number variants and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies. Article 3: Background: The epilepsies are highly heritable conditions that commonly follow complex inheritance. While monogenic causes have been identified in rare familial epilepsies, most familial epilepsies remain unsolved. We aimed to determine (1) whether common genetic variation contributes to familial epilepsy risk, and (2) whether that genetic risk is enriched in familial compared with nonfamilial (sporadic) epilepsies. Methods: Using common variants derived from the largest epilepsy genome-wide association study, we calculated polygenic risk scores (PRS) for patients with familial epilepsy (n = 1818 from 1181 families), their unaffected relatives (n = 771), sporadic patients (n = 1182), and population controls (n = 15,929). We also calculated separate PRS for genetic generalized epilepsy (GGE) and focal epilepsy. Statistical analyses used mixed-effects regression models to account for familial relatedness, sex, and ancestry. Findings: Patients with familial epilepsies had higher epilepsy PRS compared to population controls (OR 1·20, padj = 5 × 10-9), sporadic patients (OR 1·11, padj = 0.008), and their own unaffected relatives (OR 1·12, padj = 0.01). The top 1% of the PRS distribution was enriched 3.8-fold for individuals with familial epilepsy when compared to the lowest decile (padj = 5 × 10-11). Familial PRS enrichment was consistent across epilepsy type; overall, polygenic risk was greatest for the GGE clinical group. There was no significant PRS difference in familial cases with established rare variant genetic etiologies compared to unsolved familial cases. Interpretation: The aggregate effects of common genetic variants, measured as PRS, play an important role in explaining why some families develop epilepsy, why specific family members are affected while their relatives are not, and why families manifest specific epilepsy types. Polygenic risk contributes to the complex inheritance of the epilepsies, including in individuals with a known genetic etiology.