Polygenic Risk Score Scores Research Articles

Abstract 818: Association of polygenic risk score and menopausal hormone therapy for colorectal cancer risk

Abstract Background and objective Genetic predisposition and menopausal hormone therapy (MHT) are established risk and preventive factors for colorectal cancer (CRC), respectively. We aimed to evaluate the joint associations of a polygenic risk score (PRS) and MHT on CRC risk for informing CRC prevention. Methods We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent from 38 studies. MHT use was assessed as the use of any MHT, estrogen-only (E-only) or combined estrogen-progestogen (E+P) therapy at reference time. A PRS based on 141 genetic variants previously identified by genome-wide association studies of CRC was modelled as categorical variable in quartiles and also as per-standard deviation difference between PRS and minimum of PRS [(PRS-min(PRS))/SD(PRS)] (PRS.minsd). Multiplicative interaction between PRS and MHT was evaluated using standard logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). Results The use of any MHT as well as E+P and E-only were associated with reduced CRC risk (Odds ratio [OR] 0.70, 0.71, 0.65, respectively). PRS was associated with increased CRC risk, whether as continuous variable (PRS.minsd) (OR 1.53) or in quartiles (OR 1.49, 1.92, 2.87, respectively). We identified statistically significant negative multiplicative interaction (OR: 0.92; 95%CI: 0.87, 0.98) as well as negative additive interaction (RERI: -0.13; 95%CI: -0.15, -0.10) between PRS.minsd and any MHT use. Results were limited to additive interactions with PRS.minsd for E-only use (RERI: -0.14; 95%CI: -0.18, -0.11) and E+P use (RERI: -0.12; 95%CI: -0.16, -0.08). The magnitude of negative additive interactions increased with higher quartiles of PRS for all MHT variables and was consistently significant for the highest quartile compared to the lowest quartile of PRS for any MHT use (RERI: -0.78; 95%CI: -1.03, -0.52), E-only use (RERI: -0.78; 95%CI: -1.18, -0.39), and also E+P use (RERI: -0.53; 95%CI: -0.96, -0.10). Negative multiplicative interaction was also observed for higher PRS quartiles of all MHT variables but significant only for the highest quartile with E-only use (OR: 0.73; 95%CI: 0.55, 0.97). These negative interactions on both multiplicative and additive scales indicate that MHT has a relatively more protective effect on CRC risk for those women with larger PRS scores. For example, compared to women in the lowest PRS quartile with no MHT use, the risk of CRC for women in higher quartiles of PRS was more strongly reduced with MHT use (ORPRS.Q3+noMHT: 1.93 vs ORPRS.Q3+MHT: 1.38, OR MHT/noMHT in PRS.Q3: 0.71; ORPRS.Q4+noMHT: 2.81 vs ORPRS.Q4+MHT: 1.77, OR MHT/noMHT in PRS.Q4: 0.63). Conclusions The protective effect of MHT use on the risk of CRC is stronger in women with higher genetic risk. Risk prediction models incorporating PRS may need to account for potential effect modification by non-genetic risk factors. Citation Format: Yu Tian, Yi Lin, Andre E. Kim, Stephanie A. Bien, Polly A. Newcomb, Graham Casey, Elizabeth A. Platz, Loic Le Marchand, Peter T. Campbell, Hermann Brenner, Michael Hoffmeister, Feng Guo, Xuechen Chen, Marc J. Gunter, Niki Dimou, Stephen B. Gruber, Andrew T. Chan, Amit D. Joshi, Sonja I. Berndt, Emily White, Victor Moreno, Ross L. Prentice, Ulrike Peters, William Gauderman, Li Hsu, Jenny Chang-Claude. Association of polygenic risk score and menopausal hormone therapy for colorectal cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 818.

Validation of breast cancer risk assessment tools on a French-Canadian population-based cohort

ObjectivesEvaluate the accuracy of the Breast Cancer Risk Assessment Tool (BCRAT), International Breast Cancer Intervention Study risk evaluation tool (IBIS), Polygenic Risk Scores (PRS) and combined scores (BCRAT+PRS and IBIS...

Discovery of breast cancer risk genes and establishment of a prediction model based on estrogen metabolism regulation

BackgroundMultiple common variants identified by genome-wide association studies have shown limited evidence of the risk of breast cancer in Chinese individuals. In this study, we aimed to uncover the relationship between estrogen levels and the genetic polymorphism of estrogen metabolism-related enzymes in breast cancer (BC) and establish a risk prediction model composed of estrogen-metabolizing enzyme genes and GWAS-identified breast cancer-related genes based on a polygenic risk score.MethodsUnrelated BC patients and healthy subjects were recruited for analysis of estrogen levels and single nucleotide polymorphisms (SNPs) in genes encoding estrogen metabolism-related enzymes. The polygenic risk score (PRS) was used to explore the combined effect of multiple genes, which was calculated using a Bayesian approach. An independent sample t-test was used to evaluate the differences between PRS scores of BC and healthy subjects. The discriminatory accuracy of the models was compared using the area under the receiver operating characteristic (ROC) curve.ResultsThe estrogen homeostasis profile was disturbed in BC patients, with parent estrogens (E1, E2) and carcinogenic catechol estrogens (2/4-OHE1, 2-OHE2, 4-OHE2) significantly accumulating in the serum of BC patients. We then established a PRS model to evaluate the role of SNPs in multiple genes. PRS model 1 (M1) was established from SNPs in 6 GWAS-identified high risk genes. On the basis of M1, we added SNPs from 7 estrogen metabolism enzyme genes to establish PRS model 2 (M2). The independent sample t-test results showed that there was no difference between BC and healthy subjects in M1 (P = 0.17); however, there was a significant difference between BC and healthy subjects in M2 (P = 4.9*10− 5). The ROC curve results showed that the accuracy of M2 (AUC = 62.18%) in breast cancer risk identification was better than that of M1 (AUC = 54.56%).ConclusionEstrogen and related metabolic enzyme gene polymorphisms are closely related to BC. The model constructed by adding estrogen metabolic enzyme gene SNPs has a good predictive ability for breast cancer risk, and the accuracy is greatly improved compared with that of the PRS model that only includes GWAS-identified gene SNPs.

