Genome-wide investigation of alcohol response : a meta-analytic review and polygenic associations with alcohol use disorder

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI-COLUMBIA AT REQUEST OF AUTHOR.] The current study aimed to extend previous genetic studies of level of response (LR) to alcohol by conducting the largest genome-wide association study (GWAS) of LR to date through the meta-analysis of multiple samples with extant SRE (Self-rating of the Effects of Alcohol) and GWAS data. A second aim was to use summary data from the described GWAS of LR to create polygenic risk scores (PRS) in an independent sample in order to determine whether, and to what extent, the genetic influences underlying LR to alcohol serve as a risk factor for alcohol use disorder (AUD). Towards these aims, datasets were processed according to standard quality control (QC) procedures allowing for genotype imputation and GWA analysis using methods appropriate for the individual study designs. Following individual study-level GWAS analysis, results were meta-analyzed utilizing an inverse-variance weighted fixed-effects model in METAL resulting in a final sample size of N=10,635. GWAS summary statistics from the SRE meta-analysis were then used to conduct gene-based and gene-set analyses, as well as compute polygenic risk scores (PRS) in an independent target sample to examine the predictive ability of the LR to alcohol PRS for DSM-IV AD symptom counts. No individual variants, genes, or gene-sets achieved study-level significance, although multiple genetic loci of interest achieved suggestive significance. The top single variant association was in an intergenic region on chromosome 2 located near the FUNDC2P2 gene (rs12463481; p=6.35x10[superscript -8]), the top gene-based association was with the PRR16 gene on chromosome 5 (p=6.72x10 [superscript -6]), and the top gene-set was with a set of genes associated with NFE2L2 targets (p=1.21 x10 [superscript -5]). No results from the PRS analysis approached significance. These findings suggest that, similar to other alcohol use outcomes, larger sample sizes will be required for the robust detection of genetic influences contributing to level of response to alcohol.

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

10.1101/527929 ◽

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 ◽

Cell Type ◽

Polygenic Risk ◽

Consumption Level ◽

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.

Effect of polygenic risk scores on depression in childhood trauma

The British Journal of Psychiatry ◽

10.1192/bjp.bp.113.143081 ◽

2014 ◽

Vol 205 (2) ◽

pp. 113-119 ◽

Cited By ~ 105

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.

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

10.1101/2021.09.17.21263732 ◽

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 ◽

East Asians ◽

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.

Association between substance use disorder and polygenic liability to schizophrenia

10.1101/129288 ◽

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.

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

10.1101/416008 ◽

2018 ◽

Cited By ~ 2

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 ◽

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.

Age varying polygenic effects on alcohol use in African Americans and European Americans from adolescence to adulthood

Scientific Reports ◽

10.1038/s41598-021-01923-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kit K. Elam ◽

Thao Ha ◽

Zoe Neale ◽

Fazil Aliev ◽

Danielle Dick ◽

...

Keyword(s):

Alcohol Use ◽

Association Studies ◽

Genetic Effects ◽

Risk Scores ◽

Longitudinal Models ◽

Polygenic Risk ◽

Genome Wide ◽

Polygenic Scores ◽

Distal Outcome

AbstractGenetic effects on alcohol use can vary over time but are often examined using longitudinal models that predict a distal outcome at a single time point. The vast majority of these studies predominately examine effects using White, European American (EA) samples or examine the etiology of genetic variants identified from EA samples in other racial/ethnic populations, leading to inconclusive findings about genetic effects on alcohol use. The current study examined how genetic influences on alcohol use varied by age across a 15 year period within a diverse ethnic/racial sample of adolescents. Using a multi-ethnic approach, polygenic risk scores were created for African American (AA, n = 192) and EA samples (n = 271) based on racially/ethnically aligned genome wide association studies. Age-varying associations between polygenic scores and alcohol use were examined from age 16 to 30 using time-varying effect models separately for AA and EA samples. Polygenic risk for alcohol use was found to be associated with alcohol use from age 22–27 in the AA sample and from age 24.50 to 29 in the EA sample. Results are discussed relative to the intersection of alcohol use and developmental genetic effects in diverse populations.

