Background: Alcoholism and heavy smoking are highly comorbid and are cotransmitted in the general U.S. population; however little is known about comorbidity in American Indians. The catechol‐O‐methyltransferase (COMT) functional polymorphism, Val158Met, has been associated with alcoholism in Caucasians. The aims of our study were firstly to investigate patterns of alcohol and tobacco consumption and comorbidity between alcoholism and smoking in Plains American Indians and secondly to determine the influence, including sexual dimorphic effects, of COMT Val158Met and COMT haplotypes, on these behaviors.

Methods: Diagnostic and Statistical Manual‐III‐R lifetime diagnoses were assigned to 342 community‐ascertained Plains American Indians (201 women, 141 men). Lifetime drinking and smoking histories were obtained. Five COMT loci, including Val158Met, were genotyped. Haplotype‐based analyses identified 1 block with 3 common haplotypes; 2 included Val158, and 1 had the Met158 allele.

Results: The alcoholics drank heavily (12�8 drinks/drinking day) but episodically (max 10�8 d/mo). Although 62% of male alcoholics and 40% of female alcoholics were smokers (≥10 cigarettes/d), only 12% of alcoholic men and 8% of alcoholic women smoked heavily (>20/d). In women, the COMT Val158 allele frequency was maximal in alcoholic smokers (0.85), decreasing to 0.74 in nonalcoholic smokers, 0.67 in alcoholic nonsmokers, and 0.64 in nonalcoholic nonsmokers (χ²=11.1, 3 df, p=0.011). Women showed a main effect of Val158 on smoking (p=0.003). Both male and female alcoholics were more likely to have at least 1 Val158 allele compared with nonalcoholics (0.95 vs 0.88, p<0.05). Approximately 30% of all participants were long‐term, nonaddicted light, social smokers (3.6�1.7 cigarettes/d); they had the same Val158Met frequencies as nonsmokers. Haplotype analyses supported the Val158Met findings; however, only 1 of the 2 Val158 haplotypes was implicated.

Conclusions: Plains Indians have different smoking and drinking patterns and considerably less comorbidity between alcoholism and heavy smoking compared with the general U.S. population. Our COMT Val158Met results suggest that there may be both sex differences in the genetic origins of alcoholism and smoking in this population and overlap in genetic vulnerability to both addictions in women.