Evaluating Polygenic Risk Scores in “Lone” Atrial Fibrillation

BackgroundPolygenic scores incorporating varying numbers of single nucleotide polymorphisms (SNPs) have been demonstrated to exert a prominent role in atrial fibrillation (AF). We sought to compare the relative discriminatory capacities of 2 previously validated polygenic scores in “lone” AF. MethodsA total of 186 lone AF cases of European ancestry underwent SNP genotyping. A genome-wide polygenic score (GPS) and polygenic risk score (PRS) involving 6,730,541 and 1168 SNPs, respectively, were calculated for 186 cases and 423 controls of European ancestry from the 1000 Genomes (1KG) Project. The distribution of the polygenic scores was compared between the cases and controls and their discriminatory capacities were evaluated using receiver operating characteristic (ROC) curves. ResultsA total of 34.4% of patients with lone AF had GPS scores greater than the top 10th percentile of 1KG controls, corresponding to a 4.64-fold increased odds (95% confidence interval [CI], 2.99-7.18; P < 0.001) for AF. A PRS score in the top 10th percentile of 1KG controls was observed in 26.3% of cases, which equated to a 3.16-fold increased odds (95% CI, 2.01-4.98; P < 0.001) for AF. Comparison of C-statistics from ROC curves indicated improved discriminatory capacity of the GPS (0.76) relative to the PRS (0.70) (P = 0.002). ConclusionsOur study evaluating 2 polygenic scores for AF suggests that the GPS, containing more than 6.7 million SNPs, exhibits an improved discriminatory capacity in lone AF compared with a PRS possessing 1168 SNPs. Our findings suggest that genetic risk scores for AF that maximally leverage genomic data may provide improved predictive power.

Effects of complement gene-set polygenic risk score on brain volume and cortical measures in patients with psychotic disorders and healthy controls.

Multiple genome-wide association studies of schizophrenia have reported associations between genetic variants within the MHC region and disease risk, an association that has been partially accounted for by alleles of the complement component 4 (C4) gene. Following on previous findings of association between both C4 and other complement-related variants and memory function, we tested the hypothesis that polygenic scores calculated based on identified schizophrenia risk alleles within the "complement" system would be broadly associated with memory function and associated brain structure. We tested this using a polygenic risk score (PRS) calculated for complement genes, but excluding C4 variants. Higher complement-based PRS scores were observed to be associated with lower memory scores for the sample as a whole (N = 620, F change = 8.25; p = .004). A significant association between higher PRS and lower hippocampal volume was also observed (N = 216, R2 change = 0.016, p = .015). However, after correcting for further testing of association with the more general indices of cortical thickness, surface area or total brain volume, none of which were associated with complement, the association with hippocampal volume became non-significant. A post-hoc analysis of hippocampal subfields suggested an association between complement PRS and several hippocampal subfields, findings that appeared to be particularly driven by the patient sample. In conclusion, our study yielded suggestive evidence of association between complement-based schizophrenia PRS and variation in memory function and hippocampal volume.

Abstract 2322: A polygenic risk score-based genetic stratification for endometrial cancer

Abstract Endometrial cancer (EC) is the most common of gynecological cancers in the UK. There is evidence for genetic predisposition to EC, however, single nucleotide polymorphisms have not been considered in risk prediction models so far. We hypothesized that a polygenic risk score (PRS) based on a panel of robust SNPs may be useful to predict women at high risk of developing EC. We conducted a systematic review to identify the most robust SNPs which may be associated with EC risk. The resulting panel of SNPs was validated in an independent cohort comprising EC cases, and control women with intact uterus. In the present study, we used 560 cases and 1202 controls of broad-European origin to construct a PRS. Our systematic review suggested twenty four SNPs, nineteen of which were reported to reach genome-wide significance in large GWAS. Preliminary results using 560 cases and 1202 controls produced effect sizes, directions and dosages similar to published data. The mean PRS for EC cases was 0.64 (SD=0.43, 95%CI 0.60-0.68) while mean PRS for controls was 0.48 (SD=0.42, 95% CI 0.46-0.51). The AUC of the PRS achieved was 0.61. Women in the highest tertile of the PRS score had a 2.4 times increased risk of developing EC compared to women in the lowest tertile (OR=2.40, 95%CI 1.85-3.09, p = 1.47E-11). Women in the mid tertile also had a modestly increased risk of EC compared to the lowest tertile (OR=1.40, 95%CI 1.06-1.84, p = 0.017). There was a clear trend of increasing risk with category (p = 6.25E-12). There is mounting evidence for polygenic input from common variants in EC susceptibility. Our results, for the first time, validate the potential use of a PRS for risk stratification of women at high risk of EC. When considered alongside epidemiological risk factors, the PRS could provide a good discrimination for early detection and prevention of EC in a clinical setting. Citation Format: Cemsel Bafligil, Deborah J. Thompson, Artitaya Lophatananon, Miriam J. Smith, Joe Dennis, Gareth D. Evans, Emma J. Crosbie. A polygenic risk score-based genetic stratification for endometrial cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2322.

