Steve Malone

The Effects of a Pacifying Stimulus on Behavioral and Adrenocortical Responses to Circumcision in the Newborn

Eighteen, healthy male newborns, 2–5 days old, were subjects in this study of the effects of a pacifier on the newborns behavioral and adrenocortical responses to circumcision. Half of the subjects were randomly assigned to a condition in which they were encouraged to suck on a pacifier during circumcision, while half served in a no pacifier, control condition. Behavioral observations were made for 1/2 hour before, during, and after circumcision; while blood samples for serum cortisol determination were obtained immediately before circumcision and 30 min later. The results showed that stimulating the newborn with the pacifier reduced crying by about 40%. Reducing crying, however, had no significant effect on the adrenocortical response. Elevations of serum cortisol predicted average behavioral state following circumcision, whereas crying during circumcision did not. Furthermore, there was evidence that the neonatal adrenocortical system was sensitive to variations in surgical procedures. The results indicate the importance of obtaining data on both behavioral and hormonal systems in studies of stress and coping in human newborns.

Development of Substance Dependence in Two Delinquency Subgroups and Nondelinquents From a Male Twin Sample

OBJECTIVE The effect of delinquency subtype on the development of substance dependence symptoms was examined. It was proposed that early-onset delinquents possess characteristics that increase their likelihood of developing substance dependence problems earlier and more rapidly than late-onset delinquents and nondelinquents. METHOD The development of alcohol, nicotine, and cannabis dependence symptoms (DSM-III-R) was examined over a 6-year period of adolescence (age 11-17) among 36 early-onset delinquent, 86 late-onset delinquent, and 25 nondelinquent boys from a large epidemiological twin sample. Multilevel/random coefficients models were used to compare groups on the rate of growth in number of symptoms over time. RESULTS As expected, early-onset delinquents showed an earlier onset and a faster rate of increase in the number of cannabis and nicotine dependence symptoms than late-onset delinquents and controls. Both delinquent groups had a more rapid increase in alcohol dependence symptoms than controls. CONCLUSIONS The data showed that early-onset delinquency is associated with earlier onset of substance use disorder symptoms and more rapid acceleration of problems with drugs than late-onset delinquency. Treatments for boys with early-onset delinquency should account for their increased risk for drug use problems in adolescence and the potential effects of those problems on the course of antisocial behavior.

The Impact of Attention-Deficit/Hyperactivity Disorder on Preadolescent Adjustment May Be Greater for Girls than for Boys.

Whether gender differences exist in the impairment associated with attention-deficit/hyperactivity disorder (ADHD) is still largely unknown, because most samples have few affected girls or include only one sex. The current study evaluated whether ADHD affects adjustment differently for girls than boys in a population-based cohort of 11-year-olds (520 girls, 478 boys). Those with a DSM-IV diagnosis of ADHD (predominantly inattentive, hyperactive-impulsive, or combined) were compared to those without ADHD on teacher, parent, and child reports of academics, peer relationships, self-concept, clinical symptoms, and treatment. Although boys and girls with ADHD experienced difficulties in all areas, girls with ADHD, especially the inattentive subtype, were more negatively affected in academics and peer relationships. Inattentive girls were less popular and more likely to be bullied than girls without ADHD, whereas inattentive boys were not. The social isolation experienced by many girls with ADHD deserves greater attention.

Understanding the relative contributions of direct environmental effects and passive genotype-environment correlations in the association between familial risk factors and child disruptive behavior disorders.

BACKGROUND Previous work reports an association between familial risk factors stemming from parental characteristics and offspring disruptive behavior disorders (DBDs). This association may reflect (a) the direct effects of familial environment and (b) a passive gene-environment correlation (r(GE)), wherein the parents provide both the genes and the environment. The current study examined the contributions of direct environmental influences and passive r(GE) by comparing the effects of familial risk factors on child DBDs in genetically related (biological) and non-related (adoptive) families. METHOD Participants were 402 adoptive and 204 biological families. Familial environment was defined as maternal and paternal maladaptive parenting and antisociality, marital conflict and divorce; offspring DBDs included attention deficit hyperactivity disorder (ADHD), conduct disorder (CD) and oppositional defiant disorder (ODD). Mixed-level regressions estimated the main effects of familial environment, adoption status and the familial environment by adoption status interaction term, which tested for the presence of passive r(GE). RESULTS There was a main effect of maternal and paternal maladaptive parenting and marital discord on child DBDs, indicating a direct environmental effect. There was no direct environmental effect of maternal or paternal antisociality, but maternal and paternal antisociality had stronger associations with child DBDs in biological families than adoptive families, indicating the presence of a passive r(GE). CONCLUSIONS Many familial risk factors affected children equally across genetically related and non-related families, providing evidence for direct environmental effects. The relationship of parental antisociality and offspring DBDs was best explained by a passive r(GE), where a general vulnerability toward externalizing psychopathology is passed down by the parents to the children.

