David E Comings

City of Hope National Medical Center · Department of Medical Genetics

BACKGROUND: A large number of studies investigated the genetic modulation of various personality traits with mixed results. AIM: We examined the association between several previously investigated single nucleotide polymorphisms (SNPs) and personality traits, as a confirmatory analysis of literature data, in a sample of 158 healthy subjects (males:...

Cytokine gene variants are known to influence both infectious disease susceptibility and harm-avoidant behaviors, suggesting that these risk variants may be pleiotropically linked to instinctual disease-avoidant traits. The gamma-interferon (IFNG) +874 T>A polymorphism (rs2430561) is an ideal candidate gene variant for immune-behavioral studies. It...

Unlabelled: Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS). RDS results from a dysfunction in the "brain reward cascade," a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic). Individuals with a fami...

Spirituality is defined as a sense of being connected with something greater than oneself. That something can be a supernatural entity, nature, a social group or a family. Different studies show that a wide range of factors that influence temporal lobe function can produce hallucinations, paranormal, spiritual, mystical, and religious experiences....

In the last decade a large number of studies focused on the recognition of gene variants modulating temperamental traits. The gene coding for the estrogen receptor alpha (ESR1) appears to be an interesting candidate and it has been found to be linked to Harm avoidance (HA). The aim of the present study was to investigate whether the ESR1 TA dinucle...

Volume 1, Number 1 of The American Journal of Human Genetics was published in September 1949. The first paper was an 18-page preface to the journal by H. J. Muller, president of The American Society of Human Genetics, entitled "Progress and Prospects in Human Genetics." Charles W. Cotterman served as the first editor, and since that time a dozen ot...

Conflicting results have been reported as to whether genetic variations (Val66Met and C270T) of the brain-derived neurotrophic factor gene (BDNF) confer susceptibility to Alzheimer's disease (AD). We genotyped these polymorphisms in a Japanese sample of 657 patients with AD and 525 controls, and obtained weak evidence of association for Val66Met (P...

Since the discovery of the double helix, the study of brain function, in terms of both physiology and behavioral traits, has resulted in a plethora of research linking these activities to the genetic basis of neurotransmitter function. Knowledge about how genes are expressed, as well as their potential impairment due to polygenic inheritance, can s...

Background and hypothesis Based on neurochemical and genetic evidence, we suggest that both prevention and treatment of multiple addictions, such as dependence to alcohol, nicotine and glucose, should involve a biphasic approach. Thus, acute treatment should consist of preferential blocking of postsynaptic Nucleus Accumbens (NAc) dopamine receptors...

Molecular genetic studies have identified several genes that may mediate susceptibility to attention deficit hyperactivity disorder (ADHD). A consensus of the literature suggests that when there is a dysfunction in the "brain reward cascade," especially in the dopamine system, causing a low or hypo-dopaminergic trait, the brain may require dopamine...

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,...

Obesity-related medical conditions are the second leading cause of death in the US. Classified as a chronic disease in 1985, the understanding of obesity and its causes and effects has been further elucidated through additional research into the evolution of genetic and biologic influencing factors of this deadly disease. What used to be understood...

There is controversy regarding the effects and safety of chromium salts (picolinate and nicotinate) on body composition and weight loss in humans. Thus, we decided to test the hypothesis that typing the obese patients by genotyping the dopamine D2 receptor (DRD2) gene prior to treatment with Chromium Picolinate (CrP) would result in a differential...

While there is a considerable body of literature correlating the role of dopaminergic genes and obesity, body mass index, body type, overeating, carbohydrate binging, energy expenditure and low dopamine D 2 receptor (D2R) density, there is a paucity of research concerning the dopamine D 2 receptor gene (DRD2) variants and percent body fat. We propo...

Advances in our knowledge of the neurobiology of aggression have given rise to rational pharmacological treatments for these behaviors. The main biological systems which are known to be involved are certain reward neurotransmitters that include serotonin (5HT), opioid peptides (END), gamma-aminobutyric acid (γABA), and the catecholamines (dopamine...

The vast majority of common disorders affecting humans are polygenic, due to the additive and interactive effect of multiple genes, each with a small effect, interacting with the environment. Because of their importance and frequency, polygenic disorders have a great economic impact. The identification of the genes involved promises to be significa...

The identification of the genes for complex, polygenic disorders has proven difficult. This is due to the small effect size of each gene and genetic heterogeneity. An additional important factor could be the presence of unidentified epistatic factors. In the broad definition of epistasis, the effect of one unit is not predicable unless the value of...

