scholarly journals Evidence of shared genetic influences underlying schizophrenia and alcohol use disorder, but not alcohol consumption

2020 ◽  
Author(s):  
Emma C. Johnson ◽  
Manav Kapoor ◽  
Alexander S. Hatoum ◽  
Hang Zhou ◽  
Renato Polimanti ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Alcohol Use ◽  
Genetic Variants ◽  
Alcohol Use Disorder ◽  
Association Studies ◽  
Genetic Correlations ◽  
Genome Wide Association Studies ◽  
Genetic Covariance ◽  
Genome Wide ◽  
Brain Tissues

AbstractBackgroundAlcohol use disorder (AUD) and schizophrenia (SCZ) frequently co-occur, and recent genome-wide association studies (GWAS) have identified significant genetic correlations between them. In parallel, mounting evidence from GWAS suggests that alcohol consumption is only weakly genetically correlated with SCZ, but this has not yet been systematically investigated.MethodsWe used the largest published GWAS for AUD (total cases = 77,822) and SCZ (total cases = 46,827) to systematically identify genetic variants that influence both disorders (in either the same or opposite direction of effect) as well as disorder-specific loci, and contrast our findings with GWAS data for drinks per week (DPW; N = 537,349) as a measure of alcohol consumption.ResultsWe identified 55 independent genome-wide significant SNPs with the same direction of effect on AUD and SCZ, 9 with robust opposite effects, and 99 with disorder-specific effects. We also found evidence for 12 genes whose pleiotropic associations with AUD and SCZ are consistent with mediation via gene expression in the prefrontal cortex. The genetic covariance between AUD and SCZ was concentrated in genomic regions functional in brain tissues (p = 0.001). The genetic correlation between DPW and SCZ (rg = 0.102, SE = 0.022) was significantly lower than that for AUD and SCZ (rg = 0.392, SE = 0.029; p-value of the difference = 9.3e-18), and the genetic covariance between DPW and SCZ was not enriched for any meaningful tissue-specific categories.ConclusionsOur findings provide a detailed view of genetic loci that influence risk of both AUD and SCZ, suggest that biological commonalities underlying genetic variants with an effect on both disorders are manifested in brain tissues, and provide further evidence that SCZ shares meaningful genetic overlap with AUD and not merely alcohol consumption.

scholarly journals Investigation of convergent and divergent genetic influences underlying schizophrenia and alcohol use disorder

2021 ◽  
pp. 1-9
Author(s):  
Emma C. Johnson ◽  
Manav Kapoor ◽  
Alexander S. Hatoum ◽  
Hang Zhou ◽  
Renato Polimanti ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Large Scale ◽  
Association Studies ◽  
Genetic Correlations ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genetic Covariance ◽  
Specific Effects ◽  
Genome Wide

Abstract Background Alcohol use disorder (AUD) and schizophrenia (SCZ) frequently co-occur, and large-scale genome-wide association studies (GWAS) have identified significant genetic correlations between these disorders. Methods We used the largest published GWAS for AUD (total cases = 77 822) and SCZ (total cases = 46 827) to identify genetic variants that influence both disorders (with either the same or opposite direction of effect) and those that are disorder specific. Results We identified 55 independent genome-wide significant single nucleotide polymorphisms with the same direction of effect on AUD and SCZ, 8 with robust effects in opposite directions, and 98 with disorder-specific effects. We also found evidence for 12 genes whose pleiotropic associations with AUD and SCZ are consistent with mediation via gene expression in the prefrontal cortex. The genetic covariance between AUD and SCZ was concentrated in genomic regions functional in brain tissues (p = 0.001). Conclusions Our findings provide further evidence that SCZ shares meaningful genetic overlap with AUD.

scholarly journals Multivariate GWAS elucidates the genetic architecture of alcohol consumption and misuse, corrects biases, and reveals novel associations with disease

