Effects Of Polygenic Risk Score Research Articles

The effect of polygenic risk score on PD risk and phenotype in LRRK2 G2019S and GBA1 carriers

Background While LRRK2 and GBA1 variants are associated with Parkinson's disease (PD), most carriers will not develop the disease. Objective To test if polygenic risk score (PRS) modifies disease risk and phenotypes in LRRK2 G2019S carriers, GBA1 carriers, and non-carriers (NC). Methods We genotyped 786 participants using Illumina's NeuroBooster-array (NBA) and sequenced the genome of 244, all of Ashkenazi ancestry (AJ), and calculated PRS to test its effects on clinically- and biologically-defined disease risk and phenotypes (n = 715). Among LRRK2 G2019S PD, we tested PRS association with α-synuclein seed-amplification-assay (n = 11). We used the PPMI and AMP-PD databases as validation cohorts. Results In clinically-defined PD, PRS significantly modified disease risk in GBA1 carriers and in NC ( p = 0.033 and p < 0.0001, respectively), and demonstrated a trend in LRRK2 G2019S carriers ( p = 0.054), with similar effect sizes (OR = 1.55, 1.62, and 1.49, respectively). PRS association with PD risk in LRRK2 was primarily driven by the rs7938782-A risk allele, replicated in AMP-PD (268 AJs LRRK2 G2019S carriers). PRS and age-at-onset were negatively correlated in NC ( p < 0.0001). NBA GBA1 genotype calls failed at GBA1 L483P and c.115 + 1G > A mutations. False negative call rate of 10.2% was observed for the imputed GBA1 N409S carriers. Conclusions PRS contributes to PD risk across different genotypes. The genetic and epigenetic role of rs7938782 in LRRK2 PD risk should be further explored. Future PRS models should be tailored to specific genotypes to better understand penetrance and phenotypes. Furthermore, models predicting PD defined biologically rather than clinically may further identify genetic risk factors for synucleinopathies.

Mental illness and antibody responses after COVID-19 vaccination in a prospective population-based study in Catalonia.

The association between mental illness diagnoses (mood affective disorders, anxiety disorders, other) over ten years and psychotropic drug prescription based on electronic health records with antibody levels (IgG and IgA) post COVID-19 vaccination was assessed in 939 vaccinated adults from Catalonia, Spain. We employed linear regression models to assess associations between specific mental illnesses and psychotropic drugs with antibody levels, correcting for demographics, comorbidities and lifestyle factors. In a genotyped subset (n=247) we assessed the effect of polygenic risk scores (PRS) for mental illnesses and performed a two-sample mendelian randomization (MR) analysis to examine causality between mental illness and antibody responses. Mood affective disorders were associated with lower IgG to receptor binding domain (RBD) [percentage change=-26.37 (95% CI, -42.00, -6.54)]. Diagnosis of anxiety disorders was not associated with the outcome. The group of other diagnoses (mainly including insomnia and nicotine dependence) were associated with lower IgG RBD levels [percentage change: -21.53 (95% CI, -35.38, -4.71)] and recent onset cases (≤5years ago) showed greater decline in antibody levels. Participants on second-generation antipsychotics and multiple classes of psychotropic drugs in the last 6months exhibited lower antibody levels. In the genotyped population, higher genetic liability (higher PRS) to schizophrenia was associated with lower IgG RBD levels [percentage change=-35.49 (95% CI, -56.55, -4.23)]. MR analysis revealed a causal relationship between major depression genetic instrumental variables and lower IgG RBD and S levels. These findings raise concerns about the efficacy of COVID-19 vaccines and potentially of other vaccines as well, in individuals with mood affective disorders, current/recent insomnia and nicotine dependence and people on multiple psychotropic drugs. Whether these associations are translated into increased risk for breakthrough infections and immune mediated long-term sequels of the SARS-CoV-2 infection warrants further investigation.

The effect of polygenic risk score and childhood adversity on transdiagnostic symptom dimensions at first-episode psychosis: evidence for an affective pathway to psychosis

