Abstracts: Polygenic Inheritance

Comings, D.E. (1996). Polygenetic inheritance of psychiatric disorders. In K. Blum, E. P. Noble, R. S. Sparks, & P. J. Sheridan (Eds.), Handbook of Psychiatric Genetics. (pp. 235-260). Boca Raton,FL: CRC Press.
       While family, twin and adoption studies have clearly demonstrated a role of genes in many human behavioral disorders, there has been little success in the identification of which genes are involved. It is proposed that the reason for this is that the wrong genetic models and thus the wrong techniques are being used. The most popular model is that of a rare, disease specific, autosomal dominant gene with reduced penetrance and the assumption that the mutations are in exons. The most popular technique, based on this model, is linkage analysis using large families. I propose that the correct model, capable of giving identical appearing pedigrees, is that of polygenic inheritance. The best technique of identifying the genes involved in such model is the use of association studies with large numbers of severely affected probands compared to unrelated controls. It is also suggested that the polygenes (mutant genes involved in polygenic inheritance) are not disease specific but are involved in a spectrum of disorders and are fundamentally different from those involved in single gene disorders in that they have a much milder effect on gene function and tend to involve non-exon sequences. As such the carrier rate in the population can be high. Their deleterious effect comes when individuals inherit a greater than threshold number of polygenes. By binding transcription factors, dinucleotide, trinucleotide and other repeat polymorphisms may affect gene function and thus may be one cause of polygenes. One of the distinctive characteristics of polygenic inheritance is that the genes are contributed by both parents, and in psychiatric disorders the relatives on both the maternal and paternal sides often demonstrate an increased frequency of a spectrum of behavioral disorders.

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.

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.

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

Comings, D.E, Gade-Andavolu, R., Gonzalez, N., Wu, S., Muhleman, D., Blake, H., Dietz, G., Saucier , G. and MacMurray, J.P. (200). Comparison of the Role of Dopamine, Serotonin, and Noradrenaline Genes in ADHD, ODD and Conduct Disorder: Multivariate Regression Analysis of 20 Genes Clinical Genetics 57:178-196.
      The present study is based on the proposal that complex disorders that are due to the effect 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 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 ANOVA 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 %, p = .052; three serotonin genes to 3%, p = .015; and six adrenergic genes to 6.9% of the variance, p = .0006. For all genes combined, twelve genes contributed to 11.6% of the variance, p = .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. Examination of two additional comorbid phenotypes, conduct disorder (CD) 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.
       Lay summary: This was a study of the additive effect of 20 different genes on ADHD, oppositional defiant and conduct disorder in Tourette syndrome subjects with and without ADHD and in controls. The genes were those for dopamine, serotonin and norepinephrine metabolism. The results showed that for ADHD the norepinephrine genes combined were at least twice as importanct as the dopamine and serotonin genes combined. These results are consitent with the role of norepinephrine in arousal and with ADHD being primarily a disorder of arousal. They also support the use of clonidine (Catapress) in the treatment of ADHD especially in Tourette syndrome. Clonidine reduces brain levels of norepinephrine. We have observed the usefullness of clonidine in the treatment of TS/ADHD for many years. We also found that dopamine genes as well as norepinephrine genes, were more important for conduct disorder than ADHD per se. Finally, ODD tended to involve all three classes of genes.

Comings, D.E. et al. (2000). Multivariate Analysis of Associations of 42 Genes in ADHD, ODDand Conduct Disorder Clinical Genetics 58:31-40.
       In a previous study (Clinical Genetics, 57178-196, 2000) 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 ¾ .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.
        Lay Summary:   In the previous study (P#81) we examined the additive effect of 20 different genes for ADHD, conduct disorder and oppositional defiant disorder in Tourette subjects and controls. In this tudy we expanded the number of genes to 42.  The new genes included those for other neurotransmitters (colinergic, adenosine, nitric oxide, and others), genes for neuropeptides such as CCK, and gene for hormone such as armoatase (which converts testosterone to estrogen),  insulin, and others. This showed that despite the added genes, genes for norepinephrine were still the most prominent for ADHD, and that hormone genes were especially involved in conduct disorder. This is consitent with the predominance of conduct disorder in testosterone rich individuals i.e.  males. These 40 genes accounted for about 15 percent of the total genetic component of these disorders.  Plans are underway to examine a much larger number of genes, thus providing a genetic profile for individuals with TS, ADHD, CD, ODD, OCD and other parts of the spectrum. We anticipate these will be of benefit in identifying optimal treatment for individuals.  The studies continue to support the polygenic (multiple gene) mode of inheritance of TS, ADHD, and related disorders.

Comings,D.E., Gade-Andavolu,R., Gonzalez,N., Wu,S., Muhleman, D., Blake,H., Mann, M., Dietz, G., Saucier,G., MacMurray,J.P. (2000). A Multivariate Analysis of 59 Candidate Genes in Personality Traits:The Temperament Character Inventory. Clinical Genetics.58:375-385.
      Cloninger  proposed three basic personality dimensions for temperament: novelty seeking, harm avoidance and reward dependence and 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 Character Inventory (TCI) . We have utilized a previously described multivariate analysis of associations technique  to examine the relative role of 59 candidate genes on 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.

Comings, D.E. (2000). Age of first childbirth: A major selective factor for psychiatric genes in the twentieth century. In Rogers,J., Rowe,D. and Miller,W.B. Kluwer Academic Publishers Boston pp271-288.
      Many different epidemiological studies using structured psychiatric instruments have shown that when the data is analyzed by age cohorts, there is a significant trend for the frequency of these 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 disorders. Twin and adoption studies have shown that each of these disorders has a significant genetic component, due to the additive and interactive effect of multiple genes, i.e. polygenic.  While the respective authors have not been able to identify the reasons for these trends, it has generally been assumed that the changes are occurring too rapidly to be genetically based. However, one of the expectations of polygenic disorders is that as the genetic loading increases, the frequency of the disorder increases and the age of onset decreases. I propose that there is a factor, new to the 20th century, that could account for changes in the gene pool of this speed and magnitude.  This is the rapid increase in the number of individuals receiving a higher education. The percent of individuals in the U.S. attending college has increased from 2 percent in 1920 to 37 percent in 1980. The reason this can be a strong genetic selective factor is two-fold. First, there is a high degree of correlation between the age on onset of child bearing and years of education. Those who drop out of school before finishing high school initiate child bearing between 20 and 23 years of age. By contrast, those who attend college and/or graduate school initiate child bearing between ages 26 to 28 or more years of age, and have fewer children. Second, the frequency of learning disorders, addictive and other behavioral disorders is higher in those who drop out of school early compared to those who remain in school. As a result, the genes involved in these disorders turn over more rapidly than the genes of those whole remain in school. To verify or refute this hypothesis, there is a need for a new field, molecular demography, to study monitor the changes in the frequency of genes across age groups.