2020 ◽  
Author(s):  
Travis T Mallard ◽  
Jeanne E Savage ◽  
Emma C Johnson ◽  
Yuye Huang ◽  
Alexis C Edwards ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Alcohol Use ◽  
Psychiatric Disorders ◽  
Alcohol Use Disorder ◽  
Association Studies ◽  
Genetic Correlations ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Socioeconomic Outcomes ◽  
Alcohol Involvement

ABSTRACTGenome-wide association studies (GWASs) of the Alcohol Use Disorder Identification Test (AUDIT), a ten-item screener for alcohol use disorder (AUD), have elucidated novel loci for alcohol consumption and misuse. However, these studies also revealed that GWASs can be influenced by numerous biases (e.g., measurement error, selection bias), which have led to inconsistent genetic correlations between alcohol involvement and AUD, as well as paradoxically negative genetic correlations between alcohol involvement and psychiatric disorders/medical conditions. To explore these unexpected differences in genetic correlations, we conducted the first item-level and largest GWAS of AUDIT items (N=160,824), and applied a multivariate framework to mitigate previous biases. In doing so, we identified novel patterns of similarity (and dissimilarity) among the AUDIT items, and found evidence of a correlated two-factor structure at the genetic level (Consumption and Problems, rg=.80). Moreover, by applying empirically-derived weights to each of the AUDIT items, we constructed an aggregate measure of alcohol consumption that is strongly associated with alcohol dependence (rg=.67) and several other psychiatric disorders, and no longer positively associated with health and positive socioeconomic outcomes. Lastly, by performing polygenic analyses in three independent cohorts that differed in their ascertainment and prevalence of AUD, we identified novel genetic associations between alcohol consumption, alcohol misuse, and human health. Our work further emphasizes the value of AUDIT for both clinical and genetic studies of AUD, and the importance of using multivariate methods to study genetic associations that are more closely related to AUD.

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.

Genetic correlations between subcortical brain volumes and psychiatric disorders

2020 ◽  
Vol 216 (5) ◽  
pp. 280-283
Author(s):  
Kazutaka Ohi ◽  
Takamitsu Shimada ◽  
Yuzuru Kataoka ◽  
Toshiki Yasuyama ◽  
Yasuhiro Kawasaki ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Genetic Variants ◽  
Large Scale ◽  
Association Studies ◽  
Genetic Correlations ◽  
Intracranial Volume ◽  
Genome Wide Association Studies ◽  
Brain Volumes ◽  
Subcortical Brain ◽  
Genome Wide

SummaryPsychiatric disorders as well as subcortical brain volumes are highly heritable. Large-scale genome-wide association studies (GWASs) for these traits have been performed. We investigated the genetic correlations between five psychiatric disorders and the seven subcortical brain volumes and the intracranial volume from large-scale GWASs by linkage disequilibrium score regression. We revealed weak overlaps between the genetic variants associated with psychiatric disorders and subcortical brain and intracranial volumes, such as in schizophrenia and the hippocampus and bipolar disorder and the accumbens. We confirmed shared aetiology and polygenic architecture across the psychiatric disorders and the specific subcortical brain and intracranial volume.

scholarly journals Genome-wide analyses of behavioural traits are subject to bias by misreports and longitudinal changes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Angli Xue ◽  
Longda Jiang ◽  
Zhihong Zhu ◽  
Naomi R. Wray ◽  
Peter M. Visscher ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Association Studies ◽  
Genetic Correlations ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Longitudinal Changes ◽  
Genome Wide ◽  
The Uk ◽  
Almost All ◽  
Cardiovascular Traits

AbstractGenome-wide association studies (GWAS) have discovered numerous genetic variants associated with human behavioural traits. However, behavioural traits are subject to misreports and longitudinal changes (MLC) which can cause biases in GWAS and follow-up analyses. Here, we demonstrate that individuals with higher disease burden in the UK Biobank (n = 455,607) are more likely to misreport or reduce their alcohol consumption levels, and propose a correction procedure to mitigate the MLC-induced biases. The alcohol consumption GWAS signals removed by the MLC corrections are enriched in metabolic/cardiovascular traits. Almost all the previously reported negative estimates of genetic correlations between alcohol consumption and common diseases become positive/non-significant after the MLC corrections. We also observe MLC biases for smoking and physical activities in the UK Biobank. Our findings provide a plausible explanation of the controversy about the effects of alcohol consumption on health outcomes and a caution for future analyses of self-reported behavioural traits in biobank data.

