title: Identification of POMC exonic variants associated with substance dependence and body mass index.
abstract: BACKGROUND
  Risk of substance dependence (SD) and obesity has been linked to the function of melanocortin peptides encoded by the proopiomelanocortin gene (POMC).
  
  
  RESULTS
  POMC exons were Sanger sequenced in 280 African Americans (AAs) and 308 European Americans (EAs). Among them, 311 (167 AAs and 114 EAs) were affected with substance (alcohol, cocaine, opioid and/or marijuana) dependence and 277 (113 AAs and164 EAs) were screened controls. We identified 23 variants, including two common polymorphisms (rs10654394 and rs1042571) and 21 rare variants; 12 of which were novel. We used logistic regression to analyze the association between the two common variants and SD or body mass index (BMI), with sex, age, and ancestry proportion as covariates. The common variant rs1042571 in the 3'UTR was significantly associated with BMI in EAs (Overweight: P(adj) = 0.005; Obese: P(adj) = 0.018; Overweight+Obese: P(adj) = 0.002) but not in AAs. The common variant, rs10654394, was not associated with BMI and neither common variant was associated with SD in either population. To evaluate the association between the rare variants and SD or BMI, we collapsed rare variants and tested their prevalence using Fisher's exact test. In AAs, rare variants were nominally associated with SD overall and with specific SD traits (SD: P(FET,1df) = 0.026; alcohol dependence: P(FET,1df) = 0.027; cocaine dependence: P(FET,1df) = 0.007; marijuana dependence: P(FET,1df) = 0.050) (the P-value from cocaine dependence analysis survived Bonferroni correction). There was no such effect in EAs. Although the frequency of the rare variants did not differ significantly between the normal-weight group and the overweight or obese group in either population, certain rare exonic variants occurred only in overweight or obese subjects without SD.
  
  
  CONCLUSIONS
  These findings suggest that POMC exonic variants may influence risk for both SD and elevated BMI, in a population-specific manner. However, common and rare variants in this gene may exert different effects on these two phenotypes.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.forename: Joel
authors.initials: J
authors.lastname: Gelernter
authors.forename: Henry R
authors.initials: HR
authors.lastname: Kranzler
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000328:Adult; D001741:Black or African American; D000437:Alcoholism / Q000235:genetics; D015992:Body Mass Index; D019970:Cocaine-Related Disorders / Q000235:genetics; D005091:Exons / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D002189:Marijuana Abuse / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D019966:Substance-Related Disorders / Q000235:genetics*; D044465:White People
chemical_list: D011333:Pro-Opiomelanocortin