S173. GENOME-WIDE ASSOCIATION STUDIES OF SCHIZOPHRENIA AND BIPOLAR DISORDER IN A DIVERSE COHORT OF US VETERANS

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa031.239 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S103-S103

Author(s):

Tim Bigdeli ◽

Ayman Fanous ◽

Nallakkandi Rajeevan ◽

Frederick Sayward ◽

Yuli Li ◽

...

Keyword(s):

Bipolar Disorder ◽

Association Studies ◽

Meta Analysis ◽

Genome Wide Association ◽

Risk Scores ◽

Summary Statistics ◽

Polygenic Risk ◽

Genome Wide ◽

Us Veterans

Abstract Background Schizophrenia and bipolar disorder are debilitating neuropsychiatric illnesses collectively affecting 2% of the world’s population, and which cause tremendous human suffering that impacts patients, their families and their communities. Recognizing the major impact of these disorders on the psychosocial function of more than 200,000 US Veterans, the Department of Veterans Affairs (VA) recently genotyping of nearly 9,000 veterans with schizophrenia or bipolar I disorder in Cooperative Studies Program (CSP) #572: “Genetics of Functional Disability in Schizophrenia and Bipolar Illness”, all of whom were extensively assessed for neurocognitive function and disability, and genotyped using a custom Affymetrix Axiom Biobank array. Methods Primary genome-wide association studies (GWAS) of schizophrenia and bipolar disorder were performed across and within ancestry goups, with attempted replication in matched subjects from the PGC and Genomic Psychiatry Cohort (GPC). We combined results for CSP#572 with available summary statistics from the PGC, Indonesia Schizophrenia Consortium and Genetic REsearch on schizophreniA neTwork-China and Netherland (GREAT-CN) study, and multi-ethnic GPC cohorts, achieving among the largest and most diverse studies of these disorders to date. Results Polygenic risk scores based on published PGC summary statistics for schizophrenia or bipolar disorder were significantly associated with case status among EA (P<10–30) and AA (P<0.0005) participants in CSP#572. Our primary analyses of schizophrenia yielded a single genome-wide significant association with variants in CHD7 at 8q12.2 for European-American (EA) participants, which remained significant in a joint analysis of EA and African-American (AA) subjects (P=4.62e-08). While no genome-wide significant associations were detected by our within-ancestry analyses of bipolar disorder, a cross-ancestry meta-analysis of CSP#572 participants yielded a significant finding at 10q25 with variants in SORCS3 (P=2.62e-08). Among loci attaining P<0.0001 in our within-ancestry analyses, 4 and 8 subsequently achieved genome-wide significance, respectively, when jointly analyzed with matched subjects from the PGC and GPC. Combining our results with published summary statistics, we performed a cross-ancestry GWAS meta-analysis of 69,280 schizophrenia cases and 138,379 controls, identifying 200 genome-wide significant loci of which 76 are newly reported here. Cross-ancestry analysis of 28,326 bipolar cases and 90,570 controls identified 24 genome-wide significant loci, including novel associations with common variants in PAX5, DOCK2, MACROD2, BRE, KCNG1, and LINC01378. Discussion We newly describe genome-wide analyses in a diverse cohort of US Veterans with schizophrenia or bipolar disorder, benchmarking the predictive value of polygenic risk scores based on published GWAS findings. Leveraging available summary statistics from studies of global populations, we add to burgeoning lists of genomic loci implicated in the etiologies of these disorders.

High polygenic risk scores are associated with age of onset of alcohol use disorder in adolescents and young adults at risk

Biological Psychiatry Global Open Science ◽

10.1016/j.bpsgos.2021.10.007 ◽

2021 ◽

Author(s):

John I. Nurnberger ◽

Yumin Wang ◽

Yong Zang ◽

Dongbing Lai ◽

Leah Wetherill ◽

...

Keyword(s):

At Risk ◽

Young Adults ◽

Alcohol Use ◽

Alcohol Use Disorder ◽

Age Of Onset ◽

Adolescents And Young Adults ◽

Risk Scores ◽

Polygenic Risk

A meta-analysis of polygenic risk scores for mood disorders, neuroticism, and schizophrenia in antidepressant response

10.1101/2021.05.28.21257812 ◽

2021 ◽

Author(s):

Giuseppe Fanelli ◽

Katharina Domschke ◽

Alessandra Minelli ◽

Massimo Gennarelli ◽

Paolo Martini ◽

...