We examined the frequency of the T allele of the C270T polymorphism of the brain-derived nerve growth factor (BDNF) gene in a test and replication test design. Our objective was to determine if there is an association between the BDNF gene and Alzheimer's Disease (AD) in a US population. There were 106 autopsy-proven AD cases and 101 controls of si...

Attention Deficit Hyperactivity Disorder, commonly referred to as ADHD, is a common, complex, predominately genetic but highly treatable disorder, which in its more severe form has such a profound effect on brain function that every aspect of the life of an affected individual may be permanently compromised. Despite the broad base of scientific inv...

We hypothesize that pathological aggression, a complex behavioral disorder, in adolescents may in part involve polymorphisms of the dopaminergic system. While a number of neurotransmitter systems must be involved, due to polygenic inheritance, one major pathway should involve the dopaminergic system. Advances in our knowledge of the neurobiology of...

While there are many neurotransmitters involved in reward behavior the major neurotransmitter pathways include serotonergic, opioidergic, gabaergic, catecholaminergic and cholinergic. The interaction of these brain neurotransmitters provide for net dopamine release at the reward center of the brain. The net effect of neurotransmitter interaction at...

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. We examined 140 postmort...

The orexin-2/hypocretin-2 (OX2R) receptor gene is mutated in canine narcolepsy and disruption of the prepro-orexin/hypocretin ligand gene results in both an animal model of narcolepsy and sporadic cases of the human disease. This evidence suggests that the structure of the OX2R gene, and its homologue, the OX1R gene, both members of the G protein-c...

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 delta32 delet...

We report that a single-nucleotide polymorphism (SNP) in the gene (PTPN22) encoding the lymphoid protein tyrosine phosphatase (LYP), a suppressor of T-cell activation, is associated with type 1 diabetes mellitus (T1D). The variants encoded by the two alleles, 1858C and 1858T, differ in a crucial amino acid residue involved in association of LYP wit...

Background: 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...

The usual approach for using single base pair polymorphisms (SNPs) for the investigation of the genetics of behavioral disorders is to examine a single diagnostic syndrome or personality trait based on variables relating to a cluster of behavioral symptoms. However, since some of these variables may address behaviors that are associated with one al...

To understand the impact of the phenylethanolamine N-methyltransferase (PNMT) G-148A gene and nutritional variables on weight loss in obese women. One hundred forty-nine women, ages 45 to 65 with a body mass index of >30 kg/m(2), participated in a 6-month, open-label intervention that included sibutramine (15 mg/d) and a monthly health-education cl...

In most industri alize nations, and in many developing countries as well, infant and child mortality rates have dropped precipitously while fertility is under increasingly active constraint, generating the so-called “fertility transition.” Within such a context, those genetic alleles that have been maintained in populations to compens ate for varia...

The acid phosphatase (ACP1) locus codes for a low molecular weight protein tyrosine phosphatase (LMPTP) that is found ubiquitously in human tissues. The *A allele of the ACP1 gene is associated with lower total enzymatic activity than the *B and *C alleles. An association between the *A allele and extreme values of body-mass-index (BMI) and dyslipi...

To date, evidence supporting a positive association between the 7-repeat allele of the D4 dopamine receptor (DRD4) exon III 48 bp polymorphism and Novelty Seeking (NS) has been mixed, with some studies confirming and others refuting the association. A positive association between NS and the minor Taq1 A allele (A1) of the D2 dopamine receptor (DRD2...

Protein tyrosine phosphatases have been implicated in the regulation of serotonergic and dopaminergic activity in the central nervous system. In a recent study we found that nonA/nonA homozygosity at the locus codifying for the low molecular weight protein tyrosine phosphatase (ACP1) was associated with increased rates of major depression in males...

Cholinergic neurons have been implicated in depression and in the disorders of REM sleep in depression. We examined a common A-> T 1890 polymorphism in the 3' UTR of the cholinergic muscarinic receptor 2 (CHRM2) gene. There was a significant increase in the frequency of 11 homozygotes in 126 women with major depression (43.7%) compared to 304 women...

Based on an evolutionary theory of socialization, Belsky and colleagues proposed that girls exposed to a stressful environment, especially when due to father absence in the first 7 years of life, showed an early onset of puberty, precocious sexuality, and unstable relationships as adults. The authors of this article examined an alternative explanat...