Childhood adversity is associated with various clinical dimensions in psychosis; however, how genetic vulnerability shapes the adversity-associated psychopathological signature is yet to be studied. We studied data of 583 First Episode Psychosis (FEP) cases from the EU-GEI FEP case-control study, including Polygenic risk scores for major depressive disorder (MDD-PRS), bipolar disorder (BD-PRS) and schizophrenia (SZ-PRS); childhood adversity measured with the total score of the Childhood Trauma Questionnaire (CTQ); and positive, negative, depressive and manic psychopathological domains from a factor model of transdiagnostic dimensions. Genes and environment interactions were explored as a departure from a multiplicative effect of PRSs and total CTQ on each dimension. Analyses were adjusted for age, sex, 10 PCA, site of recruitment and for medication. A childhood adversity and PRS multiplicative interaction was observed between A) the CTQ and MDD-PRS on the predominance of positive (β = 0.42, 95% CI = [0.155, 0.682], p = 0.004); and depressive (β = 0.33, 95% CI = [0.071, 0.591], p = 0.013) dimensions; B) between the CTQ and BD-PRS on the positive dimension (β = 0.45, 95% CI = [0.106, 0.798], p = 0.010), and C) with the CTQ and SZ-PRS on the positive dimension (β = −0.34, 95% CI = [−0.660, −0.015], p = 0.040). Bonferroni corrected p-value of significance was set at 0.0125. In conclusion, despite being underpowered, this study suggests that genetic liability for MDD and BD may have a moderating effect on the sensibility of childhood adversity on depressive and positive psychotic dimensions. This supports the hypothesis of an affective pathway to psychosis in those exposed to childhood adversity.

Effects of polygenic risk score and sodium and potassium intake on hypertension in Asians: A nationwide prospective cohort study

Genetic factors, lifestyle, and diet have been shown to play important roles in the development of hypertension. Increased salt intake is an important risk factor for hypertension. However, research on the involvement of genetic factors in the relationship between salt intake and hypertension in Asians is lacking. We aimed to investigate the risk of hypertension in relation to sodium and potassium intake and the effects of genetic factors on their interactions. We used Korean Genome and Epidemiology Study data and calculated the polygenic risk score (PRS) for the effect of systolic and diastolic blood pressure (SBP and DBP). We also conducted multivariable logistic modeling to evaluate associations among incident hypertension, PRSSBP, PRSDBP, and sodium and potassium intake. In total, 41,351 subjects were included in the test set. The top 10% PRSSBP group was the youngest of the three groups (bottom 10%, middle, top 10%), had the highest proportion of women, and had the highest body mass index, baseline BP, red meat intake, and alcohol consumption. The multivariable logistic regression model revealed the risk of hypertension was significantly associated with higher PRSSBP, higher sodium intake, and lower potassium intake. There was significant interaction between sodium intake and PRSSBP for incident hypertension especially in sodium intake ≥2.0 g/day and PRSSBP top 10% group (OR 1.27 (1.07–1.51), P = 0.007). Among patients at a high risk of incident hypertension due to sodium intake, lifestyle modifications and sodium restriction were especially important to prevent hypertension.

The association between air pollutant exposure and cerebral small vessel disease imaging markers with modifying effects of PRS-defined genetic susceptibility

Studies have highlighted a possible link between air pollution and cerebral small vessel disease (CSVD) imaging markers. However, the exact association and effects of polygenic risk score (PRS) defined genetic susceptibility remains unclear. This cross-sectional study used data from the UK Biobank. Participants aged 40–69 years were recruited between the year 2006 and 2010. The annual average concentrations of NOX, NO2, PM2.5, PM2.5–10, PM2.5 absorbance, and PM10, were estimated, and joint exposure to multiple air pollutants was reflected in the air pollution index (APEX). Air pollutant exposure was classified into the low (T1), intermediate (T2), and high (T3) tertiles. Three CSVD markers were used: white matter hyper-intensity (WMH), mean diffusivity (MD), and fractional anisotropy (FA). The first principal components of the MD and FA measures in the 48 white matter tracts were analysed. The sample consisted of 44,470 participants from the UK Biobank. The median (T1–T3) concentrations of pollutants were as follows: NO2, 25.5 (22.4–28.7) μg/m3; NOx, 41.3 (36.2–46.7) μg/m3; PM10, 15.9 (15.4–16.4) μg/m3; PM2.5, 9.9 (9.5–10.3) μg/m3; PM2.5 absorbance, 1.1 (1.0–1.2) per metre; and PM2.5–10, 6.1 (5.9–6.3) μg/m3. Compared with the low group, the high group’s APEX, NOX, and PM2.5 levels were associated with increased WMH volumes, and the estimates (95 %CI) were 0.024 (0.003, 0.044), 0.030 (0.010, 0.050), and 0.032 (0.011, 0.053), respectively, after adjusting for potential confounders. APEX, PM10, PM2.5 absorbance, and PM2.5–10 exposure in the high group were associated with increased FA values compared to that in the low group. Sex-specific analyses revealed associations only in females. Regarding the combined associations of air pollutant exposure and PRS-defined genetic susceptibility with CSVD markers, the associations of NO2, NOX, PM2.5, and PM2.5–10 with WMH were more profound in females with low PRS-defined genetic susceptibility, and the associations of PM10, PM2.5, and PM2.5 absorbance with FA were more profound in females with higher PRS-defined genetic susceptibility. Our study demonstrated that air pollutant exposure may be associated with CSVD imaging markers, with females being more susceptible, and that PRS-defined genetic susceptibility may modify the associations of air pollutants.

