P#61

: Comings, D.E. (1998). Polygenic inheritance and micro/minisatellites Molecular Psychiatry, 3, 21-31.

While it has often been stated that the identification of the genes involved in complex polygenic traits may be extremely difficult, the principles learned in the past century about single gene-single disease inheritance may not be relevant to polygenic inheritance. A new paradigm specific to complex disorders may be needed. It is proposed that micro- and minisatellite polymorphisms play a role in the expression of many genes. As a result, these genes exist in the population with many functional alleleomorphic variants. While each variant has only a modest effect on a given phenotype, because the variants are common, and most quantitative traits are controlled by a number of genes, there is a reasonable probability that an individual will inherit a threshold number of functional variants beyond which there is an appreciable effect on the phenotype. Twelve different aspects of a such a new model for complex inheritance, some corollary implications, and three examples of its immediate application, are presented with the hope that the model may allow an acceleration of the identification of the genes involved in complex polygenic disorders.

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P#62

: Comings, D.E. (1998). The molecular genetics of pathological gambling CNS Spectrums, 3, 20-37

As gambling becomes available to more and more individuals in this country, the problem of compulsive or pathological gambling will also increase. As with other forms of addiction both environmental and genetic factors are involved. The identification of the genes involved in increasing a persons risk for pathological gambling will lead to a better understanding of the disorder and to more rational and effective treatment. While studies of the molecular genetics of pathological gambling are just beginning, a number of interesting observations made to date are reviewed. As with other addictive behaviors, abnormalities in dopaminergic reward pathways are likely to be involved. Consistent with this, we have observed a significant association between pathological gambling and the dopamine D1 (DRD1), dopamine D₂ (DRD2), dopamine D₃ (DRD3) and dopamine D₄ (DRD4) genes. The additive effect of these is consistent with the polygenic inheritance of a susceptibility to pathological gambling. The involvement of multiple dopamine genes is consistent with the 'reward deficiency syndrome' which suggests that addictive, impulsive disorders are due, at least in part, to genetic abnormalities of the dopamine reward pathways. One the basis of this hypothesis, other genes likely to also play a role in a person's susceptibility to pathological gambling, are described.

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P#66

: Comings, D.E., Blake, H., Dietz, G., Gade-Andavolu, R., Legro, R., Saucier, G., Johnson, P., Verde, R., & MacMurray, J.P. (1999). The proenkephalin gene (PENK) and opioid dependence NeuroReport, 10, 1133-1135

We tested the hypothesis that the alleles at the (CA)n repeat of the proenkephalin gene (PENK) might be associated with opioid addiction in 31 non-Hispanic Caucasian subjects with opioid dependence (heroin), 89 ethnically matched subjects with substance dependence other than opioid dependence, and 132 controls. In the subjects with opioid dependence, 66% carried the 81 bp allele compared to 40 percent of subjects with other types of substance abuse (c2 = 11.31, p < .004), and 49% of controls (c2 = 6.0, p < .015). These results are consistent with a role of the PENKgene in opioid dependence.

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P#67

: Comings, D.E., Gade-Andavolu, R., Gonzalez, N., Blake, H., Wu, S., & MacMurray, J.P. (1999). Additive effect of three noradrenergic genes (ADRA2A, ADRA2C, DBH) on attention deficit hyperactivity disorder and learning disabilities in Tourette syndrome subjects Clin.Genet., 55, 160-172

