scholarly journals Polygenic risk scores implicate genetic pathways involved in neurodevelopmental disorders in hearing thresholds and hearing asymmetry in children

2020 ◽  
Author(s):  
Judith Schmitz ◽  
Filippo Abbondanza ◽  
Silvia Paracchini
Keyword(s):  
Psychosocial Development ◽  
Neurodevelopmental Disorders ◽  
Cognitive Skills ◽  
Autism Spectrum ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Genome Wide ◽  
Hearing Thresholds ◽  
Ear Advantage

AbstractAn efficient auditory system contributes to cognitive and psychosocial development. A right ear advantage in hearing thresholds (HT) has been described in adults and atypical patterns of left/right hearing threshold asymmetry (HTA) have been described for psychiatric and neurodevelopmental conditions. Previous genome-wide association studies (GWAS) on HT have mainly been conducted in elderly participants whose hearing is more likely to be affected by environmental effects. We analysed HT and HTA in a children population cohort (ALSPAC, n = 6,743, 7.6 years). Better hearing was associated with more advanced cognitive skills and higher socioeconomic status (SES). Mean HTA was negative (−0.28 dB), suggesting a left ear advantage in children but mainly driven by females (−0.48 dB in females v -0.09 dB in males). We performed the first GWAS on HT in children and the very first GWAS on HTA (n = 5,344). Single marker trait association analysis did not yield significant hits. Polygenic risk score (PRS) analysis revealed associations of PRS for schizophrenia with HT, which remained significant after controlling for SES and cognitive skills, and of PRS for autism spectrum disorders (ASD) with HTA. Gene-based analysis for HTA reached genome-wide significance for MCM5, which is implicated in axon morphogenesis. This analysis also highlighted other genes associated with contralateral axon crossing. Some of these genes have previously been reported for ASD. These results further support the hypothesis that pathways distinguishing the left/right axis of the brain (i.e. commissural crossing) contribute to both different types of asymmetries (i.e. HTA) and neurodevelopmental disorders.

scholarly journals Polygenic risk scores for major psychiatric and neurodevelopmental disorders contribute to sleep disturbance in childhood: Adolescent Brain Cognitive Development (ABCD) Study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kazutaka Ohi ◽  
Ryo Ochi ◽  
Yoshihiro Noda ◽  
Masataka Wada ◽  
Shunsuke Sugiyama ◽  
...  
Keyword(s):  
Cognitive Development ◽  
Anxiety Disorders ◽  
Sleep Disturbance ◽  
Neurodevelopmental Disorders ◽  
Association Studies ◽  
Autism Spectrum ◽  
Polygenic Risk Score ◽  
Common Symptom ◽  
Genome Wide Association Studies ◽  
Polygenic Risk

AbstractSleep disturbance is a common symptom of psychiatric and neurodevelopmental disorders and, especially in childhood, can be a precursor to various mental disorders. However, the genetic etiology of mental illness that contributes to sleep disturbance during childhood is poorly understood. We investigated whether the polygenic features of psychiatric and neurodevelopmental disorders are associated with sleep disturbance during childhood. We conducted polygenic risk score (PRS) analyses by utilizing large-scale genome-wide association studies (GWASs) (n = 46,350–500,199) of five major psychiatric and neurodevelopmental disorders (autism spectrum disorder, schizophrenia, attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and bipolar disorder) and, additionally, anxiety disorders as base datasets. We used the data of 9- to 10-year-olds from the Adolescent Brain Cognitive Development study (n = 9683) as a target dataset. Sleep disturbance was assessed based on the Sleep Disturbance Scale for Children (SDSC) scores. The effects of PRSs for these psychiatric and neurodevelopmental disorders on the total scores and six subscale scores of the SDSC were investigated. Of the PRSs for the five psychiatric and neurodevelopmental disorders, the PRSs for ADHD and MDD positively correlated with sleep disturbance in children (ADHD: R2 = 0.0033, p = 6.19 × 10−5, MDD: R2 = 0.0042, p = 5.69 × 10−6). Regarding the six subscale scores of the SDSC, the PRSs for ADHD positively correlated with both disorders of initiating and maintaining sleep (R2 = 0.0028, p = 2.31 × 10−4) and excessive somnolence (R2 = 0.0023, p = 8.44 × 10−4). Furthermore, the PRSs for MDD primarily positively correlated with disorders of initiating and maintaining sleep (R2 = 0.0048, p = 1.26 × 10−6), followed by excessive somnolence (R2 = 0.0023, p = 7.74 × 10−4) and sleep hyperhidrosis (R2 = 0.0014, p = 9.55 × 10−3). Despite high genetic overlap between MDD and anxiety disorders, PRSs for anxiety disorders correlated with different types of sleep disturbances such as disorders of arousal or nightmares (R2 = 0.0013, p = 0.011). These findings suggest that greater genetic susceptibility to specific psychiatric and neurodevelopmental disorders, as represented by ADHD, MDD, and anxiety disorders, may contribute to greater sleep problems among children.

scholarly journals Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis

2019 ◽  
Author(s):  
Richard J Allen ◽  
Beatriz Guillen-Guio ◽  
Justin M Oldham ◽  
Shwu-Fan Ma ◽  
Amy Dressen ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Telomere Maintenance ◽  
Genome Wide Association ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Genome Wide

