Copy number variations in 6q14.1 and 5q13.2 are associated with alcohol dependence.
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.
Department of Psychiatry, Washington University, St. Louis, Missouri, USA.
Peng
P
Lin
Sarah M
SM
Hartz
Jen-Chyong
JC
Wang
Arpana
A
Agrawal
Tian-Xiao
TX
Zhang
Nicholas
N
McKenna
Kathleen
K
Bucholz
Andrew I
AI
Brooks
Jay A
JA
Tischfield
Howard J
HJ
Edenberg
Victor M
VM
Hesselbrock
John R
JR
Kramer
Samuel
S
Kuperman
Marc A
MA
Schuckit
Alison M
AM
Goate
Laura J
LJ
Bierut
John P
JP
Rice
D000328:Adult; D017668:Age of Onset; D000428:Alcohol Drinking / Q000235:genetics / Q000523:psychology; D000437:Alcoholism / Q000235:genetics*; D056915:DNA Copy Number Variations; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011786:Quality Control; D015203:Reproducibility of Results; D044465:White People