P#81

: David E. Comings, Radhika Gade-Andavolu, Nancy Gonzalez, Shijuan Wu, Donn Muhleman, Hezekiah Blake, George Dietz, Gerard Saucier , and James P. MacMurray. Comparison of the Role of Dopamine, Serotonin, and Noradrenaline Genes in ADHD, ODD and Conduct Disorder: Multivariate Regression Analysis of 20 Genes Clinical Genetics 57:178-196, 2000

The present study is based on the proposal that complex disorders that are due to the effect of multiple genes are best investigated by simultaneously examining multiple candidate genes in the same group of subjects. We have examined the effect of 20 genes for dopamine, serotonin, and noradrenergic metabolism on a quantitative score for ADHD in 336 unrelated Caucasian subjects. The genotypes of each gene were assigned a score from 0 to 2 based on results from the literature or studies in an independent set of subjects (literature based scoring), or results based on ANOVA for the sample (optimized gene scoring). Multivariate linear regression analysis with backward elimination was used to determine which genes contributed most to the phenotype for both coding methods. For optimized gene scoring three dopamine genes contributed to 2.3 %, p = .052; three serotonin genes to 3%, p = .015; and six adrenergic genes to 6.9% of the variance, p = .0006. For all genes combined, twelve genes contributed to 11.6% of the variance, p = .0001. These results indicate that the adrenergic genes play a greater role in ADHD than either the dopaminergic or serotonergic genes combined. The results using literature based gene scoring were similar. Examination of two additional comorbid phenotypes, conduct disorder (CD) and oppositional defiant disorder (ODD), indicated they shared genes with ADHD. For ODD different genotypes of the same genes were often used. These results support the value of the simultaneous examination of multiple candidate genes.

Translation: This was a study of the additive effect of 20 different genes on ADHD, oppositional defiant and conduct disorder in Tourette syndrome subjects with and without ADHD and in controls. The genes were those for dopamine, serotonin and norepinephrine metabolism. The results showed that for ADHD the norepinephrine genes combined were at least twice as importanct as the dopamine and serotonin genes combined. These results are consitent with the role of norepinephrine in arousal and with ADHD being primarily a disorder of arousal. They also support the use of clonidine (Catapress) in the treatment of ADHD especially in Tourette syndrome. Clonidine reduces brain levels of norepinephrine. We have observed the usefullness of clonidine in the treatment of TS/ADHD for many years. We also found that dopamine genes as well as norepinephrine genes, were more important for conduct disorder than ADHD per se. Finally, ODD tended to involve all three classes of genes.

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P#82

: Comings, D.E. et al. Multivariate Analysis of Associations of 42 Genes in ADHD, ODD and Conduct Disorder Clinical Genetics 58:31-40, 2000

In a previous study (Clinical Genetics, 57178-196, 2000) we examined the role of 20 dopamine, serotonin and norepinephrine genes in attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD), using a Multivariate Analysis of Associations (MAA) technique. We have now brought the total number of genes examined to 42 by adding an additional 22 candidate genes. These results indicate that even with the inclusion of these additional genes the noradrenergic genes still played a greater role in ADHD than any other group. Six other neurotransmitter genes were included in the regression equation - cholinergic, nicotinic, alpha 4 receptor (CHNRA4), adenosine A2A receptor (ADOA2A),  nitric oxide synthase (NOS3), NMDAR1, GRIN2B, and GABRB3. In contrast to ADHD and ODD, CD preferentially utilized hormone and neuropeptide genes These included CCK, CYP19 (aromatase cytochrome P-450), ESR1, and INS, p ¾ .005).   This is consistent with our prior studies indicating a role of the androgen receptor (AR) gene in a range of externalizing behavors. We propose that the MAA technique, by focusing on the additive effect of multiple genes and on the cummulative effect of functionally related groups of genes, provides a powerful approach to the dissection of the genetic basis of polygenic disorders.

Translation:   In the previous study (P#81) we examined the additive effect of 20 different genes for ADHD, conduct disorder and oppositional defiant disorder in Tourette subjects and controls. In this tudy we expanded the number of genes to 42.  The new genes included those for other neurotransmitters (colinergic, adenosine, nitric oxide, and others), genes for neuropeptides such as CCK, and gene for hormone such as armoatase (which converts testosterone to estrogen),  insulin, and others. This showed that despite the added genes, genes for norepinephrine were still the most prominent for ADHD, and that hormone genes were especially involved in conduct disorder. This is consitent with the predominance of conduct disorder in testosterone rich individuals i.e.  males. These 40 genes accounted for about 15 percent of the total genetic component of these disorders.  Plans are underway to examine a much larger number of genes, thus providing a genetic profile for individuals with TS, ADHD, CD, ODD, OCD and other parts of the spectrum. We anticipate these will be of benefit in identifying optimal treatment for individuals.  The studies continue to support the polygenic (multiple gene) mode of inheritance of TS, ADHD, and related disorders.