Halperin et al., (1997) reported a significant increase in plasma norepinephrine (NE) in attention deficit hyperactivity disorder (ADHD) children with reading and other cognitive disabilities compared to ADHD children without learning disabilities (LD). We examined the hypothesis that ADHD ± LD was associated with NE dysfunction at a molecular genetic level by testing for associations and additive effects between polymorphisms at three noradrenergic genes - the adrenergic a2A receptor (ADRA2A), adrenergic a2C receptor (ADRA2C), and dopamine b-hydroxylase (DBH) genes. A total of 336 subjects consisting of 274 individuals with Tourette syndrome (TS) and 62 normal controls were genotyped. Regression analysis showed a significant correlation between scores for ADHD, a history of learning disorders, and poor grade school academic performance that was greatest for the additive effect of all three genes. Combined these three genes accounted for 3.5 percent of the variance the ADHD score (p = .0005). There was a significant increase in the number of variant NE genes progressing from subjects without ADHD (A-) or learning disorders (LD-), to A+LD-, to A-LD+, to A+LD+ (p =.0017), but no comparable effect for dopamine genes. These data support an association between NE genes and ADHD, especially in ADHD+LD subjects.

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P#68.

: Miller WB, Pasta DJ, MacMurray J, Chiu C, Wu H, Comings DE (1999) Dopamine receptor genes are associated with age at first sexual intercourse J Biosoc Sci 1999 Jan;31(1):43-54

The dopaminergic system in the brain seems to play an important role in the regulation of sexual behaviour. The relationship between genes for the D1, D2 and D4 dopamine receptors and age at first sexual intercourse (AFSI) was examined in a sample of 414 non-Hispanic, European-American men and women. A significant association was observed between a DRD2 allele and AFSI and an even stronger association when the DRD2 allele was interacted with a DRD1 allele. A constrained regression model was constructed predicting AFSI using sex and a group of nine psychosocial variables as predictors. Adding the DRD2 and the DRD2-by-DRD1 predictors to this model increased the explained variance by 23 and 55%, respectively. Although these findings suggest a stronger association among males than among females, further research will be necessary to clarify this question, as well as to establish whether the observed association holds in other racial/ethnic groups.

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P#69

: Comings DE, Chen C, Wu S, Muhleman D. Association of the androgen receptor gene (AR) with ADHD and conduct disorder 10: 1589-1592, 1999

The male predominance of externalizing behaviors suggests that the X-linked androgen gene might be involved. Since the shorter alleles of the CAG and GGC polymorphisms of the AR gene are associated with increased gene expression we sought to determine if they were also associated with externalizing behaviors. We examined 302 subjects consisting of Tourette syndrome probands and controls. ANOVA showed a significant association between the AR haplotypes and ADHD (p < .0001), conduct disorder (CD) (p ¥= .017), and oppositional defiant disorder (ODD) (p ¥= .004) with the lowest scores in those with the longer alleles at both polymorphisms. These results suggest that genetic variation at the human ARgene plays a role in human externalizing disorders.

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P#70

: Comings DE, MacMurray JP, Gonzalez N, Ferry L, Peters,WR. Association of the serotonin transporter gene with serum cholesterol levels and heart disease Molecular Genetics and Metabolism 67:248-253, 1999

Background In a study of a group of elderly athletes we observed an unexpected association between serum cholesterol levels and the HTTLPR insertion /deletion polymorphism of the promoter region of the serotonin transporter gene ( HTT, SLC6A4). As a follow-up we examined the potential association of this polymorphism with cholesterol and triglyceride levels, or heart disease, in two other groups of subjects.

Methods We examined the possible association between cholesterol levels and heart disease and genotypes of the HTTLPR insertion /deletion polymorphism of the promoter region of the HTTgene, in three independent study populations ranging from 42 to 90 years of age.

Results For subjects 55 to 70 years of age in group 1, cholesterol levels were significantly greater in the LS heterozygotes than either LL or SS homozygotes indicating a heterosis effect (p ¥= .0001). This was replicated in group 2 (p ¥= .015). Triglyceride levels were also significantly elevated in the LS subjects (p ¥= .002). In groups 1 and 3 there was a significant association between the LS heterozygosity and heart disease, angina, and heart attacks in subjects 70 years of age or less. All of these associations were absent in subjects > 70 years of age.

Conclusion While these studies are preliminary and exploratory, they are consistent with a relationship of the HTTgene to cholesterol levels and a risk for heart disease. Replication of these findings in independent, epidemiologically based studies is required.

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