Association Of Polygenic Risk Scores Research Articles

Polygenic Risk Score Modifies the Association of HbA1c With Hearing Loss in Middle-Aged and Older Chinese: The Dongfeng-Tongji Cohort.

Evidence regarding the modifying effect of the polygenic risk score (PRS) on the associations between glycemic traits and hearing loss (HL) was lacking. We aimed to examine whether these associations can be influenced by genetic susceptibility. This cross-sectional study included 13,275 participants aged 64.9 years from the Dongfeng-Tongji cohort. HL was defined according to a pure tone average >25 dB in the better ear and further classified by severity. Prediabetes and type 2 diabetes (T2D) were defined based on the 2013 criteria from the American Diabetes Association. A PRS was derived from 37 single-nucleotide polymorphisms associated with HL. Multivariable logistic regression models were fitted to estimate the associations of PRS and glycemic traits with HL and its severity. Elevated fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), and T2D were positively associated with higher HL risks and its severity, with odds ratios (ORs) ranging from 1.04 (95% CI 1.00, 1.08) to 1.25 (95% CI 1.06, 1.46). We also found significant interaction between HbA1c and PRS on risks of overall HL and its severity (P for multiplicative interaction <0.05), and the effects of HbA1c on HL risks were significant only in high PRS. Additionally, compared with normoglycemiain the low PRS, T2D was respectively associated with an OR of up to 2.00 and 2.40 for overall HL and moderate to severe HL in the high PRS (P for additive interaction <0.05). PRS modifies the association of HbA1c with HL prevalence among middle-aged and older Chinese.

Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits.

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

Abstract 6143: Association of polygenic risk score and prostate tumor biomarkers with lethal prostate cancer

Abstract Prostate cancer (PCa) is a highly heritable cancer. While polygenic risk scores (PRS) stratify overall PCa risk among cancer-free men, they have not been reported to predict lethal outcomes in PCa patients. We aimed to examine to what extent PRS modifies associations between tumor biomarkers with cancer prognosis after diagnosis. We included men with primary, non-metastatic PCa in the Health Professionals Follow-up Study (HPFS) and Physicians’ Health Study (PHS). The PRS was constructed with 451 risk variants identified from prior PCa GWAS, measured on DNA from blood or buccal, standardized by adjusting for mean and standard deviation (SD) based on men without PCa with array-based genotyping data in HPFS/PHS. Prostate tumor biomarkers of molecular subtypes (TMPRSS2:ERG fusion, PTEN loss, and TP53 missense mutations from validated immunohistochemistry assays), insulin/lipid signaling pathways (FASN, IR, and IGF1-R), and cellular proliferation and tumor microenvironment (Ki-67, apoptosis rates, and angiogenesis) were measured on tumor tissue from radical prostatectomy or TURMP. Sample sizes varied by tumor biomarkers, ranging from 214 for angiogenesis markers to 598 for ERG protein expression. We first used either logistic or negative binomial regression to evaluate the association between the PRS and the protein expression (levels) of each individual biomarker, and then evaluated the addition of multiplicative interaction terms between PRS and biomarkers to logistic regression models for lethal PCa, defined as metastases or death from PCa. Lastly, we evaluated the predictive performance for lethal PCa by area under the curve (AUC). All models adjusted for age at diagnosis and Gleason score. Among all patients included in the analysis, the median age at diagnosis was 66 (interquartile range: 62-70) years, with 20% having a Gleason score≥8 and 10% having lethal PCa. PRS showed no association with lethal PCa (OR per SD increase PRS=0.95, 95%CI 0.85-1.06) or most tumor biomarkers, except for the apoptosis index (per SD in PRS corresponding to 0.22 units increase, 95%CI 0.02-0.42). Statistically significant interactions were found between PRS and p53 overexpression (p interaction = 1.6x10-5), PTEN loss (p=3.7x10-3), FASN (p=0.03), and Ki-67 (p=1.6x10-3), suggesting that compared to men with a PRS higher than the median, TP53 missense mutation, PTEN loss, higher FASN intensity, and higher Ki-67 indices were more strongly associated with lethal PCa in patients with lower PRS. Incorporating PRS with tumor biomarkers into predictive models enhanced the AUC beyond a model with tumor biomarker and age. The largest improvements were observed when combining the PRS with Ki-67 and apoptosis, showing absolute increases of 5% and 7% respectively. In conclusion, PRS integration with tumor biomarkers at diagnosis potentially improves the prediction of lethal PCa, thereby informing more targeted management strategies. Citation Format: Anqi Wang, Anna Plym, Konrad H. Stopsack, Lorelei A. Mucci, Kathryn L. Penney. Association of polygenic risk score and prostate tumor biomarkers with lethal prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6143.

