Radhika Gade-Andavolu

The additive effect of neurotransmitter genes in pathological gambling.

As access to gambling increases there is a corresponding increase in the frequency of addiction to gambling, known as pathological gambling. Studies have shown that a number of different neurotransmitters are affected in pathological gamblers and that genetic factors play a role. Polymorphisms at 31 different genes involved in dopamine, serotonin, norepinephrine, GABA and neurotransmitters were genotyped in 139 pathological gamblers and 139 age, race, and sex‐matched controls. Multivariate regression analysis was used with the presence or absence of pathological gambling as the dependent variable, and the 31 coded genes as the independent variables. Fifteen genes were included in the regression equation. The most significant were the DRD2, DRD4, DAT1, TPH, ADRA2C, NMDA1, and PS1 genes. The r2 or fraction of the variance was less than 0.02 for most genes. Dopamine, serotonin, and norepinephrine genes contributed approximately equally to the risk for pathological gambling. These results indicate that genes influencing a range of brain functions play an additive role as risk factors for pathological gambling. Multi‐gene profiles in specific individuals may be of assistance in choosing the appropriate treatment.

Comparison of the role of dopamine, serotonin, and noradrenaline genes in ADHD, ODD and conduct disorder: multivariate regression analysis of 20 genes

The present study is based on the proposal that complex disorders resulting from the effects 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 attention deficit hyperactivity disorder (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 analysis of variance 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% of the variance, p=0.052; three serotonin genes contributed to 3%, p=0.015; and six adrenergic genes contributed to 6.9%, p=0.0006. For all genes combined, 12 genes contributed to 11.6% of the variance, p=0.0001. 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. An examination of two additional comorbid phenotypes, conduct disorder 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.

Multivariate analysis of associations of 42 genes in ADHD, ODD and conduct disorder

In a previous study (Comings DE et al. Comparison of the role of dopamine, serotonin, and noradrenergic genes in ADHD, ODD and conduct disorder. Multivariate regression analysis of 20 genes. Clin Genet 2000: 57: 178–196) 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=0.005). 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.

A multivariate analysis of 59 candidate genes in personality traits: the temperament and character inventory

Cloninger (Cloninger CR. Neurogenetic adaptive mechanisms in alcoholism. Science 1987: 236: 410–416) proposed three basic personality dimensions for temperament: novelty seeking, harm avoidance, and reward dependence. He 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 and character inventory (TCI). We have utilized a previously described multivariate analysis technique (Comings DE, Gade‐Andavolu R, Gonzalez N et al. Comparison of the role of dopamine, serotonin, and noradrenergic genes in ADHD, ODD and conduct disorder. Multivariate regression analysis of 20 genes. Clin Genet 2000: 57: 178–196; Comings DD, Gade‐Andavolu R, Gonzalez N et al. Multivariate analysis of associations of 42 genes in ADHD, ODD and conduct disorder. Clin Genet 2000: in press) to examine the relative role of 59 candidate genes in 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.

Additive effect of three noradrenergic genes (ADRA2A, ADRA2C, DBH) on attention-deficit hyperactivity disorder and learning disabilities in Tourette syndrome subjects

Halperin et al. (Halperin JM, Newcorn JH, Koda VH, Pick L, McKay KE, Knott P. Noradrenergic mechanisms in ADHD children with and without reading disabilities: a replication and extension. J Am Acad Child Adolesc Psychiatry 1997: 36: 1688–1696) 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 α2A receptor (ADRA2A), adrenergic α2C receptor (ADRA2C), and dopamine β‐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 LD, 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% of the variance of the ADHD score (p=0.0005). 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=0.0017), but no comparable effect for dopamine genes. These data support an association between NE genes and ADHD, especially in ADHD+LD subjects.

Association of CCR5 Δ32 deletion with early death in multiple sclerosis

Purpose: The interaction between chemokines and their receptors is extremely important in controlling T cell migration into sites of CNS inflammation. Because trafficking of inflammatory T cells into the central nervous system (CNS) is a key player in the pathogenesis of multiple sclerosis (MS), we investigated the possible association of CCR5 Δ32 deletion in this disorder.Methods: DNA isolated from postmortem brain tissue samples of 132 patients with MS and from blood tissue samples of 163 gender and ethnicity-matched healthy controls was used to screen for the CCR5 Δ32 deletion allele.Results: An increased frequency of 32-bp deletion allele was found to be associated with early death (P = 0.00005) and with a progressive reduction in the years of survival (onset to death). The death hazard ratio of CCR5 with deletion versus no deletion was 2.12, suggesting that MS patients with the 32-bp deletion have twice the mortality rate of patients with the normal genotype. This effect was more significant in females (hazard ratio 3.58).Conclusion: A strong association of the CCR5 Δ32 deletion with early death could serve as a prognostic marker for MS.