Sibling validation of polygenic risk scores and complex trait prediction

We test 26 polygenic predictors using tens of thousands of genetic siblings from the UK Biobank (UKB), for whom we have SNP genotypes, health status, and phenotype information in late adulthood. Siblings have typically experienced similar environments during childhood, and exhibit negligible population stratification relative to each other. Therefore, the ability to predict differences in disease risk or complex trait values between siblings is a strong test of genomic prediction in humans. We compare validation results obtained using non-sibling subjects to those obtained among siblings and find that typically most of the predictive power persists in between-sibling designs. In the case of disease risk we test the extent to which higher polygenic risk score (PRS) identifies the affected sibling, and also compute Relative Risk Reduction as a function of risk score threshold. For quantitative traits we examine between-sibling differences in trait values as a function of predicted differences, and compare to performance in non-sibling pairs. Example results: Given 1 sibling with normal-range PRS score (< 84 percentile, < + 1 SD) and 1 sibling with high PRS score (top few percentiles, i.e. > + 2 SD), the predictors identify the affected sibling about 70–90% of the time across a variety of disease conditions, including Breast Cancer, Heart Attack, Diabetes, etc. 55–65% of the time the higher PRS sibling is the case. For quantitative traits such as height, the predictor correctly identifies the taller sibling roughly 80 percent of the time when the (male) height difference is 2 inches or more.

In This Issue

HomeCirculation ResearchVol. 126, No. 2In This Issue Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIn This Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published16 Jan 2020https://doi.org/10.1161/RES.0000000000000321Circulation Research. 2020;126:159is related toMonogenic and Polygenic Contributions to Atrial Fibrillation RiskMetabolic Remodeling Promotes Cardiac Hypertrophy by Directing Glucose to Aspartate Biosynthesisis related toActivated Endothelial TGFβ1 Signaling Promotes Venous Thrombus Nonresolution in Mice Via Endothelin-1TGFβ Signaling and Defective Thrombus Resolution (p 162)Aberrant TGFβ1 signaling is a likely driver of chronic thromboembolic pulmonary hypertension, say Bochenek et al.Download figureDownload PowerPointChronic thromboembolic pulmonary hypertension (CTEPH) is a rare, life-threatening form of pulmonary hypertension characterized by persistent blood clots in the lung arteries that ultimately result in the formation of fibrotic lesions containing irregular vasculature. The mechanisms underlying CTEPH are largely unknown, but because the cytokine TGFβ1 regulates fibrosis and angiogenesis, and because mutations affecting TGFβ1 signaling have been implicated in another form of pulmonary hypertension, Bochenek and colleagues hypothesized this factor’s involvement. Sure enough, they found that, in CTEPH patient tissue, components of the TGFβ1 pathway were upregulated, including TGFβ1 itself and endothelin-1—a vasoconstrictor and promoter of fibrosis. The team also showed that mice engineered to lack TGFβ1 in platelet cells had faster resolution of experimental thrombosis than did control animals. Furthermore, inhibition of endothelin-1 activity prevented human and mouse endothelial cells converting to a fibrotic phenotype. The results suggest the TGFβ1-to-endothelin-1 pathway plays a pathological role in CTEPH and lends supporting evidence that the clinical use of endothelin-1 receptor blockers—prescribed to some patients with CTEPH—is a worthwhile therapy.ACC2 Deletion Prevents Aspartate Synthesis(p 182)Boosting fatty acid oxidation prevents aspartate synthesis and cardiac hypertrophy, report Ritterhoff et al.Download figureDownload PowerPointCardiac hypertrophy, in which the heart and its component cells become enlarged, can be a normal physiological process to cope with increased demand—for example, in pregnancy or elite athletes—but can also be pathological—caused by high blood pressure and other cardiovascular conditions. Pathological hypertrophy is associated with a metabolic switch in the heart from primarily fatty acid-based to glucose-based. And, boosting fatty acid oxidation (FAO) can protect against hypertrophy in cultured cardiomyocytes and animals. The mechanism underlying this protection is unknown, however. Now, Ritterhoff and colleagues show that in addition to increased glucose consumption, hypertrophic rat cardiomyocytes ramp up their levels of aspartate—a molecule involved in cell growth via synthesis of nucleic acids, RNAs, and proteins. And, boosting FAO (by genetic manipulation) prevents both the aspartate rise and hypertrophy in the cells as well as in live mice. Adding aspartate to such FAO-boosted cells could reinstate the hypertrophic phenotype. The discovery of this relationship between glucose metabolism, aspartate, and FAO may inform the design of new therapies aimed at manipulating heart cell metabolism to manage hypertrophy, say the authors.Genetic Basis of Atrial Fibrillation (p 200)Choi et al examine poly-and mono-genetic predisposition to atrial fibrillation.Download figureDownload PowerPointAffecting ≈30 million individuals worldwide, atrial fibrillation (AF) is a common cardiac arrhythmia associated with an increased risk of heart failure, stroke, dementia, and death. While the condition can be idiopathic, there is also evidence of inheritance. Indeed, a quarter of patients have a parent, sibling, or child with the condition. Genome-wide association studies have identified numerous common genetic variants linked to AF, and the more of these variants a person carries, the greater the risk—referred to as their polygenic risk score (PRS). Studies of families with AF have also revealed rarer monogenic variants, such as loss-of-function (LOF) mutations in the sarcomeric gene titin (TTN). Now, Choi and colleagues look at these common polygenic and rare monogenic variants together to examine their relative contributions. Studying the genomes of 1546 AF patients and more than 41 000 controls, the team discovered a significant association between AF and rare LOF variants at TTN. Indeed, 14% of individuals with such variants had AF. However, the team also showed that while TTN variants were highly penetrant, PRS scores accounted for considerably more of the variance in AF susceptibility. Thus, the study indicates that, generally speaking, a person’s PRS is a better indicator of overall AF risk. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesMonogenic and Polygenic Contributions to Atrial Fibrillation RiskSeung Hoan Choi, et al. Circulation Research. 2020;126:200-209Metabolic Remodeling Promotes Cardiac Hypertrophy by Directing Glucose to Aspartate BiosynthesisJulia Ritterhoff, et al. Circulation Research. 2020;126:182-196Activated Endothelial TGFβ1 Signaling Promotes Venous Thrombus Nonresolution in Mice Via Endothelin-1Magdalena L. Bochenek, et al. Circulation Research. 2020;126:162-181 January 17, 2020Vol 126, Issue 2 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000321 Originally publishedJanuary 16, 2020 PDF download Advertisement

