A common oxytocin receptor gene (OXTR) polymorphism modulates intranasal oxytocin effects on the neural response to social cooperation in humans.

Intranasal oxytocin (OT) can modulate social-emotional functioning and related brain activity in humans. Consequently, OT has been discussed as a potential treatment for psychiatric disorders involving social behavioral deficits. However, OT effects are often heterogeneous across individuals. Here we explore individual differences in OT effects on the neural response to social cooperation as a function of the rs53576 polymorphism of the oxytocin receptor gene (OXTR). Previously, we conducted a double-blind, placebo-controlled study in which healthy men and women were randomized to treatment with intranasal OT or placebo. Afterwards, they were imaged with functional magnetic resonance imaging while playing an iterated Prisoner's Dilemma Game with same-sex partners. Within the left ventral caudate nucleus, intranasal OT treatment increased activation to reciprocated cooperation in men, but tended to decrease activation in women. Here, we show that these sex differences in OT effects are specific to individuals with the rs53576 GG genotype, and are not found for other genotypes (rs53576 AA/AG). Thus, OT may increase the reward or salience of positive social interactions for male GG homozygotes, while decreasing those processes for female GG homozygotes. These results suggest that rs53576 genotype is an important variable to consider in future investigations of the clinical efficacy of intranasal OT treatment.

The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: a meta-analysis.

The oxytocin receptor gene (OXTR) has been studied as a risk factor for autism spectrum disorder (ASD) owing to converging evidence from multiple levels of analysis that oxytocin (OXT) has an important role in the regulation of affiliative behavior and social bonding in both nonhuman mammals and humans. Inconsistency in the effect sizes of the OXTR variants included in association studies render it unclear whether OXTR is truly associated with ASD, and, if so, which OXTR single-nucleotide polymorphisms (SNPs) are associated. Thus, a meta-analytic review of extant studies is needed to determine whether OXTR shows association with ASD, and to elucidate which specific SNPs have a significant effect on ASD. The current meta-analysis of 16 OXTR SNPs included 3941 individuals with ASD from 11 independent samples, although analyses of each individual SNP included a subset of this total. We found significant associations between ASD and the SNPs rs7632287, rs237887, rs2268491 and rs2254298. OXTR was also significantly associated with ASD in a gene-based test. The current meta-analysis is the largest and most comprehensive investigation of the association of OXTR with ASD and the findings suggest directions for future studies of the etiology of ASD.

Label-free, live optical imaging of reprogrammed bipolar disorder patient-derived cells reveals a functional correlate of lithium responsiveness.

Development of novel treatments and diagnostic tools for psychiatric illness has been hindered by the absence of cellular models of disease. With the advent of cellular reprogramming, it may be possible to recapitulate the disease biology of psychiatric disorders using patient skin cells transdifferentiated to neurons. However, efficiently identifying and characterizing relevant neuronal phenotypes in the absence of well-defined pathophysiology remains a challenge. In this study, we collected fibroblast samples from patients with bipolar 1 disorder, characterized by their lithium response (n=12), and healthy control subjects (n=6). We identified a cellular phenotype in reprogrammed neurons using a label-free imaging assay based on a nanostructured photonic crystal biosensor and found that an optical measure of cell adhesion was associated with clinical response to lithium treatment. This cellular phenotype may represent a useful biomarker to evaluate drug response and screen for novel therapeutics.

Alcohol and aggressive behavior in men--moderating effects of oxytocin receptor gene (OXTR) polymorphisms.

We explored if the disposition to react with aggression while alcohol intoxicated was moderated by polymorphic variants of the oxytocin receptor gene (OXTR). Twelve OXTR polymorphisms were genotyped in 116 Finnish men [aged 18-30, M = 22.7, standard deviation (SD) = 2.4] who were randomly assigned to an alcohol condition in which they received an alcohol dose of 0.7 g pure ethanol/kg body weight or a placebo condition. Aggressive behavior was measured using a laboratory paradigm in which it was operationalized as the level of aversive noise administered to a fictive opponent. No main effects of the polymorphisms on aggressive behavior were found after controlling for multiple testing. The interactive effects between alcohol and two of the OXTR polymorphisms (rs4564970 and rs1488467) on aggressive behavior were nominally significant and remained significant for the rs4564970 when controlled for multiple tests. To the best of our knowledge, this is the first experimental study suggesting interactive effects of specific genetic variants and alcohol on aggressive behavior in humans.

Association and linkage of alpha-2A adrenergic receptor gene polymorphisms with childhood ADHD.

