EXPLORING THE ROLE OF GENETIC REGULATION OF GENE EXPRESSION IN SUBSTANCE USE AND DEPENDENCE

Eske Derks, Andries Marees, Eric Gamazon, Florence VORSPAN, Wim van den Brink, Karin Verweij, Henry Kranzler, Richard Sherva, Lindsay Farrer, Joel Gelernter

Research output: Contribution to JournalArticleAcademic

Abstract

Background Recent large-scale Genome-Wide Association Studies (GWAS) have identified genetic loci associated with various substance use traits. However, little is known about the functional mechanisms through which these genetic loci ascertain their effect. This study aims to identify and functionally annotate genetic loci associated with substance use traits based on their role in genetic regulation of gene expression. Methods We evaluated expression quantitative trait loci (eQTLs) in human post mortem tissue from 10 brain regions and whole blood of the Genotype-Tissue Expression (GTEx) database. The role of eQTLs was examined for eight substance use traits, using summary statistics from GWAS of: alcohol consumption (N=70,460), cigarettes per day (CPD; N=38,181), former vs. current smoker (N=41,278), age of smoking initiation (N=24,114), ever smoker (N= 74,035), cocaine dependence (N=4,769), cannabis dependence (N=12,168), and lifetime cannabis use (N=32,330). Results eQTLs with significant trait association (FDR <0.05) were found for alcohol consumption, CPD, former vs. current smoker, cocaine dependence, and cannabis dependence in various tissues. The eGenes targeted by these significant eQTLs often differed from their nearest genes, indicating that proximity alone is a limited measure to determine the causal gene. Using this methodology, we elucidated eQTLs and eGenes which were not picked up by the original GWAS, and were able to determine through which tissue these loci exert their effects. Discussion Annotating genes based on transcriptomic regulation in brain and non-brain tissues improves the identification of novel loci and the functional characterization of genetic risk loci for substance use traits.
Original languageEnglish
Article number41
Pages (from-to)S803-S804
Number of pages2
JournalEuropean Neuropsychopharmacology
Volume29
Issue numberSupplement 3
Early online date25 Mar 2019
DOIs
Publication statusPublished - 2019

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Gene Expression Regulation
Genetic Loci
Quantitative Trait Loci
Substance-Related Disorders
Genome-Wide Association Study
Marijuana Abuse
Cocaine-Related Disorders
Alcohol Drinking
Genes
Brain
Cannabis
Tobacco Products
Smoking
Genotype
Databases

Bibliographical note

Special issue: Abstracts of the XXVth World Congress of Psychiatric Genetics (WCPG), 13 - 17 October 2017, Orlando, Florida

Cite this

Derks, E., Marees, A., Gamazon, E., VORSPAN, F., van den Brink, W., Verweij, K., ... Gelernter, J. (2019). EXPLORING THE ROLE OF GENETIC REGULATION OF GENE EXPRESSION IN SUBSTANCE USE AND DEPENDENCE. European Neuropsychopharmacology, 29(Supplement 3), S803-S804. [41]. https://doi.org/10.1016/j.euroneuro.2017.08.042
Derks, Eske ; Marees, Andries ; Gamazon, Eric ; VORSPAN, Florence ; van den Brink, Wim ; Verweij, Karin ; Kranzler, Henry ; Sherva, Richard ; Farrer, Lindsay ; Gelernter, Joel. / EXPLORING THE ROLE OF GENETIC REGULATION OF GENE EXPRESSION IN SUBSTANCE USE AND DEPENDENCE. In: European Neuropsychopharmacology. 2019 ; Vol. 29, No. Supplement 3. pp. S803-S804.
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abstract = "Background Recent large-scale Genome-Wide Association Studies (GWAS) have identified genetic loci associated with various substance use traits. However, little is known about the functional mechanisms through which these genetic loci ascertain their effect. This study aims to identify and functionally annotate genetic loci associated with substance use traits based on their role in genetic regulation of gene expression. Methods We evaluated expression quantitative trait loci (eQTLs) in human post mortem tissue from 10 brain regions and whole blood of the Genotype-Tissue Expression (GTEx) database. The role of eQTLs was examined for eight substance use traits, using summary statistics from GWAS of: alcohol consumption (N=70,460), cigarettes per day (CPD; N=38,181), former vs. current smoker (N=41,278), age of smoking initiation (N=24,114), ever smoker (N= 74,035), cocaine dependence (N=4,769), cannabis dependence (N=12,168), and lifetime cannabis use (N=32,330). Results eQTLs with significant trait association (FDR <0.05) were found for alcohol consumption, CPD, former vs. current smoker, cocaine dependence, and cannabis dependence in various tissues. The eGenes targeted by these significant eQTLs often differed from their nearest genes, indicating that proximity alone is a limited measure to determine the causal gene. Using this methodology, we elucidated eQTLs and eGenes which were not picked up by the original GWAS, and were able to determine through which tissue these loci exert their effects. Discussion Annotating genes based on transcriptomic regulation in brain and non-brain tissues improves the identification of novel loci and the functional characterization of genetic risk loci for substance use traits.",
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Derks, E, Marees, A, Gamazon, E, VORSPAN, F, van den Brink, W, Verweij, K, Kranzler, H, Sherva, R, Farrer, L & Gelernter, J 2019, 'EXPLORING THE ROLE OF GENETIC REGULATION OF GENE EXPRESSION IN SUBSTANCE USE AND DEPENDENCE' European Neuropsychopharmacology, vol. 29, no. Supplement 3, 41, pp. S803-S804. https://doi.org/10.1016/j.euroneuro.2017.08.042