Association between a Polygenic Risk Score for Multiple Myeloma Risk and Overall Survival

Background Genome-wide association studies (GWAS) conducted in populations of European ancestry (EA) have identified and confirmed 23 germline susceptibility loci for multiple myeloma (MM). The effect sizes of single nucleotide polymorphisms (SNPs) at these loci are small, therefore combining them into a single summary measure, known as a polygenic risk score (PRS), may provide a more meaningful risk factor. We have previously shown a PRS comprised of the 23 SNPs for MM contributes to increased risk of MM, with a 2.7-fold increase for highest vs. lowest PRS quintiles. Whether the MM-PRS is also associated with overall survival (OS) in MM cases has not been evaluated. We examined the association between MM-PRS and OS in two EA studies. Methods The first study consisted of 2,179 EA MM cases from ten studies included in the Multiple Myeloma Working Group within the International Lymphoma Consortium (InterLymph). Cases were diagnosed between 1970 and 2015 and genotyped using multiple platforms (Oncoarray, Affymetrix, Human660W-quad Beadchip, and Illumina arrays); 885 cases also had stage [based on International Staging System (ISS)] available. Each of the GWAS was subjected to rigorous standard quality control independently (prior to imputation via the Michigan imputation server based on the Haplotype Reference Consortium (HRC). The second study consisted of 515 newly diagnosed EA MM cases from CoMMpass (Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile), diagnosed from 2011-2013, who had whole genome sequencing (WGS) performed on germline DNA. The WGS data was used to call common germline genetic variants through the Mayo Clinic bioinformatics pipeline. Briefly, genetic variants were detected with GenomeGPS, aligned to the hg19 reference genome, called using the GATK (V3.6) Haplotype Caller, and merged for multiple-sample joint calling. To reduce the false positive variants, variant quality score recalibration (VQSR) was applied for both SNPs and INDELs. After quality control, 458 EA samples remained. Follow-up was available for both studies and consisted of time from MM diagnosis date until death or date of last known follow-up. The PRS was constructed from the 23 MM SNPs using the published per allele odds ratio associated with MM risk. The published log odds ratios for each SNP were multiplied by the number of risk alleles (0, 1, 2) for the corresponding SNP, and summed, resulting in a unique score per person. Kaplan-Meier curves and Cox proportional hazard models were used to assess the association between PRS with MM OS considering two models: 1) adjusted for age, sex, study and 2) additional adjustment by stage (ISS). Hazard ratios (OR) and 95% confidence intervals (CI) were estimated. The PRS was evaluated both as a continuous variable, per standard deviation (SD), and as a categorical variable (quintiles). Results MM cases (N=2,179) in the InterLymph study were 59% male and 41% female and the median age was 61.0 years (26-90 years). Median follow-up time was 57.2 months (1.0-509.0 months) with 868 reported deaths. MM cases with stage information available consisted of 20% stage I (n=178), 53% stage II (n=466), and 27% stage III (n=241). No association was observed between PRS and OS in MM patients regardless of adjustment for stage (continuous PRS (HR: 1.03, 95% CI: 0.83-1.28, P=0.80) or by quintile PRS (p&gt;0.05)) (Table). The CoMMpass EA MM cases (n=458) had similar distributions for sex (61% male and 39% females) but were slightly older 65 years (27-93 years) and had shorter follow-up time (median=39.75 months (0.13-77.2)) with 117 deaths. Stage was available for 96% of CoMMpass cases including 36% stage I (n=159), 33% stage II (n=146), and 31% stage III (n=134). We also observed no association of PRS and OS in the CoMMpass study (HR=1.02, 95% CI: 0.72 -1.46, P= 0.89), adjusted for age, sex, and stage (Table). Discussion A PRS score for MM risk is not associated with OS for MM cases in two EA populations. Given that prior studies have shown association of genetic variation with MM survival, efforts to identify additional loci associated with OS or MM specific survival are warranted. Future studies should also consider germline variants impact on molecular subtypes, specific therapies, and outcomes. Disclosures Kumar: Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

Do ADHD-impulsivity and BMI have shared polygenic and neural correlates?