Abstract 6616: Polygenic risk score associated with risk of upgrading and tumor features in a prospective cohort of prostate cancer patients on active surveillance

Abstract BACKGROUND: Active surveillance (AS) is now the preferred treatment strategy for the &amp;gt;50% of prostate cancer (PCa) patients diagnosed with low-risk disease, where five-year survival rates are &amp;gt;99%. However, AS requires frequent and costly healthcare visits. In a case-only study of AS patients, we investigated whether polygenic risk scores (PRS) could identify patients who may benefit from intensive vs passive surveillance to reduce these burdens. METHODS: This study included 1,220 PCa patients on AS in the Canary Prostate Active Surveillance Study (PASS). A previously developed multi-ancestry PRS of 451 PCa risk variants (PRS451) was constructed in PASS, along with a PRS of 400 variants, excluding 51 PSA-associated variants (PRS400). Outcomes included upgrading and extreme upgrading at follow up and prostate volume, PSA, percent of biopsy cores with cancer, and Gleason grade at diagnosis. We investigated PRS associations with risk of upgrading with Cox proportional hazards regression adjusting for age at diagnosis and 10 principal components (PCs) of ancestry. Associations with risk of extreme upgrading were performed similarly but with a competing risk analysis, where the competing event was treatment. Discriminative ability was evaluated with Harrell’s C-index. To better account for population structure, we also fit mixed models with fixed effects for PRS, age at diagnosis, and 10 PCs, with a random effect for a genetic relationship matrix. RESULTS: Of the 1,220 AS patients, 38.5% (n=470) upgraded during the median 4.2 years of follow up and 85% (n=1041) self-reported as non-Hispanic White. In time-to-event analyses, each SD unit increase in PRS451 was associated with a 23% increased risk of upgrading (P=4.2 × 10−5), while PRS400 was associated with a 27% increased risk (P=1.6 × 10−6). PRS were similarly associated with 21% (95% CI=1.02-1.44, P=0.03) and 27% (95% CI=1.06-1.52, P=0.01) increased risk of extreme upgrading, respectively. Compared to a model with age at diagnosis, PCs, and clinical risk factors (C-index=0.617, 95% CI=0.590-0.644), including PRS400 slightly improved the ability to detect risk of upgrading (C-index=0.632, 95% CI=0.604-0.659). Mixed model results were highly consistent. Each SD unit increase in PRS400 was associated with 1.38 higher percentage points of biopsy cores with cancer (95% CI=0.76-2.00, P=1.1 × 10−5), 1.48 cc smaller prostate volume (95% CI=-2.82, -0.14, P=0.03), and 0.18 ng/mL higher PSA (95% CI=0.01-0.35, P=0.05) at diagnosis. Except for PSA, associations were similar or weaker for PRS451. CONCLUSION: In patients on AS, high PRS was associated with increased risk of upgrading, extreme upgrading, smaller prostate volume, and possibly tumor multifocality. As such, PRS could inform the intensity of surveillance for low-risk PCa patients, reducing the burden of AS for patients with low risk of disease progression. Citation Format: Louisa B. Goss, Menghan Liu, Yingye Zheng, Boya Guo, David V. Conti, Christopher A. Haiman, William J. Catalona, John S. Witte, Daniel W. Lin, Lisa F. Newcomb, Burcu F. Darst. Polygenic risk score associated with risk of upgrading and tumor features in a prospective cohort of prostate cancer patients on active surveillance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6616.

Investigating the Association of Polygenic Risk Scores With Thyroid Cancer Susceptibility in a Han Chinese Population.

Thyroid cancer, the leading endocrine tumor with a rising global incidence, especially in women, is influenced by both genetic and environmental factors. This study examines the relationship between polygenic risk scores (PRS) and thyroid cancer susceptibility in the Han Chinese population, as well as the impact of genetic variants on clinical outcomes. Analyzing data from 57 257 participants in the Taiwan Precision Medicine Initiative, the study employed the Affymetrix Genome-Wide TWB 2.0 SNP Array for genotyping. PRS were calculated using single nucleotide polymorphisms (SNPs) from prior genome-wide association studies, specifically PGS000087 and PGS000797, and correlated with clinical parameters like age, sex, comorbidities, and treatment methods. Among 4063 participants with thyroid tumors (839 malignant, 3224 benign), higher PRS quartiles correlated significantly with increased thyroid cancer incidence. The highest quartile showed a 1.15-fold (PGS000797) and 1.14-fold (PGS000087) greater risk than the lowest quartile. Key findings included an association between higher PRS quartiles and younger onset age, along with a notable link to chronic kidney disease and thyroid hormone levels in specific SNPs. The study demonstrates PRS's utility in predicting thyroid cancer risk in the Han Chinese population, with higher PRS associated with increased risk and distinct clinical features. While this study focuses on the Han Chinese population, we recognize the importance of comparing PRS performance across different ancestries to fully understand ethnic genetic diversity in cancer risk assessment. Future studies should aim to include such comparative analysis.