Attention-deficit hyperactivity disorder (ADHD) is a heritable disorder, prevalent from childhood through adulthood. Although the noradrenergic (NA) system is thought to mediate a portion of the pathophysiology of ADHD, genes in this pathway have not been investigated as frequently as those in the dopaminergic system. Previous association studies of one candidate gene in the NA system, ADRA2A, showed inconsistent results with regard to an MspI polymorphism. In the current study, two nearby single-nucleotide polymorphisms, which define HhaI and DraI restriction fragment length polymorphisms, were also genotyped and were in significant linkage disequilibrium with the MspI RFLP. Transmission disequilibrium tests (TDTs) in a sample of 177 nuclear families showed significant association and linkage of the DraI polymorphism with the ADHD combined subtype (P=0.03), and the quantitative TDT showed association of this polymorphism with the inattentive (P=0.003) and hyperactive-impulsive (P=0.015) symptom dimensions. The haplotype that contained the less common allele of the DraI polymorphism likewise showed a strong relationship with the inattentive (P=0.001) and hyperactive-impulsive (P=0.004) symptom dimensions. This study supports the hypothesis that an allele of the ADRA2A gene is associated and linked with the ADHD combined subtype and suggests that the DraI polymorphism of ADRA2A is linked to a causative polymorphism.

Linkage of the dopamine receptor D1 gene to attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) has a strong genetic basis, and evidence from human and animal studies suggests the dopamine receptor D1 gene, DRD1, to be a good candidate for involvement. Here, we tested for linkage of DRD1 to ADHD by examining the inheritance of four biallelic DRD1 polymorphisms [D1P.5 (-1251HaeIII), D1P.6 (-800HaeIII), D1.1 (-48DdeI) and D1.7 (+1403Bsp1286I)] in a sample of 156 ADHD families. Owing to linkage disequilibrium between alleles at the four markers, only three haplotypes are common in our sample. Using the transmission/disequilibrium test (TDT), we observed a strong bias for transmission of Haplotype 3 (1.1.1.2) from heterozygous parents to their affected children (P=0.008). Furthermore, using quantitative trait TDT analyses, we found significant and positive relationships between Haplotype 3 transmission and the inattentive symptoms, but not the hyperactive/impulsive symptoms, of ADHD. These findings support the proposed involvement of DRD1 in ADHD, and implicate Haplotype 3, in particular, as containing a potential risk factor for the inattentive symptom dimension of the disorder. Since none of the four marker alleles comprising Haplotype 3 is predicted to alter DRD1 function, we hypothesize that a functional DRD1 variant, conferring susceptibility to ADHD, is on this haplotype. To search for such a variant we screened the DRD1 coding region, by sequencing, focusing on the children who showed preferential transmission of Haplotype 3. DNA from 41 children was analysed, and no sequence variations were identified, indicating that the putative DRD1 risk variant for ADHD resides outside of the coding region of the gene.

Two dopamine genes related to reports of childhood retrospective inattention and conduct disorder symptoms.

The 7-repeat allele of the dopamine receptor D4 gene (DRD4) and the 10 repeat allele of the dopamine transporter gene (DAT1) have shown association and linkage with symptoms of attention deficit hyperactivity disorder (ADHD) in childhood. The parents of ADHD children (clinic group, n = 80 fathers and 107 mothers) and control children (control group, n = 42 fathers and 51 mothers) were the focus of this study. These parents reported retrospectively on their level of ADHD Inattention and Conduct Disorder symptoms in adolescence. In analyses of the relation of symptom levels to the DRD4 and DAT1 genotypes, fathers possessing the 7 repeat DRD4 allele had greater levels of both inattention and conduct disorder symptoms. Mothers with the 10/10 genotype had higher levels of inattention symptoms. Thus, genetic associations found in children may be replicable in their parents.

Genetic and environmental influences on separation anxiety disorder symptoms and their moderation by age and sex.

We estimated genetic and environmental influences on mother-rated DSM-III-R separation anxiety disorder (SAD) symptoms in 2043 3 to 18-year-old male and female twin pairs and their siblings (348 pairs) recruited from the Australian NH&MRC Twin Registry. Using DeFries and Fulker's (1985) multiple regression analysis, we found that genetic and shared environmental influences both contributed appreciably to variation in SAD symptoms (h2 = .47, SE = .07; c2 = .21, SE = .05) and were significantly moderated by both sex and age. Genetic influences were greater for girls than boys (h2 = .50 and .14, respectively), whereas shared environmental influences were greater for boys than girls (c2 = .51 and .21, respectively). Genetic influences increased with age. whereas shared environmental influences decreased with age. Shared environmental influences were greater in magnitude for twins than for nontwin siblings (c2 = .28 versus .13, respectively). Implications of these findings for theories of the cause of separation anxiety are discussed.

Meta-analysis of sib pair linkage studies of asthma and the interleukin-9 gene (IL9).