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P#83

: Comings,D.E., Gade-Andavolu,R., Gonzalez,N., Wu,S., Muhleman, D., Blake,H., Mann, M., Dietz, G., Saucier,G., MacMurray,J.P. A Multivariate Analysis of 59 Candidate Genes in Personality Traits:The Temperament Character Inventory Clinical Genetics 58:375-385, 2000.

Cloninger  proposed three basic personality dimensions for temperament: novelty seeking, harm avoidance and reward dependence and suggested that novelty seeking primarily utilized dopamine pathways, harm avoidance utilized serotonin pathways and reward dependence utilized norepinephrine pathways. Subsequently, one additional temperament dimension (persistence), and three character dimensions (cooperativeness, self-directedness and self-transcendence) were added to form the Temperament Character Inventory (TCI) . We have utilized a previously described multivariate analysis of associations technique  to examine the relative role of 59 candidate genes on the seven TCI traits and test the hypothesis that specific personality traits were associated with specific genes. While there was some tendency for this to be true, a more important trend was the involvement of different ratios of functionally related groups of genes, and of different genotypes of the same genes, for different traits.

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P#84

: Comings,D.E. and Blum,K. Reward deficiency syndrome: genetic aspects of behavioral disorders In Uylings,H.B.M., Van Eden,C.G., DeBruin,J.C.P., Feenstra,M.G.P. and Pennatz,C.M.A.  (editors) Progress in Brain Research  126: 325-341, 2000

The dopaminergic and opioidergic reward pathways of the brain are critical for survival since they provide the pleasure drives for eating, love and reproduction. These are called 'natural rewards' and involve the release of dopamine in the nucleus accumbens and frontal lobes. However, the same release of dopamine and production of sensations of pleasure can be produced by 'unnatural rewards' such as alcohol, cocaine, methamphetamine, heroin, nicotine, marijuana, and other drugs, and by compulsive activities such as gambling, eating, and sex, and by risk taking behaviors. Since only a minority of individuals become addicted to these compounds or behaviors, it is reasonable to ask what factors distinguish those who do become addicted from those who do not. It has usually been assumed that these behaviors are entirely voluntary and that environmental factors play the major role.  However, since all of these behaviors have a significant genetic component, the presence of one or more variant genes presumably act as risk factors for these behaviors. Since the primary neurotransmitter of the reward pathway is dopamine, genes for dopamine synthesis, degradation, receptors, and transporters are reasonable candidates. However, serotonin, norepinphrine, GABA, opioid, and cannabinoid neurons all modify dopamine metabolism and dopamine neurons. We have proposed that defects in various combinations of the genes for these neurotransmitters result in a Reward Deficiency Syndrome (RDS) and that such individuals are at risk for abuse of the unnatural rewards. Because of its importance, the gene for the dopamine D₂ receptor was a major candidate gene. Studies in the past decade have shown that in various subject groups the Taq I A1 allele of the DRD2 gene is associated with alcoholism, drug abuse, smoking, obesity, compulsive gambling, and several personality traits. A range of other dopamine, opioid, cannabinoid, norepinephrine, and related genes have since been added to the list. Like other behavioral disorders, these are polygenically inherited and each gene accounts for only a small percent of the variance. Techniques such as the Multivariate Analysis of Associations, which simultaneously examine the contribution of multiple genes, holds promise for understanding the genetic make up of polygenic disorders.

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P#85

: Blum,K., Braverman,E.R., Holder,J.M., Holder,J.M., Lubar,J.F., Monastra,V.J., Miller,.D., Lubar,J.O., Chen,J.T.H., Comings,D.E. Reward deficiency syndrome (RDS): A biogenic model for the diagnosis and treatment of impulsive, addicitive and compulsive behaviors J. Psychoactive Drugs  32 Supplement: 1-112, 2000

This is an extensive 112 page review that further expands on above concept that genetic defects in the dopamine and other reward pathways play a role in an individual's  susceptibility to a range of addictive behaviors and to ADHD and its spectrum of disorders. This lays much of the scientific basis to the material covered in the Miller and Blum book, Overload.