Effect of polygenic risk score for clinically significant prostate cancer in a screening program: The BARCODE 1 study results.

10500 Background: Incidence of prostate cancer (PCa) is increasing, but there is no internationally agreed population screening program. Studies using an age-based PSA approach show a high rate of false-positive results as well as over-diagnosis of indolent PCa. Genome wide association studies identify common germline variants to calculate a polygenic risk score (PRS) associated with PCa risk. The BARCODE1 study used PRS to target PCa screening to those at higher risk based on genotype. Methods: European men aged 55-69yrs were recruited via Primary Care in the UK. PRS was constructed by summing weighted risk alleles for 130 PCa risk variants using germline DNA from saliva samples via mailed kits. Men with a PRS > 90th centile were invited for PCa screening using MRI and 12-core transperineal biopsy (including MRI fusion to target additional lesions where identified) irrespective of PSA result. Results: Invitation letters were sent to 40,292 men. 8,953 (22%) expressed an interest; 8,014 were eligible and sent a saliva kit. 6,644 consented; 6,393 were genotyped; 251 failed QC. A total of 6,142 participants had PRS calculated: 745 (12.1%) had a PRS > 90th centile and were invited to screening. 558/745 participants attended screening (121 declined, 66 excluded on health grounds). 551 underwent MRI and 468 had prostate biopsy resulting in 187 (40.0%) diagnoses of PCa, overall PCa detection rate 2.8%. Mean age at diagnosis 64.1yrs (range 57-73; median 64). Using NCCN criteria (2023) 103/187 (55.1%) of cancers were Intermediate or High Risk; 40/187 (21.4%) were Intermediate Unfavourable/High/Very High Risk. 119/187 (63.6%) men had a PSA <3.0ug/L; PPV of biopsy for PSA > 3.0ug/L was 49.6%. PPV of MRI (presence of PI-RADS 3-5 lesion) 60.4%. PPV of PRS alone 40%. 103/187 (55.1%) had Gleason >7; compared with 360/1014 (35.5%) p < 0.001 in the PSA directed ERSPC study. Conclusions: A population PCa screening program using PRS risk-stratification enriches for clinically significant PCa requiring treatment. It detects a high proportion of clinically significant disease compared with PSA or MRI based screening programs and MRI missed a significant proportion (17-67%) of cancers found on biopsy. This is the first study to assess if this approach will be useful in population screening programs. Clinical trial information: NCT03857477 . [Table: see text]

Impact of polygenic risk score for triglyceride trajectory and diabetic complications in subjects with type 2 diabetes based on large electronic medical record data from Taiwan: a case control study.

The prevalence of diabetic dyslipidemia has gradually increased worldwide and individuals with hypertriglyceridemia often have a high polygenic burden of triglyceride (TG)-increasing variants. However, the contribution of genetic variants to dyslipidemia in patients with type 2 diabetes (T2D) remains limited. Therefore, in this study, we aimed to investigate the genetic characteristics of longitudinal changes in TG levels among patients with T2D and summarize the genetic effects of polygenic risk score (PRS) on TG trajectory and risk of diabetic complications. We conducted a case-control study. A total of 11,312 patients with T2D with longitudinal TG and genetic data were identified from a large hospital database in Taiwan. We then performed a genome-wide association study and calculated the relative PRS. In total, 21 single-nucleotide polymorphisms (SNPs) related to TG trajectory were identified and yielded an area under the receiver operating characteristic curve (ROC) of 0.712 for high TG trajectory risk among Taiwanese patients with T2D. A cumulative genetic effect was observed for high TG trajectory, even when considering the adherence of a lipid-lowering agent in stratified analysis. An increased PRS increases high TG trajectory risk in a logistic regression model (odds ratio = 1.55; 95% confidence interval [CI] = 1.31-1.83 in the validation cohort). The TG-specific PRS was associated with the risk of diabetic microvascular complications, including diabetic retinopathy and nephropathy (with hazard ratios of 1.11 [95% CI = 1.01-1.21, P = 0.027] and 1.05 [95% CI = 1.01-1.1, P = 0.018], respectively). This study may contribute to the identification of patients with T2D who are at risk of abnormal TG levels and diabetic microvascular complications using polygenic information.

The interaction between early life complications and a polygenic risk score for schizophrenia is associated with brain activity during emotion processing in healthy participants.

