scholarly journals Polygenic risk for obesity and its interaction with lifestyle and sociodemographic factors in European children and adolescents

2021 ◽  
Author(s):  
Anke Hüls ◽  
Marvin N. Wright ◽  
Leonie H. Bogl ◽  
Jaakko Kaprio ◽  
Lauren Lissner ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Risk Score ◽  
Lifestyle Factors ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Genetic Liability ◽  
Level Of Education ◽  
Polygenic Risk ◽  
Genome Wide ◽  
A Genome

Abstract Background Childhood obesity is a complex multifaceted condition, which is influenced by genetics, environmental factors, and their interaction. However, these interactions have mainly been studied in twin studies and evidence from population-based cohorts is limited. Here, we analyze the interaction of an obesity-related genome-wide polygenic risk score (PRS) with sociodemographic and lifestyle factors for BMI and waist circumference (WC) in European children and adolescents. Methods The analyses are based on 8609 repeated observations from 3098 participants aged 2–16 years from the IDEFICS/I.Family cohort. A genome-wide polygenic risk score (PRS) was calculated using summary statistics from independent genome-wide association studies of BMI. Associations were estimated using generalized linear mixed models adjusted for sex, age, region of residence, parental education, dietary intake, relatedness, and population stratification. Results The PRS was associated with BMI (beta estimate [95% confidence interval (95%—CI)] = 0.33 [0.30, 0.37], r2 = 0.11, p value = 7.9 × 10−81) and WC (beta [95%—CI] = 0.36 [0.32, 0.40], r2 = 0.09, p value = 1.8 × 10−71). We observed significant interactions with demographic and lifestyle factors for BMI as well as WC. Children from Southern Europe showed increased genetic liability to obesity (BMI: beta [95%—CI] = 0.40 [0.34, 0.45]) in comparison to children from central Europe (beta [95%—CI] = 0.29 [0.23, 0.34]), p-interaction = 0.0066). Children of parents with a low level of education showed an increased genetic liability to obesity (BMI: beta [95%—CI] = 0.48 [0.38, 0.59]) in comparison to children of parents with a high level of education (beta [95%—CI] = 0.30 [0.26, 0.34]), p-interaction = 0.0012). Furthermore, the genetic liability to obesity was attenuated by a higher intake of fiber (BMI: beta [95%—CI] interaction = −0.02 [−0.04,−0.01]) and shorter screen times (beta [95%—CI] interaction = 0.02 [0.00, 0.03]). Conclusions Our results highlight that a healthy childhood environment might partly offset a genetic predisposition to obesity during childhood and adolescence.

Polygenic Risk Scores for Kidney Function and Their Associations with Circulating Proteome, and Incident Kidney Diseases

2021 ◽  
pp. ASN.2020111599
Author(s):  
Zhi Yu ◽  
Jin Jin ◽  
Adrienne Tin ◽  
Anna Köttgen ◽  
Bing Yu ◽  
...  
Keyword(s):  
Kidney Function ◽  
Kidney Diseases ◽  
Association Studies ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Plasma Proteome ◽  
Uk Biobank ◽  
Polygenic Risk ◽  
Genome Wide ◽  
A Genome

Background: Genome-wide association studies (GWAS) have revealed numerous loci for kidney function (estimated glomerular filtration rate, eGFR). The relationship of polygenic predictors of eGFR, risk of incident adverse kidney outcomes, and the plasma proteome is not known. Methods: We developed a genome-wide polygenic risk score (PRS) for eGFR by applying the LDpred algorithm to summary statistics generated from a multiethnic meta-analysis of CKDGen Consortium GWAS (N=765,348) and UK Biobank GWAS (90% of the cohort; N=451,508), followed by best parameter selection using the remaining 10% of UK Biobank (N=45,158). We then tested the association of the PRS in the Atherosclerosis Risk in Communities (ARIC) study (N=8,866) with incident chronic kidney disease, kidney failure, and acute kidney injury. We also examined associations between the PRS and 4,877 plasma proteins measured at at middle age and older adulthood and evaluated mediation of PRS associations by eGFR. Results: The developed PRS showed significant associations with all outcomes with hazard ratios (95% CI) per 1 SD lower PRS ranged from 1.06 (1.01, 1.11) to 1.33 (1.28, 1.37). The PRS was significantly associated with 132 proteins at both time points. The strongest associations were with cystatin-C, collagen alpha-1(XV) chain, and desmocollin-2. Most proteins were higher at lower kidney function, except for 5 proteins including testican-2. Most correlations of the genetic PRS with proteins were mediated by eGFR. Conclusions: A PRS for eGFR is now sufficiently strong to capture risk for a spectrum of incident kidney diseases and broadly influences the plasma proteome, primarily mediated by eGFR.