Causation and familial confounding as explanations for the associations of polygenic risk scores with breast cancer: Evidence from innovative ICE FALCON and ICE CRISTAL analyses.

A polygenic risk score (PRS) combines the associations of multiple genetic variants that could be due to direct causal effects, indirect genetic effects, or other sources of familial confounding. We have developed new approaches to assess evidence for and against causation by using family data for pairs of relatives (Inference about Causation from Examination of FAmiliaL CONfounding [ICE FALCON]) or measures of family history (Inference about Causation from Examining Changes in Regression coefficients and Innovative STatistical AnaLyses [ICE CRISTAL]). Inference is made from the changes in regression coefficients of relatives' PRSs or PRS and family history before and after adjusting for each other. We applied these approaches to two breast cancer PRSs and multiple studies and found that(a) for breast cancer diagnosed at a young age, for example,<50 years, there was no evidence that the PRSs were causal, while (b) for breast cancer diagnosed at later ages, there was consistent evidence for causation explaining increasing amounts of the PRS-disease association. The genetic variants in the PRS might be in linkage disequilibrium with truly causal variants and not causal themselves. These PRSs cause minimal heritability of breast cancer at younger ages. There is also evidence for nongenetic factors shared by first-degree relatives that explain breast cancer familial aggregation. Familial associations are not necessarily due to genes, and genetic associations are not necessarily causal.

Integrating Electronic Health Records and Polygenic Risk to Identify Genetically Unrelated Comorbidities of Schizophrenia That May Be Modifiable

BackgroundPatients with schizophrenia have substantial comorbidity that contributes to reduced life expectancy of 10 to 20 years. Identifying modifiable comorbidities could improve rates of premature mortality. Conditions that frequently co-occur but lack shared genetic risk with schizophrenia are more likely to be products of treatment, behavior, or environmental factors and therefore are enriched for potentially modifiable associations. MethodsPhenome-wide comorbidity was calculated from electronic health records of 250,000 patients across 2 independent health care institutions (Vanderbilt University Medical Center and Mass General Brigham); associations with schizophrenia polygenic risk scores were calculated across the same phenotypes in linked biobanks. ResultsSchizophrenia comorbidity was significantly correlated across institutions (r = 0.85), and the 77 identified comorbidities were consistent with prior literature. Overall, comorbidity and polygenic risk score associations were significantly correlated (r = 0.55, p = 1.29 × 10−118). However, directly testing for the absence of genetic effects identified 36 comorbidities that had significantly equivalent schizophrenia polygenic risk score distributions between cases and controls. This set included phenotypes known to be consequences of antipsychotic medications (e.g., movement disorders) or of the disease such as reduced hygiene (e.g., diseases of the nail), thereby validating the approach. It also highlighted phenotypes with less clear causal relationships and minimal genetic effects such as tobacco use disorder and diabetes. ConclusionsThis work demonstrates the consistency and robustness of electronic health record–based schizophrenia comorbidities across independent institutions and with the existing literature. It identifies known and novel comorbidities with an absence of shared genetic risk, indicating other causes that may be modifiable and where further study of causal pathways could improve outcomes for patients.

Sex-specific genetic risks for adverse outcomes after coronary revascularization procedures.

Men and women have differing risks of adverse events after revascularization procedures and these differences could be partially driven by genetics. We studied the sex-specific differences in associations of polygenic risk scores (PRSs) with atrial fibrillation (AF), ischaemic stroke (STR), intracranial haemorrhage (ICH), myocardial infarction (MI) and gastrointestinal haemorrhage (GIH) in coronary revascularization patients. The study cohort comprised 5561 and 17578 revascularized women and men. All participants underwent genotyping and register-based follow-up from 1961 to 2021. We calculated PRSs for all individuals and used Cox models with interaction term to examine the sex-specific associations between the PRSs and adverse outcomes after revascularization. The AF-PRS was more strongly associated with AF in men [hazard ratio (HR) per 1 standard deviation increase, 1.16; 95% confidence interval (CI), 1.12-1.19; P = 7.6 × 10-22) than in women (P for interaction 0.006). Conversely, ICH-PRS was more strongly associated with ICH after revascularization in women (HR, 1.32; 95% CI, 1.08-1.62; P = 0.008) than in men (P for interaction 0.008). We observed no sex-specific differences for the associations of PRSs with STR, MI or GIH. The genetic risk of AF after revascularization is greater in men than in women, and vice versa for ICH. Sex-specific PRSs could be used to identify individuals in high genetic risk for these complications.

