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The role of multiple genes in susceptibility to smoking

Institution: Beckman Research Institute of the City of Hope
Investigator(s): David Comings, M.D.
Award Cycle: 1997 (Cycle 6) Grant #: 6RT-0440 Award: $557,829
Subject Area: Epidemiology
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
The pleasure or reward pathways of the brain are central to understanding substance abuse. All drugs of abuse result in an increase in the release in the brain reward pathways of the chemical dopamine that leads to feelings of pleasure and euphoria. We have previously shown that genetic variants of five different genes involved in dopamine metabolism have an additive effect on the risk for cigarette smoking. We have hypothesized that genetic defects in dopamine genes, or genes that modify dopamine metabolism, can result in a reward deficiency syndrome. Such individuals find that natural rewards, such a normal amounts of food and sex, are not adequate and they are more likely to turn to unnatural rewards such as tobacco, cocaine, amphetamines, gambling, and compulsive eating and sexual behaviors, for added stimulation of their reward pathways.

We propose to examine genetic variants at a number of genes that modify the function of the dopamine reward pathways and determine the degree to which they are additive in their effect on contributing to an individual’s risk for using and abusing tobacco. Some of the genes to be tested include the nicotine, GABA, serotonin, and norepinephrine receptor genes. The frequencies of the genetic variants at these genes, and the additive effects of multiple genes will be compared in smokers versus controls screened to exclude those with substance abuse. Our eventual goal is the identification of a set of 10 to 20 genes which may explain why individuals turn to using and abusing tobacco. This would allow the identification of individuals at high risk for substance abuse, increase our understanding of the biology of substance abuse, and lead to better methods of prevention and treatment. Most importantly, this research could lead to the identification of those adolescents who are most likely to be at high risk for becoming addicted to tobacco - before they become addicted.

Final Report
Over the past years we have identified a number of genes that are significantly associated with tobacco dependence (see attached bibliography of papers funded by the TRDPG). Despite the insight that the studies have provided into the genetic risk factors for smoking, we have consistently found that even though there was a the high level of significance of many of these studies, regression analysis showed that each gene accounted for only 0.5 to 5% of the total variance of smoking risk. The usual range was 0.5 to 1.0%. Our studies of smoking and other comorbid disorders has indicated that all of these behavioral disorders are polygenic, that is they are due to the additive effect of multiple genes, each with a modest effect. To study these complex disorders it was necessary do develop new techniques that allowed the examination of the additive effect of multiple candidate genes. We term this a Multiple Additive Associations-(MAA) technique. With the eventual goal of understanding the genetic risk factors for initiation of smoking in adolescence, we have focused on disorders that are significant risk factors to teen-age smoking. These include attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder. Using the MAA technique, we first examined the role of 20 dopamine, serotonin and norepinephrine genes, then a total of 42 genes, as risk factors for ADHD, ODD and CD. These studies indicate that the examination of a much larger number of candidate genes has the potential of providing an understanding of most of the genetic contribution adolescent tobacco dependence, i.e. why do some adolescents start smoking while most others do not.
Publications

Cannabinoid receptor gene (CNRI): association with IV drug use
Periodical: Molecular Psychiatry Index Medicus:
Authors: Comings DE, Muhleman D, Gade R, et al ART
Yr: 1997 Vol: 2 Nbr: Abs: Pg: 161-168

Association of polymorphisms of dopamine D2 receptor (DRD2), and dopamine transporter (DAT1) genes with schizoid/avoidant behaviors (SAB)
Periodical: Molecular Psychiatry Index Medicus:
Authors: Blum K, Braverman ER, Comings DE ART
Yr: 1997 Vol: 2 Nbr: Abs: Pg: 239-246

Polygenic inheritance and micro/minisatellites
Periodical: Molecular Psychiatry Index Medicus:
Authors: Comings DE ART
Yr: 1998 Vol: 3 Nbr: Abs: Pg: 21-31

Why different rules are required for polygenic inheritance: lessons from studies of the DRD2 gene
Periodical: Alcohol Index Medicus:
Authors: Comings DE ART
Yr: 1998 Vol: 16 Nbr: Abs: Pg: 61-70

Correlation of length of VNTR alleles of the X-linked MAOA gene and phenotypic effect in Tourette syndrome and drug abuse
Periodical: Molecular Psychiatry Index Medicus:
Authors: Gade R, Muhleman D, Blake H, et al ART
Yr: 1998 Vol: 3 Nbr: Abs: Pg: 50-60

Phenotypic expression of neuronal nicotinic acetylcholine receptor gene (CHRNA4) in stressted and unstressed subjects
Periodical: American Journal of Medical Genetics Index Medicus:
Authors: Comings De, Wu S, Johnson JP, MacMurray J ABS
Yr: 1998 Vol: 81 Nbr: Abs: Pg: 509

