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P#72

: Comings DE, Gonzalez N,Wu S, Gade R, Muhleman,D, Saucier G, Johnson P,Verde R, Rosenthal RJ, Lesieur HR, Rugle LJ, Miller WR, MacMurray JP. Studies of the 48 bp repeat of the DRD4 gene in impulsive-addictive behaviors: Tourette syndrome, ADHD, pathological gambling, and substance abuse. Am. J. Med. Gen. (Neuropsych.Genet.) 88:358-368, 1999

ABSTRACT:

Prior studies have reported an association between the presence of the 7 repeat allele of the 48 bp repeat polymorphism of the third cytoplasmic loop of the dopamine D4 receptor gene (DRD4) and novelty seeking behaviors, ADHD, Tourette syndrome, pathological gambling, and substance abuse. However, other studies have failed to replicate some of these observations. To determine if we could replicate these associations we genotyped 737 individuals from four different groups of control subjects, and 707 index subjects from four different groups of impulsive, compulsive addictive behaviors including substance abuse, pathological gambling, Tourette syndrome (TS), and ADHD. Chi square analysis of those carrying the 7 allele versus non-7 allele carriers were not significant for any of the groups using a Bonferroni corrected

a of .0125. However, chi square analysis of those carrying any 5 to 8 allele versus non-carriers was significant for pathological gambling (p < .0001), ADHD (p ¥= .01) and the total index group (p ¥= .0004). When the comparison included all 7 alleles the results were significant for gamblers (p < .0001), Tourette syndrome (p ¥= .003), ADHD (p ¥= .003) and the total group (p ¥= .0002). There was a significant increase in the frequency of heterozygosity versus homozygosity for all alleles for pathological gamblers (p ¥= .0031) and the total index group (p ¥= .0015), suggesting that heterosis played a role. In the substance abuse subjects a quantitative summary variable for the severity of drug dependence, based on the Addiction Severity Index, showed that the scores varied by increasing severity across the following genotypes: 44 < heterozygotes < 77 < 22. Studies of other quantitative traits indicated an important role for the 2 allele and the 22, 24 and 27 genotypes. All studies indicated that the role of the DRD4gene in impulsive, compulsive, addictive behaviors is more complex than a sole focus on the 7 versus non-7 alleles. Am. J. Med. Gen. (Neuropsych.Genet.) 88:358-368, 1999.

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P#73

: Comings, DE. Molecular heterosis as the explanation for the controversy about the effect of the DRD2 gene on dopamine D2 receptor density Molecular Psychiatry 4:213-215, 1999

ABSTRACT:

Points out that heterosis explains the apparent controversy abut whether the A1 allele of the dopamine DRD2 gene is associated with a lower density of receptor in the brain than the A2 allele. When analyzed on the basis of genotype, those with the 12 genotype have a significantly lower D2 density than whose with the 22 genotype.

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P#74

: Comings DE. Tourette syndrome a polygenic disorder CNS Spectrums 4:14-15, 1999

ABSTRACT:

Letter: In your recent fine symposium on Tourette syndrome (TS), Walkup 1 struggles with the relationship between TS and the many other disorders which are commonly comorbid with TS. In his Table 4, in addition to ADHD and OCD he lists major depression, separation anxiety disorder, social phobia, generalized anxiety disorder, PTSD, bipolar disorder, PDD, substance abuse, ODD, CD, and others. We have previously shown that most of these symptom complexes are significantly increased in frequency in the TS relatives of TS probands, compared to relatives without TS 2-6. This rules out ascertainment bias and suggests these conditions all share one or more common etiologies. In Table 3, Walkup proposes nine possible explanations for this range of comorbidity, including TS being the cause, a risk factor for, or a precursor for other psychiatric disorders; or other psychiatric disorders being the cause, a risk factor for, or a precursor for TS. I suggest that none of these nine possibilities accurately portrays the real reason for these comorbidities and that the following sentence is all that is needed to explain both Table 3 and 4: "Psychiatric disorders, including TS, are polygenically inherited and each share many but not all genes in common." To keep things simple this concept is illustrated in Figure 1 just for TS, ADHD and ODD, but the concept applies to all comorbid conditions. Thus, depending on the polygenic mix individuals can have TS only, ADHD only, OCD only, TS + ADHD, TS + OCD or TS + ADHD + OCD. The higher the genetic loading the greater the risk they will have all three.