There is an extensive body of literature linking ADHD to overweight and obesity. Research indicates that impulsivity features of ADHD account for a degree of this overlap. The neural and polygenic correlates of this association have not been thoroughly examined. In participants of the IMAGEN study, we found that impulsivity symptoms and body mass index (BMI) were associated (r = 0.10, n = 874, p = 0.014 FWE corrected), as were their respective polygenic risk scores (PRS) (r = 0.17, n = 874, p = 6.5 × 10−6 FWE corrected). We then examined whether the phenotypes of impulsivity and BMI, and the PRS scores of ADHD and BMI, shared common associations with whole-brain grey matter and the Monetary Incentive Delay fMRI task, which associates with reward-related impulsivity. A sparse partial least squared analysis (sPLS) revealed a shared neural substrate that associated with both the phenotypes and PRS scores. In a last step, we conducted a bias corrected bootstrapped mediation analysis with the neural substrate score from the sPLS as the mediator. The ADHD PRS associated with impulsivity symptoms (b = 0.006, 90% CIs = 0.001, 0.019) and BMI (b = 0.009, 90% CIs = 0.001, 0.025) via the neuroimaging substrate. The BMI PRS associated with BMI (b = 0.014, 95% CIs = 0.003, 0.033) and impulsivity symptoms (b = 0.009, 90% CIs = 0.001, 0.025) via the neuroimaging substrate. A common neural substrate may (in part) underpin shared genetic liability for ADHD and BMI and the manifestation of their (observable) phenotypic association.

Alzheimer\u2019s disease polygenic risk score as a predictor of conversion from mild-cognitive impairment

Mild-cognitive impairment (MCI) occurs in up to one-fifth of individuals over the age of 65, with approximately a third of MCI individuals converting to dementia in later life. There is a growing necessity for early identification for those at risk of dementia as pathological processes begin decades before onset of symptoms. A cohort of 122 individuals diagnosed with MCI and followed up for a 36-month period for conversion to late-onset Alzheimer’s disease (LOAD) were genotyped on the NeuroChip array along with pathologically confirmed cases of LOAD and cognitively normal controls. Polygenic risk scores (PRS) for each individual were generated using PRSice-2, derived from summary statistics produced from the International Genomics of Alzheimer’s Disease Project (IGAP) genome-wide association study. Predictability models for LOAD were developed incorporating the PRS with APOE SNPs (rs7412 and rs429358), age and gender. This model was subsequently applied to the MCI cohort to determine whether it could be used to predict conversion from MCI to LOAD. The PRS model for LOAD using area under the precision-recall curve (AUPRC) calculated a predictability for LOAD of 82.5%. When applied to the MCI cohort predictability for conversion from MCI to LOAD was 61.0%. Increases in average PRS scores across diagnosis group were observed with one-way ANOVA suggesting significant differences in PRS between the groups (p < 0.0001). This analysis suggests that the PRS model for LOAD can be used to identify individuals with MCI at risk of conversion to LOAD.

Impact of a breast cancer (BC) polygenic risk score (PRS) on the decision to take preventive endocrine therapy (ET): The Genetic Risk Estimate (GENRE) trial.

1501 Background: Despite BC risk reduction of 50-65% by preventive endocrine therapy (ET), very few at-risk women choose to take them. A woman’s perceived BC risk correlates with uptake of ET. A PRS comprised of 77 BC genetic susceptibility loci (Single Nucleotide Polymorphisms (SNP) improves the accuracy of risk prediction for BC. We examined the impact of the addition of individualized PRS BC risk prediction to standard risk calculator estimates on intent to take BC prevention medication. Methods: Eligible women had ≥5% 10 yr BC Tyrer-Cuzick risk (IBIS) or 5 year Gail score ≥3%, with no history of BC or hereditary BC syndrome. Standard BC risk estimates (IBIS or Gail) were incorporated into the counselling on BC preventive ET. A self-reported questionnaire at baseline quantified intention to take ET and explored factors associated with this decision. Blood samples were obtained and genotyped for 77 SNPs, individualized PRS were calculated then incorporated into IBIS and Gail predictions for 5 yr, 10 yr, &amp; lifetime BC risk. At a second visit, PRS risk &amp; prevention recommendations were revisited. Post visit questionnaires assessed change in intent to take ET. Multivariable linear regression was performed to assess impact of baseline variables on change in intent to take medication. Results: From 2016 to 2017, 151 women in Canada &amp; USA were enrolled, median age: 56.1 (range 36-76.4), 35.6% were premenopausal, 98.7% were Caucasian. Median 5yr, 10yr, &amp; lifetime IBIS risk estimates were 3.8% (2.0-11.5), 7.9% (5.0-23.1), and 25.3% (5.5 to 92.2). PRS increased BC risk estimates in 84 (55.6%) and reduced BC risk estimates in 67 (44%) women. After PRS risk counselling, intention to take ET significantly changed (p&lt;0.001): 41.9% of those with increased PRS were more inclined, and 46.7% of women with decreased PRS were less inclined to take ET. On multivariable regression, increase in PRS (p&lt;0.0001) and less concern about ET side effects (p&lt;0.0001) were associated with greater intent to take ET. Conclusions: In high risk women, PRS significantly changed BC risk estimates &amp; intent to take preventive ET. Further assessments of the impact of PRS scores on compliance with ET are warranted. Clinical trial information: NCT02517593.

SU48 - HERITABILITY OF HAIR CORTISOL AND GENETIC OVERLAP WITH PSYCHOLOGICAL VARIABLES

Background Measuring cortisol in hair is a promising method to assess the regulation of the Hypothalamus-Pituitary-Adrenal (HPA) axis which is altered in psychiatric disorders. First studies indicate a contribution of genetic factors to inter-individual variance in Hair Cortisol Concentration (HCC). Evidence for a genetic overlap between HCC and psychological variables would indicate a true biological link pointing at a causal involvement of the HPA axis in the vulnerability for psychiatric disorders. The aims of the present study were (1) to assess the heritability of HCC (2) to estimate the genetic and environmental association of HCC and perceived stress, depressive symptoms and neuroticism using twin models and a molecular genetic approach, i.e. Polygenic Risk Scores (PRS). Methods Hair samples from 671 individuals (mean age=14.5 years) including 183 dizygotic twin-pairs were analyzed. PRS scores were based on large published genome-wide association studies for depression, neuroticism and plasma cortisol, and analyzed in 432 individuals. Results The twin model revealed (1) a heritability of HCC of 72%, but (2) no phenotypic nor genetic overlap of HCC with psychological variables. Discussion HCC is highly heritable, but shows no phenotypic / genetic correlation with any of the studied psychological variables in our young individuals from the general population.

