scholarly journals Association between substance use disorder and polygenic liability to schizophrenia

2017 ◽  
Author(s):  
Sarah M. Hartz ◽  
Amy Horton ◽  
Mary Oehlert ◽  
Caitlin E. Carey ◽  
Arpana Agrawal ◽  
...  
Keyword(s):  
Substance Use ◽  
Substance Use Disorder ◽  
Meta Analysis ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
Individual Substance ◽  
Polygenic Risk ◽  
Genome Wide ◽  
Individual Dataset ◽  
Shared Genetic

AbstractBackgroundThere are high levels of comorbidity between schizophrenia and substance use disorder, but little is known about the genetic etiology of this comorbidity.MethodsHere, we test the hypothesis that shared genetic liability contributes to the high rates of comorbidity between schizophrenia and substance use disorder. To do this, polygenic risk scores for schizophrenia derived from a large meta-analysis by the Psychiatric Genomics Consortium were computed in three substance use disorder datasets: COGEND (ascertained for nicotine dependence n=918 cases, 988 controls), COGA (ascertained for alcohol dependence n=643 cases, 384 controls), and FSCD (ascertained for cocaine dependence n=210 cases, 317 controls). Phenotypes were harmonized across the three datasets and standardized analyses were performed. Genome-wide genotypes were imputed to 1000 Genomes reference panel.ResultsIn each individual dataset and in the mega-analysis, strong associations were observed between any substance use disorder diagnosis and the polygenic risk score for schizophrenia (mega-analysis pseudo R2 range 0.8%-3.7%, minimum p=4×10-23).ConclusionsThese results suggest that comorbidity between schizophrenia and substance use disorder is partially attributable to shared polygenic liability. This shared liability is most consistent with a general risk for substance use disorder rather than specific risks for individual substance use disorders and adds to increasing evidence of a blurred boundary between schizophrenia and substance use disorder.

scholarly journals Genome-wide Association Study of Pediatric Obsessive-Compulsive Traits: Shared Genetic Risk between Traits and Disorder

2019 ◽  
Author(s):  
Christie L. Burton ◽  
Mathieu Lemire ◽  
Bowei Xiao ◽  
Elizabeth C. Corfield ◽  
Lauren Erdman ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Genetic Risk ◽  
Meta Analysis ◽  
Case Control ◽  
Genome Wide Association ◽  
Polygenic Risk Score ◽  
Obsessive Compulsive ◽  
Polygenic Risk ◽  
Genome Wide ◽  
Shared Genetic

AbstractObjectiveTo identify genetic variants associated with obsessive-compulsive (OC) traits and test for sharing of genetic risks between OC traits and obsessive-compulsive disorder (OCD).MethodsWe conducted a genome-wide association analysis of OC traits using the Toronto Obsessive-Compulsive Scale (TOCS) in 5018 unrelated Caucasian children and adolescents from the community (Spit for Science sample). We tested the hypothesis that genetic variants associated with OC traits from the community would be associated with clinical OCD using a meta-analysis of three OCD case-controls samples (cases=3384, controls=8363). Shared genetic risk was examined between OC traits and OCD in the respective samples using polygenic risk score and genetic correlation analyses.ResultsA locus tagged by rs7856850 in an intron of PTPRD (protein tyrosine phosphatase δ) was significantly associated with OC traits at the genome-wide significance level (p=2.48×10−8). The rs7856850 locus was also associated with OCD in a meta-analysis of three independent OCD case/control genome-wide datasets (p=0.0069). Polygenic risk scores derived from OC traits were significantly associated with OCD in a sample of childhood-onset OCD and vice versa (p’s<0.01). OC traits were highly but not significantly genetically correlated with OCD (rg=0.83, p=0.07).ConclusionsWe report the first validated genome-wide significant variant for OC traits. OC traits measured in the community sample shared genetic risk with OCD case/control status. Our results demonstrate the importance of the type of measure used to measure traits as well as the feasibility and power of using trait-based approaches in community samples for genetic discovery.

scholarly journals Effect of polygenic risk scores on depression in childhood trauma