Previous evidence suggests that early life complications (ELCs) interact with polygenic risk for schizophrenia (SCZ) in increasing risk for the disease. However, no studies have investigated this interaction on neurobiological phenotypes. Among those, anomalous emotion-related brain activity has been reported in SCZ, even if evidence of its link with SCZ-related genetic risk is not solid. Indeed, it is possible this relationship is influenced by non-genetic risk factors. Thus, this study investigated the interaction between SCZ-related polygenic risk and ELCs on emotion-related brain activity. 169 healthy participants (HP) in a discovery and 113 HP in a replication sample underwent functional magnetic resonance imaging (fMRI) during emotion processing, were categorized for history of ELCs and genome-wide genotyped. Polygenic risk scores (PRSs) were computed using SCZ-associated variants considering the most recent genome-wide association study. Furthermore, 75 patients with SCZ also underwent fMRI during emotion processing to verify consistency of their brain activity patterns with those associated with risk factors for SCZ in HP. Results in the discovery and replication samples indicated no effect of PRSs, but an interaction between PRS and ELCs in left ventrolateral prefrontal cortex (VLPFC), where the greater the activity, the greater PRS only in presence of ELCs. Moreover, SCZ had greater VLPFC response than HP. These results suggest that emotion-related VLPFC response lies in the path from genetic and non-genetic risk factors to the clinical presentation of SCZ, and may implicate an updated concept of intermediate phenotype considering early non-genetic factors of risk for SCZ.

Risk factors associated with age at onset of Parkinson’s disease in the UK Biobank

Substantial evidence shown that the age at onset (AAO) of Parkinson’s disease (PD) is a major determinant of clinical heterogeneity. However, the mechanisms underlying heterogeneity in the AAO remain unclear. To investigate the risk factors with the AAO of PD, a total of 3156 patients with PD from the UK Biobank were included in this study. We evaluated the effects of polygenic risk scores (PRS), nongenetic risk factors, and their interaction on the AAO using Mann–Whitney U tests and regression analyses. We further identified the genes interacting with nongenetic risk factors for the AAO using genome-wide environment interaction studies. We newly found physical activity (P < 0.0001) was positively associated with AAO and excessive daytime sleepiness (P < 0.0001) was negatively associated with AAO, and reproduced the positive associations of smoking and non-steroidal anti-inflammatory drug intake and the negative association of family history with AAO. In the dose-dependent analyses, smoking duration (P = 1.95 × 10−6), coffee consumption (P = 0.0150), and tea consumption (P = 0.0008) were positively associated with AAO. Individuals with higher PRS had younger AAO (P = 3.91 × 10−5). In addition, we observed a significant interaction between the PRS and smoking for AAO (P = 0.0316). Specifically, several genes, including ANGPT1 (P = 7.17 × 10−7) and PLEKHA6 (P = 4.87 × 10−6), may influence the positive relationship between smoking and AAO. Our data suggests that genetic and nongenetic risk factors are associated with the AAO of PD and that there is an interaction between the two.

Genetic and vascular risk factors for ischemic stroke and cortical morphometry in individuals without a history of stroke: A UK Biobank observational cohort study

BackgroundStroke risk factors may contribute to cognitive decline and dementia by altering brain tissue integrity. If their effects on brain are nonnegligible, the target regions for stroke rehabilitation with brain stimulation identified by cross-sectional case-control studies may be biased due to the pre-existing brain differences caused by these risk factors. Here, we investigated the effects of stroke risk factors on cortical thickness (CT) and surface area (SA) in individuals without a history of stroke. MethodsIn this observational study, we used data from the UK Biobank cohort to explore the effects of polygenic risk score for ischemic stroke (PRSIS), systolic blood pressure (SBP), diastolic blood pressure (DBP), glycated hemoglobin (HbA1c), triglycerides (TG), and low-density lipoprotein (LDL) on CT and SA of 62 cerebral regions. We excluded non-Caucasian participants and participants with missing data, unqualified brain images, or a history of stroke or any other brain diseases. We constructed a multivariate linear regression model for each phenotype to simultaneously test the effect of each factor and interaction between factors. The results were verified by sensitivity analyses of SDP or DBP input and adjusting for body-mass index, high-density lipoprotein cholesterol, or smoking and alcohol intake. By excluding participants with abnormal blood pressure, glucose, or lipid, we tested whether vascular risk factor within normal range also affected cortical phenotypes. To determine clinical relevance of our findings, we also investigated the effects of stroke risk factors and cortical phenotypes on cognitive decline assessed by fluid intelligence score (FIQ) and the mediation of cortical phenotype for the association between stroke risk factor and FIQ. ResultsThe study consisted of 27 120 eligible participants. Stroke risk factors were associated with 16 CT and two SA phenotypes in both main and sensitivity analyses (all p < 0.0004, Bonferroni corrected), which could explain portions of variances (partial R2, median 0.62 % [IQR 0.44–0.75 %] in main analyses) in these phenotypes. Among the 18 cortical phenotypes associated with stroke risk factors, we identified 26 specific predictor-phenotype associations (all p < 0.0026), including the positive associations between PRSIS and SA and between HbA1c and CT, negative associations of SBP and TG with CT, and mixed associations of PRSIS and DBP with CT. Neither LDL nor interactions between risk factors affected cortical phenotypes. Of the 16 associations between vascular risk factors and cortical phenotypes, ten were still significant after excluding participants with abnormal vascular risk assessments and diagnoses. Stroke risk factors were associated with FIQ in all analyses (p < 0.0004; partial R2, range 0.22–0.3 %), of which the associations of PRSIS and SBP with cognitive decline were mediated by CT phenotypes. ConclusionsStroke risk factors have substantial effects on cortical morphometry and cognitive decline in middle-aged and older people, which should be considered in the prevention of dementia and in the identification of target regions for stroke rehabilitation with brain stimulation.