EXPLORING THE ROLE OF GENETIC REGULATION OF GENE EXPRESSION IN SUBSTANCE USE AND DEPENDENCE. / Derks, Eske; Marees, Andries; Gamazon, Eric; VORSPAN, Florence; van den Brink, Wim; Verweij, Karin; Kranzler, Henry; Sherva, Richard; Farrer, Lindsay; Gelernter, Joel.

In: European Neuropsychopharmacology, Vol. 29, No. Supplement 3, 41, 2019, p. S803-S804.

Research output: Contribution to JournalArticleAcademic

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T1 - EXPLORING THE ROLE OF GENETIC REGULATION OF GENE EXPRESSION IN SUBSTANCE USE AND DEPENDENCE

AU - Derks, Eske

AU - Marees, Andries

AU - Gamazon, Eric

AU - VORSPAN, Florence

AU - van den Brink, Wim

AU - Verweij, Karin

AU - Kranzler, Henry

AU - Sherva, Richard

AU - Farrer, Lindsay

AU - Gelernter, Joel

N1 - Special issue: Abstracts of the XXVth World Congress of Psychiatric Genetics (WCPG), 13 - 17 October 2017, Orlando, Florida

PY - 2019

Y1 - 2019

N2 - Background Recent large-scale Genome-Wide Association Studies (GWAS) have identified genetic loci associated with various substance use traits. However, little is known about the functional mechanisms through which these genetic loci ascertain their effect. This study aims to identify and functionally annotate genetic loci associated with substance use traits based on their role in genetic regulation of gene expression. Methods We evaluated expression quantitative trait loci (eQTLs) in human post mortem tissue from 10 brain regions and whole blood of the Genotype-Tissue Expression (GTEx) database. The role of eQTLs was examined for eight substance use traits, using summary statistics from GWAS of: alcohol consumption (N=70,460), cigarettes per day (CPD; N=38,181), former vs. current smoker (N=41,278), age of smoking initiation (N=24,114), ever smoker (N= 74,035), cocaine dependence (N=4,769), cannabis dependence (N=12,168), and lifetime cannabis use (N=32,330). Results eQTLs with significant trait association (FDR <0.05) were found for alcohol consumption, CPD, former vs. current smoker, cocaine dependence, and cannabis dependence in various tissues. The eGenes targeted by these significant eQTLs often differed from their nearest genes, indicating that proximity alone is a limited measure to determine the causal gene. Using this methodology, we elucidated eQTLs and eGenes which were not picked up by the original GWAS, and were able to determine through which tissue these loci exert their effects. Discussion Annotating genes based on transcriptomic regulation in brain and non-brain tissues improves the identification of novel loci and the functional characterization of genetic risk loci for substance use traits.

AB - Background Recent large-scale Genome-Wide Association Studies (GWAS) have identified genetic loci associated with various substance use traits. However, little is known about the functional mechanisms through which these genetic loci ascertain their effect. This study aims to identify and functionally annotate genetic loci associated with substance use traits based on their role in genetic regulation of gene expression. Methods We evaluated expression quantitative trait loci (eQTLs) in human post mortem tissue from 10 brain regions and whole blood of the Genotype-Tissue Expression (GTEx) database. The role of eQTLs was examined for eight substance use traits, using summary statistics from GWAS of: alcohol consumption (N=70,460), cigarettes per day (CPD; N=38,181), former vs. current smoker (N=41,278), age of smoking initiation (N=24,114), ever smoker (N= 74,035), cocaine dependence (N=4,769), cannabis dependence (N=12,168), and lifetime cannabis use (N=32,330). Results eQTLs with significant trait association (FDR <0.05) were found for alcohol consumption, CPD, former vs. current smoker, cocaine dependence, and cannabis dependence in various tissues. The eGenes targeted by these significant eQTLs often differed from their nearest genes, indicating that proximity alone is a limited measure to determine the causal gene. Using this methodology, we elucidated eQTLs and eGenes which were not picked up by the original GWAS, and were able to determine through which tissue these loci exert their effects. Discussion Annotating genes based on transcriptomic regulation in brain and non-brain tissues improves the identification of novel loci and the functional characterization of genetic risk loci for substance use traits.

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Derks E, Marees A, Gamazon E, VORSPAN F, van den Brink W, Verweij K et al. EXPLORING THE ROLE OF GENETIC REGULATION OF GENE EXPRESSION IN SUBSTANCE USE AND DEPENDENCE. European Neuropsychopharmacology. 2019;29(Supplement 3):S803-S804. 41. https://doi.org/10.1016/j.euroneuro.2017.08.042