2014 ◽  
Vol 205 (2) ◽  
pp. 113-119 ◽  
Author(s):  
Wouter J. Peyrot ◽  
Yuri Milaneschi ◽  
Abdel Abdellaoui ◽  
Patrick F. Sullivan ◽  
Jouke J. Hottenga ◽  
...  
Keyword(s):  
Childhood Trauma ◽  
Meta Analysis ◽  
Genetic Effect ◽  
Risk Scores ◽  
Environment Interaction ◽  
Polygenic Risk ◽  
Gene Environment Interaction ◽  
Gene Environment ◽  
Genome Wide ◽  
Direct Genetic Effect

BackgroundResearch on gene×environment interaction in major depressive disorder (MDD) has thus far primarily focused on candidate genes, although genetic effects are known to be polygenic.AimsTo test whether the effect of polygenic risk scores on MDD is moderated by childhood trauma.MethodThe study sample consisted of 1645 participants with a DSM-IV diagnosis of MDD and 340 screened controls from The Netherlands. Chronic or remitted episodes (severe MDD) were present in 956 participants. The occurrence of childhood trauma was assessed with the Childhood Trauma Interview and the polygenic risk scores were based on genome-wide meta-analysis results from the Psychiatric Genomics Consortium.ResultsThe polygenic risk scores and childhood trauma independently affected MDD risk, and evidence was found for interaction as departure from both multiplicativity and additivity, indicating that the effect of polygenic risk scores on depression is increased in the presence of childhood trauma. The interaction effects were similar in predicting all MDD risk and severe MDD risk, and explained a proportion of variation in MDD risk comparable to the polygenic risk scores themselves.ConclusionsThe interaction effect found between polygenic risk scores and childhood trauma implies that (1) studies on direct genetic effect on MDD gain power by focusing on individuals exposed to childhood trauma, and that (2) individuals with both high polygenic risk scores and exposure to childhood trauma are particularly at risk for developing MDD.

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 Prenatal smoking, alcohol and caffeine exposure and ADHD risk in childhood: parental comparisons and polygenic risk score (PRS) analyses

2021 ◽  
Author(s):  
Elis Haan ◽  
Hannah M Sallis ◽  
Luisa Zuccolo ◽  
Jeremy Labrecque ◽  
Eivind Ystrom ◽  
...  
Keyword(s):  
Substance Use ◽  
Coffee Consumption ◽  
Negative Control ◽  
Sensitivity Analyses ◽  
Risk Scores ◽  
Prenatal Smoking ◽  
Polygenic Risk Score ◽  
Caffeine Consumption ◽  
Polygenic Risk ◽  
Prenatal Substance Use

Background and aims: Several studies have indicated that maternal prenatal substance use may be associated with offspring ADHD via intrauterine effects. We investigated associations between maternal prenatal smoking, alcohol and caffeine consumption with childhood ADHD risk accounting for shared familial factors. Design: First, we used a negative control design comparing maternal and paternal substance use. Three models were used for negative control analyses: unadjusted (without confounders); adjusted (including confounders) and mutually adjusted (including confounders and partners substance use). The results were meta-analysed across the cohorts. Second, we used polygenic risk scores (PRS) as proxies for exposures. Maternal PRS for genetic variants of smoking, alcohol and coffee consumption were regressed against ADHD risk. We triangulated the results across the two approaches to infer causality. Setting: We used data from three longitudinal pregnancy cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) in the UK, Generation R study (GenR) in the Netherlands and Norwegian Mother, Father and Child Cohort study (MoBa) in Norway. Participants: Phenotype data available for children was: N(ALSPAC)=7,850; N(GENR)=3,849 and N(MOBA)=43,512. Genotype data available for mothers was: N(ALSPAC)=7,074 and N(MOBA)=14,583. Measurements: Offspring ADHD risk around age 7-8 was derived by dichotomising symptom scores from multiple questionnaires and parental self-reported substance use was measured at the 2nd pregnancy trimester. Findings: The pooled estimate for maternal prenatal substance use showed an association with ADHD risk (OR_SMOKING=1.11, 95%CI 1.00-1.23; OR_ALCOHOL=1.27, 95%CI 1.08-1.49; OR_CAFFEINE=1.05, 95%CI 1.00-1.11), while not for fathers (OR_SMOKING=1.03, 95%CI 0.95-1.13; OR_ALCOHOL=0.83, 95%CI 0.47-1.48; OR_CAFFEINE=1.02, 95%CI 0.97-1.07). However, maternal associations did not persist in sensitivity analyses (substance use before pregnancy, adjustment for maternal ADHD in MoBa). The PRS analyses did not show evidence of association in ALSPAC or MoBa. Conclusions: Our results do not provide support for a causal intrauterine effect of maternal prenatal substance use on offspring attention-deficit hyperactivity disorder risk.