Asthma is a complex disease, with an etiology that includes both genetic and environmental influences that may interact. The moderate heritability of asthma has led researchers to investigate its molecular genetic basis using both exploratory investigations of linkage via genome scans, as well as targeted studies of specific candidate genes. Promising candidate genes include the cytokine genes on chromosome 5q23-31. Both genome scans and association studies of these candidate genes/genomic regions have yielded mixed findings, which raise the possibilities of a true relation that emerges more strongly in certain samples simply due to sampling variability, as well as of genetic heterogeneity. Meta-analytic approaches that combine data across samples and examine how findings may vary as a function of effect modifiers can address both of these possibilities. In this study, we used a meta-analytic approach to examine linkage between the interleukin-9 gene (IL9), one of the cytokine genes located on chromosome 5q31, and asthma diagnoses and serum IgE levels in four samples. We analyzed IBD allele sharing for affected, unaffected, and discordant sib pairs, and as a function of sibling differences in IgE levels. We used a recently developed logistic regression-based method that allows for the inclusion of covariates and/or effect modifiers in the analysis of allele sharing in sib-pairs [Rice et al., Genet Epidemiol 17(Suppl. 1):S691-5, 1999]. Sex of the siblings and transmitting parent were considered both as covariates and effect modifiers in analyses. The results provided little evidence for linkage, or for heterogeneity therein due to sex or transmitting parent, either within or across samples.

Age and gender differences in oppositional behavior and conduct problems: a cross-sectional household study of middle childhood and adolescence.

Behavior problems among youths cannot be understood without explaining their age and gender differences, but age and gender differences cannot be explained until they have been accurately described. In a household survey of 1,285 youths aged 9 to 17 years, there were no gender differences in oppositional behavior, but aggression, property offenses, and status offenses were more common among boys. Levels of oppositional behavior were greater at younger ages, aggression peaked near the middle of this age range, and property and status offenses were more prevalent at older ages. These findings are generally consistent with developmental models of conduct problems but are inconsistent with a recent model of gender differences and raise questions about the external validity of current taxonomies.

Association and linkage of DRD4 and DRD5 with attention deficit hyperactivity disorder (ADHD) in a sample of Turkish children.

The search for genetic factors predisposing to Attention Deficit Hyperactivity Disorder (ADHD) has focused on genes that regulate dopaminergic pathways such as dopamine receptors and enzymes that regulate levels of dopamine in the synapse. There have been several reports of association between ADHD and polymorphic variants within or near DRD4, DRD5, DAT1, DBH and COMT. In this study we set out to investigate specific alleles of DRD4 and DRD5, previously reported to be associated with ADHD, in a sample of Turkish children with DSM-IV ADHD children, as well as their relation to methylphenidate response and dimensional measures of symptom domains. One hundred and four independent trios and seven dyads were analysed using the transmission disequilibrium test (TDT). We found increased transmission of the DRD4 7-repeat allele (DRD4*7) (TDT chi2 = 2.79, P = 0.047). Given that we were testing specific a priori hypotheses regarding the associated alleles, we have used one-tailed P-values throughout. There was evidence of an interaction with methlyphenidate (MPH) response and analysis of the sample excluding non-responders revealed more significant evidence for the association (TDT chi2 = 4.48, P = 0.017). We also detected a trend for linkage and association in the DRD5 polymorphism (TDT chi2 = 2. 38, P = 0.06). Similar findings were obtained in relation to MPH response as analysis of MPH responders alone gave rise to a more significant association than that of the group as a whole (TDT chi2 = 4.9, P = 0.013). t-Test and logistic regression TDT analyses of DRD4*7 transmission with respect to dimensional rating scales of hyperactivity and impulsivity showed an inverse relation suggesting that in this sample DRD4*7 is associated with a lower level of ADHD symptomatology. While this may be due to stratification along a dimension of severity such that severe cases belong to a more extreme group with other specific genetic and environmental causes, similar to the model for low cognitive ability, it is more likely the result of a chance selection bias in this sample.

Antisocial behavior and alcoholism: a behavioral genetic perspective on comorbidity.

Similar to many domains in the psychopathology literature, overlap and covariation between antisocial behavior (ASB) and alcohol dependence (AD) are oft documented but little understood. Although the relation between ASB and AD is reliably found and of substantial magnitude, it is not possible given the extant research to discriminate among alternative causal models that could give rise to this relation (e.g., ASB-->AD, AD-->ASB, reciprocal causation between ASB and AD, common causes of ASB and AD). In our opinion, true comorbidity among disorders can only be demonstrated and understood in the context of considerable knowledge regarding the disorders' underlying causes (viz., pathology and etiology). In this article, we present a number of behavior genetic models that may be useful for illuminating the causes of comorbidity among two or more disorders, as well as for understanding the etiology of each disorder individually. Using these behavior genetic approaches, psychopathology researchers can directly test alternative models for the comorbidity among disorders, as well as estimate the magnitude of different etiological factors (i.e., genetic and environmental influences) on comorbidity. Although not a panacea and somewhat demanding technically, behavior genetic approaches can shed new light on the comorbidity among disorders.

