DISSECTING ALCOHOL USE AND MISUSE: A GENOME-WIDE AND POLYGENIC RISK SCORING APPROACH

2019 ◽  
Vol 29 ◽  
pp. S11-S12
Author(s):  
Sandra Sanchez-Roige ◽  
Emma Johnson ◽  
Abraham Palmer ◽  
Arpana Agrawal ◽  
Toni Clarke ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Polygenic Risk ◽  
Genome Wide ◽  
A Genome ◽  
Risk Scoring

scholarly journals Genome-wide Association Study identifies two novel loci for Gilles de la Tourette Syndrome

2021 ◽  
Author(s):  
Fotis Tsetsos ◽  
Apostolia Topaloudi ◽  
Pritesh Jain ◽  
Zhiyu Yang ◽  
Dongmei Yu ◽  
...  
Keyword(s):  
Tourette Syndrome ◽  
Genome Wide Association Study ◽  
Neurodevelopmental Disorder ◽  
Published Data ◽  
Volume Data ◽  
Polygenic Risk ◽  
Genome Wide ◽  
A Genome ◽  
Risk Scoring ◽  
Significant Locus

Tourette Syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture, characterized by multiple motor tics and at least one vocal tic persisting for more than one year. We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6,133 TS individuals and 13,565 ancestry-matched controls. We identified a genome-wide significant locus on chromosome 5q15 and one array-wide significant locus on chromosome 2q24.2. Integration of eQTL, Hi-C and GWAS data implicated the NR2F1 gene and associated lncRNAs within the 5q15 locus, and the RBMS1 gene within the 2q24.2 locus. Polygenic risk scoring using previous GWAS results demonstrated statistically significant ability to predict TS status in the novel cohort. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring on brain volume data identified statistically significant associations with right and left putamen volumes. Our work presents novel insights in the neurobiology of TS opening up new directions for future studies.

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.

scholarly journals Surrogate phenotype definition for alcohol use disorders: a genome-wide search for linkage and association

BMC Genetics ◽  
2005 ◽  
Vol 6 (Suppl 1) ◽  
pp. S55 ◽  
Author(s):  
Albert Rosenberger ◽  
Nico Janicke ◽  
Karola Köhler ◽  
Katrin Korb ◽  
Bettina Kulle ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorders ◽  
Phenotype Definition ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Search

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 Genome-Wide Association Study and Polygenic Risk Score Analysis of Posttraumatic Stress Disorder and Metabolic Syndrome in a South African Population

2021 ◽  
Vol 15 ◽  
Author(s):  
Patricia C. Swart ◽  
Leigh L. van den Heuvel ◽  
Cathryn M. Lewis ◽  
Soraya Seedat ◽  
Sian M. J. Hemmings
Keyword(s):  
Metabolic Syndrome ◽  
South African ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Stress Disorder ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Polygenic Risk ◽  
Genome Wide ◽  
A Genome

Posttraumatic stress disorder (PTSD) is a trauma-related disorder that frequently co-occurs with metabolic syndrome (MetS). MetS is characterized by obesity, dyslipidemia, and insulin resistance. To provide insight into these co-morbidities, we performed a genome-wide association study (GWAS) meta-analysis to identify genetic variants associated with PTSD, and determined if PTSD polygenic risk scores (PRS) could predict PTSD and MetS in a South African mixed-ancestry sample. The GWAS meta-analysis of PTSD participants (n = 260) and controls (n = 343) revealed no SNPs of genome-wide significance. However, several independent loci, as well as five SNPs in the PARK2 gene, were suggestively associated with PTSD (p < 5 × 10–6). PTSD-PRS was associated with PTSD diagnosis (Nagelkerke’s pseudo R2 = 0.0131, p = 0.00786), PTSD symptom severity [as measured by CAPS-5 total score (R2 = 0.00856, p = 0.0367) and PCL-5 score (R2 = 0.00737, p = 0.0353)], and MetS (Nagelkerke’s pseudo R2 = 0.00969, p = 0.0217). These findings suggest an association between PTSD and PARK2, corresponding with results from the largest PTSD-GWAS conducted to date. PRS analysis suggests that genetic variants associated with PTSD are also involved in the development of MetS. Overall, the results contribute to a broader goal of increasing diversity in psychiatric genetics.

scholarly journals Identification of genetic factors influencing metabolic dysregulation and retinal support for MacTel, a retinal disorder

2020 ◽  
Author(s):  
Roberto Bonelli ◽  
Victoria E Jackson ◽  
Aravind Prasad ◽  
Jacob E Munro ◽  
Samaneh Farashi ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Retinal Disease ◽  
Causative Role ◽  
Macular Telangiectasia ◽  
Metabolic Dysregulation ◽  
Genome Wide ◽  
A Genome ◽  
Risk Scoring ◽  
Macular Telangiectasia Type 2

Macular Telangiectasia Type 2 (MacTel) is a rare degenerative retinal disease with complex genetic architecture. We performed a genome-wide association study on 1,067 MacTel patients and 3,799 controls, which identified eight novel genome-wide significant loci (p<5E-8), and confirmed all three previously reported loci. Using MAGMA, eQTL and transcriptome-wide association analysis, we prioritised 48 genes implicated in serine-glycine biosynthesis, metabolite transport, and retinal vasculature and thickness. Mendelian randomization indicated a likely causative role of serine (FDR=3.9E-47) and glycine depletion (FDR=0.006) as well as alanine abundance (FDR=0.009). Polygenic risk scoring achieved an accuracy of 0.74 and was associated in UKBiobank with retinal damage (p=0.009). This represents the largest genetic study on MacTel to date, and further highlights genetically-induced systemic and tissue-specific metabolic dysregulation in MacTel patients, which impinges on retinal health.

scholarly journals Cognitive Decline in Alzheimer’s Disease: Limited Clinical Utility for GWAS or Polygenic Risk Scores in a Clinical Trial Setting

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 501
Author(s):  
Jack Euesden ◽  
Sivakumar Gowrisankar ◽  
Angela Xiaoyan Qu ◽  
Pamela St. Jean ◽  
Arlene R. Hughes ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Decline ◽  
Clinical Utility ◽  
Phase Iii ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Genome Wide ◽  
A Genome

Introduction: Alzheimer’s disease (AD) is a progressive and irreversible neurological disease. The genetics and molecular mechanisms underpinning differential cognitive decline in AD are not well understood; the genetics of AD risk have been studied far more assiduously. Materials and Methods: Two phase III clinical trials measuring cognitive decline over 48 weeks using Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog, n = 2060) and Clinical Dementia Rating-Sum of Boxes (CDR-SB, n = 1996) were retrospectively genotyped. A Genome-Wide Association Study (GWAS) was performed to identify and replicate genetic variants associated with cognitive decline. The relationship between polygenic risk score (PRS) and cognitive decline was tested to investigate the predictive power of aggregating many variants of individually small effect. Results: No loci met candidate gene or genome-wide significance. PRS explained a very small percentage of variance in rates of cognitive decline (ADAS-cog: 0.54%). Conclusions: These results suggest that incorporating genetic information in the prediction of cognitive decline in AD currently appears to have limited utility in clinical trials, consistent with small effect sizes estimated elsewhere. If AD progression is more heritable soon after disease onset, genetics may have more clinical utility.

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