Risk Assessment for Gastrointestinal Diseases via Clinical Dimension and Genome-Wide Polygenic Risk Scores of Type 2 Diabetes: A Population-Based Cohort Study.

We aimed to evaluate whether individuals with type 2 diabetes (T2D) were at higher risk of developing a wide range of gastrointestinal diseases based on a population-based cohort study. This study included 374,125 participants free of gastrointestinal disorders at baseline; of them, 19,719 (5.27%) with T2D were followed-up by linking to multiple medical records to record gastrointestinal disease diagnoses. Multivariable Cox models were used to estimate the hazard ratios (HRs) and CIs. Logistic models were used to examine the associations between polygenic risk scores (PRS) and clinical gastrointestinal phenotypes. During a median follow-up of 12.0 years, we observed the new onset of 15 gastrointestinal diseases. Compared with nondiabetes, participants with T2D had an increased risk of gastritis and duodenitis (HR 1.58, 95% CI 1.51-1.65), peptic ulcer (HR 1.56, 95% CI 1.43-1.71), diverticular disease (HR 1.19, 95% CI 1.14-1.24), pancreatitis (HR 1.45, 95% CI 1.24-1.71), nonalcoholic fatty liver disease (HR 2.46, 95% CI 2.25-2.69), liver cirrhosis (HR 2.92, 95% CI 2.58-3.30), biliary disease (HR 1.18, 95% CI 1.10-1.26), gastrointestinal tract cancers (HR 1.28, 95% CI 1.17-1.40), and hepatobiliary and pancreatic cancer (HR 2.32, 95% CI 2.01-2.67). Positive associations of PRS of T2D with gastritis, duodenitis, and nonalcoholic fatty liver disease were also observed. In this large cohort study, we found that T2D was associated with increased risks of a wide range of gastrointestinal outcomes. We suggest the importance of early detection and prevention of gastrointestinal disorders among patients with T2D.

DIGITAL CLOCK DRAWING PERFORMANCE ASSOCIATIONS WITH ALZHEIMER’S DISEASE GENETIC RISK SCORE AND APOE IN OLDER ADULTS

Abstract Alzheimer’s disease (AD) is the leading cause of dementia in older adults, but most people are not diagnosed until clinical signs and symptoms are present. Non-invasive and cost-effective digital biomarkers for AD have the potential to improve early detection. We examined the validity of DCTclockTM (a digitized clock drawing task) as an AD susceptibility biomarker. We used two primary independent variables, Apolipoprotein E (APOE) ɛ4 allele carrier status and polygenic risk score (PRS). We examined APOE and PRS associations with DCTclockTM composite scores as dependent measures. We used existing data from the Framingham Heart Study (FHS), a community-based study with the largest dataset of digital clock drawing data to date. The sample consisted of 2,398 older adults ages 60-94 with DCTclockTM data (mean age of 72.3, 55% female and 92% White). PRS was calculated using 38 variants identified in a recent large genome-wide association study (GWAS) and meta-analysis of late-onset AD (LOAD). Results showed that DCTclockTM performance decreased with advancing age, lower education, and the presence of one or more copies of APOE ε4. Lower DCTclockTM Total Score as well as lower composite scores for Information Processing Speed and Drawing Efficiency were significantly associated with higher PRS levels and more copies of APOE ε4. Associations displayed similar effect sizes in men and women. This is the first study to demonstrate significant differences in clock drawing performance on the basis of APOE status or PRS.