Keyword(s):

Antidepressant Treatment ◽

Association Studies ◽

Meta Analysis ◽

Predictive Performance ◽

Risk Scores ◽

Clinical Samples ◽

Bonferroni Correction ◽

Polygenic Risk ◽

About two-thirds of patients with major depressive disorder (MDD) fail to achieve symptom remission after the initial antidepressant treatment. Despite a role of genetic factors was proven, the specific underpinnings are not fully understood yet. Polygenic risk scores (PRSs), which summarise the additive effect of multiple risk variants across the genome, might provide insights into the underlying genetics. This study aims to investigate the possible association of PRSs for bipolar disorder, MDD, neuroticism, and schizophrenia (SCZ) with antidepressant non-response or non-remission in patients with MDD. PRSs were calculated at eight genome-wide P-thresholds based on publicly available summary statistics of the largest genome-wide association studies. Logistic regressions were performed between PRSs and non-response or non-remission in six European clinical samples, adjusting for age, sex, baseline symptom severity, recruitment sites, and population stratification. Results were meta-analysed across samples, including up to 3,637 individuals. Bonferroni correction was applied. In the meta-analysis, no result was significant after Bonferroni correction. The top result was found for MDD-PRS and non-remission (p=0.004), with patients in the highest vs. lowest PRS quintile being more likely not to achieve remission (OR=1.5, 95% CI=1.11-1.98, p=0.007). Nominal associations were also found between MDD-PRS and non-response (p=0.013), as well as between SCZ-PRS and non-remission (p=0.035). Although PRSs are still not able to predict non-response or non-remission, our results are in line with previous works; methodological improvements in PRSs calculation may improve their predictive performance and have a meaningful role in precision psychiatry.

Serotonin functioning and adolescents' alcohol use: A genetically informed study examining mechanisms of risk

Development and Psychopathology ◽

10.1017/s095457941700058x ◽

2017 ◽

Vol 30 (1) ◽

pp. 213-233 ◽

Cited By ~ 2

Author(s):

Frances L. Wang ◽

Laurie Chassin ◽

John E. Bates ◽

Danielle Dick ◽

Jennifer E. Lansford ◽

...

Keyword(s):

Depressive Symptoms ◽

Alcohol Use ◽

Parental Education ◽

Genome Wide Association Study ◽

Self Regulation ◽

Risk Scores ◽

Polygenic Risk ◽

Genome Wide ◽

Two Samples ◽

Hydroxyindoleacetic Acid

AbstractThe current study used data from two longitudinal samples to test whether self-regulation, depressive symptoms, and aggression/antisociality were mediators in the relation between a polygenic score indexing serotonin (5-HT) functioning and alcohol use in adolescence. The results from an independent genome-wide association study of 5-hydroxyindoleacetic acid in the cerebrospinal fluid were used to create 5-HT polygenic risk scores. Adolescents and/or parents reported on adolescents’ self-regulation (Time 1), depressive symptoms (Time 2), aggression/antisociality (Time 2), and alcohol use (Time 3). The results showed that 5-HT polygenic risk did not predict self-regulation. However, adolescents with higher levels of 5-HT polygenic risk showed greater depression and aggression/antisociality. Adolescents’ aggression/antisociality mediated the relation between 5-HT polygenic risk and later alcohol use. Deficits in self-regulation also predicted depression and aggression/antisociality, and indirectly predicted alcohol use through aggression/antisociality. Pathways to alcohol use were especially salient for males from families with low parental education in one of the two samples. The results provide insights into the longitudinal mechanisms underlying the relation between 5-HT functioning and alcohol use (i.e., earlier aggression/antisociality). There was no evidence that genetically based variation in 5-HT functioning predisposed individuals to deficits in self-regulation. Genetically based variation in 5-HT functioning and self-regulation might be separate, transdiagnostic risk factors for several types of psychopathology.