Association of catechol-O-methyltransferase (COMT) gene with frontal lobe function, memory and creativity
Periodical: American Journal of Medical Genetics Index Medicus:
Authors: Harrelson J, Muhleman D, Date-Andavolu R, et al ART
Yr: 1998 Vol: Nbr: Abs: Pg:

Androgen receptor gene, conduct disorder and oppositional defiant disorder
Periodical: American Journal of Medical Genetics Index Medicus:
Authors: Comings DE, Wu S, Muhleman D ART
Yr: 1998 Vol: 81 Nbr: Abs: Pg: 549-550

Association of DRD5 dinucleotide repeat polymorphism with substance abuse, depression and adult ADD
Periodical: American Journal of Medical Genetics Index Medicus:
Authors: Comings DE, MacMurray J, Dade-Andavolu R, et al ART
Yr: 1998 Vol: Nbr: Abs: Pg:

Association of endopeptidase (CD10NE) dinucleotide repeat polymorphism with anxiety, depression, and P300 amplitude
Periodical: American Journal of Medical Genetics Index Medicus:
Authors: Johnson JP, Dietz G, Gade-Andavolu R, et al ART
Yr: 1998 Vol: 81 Nbr: Abs: Pg: 524

Multiple additive associations: a technique for the identification of genes in polygenic disorders
Periodical: American Journal of Human Genetics Index Medicus:
Authors: Comings JP, Dietz G, Gade-Andavolu R, et al ABS
Yr: 1998 Vol: 61 Nbr: Abs: A323 Pg:

Gene-environment interactions in the behavioral expression of the melanocortin-3 (MC3R) gene
Periodical: American Journal of Medical Genetics Index Medicus:
Authors: Gade-Andavolu R, MacMurray J, Muhleman D, et al ART
Yr: 1998 Vol: Nbr: Abs: Pg:

Norepinephrine genes, ADHD and learning disorders
Periodical: American Journal of Medical Genetics Index Medicus:
Authors: Comings DE, Gade-Andavolu R, Gonzalez N, et al ART
Yr: 1998 Vol: Nbr: Abs: Pg:

The DRD4 gene and spiritual transcendence scale of character temperament index
Periodical: Psychiatric Genetics Index Medicus:
Authors: Comings DE, Gonzales N, Saucier G, Johnson JP, MacMurray JP ART
Yr: 2001 Vol: Nbr: Abs: Pg:

Comparison of the role of dopamine, serotonin, and noradrenaline genes in ADHD, ODD and conduct disorder: multivariate regression analysis of 20 genes
Periodical: Clinical Genetics Index Medicus:
Authors: Comings DE, Gade-Andavolu R, Gonzalez N, et al ART
Yr: 2000 Vol: 57 Nbr: Abs: Pg: 178-196

Multivariate analysis of associations of 42 genes in ADHD, ODD and conduct disorder
Periodical: Clinical Genetics Index Medicus:
Authors: Comings DE, Gade-Andavolu R, Gonzalez N, et al ART
Yr: 2000 Vol: 58 Nbr: Abs: Pg: 31-40

Multivariate analysis of 59 candidate genes in personality traits: the temperament character inventory
Periodical: Clinical Genetics Index Medicus:
Authors: Comings DE, Gade-Andavolu R, Gonzalez N, et al ART
Yr: 2000 Vol: 58 Nbr: Abs: Pg: 375-385

Studies of the potential role of the dopamine D1 receptor gene in addictive behaviors
Periodical: Molecular Psychiatry Index Medicus:
Authors: Comings DE, et al ART
Yr: 1997 Vol: 2 Nbr: Abs: Pg: 44-56

Association between the cannabinoid receptor gene (CNR1), and the P300 wave of event-related potentials, and drug dependence
Periodical: Molecular Psychiatry Index Medicus:
Authors: Johnson JP, et al ART
Yr: 1997 Vol: 2 Nbr: Abs: Pg: 169-171

A simple restriction endonuclease based test for the dopamine D2 receptor gene (DRD2) haplotypes: linkage disequilibrium of of the haplotypes with the Taq A1 allele
Periodical: Psychiatric Genetics Index Medicus:
Authors: Dietz G, Comings DE ART
Yr: 1997 Vol: 7 Nbr: Abs: Pg: 133-135

The molecular genetics of pathological gambling
Periodical: CNS Spectrums Index Medicus:
Authors: Comings DE ART
Yr: 1998 Vol: 3 Nbr: Abs: Pg: 20-37

G5644A polymorphism in the interferon-gamma (INFG) gene
Periodical: Psychiatric Genetics Index Medicus:
Authors: Wu S, Comings DE ART
Yr: 1998 Vol: 8 Nbr: Abs: Pg: 57

