Claudia R. Harris

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.

Does a reduced sensitivity to bitter taste increase the risk of becoming nicotine addicted

Cigarette smoking appears to be on the increase in adolescents. The initiation of regular smoking nearly always begins before adulthood. It is therefore crucial to find ways of identifying those children most vulnerable to nicotine addiction and prioritizing them for preventive measures. We hypothesized that individuals who, in a simple taste test, perceive phenylthiocarbamide (PTC) as bitter may find the taste of cigarettes aversively bitter and could therefore have a reduced vulnerability to nicotine addiction compared to nontasters, who would be the group at greater risk of addiction. We studied 242 Plains American Indians, 136 women and 106 men aged 18-59 years, and found that (allowing for gender differences and the possible direct effects of smoking on taste) the proportion of PTC nontasters to tasters in smokers, even light smokers, was significantly greater than in both nonsmokers and social smokers (chi2= 15.875, 4 df; P=.003), suggesting that nontasters, who are not aversive to the bitter taste of cigarettes, may be more at risk for heavy smoking and therefore more vulnerable to nicotine addiction.

COMT Val158Met and cognition: main effects and interaction with educational attainment

Studies in children have shown that the genetic influence on cognition is positively correlated with socioeconomic status. Catechol‐O‐methyltransferase (COMT) Val158Met, a common, functional polymorphism, has been implicated in executive cognition and working memory. Imaging studies have shown that the variant Met allele is associated with more efficient prefrontal cortical processing and better attention but also emotional vulnerability to stress. We hypothesized that COMT Val158Met genotype would interact with years of education (yrs ed), one indicator of socioeconomic adversity, to predict cognitive task performance. We therefore administered the Wechsler Adult Intelligence Scale‐Revised (WAIS‐R) to 328 community‐derived, genotyped, Plains American Indians (mean yrs ed = 12; range = 5–18). We found significant genotypic effects on WAIS‐R measures of long‐term memory, working memory and attention. The Met allele was associated with improved performance in the Information and Picture Completion subscales; Met/Met homozygotes performed the best. COMT genotype interacted with yrs ed to influence Information and Block Design scores: Met allele carriers’ scores improved markedly with increasing yrs ed, whereas the scores of Val/Val individuals were only marginally influenced by yrs ed. There was a crossover of effects at 11–12 yrs ed: in the less educated group, Met allele carriers actually performed worse than Val/Val individuals perhaps because of emotional vulnerability to educational adversity, but in the better educated group, Met allele carriers excelled. Our study in Plains American Indians has shown that COMT Val158Met influences several aspects of cognition and some of its effects are moderated by educational adversity.

Failure to detect DUP25 in lymphoblastoid cells derived from patients with panic disorder and control individuals representing European and American populations

Investigation of the co-occurrence of panic and phobic disorders with joint laxity led to the identification of interstitial duplications involving human chromosome 15q24–26 (named ‘DUP25’) in a Spanish population. DUP25 was observed in 97% of patients and in 7% of control individuals. In the present study, we used two different methods to detect DUP25: high-throughput molecular gene dosage analysis and fluorescence in situ hybridization (FISH). We evaluated 56 lymphoblastoid cell lines derived from 26 unrelated patients with panic disorder obtained from several European and American populations and 30 normal controls. We could not find any cell line showing a result consistent with DUP25. These data do not support any association of DUP25 with panic disorder.