Genome-wide association study of alcohol dependence implicates a region on chromosome 11.
BACKGROUND
Alcohol dependence is a complex disease, and although linkage and candidate gene studies have identified several genes associated with the risk for alcoholism, these explain only a portion of the risk.


METHODS
We carried out a genome-wide association study (GWAS) on a case-control sample drawn from the families in the Collaborative Study on the Genetics of Alcoholism. The cases all met diagnostic criteria for alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition; controls all consumed alcohol but were not dependent on alcohol or illicit drugs. To prioritize among the strongest candidates, we genotyped most of the top 199 single nucleotide polymorphisms (SNPs) (p < or = 2.1 x 10(-4)) in a sample of alcohol-dependent families and performed pedigree-based association analysis. We also examined whether the genes harboring the top SNPs were expressed in human brain or were differentially expressed in the presence of ethanol in lymphoblastoid cells.


RESULTS
Although no single SNP met genome-wide criteria for significance, there were several clusters of SNPs that provided mutual support. Combining evidence from the case-control study, the follow-up in families, and gene expression provided strongest support for the association of a cluster of genes on chromosome 11 (SLC22A18, PHLDA2, NAP1L4, SNORA54, CARS, and OSBPL5) with alcohol dependence. Several SNPs nominated as candidates in earlier GWAS studies replicated in ours, including CPE, DNASE2B, SLC10A2, ARL6IP5, ID4, GATA4, SYNE1, and ADCY3.


CONCLUSIONS
We have identified several promising associations that warrant further examination in independent samples.
Edenberg
Howard J
HJ
Department of Biochemistry, Indiana University School of Medicine, Indianapolis, 46202-5122, USA. edenberg@iupui.edu <edenberg@iupui.edu>
Koller
Daniel L
DL
Xuei
Xiaoling
X
Wetherill
Leah
L
McClintick
Jeanette N
JN
Almasy
Laura
L
Bierut
Laura J
LJ
Bucholz
Kathleen K
KK
Goate
Alison
A
Aliev
Fazil
F
Dick
Danielle
D
Hesselbrock
Victor
V
Hinrichs
Anthony
A
Kramer
John
J
Kuperman
Sam
S
Nurnberger
John I
JI
Rice
John P
JP
Schuckit
Marc A
MA
Taylor
Robert
R
Todd Webb
B
B
Tischfield
Jay A
JA
Porjesz
Bernice
B
Foroud
Tatiana
T
D000293:Adolescent; D000328:Adult; D000437:Alcoholism / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods* / Q000639:trends; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055815:Young Adult