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P#88

: Comings, D.E.: Age of first childbirth: A major selective factor for psychiatric genes in the twentieth century In Rogers,J., Rowe,D. and Miller,W.B. Kluwer Academic Publishers Boston pp271-288, 2000

Many different epidemiological studies using structured psychiatric instruments have shown that when the data is analyzed by age cohorts, there is a significant trend for the frequency of these disorders to increase, and for the age of onset to decrease, in younger cohorts. This trend, occurring over the past 60 years, has been true of a wide range of psychiatric disorders. Twin and adoption studies have shown that each of these disorders has a significant genetic component, due to the additive and interactive effect of multiple genes, i.e. polygenic.  While the respective authors have not been able to identify the reasons for these trends, it has generally been assumed that the changes are occurring too rapidly to be genetically based. However, one of the expectations of polygenic disorders is that as the genetic loading increases, the frequency of the disorder increases and the age of onset decreases. I propose that there is a factor, new to the 20^th century, that could account for changes in the gene pool of this speed and magnitude.  This is the rapid increase in the number of individuals receiving a higher education. The percent of individuals in the U.S. attending college has increased from 2 percent in 1920 to 37 percent in 1980. The reason this can be a strong genetic selective factor is two-fold. First, there is a high degree of correlation between the age on onset of child bearing and years of education. Those who drop out of school before finishing high school initiate child bearing between 20 and 23 years of age. By contrast, those who attend college and/or graduate school initiate child bearing between ages 26 to 28 or more years of age, and have fewer children. Second, the frequency of learning disorders, addictive and other behavioral disorders is higher in those who drop out of school early compared to those who remain in school. As a result, the genes involved in these disorders turn over more rapidly than the genes of those whole remain in school. To verify or refute this hypothesis, there is a need for a new field, molecular demography, to study monitor the changes in the frequency of genes across age groups.

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P#89

: Comings,D.E., Johnson,J.P., Gonzalez,N.S., Huss,M., Saucier,G. and MacMurray,J. Association between the adrenergic a2A receptor gene (ADRA2A) and measures of irritability, hostility, impulsivity and memory in normal subjects: A study and a replication Psychiatric Genetics 55: 160-172, 2000

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 we examined the potential association between measures of these traits and genetic variation at the adrenergic_2A receptor gene (ADRA2A) , using  a common  SNP polymorphism of the promoter region, 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-Durkey Hostility Inventory (BDHI) score and BDHI subscores of indirect hostility, irritability, negativity,  and verbal aggression. A MANOVA  of all the BADD and BDHI subscores was significant at p ¥ .009. For the twins group the same genotype associations were significant for the Multidimensional Personality Questionnaire impulsivity scores but not for the MPQ aggression or harm avoidance scores. The ADRA2A gene accounted for 1.8 to 8.3 percent of the variance of these scores.

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P#90

: Comings, D.E. and MacMurray, J.P. Molecular Heterosis: A Review Molecular Genetics and Metabolism. 71:19-31, 2000

Molecular heterosis occurs when subjects heterozygous for a specific genetic polymorphism show a significantly greater effect (positive heterosis) or lesser effect (negative heterosis) for a quantitative or dichotomous trait than subjects homozygous for either allele. At a molecular level heterosis appears counter-intuitive to the expectation that if the 1 allele of a two allele polymorphism is associated a decrease in gene expression, those carrying the 11 genotype should show the greatest effect, 12 heterozygotes should be intermediate, and 22 homozygotes should show the least effect. We review the accumulating evidence that molecular heterosis is common in humans and may occur in up to fifty percent of all gene associations. A number of examples are reviewed including the following genes: ADRA2C, C3 complement, DRD1, DRD2, DRD3, DRD4, ESR1, HP, HBB, HLA-DR DQ, HTR2A, properdin B, SLC6A4, PNMT, and secretor. Several examples are given in which the heterosis is gender specific. Three explanations for molecular heterosis are proposed. The first is based on an inverted U shaped response curve in which either to little or too much gene expression is deleterious with optimal gene expression occurring in 12 heterozygotes. The second, proposes an independent third factor causing a hidden stratification of the sample such that for in one set of subjects 11 homozygosity is associated with the highest phenotype score while in the other set, 22 homozygosity is associated with the highest phenotype score. The third explanation suggests greater fitness in 12 heterozygotes because they show a broader range of gene expression than 11 or 22 homozygotes. Allele based linkage techniques usually miss heterotic associations. Because up to 50 percent of association studies show a heterosis effect, this can significantly diminish the power of family based linkage and association studies.