Performance of polygenic risk scores for cancer prediction in an academic biobank.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1528-1528
Author(s):  
Heena Desai ◽  
Anh Le ◽  
Ryan Hausler ◽  
Shefali Verma ◽  
Anurag Verma ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Variants ◽  
Association Studies ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
European Americans ◽  
Genome Wide ◽  
Common Genetic Variants

1528 Background: The discovery of rare genetic variants associated with cancer have a tremendous impact on reducing cancer morbidity and mortality when identified; however, rare variants are found in less than 5% of cancer patients. Genome wide association studies (GWAS) have identified hundreds of common genetic variants significantly associated with a number of cancers, but the clinical utility of individual variants or a polygenic risk score (PRS) derived from multiple variants is still unclear. Methods: We tested the ability of polygenic risk score (PRS) models developed from genome-wide significant variants to differentiate cases versus controls in the Penn Medicine Biobank. Cases for 15 different cancers and cancer-free controls were identified using electronic health record billing codes for 11,524 European American and 5,994 African American individuals from the Penn Medicine Biobank. Results: The discriminatory ability of the 15 PRS models to distinguish their respective cancer cases versus controls ranged from 0.68-0.79 in European Americans and 0.74-0.93 in African Americans. Seven of the 15 cancer PRS trended towards an association with their cancer at a p<0.05 (Table), and PRS for prostate, thyroid and melanoma were significantly associated with their cancers at a bonferroni corrected p<0.003 with OR 1.3-1.6 in European Americans. Conclusions: Our data demonstrate that common variants with significant associations from GWAS studies can distinguish cancer cases versus controls for some cancers in an unselected biobank population. Given the small effects, future studies are needed to determine how best to incorporate PRS with other risk factors in the precision prediction of cancer risk. [Table: see text]

scholarly journals The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia

2019 ◽  
Author(s):  
Alexander L Richards ◽  
Antonio F Pardiñas ◽  
Aura Frizzati ◽  
Katherine E Tansey ◽  
Amy J Lynham ◽  
...  
Keyword(s):  
Association Studies ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Related Factors ◽  
Polygenic Risk ◽  
Genome Wide ◽  
A Genome ◽  
Genetic Overlap ◽  
Individual Variant

Abstract Background Cognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases. Methods We combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases. Results PRS for both population IQ (P = 4.39 × 10–28) and EA (P = 1.27 × 10–26) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS. Conclusions Cognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.

scholarly journals A polygenic risk score for multiple myeloma risk prediction

2021 ◽  
Author(s):  
Federico Canzian ◽  
Chiara Piredda ◽  
Angelica Macauda ◽  
Daria Zawirska ◽  
Niels Frost Andersen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Risk Score ◽  
Association Studies ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Epidemiologic Evidence ◽  
Risk Variants ◽  
Genome Wide ◽  
Weighted Score

AbstractThere is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53–4.69, p = 3.55 × 10−15 for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34–4.33, p = 1.62 × 10−13 for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population.

Genetic Background of Mesalamine-induced Fever and Diarrhea in Japanese Patients with Inflammatory Bowel Disease

2021 ◽  
Author(s):  
Kaoru Suzuki ◽  
Yoichi Kakuta ◽  
Takeo Naito ◽  
Tetsuya Takagawa ◽  
Hiroyuki Hanai ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Background ◽  
Association Studies ◽  
Meta Analysis ◽  
Area Under The Curve ◽  
Genome Wide Association ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Genome Wide