scholarly journals Genetic analysis identifies molecular systems and biological pathways associated with household income

2019 ◽  
Author(s):  
W. David Hill ◽  
Neil M. Davies ◽  
Stuart J. Ritchie ◽  
Nathan G. Skene ◽  
Julien Bryois ◽  
...  
Keyword(s):  
Cognitive Ability ◽  
Genetic Variants ◽  
Household Income ◽  
Association Studies ◽  
Genetic Correlations ◽  
Functional Enrichment ◽  
Genome Wide Association Studies ◽  
Income Differences ◽  
Genome Wide ◽  
Common Genetic Variants

AbstractSocio-economic position (SEP) is a multi-dimensional construct reflecting (and influencing) multiple socio-cultural, physical, and environmental factors. Previous genome-wide association studies (GWAS) using household income as a marker of SEP have shown that common genetic variants account for 11% of its variation. Here, in a sample of 286,301 participants from UK Biobank, we identified 30 independent genome-wide significant loci, 29 novel, that are associated with household income. Using a recently-developed method to meta-analyze data that leverages power from genetically-correlated traits, we identified an additional 120 income-associated loci. These loci showed clear evidence of functional enrichment, with transcriptional differences identified across multiple cortical tissues, in addition to links with GABAergic and serotonergic neurotransmission. We identified neurogenesis and the components of the synapse as candidate biological systems that are linked with income. By combining our GWAS on income with data from eQTL studies and chromatin interactions, 24 genes were prioritized for follow up, 18 of which were previously associated with cognitive ability. Using Mendelian Randomization, we identified cognitive ability as one of the causal, partly-heritable phenotypes that bridges the gap between molecular genetic inheritance and phenotypic consequence in terms of income differences. Significant differences between genetic correlations indicated that, the genetic variants associated with income are related to better mental health than those linked to educational attainment (another commonly-used marker of SEP). Finally, we were able to predict 2.5% of income differences using genetic data alone in an independent sample. These results are important for understanding the observed socioeconomic inequalities in Great Britain today.

scholarly journals Modifiable lifestyle factors and severe COVID-19 risk: a Mendelian randomisation study

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Shuai Li ◽  
Xinyang Hua
Keyword(s):  
Physical Activity ◽  
Alcohol Consumption ◽  
Genetic Variants ◽  
Association Studies ◽  
Lifestyle Factors ◽  
Mendelian Randomisation ◽  
Severe Illness ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Increased Risk

Abstract Background Lifestyle factors including obesity and smoking are suggested to be correlated with increased risk of COVID-19 severe illness or related death. However, whether these relationships are causal is not well known; neither for the relationships between COVID-19 severe illness and other common lifestyle factors, such as physical activity and alcohol consumption. Methods Genome-wide significant genetic variants associated with body mass index (BMI), lifetime smoking, physical activity and alcohol consumption identified by large-scale genome-wide association studies (GWAS) of up to 941,280 individuals were selected as instrumental variables. Summary statistics of the genetic variants on severe illness of COVID-19 were obtained from GWAS analyses of up to 6492 cases and 1,012,809 controls. Two-sample Mendelian randomisation analyses were conducted. Results Both per-standard deviation (SD) increase in genetically predicted BMI and lifetime smoking were associated with about two-fold increased risks of severe respiratory COVID-19 and COVID-19 hospitalization (all P < 0.05). Per-SD increase in genetically predicted physical activity was associated with decreased risks of severe respiratory COVID-19 (odds ratio [OR] = 0.19; 95% confidence interval [CI], 0.05, 0.74; P = 0.02), but not with COVID-19 hospitalization (OR = 0.44; 95% CI 0.18, 1.07; P = 0.07). No evidence of association was found for genetically predicted alcohol consumption. Similar results were found across robust Mendelian randomisation methods. Conclusions Evidence is found that BMI and smoking causally increase and physical activity might causally decrease the risk of COVID-19 severe illness. This study highlights the importance of maintaining a healthy lifestyle in protecting from COVID-19 severe illness and its public health value in fighting against COVID-19 pandemic.