Effects of polygenes, parent-child relationship and frustration on junior high school students' aggressive behaviors.

The effects of the interaction between polygenes and the parent-child relationship on junior high school students' aggressive behaviors were explored through the frameworks of gene-endophenotype-behavior and neurophysiological basis. A total of 892 junior high school students participated in this study. They were asked to complete self-reported questionnaires, and saliva samples were collected. Results showed that 5-HTTLPR, MAOA-uVNTR, COMT (rs4680), and Taq1 (rs1800497) of the DRD2 gene affected students' aggressive behaviors in an accumulative way. The polygenic risk score explained 3.4% of boys' aggression and 1.1% of girls' aggression. The interactions between polygenic risk score and parent-child conflict significantly affected the aggressive behaviors of male students, but did not show any significant effect on those of female students. The interactional effect of polygenic risk score and parent-child conflict on junior high school students' aggressive behaviors was completely mediated by frustration. However, the interaction effect of polygenic risk score and parent-child affinity on aggression was not affected by frustration. This study helps us better understand junior high school students' aggressive behaviors and promotes the prevention and correction of adolescents' problem behaviors.

Performance of polygenic risk scores in screening, prediction, and risk stratification: secondary analysis of data in the Polygenic Score Catalog

ObjectiveTo clarify the performance of polygenic risk scores in population screening, individual risk prediction, and population risk stratification.DesignSecondary analysis of data in the Polygenic Score Catalog.SettingPolygenic Score Catalog, April 2022....

Effect of polygenic risk score, family load of schizophrenia and exposome risk score, and their interactions, on the long-term outcome of first-episode psychosis.

Consistent evidence supports the involvement of genetic and environmental factors, and their interactions, in the etiology of psychosis. First-episode psychosis (FEP) comprises a group of disorders that show great clinical and long-term outcome heterogeneity, and the extent to which genetic, familial and environmental factors account for predicting the long-term outcome in FEP patients remains scarcely known. The SEGPEPs is an inception cohort study of 243 first-admission patients with FEP who were followed-up for a mean of 20.9 years. FEP patients were thoroughly evaluated by standardized instruments, with 164 patients providing DNA. Aggregate scores estimated in large populations for polygenic risk score (PRS-Sz), exposome risk score (ERS-Sz) and familial load score for schizophrenia (FLS-Sz) were ascertained. Long-term functioning was assessed by means of the Social and Occupational Functioning Assessment Scale (SOFAS). The relative excess risk due to interaction (RERI) was used as a standard method to estimate the effect of interaction of risk factors. Our results showed that a high FLS-Sz gave greater explanatory capacity for long-term outcome, followed by the ERS-Sz and then the PRS-Sz. The PRS-Sz did not discriminate significantly between recovered and non-recovered FEP patients in the long term. No significant interaction between the PRS-Sz, ERS-Sz or FLS-Sz regarding the long-term functioning of FEP patients was found. Our results support an additive model of familial antecedents of schizophrenia, environmental risk factors and polygenic risk factors as contributors to a poor long-term functional outcome for FEP patients.

