J. Johnson

Association between the adrenergic alpha 2A receptor gene (ADRA2A) and measures of irritability, hostility, impulsivity and memory in normal subjects.

The noradrenergic system has been implicated in arousal, vigilance, irritability hostility, and memory. This suggests the hypothesis that genetic variants at noradrenergic receptors may be risk factors of these behaviors. To test this hypothesis, the potential association between measures of these traits and genetic variation at the adrenergic2A receptor gene (ADRA2A), using a common single nucleotide polymorphism (SNP) polymorphism of the promoter region, were examined in two independent sets of subjects: university students (student group), and parents of twins in the Minnesota Twin Study (twin group). In the student group, there was a significant linear association by genotype (11 > 12 > 22) for the total Brown ADD score (BADD), and BADD subscores of memory and irritability, and with the total Buss-Durkee Hostility Inventory (BDHI) score and BDHI subscores of indirect hostility, irritability, negativity, and verbal aggression. A multiple analysis of variance (MANOVA) of all the BADD and BDHI subscores was significant at P < or = 0.009. For the twin group, the same genotype associations were significant for the Multidimensional Personality Questionnaire (MPQ) impulsivity scores but not for the MPQ aggression or harm avoidance scores. The ADRA2A gene accounted for 1.8-8.3% of the variance of these scores.

Exon and intron variants in the human tryptophan 2,3-dioxygenase gene: potential association with Tourette syndrome, substance abuse and other disorders.

Defects in serotonin metabolism, and abnormalities in both blood serotonin and tryptophan levels, have been reported in many psychiatric disorders. Tryptophan 2,3-dioxygenase (TDO2) is the rate limiting enzyme for the breakdown of tryptophan to N-formyl kenurenine. Functional variants of this gene could account for the observed simultaneous increases or decreases of both serotonin and tryptophan in various disorders. We have identified four different polymorphisms of the human TDO2 gene. Association studies show a significant association of one or more of these polymorphisms and Tourette syndrome (TS), attention deficit hyperactivity disorder (ADHD) and drug dependence. The intron 6G-->T variant was significantly associated with platelet serotonin levels. Only the association with TS was significant with a Bonferroni correction (p = 0.005). Our purpose here is not to claim these associations are proven, but rather to report preliminary results and show that easily testable polymorphisms are available. We hope to encourage additional research into the potential role the TDO2 gene in these and other psychiatric disorders.

Associations Between the Endothelial Nitric Oxide Synthase Gene (NOS3), Reproductive Behaviors, and Twinning

Fertility decline in industrialized nations, fuelled by increased educational opportunity and delayed marriage/childbearing, is a driving force in reshaping contemporary population structure. These same forces have contributed to an increase in twinning, due to fertility drugs, but a possible decline in natural dizygotic twinning. Twinning has been linked to elevations in testosterone and age-related increases in follicle-stimulating hormone. Using data from 473 females, we examined the role of the regulatory gene for nitric oxide synthase (NOS3) in fertility-related events and in the vulnerability to preeclampsia, or pregnancy-induced hypertension (PIH). We found that the 2-allele of a biallelic marker for this gene was associated with increased risk of PIH, with testosterone, with LH/FSH ratio, and with earlier age at menarche. Subsequent studies of the mothers of twins revealed that the NOS3 2-allele was associated with earlier maternal age at the birth of the twins, less education, and increased monozygotic twinning rate among females with birth ages <30. Additionally, 2-allele carriers evaluated by the multiphasic personality questionnaire had elevated scores for aggression and decreased scores for achievement orientation. These data suggest that, other events equal, the NOS3 2-allele carriers would outproduce NOS3 1-allele carriers, eventually threatening the viability of the 1-allele. However, prior to recent advances in medicine, preeclampsia, linked to the 2-allele, is thought to have had a roughly 40% rate of maternal/fetal mortality, balancing the selective advantages otherwise conferred upon the 2-allele.