scholarly journals Genome-wide association study of pediatric obsessive-compulsive traits: shared genetic risk between traits and disorder

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Christie L. Burton ◽  
◽  
Mathieu Lemire ◽  
Bowei Xiao ◽  
Elizabeth C. Corfield ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Genetic Risk ◽  
Meta Analysis ◽  
Community Sample ◽  
Case Control ◽  
Genome Wide Association ◽  
Obsessive Compulsive ◽  
Polygenic Risk ◽  
Genome Wide ◽  
Shared Genetic

Abstract Using a novel trait-based measure, we examined genetic variants associated with obsessive-compulsive (OC) traits and tested whether OC traits and obsessive-compulsive disorder (OCD) shared genetic risk. We conducted a genome-wide association analysis (GWAS) of OC traits using the Toronto Obsessive-Compulsive Scale (TOCS) in 5018 unrelated Caucasian children and adolescents from the community (Spit for Science sample). We tested the hypothesis that genetic variants associated with OC traits from the community would be associated with clinical OCD using a meta-analysis of all currently available OCD cases. Shared genetic risk was examined between OC traits and OCD in the respective samples using polygenic risk score and genetic correlation analyses. A locus tagged by rs7856850 in an intron of PTPRD (protein tyrosine phosphatase δ) was significantly associated with OC traits at the genome-wide significance level (p = 2.48 × 10−8). rs7856850 was also associated with OCD in a meta-analysis of OCD case/control genome-wide datasets (p = 0.0069). The direction of effect was the same as in the community sample. Polygenic risk scores from OC traits were significantly associated with OCD in case/control datasets and vice versa (p’s < 0.01). OC traits were highly, but not significantly, genetically correlated with OCD (rg = 0.71, p = 0.062). We report the first validated genome-wide significant variant for OC traits in PTPRD, downstream of the most significant locus in a previous OCD GWAS. OC traits measured in the community sample shared genetic risk with OCD case/control status. Our results demonstrate the feasibility and power of using trait-based approaches in community samples for genetic discovery.

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 Genetic liability to rheumatoid arthritis on autism and autistic traits: polygenic risk score and Mendelian randomization analyses

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Amanda Ly ◽  
Beate Leppert ◽  
Dheeraj Rai ◽  
Hannah Jones ◽  
Christina Dardani ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Autistic Traits ◽  
Causal Effects ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
Genetic Liability ◽  
Polygenic Risk ◽  
Genome Wide

AbstractHigher prevalence of autism in offspring born to mothers with rheumatoid arthritis has been reported in observational studies. We investigated (a) the associations between maternal and offspring’s own genetic liability for rheumatoid arthritis and autism-related outcomes in the offspring using polygenic risk scores (PRS) and (b) whether the effects were causal using Mendelian randomization (MR). Using the latest genome-wide association (GWAS) summary data on rheumatoid arthritis and individual-level data from the Avon Longitudinal Study of Parents and Children, United Kingdom, we constructed PRSs for maternal and offspring genetic liability for rheumatoid arthritis (single-nucleotide polymorphism [SNP] p-value threshold 0.05). We investigated associations with autism, and autistic traits: social and communication difficulties, coherence, repetitive behaviours and sociability. We used modified Poisson regression with robust standard errors. In two-sample MR analyses, we used 40 genome-wide significant SNPs for rheumatoid arthritis and investigated the causal effects on risk for autism, in 18,381 cases and 27,969 controls of the Psychiatric Genetics Consortium and iPSYCH. Sample size ranged from 4992 to 7849 in PRS analyses. We found little evidence of associations between rheumatoid arthritis PRSs and autism-related phenotypes in the offspring (maternal PRS on autism: RR 0.89, 95%CI 0.73–1.07, p = 0.21; offspring’s own PRS on autism: RR 1.11, 95%CI 0.88–1.39, p = 0.39). MR results provided little evidence for a causal effect (IVW OR 1.01, 95%CI 0.98–1.04, p = 0.56). There was little evidence for associations between genetic liability for rheumatoid arthritis on autism-related outcomes in offspring. Lifetime risk for rheumatoid arthritis has no causal effects on autism.