Association of Polygenic Risk Score of Alzheimer’s disease with A/T/N Biomarkers and Cognitive Decline

AbstractBackgroundPolygenic risk scores (PRS) quantify the combined effects of genetic variants to enable the prediction of an individual’s risk of developing the disease. Alzheimer’s disease (AD) is a complex disorder in which the relationship among PRS, neuropathological substrates, and related cognitive decline remain especially understudied in Asian populations. We investigated the associations of PRS with AD neuroimaging biomarkers and cognitive phenotypes in a Korean Cohort.MethodThe study included 501 older adults (264 cognitively normal [CN], 146 mild cognitive impairment [MCI], and 91 AD dementia) from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE). Comprehensive clinical and neuropsychological evaluations, as well as multi‐modal neuroimaging including 3T MRI and 11C‐PiB‐PET were administered. A subset of participants underwent 18F‐AV‐1451 PET (n = 167). Imaging phenotypes including beta‐amyloid (Aβ) positivity, global tau deposition, and adjusted hippocampal volume (HVa) were used for amyloid (A), tau (T), and neurodegeneration (N) biomarkers, respectively., which was imputed using the TOPMed reference panel. PRS was calculated using the summary statistics of a recent large‐scale GWAS study for AD by PRS‐CS. The Apolipoprotein E (APOE) region was excluded in the calculation. The associations between standardized PRS and imaging/cognitive phenotypes were examined using either multiple linear or logistic regression analysis with covariates (age and sex for neuroimaging biomarker phenotypes; age, sex and education for cognitive phenotypes).ResultPRS was significantly higher in the AD dementia group compared to the CN group. Higher PRS was associated with greater CDR‐sum‐of‐boxes (β[SE] = 0.233[0.083], t = 2.818, p = 0.005) and lower MMSE scores (β[SE] = ‐0.648[0.198], t = ‐3.271, p = 0.001). In terms of AD neuroimaging biomarkers (Figure 1), higher PRS was significantly associated with an increased likelihood of Aβ positivity (OR = 1.233, 95%CI = 1.024‐1.491), and lower HVa (β[SE] = ‐132.79[49.624], t = ‐2.676, p = 0.008), but not with global tau deposition (β[SE] = 0.075[0.048], t = 1.573, p = 0.118).ConclusionThese findings suggest that higher PRS predicts increased pathological Aβ deposition and accelerated neurodegeneration, as well as greater cognitive decline. Further investigation in larger and multiethnic samples are needed to determine generalizability to other ethnoracial populations.

Sex‐specific effects of genetically predicted BMI and education on risk of AD

AbstractBackgroundExamining sex differences on the impact of modifiable risk factors in Alzheimer’s disease (AD) risk can help us better understand the mechanisms underlying sex differences in the prevalence and incidence of AD. Here, we used polygenic risk scores (PRS) and Mendelian randomization (MR) to investigate sex‐specific effects of sleep duration, insomnia, blood pressure, diabetes, alcohol intake, smoking, body mass index, high cholesterol, and education on AD risk.MethodWe obtained combined and sex‐stratified genome‐wide association study (GWAS) summary statistics for each risk factor from the UK Biobank and used them as the base dataset for constructing PRS and exposure datasets in the MR analysis. Linkage disequilibrium clumping was performed to identify independent genome‐wide significant single nucleotide polymorphisms (SNPs) across the sex‐combined, male‐specific, and female‐specific GWAS. The combined lead SNPs were then weighted by their strata‐specific effect sizes in the stratified PRS and MR analyses. PRS were constructed for each risk factor in participants from the Alzheimer’s Disease Genetics Consortium. Linear regression was used to investigate the association of each PRS with AD risk, adjusting for age, principal components, and cohort. MR was used to estimate sex‐stratified causal effects of each risk factor on AD. Sex differences in PRS associations and MR causal estimates were determined using Fisher’s Z score method.ResultsAssociation testing of the PRS with AD risk in sex stratified cohorts revealed that the BMI PRS was associated with differential effects in men and women (OR [95%CI]: males: 1.05 [1.00, 1.10] vs females: 0.96 [0.93, 0.99], p = 0.003). Furthermore, the university completion PRS was non‐significant in men but was associated with reduced risk in women (OR [95%CI]: males: 0.96 [0.92, 1.01] vs females: 0.92 [0.89, 0.96], p = 0.12). In the follow‐up MR analysis, university completion was also causally associated with reduced risk in women only (OR [95%CI]: males: 1.09 [0.77, 1.53] vs females: 0.55 [0.42, 0.72], p = 0.002) (Figure 1). No other risk factors showed evidence of sex‐differences.ConclusionOur study found sex‐specific effects of genetically predicted BMI and educational attainment on AD risk. These findings suggest the need for sex‐specific approaches to AD prevention and management.

