Pro-opiomelanocortin gene variation related to alcohol or drug dependence: evidence and replications across family- and population-based studies.
BACKGROUND
Opioidergic neurotransmission is critical in many, possibly all, forms of substance dependence. Several opioid-system genes have been shown to be associated with substance dependence disorders. The pro-opiomelanocortin gene (POMC) encodes several peptides important for endogenous opioidergic neurotransmission. We tested whether POMC genetic variation affects risk for substance dependence.


METHODS
Five single nucleotide polymorphisms spanning POMC were examined in independent family and case-control samples. Family-based studies included 854 subjects from 319 African American (AA) families and 761 subjects from 313 European American (EA) families. Each family had a pair of siblings affected with cocaine and/or opioid dependence. Case-control studies included 791 cases (455 AAs and 336 EAs) affected with alcohol, cocaine, and/or opioid dependence and 682 control subjects (199 AAs and 483 EAs).


RESULTS
Family-based analyses revealed an association of rs6719226 with opioid dependence in AA families and rs6713532 with cocaine dependence in EA families (p = .010-.044). Case-control analyses demonstrated an association of rs6713532 with alcohol or cocaine dependence in EAs (p(allele-wise) = .003-.008). Moreover, the minor allele of rs1866146 was found to be a risk factor for cocaine or opioid dependence in AAs (p(allele-wise) = .010-.017) and for alcohol, cocaine, or opioid dependence in EAs (p(allele-wise) = .001-.003). Logistic regression analyses in which sex and age were considered and population stratification analyses confirmed these findings. Additionally, specific haplotypes increased risk for cocaine dependence (p = .023) in AAs and opioid dependence (p = .012) in EAs.


CONCLUSIONS
Given these replicated results, we conclude that variation in POMC confers vulnerability to multiple forms of substance dependence.
Zhang
Huiping
H
Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06516, USA.
Kranzler
Henry R
HR
Weiss
Roger D
RD
Luo
Xingguang
X
Brady
Kathleen T
KT
Anton
Raymond F
RF
Farrer
Lindsay A
LA
Gelernter
Joel
J
D000328:Adult; D001741:Black or African American; D000437:Alcoholism / Q000453:epidemiology / Q000235:genetics* / Q000523:psychology; D016022:Case-Control Studies; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D005190:Family; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D011153:Population; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D019966:Substance-Related Disorders / Q000453:epidemiology / Q000235:genetics* / Q000523:psychology; D014481:United States / Q000453:epidemiology; D044465:White People
D005819:Genetic Markers; D011333:Pro-Opiomelanocortin