The Combined Effect of Polygenic Risk Score and Prostate Health Index in Chinese Men Undergoing Prostate Biopsy

To date, the combined effect of polygenic risk score (PRS) and prostate health index (phi) on PCa diagnosis in men undergoing prostate biopsy has never been investigated. A total of 3166 patients who underwent initial prostate biopsy in three tertiary medical centers from August 2013 to March 2019 were included. PRS was calculated on the basis of the genotype of 102 reported East-Asian-specific risk variants. It was then evaluated in the univariable or multivariable logistic regression models that were internally validated using repeated 10-fold cross-validation. Discriminative performance was assessed by area under the receiver operating curve (AUC) and net reclassification improvement (NRI) index. Compared with men in the first quintile of age and family history adjusted PRS, those in the second, third, fourth, and fifth quintiles were 1.86 (odds ratio, 95% confidence interval (CI): 1.34-2.56), 2.07 (95%CI: 1.50-2.84), 3.26 (95%CI: 2.36-4.48), and 5.06 (95%CI: 3.68-6.97) times as likely to develop PCa (all p < 0.001). Adjustment for other clinical parameters yielded similar results. Among patients with prostate-specific antigen (PSA) at 2-10 ng/mL or 2-20 ng/mL, PRS still had an observable ability to differentiate PCa in the group of prostate health index (phi) at 27-36 (Ptrend < 0.05) or >36 (Ptrend ≤ 0.001). Notably, men with moderate phi (27-36) but highest PRS (top 20% percentile) would have a comparable risk of PCa (positive rate: 26.7% or 31.3%) than men with high phi (>36) but lowest PRS (bottom 20% percentile positive rate: 27.4% or 34.2%). The combined model of PRS, phi, and other clinical risk factors provided significantly better performance (AUC: 0.904, 95%CI: 0.887-0.921) than models without PRS. Adding PRS to clinical risk models could provide significant net benefit (NRI, from 8.6% to 27.6%), especially in those early onset patients (NRI, from 29.2% to 44.9%). PRS may provide additional predictive value over phi for PCa. The combination of PRS and phi that effectively captured both clinical and genetic PCa risk is clinically practical, even in patients with gray-zone PSA.

Stress-related exposures amplify the effects of genetic susceptibility on depression and anxiety

It is unclear whether and to what extent stress-related exposures moderate the effects of polygenic risk scores (PRSs) on depression and anxiety. We aimed to examine such moderation effects for a variety of stress-related exposures on depression and anxiety. We included 41,810 participants with both genome-wide genetic data and measurements of depression and anxiety in the Lifelines Cohort Study. Current depression and anxiety were measured by the MINI International Neuropsychiatric Interview. Stress-related exposures included long-term difficulties, stressful life events, reduced social support, childhood trauma, and loneliness, which were measured by self-report questionnaires. PRSs were calculated based on recent large genome-wide association studies for depression and anxiety. We used linear mixed models adjusting for family relationships to estimate the interactions between PRSs and stress-related exposures. Nine of the ten investigated interactions between the five stress-related exposures and the two PRSs for depression and anxiety were significant (Ps < 0.001). Reduced social support, and higher exposure to long-term difficulties, stressful life events, and loneliness amplified the genetic effects on both depression and anxiety. As for childhood trauma exposure, its interaction with the PRS was significant for depression (P = 1.78 × 10–05) but not for anxiety (P = 0.32). Higher levels of stress-related exposures significantly amplify the effects of genetic susceptibility on depression and anxiety. With a large sample size and a comprehensive set of stress-related exposures, our study provides powerful evidence on the presence of polygenic risk-by-environment interactions in relation to depression and anxiety.

Novel Genetic Variants Associated with Chronic Kidney Disease Progression.

eGFR slope has been used as a surrogate outcome for progression of CKD. However, genetic markers associated with eGFR slope among patients with CKD were unknown. We aimed to identify genetic susceptibility loci associated with eGFR slope. A two-phase genome-wide association study identified single nucleotide polymorphisms (SNPs) in TPPP and FAT1-LINC02374 , and 22 of them were used to derive polygenic risk scores that mark the decline of eGFR by disrupting binding of nearby transcription factors. This work is the first to identify the impact of TPPP and FAT1-LINC02374 on CKD progression, providing predictive markers for the decline of eGFR in patients with CKD. The incidence of CKD is associated with genetic factors. However, genetic markers associated with the progression of CKD have not been fully elucidated. We conducted a genome-wide association study among 1738 patients with CKD, mainly from the KoreaN cohort study for Outcomes in patients With CKD. The outcome was eGFR slope. We performed a replication study for discovered single nucleotide polymorphisms (SNPs) with P <10 -6 in 2498 patients with CKD from the Chronic Renal Insufficiency Cohort study. Several expression quantitative trait loci (eQTL) studies, pathway enrichment analyses, exploration of epigenetic architecture, and predicting disruption of transcription factor (TF) binding sites explored potential biological implications of the loci. We developed and evaluated the effect of polygenic risk scores (PRS) on incident CKD outcomes. SNPs in two novel loci, TPPP and FAT1-LINC02374 , were replicated (rs59402340 in TPPP , Pdiscovery =7.11×10 -7 , PCRIC =8.13×10 -4 , Pmeta =7.23×10 -8 ; rs28629773 in FAT1-LINC02374 , Pdiscovery =6.08×10 -7 , PCRIC =4.33×10 -2 , Pmeta =1.87×10 -7 ). The eQTL studies revealed that the replicated SNPs regulated the expression level of nearby genes associated with kidney function. Furthermore, these SNPs were near gene enhancer regions and predicted to disrupt the binding of TFs. PRS based on the independently significant top 22 SNPs were significantly associated with CKD outcomes. This study demonstrates that SNP markers in the TPPP and FAT1-LINC02374 loci could be predictive markers for the decline of eGFR in patients with CKD.