Polygenic disorders are due to the additive effect of multiple genes, each accounting for a small percent of the variance 7,8. Lod score and most other linkage techniques lack the power to identify genes with such small effects 9. This explains why none of the linkage studies of TS have identified any TS genes. By contrast, association studies do have the power to identify these small effects 9. With this technique we have identified over 20 genes for dopamine, serotonin, norepinephrine, GABA, and other neurotransmitters and neuropeptides that have a significant additive effect on ADHD in TS probands 10,11. Tics per se, CD, ODD and other comorbid conditions, used a subset of these genes. I have suggested elsewhere that because polygenic disorders are much more common than single gene disorders, and because they are caused by the additive effect of multiple genes, the gene defects must be fundamentally different than the mutations causing single gene disorders 7,8,12, i.e. they must be common and they must have only a moderate effect on gene function. If they had a major effect they would be single gene disorders. As a corollary to this, I have suggested that all genes come in a wide range of common hypo- and hyper-functional variants 13. As a result, everyone is at risk to inherit a number of these variants. When the number passes a certain threshold, and the genes affect the function of neurotransmitters and neuropeptides, they are at risk to develop a range of behavioral disorders. The greater the genetic loading for these variants the greater the severity of the disorder and the greater the number and likelihood of comorbid conditions.

Segregation analyses of TS, using only tics or OCD as the phenotype, have suggested TS is inherited as a autosomal dominant or co-dominant trait. While some have suggested I define TS differently than others, I use the same DSM criteria for diagnosing TS probands as others. However, if TS is consistently and significantly associated with a wide range of other phenotypes that share similar hypo- and hyper-functional genetic variants, and this spectrum of phenotypes is not taken into account in the segregation analyses, then the true polygenic nature of TS is likely to be missed. One way around these flawed segregation analyses is to examine the individual genes themselves, as we have done.

These issues are important because the identification of the genes involved in TS as well as other psychiatric disorders will provide significant insights into their cause and effective treatment. If the wrong models and the wrong techniques are used, these genes will never be identified.

 

References

1. Walkup, JT. The psychiatry of Tourette syndrome. CNS Spectrums 1999; 4: 54-61

2. Comings, DE. Tourette syndrome: A hereditary neuropsychiatric spectrum disorder. Ann Clin Psychiatry 1995; 6: 235-247

3. Comings, DE. The role of genetic factors in conduct disorder based on studies of Tourette syndrome and ADHD probands and their relatives. J Dev Behav Pediatr 1995; 16: 142-157

4. Comings, DE. Genetic factors in depression based on studies of Tourette syndrome and Attention Deficit Hyperactivity Disorder probands and relatives. Am J Med Gen (Neuropsych Genet) 1995; 60: 111-121

5. Comings, DE. Genetic factors in substance abuse based on studies of Tourette syndrome and ADHD probands and relatives. I. Drug abuse. Drug and Alcohol Dependence 1994; 35: 1-16

6. Comings, DE. Genetic factors in substance abuse based on studies of Tourette syndrome and ADHD probands and relatives. II. Alcohol abuse. Drug and Alcohol Dependence 1994; 35: 17-24

7. Comings, D E. Polygenetic inheritance of psychiatric disorders. In: edited by Blum, K, Noble, EP, Sparks, RS, Sheridan, PJ (eds). Handbook of Psychiatric Genetics. CRC Press: Boca Raton,FL, 1996, pp 235-260

8. Comings, DE. Why Different Rules are Required for Polygenic Inheritance: Lessons from Studies of the DRD2 Gene. Alcohol 1998; 16: 61-70

9. Risch, N, Merikangas, K. The future of genetic studies of complex human diseases. Science 1996; 273: 1516-1517

10. Comings, DE, Gade-Andavolu, R, Gonzalez, N, Wu, S, CHen, C, Koh, P, Farwell, K, Blake, H, Dietz, G, Saucier, G, MacMurray, JP. Comparision of the role of dopamine, serotonin, and norepinephrine genes in ADHD: The additive effect of 19 genes. (submitted) 1999.

