A Systematic Single Nucleotide Polymorphism Screen to Fine-Map Alcohol Dependence Genes on Chromosome 7 Identifies Association With a Novel Susceptibility Gene ACN9

Danielle M. Dick, Fazil Aliev, Jen C. Wang, Scott Saccone, Anthony Hinrichs, Sarah Bertelsen, John Budde, Nancy Saccone, Tatiana Foroud, John Nurnberger, Xiaoling Xuei, P. M. Conneally, Marc Schuckit, Laura Almasy, Raymond Crowe, Samuel Kuperman, John Kramer, Jay A. Tischfield, Victor Hesselbrock, Howard J. Edenberg & 4 others Bernice Porjesz, John P. Rice, Laura Bierut, Alison Goate

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Background: Chromosome 7 has shown consistent evidence of linkage with a variety of phenotypes related to alcohol dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) project. With a sample of 262 densely affected families, a peak logarithm of odds (LOD) score for alcohol dependence of 2.9 was observed at D7S1799. The LOD score in the region increased to 4.1 when a subset of the sample was genotyped with the Illumina Linkage III panel for the Genetic Analysis Workshop 14 (GAW14). To follow up on this linkage region, we systematically screened single nucleotide polymorphisms (SNPs) across a 2 LOD support interval surrounding the alcohol dependence peak. Methods: The SNPs were selected from the HapMap Phase I CEPH data to tag linkage disequilibrium bins across the region. Across the 18-Mb region, genotyped by the Center for Inherited Disease Research (CIDR), 1340 SNPs were analyzed. Family-based association analyses were performed on a sample of 1172 individuals from 217 Caucasian families. Results: Eight SNPs showed association with alcohol dependence at p < .01. Four of the eight most significant SNPs were located in or very near the ACN9 gene. We conducted additional genotyping across ACN9 and identified multiple variants with significant evidence of association with alcohol dependence. Conclusions: These analyses suggest that ACN9 is involved in the predisposition to alcohol dependence. Data from yeast suggest that ACN9 is involved in gluconeogenesis and the assimilation of ethanol or acetate into carbohydrate.

Original languageEnglish (US)
Pages (from-to)1047-1053
Number of pages7
JournalBiological Psychiatry
Volume63
Issue number11
DOIs
StatePublished - Jun 1 2008
Externally publishedYes

Fingerprint

Chromosomes, Human, Pair 7
Alcoholism
Single Nucleotide Polymorphism
Genes
HapMap Project
Gluconeogenesis
Linkage Disequilibrium
Acetates
Ethanol
Yeasts
Carbohydrates
Phenotype
Education
Research

Keywords

  • ACN9
  • alcohol dependence
  • association
  • genetics
  • linkage disequilibrium

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

A Systematic Single Nucleotide Polymorphism Screen to Fine-Map Alcohol Dependence Genes on Chromosome 7 Identifies Association With a Novel Susceptibility Gene ACN9. / Dick, Danielle M.; Aliev, Fazil; Wang, Jen C.; Saccone, Scott; Hinrichs, Anthony; Bertelsen, Sarah; Budde, John; Saccone, Nancy; Foroud, Tatiana; Nurnberger, John; Xuei, Xiaoling; Conneally, P. M.; Schuckit, Marc; Almasy, Laura; Crowe, Raymond; Kuperman, Samuel; Kramer, John; Tischfield, Jay A.; Hesselbrock, Victor; Edenberg, Howard J.; Porjesz, Bernice; Rice, John P.; Bierut, Laura; Goate, Alison.

In: Biological Psychiatry, Vol. 63, No. 11, 01.06.2008, p. 1047-1053.

Research output: Contribution to journalArticle

Dick, DM, Aliev, F, Wang, JC, Saccone, S, Hinrichs, A, Bertelsen, S, Budde, J, Saccone, N, Foroud, T, Nurnberger, J, Xuei, X, Conneally, PM, Schuckit, M, Almasy, L, Crowe, R, Kuperman, S, Kramer, J, Tischfield, JA, Hesselbrock, V, Edenberg, HJ, Porjesz, B, Rice, JP, Bierut, L & Goate, A 2008, 'A Systematic Single Nucleotide Polymorphism Screen to Fine-Map Alcohol Dependence Genes on Chromosome 7 Identifies Association With a Novel Susceptibility Gene ACN9', Biological Psychiatry, vol. 63, no. 11, pp. 1047-1053. https://doi.org/10.1016/j.biopsych.2007.11.005
Dick, Danielle M. ; Aliev, Fazil ; Wang, Jen C. ; Saccone, Scott ; Hinrichs, Anthony ; Bertelsen, Sarah ; Budde, John ; Saccone, Nancy ; Foroud, Tatiana ; Nurnberger, John ; Xuei, Xiaoling ; Conneally, P. M. ; Schuckit, Marc ; Almasy, Laura ; Crowe, Raymond ; Kuperman, Samuel ; Kramer, John ; Tischfield, Jay A. ; Hesselbrock, Victor ; Edenberg, Howard J. ; Porjesz, Bernice ; Rice, John P. ; Bierut, Laura ; Goate, Alison. / A Systematic Single Nucleotide Polymorphism Screen to Fine-Map Alcohol Dependence Genes on Chromosome 7 Identifies Association With a Novel Susceptibility Gene ACN9. In: Biological Psychiatry. 2008 ; Vol. 63, No. 11. pp. 1047-1053.
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AU - Aliev, Fazil

AU - Wang, Jen C.

AU - Saccone, Scott

AU - Hinrichs, Anthony

AU - Bertelsen, Sarah

AU - Budde, John

AU - Saccone, Nancy

AU - Foroud, Tatiana

AU - Nurnberger, John

AU - Xuei, Xiaoling

AU - Conneally, P. M.

AU - Schuckit, Marc

AU - Almasy, Laura

AU - Crowe, Raymond

AU - Kuperman, Samuel

AU - Kramer, John

AU - Tischfield, Jay A.

AU - Hesselbrock, Victor

AU - Edenberg, Howard J.

AU - Porjesz, Bernice

AU - Rice, John P.

AU - Bierut, Laura

AU - Goate, Alison

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N2 - Background: Chromosome 7 has shown consistent evidence of linkage with a variety of phenotypes related to alcohol dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) project. With a sample of 262 densely affected families, a peak logarithm of odds (LOD) score for alcohol dependence of 2.9 was observed at D7S1799. The LOD score in the region increased to 4.1 when a subset of the sample was genotyped with the Illumina Linkage III panel for the Genetic Analysis Workshop 14 (GAW14). To follow up on this linkage region, we systematically screened single nucleotide polymorphisms (SNPs) across a 2 LOD support interval surrounding the alcohol dependence peak. Methods: The SNPs were selected from the HapMap Phase I CEPH data to tag linkage disequilibrium bins across the region. Across the 18-Mb region, genotyped by the Center for Inherited Disease Research (CIDR), 1340 SNPs were analyzed. Family-based association analyses were performed on a sample of 1172 individuals from 217 Caucasian families. Results: Eight SNPs showed association with alcohol dependence at p < .01. Four of the eight most significant SNPs were located in or very near the ACN9 gene. We conducted additional genotyping across ACN9 and identified multiple variants with significant evidence of association with alcohol dependence. Conclusions: These analyses suggest that ACN9 is involved in the predisposition to alcohol dependence. Data from yeast suggest that ACN9 is involved in gluconeogenesis and the assimilation of ethanol or acetate into carbohydrate.

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