scholarly journals Modifiable lifestyle factors and severe COVID-19 risk: Evidence from Mendelian randomization analysis

2020 ◽  
Author(s):  
Shuai Li
Keyword(s):  
Physical Activity ◽  
Alcohol Consumption ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Lifestyle Factors ◽  
Severe Illness ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Increased Risk

AbstractBackgroundLifestyle factors including obesity and smoking are suggested to be related to increased risk of COVID-19 severe illness or related death. However, little is known about whether these relationships are causal, or the relationships between COVID-19 severe illness and other lifestyle factors, such as alcohol consumption and physical activity.MethodsGenome-wide significant genetic variants associated with body mass index (BMI), lifetime smoking, alcohol consumption and physical activity identified by large-scale genome-wide association studies (GWAS) were selected as instrumental variables. GWAS summary statistics of these genetic variants for relevant lifestyle factors and severe illness of COVID-19 were obtained. Two-sample Mendelian randomization (MR) analyses were conducted.ResultsBoth genetically predicted BMI and lifetime smoking were associated with about 2-fold increased risks of severe respiratory COVID-19 and COVID-19 hospitalization (all P<0.05). Genetically predicted physical activity was associated with about 5-fold (95% confidence interval [CI], 1.4, 20.3; P=0.02) decreased risk of severe respiratory COVID-19, but not with COVID-19 hospitalization, though the majority of the 95% CI did not include one. No evidence of association was found for genetically predicted alcohol consumption, but associations were found when using pleiotropy robust methods.ConclusionEvidence is found that BMI and smoking causally increase and physical activity causally decreases the risk of COVID-19 severe illness. This study highlights the importance of maintaining a healthy lifestyle in protecting from COVID-19 severe illness and its public health value in fighting against COVID-19 pandemic.

scholarly journals Genetic underpinnings of the transition from alcohol consumption to alcohol use disorder: shared and unique genetic architectures in a cross-ancestry sample

2021 ◽  
Author(s):  
Rachel L Kember ◽  
Rachel A. Vickers-Smith ◽  
Hang Zhou ◽  
Heng Xu ◽  
Cecilia Dao ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Alcohol Use ◽  
Genetic Variants ◽  
Alcohol Use Disorder ◽  
Genetic Factors ◽  
Genetic Correlations ◽  
Heavy Drinking ◽  
Direct Effects ◽  
Heavy Alcohol Consumption ◽  
Program Sample

Recent GWAS of alcohol-related traits have uncovered key differences in the underlying genetic architectures of alcohol consumption and alcohol use disorder (AUD), with the two traits having opposite genetic correlations with psychiatric disorders. Understanding the genetic factors that underlie the transition from heavy drinking to AUD has important theoretical and clinical implications. We utilized longitudinal data from the cross-ancestry Million Veteran Program sample to identify 1) novel loci associated with AUD and alcohol consumption [measured by the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C)] and 2) genetic variants with direct effects on AUD not mediated through alcohol consumption. We identified 26 loci associated with AUD, including 5 ancestry-specific and 6 novel loci and 22 loci associated with AUDIT-C, including 3 ancestry-specific and 8 novel loci. In secondary GWAS that excluded individuals who report abstinence, we identify 7 additional loci for AUD and 8 additional loci for AUDIT-C. We demonstrate that, although the heterogeneity of the abstinent group biases the GWAS findings, unique variance between alcohol consumption and disorder remains after the group is excluded. Finally, using mediation analysis, we identified a set of variants with effects on AUD that are not mediated through alcohol consumption. The distinct genetic architectures of alcohol consumption and AUD suggest different biological contributions to the traits. Genetic variants with direct effects on AUD are potentially relevant to understanding the transition from heavy alcohol consumption to AUD and targets for translational prevention and treatment efforts.

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