Many studies have shown that genes contribute to at least 50% of most behavioural traits and disorders, and in some cases as much as 90%. In the coming years genetic testing will be used to assist in the diagnosis and choice of treatment of most behavioural problems. Keywords: polygenic inheritance; twin studies; molecular genetics

Phenylethanolamine N-methyltransferase (PNMT), the terminal enzyme of the catecholamine biosynthesis pathway, catalyzes the conversion of norepinephrine (NE) to epinephrine (EPI). PNMT is a candidate gene for multiple sclerosis (MS) for two reasons. PNMT is known to map to a region identified in two genome screens for MS and it directly regulates t...

It is commonly assumed that hidden ethnic stratification is the major cause of variability in association studies. We have pointed out that in polygenic disorders the small effect size of each gene, genetic heterogeneity, and stress, are more likely causes of such variability. We report here an additional important confound-age of the mother at the...

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,...

CCK is a satiety neuropeptide. Animal studies have shown that both acute and chronic exposure to nicotine results in weight loss which is associated with an increase in hypothalamic CCK and that CCK antagonists ameliorate symptoms of nicotine withdrawal. A major detriment to smoking cessation, especially in women, is the fear of gaining weight. The...

Leptin has a powerful effect on fertility and the initiation of puberty in addition to its effect on obesity. It has been suggested that that in times of fasting, infertility induced by low leptin levels protect the female from the energy demands of pregnancy. Despite this there have been no studies of the potential role of LEP gene variants on the...

ADHD is a polygenic disorder due to the additive effect of genes affecting dopamine, norepinephrine, serotonin, GABA, and other neurotransmitters. Some of the specific loci involved are dopamine genes--DRD2, DRD4, DRD5, and the dopamine transporter; norepinephrine (NE) and epinephrine (EPI) genes--dopamine beta-hydroxylase, ADRA2A, ADRA2C, PNMT, no...

The activity of human phenylethanolamine N-methyltransferase (PNMT) is reduced in the neurons of those cells in many subcortical areas of the brain that are known to undergo neurodegeneration in Alzheimer disease (AD). Others have reported that PNMT is decreased in brains of persons with AD and that the decrease in enzymatic activity is due to a re...

Results of earlier studies have shown that rating of prior stress exposure in preadolescent boys influenced the association between DRD2 genotypes and alcoholism risk factors, suggesting that variability in stress exposure, either in patient or control samples, could readily account for at least part of the confusion in DRD2 study outcomes. In orde...

Two hundred male subjects (81 college students and 119 subjects from an addiction treatment unit) were administered the Temperament and Character Inventory (TCI) and genotyped at the 48 base pair repeat polymorphism of the DRD4 gene. Subjects were divided by genotype into those carrying any < 4 repeat allele, those homozygous for the 4 repeat allel...

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 depen...

The serotonin transporter (5-HTT) gene is a candidate gene in alcohol dependence because serotonin reuptake inhibitors (SRIs) can alleviate alcohol withdrawal. Studies of the 5-HTT gene in alcohol dependence have not resulted in a consensus. Recent studies have examined the transcriptionally active promoter polymorphism, a 44-bp deletion resulting...

"The reward cascade" is the release of serotonin, which in turn at the hypothalamus stimulates enkephalin, which in turn inhibits gamma-aminobutyric acid (GABA) at the substantia nigra, which in turn fine tunes the amount of dopamine (DA) released at the nucleus accumbens or "reward site." When DA is released into the synapse, it stimulates a numbe...

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 counterintuitive to the expectation that i...

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), oppos...

Enkephalins have been implicated in the regulation of mood, anxiety, reward, euphoria and pain. One of the major enzymes for enkephalin degradation is neutral endopeptidase [enkephalinase, membrane metalloendopeptidase (MME)]. We identified a dinucleotide polymorphism in the 5' region of the MME gene. Subjects were placed into three genotypes, 3/3,...

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), oppos...

The dopamine transporter (DAT) provides major regulation of the synaptic levels of dopamine and is a principal target of psychostimulant drugs. Associations between DAT gene polymorphisms and human disorders with possible links to dopaminergic neurotransmission, including attention-deficit/hyperactivity disorder (ADHD) and consequences of cocaine a...

We observed a significant increase in the number subjects carrying the NAT1*10 allele of the N-acetyl transferase 1 (NAT1) gene in controls with a MAST-R score of greater than or equal to 4 and in subjects with drug and/or alcohol dependence (p=0.003), compared with controls with a MAST-R <4. These results suggest that alterations in the acetylatio...

