scholarly journals Polygenic risk prediction based on singular value decomposition with applications to alcohol use disorder

2022 ◽  
Vol 23 (1) ◽  
Author(s):  
James J. Yang ◽  
Xi Luo ◽  
Elisa M. Trucco ◽  
Anne Buu
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Large Scale ◽  
Methodological Issue ◽  
Secondary Data ◽  
Principal Component ◽  
Polygenic Risk Score ◽  
Adult Health ◽  
Polygenic Risk ◽  
Target Data

Abstract Background/aim The polygenic risk score (PRS) shows promise as a potentially effective approach to summarize genetic risk for complex diseases such as alcohol use disorder that is influenced by a combination of multiple variants, each of which has a very small effect. Yet, conventional PRS methods tend to over-adjust confounding factors in the discovery sample and thus have low power to predict the phenotype in the target sample. This study aims to address this important methodological issue. Methods This study proposed a new method to construct PRS by (1) approximating the polygenic model using a few principal components selected based on eigen-correlation in the discovery data; and (2) conducting principal component projection on the target data. Secondary data analysis was conducted on two large scale databases: the Study of Addiction: Genetics and Environment (SAGE; discovery data) and the National Longitudinal Study of Adolescent to Adult Health (Add Health; target data) to compare performance of the conventional and proposed methods. Result and conclusion The results show that the proposed method has higher prediction power and can handle participants from different ancestry backgrounds. We also provide practical recommendations for setting the linkage disequilibrium (LD) and p value thresholds.

scholarly journals An atlas of polygenic risk score associations to highlight putative causal relationships across the human phenome

2018 ◽  
Author(s):  
Tom G. Richardson ◽  
Sean Harrison ◽  
Gibran Hemani ◽  
George Davey Smith
Keyword(s):  
Web Application ◽  
Large Scale ◽  
Complex Disease ◽  
Association Studies ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Genetic Liability ◽  
Polygenic Risk ◽  
The Uk

AbstractThe age of large-scale genome-wide association studies (GWAS) has provided us with an unprecedented opportunity to evaluate the genetic liability of complex disease using polygenic risk scores (PRS). In this study, we have analysed 162 PRS (P<5×l0 05) derived from GWAS and 551 heritable traits from the UK Biobank study (N=334,398). Findings can be investigated using a web application (http://mrcieu.mrsoftware.org/PRS_atlas/), which we envisage will help uncover both known and novel mechanisms which contribute towards disease susceptibility.To demonstrate this, we have investigated the results from a phenome-wide evaluation of schizophrenia genetic liability. Amongst findings were inverse associations with measures of cognitive function which extensive follow-up analyses using Mendelian randomization (MR) provided evidence of a causal relationship. We have also investigated the effect of multiple risk factors on disease using mediation and multivariable MR frameworks. Our atlas provides a resource for future endeavours seeking to unravel the causal determinants of complex disease.

scholarly journals Microstructural damage of white-matter tracts connecting large-scale networks is related to impaired executive profile in alcohol use disorder

2020 ◽  
Vol 25 ◽  
pp. 102141 ◽  
Author(s):  
Chiara Crespi ◽  
Caterina Galandra ◽  
Nicola Canessa ◽  
Marina Manera ◽  
Paolo Poggi ◽  
...  
Keyword(s):  
White Matter ◽  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Large Scale ◽  
White Matter Tracts ◽  
Microstructural Damage ◽  
Large Scale Networks

scholarly journals Genome-wide Meta-analysis of Alcohol Use Disorder in East Asians

2021 ◽  
Author(s):  
Hang Zhou ◽  
Rasmon Kalayasiri ◽  
Yan Sun ◽  
Yaira Z. Nuñez ◽  
Hong-Wen Deng ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Association Studies ◽  
Meta Analysis ◽  
East Asian ◽  
Han Chinese ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
East Asians ◽  
Genome Wide

AbstractBACKGROUNDAlcohol use disorder (AUD) is a leading cause of death and disability worldwide. Genome-wide association studies (GWAS) have identified ∼30 AUD risk genes in European populations, but many fewer in East Asians.METHODSWe conducted GWAS and genome-wide meta-analysis of AUD in 13,551 subjects with East Asian ancestry, using published summary data and newly genotyped data from four cohorts: 1) electronic health record (EHR)-diagnosed AUD in the Million Veteran Program (MVP)sample; 2) DSM-IV diagnosed alcohol dependence (AD) in a Han Chinese-GSA (array) cohort;3) AD in a Han Chinese-Cyto (array) cohort; and 4) two AD datasets in a Thai cohort. The MVP and Thai samples included newly genotyped subjects from ongoing recruitment. In total, 2,254 cases and 11,297 controls were analyzed. An AUD polygenic risk score was analyzed in an independent sample with 4,464 East Asians (Kaiser Permanente data from dbGaP). Phenotypes from survey data and ICD-9-CM diagnoses were tested for association with the AUD PRS.RESULTSTwo risk loci were detected: the well-known functional variant rs1229984 in ADH1B and rs3782886 in BRAP (near the ALDH2 gene locus) are the lead variants. AUD PRS was significantly associated with days per week of alcohol consumption (beta = 0.43, se = 0.067, p = 2.47×10−10) and nominally associated with pack years of smoking (beta = 0.09, se = 0.05, p = 4.52×10−2) and ever vs. never smoking (beta = 0.06, se = 0.02, p = 1.14×10−2).CONCLUSIONSThis is the largest GWAS of AUD in East Asians to date. Building on previous findings, we were able to analyze pleiotropy, but did not identify any new risk regions, underscoring the importance of recruiting additional East Asian subjects for alcohol GWAS.

scholarly journals Genomic Prediction of Depression Risk and Resilience Under Stress

2019 ◽  
Author(s):  
Yu Fang ◽  
Laura Scott ◽  
Peter Song ◽  
Margit Burmeister ◽  
Srijan Sen
Keyword(s):  
Risk Score ◽  
Large Scale ◽  
Association Studies ◽  
Health Study ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Risk And Resilience ◽  
Polygenic Risk ◽  
Response To Stress ◽  
Training Stress

AbstractAdvancing our ability to predict who is likely to develop depression in response to stress holds great potential in reducing the burden of the disorder. Large-scale genome-wide association studies (GWAS) of depression have, for the first time, provided a basis for meaningful depression polygenic risk score construction (MDD-PRS). The Intern Health Study utilizes the predictable and large increase in depression with physician training stress to identify predictors of depression. Applying the MDD-PRS derived from the PGC2/23andMe GWAS to 5,227 training physicians, we found that MDD-PRS predicted depression under training stress (beta=0.082, p=2.1×10−12) and that MDD-PRS was significantly more strongly associated with depression under stress than at baseline (MDD-PRS × stress interaction - beta=0.029, p=0.02). While known risk factors accounted for 85.6% of the association between MDD-PRS and depression at baseline, they only accounted for 55.4% of the association between MDD-PRS and depression under stress, suggesting that MDD-PRS can add unique predictive power to existing models of depression under stress. Further, we found that low MDD-PRS may have particular utility in identifying individuals with high resilience. Together, these findings suggest that polygenic risk score holds promise in furthering our ability to predict vulnerability and resilience under stress.

scholarly journals The association of alcohol polygenic risk scores with mental health outcomes: A multi-generational analysis in the Avon Longitudinal Study of Parents and Children

2020 ◽  
Author(s):  
Kayleigh E Easey ◽  
Robyn E Wootton ◽  
Hannah M Sallis ◽  
Elis Haan ◽  
Laura Schellhas ◽  
...  
Keyword(s):  
Mental Health ◽  
Longitudinal Study ◽  
Alcohol Consumption ◽  
Alcohol Use ◽  
Mental Health Problems ◽  
Intellectual Ability ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Parents And Children ◽  
Avon Longitudinal Study

AbstractBackgroundIncreased alcohol consumption often co-occurs with mental health problems; however, we do not currently fully understand whether this is due to confounding, shared biological mechanisms, or causal effects.DesignWe analysed a polygenic risk score (PRS) composed of single nucleotide polymorphisms (SNPs) reliably associated with patterns of adult alcohol consumption to test: 1) if this PRS is associated with consumption during pregnancy and adolescence, 2) if child alcohol PRS is associated with mental health phenotypes, and 3) if maternal alcohol PRS is associated with offspring alcohol phenotypes and mental health. We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Additional substance abuse behaviours and mental health/behavioural outcomes were also investigated at different life stages across both generations (alcohol phenotypes n =22; health phenotypes n = 91). The availability of data from early life on the same participants (pre-alcohol use around ages 7-10 years) provided a negative control, in contrast to that in ages of alcohol use (13-24 years).FindingsThe adult alcohol PRS was associated with consumption phenotypes during pregnancy (strongest signal for alcohol frequency at 18 weeks’ gestation: p=1.01×10-5) but offspring alcohol PRS did not predict offspring alcohol consumption at age 13-24 years. We found evidence for an association of maternal PRS with own perinatal depression (p=0.02) and decreased offspring intellectual ability (p=0.016).ConclusionsAn alcohol PRS derived from GWAS of alcohol use in the general population was shown to be associated with frequency and amount of alcohol consumed during pregnancy, and maternal depression at 32 weeks gestation. The associations between alcohol PRS with mother’s depression and offspring intellectual ability are consistent with previous studies, adding to the validity of using this alcohol PRS in future aetiological studies.

scholarly journals Validation of the AUDIT scale and factors associated with alcohol use disorder in adolescents: results of a national Lebanese study

2020 ◽  
Author(s):  
Jennyfer Hallit ◽  
Pascale Salameh ◽  
Chadia Haddad ◽  
Hala Sacre ◽  
Michel Soufia ◽  
...  
Keyword(s):  
Factor Analysis ◽  
Alcohol Use ◽  
Alcohol Dependence ◽  
Internet Addiction ◽  
Alcohol Use Disorder ◽  
Principal Component ◽  
Cross Sectional Study ◽  
Cross Sectional ◽  
Study Objective ◽  
Audit Score