SA87 - POLYGENIC RISK SCORE ANALYSES OF SYMPTOMS AND TREATMENT RESPONSE IN A FIRST EPISODE SCHIZOPHRENIA COHORT

Background Schizophrenia (SCZ) is a severe mental disorder affecting ~1% of the population and is characterized by the presence of psychosis and other features, such as negative (i.e., flattened affect and social withdrawal) and disorganization symptoms (e. g. impaired cognitive function, disorganized speech and behavior). Symptomatic and psychosocial deterioration progress rapidly during the period just after the onset of the disorder, termed the First Episode of Schizophrenia (FES). In this study, we aimed to test if the SCZ Polygenic Risk Score (PRS) was associated with clinical symptoms at the FES, nine weeks after initiation of risperidone treatment (FES-9W) and with the response to risperidone. Methods We performed a detailed clinical assessment of 60 antipsychotic naive patients in their FES and, again, after nine weeks of standardized treatment with Risperidone. After blood collection and DNA isolation, the samples were genotyped using the Illumina PsychArrayChip and then imputed. To calculate PRS we used the latest available GWAS summary statistics from the Psychiatric Genomics Consortium wave-2 SCZ group as a training set. We used Poisson Regression to test association between PRS and clinical measurements correcting for the four principal components (genotyping). We considered as significant a p-value Results The polygenic risk score was significantly different between cases and controls with a best p-threshold of 0.0112 (NSNPs=21,622) and an explained variance of 0.19 (Naegelkerk's pseudo-r2). Within-cases, we found a positive association of the best PRS score with the PANSS excitement factor (five-factor model) (p-value=0.0003). The PRS was slightly positively correlated with depressive symptoms at baseline (CDSS total, p-value=0.003) but was negatively associated with depressive symptoms after risperidone treatment (CDSS total, p-value=0.001). Looking at response to risperidone, we observed a positive association for ΔCDSS (p-value=0.0006). However, there was no correlation between Δtotal PANSS and PRS. Discussion We verified that the schizophrenia PRS was also able to distinguish cases from control in this south-eastern Brazilian sample, with a similar variance explained (~0.19, observed scale) to that seen in Northern European populations. One strength of our study is that all patients were antipsychotic-naive at the baseline and received the same antipsycotic treatment for relatively the same time. It is well known that some patients may have an increase of depressive symptoms once the positive symptoms remit, however, there is no study so far that evaluated the relation between PRS and post-schizophrenia depression. Taken together, these results suggest that FES patients who present with higher depressive and excitement symptoms and who show reduction in these dimensions after treatment with risperidone have a significantly higher genetic risk for SCZ (as measured by PRS). These results highlight the importance of studying schizophrenia, and other disorders, in the early stages to understand the relationship between polygenic genetic risk and phenotypic features.

T102. AN INVESTIGATION OF SCHIZOPHRENIA-BIPOLAR SUBGROUPS WITH GENETIC AND PROGNOSTIC VALIDATION

BackgroundSeparation of individuals into schizophrenia and bipolar diagnoses has long been questioned, with some suggesting that the classification impairs the understanding of etiology, the accuracy of prognoses, and treatment selection. In this study, we employed unbiased statistical techniques to identify subgroups of individuals with chronic illness using a large array of variables commonly evaluated at the bedside. We then validated the resulting groups by investigating age of onset, schizophrenia polygenic risk scores (PRS), and functional outcomes at a 1-year follow-up period. Our hypothesis was that transdiagnostic subgroups would be stratified based on illness onset whereby individuals with earlier onset would have higher genetic risk loading and poorer functional outcomes.MethodsParticipants were selected from a longitudinal, naturalistic, multi-site project (PsyCourse) designed to investigate psychiatric illness course and outcomes. A total of 329 participants (age(SD)=45.7(12.6); 54% female; years of illness duration(SD) = 13.7(10.3)) with a DSM-IV diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder were assessed from 17 centers at baseline and 1-year follow-up periods. A clinical battery measuring sociodemographic, illness history, symptoms, cognition, and personality questionnaires (199 variables) was used to subgroup individuals. A non-negative factor analytic consensus clustering MATLAB toolbox was created based on previous methodological work in oncology. PRS were generated using widely used strategies, and differences between resulting subgroups were investigated with MANCOVA controlling for ancestry effects. Differences in functional outcomes were investigated with repeated measures ANOVA.ResultsA 4-subgroup solution was robustly defined as the optimal solution using resampling techniques and cluster validity indices. Diagnoses were mixed in two subgroups, but predominantly bipolar or schizophrenia in the other two. All subgroups had equal illness durations (p>0.05), but the age of onset showed a decreasing trend with the earliest age being linked to two subgroups: a mixed bipolar-schizophrenia group with intermediate levels of general functioning and in a schizophrenia group with low levels of functioning (p<0.001). PRS scores were significantly increased in the early-onset, mixed bipolar-schizophrenia subgroup (p=0.007, uncorrected) and in the schizophrenia group (p=0.025, uncorrected). Prognoses differed between the four groups (p=0.003), with the greatest increases in functional outcomes in a late-onset mixed diagnostic subgroup (p=0.006) and in the schizophrenia group (p=0.002).DiscussionFour subgroups were detected and our hypothesis was supported by a relationship between earlier illness onset and higher schizophrenia genetic risk loading. While one of the subgroups with an earlier onset mostly consisted of individuals with schizophrenia, the other subgroup was diagnostically mixed. Our results tentatively suggest that transdiagnostic clustering may identify subgroups that could be effectively used to understand etiology and prognoses. Future research will investigate the possibility of differential treatment effects in these subgroups.