Abstract Background Some patients with inflammatory bowel disease (IBD) who were under mesalamine treatment develop adverse reactions called “mesalamine allergy,” which includes high fever and worsening diarrhea. Currently, there is no method to predict mesalamine allergy. Pharmacogenomic approaches may help identify these patients. Here we analyzed the genetic background of mesalamine intolerance in the first genome-wide association study of Japanese patients with IBD. Methods Two independent pharmacogenetic IBD cohorts were analyzed: the MENDEL (n = 1523; as a discovery set) and the Tohoku (n = 788; as a replication set) cohorts. Genome-wide association studies were performed in each population, followed by a meta-analysis. In addition, we constructed a polygenic risk score model and combined genetic and clinical factors to model mesalamine intolerance. Results In the combined cohort, mesalamine-induced fever and/or diarrhea was significantly more frequent in ulcerative colitis vs Crohn’s disease. The genome-wide association studies and meta-analysis identified one significant association between rs144384547 (upstream of RGS17) and mesalamine-induced fever and diarrhea (P = 7.21e-09; odds ratio = 11.2). The estimated heritability of mesalamine allergy was 25.4%, suggesting a significant correlation with the genetic background. Furthermore, a polygenic risk score model was built to predict mesalamine allergy (P = 2.95e-2). The combined genetic/clinical prediction model yielded a higher area under the curve than did the polygenic risk score or clinical model alone (area under the curve, 0.89; sensitivity, 71.4%; specificity, 90.8%). Conclusions Mesalamine allergy was more common in ulcerative colitis than in Crohn’s disease. We identified a novel genetic association with and developed a combined clinical/genetic model for this adverse event.

scholarly journals A genome-wide association and polygenic risk score study on abnormal electrocardiogram in a Chinese population

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mengqiao Wang ◽  
Jiaqi Gao ◽  
Yang Shi ◽  
Xing Zhao
Keyword(s):  
Risk Score ◽  
Chinese Population ◽  
Genome Wide Association ◽  
Physical Parameters ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Genome Wide ◽  
A Genome ◽  
Potential Biomarker ◽  
Increased Risk

AbstractElectrocardiography is a common and widely-performed medical examination based on the measurement and evaluation of electrocardiogram (ECG) to assess the up-to-date cardiac rhythms and thus suggest the health conditions of cardiovascular system and on a larger level the individual’s wellness. Abnormal ECG assessment from the detection of abnormal heart rhythms may have clinical implications including blood clots in formation, ongoing heart attack, coronary artery blockage, etc. Past genetic-phenotypic research focused primarily on the physical parameters of ECG but not the medical evaluation. To unbiasedly uncover the underlying links of genetic variants with normal vs. abnormal ECG assessment, a genome-wide association study (GWAS) is carried out in a 1006-participant cohort of Chinese population effectively genotyped for 243487 single nucleotide polymorphisms (SNPs). Both age and sex are influential factors, and six novel SNPs are identified for potential association with abnormal ECG. With the selected SNPs, a polygenic risk score (PRS) differentiates the case–control subgroups, and correlates well with increased risk of abnormal ECG. The findings are reproduced in an independent validation cohort. The derived PRS may function as a potential biomarker for prospectively screening the high-risk subgroup of heart issues in the Chinese population.

scholarly journals Polygenic risk for aggressive behaviour from late childhood through early adulthood

2021 ◽  
Author(s):  
Tina Kretschmer ◽  
Isabelle Ouellet-Morin ◽  
Charlotte Vrijen ◽  
Ilja Maria Nolte ◽  
Catharina A. Hartman
Keyword(s):  
High Risk ◽  
Risk Score ◽  
Genetic Information ◽  
Aggressive Behaviour ◽  
Population Sample ◽  
Genome Wide Association ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Genome Wide

Twin studies suggest a substantial role for genes in explaining individual differences in aggressive behaviour across development. It is unclear, however, how directly measured genetic risk is associated with aggressive behaviour at different moments across adolescence and how genes might distinguish developmental trajectories of aggressive behaviour. Here, a polygenic risk score derived from the EAGLE-Consortium genome-wide association study of aggressive behaviour in children was tested as predictor of latent growth classes derived from those measures in an adolescent population (n = 2229, of which n = 1259 with genetic information) and a high-risk sample (n = 543, of which n = 339 with genetic information). In the population sample, the polygenic risk score explained variation in parent-reported aggressive behaviour at all ages and distinguished between stable low aggressive behaviour and moderate and high-decreasing trajectories based on parent-report. In contrast, the polygenic risk score was not associated with self- and teacher-reported aggressive behaviour, and no associations were found in the high-risk sample. This pattern of results suggests that methodological choices made in genome-wide association studies impact the predictive power of polygenic risk scores, not just with respect to power but likely also in terms of generalizability and specificity.