In search of rare variants

Whole genome sequencing was completed on 1,325 individuals from 602 families, identifying 27 million autosomal variants. Genetic association tests were conducted for those individuals who had been assessed for one or more of 17 endophenotypes (N range = 802-1,185). No significant associations were found. These 27 million variants were then imputed into the full sample of individuals with psychophysiological data (N range = 3,088-4,469) and again tested for associations with the 17 endophenotypes. No association was significant. Using a gene-based variable threshold burden test of nonsynonymous variants, we obtained five significant associations. These findings are preliminary and call for additional analysis of this rich sample. We argue that larger samples, alternative study designs, and additional bioinformatics approaches will be necessary to discover associations between these endophenotypes and genomic variation.

The structure of DSM-IV ADHD, ODD, and CD criteria in adolescent boys: A hierarchical approach

Numerous studies have examined the structure of the childhood externalizing disorder symptoms of Attention Deficit Hyperactivity Disorder (ADHD), Oppositional Defiant Disorder (ODD), and Conduct Disorder (CD), both separately as well as simultaneously. The present study expanded on previous findings by implementing a multi-level hierarchical approach to investigating the component structure of ADHD, ODD, and CD criteria in 487 14-year-old boys from the Minnesota Twin Family Study (MTFS). We found support for a hierarchical conceptualization of externalizing behavior criteria in early adolescent boys by specifying how one-, two-, three-, four-, five- and six-factor models of externalizing criteria can be integrated. These results suggest that it may be more beneficial to conceptualize different levels of this hierarchy as relevant to different issues in case conceptualization and research design, from the broad level of an overall externalizing spectrum, to the level of finer-grained subtypes within specific disorders.

Psychophysiological endophenotypes to characterize mechanisms of known schizophrenia genetic loci

BACKGROUND Endophenotypes are laboratory-based measures hypothesized to lie in the causal chain between genes and clinical disorder, and to serve as a more powerful way to identify genes associated with the disorder. One promise of endophenotypes is that they may assist in elucidating the neurobehavioral mechanisms by which an associated genetic polymorphism affects disorder risk in complex traits. We evaluated this promise by testing the extent to which variants discovered to be associated with schizophrenia through large-scale meta-analysis show associations with psychophysiological endophenotypes. METHOD We genome-wide genotyped and imputed 4905 individuals. Of these, 1837 were whole-genome-sequenced at 11× depth. In a community-based sample, we conducted targeted tests of variants within schizophrenia-associated loci, as well as genome-wide polygenic tests of association, with 17 psychophysiological endophenotypes including acoustic startle response and affective startle modulation, antisaccade, multiple frequencies of resting electroencephalogram (EEG), electrodermal activity and P300 event-related potential. RESULTS Using single variant tests and gene-based tests we found suggestive evidence for an association between contactin 4 (CNTN4) and antisaccade and P300. We were unable to find any other variant or gene within the 108 schizophrenia loci significantly associated with any of our 17 endophenotypes. Polygenic risk scores indexing genetic vulnerability to schizophrenia were not related to any of the psychophysiological endophenotypes after correction for multiple testing. CONCLUSIONS The results indicate significant difficulty in using psychophysiological endophenotypes to characterize the genetically influenced neurobehavioral mechanisms by which risk loci identified in genome-wide association studies affect disorder risk.

Heritability and molecular genetic basis of electrodermal activity

The molecular genetic basis of electrodermal activity (EDA) was analyzed using 527,829 single nucleotide polymorphisms (SNPs) in a large population-representative sample of twins and parents (N = 4,424) in relation to various EDA indices. Biometric analyses suggested that approximately 50% or more of variance in all EDA indices was heritable. The combined effect of all SNPs together accounted for a significant amount of variance in each index, affirming their polygenic basis and heritability. However, none of the SNPs were genome-wide significant for any EDA index. Previously reported SNP associations with disorders such as substance dependence or schizophrenia, which have been linked to EDA abnormalities, were not significant; nor were associations between EDA and genes in specific neurotransmitter systems. These results suggest that EDA is influenced by multiple genes rather than by polymorphisms with large effects.