Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans

Leah Wetherill, Dongbing Lai, Emma C. Johnson, Andrey Anokhin, Lance Bauer, Kathleen K. Bucholz, Danielle M. Dick, Ahmad R. Hariri, Victor Hesselbrock, Chella Kamarajan, John Kramer, Samuel Kuperman, Jacquelyn L. Meyers, John Nurnberger, Marc Schuckit, Denise M. Scott, Robert E. Taylor, Jay Tischfield, Bernice Porjesz, Alison M. GoateHoward Edenberg, Tatiana Foroud, Ryan Bogdan, Arpana Agrawal

Research output: Contribution to journalArticle

Abstract

Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk.

Original languageEnglish (US)
Article numbere12580
JournalGenes, Brain and Behavior
DOIs
StatePublished - Jan 1 2019

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Genome-Wide Association Study
Reward
African Americans
Alcoholism
Substance-Related Disorders
Alcohols
Chromosomes, Human, Pair 13
Chromosomes, Human, Pair 5
Chromosomes, Human, Pair 3
Chromosomes, Human, Pair 1
Genetic Association Studies
Street Drugs
Hemostasis
Genetic Markers
Individuality
Genes
Single Nucleotide Polymorphism
Meta-Analysis
Signal Transduction
Genotype

Keywords

  • African-American
  • alcohol dependence
  • drug dependence
  • European-American
  • fMRI
  • genetics
  • GWAS
  • heritability
  • neural reward
  • ventral striatum

ASJC Scopus subject areas

  • Genetics
  • Neurology
  • Behavioral Neuroscience

Cite this

Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans. / Wetherill, Leah; Lai, Dongbing; Johnson, Emma C.; Anokhin, Andrey; Bauer, Lance; Bucholz, Kathleen K.; Dick, Danielle M.; Hariri, Ahmad R.; Hesselbrock, Victor; Kamarajan, Chella; Kramer, John; Kuperman, Samuel; Meyers, Jacquelyn L.; Nurnberger, John; Schuckit, Marc; Scott, Denise M.; Taylor, Robert E.; Tischfield, Jay; Porjesz, Bernice; Goate, Alison M.; Edenberg, Howard; Foroud, Tatiana; Bogdan, Ryan; Agrawal, Arpana.

In: Genes, Brain and Behavior, 01.01.2019.

Research output: Contribution to journalArticle

Wetherill, L, Lai, D, Johnson, EC, Anokhin, A, Bauer, L, Bucholz, KK, Dick, DM, Hariri, AR, Hesselbrock, V, Kamarajan, C, Kramer, J, Kuperman, S, Meyers, JL, Nurnberger, J, Schuckit, M, Scott, DM, Taylor, RE, Tischfield, J, Porjesz, B, Goate, AM, Edenberg, H, Foroud, T, Bogdan, R & Agrawal, A 2019, 'Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans', Genes, Brain and Behavior. https://doi.org/10.1111/gbb.12580
Wetherill, Leah ; Lai, Dongbing ; Johnson, Emma C. ; Anokhin, Andrey ; Bauer, Lance ; Bucholz, Kathleen K. ; Dick, Danielle M. ; Hariri, Ahmad R. ; Hesselbrock, Victor ; Kamarajan, Chella ; Kramer, John ; Kuperman, Samuel ; Meyers, Jacquelyn L. ; Nurnberger, John ; Schuckit, Marc ; Scott, Denise M. ; Taylor, Robert E. ; Tischfield, Jay ; Porjesz, Bernice ; Goate, Alison M. ; Edenberg, Howard ; Foroud, Tatiana ; Bogdan, Ryan ; Agrawal, Arpana. / Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans. In: Genes, Brain and Behavior. 2019.
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abstract = "Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk.",
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T1 - Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans

AU - Wetherill, Leah

AU - Lai, Dongbing

AU - Johnson, Emma C.

AU - Anokhin, Andrey

AU - Bauer, Lance

AU - Bucholz, Kathleen K.

AU - Dick, Danielle M.

AU - Hariri, Ahmad R.

AU - Hesselbrock, Victor

AU - Kamarajan, Chella

AU - Kramer, John

AU - Kuperman, Samuel

AU - Meyers, Jacquelyn L.

AU - Nurnberger, John

AU - Schuckit, Marc

AU - Scott, Denise M.

AU - Taylor, Robert E.

AU - Tischfield, Jay

AU - Porjesz, Bernice

AU - Goate, Alison M.

AU - Edenberg, Howard

AU - Foroud, Tatiana

AU - Bogdan, Ryan

AU - Agrawal, Arpana

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk.

AB - Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk.

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KW - alcohol dependence

KW - drug dependence

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KW - fMRI

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KW - heritability

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