Abstract Background This study objective was to evaluate the prevalence as well as factors (smoking, internet addiction, social phobia, depression, child abuse and bullying) associated with alcohol use disorder among a representative sample of Lebanese young people, in addition to validating and confirming psychometric properties of the AUDIT scale. Methods A cross-sectional study, conducted between January and May 2019, enrolled 1810 adolescents aged between 14 and 17. Alcohol dependence was defined as a high AUDIT score. A principal component analysis technique to confirm the validity of the construct of the AUDIT scale score was done and a confirmatory analysis to assess the structure of the instrument was conducted. Results The mean AUDIT score was 6.46 ± 8.44 and high risk of hazardous alcohol drinking was found in 28% of adolescents. One factor solution of the AUDIT scale had been found after running the factor analysis and the confirmatory factor analysis demonstrated that the χ2/df=2.4, the Steiger-Lind RMSEA was 0.10 [0.084-0.155] and the Joreskog GFI equaled 0.91 and AGFI equaled 0.92. Higher cigarette (Beta=0.372) and waterpipe (Beta=0.319) dependence, higher child sexual (Beta=0.581) and neglect (Beta=0.106) abuse, higher internet addiction (Beta=0.088), separated parents compared to living together (Beta=3.202) and higher bullying victimization (Beta=0.143) were significantly associated with higher AUDIT scores. Conclusion Alcohol dependence seems to be influenced by several risk factors among the Lebanese adolescents such as cigarette and waterpipe dependence, higher internet addiction, bullying, and child sexual and neglect abuse. Parents and healthcare professionals could use this data to influence intervention efforts.

scholarly journals Polygenic Associations and Causal Inferences between Serum Immunoglobulins and Amyotrophic Lateral Sclerosis

2020 ◽  
Author(s):  
Xu Chen ◽  
Xiaojun Shen ◽  
Yiqiang Zhan ◽  
Fang Fang
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Chronic Inflammation ◽  
Large Scale ◽  
Association Studies ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Causal Association ◽  
Polygenic Risk ◽  
Serum Immunoglobulins ◽  
Lateral Sclerosis

AbstractChronic inflammation might contribute to the development of amyotrophic lateral sclerosis (ALS). The relationship between serum immunoglobulins and risk of ALS remains however greatly unknown. In order to overcome limitations like reverse causation and residual confounding commonly seen in observational studies, we applied polygenic risk score (PRS) and Mendelian randomization (MR) analyses on summary statistics from the large-scale genome-wide association studies (GWAS), to examine the polygenic and causal associations between three serum immunoglobulins (IgA, IgM, and IgG) and risk of ALS (first in a discovery phase and then in a replication phase). An inverse polygenic association was discovered between IgA and ALS as well as between IgM and ALS. Such associations were however not replicated using a larger ALS GWAS and no causal association was observed for either IgA-ALS or IgM-ALS. A positive polygenic association was both discovered [odds ratio (OR) = 1.18; 95% confidence interval (CI): 1.12-1.25, P=5.9×10−7] and replicated (OR=1.13, 95% CI: 1.06-1.20, P=0.001) between IgG and ALS. A causal association between IgG and ALS was also suggested in both the discovery (OR=1.06, 95%CI: 1.02-1.10, P=0.009) and replication (OR=1.07, 95%CI: 0.90-1.24, P=0.420) analyses, although the latter was not statistically significant. This study suggests a shared polygenic risk between serum IgG (as a biomarker for chronic inflammation) and ALS.

scholarly journals Genome-wide Association Study of Alcohol Consumption and Use Disorder in Multiple Populations (N = 274,424)

2019 ◽  
Author(s):  
Henry R. Kranzler ◽  
Hang Zhou ◽  
Rachel L. Kember ◽  
Rachel Vickers Smith ◽  
Amy C. Justice ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Genome Wide Association ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Cell Type ◽  
Polygenic Risk ◽  
Consumption Level ◽  
Genome Wide

SummaryAlthough alcohol consumption level and alcohol use disorder (AUD) diagnosis are both moderately heritable, their genetic risks and overlap are not well understood. We conducted genome-wide association studies of these traits using longitudinal Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) scores (reflecting alcohol consumption) and AUD diagnoses from electronic health records (EHRs) in a single, large multi-ancestry Million Veteran Program sample. Meta-analysis across population groups (N = 274,424) identified 18 genome-wide significant loci, 5 of which were associated with both traits and 13 with either AUDIT-C (N = 8) or AUD (N = 5). A significant genetic correlation between the traits reflects this overlap. However, downstream analyses revealed biologically meaningful points of divergence. Cell-type group partitioning heritability enrichment analyses indicated that central nervous system was the most significant cell type for AUDIT-C and the only significant cell type for AUD. Polygenic risk scores (PRS) for both traits were associated with alcohol-related disorders in two independent samples. Genetic correlations for 188 non-alcohol-related traits were significantly different for the two traits, as were the phenotypes associated with the traits’ polygenic risk scores. We conclude that EHR-derived, longitudinal, repeated measures of alcohol consumption level and AUD diagnosis can facilitate genetic discovery and help to elucidate the relationship between drinking level and AUD risk. Finally, although heavy drinking is a key risk factor for AUD, it is not a sufficient cause of the disorder.

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