Association of the interaction between mosaic chromosomal alterations and polygenic risk score with the risk of lung cancer: an array-based case-control association and prospective cohort study.

Mosaic chromosomal alterations (mCAs) detected from blood-derived DNA are large structural alterations of clonal haematopoietic origin and are associated with various diseases, such as haematological malignancies, infections, and solid cancers. We aimed to investigate whether mCAs contribute to the risk of lung cancer and modify the effect of polygenic risk score (PRS) on lung cancer risk prediction. The blood-derived DNA of patients with lung cancer and cancer-free controls with Chinese ancestry from the Nanjing Lung Cancer Cohort (NJLCC) study were genotyped with a Global Screening Array, and mCAs were detected with the Mosaic Chromosomal Alterations (MoChA) pipeline. mCA call sets of individuals with European ancestry were obtained from the prospective cohort UK Biobank (UKB) study, including documented incident lung cancer. All patients with lung cancer from the NJLCC study (aged 15 years or older at diagnosis) were histopathologically confirmed as new lung cancer cases by at least two pathologists and were free of chemotherapy or radiotherapy before diagnosis. Participants with incident lung cancer (aged 37-73 years at assessment) diagnosed after recruitment to the UKB were identified through linkage to national cancer registries. Logistic regression and Cox proportional hazard models were applied to evaluate associations between mCAs and risk of lung cancer in the NJLCC (logistic regression) and UKB (Cox proportional hazard model) studies. The NJLCC study included 10 248 individuals (6445 [62·89%] men and 3803 [37·11%] women; median age 60·0 years [IQR 53·0-66·0]) with lung cancer and 9298 individuals (5871 [63·14%] men and 3427 [36·86%] women; median age 60·0 years [52·0-65·0]) without lung cancer recruited from three sub-regions (north, central, and south) across China between April 15, 2003, and Aug 18, 2017. The UKB included 450 821 individuals recruited from 22 centres across the UK between March 13, 2006, and Nov 1, 2010, including 2088 individuals with lung cancer (1075 [51·48%] men and 1013 [48·52%] women; median age 63·0 years [IQR 59·0-66·0]), and 448 733 participants were free of lung cancer (204 713 [45·62%] men and 244 020 [54·38%] women; median age 58·0 years [IQR 50·0-63·0]). Compared with non-carriers of mosaic losses, carriers had a significantly increased risk of lung cancer in the NJLCC (odds ratio [OR] 1·81, 95% CI 1·43-2·28; p=6·69 × 10-7) and UKB (hazard ratio [HR] 1·40, 95% CI 1·00-1·95; p=0·048) studies. This increased risk was even higher in patients with expanded cell fractions of mCAs (ie, cell fractions ≥10% vs cell fractions <10%) in the NJLCC (OR 1·61 [95% CI 1·26-2·08] vs 1·03 [0·83-1·26]; p for heterogeneity test=6·41 × 10-3). A significant multiplicative interaction was observed between PRS and mosaic losses on the risk of lung cancer in both the NJLCC (interaction p value=0·030) and UKB (p=0·043). Compared with non-carriers of mosaic loss abnormalities with low genetic risk, participants with expanded mosaic losses (cell fractions ≥10%) and high genetic risk had around a six-times increased risk of lung cancer in the NJLCC study (OR 6·40 [95% CI 3·22-12·69]), and an almost four-times increased risk of lung cancer (HR 3·75 [95% CI 1·86-7·55]) in the UKB study. The additive interaction also contributed a 3·67 (95% CI 0·49-6·85) relative excess risk of developing lung cancer in the NJLCC study, and a 2·15 (0·12-4·19) relative excess risk in the UKB study. mCAs act as a new endogenous indicator for the risk of lung cancer and might be jointly used with PRS to optimise personalised risk stratification for lung cancer. National Natural Science Foundation of China, Outstanding Youth Foundation of Jiangsu Province, Natural Science Foundation of Jiangsu Province, and Postdoctoral Science Foundation of China. For the Chinese translation of the abstract see Supplementary Materials section.