Hair Cortisol in Twins: Heritability and Genetic Overlap with Psychological Variables and Stress-System Genes

Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.

T6 - An Investigation Of Assortative Mating Patterns And Underlying Genetic Correlates In Parents Of Offspring With Asd

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a complex genetic etiology. Little is known about the role of inherited common variants in the development of ASD and it’s persistent, and perhaps increased, frequency in our population, despite decreased fecundity in ASD individuals. One possible explanation for this phenomenon is assortative mating. Individuals with elevated, but sub-diagnostic ASD behaviors may be more likely than chance to mate, and thus increase the likelihood of their offspring of inheriting an underlying genetic load that pushes them over the ASD diagnostic threshold. In parents of children with ASD, we investigate 1) If genetic risk for ASD, schizophrenia (SCZ) or height can predict ASD-like behaviors 2) If they are more similar than chance in their ASD-like behaviors and their genetic risk for ASD, SCZ or height and 3) If there is a correlation between ASD behavioral and genetic similarity. Analyses were performed on 2727 Caucasian parental pairs of children with ASD in the Simons Simplex Collection. All parents completed the Broad Autism Phenotype Questionnaire (BAPQ) and were genotyped via microarray. After standard quality control measures, Polygenic Risk Scores (PRS) were calculated in PLINK using summary data from published GWAS for SCZ, ASD, and height. Linear regression was performed in R to predict individual PRS based on individual BAPQ scores for all phenotypes. Degree of correlation between mothers and fathers was calculated for both BAPQ scores and PRS for SCZ, ASD, and height. Finally, the degree of correlation was calculated between the squared difference of mother and father BAPQ scores and the squared difference between mother and father PRS for all phenotypes. For parents of children with ASD, individual PRS for ASD, SCZ or height did not predict individual BAPQ total or subscale scores (b = -0.06 – 0.3 , p > 0.01). Total BAPQ score and BAPQ pragmatic subscale scores were strongly correlated between parents (r = 0.14 , p = 1.4e-12 ; r = 0.11 , p = 2.4e-8). PRS for both ASD and SCZ were also strongly correlated between parents (r = 0.16, p = 1.1e-9; r = 0.19, p = 3.9e-14). Height PRS were more weakly correlated (r = 0.08, p = 0.003). Squared difference of parental PRS scores for all phenotypes were not predictive of the squared difference of parental total BAPQ scores or any subscales (b = -0.07 – 0.02, p ≥ 0.01). Assortative mating is an established phenomenon in individuals with ASD. Here, we show that parents of individuals with ASD are also more likely than chance to highly correlate on broad autism phenotype measures, primarily on pragmatic language measures. Pragmatic language measures are, for example, when someone says inappropriate or unrelated things during conversations or has little variety in language use. Further, we found that parents of children with ASD have highly correlated PRS for both ASD and SCZ, but not height (our non-psychiatric control phenotype). Therefore, we hypothesized that the degree of correlation between ASD and SCZ genetic risk may predict correlation on total BAPQ measures or on the BAPQ pragmatic language subscale. However, the results of this analysis found that there was no significant correlation between these measures. This suggests that the genetic similarity we captured through PRS may reflect assortative mating in parents of ASD individuals due to factors other than autistic-like behaviors and that there are yet unknown factors underlying BAPQ similarities between parents of ASD individuals.

Polygenic Risk Score associated with specific symptom dimensions in first-episode psychosis

Recent Genome-Wide Association Studies (GWAS) have provided evidence for the involvement of a number of genetic variants in schizophrenia (SCZ). The objective of the current study was to examine the association between these variants and symptom dimensions, evaluated prospectively over a period of 24months, in a clinically well-characterized sample of individuals (n=241) with first-episode psychosis (FEP). The genetic variants were analyzed collectively as captured through a Polygenic Risk Score (PRS), calculated for each individual. At each evaluation time point (baseline, 1, 2, 6 and 24months), correlation analysis was conducted with PRS and symptom dimension scores assessed by the Positive and Negative Syndrome Scale (PANSS). We also examined the association of PRS with global symptom rating, depression, anxiety, social and occupational functioning as measured by widely used and well validated scales. At baseline, significant positive correlation was observed between PRS and the general psychopathology dimension of the PANSS but no associations were observed with the positive or negative symptom dimensions. Anxiety, assessed using the Hamilton Anxiety Rating Scale, was also significantly correlated with the PRS. No significant correlation was observed with other symptom dimensions or with the PANSS score at the later evaluations. These results provide novel evidence of an association between general psychopathology and PRS in young people with first episode psychosis. They also demonstrate that it is important to note the dynamic changes of symptoms over time when trying to refine the relationship between genetic factors and phenotypes.