A multigene test for the risk of sporadic breast carcinoma

Although the identification of the BRCA1 and BRCA2 genes have been of great interest, these genes account for less than 5% of all breast carcinoma cases. The remaining cases are sporadic. Reanalysis of a large twin study suggested that genetic factors may play a significant role in sporadic breast and other carcinomas. Sporadic breast carcinoma is polygenically inherited. Multiple genes are likely to have an additive effect, each gene accounting for a fraction of the variance. One factor that may have an impact on the development of hormonally responsive breast tumors is the duration of exposure of the breast to estrogen. Therefore, one of the demographic risk factors for breast carcinoma is an early age of onset of menarche. The current study was based on the hypothesis that genes that play a role in demographic risk factors may be breast carcinoma risk genes in their own right. The authors hypothesized that six genes relevant to the timing of the onset of menarche and related risk factors might be candidate genes for breast carcinoma. These were the leptin gene (LEP), the leptin receptor gene (LEPR), the catechol‐0‐methyltransferase gene (COMT), the dopamine D2 receptor gene (DRD2), the estrogen 1 receptor gene (ESR1), and the androgen receptor gene (AR).

RANTES: a genetic risk marker for multiple sclerosis

Regulated upon activation, normal T-cell expressed and secreted (RANTES) is a beta-chemokine and has been detected in brain lesions of multiple sclerosis (MS) patients. Considering its potential role in MS, we screened two functional polymorphisms in the proximal promoter region of the RANTES in MS patients versus controls. Methods: We examined 140 postmortem brain samples from subjects with a primary diagnosis of MS, and peripheral blood samples from 216 control subjects. The RANTES-28C/G and -403G/A promoter polymorphisms were examined. All subjects were non-Hispanic Caucasians. Results: MS cases differed from controls showing a significant association with the 403G/A polymorphism (odds ratio, 2.359, [1.465-3.799]; P-0.0001), but not the -28C/G (P-NS) polymorphism. There was a significant association of the -28G allele with both early onset (P-0.031) and longer survival (P-0.006). Conclusion: There is a significant but complex association of the RANTES gene with MS.

The proenkephalin gene (PENK) and opioid dependence.

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. Among the subjects with opioid dependence, 66% carried the > or = 81 bp allele compared with 40% of subjects with other types of substance abuse (chi2 = 11.31, p < 0.004) and 49% of controls (chi2 = 6.0, p < 0.015). These results are consistent with a role of the PENK gene in opioid dependence.

Molecular interactions of leptin and prostate cancer.

BACKGROUNDEpidemiological studies have found obesity to be a risk factor for prostate cancer. Our prior independent studies in women have reported a strong relationship between variants of OB (leptin) gene, body mass index, and age at menarche and sporadic breast cancer. The current study investigates an association between genetic variants of the human obesity gene, serum leptin levels, and body mass index in subjects with prostate carcinoma and in age- and gender-matched normal subjects. METHODSBlood samples from 69 patients with prostate cancer and 137 age-matched control subjects were collected. Serum leptin level was investigated by radioimmunoassay, and body mass index was calculated. Allele sizes were determined via standard polymerase chain reaction. Statistical analysis was performed using SPSS10.0 computer software. RESULTSThere was a strong association with significantly elevated serum leptin levels, high body mass index, and higher frequency of LEPR longer alleles in patients with prostate cancer than in control subjects. By contrast, a modest but not significant increase in the frequency of LEP short alleles was found in patients with prostate cancer as compared with control subjects. Analysis within groups 1 (low leptin level and low body mass index) and 2 (other) showed a significant association only in group 2, with high frequency of OB gene variants (LEPR long alleles and LEP short alleles) in patients with prostate cancer but not in control subjects. CONCLUSIONSThese results represent the first report of a significant association between specific leptin gene alleles, serum leptin levels, and body mass index in subjects with prostate cancer. Consistent with prior reports, we also report a significantly elevated serum leptin level in patients with prostate cancer, suggesting a strong link with obesity as an increased risk factor.