Meta-GWAS identifies the heritability of acute radiation-induced toxicities in head and neck cancer

Background and purposeWe aimed to the genetic components and susceptibility variants associated with acute radiation-induced toxicities (RITs) in patients with head and neck cancer (HNC). Materials and methodsWe performed the largest meta-GWAS of seven European cohorts (n = 4,042). Patients were scored weekly during radiotherapy for acute RITs including dysphagia, mucositis, and xerostomia. We analyzed the effect of variants on the average burden (measured as area under curve, AUC) per each RIT, and standardized total average acute toxicity (STATacute) score using a multivariate linear regression. We tested suggestive variants (p < 1.0x10-5) in discovery set (three cohorts; n = 2,640) in a replication set (four cohorts; n = 1,402). We meta-analysed all cohorts to calculate RITs specific SNP-based heritability, and effect of polygenic risk scores (PRSs), and genetic correlations among RITS. ResultsFrom 393 suggestive SNPs identified in discovery set; 37 were nominally significant (preplication < 0.05) in replication set, but none reached genome-wide significance (pcombined < 5 × 10-8). In-silico functional analyses identified “3′-5'-exoribonuclease activity” (FDR = 1.6e-10) for dysphagia, “inositol phosphate-mediated signalling” for mucositis (FDR = 2.20e-09), and “drug catabolic process” for STATacute (FDR = 3.57e-12) as the most enriched pathways by the RIT specific suggestive genes. The SNP-based heritability (±standard error) was 29 ± 0.08 % for dysphagia, 9 ± 0.12 % (mucositis) and 27 ± 0.09 % (STATacute). Positive genetic correlation was rg = 0.65 (p = 0.048) between dysphagia and STATacute. PRSs explained limited variation of dysphagia (3 %), mucositis (2.5 %), and STATacute (0.4 %). ConclusionIn HNC patients, acute RITs are modestly heritable, sharing 10 % genetic susceptibility, when PRS explains < 3 % of their variance. We identified numerus suggestive SNPs, which remain to be replicated in larger studies.

Age at onset as stratifier in idiopathic Parkinson’s disease – effect of ageing and polygenic risk score on clinical phenotypes

Several phenotypic differences observed in Parkinson’s disease (PD) patients have been linked to age at onset (AAO). We endeavoured to find out whether these differences are due to the ageing process itself by using a combined dataset of idiopathic PD (n = 430) and healthy controls (HC; n = 556) excluding carriers of known PD-linked genetic mutations in both groups. We found several significant effects of AAO on motor and non-motor symptoms in PD, but when comparing the effects of age on these symptoms with HC (using age at assessment, AAA), only positive associations of AAA with burden of motor symptoms and cognitive impairment were significantly different between PD vs HC. Furthermore, we explored a potential effect of polygenic risk score (PRS) on clinical phenotype and identified a significant inverse correlation of AAO and PRS in PD. No significant association between PRS and severity of clinical symptoms was found. We conclude that the observed non-motor phenotypic differences in PD based on AAO are largely driven by the ageing process itself and not by a specific profile of neurodegeneration linked to AAO in the idiopathic PD patients.

Effects of polygenic risk score of type 2 diabetes on the hippocampal topological property and episodic memory.

Type 2 diabetes is associated with a higher risk of dementia. The pathogenesis is complex and partly influenced by genetic factors. The hippocampus is the most vulnerable brain region in individuals with type 2 diabetes. However, whether the genetic risk of type 2 diabetes is associated with the hippocampus and episodic memory remains unclear. This study explored the influence of polygenic risk score (PRS) of type 2 diabetes on the white matter topological properties of the hippocampus among individuals with and without type 2 diabetes and its associations with episodic memory. This study included 103 individuals with type 2 diabetes and 114 well-matched individuals without type 2 diabetes. All the participants were genotyped, and a diffusion tensor imaging-based structural network was constructed. PRS was calculated based on a genome-wide association study of type 2 diabetes. The PRS-by-disease interactions on the bilateral hippocampal topological network properties were evaluated by analysis of covariance (ANCOVA). There were significant PRS-by-disease interaction effects on the nodal topological properties of the right hippocampus node. In the individuals with type 2 diabetes, the PRS was correlated with the right hippocampal nodal properties, and the nodal properties were correlated with the episodic memory. In addition, the right hippocampal nodal properties mediated the effect of PRS on episodic memory in individuals with type 2 diabetes. Our results suggested a gene-brain-cognition biological pathway, which might help understand the neural mechanism of the genetic risk of type 2 diabetes affects episodic memory in type 2 diabetes.