Abstract B061: Nonalcoholic fatty liver disease (NAFLD) polygenic risk score and risk of hepatocellular carcinoma in a multiethnic population

Abstract Purpose: Hepatocellular carcinoma (HCC) is the third cause of cancer mortality globally, with 10%-12% of cases attributable to nonalcoholic fatty liver disease (NAFLD). Genetic variants included in NAFLD polygenic risk scores (PRS) have been associated with HCC risk. Since these associations have been studied primarily among European ancestry populations, in the current study we assessed the transportability of a NAFLD PRS associated with HCC risk in a racially/ethnically diverse population. Methods: We conducted a nested case-control study including 275 incident HCC cases and 73,045 controls from the Multiethnic Cohort Study, using a 21-variant PRS for NAFLD created based on prior GWAS and replication studies on MEC participants and other populations. Associations between PRS (per standard deviation) and HCC were estimated using logistic regression adjusting for age, sex, and global ancestry. A stratified analysis was conducted by body mass index (BMI) due to the direct relationship of obesity with NAFLD and HCC. Results: The PRS was associated with HCC risk in the combined sample (ORper SD= 1.84, 95% CI: 1.64-2.06). Signifcant associations were observed in Japanese Americans [ORper SD=2.26 (1.87-2.72)], Latinos [ORper SD=1.89 (1.52-2.35)], Native Hawaiians [ORper SD=1.84 (1.26-2.69)], and with the associations being weaker and non-significant in whites [ORper SD=1.33 (0.92-1.93)] and African Americans [ORper SD=1.25 (0.90-1.75)]. The PRS association was stronger among those with BMI &amp;gt;= 25 kg/m2 for the combined sample (ORper SD :2.46, 95% CI:1.92-3.14), (P heterogeneity &amp;lt;0.0001); and all racial/ethnic groups [Latino: 3.01(1.88-4.81), African American: 2.72 (95% CI: 1.18-6.27), Hawaiian: 2.25 (1.17-4.32), Japanese: 2.13 (1.36-3.36), and White:2.11(1.10-4.04)]. Conclusion: A NAFLD PRS is applicable for HCC risk prediction across racial/ethnic populations. BMI may modifiy this PRS-HCC risk association. Citation Format: Homa Sadeghi, David Bogumil, David V. Conti, Christopher Haiman, Loïc Le Marchand, Veronica Wendy Setiawan. Nonalcoholic fatty liver disease (NAFLD) polygenic risk score and risk of hepatocellular carcinoma in a multiethnic population [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B061.

Healthy dietary patterns, genetic risk, and gastrointestinal cancer incident risk: a large-scale prospective cohort study

BackgroundDietary patterns have been associated with several cancers, especially gastrointestinal cancer (GIC). However, whether a healthy dietary pattern could modify the risk of GIC among people with different genetic backgrounds is not clear. ObjectiveThe objective of the study was to investigate how dietary patterns and genetic susceptibility contribute to the risk of GIC independently and jointly. MethodsThis large-scale prospective cohort study included 105,463 participants in UK Biobank who were aged 40–72 y and cancer-free at baseline. Dietary intake (Oxford WebQ) was used to calculate dietary pattern scores including dietary approach to stop hypertension (DASH) score and healthful plant-based diet index (hPDI). Genetic risk was quantified by a polygenic risk score (PRS) comprising 129 known GIC-associated loci. Cox proportional hazards regression was performed to estimate the associations of dietary patterns and PRS with GIC incidence after adjusting for potential confounders. ResultsOver a median follow-up of 11.70 y, 1,661 participants were diagnosed with GIC. DASH and hPDI were associated with 20% and 36% reductions, respectively, in GIC risk. Low PRS was associated with a 30 % decrease in GIC risk (HR: 0.70; 95% CI: 0.62, 0.79). Participants with healthy dietary scores at high-genetic risk had a lower GIC risk with HR of 0.77 (95% CI: 0.60, 0.98) for DASH and 0.66 (95% CI: 0.52, 0.84) for hPDI than those with unhealthy dietary score. Participants with both high-dietary score and low-genetic risk showed the lowest risk of GIC, with HR of 0.58 (95% CI: 0.45, 0.75) for DASH and 0.45 (95% CI: 0.34, 0.58) for hPDI. ConclusionsAdherence to DASH and hPDI were associated with a lower risk of some gastrointestinal cancers, and these 2 dietary patterns may partly compensate for genetic predispositions to cancer. Our results advance the development of precision medicine strategies that consider both dietary patterns and genetics to improve gastrointestinal health.