Genome-wide polygenic risk score for retinopathy of type 2 diabetes

2021 ◽  
Author(s):  
Iain S Forrest ◽  
Kumardeep Chaudhary ◽  
Ishan Paranjpe ◽  
Ha My T Vy ◽  
Carla Marquez-Luna ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Risk Score ◽  
Large Scale ◽  
European Ancestry ◽  
Polygenic Risk Score ◽  
Standard Deviation Increase ◽  
Polygenic Risk ◽  
Genome Wide ◽  
A Genome

Abstract Diabetic retinopathy (DR) is a common consequence in type 2 diabetes (T2D) and a leading cause of blindness in working-age adults. Yet, its genetic predisposition is largely unknown. Here, we examined the polygenic architecture underlying DR by deriving and assessing a genome-wide polygenic risk score (PRS) for DR. We evaluated the PRS in 6079 individuals with T2D of European, Hispanic, African and other ancestries from a large-scale multi-ethnic biobank. Main outcomes were PRS association with DR diagnosis, symptoms and complications, and time to diagnosis, and transferability to non-European ancestries. We observed that PRS was significantly associated with DR. A standard deviation increase in PRS was accompanied by an adjusted odds ratio (OR) of 1.12 [95% confidence interval (CI) 1.04–1.20; P = 0.001] for DR diagnosis. When stratified by ancestry, PRS was associated with the highest OR in European ancestry (OR = 1.22, 95% CI 1.02–1.41; P = 0.049), followed by African (OR = 1.15, 95% CI 1.03–1.28; P = 0.028) and Hispanic ancestries (OR = 1.10, 95% CI 1.00–1.10; P = 0.050). Individuals in the top PRS decile had a 1.8-fold elevated risk for DR versus the bottom decile (P = 0.002). Among individuals without DR diagnosis, the top PRS decile had more DR symptoms than the bottom decile (P = 0.008). The PRS was associated with retinal hemorrhage (OR = 1.44, 95% CI 1.03–2.02; P = 0.03) and earlier DR presentation (10% probability of DR by 4 years in the top PRS decile versus 8 years in the bottom decile). These results establish the significant polygenic underpinnings of DR and indicate the need for more diverse ancestries in biobanks to develop multi-ancestral PRS.

scholarly journals Genome-Wide Polygenic Risk Score Identifies Individuals at Elevated Parkinson’s Disease Risk

2020 ◽  
Author(s):  
Yingnan Han ◽  
Erin Teeple ◽  
Srinivas Shankara ◽  
Mahdiar Sadeghi ◽  
Cheng Zhu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Risk Score ◽  
Age Of Onset ◽  
Polygenic Risk Score ◽  
List Type ◽  
Polygenic Risk ◽  
Genome Wide ◽  
A Genome ◽  
Dopamine Signaling

SUMMARYParkinson’s Disease (PD) is the second most common and fastest-growing neurological disorder. Polygenic Risk Scores (PRS) using hundreds to thousands of PD-associated variants support polygenic heritability. Here, for the first time, we apply a genome-wide polygenic risk score approach using 6.2 million variants to compute a PD genome-wide polygenic risk score (PD-GPRS) via the LDPred algorithm. PD-GPRS validation and testing used Accelerating Medicines Partnership – Parkinson’s Disease (AMP-PD) and FinnGen Consortia genomic data from 1,654 PD Cases and 79,123 Controls. PD odds for the top 8%, 2.5%, and 1% of PD-GPRS were three-, four-, and seven times greater compared with lower percentiles, respectively (p<1e-10). PD age of onset and MDS-UPDRS motor scores also differed by PD-GPRS decile. Enrichment for phagosome related, dopamine signaling, immune related, and neuronal signaling pathways was found for genes nearest high PD-GPRS variants identified by MAF analysis. PD-GPRS offers a promising screening tool to identify high-risk individuals for preventive lifestyle or new drug therapy trials.In BriefIn Han and Teeple et al., Parkinson’s Disease inherited risk is quantified by a genome-wide polygenic risk score (PD-GPRS) approach using 6.2 million variants and data from 80,777 individuals. For the top 2.5% and 1% of PD-GPRS, individuals had five- and seven-fold greater odds of PD, respectively. PD-GPRS was found to be associated with overall PD risk, earlier age of onset, and MDS-UPDRS motor scores. Genes nearest to variants observed at higher frequencies among high-GPRS individuals are enriched for PD-implicated pathways.HIGHLIGHTS-Parkinson’s Disease genome-wide polygenic risk score (PD-GPRS) calculated from 6.2 million variants identifies individuals with inherited clinically significant increased neurodegeneration risk.-Top percentile PD-GPRS individuals were found to have up to seven-fold greater odds of PD and earlier age at PD diagnosis.-PD-GPRS scores correlated with all-subjects cohort mean MDS-UPDRS motor scores.-Pathway analysis of genes adjacent to frequently occurring variants in the high PD-GPRS population identified polygenic risk contributions for variations in PD-implicated pathways including dopamine signaling, immune responses, and autophagy pathways.

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