11. Comings, DE, Gade-Andavolu, R, Gonzalez, BS, Wu, S, Dietz, G, Muhleman, D, MacMurray, J. Multiple additive associations (MAA) - A powerful method of identifying the genes in polygenic disorders: ADHD, ODD, CD, Alcoholism and pathological gambling. Am J Hum Genetics 1998; 61: A323

12. Comings, DE. Polygenic inheritance and micro/minisatellites. Molecular Psychiatry 1998; 3: 21-31

13. Comings, DE. SNPs and polygenic disorders: A less gloomy view. Molecular Psychiatry 4:314-16

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P#75

: Comings,D.E.//Dietz.G.//Johnson,J.P./MacMurray,J.P.: Association of the enkephalinase gene with low amplitude P300 waves. Neuroreport 10:2283-2285,1999

ABSTRACT:

Low amplitude of the P300 evoked potential waves has been linked to substance abuse. Defects in opioidergic genes regulating reward pathways have been implicated as risk factors in substance abuse. Since the rate of degradation of enkephalins regulates their CNS level, we focused on the MME gene for metalomembrane endopeptidase (neutral endopeptidase, enkephalinase). We identified a GT repeat polymorphism 5' to the gene and examined its potential association with P300 wave amplitude in 25 male subjects with substance abuse. There was significant association of low molecular weight alleles with low amplitude of the P300 wave at the parietal (p = .0087) and coronal (p = .009) leads. These results support a role of endogenous opioids in the regulation of P300 wave amplitude.

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P#76

: Comings, D. E. 1999. SNPs and Polygenic Disorders: A Less Gloomy View Molecular Psychiatry 4:314-16

ABSTRACT:

Points out that polygenic disorders are fundamentally different than single gene disorders. If the genetic variants involved in these complex disorders are due to different sized alleles of short tandem repeats (Comings Mol.Psychiatyr 3:21-31, 1998) then any common single nucleotide polymorphism (SNP) is likely to divide individuals into groups where that gene is either hypo- or hypofunctional. As such most common SNPs will be useful in association studies.

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P#77

: Comings, D. E., N. Gonzalez, S. Wu, G. Saucier, P. Johnson, R. Verde, and J. P. MacMurray. 1999. Association of the Dopamine DRD3 Receptor Gene With Cocaine Dependence. Molecular Psychiatry 4:484-87

ABSTRACT:

We examined the hypothesis that the dopamine D3 receptor gene (DRD3) is a susceptibility factor for cocaine dependence. The Msc I/Bal I polymorphism of the DRD3 gene was examined in 47 Caucasian subjects with cocaine dependence and 305 Caucasian controls. Based on prior studies with a range of psychiatric disorders we hypothesized there would be a decrease in the frequency of the 12 genotype in the patient sample (increased homozygosity). We observed a significant decrease in the frequency of 12 heterozygotes in subjects with cocaine dependence (29.8%) versus controls (46.9%) (p ¥= .028). This percentage was still lower in those had who chronically used cocaine for more than 10 years (25%), or more than 15 years (21.5%). There was not a significant decrease in DRD3 12 heterozygosity for subjects with amphetamine, opioid, or alcohol dependence in the absence of cocaine dependence. The DRD3 gene accounted for 1.5% of the variance of cocaine dependence (p ¥= .02). The DRD2 gene had an independent and additive effect on cocaine dependence. These findings support a role of the DRD3 gene in susceptibility to cocaine dependence.

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P#78

: Comings, D. E., D. Muhleman, P. Johnson, and J. P. MacMurray. 1999. Potential Role of the Estrogen Receptor Gene (ESR1) in Anxiety Molecular Psychiatry 4:374-77

ABSTRACT:

In addition to neurotransmitters, hormones, acting through the blood stream, also play a role in behavior. To test the potential contribution of genetic variations in hormone receptors we have examined the association between the alleles of the dinucleotide repeat of the estrogen receptor 1 gene (ESR1) and the 9 subscores and total score of the SCL-90 in a group of 179 adult males treated for substance abuse. Based on our prior hypothesis that the length of repeat polymorphisms may play a direct role in gene regulation, the alleles were divided into two groups, short (S) and long (L). ANOVA of the SS, LS, and LL genotypes showed a significant association at ¥= .05 for three of the SCL-90 scores: anxiety, phobic anxiety, and Total Symptoms. Of these the anxiety score remained significant at a Bonferroni corrected of ¥= .005. By regression analysis, the ESR1 gene accounted for 7 percent of the variance of the anxiety score (p ¥= .0004). These results are consistent with a role of the ESR1 gene in human behavior. Since estrogen levels are much higher in women than men, this could account for the increased frequency of anxiety in women.

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P#79

: Winsberg, B. and D. Comings. 1999. Association of the Dopamine Transporter Gene (DAT1) With Poor Methylphenidate Response. J.Am.Acad.Child.Adolesc.Psychiatry 38:1474-77

ABSTRACT:

Poor Ritalin response in African American boys with ADHD was associated with homozygosity at the 10 allele of the dopamine transporter gene.

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