Copy Number Variations in 6q14.1 and 5q13.2 are Associated with Alcohol Dependence

Peng Lin, Sarah M. Hartz, Jen Chyong Wang, Arpana Agrawal, Tian Xiao Zhang, Nicholas McKenna, Kathleen Bucholz, Andrew I. Brooks, Jay A. Tischfield, Howard Edenberg, Victor M. Hesselbrock, John R. Kramer, Samuel Kuperman, Marc A. Schuckit, Alison M. Goate, Laura J. Bierut, John P. Rice

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background: Excessive alcohol use is the third leading cause of preventable death and is highly correlated with alcohol dependence, a heritable phenotype. Many genetic factors for alcohol dependence have been found, but many remain unknown. In search of additional genetic factors, we examined the association between Diagnostic and StatisticalManual of Mental Disorders, Fourth Edition (DSM-IV) alcohol dependence and all common copy number variations (CNVs) with good reliability in the Study of Addiction: Genetics and Environment (SAGE). Methods: All participants in SAGE were interviewed using the Semi-Structured Assessment for the Genetics of Alcoholism, as a part of 3 contributing studies. A total of 2,610 non-Hispanic European American samples were genotyped on the Illumina Human 1M array. We performed CNV calling by CNVPartition, PennCNV, and QuantiSNP, and only CNVs identified by all 3 software programs were examined. Association was conducted with the CNV (as a deletion/duplication) as well as with probes in the CNV region. Quantitative polymerase chain reaction (qPCR) was used to validate the CNVs in the laboratory. Results: CNVs in 6q14.1 (p = 1.04 × 10-6) and 5q13.2 (p = 3.37 × 10-4) were significantly associated with alcohol dependence after adjusting multiple tests. On chromosome 5q13.2, there were multiple candidate genes previously associated with various neurological disorders. The region on chromosome 6q14.1 is a gene desert that has been associated with mental retardation and language delay. The CNV in 5q13.2 was validated, whereas only a component of the CNV on 6q14.1 was validated by qPCR. Thus, the CNV on 6q14.1 should be viewed with caution. Conclusions: This is the first study to show an association between DSM-IV alcohol dependence and CNVs. CNVs in regions previously associated with neurological disorders may be associated with alcohol dependence.

Original languageEnglish
Pages (from-to)1512-1518
Number of pages7
JournalAlcoholism: Clinical and Experimental Research
Volume36
Issue number9
DOIs
StatePublished - Sep 2012

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Alcoholism
Alcohols
Polymerase chain reaction
Chromosomes
Nervous System Diseases
Diagnostic and Statistical Manual of Mental Disorders
Genes
Language Development Disorders
Polymerase Chain Reaction
Mental Disorders
Intellectual Disability
Cause of Death
Software
Phenotype
Genetics

Keywords

  • Alcohol dependence
  • CNV accuracy
  • Copy number variations

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Psychiatry and Mental health
  • Toxicology

Cite this

Lin, P., Hartz, S. M., Wang, J. C., Agrawal, A., Zhang, T. X., McKenna, N., ... Rice, J. P. (2012). Copy Number Variations in 6q14.1 and 5q13.2 are Associated with Alcohol Dependence. Alcoholism: Clinical and Experimental Research, 36(9), 1512-1518. https://doi.org/10.1111/j.1530-0277.2012.01758.x

Copy Number Variations in 6q14.1 and 5q13.2 are Associated with Alcohol Dependence. / Lin, Peng; Hartz, Sarah M.; Wang, Jen Chyong; Agrawal, Arpana; Zhang, Tian Xiao; McKenna, Nicholas; Bucholz, Kathleen; Brooks, Andrew I.; Tischfield, Jay A.; Edenberg, Howard; Hesselbrock, Victor M.; Kramer, John R.; Kuperman, Samuel; Schuckit, Marc A.; Goate, Alison M.; Bierut, Laura J.; Rice, John P.

In: Alcoholism: Clinical and Experimental Research, Vol. 36, No. 9, 09.2012, p. 1512-1518.