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 Improving reporting standards for polygenic scores in risk prediction studies

2020 ◽  
Author(s):  
Hannah Wand ◽  
Samuel A. Lambert ◽  
Cecelia Tamburro ◽  
Michael A. Iacocca ◽  
Jack W. O’Sullivan ◽  
...  
Keyword(s):  
Complex Disease ◽  
Public Health Practice ◽  
Internal Validity ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
Reporting Standards ◽  
Polygenic Risk ◽  
Genome Wide ◽  
Polygenic Scores ◽  
Study Population

SummaryIn recent years, polygenic risk scores (PRS) have become an increasingly studied tool to capture the genome-wide liability underlying many human traits and diseases, hoping to better inform an individual’s genetic risk. However, a lack of adherence to previous reporting standards has hindered the translation of this important tool into clinical and public health practice with the heterogeneous underreporting of details necessary for benchmarking and reproducibility. To address this gap, the ClinGen Complex Disease Working Group and Polygenic Score (PGS) Catalog have collaborated to develop the 33-item Polygenic Risk Score Reporting Statement (PRS-RS). This framework provides the minimal information expected of authors to promote the internal validity, transparency, and reproducibility of PRS by requiring authors to detail the study population, statistical methods, and clinical utility of a published score. The widespread adoption of this framework will encourage rigorous methodological consideration and facilitate benchmarking to ensure high quality scores are translated into the clinic.

scholarly journals Genome-wide association study of suicide attempt in psychiatric disorders identifies association with major depression polygenic risk scores

2018 ◽  
Author(s):  
Niamh Mullins ◽  
Tim B. Bigdeli ◽  
Anders D Børglum ◽  
Jonathan R I Coleman ◽  
Ditte Demontis ◽  
...  
Keyword(s):  
Major Depression ◽  
Suicide Attempt ◽  
Psychiatric Disorders ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Risk Scores ◽  
Genetic Associations ◽  
Suicide Attempters ◽  
Polygenic Risk ◽  
Genome Wide

AbstractObjectiveOver 90% of suicide attempters have a psychiatric diagnosis, however twin and family studies suggest that the genetic etiology of suicide attempt (SA) is partially distinct from that of the psychiatric disorders themselves. Here, we present the largest genome-wide association study (GWAS) on suicide attempt using major depressive disorder (MDD), bipolar disorder (BIP) and schizophrenia (SCZ) cohorts from the Psychiatric Genomics Consortium.MethodSamples comprise 1622 suicide attempters and 8786 non-attempters with MDD, 3264 attempters and 5500 non-attempters with BIP and 1683 attempters and 2946 non-attempters with SCZ. SA GWAS were performed comparing attempters to non-attempters in each disorder followed by meta-analysis across disorders. Polygenic risk scoring investigated the genetic relationship between SA and the psychiatric disorders.ResultsThree genome-wide significant loci for SA were found: one associated with SA in MDD, one in BIP, and one in the meta-analysis of SA in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. Polygenic risk scores for major depression were significantly associated with SA in MDD (P=0.0002), BIP (P=0.0006) and SCZ (P=0.0006).ConclusionsThis study provides new information on genetic associations and the genetic etiology of SA across psychiatric disorders. The finding that polygenic risk scores for major depression predict suicide attempt across disorders provides a possible starting point for predictive modelling and preventative strategies. Further collaborative efforts to increase sample size hold potential to robustly identify genetic associations and gain biological insights into the etiology of suicide attempt.

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