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 hypothesis, the potential association between measures of these traits and genetic variation at the adrenergic2A re...

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 d...

The dopaminergic and opiodergic 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 plea...

This study attempted to relate the alleles of the D2 (DRD2), D4 (DRD4), and dopamine transporter (DAT1) genes to the behavioral outcome of methylphenidate therapy. African-American children with attention-deficit hyperactivity disorder were treated with methylphenidate in doses not in excess of 60 mg/day. The dosage was increased until behavioral c...

In a previous paper (Miller et al., 1999), we developed and tested a theoretical framework linking human childbearing motivation to a neural substrate in the central nervous system. Central to this motivational model was a four-step psychological sequence that we postulated to underlie reproductive decision-making. The sequence begins with motivati...

In many different epidemiological studies using structured psychiatric instruments, when the data are analyzed by age cohorts there is a significant trend for the frequency of 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 di...

Fertility decline in industrialized nations, fuelled by increased educational opportunity and delayed marriage/childbearing, is a driving force in reshaping contemporary population structure. These same forces have contributed to an increase in twinning, due to fertility drugs, but a possible decline in natural dizygotic twinning. Twinning has been...

We examined the hypothesis that the dopamine D3 receptor gene (DRD3) is a susceptibility factor for cocaine dependence. The MscI/BalI 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 de...

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 metallo-membrane endopeptidase (neutral endopepti...

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, attention deficit hyperactivity disorder (ADHD), Tourette syndrome (TS), pathological gambling, and substance abuse. However, oth...

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...

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 nine subscores and total score of the...

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 whether they were also associated with externalizing behaviors. We examined 302 subjects consistin...

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...

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 depende...

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...

Objectives: The opioid system is thought to have a mediating role in anxiety and depression, to exert regulatory influence over learning and memory formation, and to modify both amplitude and latency of the P300 wave of evoked related potentials. The present study sought to determine the relevance of a dinucleotide repeat polymorphism of the endope...

Objectives: Develop methods to allow the identification of genes involved in polygenic disorders. We hypothesized that the most powerful way to study disorders that are due to the additive effect of multiple genes is to examine the additive effect of multiple genes. Methods: Based on independent studies, the genotypes of 29 genes were scored as 0,...

Objectives: Halperin et al. [JAACAP 36:1688, 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 cognitive disabilities. They proposed that the ADHD + cognitive disabilities was associated with...

It has been demonstrated that stress exposure during pregnancy impairs biological and behavioral responses to stress in the adult offspring, and that acetylcholine plays a role in this phenomenon. This prompted us to examine anxiety-related features of CHRNA4-genotyped subjects reared in stressed and unstressed conditions. Methods: One hundred seve...

Objectives: To determine if the shorter alleles of the GGC trinucleotide repeat polymorphism of the human androgen receptor gene (AR) are associated with the symptoms of conduct disorder (CD), oppositional defiant disorder (ODD), or attention deficit hyperactivity disorder (ADHD). Methods: The frequency of the alleles was determined in 326 subjects...

Objectives: Gender differences in apolipoprotein-E (APOE) ε4 frequencies have been described in elderly non-Alzheimer's disease (AD) subjects, and ε4 heterozygosity has been reported to increase AD risk in females while decreasing risk in males. It has also been suggested that vulnerability to AD varies as a function of so-called "brain reserve cap...

Objectives: Asthenia, or heightened fatiguability, is typically characterized by a positive energy balance, often disposes to weight gain, and is comorbid with depression. Conversely, cachexia is characterized by increased energy expenditure despite falling caloric intake, resulting in loss of adipose tissue and muscle mass. The cytokine gammainter...

In 1990 Blum, Noble and coworkers reported a significant association between the 1 allele of the Tarq1A polymorphism of the D2 dopamine receptor gene (DRD2) and severe alcoholism. Subsequently, some reports using both linkage and association techniques supported this finding whereas others either did not, or seemed not to support this association....

We report a single stranded conformational polymorphism (SSCP) analysis of the coding region of the dopamine D1 receptor (DRD1) in Tourette's syndrome (n = 50) and control (n = 50) subjects. Tourette's syndrome populations with comorbidity for attention deficit-hyperactivity disorder (AD-HD) (n = 35) and obsessive compulsive disorder (OCD) (n = 30)...