Research output: Contribution to journalArticle

Lin, P, Hartz, SM, Wang, JC, Agrawal, A, Zhang, TX, McKenna, N, Bucholz, K, Brooks, AI, Tischfield, JA, Edenberg, H, Hesselbrock, VM, Kramer, JR, Kuperman, S, Schuckit, MA, Goate, AM, Bierut, LJ & Rice, JP 2012, 'Copy Number Variations in 6q14.1 and 5q13.2 are Associated with Alcohol Dependence', Alcoholism: Clinical and Experimental Research, vol. 36, no. 9, pp. 1512-1518. https://doi.org/10.1111/j.1530-0277.2012.01758.x
Lin, Peng ; Hartz, Sarah M. ; Wang, Jen Chyong ; Agrawal, Arpana ; Zhang, Tian Xiao ; McKenna, Nicholas ; Bucholz, Kathleen ; Brooks, Andrew I. ; Tischfield, Jay A. ; Edenberg, Howard ; Hesselbrock, Victor M. ; Kramer, John R. ; Kuperman, Samuel ; Schuckit, Marc A. ; Goate, Alison M. ; Bierut, Laura J. ; Rice, John P. / Copy Number Variations in 6q14.1 and 5q13.2 are Associated with Alcohol Dependence. In: Alcoholism: Clinical and Experimental Research. 2012 ; Vol. 36, No. 9. pp. 1512-1518.
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abstract = "Background: Excessive alcohol use is the third leading cause of preventable death and is highly correlated with alcohol dependence, a heritable phenotype. Many genetic factors for alcohol dependence have been found, but many remain unknown. In search of additional genetic factors, we examined the association between Diagnostic and StatisticalManual of Mental Disorders, Fourth Edition (DSM-IV) alcohol dependence and all common copy number variations (CNVs) with good reliability in the Study of Addiction: Genetics and Environment (SAGE). Methods: All participants in SAGE were interviewed using the Semi-Structured Assessment for the Genetics of Alcoholism, as a part of 3 contributing studies. A total of 2,610 non-Hispanic European American samples were genotyped on the Illumina Human 1M array. We performed CNV calling by CNVPartition, PennCNV, and QuantiSNP, and only CNVs identified by all 3 software programs were examined. Association was conducted with the CNV (as a deletion/duplication) as well as with probes in the CNV region. Quantitative polymerase chain reaction (qPCR) was used to validate the CNVs in the laboratory. Results: CNVs in 6q14.1 (p = 1.04 × 10-6) and 5q13.2 (p = 3.37 × 10-4) were significantly associated with alcohol dependence after adjusting multiple tests. On chromosome 5q13.2, there were multiple candidate genes previously associated with various neurological disorders. The region on chromosome 6q14.1 is a gene desert that has been associated with mental retardation and language delay. The CNV in 5q13.2 was validated, whereas only a component of the CNV on 6q14.1 was validated by qPCR. Thus, the CNV on 6q14.1 should be viewed with caution. Conclusions: This is the first study to show an association between DSM-IV alcohol dependence and CNVs. CNVs in regions previously associated with neurological disorders may be associated with alcohol dependence.",
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AU - Hartz, Sarah M.

AU - Wang, Jen Chyong

AU - Agrawal, Arpana

AU - Zhang, Tian Xiao

AU - McKenna, Nicholas

AU - Bucholz, Kathleen

AU - Brooks, Andrew I.

AU - Tischfield, Jay A.

AU - Edenberg, Howard

AU - Hesselbrock, Victor M.

AU - Kramer, John R.

AU - Kuperman, Samuel

AU - Schuckit, Marc A.

AU - Goate, Alison M.

AU - Bierut, Laura J.

AU - Rice, John P.

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N2 - Background: Excessive alcohol use is the third leading cause of preventable death and is highly correlated with alcohol dependence, a heritable phenotype. Many genetic factors for alcohol dependence have been found, but many remain unknown. In search of additional genetic factors, we examined the association between Diagnostic and StatisticalManual of Mental Disorders, Fourth Edition (DSM-IV) alcohol dependence and all common copy number variations (CNVs) with good reliability in the Study of Addiction: Genetics and Environment (SAGE). Methods: All participants in SAGE were interviewed using the Semi-Structured Assessment for the Genetics of Alcoholism, as a part of 3 contributing studies. A total of 2,610 non-Hispanic European American samples were genotyped on the Illumina Human 1M array. We performed CNV calling by CNVPartition, PennCNV, and QuantiSNP, and only CNVs identified by all 3 software programs were examined. Association was conducted with the CNV (as a deletion/duplication) as well as with probes in the CNV region. Quantitative polymerase chain reaction (qPCR) was used to validate the CNVs in the laboratory. Results: CNVs in 6q14.1 (p = 1.04 × 10-6) and 5q13.2 (p = 3.37 × 10-4) were significantly associated with alcohol dependence after adjusting multiple tests. On chromosome 5q13.2, there were multiple candidate genes previously associated with various neurological disorders. The region on chromosome 6q14.1 is a gene desert that has been associated with mental retardation and language delay. The CNV in 5q13.2 was validated, whereas only a component of the CNV on 6q14.1 was validated by qPCR. Thus, the CNV on 6q14.1 should be viewed with caution. Conclusions: This is the first study to show an association between DSM-IV alcohol dependence and CNVs. CNVs in regions previously associated with neurological disorders may be associated with alcohol dependence.

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