Abstract 940: The contribution of common breast cancer susceptibility loci to the breast density and breast cancer association and the Breast Cancer Surveillance Consortium (BCSC) risk model

Abstract Purpose: Mammographic breast density is an established and strong risk factor for breast cancer. Recently, a number of common genetic susceptibility loci have been identified as risk factors for breast cancer. We present the first report on the relative contribution of 76 validated breast cancer susceptibility loci, in the context of a polygenic risk score (PRS), to the breast density and breast cancer association. We also examine whether the PRS improves prediction of the Breast Cancer Surveillance Consortium (BCSC) 5-year risk model above and beyond breast density and clinical factors included in the model. Methods: The study population included 1643 cases and 2397 controls from three independent epidemiologic studies: the Mayo Mammography Health Study (MMHS), the Mayo Clinic Breast Cancer Study (MCBCS), and the Bavarian Breast Cancer Cases and Control Study (BBCC). Data collected on patients in each of the studies included clinical risk factor, BI-RADS breast density [a) almost entirely fat; b) scattered fibroglandular densities; c) heterogeneously dense; and d) extremely dense] and genotypes for the 76 breast cancer susceptibility loci known at the time of the study. We formed a PRS from the reported per-SNP odds ratios (OR) for 76 known breast cancer susceptibility loci, and evaluated whether BI-RADS density and the PRS were independent risk factors for breast cancer, when adjusted for age, 1/BMI and study. We also incorporated the PRS (OR) into the BCSC 5-year risk model and estimated 5-year risk for the MMHS nested case-control study of 339 invasive cases, 765 controls. Results: BI-RADS density (p&amp;lt;0.0001) and PRS (p&amp;lt;0.0001) were independent risk factors for breast cancer that together showed greater discrimination of risk (AUC=0.69) than density (AUC=0.66; ΔAUC=0.029) or PRS score alone (AUC=0.68; ΔAUC=0.013; p&amp;lt;0.001). Relative to those with scattered fibroglandular densities and average (2nd quartile) PRS, women with extremely dense breasts and in the highest PRS quartile, had a 2.7 fold (95%CI: 1.7-4.1) increased risk of breast cancer, while those with fatty breasts and in the lowest PRS quartile had a reduced risk (OR=0.30, 95%CI: 0.18-0.51). Incorporation of the PRS into the BCSC risk model improved discrimination (ΔAUC=0.031, p=0.001), for a net reclassification improvement of 20% (95%CI: 11%-28%), split equally among cases (9%) and controls (11%). Conclusion: BI-RADS density and the PRS are both important risk factors for breast cancer that can be included in breast cancer risk models to improve prediction of this disease. Using these models to identify high and low-risk risk groups will facilitate improved tailored screening and primary prevention interventions. Citation Format: Celine M. Vachon, V. Shane Pankratz, Christopher G. Scott, Lothar Haeberle, Elad Ziv, Matthew R. Jensen, Kathleen R. Brandt, Dana H. Whaley, Janet E. Olson, Katharina Heusinger, Carolin C. Hack, Sebastian M. Jud, Matthias W. Beckmann, Jeffrey A. Tice, Kristen S. Purrington, Thomas A. Sellers, Karla Kerlikowske, Peter A. Fasching, Fergus J. Couch. The contribution of common breast cancer susceptibility loci to the breast density and breast cancer association and the Breast Cancer Surveillance Consortium (BCSC) risk model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 940. doi:10.1158/1538-7445.AM2014-940

Abstract 2567: Genetic risk stratification for breast cancer based on a polygenic risk score and family history.

Abstract Background: Breast cancer is the most common cancer among Western women. Risk stratification of women can aid surveillance for and prevention of breast cancer. However, the value of genetic profiling in risk stratification has been widely debated. Early studies were based on risk profiles generated from only a few genetic variants, while recent genome-wide association studies (GWAS) have led to the identification of many more loci. We investigated the value of using 77 single nucleotide polymorphisms (SNPs) in breast cancer susceptibility loci identified to date for risk stratification of women both with and without a family history of breast cancer. Methods: We tested for all possible pair-wise multiplicative SNP interactions between 77 SNPs using 46,450 cases and 42,599 controls of European origin in the Breast Cancer Association Consortium (BCAC) using logistic regression analyses. A subset of 33,673 cases and 33,381 controls from studies not selected for family history was used to construct a polygenic risk score (PRS) based on the 77 SNPs. Estimates of the relative risk for breast cancer by levels of the PRS and population-based breast cancer incidence and mortality rates were used to derive absolute risks of developing breast cancer for percentiles of the PRS. Results: There was no strong evidence for multiplicative interaction between any particular SNP pair, but there was a suggestion of a larger number of observed significant interactions over those expected by chance. Women in the highest 1% of the PRS score had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (40-60thpctile)(OR=3.36 95%CI:2.95-3.83). The corresponding relative risks for PRSs derived separately for ER-positive and ER-negative disease were 3.73 95%CI:3.24-4.30 and 2.80 95%CI: 2.26-3.46, respectively. The OR for family history (1 or more first degree relatives with breast cancer) was slightly attenuated, from 1.85 to 1.74, after adjusting for the PRS, consistent with the estimated fraction (∼14%) of the familial relative risk explained by the 77 SNPs under a multiplicative polygenetic model of inheritance. The combined effects of PRS and family history of breast cancer were consistent with a multiplicative model (P-interaction=0.34). The 10-year absolute risk of breast cancer for a 50 year old woman without family history of breast cancer ranged from 0.70 % for women in the lowest 1% of the PRS, 2.4% for the middle quintile, to 7.1 % for the highest 1% of the PRS. For a 50 year old woman with a family history, the corresponding risk ranged from 1.2%, 4.0% and 11.2%, respectively. Conclusion: The PRS provides good discrimination of breast cancer risk across women without a family history of breast cancer, and can also be used to further refine the genetic risk among women with a family history. The observed level of risk discrimination could be useful to inform targeted screening or prevention strategies. Citation Format: Nasim Mavaddat, Paul Pharoah, Per Hall, Douglas Easton, Montserrat Garcia-Closas, for the Breast Cancer Association Consortium. Genetic risk stratification for breast cancer based on a polygenic risk score and family history. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2567. doi:10.1158/1538-7445.AM2013-2567 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.