The impact of genetic risk for schizophrenia on eating disorder clinical presentations

A growing body of literature recognizes associations between eating disorders (EDs) and schizophrenia and suggests that familial liability to schizophrenia in individuals with anorexia nervosa (AN) reveals distinct patterns of clinical outcomes. To further investigate the influence of schizophrenia genetic liability among individuals with EDs, we evaluated the associations between schizophrenia polygenic risk scores (PRS) and clinical presentations of individuals with EDs including their overall health condition and ED-related symptoms. Using data from two previous studies of the genetics of EDs comprising 3,573 Anorexia Nervosa Genetics Initiative (ANGI) cases and 696 Binge Eating Genetics Initiative (BEGIN) cases born after 1973 and linked to the Swedish National Patient Register, we examined the association of schizophrenia PRS on ED clinical features, psychiatric comorbidities, and somatic and mental health burden. Among ANGI cases, higher schizophrenia PRS was statistically significantly associated with higher risk of major depressive disorder (MDD) measured by hazard ratio (HR) with 95% confidence interval (CI) (HR [95% CI]: 1.07 [1.02, 1.13]) and substance abuse disorder (SUD) (HR [95% CI]: 1.14 [1.03, 1.25]) after applying multiple testing correction. Additionally, higher schizophrenia PRS was associated with decreased clinical impairment assessment scores (−0.56, 95% CI: [−1.04, −0.08]) at the conventional significance level (p < 0.05). Further, in BEGIN cases, higher schizophrenia PRS was statistically significantly associated with earlier age at first ED symptom (−0.35 year, 95% CI: [−0.64, −0.06]), higher ED symptom scores (0.16, 95% CI: [0.04, 0.29]), higher risk of MDD (HR [95% CI]: 1.18 [1.04, 1.34]) and SUD (HR [95% CI]: 1.36 [1.07, 1.73]). Similar, but attenuated, patterns held in the subgroup of exclusively AN vs other eating disorder (OED) cases. These results suggest a similar pattern of influence of schizophrenia PRS for AN and OED cases in terms of psychiatric comorbidities, but a different pattern in terms of ED-related clinical features. The disparity of the effect of schizophrenia PRS on AN vs OED merits further investigation.

Associations of polygenic risk scores with risks of stroke and its subtypes in Chinese

Background and purposePrevious studies, mostly focusing on the European population, have reported polygenic risk scores (PRSs) might achieve risk stratification of stroke. We aimed to examine the association strengths of...

The influence of interaction between polygenic risk score and intestinal fungal microbiota on the risk of schizophrenia

Objective: To investigate the effect of interaction between polygenic risk score (PRS) and intestinal fungal microbiota on the risk of Schizophrenia (SCH). Methods: A case-control study was carried out. Drug-naïve, first-episode SCH patients were selected from the Psychiatric Department of the First Affiliated Hospital of Zhengzhou University between October 2017 and October 2019. Meanwhile, healthy controls (HCs) were recruited from local communities through online advertisement or physical examination center. Intestinal fungal microbiota was characterized by the 18S rRNA sequencing platform. The association of fungal microbial dysbiosis (F_MD) index, α-diversity indices and PRS with SCH was detected by logistic regression analysis. Results: A total of 137 SCH patients (62 males and 75 females) and 76 HCs (31 males and 45 females) were included in the study. The age of SCH patients and HCs was (22.5±7.5) years and (22.8±2.3) years, respectively. The results of logistic regression analysis revealed that PRS (OR=1.111, 95%CI: 1.036-1.178, P=0.002) and the increase of F_MD index (OR=1.200, 95%CI: 1.124-1.281, P<0.001) were risk factors for developing SCH. The increase of fungal α-diversity Shannon (OR=0.813, 95%CI: 0.755-0.874, P<0.001) index, Simpson index (OR=0.218, 95%CI: 0.091-0.523, P<0.001) and abundance of key Aspergillus (OR=0.928, 95%CI: 0.864-0.996, P=0.040) decreased the risk of SCH. Aspergillus abundance was positively correlated with cognitive domains including working memory (r=0.280, P=0.001), verbal learning (r=0.253, P=0.003), reasoning and problem solving (r=0.191, P=0.028). Conclusion: The increase of PRS may increase the risk of SCH. The increase of fungal α-diversity indices and Aspergillus abundance may decrease the risk of SCH. The interaction between PRS and intestinal fungi (Shannon index, Simpson index and Aspergillus) is a related factor for the risk of SCH.

A Polygenic Risk Score for Idiopathic Pulmonary Fibrosis and Interstitial Lung Abnormalities.