Potential role of the estrogen receptor gene (ESR1) in anxiety
Periodical: Molecular Psychiatry Index Medicus:
Authors: Comings DE, Muhleman D, Johnson P, MacMurray JP ART
Yr: 1999 Vol: 4 Nbr: Abs: Pg: 374-377

Clinical implications of dopamine D2 receptor gene susceptibility of posttraumatic stress disorder
Periodical: Essential Pharmacology Index Medicus:
Authors: Comings DE ART
Yr: 1999 Vol: 1 Nbr: Abs: Pg: 93-104

Studies of the 48 bp repeat of the DRD4 gene in impulsive-addictive behaviors: tourette syndrome, ADHD, pathological gambling and substance abuse
Periodical: American Journal of Medical Genetics Index Medicus:
Authors: Coming DE, et al ART
Yr: 1999 Vol: 88 Nbr: Abs: Pg: 358-368

Association of the dopamine DRD3 receptor gene with cocaine dependence
Periodical: Molecular Psychiatry Index Medicus:
Authors: Comings DE, et al ART
Yr: 1999 Vol: 4 Nbr: Abs: Pg: 484-487

The proenkephalin gene (PENK) and opioid dependence
Periodical: NeuroReport Index Medicus:
Authors: Comings DE, et al ART
Yr: 1999 Vol: 10 Nbr: Abs: Pg: 1133-1135

Addictive effect of three noradrenergic genes (ADRA2A, ADRA2C, DBH) on attention deficit hyperactivity disorder and learning disabilities in Tourette syndrome subjects
Periodical: Clinical Genetics Index Medicus:
Authors: Comings DE, et al ART
Yr: 1999 Vol: 55 Nbr: Abs: Pg: 160-172

SNPs and polygenic disorders: a less gloomy view
Periodical: Molecular Psychiatry Index Medicus:
Authors: Comings DE ART
Yr: 1999 Vol: 4 Nbr: Abs: Pg: 314-316

A common C-1018G polymorphism in the human 5-HTR1A receptor gene
Periodical: Psychiatric Genetics Index Medicus:
Authors: Wu S, Comings DE ART
Yr: 1999 Vol: 9 Nbr: Abs: Pg: 105-106

Association of the enkephalinase gene with low amplitude P300 waves
Periodical: NeuroReport Index Medicus:
Authors: Comings DE, Dietz G, Johnson JPMJP ART
Yr: 1999 Vol: 10 Nbr: Abs: Pg: 2283-2285

Association of the androgen receptor gene (AR) with ADHD and conduct disorder
Periodical: NeuroReport Index Medicus:
Authors: Comings DE, Chen C, Wu S, Muhleman D ART
Yr: 1999 Vol: 10 Nbr: Abs: Pg: 1589-1592

Two single polymorphisms in the promoter region of the human phenylethanolamine N-methyltransferase PNMT gene
Periodical: Psychiatric Genetics Index Medicus:
Authors: Wu S, Comings DE ART
Yr: 2000 Vol: 9 Nbr: Abs: Pg: 187-188

Association between the adrenergic alpha2A, receptor gene (ADRA2A) and measures of irritability, hostility, impulsivity and memory in normal subjects
Periodical: Psychiatric Genetics Index Medicus:
Authors: Comings DE, et al ART
Yr: 2000 Vol: 10 Nbr: Abs: Pg: 160-172

The additive effect of neurotransmitter genes in pathological gambling: the interaction of 31 candidate genes
Periodical: Clinical Genetics Index Medicus:
Authors: Comings DE, Gade-Andavolu R, Gonzalez N, et al ART
Yr: 0 Vol: Nbr: Abs: Pg:

Different genes for susceptibility to drug versus alcohol dependence
Periodical: Biological Psychiatry Index Medicus:
Authors: Comings DE, MacMurray JM ABS
Yr: 1997 Vol: 42 Nbr: Abs: Pg: 295S-296S

Molecular heterosis: implications for complex inheritance
Periodical: American Journal of Human Genetics Index Medicus:
Authors: Comings DE, MacMurray JM ABS
Yr: 1997 Vol: 61 Nbr: Abs: A196 Pg:

Gender differences in depression, stress, and agression in smokers
Periodical: American Journal of Human Genetics Index Medicus:
Authors: Ferry LH, MacMurray J, Comings DE ABS
Yr: 1999 Vol: Nbr: Abs: Pg:

Associations between the gamma-interferon gene (INFG3), asthenia, and obesity
Periodical: American Journal of Medical Genetics Index Medicus:
Authors: MacMurray J, et al ABS
Yr: 1998 Vol: 81 Nbr: Abs: 524 Pg: