Sex differences in the influence of COMT Val158Met on alcoholism and smoking in plains American Indians.

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 (> or =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 (chi2 = 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.

BDNF variation and mood disorders: a novel functional promoter polymorphism and Val66Met are associated with anxiety but have opposing effects.

The brain-derived neurotrophic factor (BDNF) gene is critical for neuronal function and survival, and is likely to be important in psychiatric disorders. In this study, we used single-nucleotide polymorphism (SNP) discovery, functional analyses, and genetic association studies to better understand the potential role of BDNF sequence variation in behavior. Screening 480 unrelated individuals for SNPs and genotyping was performed in US Caucasian, American Indian, and African American populations. Lifetime DSM-III-R psychiatric diagnoses were assigned and the Tridimensional Personality Questionnaire (TPQ) was administered to measure anxious temperament (harm avoidance (HA)) and novelty seeking (NS). A novel SNP (-281 C>A) in promoter 1 was discovered that had decreased DNA binding in vitro and decreased basal reporter gene activity in transfected rat hippocampal neurons. The frequency of the -281 A allele was 0.03 in a Caucasian sample, but was virtually absent in other populations. Association analyses in a community-based sample showed that individuals with the -281 A allele (13 heterozygotes) had lower TPQ HA (F=4.8, p<0.05). In contrast, the Met 66 allele was associated with increased HA (F=4.1, p=0.02) and was most abundant in individuals with both anxiety disorders and major depression (p<0.05). Among the Val66Val homozygotes, individuals who were -281 CA heterozygotes had significantly lower HA than the -281 CC homozygotes (p<0.01). Our results suggest that in this population, the low activity -281 A allele may be protective against anxiety and psychiatric morbidity, whereas Met 66 may be a risk allele.