Rationale: In addition to rare genetic variants and the MUC5B locus, common genetic variants contribute to idiopathic pulmonary fibrosis (IPF) risk. The predictive power of common variants outside the MUC5B locus for IPF and interstitial lung abnormalities (ILAs) is unknown. Objectives: We tested the predictive value of IPF polygenic risk scores (PRSs) with and without the MUC5B region on IPF, ILA, and ILA progression. Methods: We developed PRSs that included (PRS-M5B) and excluded (PRS-NO-M5B) the MUC5B region (500-kb window around rs35705950-T) using an IPF genome-wide association study. We assessed PRS associations with area under the receiver operating characteristic curve (AUC) metrics for IPF, ILA, and ILA progression. Measurements and Main Results: We included 14,650 participants (1,970 IPF; 1,068 ILA) from six multi-ancestry population-based and case-control cohorts. In cases excluded from genome-wide association study, the PRS-M5B (odds ratio [OR] per SD of the score, 3.1; P = 7.1 × 10-95) and PRS-NO-M5B (OR per SD, 2.8; P = 2.5 × 10-87) were associated with IPF. Participants in the top PRS-NO-M5B quintile had ∼sevenfold odds for IPF compared with those in the first quintile. A clinical model predicted IPF (AUC, 0.61); rs35705950-T and PRS-NO-M5B demonstrated higher AUCs (0.73 and 0.7, respectively), and adding both genetic predictors to a clinical model yielded the highest performance (AUC, 0.81). The PRS-NO-M5B was associated with ILA (OR, 1.25) and ILA progression (OR, 1.16) in European ancestry participants. Conclusions: A common genetic variant risk score complements the MUC5B variant to identify individuals at high risk of interstitial lung abnormalities and pulmonary fibrosis.

Genome-wide polygenic risk score for type 2 diabetes in Indian population

Genome-wide polygenic risk scores (PRS) for lifestyle disorders, like Type 2 Diabetes (T2D), are useful in identifying at-risk individuals early on in life, and to guide them towards healthier lifestyles. The current study was aimed at developing PRS for the Indian population using imputed genotype data from UK Biobank and testing the developed PRS on data from GenomegaDB of Indians living in India. 959 T2D cases and 2,818 controls were selected from Indian participants of UK Biobank to develop the PRS. Summary statistics available for South Asians, from the DIAMANTE consortium, were used to weigh genetic variants. LDpred2 algorithm was used to adjust the effect of linkage disequilibrium among the variants. The association of PRS with T2D, after adjusting for age, sex and top ten genetic principal components, was found to be very significant (AUC = 0.7953, OR = 2.9856 [95% CI: 2.7044–3.2961]). When participants were divided into four PRS quartile groups, the odds of developing T2D increased sequentially with the higher PRS groups. The highest PRS group (top 25%) showed 5.79 fold increased risk compared to the rest of the participants (75%). The PRS derived using the same set of variants was found to be significantly associated with T2D in the test dataset of 445 Indians (AUC = 0.7781, OR = 1.6656 [95%CI = 0.6127–4.5278]). Our study demonstrates a framework to derive Indian-specific PRS for T2D. The accuracy of the derived PRS shows it’s potential to be used as a prognostic metric to stratify individuals, and to recommend personalized preventive strategies.

Associations of polygenic risk scores for smoking heaviness and lifetime cannabis use with tobacco and cannabis co-use trajectories among African Americans

BackgroundWe aimed to identify distinct trajectories of tobacco, cannabis, and their co-use among African Americans, and to investigate whether these patterns were associated with polygenic risk scores (PRS) for tobacco and cannabis use. MethodParticipants (N=428 participants; 50.9% male) were initially recruited for an elementary school-based prevention in a Mid-Atlantic city when they were in first grade. From ages 14–26, participants reported on their frequency of tobacco and cannabis use in the past year during annual assessments. DNA was collected from participants at age 21. PRS for smoking heaviness (i.e., cigarettes per day) and lifetime cannabis use were created based on genome-wide association study results derived from Liu et al. (2019) and Pasman et al. (2018), respectively. ResultsWe identified five distinct trajectories of tobacco and cannabis co-use, including (1) Low Tobacco and Cannabis Use, (2) Adolescent Limited Tobacco and Cannabis Use, (3) Experimental Cannabis, Young Adult Increasing Tobacco, (4) Experimental Tobacco, Young Adult Increasing Cannabis, and (5) High, Chronic Tobacco and Cannabis Use. Compared to the Low Tobacco and Cannabis Use subgroup, individuals in the High, Chronic Tobacco and Cannabis Use subgroup had greater PRS for smoking heaviness, and individuals in the Experimental Cannabis, Young Adult Increasing Tobacco subgroup had higher PRS for lifetime cannabis use. ConclusionsPolygenic risk for lifetime cannabis use and smoking heaviness is associated with the developmental progression of tobacco and cannabis co-use among African Americans, furthering knowledge on the etiology of co-use in this population.