Copy Number Variations in 6q14.1 and 5q13.2 are Associated with Alcohol Dependence
Article first published online: 15 JUN 2012
Copyright © 2012 by the Research Society on Alcoholism
Alcoholism: Clinical and Experimental Research
Volume 36, Issue 9, pages 1512–1518, September 2012
How to Cite
Lin, P., Hartz, S. M., Wang, J.-C., Agrawal, A., Zhang, T.-X., McKenna, N., Bucholz, K., Brooks, A. I., Tischfield, J. A., Edenberg, H. J., Hesselbrock, V. M., Kramer, J. R., Kuperman, S., Schuckit, M. A., Goate, A. M., Bierut, L. J., Rice, J. P. (2012), Copy Number Variations in 6q14.1 and 5q13.2 are Associated with Alcohol Dependence. Alcoholism: Clinical and Experimental Research, 36: 1512–1518. doi: 10.1111/j.1530-0277.2012.01758.x
- Issue published online: 6 SEP 2012
- Article first published online: 15 JUN 2012
- Manuscript Accepted: 25 DEC 2011
- Manuscript Received: 20 JUL 2011
- NIH Genes, Environment and Health Initiative [GEI]. Grant Numbers: U01 HG004422, U01 HG004446, U10 AA008401, P01 CA089392
- Family Study of Cocaine Dependence (FSCD. Grant Numbers: R01 DA019963, R01 DA013423
- NIH GEI. Grant Numbers: U01 HG004446, U10 AA008401, P01 CA089392, R01 DA019963, R01 DA013423
- Gene Environment Association Studies (GENEVA)
- GENEVA Coordinating Center. Grant Number: U01 HG004446
- National Center for Biotechnology Information. Grant Numbers: U10 AA008401, P01 CA089392, R01 DA019963, U01HG004438, HHSN268200782096C, R01 DA013423
- ABMRF/The Foundation for Alcohol Research. Grant Numbers: U01 HG004422, U01 HG004446, U10 AA008401, P01 CA089392, R01 DA019963, U01HG004438, HHSN268200782096C, R01 DA013423
- Study of Addiction: Genetics and Environment (SAGE). Grant Number: U01 HG004422
- SAGE. Grant Number: U01 HG004446
- Collaborative Study on the Genetics of Alcoholism (COGA. Grant Number: U10 AA008401
- Collaborative Genetic Study of Nicotine Dependence (COGEND. Grant Numbers: P01 CA089392, R01 DA019963, U01HG004438, HHSN268200782096C, R01 DA013423
- Copy Number Variations;
- Alcohol Dependence;
- CNV Accuracy
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).
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.
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.
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.