AbstractRationaleIdiopathic pulmonary fibrosis (IPF) is a complex lung disease characterised by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. The mechanisms by which this arises are poorly understood and it is likely that multiple pathways are involved. The strongest genetic association with IPF is a variant in the promoter of MUC5B where each copy of the risk allele confers a five-fold risk of disease. However, genome-wide association studies have reported additional signals of association implicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion.ObjectivesTo improve our understanding of mechanisms that increase IPF susceptibility by identifying previously unreported genetic associations.Methods and measurementsWe performed the largest genome-wide association study undertaken for IPF susceptibility with a discovery stage comprising up to 2,668 IPF cases and 8,591 controls with replication in an additional 1,467 IPF cases and 11,874 controls. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.Main resultsWe identified and replicated three new genome-wide significant (P<5×10-8) signals of association with IPF susceptibility (near KIF15, MAD1L1 and DEPTOR) and confirm associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as-yet unreported IPF risk variants contribute to IPF susceptibility.ConclusionsNovel association signals support the importance of mTOR signalling in lung fibrosis and suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.

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 Genome-wide Association Study of Creativity Reveals Genetic Overlap With Psychiatric Disorders, Risk Tolerance, and Risky Behaviors

2020 ◽  
Vol 46 (5) ◽  
pp. 1317-1326 ◽  
Author(s):  
Huijuan Li ◽  
Chuyi Zhang ◽  
Xin Cai ◽  
Lu Wang ◽  
Fang Luo ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Genetic Basis ◽  
Risky Behaviors ◽  
Risk Tolerance ◽  
Genome Wide Association ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
Genome Wide ◽  
Genetic Overlap

Abstract Creativity represents one of the most important and partially heritable human characteristics, yet little is known about its genetic basis. Epidemiological studies reveal associations between creativity and psychiatric disorders as well as multiple personality and behavioral traits. To test whether creativity and these disorders or traits share genetic basis, we performed genome-wide association studies (GWAS) followed by polygenic risk score (PRS) analyses. Two cohorts of Han Chinese subjects (4,834 individuals in total) aged 18–45 were recruited for creativity measurement using typical performance test. After exclusion of the outliers with significantly deviated creativity scores and low-quality genotyping results, 4,664 participants were proceeded for GWAS. We conducted PRS analyses using both the classical pruning and thresholding (P+T) method and the LDpred method. The extent of polygenic risk was estimated through linear regression adjusting for the top 3 genotyping principal components. R2 was used as a measurement of the explained variance. PRS analyses demonstrated significantly positive genetic overlap, respectively, between creativity with schizophrenia ((P+T) method: R2(max) ~ .196%, P = .00245; LDpred method: R2(max) ~ .226%, P = .00114), depression ((P+T) method: R2(max) ~ .178%, P = .00389; LDpred method: R2(max) ~ .093%, P = .03675), general risk tolerance ((P+T) method: R2(max) ~ .177%, P = .00399; LDpred method: R2(max) ~ .305%, P = .00016), and risky behaviors ((P+T) method: R2(max) ~ .187%, P = .00307; LDpred method: R2(max) ~ .155%, P = .00715). Our results suggest that human creativity is probably a polygenic trait affected by numerous variations with tiny effects. Genetic variations that predispose to psychiatric disorders and risky behaviors may underlie part of the genetic basis of creativity, confirming the epidemiological associations between creativity and these traits.

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.

scholarly journals Genome-wide polygenic risk score method for diabetic kidney disease in patients with type 2 diabetes

2021 ◽  
Author(s):  
Ha My T Vy ◽  
Sergio Dellepiane ◽  
Kumardeep Chaudhary ◽  
Alexander Blair ◽  
Benjamin S Glicksberg ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Summary Statistics ◽  
Diabetic Kidney ◽  
Polygenic Risk ◽  
Genome Wide

Diabetic kidney disease (DKD) is considered partially hereditary, but the genetic factors underlying disease remain largely unknown. A key barrier to our understanding stems from its heterogeneity, and likely polygenic etiology. Proteinuric and non-proteinuric DKD are two sub-classes of DKD, defined by high urinary albumin-to-creatinine ratio (UACR) and low creatinine estimated glomerular filtration rate (eGFR). Prior genome-wide association studies (GWAS) have identified multiple loci associated with eGFR and UACR. We aimed to combine summary statistics from previous GWASs for eGFR and UACR in one prediction model and associate it with DKD prevalence. We then tested this using genetic data from 18,841 individuals diagnosed with type 2 diabetes in UK Biobank. We computed two genome-wide polygenic risk scores (GPS) aggregating effects of common variants associated with the two measurements, eGFR and UACR. We show that including both GPS in a single model confers significant improvement in comparison with the single GPS model generated from GWAS summary statistics for DKD. We also find in replication analysis in 5,389 individuals in the multi-ethnic BioMe Biobank, that although the combined model had consistent direction of association, the lowest performance was in individuals with recent African ancestry. In summary, we show that joint modeling of polygenic associations of eGFR and UACR is more significantly associated with DKD than individual modeling as well as a GPS comprised of only DKD summary statistics and may be used to gain insights into biology and progression. However, efforts should be made to develop and validate polygenic approaches in diverse populations.

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