A logistic regression extension of the transmission disequilibrium test for continuous traits: application to linkage disequilibrium between alcoholism and the candidate genes DRD2 and ADH3.

The transmission disequilibrium test (TDT) recently has become a popular method of testing for linkage in the presence of association due to its simplicity and advantages over other within-family analytic methods. In this paper, we describe a logistic regression extension to the TDT that can be used to test for differences in linkage disequilibrium as a function of one or more continuous and/or categorical explanatory variables. We highlight important features of this method and demonstrate some of its possible uses. We applied these analyses to test for linkage disequilibrium between the dopamine receptor D2 (DRD2) and alcohol dehydrogenase 3 (ADH3) genes and both diagnostic and quantitative indices of alcoholism. Using data from the Collaborative Study on the Genetics of Alcoholism data set, we found evidence suggesting linkage disequilibrium between DRD2 and ADH3 and quantitative indices of alcoholism and correlated phenotypes corresponding to smoking and personality. None of the evidence for linkage disequilibrium varied by sex or age.

The DRD2 TaqI polymorphism and symptoms of attention deficit hyperactivity disorder.

The relationship of the DRD2 TaqI-A1 allele to hyperactive/impulsive and inattentive symptoms of attention deficit hyperactivity disorder (ADHD) in children and adolescents was examined in a sample of clinic-referred children and their siblings, and control children and their siblings (n = 236). The contribution of genetic dominance and additivity to mean differences among the A2A2, A1A2, and A1A1 genotypes was estimated using structural equation modeling. The effect of genetic additivity was statistically significant for both traits in an analysis of all children. The heritability from the DRD2 locus was estimated at 4.27% for hyperactive-impulsive symptoms and 2.12% for inattentive symptoms. Children with the A2A2 genotype had the highest mean level of symptoms. To control for any possible effects of population stratification, this analysis was repeated with parental genotypes as controls. In this smaller sample, although the direction of the effect was the same as that in the whole sample, the genotypic differences failed to reach conventional significance levels and the effect sizes were smaller (h2 = 1.62% and 0.79%, respectively). Furthermore, a genotype relative risk test of children who had questionnaire-based diagnoses of ADHD also failed to yield evidence of either association or linkage. Given that the A1 allele was expected to be the high risk allele, and that results were non-significant in tests that controlled for population heterogeneity, we doubt that this DRD2 polymorphism influences symptoms of ADHD in childhood.

Relation of age of onset to the type and severity of child and adolescent conduct problems.

In a cross-sectional household sample of 9-through 17-year-old youths from 4 U.S. communities, youths with earlier ages of onset of conduct problems engaged in more conduct problems than youths with later ages of onset when current age and gender were controlled. Specifically, youths with earlier ages of onset were more likely to engage in several types of physical aggression, frequent lying, theft, and vandalism and were less likely to engage in only truancy. There also was an inverse relation between age of onset and level of functional impairment, mental health service use, and meeting diagnostic criteria for conduct disorder, attention-deficit hyperactivity disorder, and oppositional defiant disorder. Within the limits of cross-sectional data, these results support the hypothesis that key aspects of the heterogeneity of conduct problems among youths are related to the age of onset of conduct problems.

Annotation: the development of antisocial behavior: an integrative causal model.

In this paper we have described an integrative causal model of the development of antisocial behavior in children and adolescents. The present model primarily integrates several previous models, but offers some new testable hypotheses. We believe that stable individual differences in propensity to antisocial behavior reflect variations in a number of dimensions of predisposing temperament and cognitive ability, each with its own genetic and environmental influences. The dimensions of predisposing temperament include oppositionality, harm avoidance, and callousness. Genetic influences are predicted to have only indirect effects on antisocial behavior via their influence on predisposition and on the youth's social environment. Environmental influences are expected to be important contributors to antisocial propensity, but these environmental influences reflect, in part, the genetic influences on the dimensions of predisposition (i.e. genotype-environment covariance). We also hypothesize that the levels of influence of the factors that determine individual differences in antisocial propensity change with development, such that genetic influences are of greater magnitude in early childhood and social influences contribute more strongly during later childhood and adolescence (both through independent effects and genotype-environment covariance). However, low levels of heritable predisposing child characteristics may protect against peer influences at all ages.