M. Anne Spence

Evidence of positive selection acting at the human dopamine receptor D4 gene locus

Associations have been reported of the seven-repeat (7R) allele of the human dopamine receptor D4 (DRD4) gene with both attention-deficit/hyperactivity disorder and the personality trait of novelty seeking. This polymorphism occurs in a 48-bp tandem repeat in the coding region of DRD4, with the most common allele containing four repeats (4R) and rarer variants containing 2–11. Here we show by DNA resequencing/haplotyping of 600 DRD4 alleles, representing a worldwide population sample, that the origin of 2R–6R alleles can be explained by simple one-step recombination/mutation events. In contrast, the 7R allele is not simply related to the other common alleles, differing by greater than six recombinations/mutations. Strong linkage disequilibrium was found between the 7R allele and surrounding DRD4 polymorphisms, suggesting that this allele is at least 5–10-fold “younger” than the common 4R allele. Based on an observed bias toward nonsynonymous amino acid changes, the unusual DNA sequence organization, and the strong linkage disequilibrium surrounding the DRD4 7R allele, we propose that this allele originated as a rare mutational event that nevertheless increased to high frequency in human populations by positive selection.

Extensions to pedigree analysis III. Variance components by the scoring method

The classic variance components for simple polygenic traits - additive, dominance, and environmental variance - have traditionally been estimated from sample covariances between first-degree relatives. If data is gathered on pedigrees, this statistical procedure wastes information. Recently Elston & Stewart suggested an alternative likelihood procedure that uses all the information in a set of pedigrees. A refinement of their method based on the scoring technique gives rapidly converging maximum likelihood estimates of the variance components and of the male and female means. Tests of statistical hypotheses about the various parameters can then be made by the likelihood ratio method. Furthermore, using classical regression analysis, the estimated parameter values allow prediction of unknown trait values from known trait values within a pedigree. These methods should apply to traits like total finger ridge count and to quantitative measurements associated with disease traits. Since the model postulates independent environmental effects and no assortative mating, its utility in human behaviour genetics seems limited.

Dopamine genes and ADHD

Family, twin, and adoption studies have documented a strong genetic basis for ADHD/HKD, but these studies do not identify specific genes linked to the disorder. Molecular genetic studies can identify allelic variations of specific genes that are functionally associated with ADHD/HKD, and dopamine genes have been the initial candidates based on the site of action of the stimulants drugs, which for a half century have provided the primary pharmacological treatment for ADHD/HKD. Two candidate dopamine genes have been investigated and reported to be associated with ADHD/HKD: the dopamine transporter (DAT1) gene [Cook et al., American Journal of Human Genetics 1995;56:993-998, Gill et al., Molecular Psychiatry 1997;2:311-313] and the dopamine receptor D4 (DRD4) gene [LaHoste et al., Molecular Psychiatry 1996;1:121-124: Smalley et al., 1998;3:427-430; Swanson et al., Molecular Psychiatry 1998;3:38-41]. Speculative hypotheses [Swanson and Castellanos, NIH Consensus Development Conference: Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder, November 1998. p. 37-42] have suggested that specific alleles of these dopamine genes may alter dopamine transmission in the neural networks implicated in ADHD/HKD (e.g. that the 10-repeat allele of the DAT1 gene may be associated with hyperactive re-uptake of dopamine or that the 7-repeat allele of the DRD4 gene may be associated with a subsensitive postsynaptic receptor). These and other variants of the dopamine hypothesis of ADHD will be discussed.

A replication of the Autism Diagnostic Observation Schedule (ADOS) revised algorithms

OBJECTIVE To replicate the factor structure and predictive validity of revised Autism Diagnostic Observation Schedule algorithms in an independent dataset (N = 1,282). METHOD Algorithm revisions were replicated using data from children ages 18 months to 16 years collected at 11 North American sites participating in the Collaborative Programs for Excellence in Autism and the Studies to Advance Autism Research and Treatment. RESULTS Sensitivities and specificities approximated or exceeded those of the old algorithms except for young children with phrase speech and a clinical diagnosis of pervasive developmental disorders not otherwise specified. CONCLUSIONS Revised algorithms increase comparability between modules and improve the predictive validity of the Autism Diagnostic Observation Schedule for autism cases compared to the original algorithms.

Head circumference and height in autism : A study by the collaborative program of excellence in autism

Data from 10 sites of the NICHD/NIDCD Collaborative Programs of Excellence in Autism were combined to study the distribution of head circumference and relationship to demographic and clinical variables. Three hundred thirty‐eight probands with autism‐spectrum disorder (ASD) including 208 probands with autism were studied along with 147 parents, 149 siblings, and typically developing controls. ASDs were diagnosed, and head circumference and clinical variables measured in a standardized manner across all sites. All subjects with autism met ADI‐R, ADOS‐G, DSM‐IV, and ICD‐10 criteria. The results show the distribution of standardized head circumference in autism is normal in shape, and the mean, variance, and rate of macrocephaly but not microcephaly are increased. Head circumference tends to be large relative to height in autism. No site, gender, age, SES, verbal, or non‐verbal IQ effects were present in the autism sample. In addition to autism itself, standardized height and average parental head circumference were the most important factors predicting head circumference in individuals with autism. Mean standardized head circumference and rates of macrocephaly were similar in probands with autism and their parents. Increased head circumference was associated with a higher (more severe) ADI‐R social algorithm score. Macrocephaly is associated with delayed onset of language. Although mean head circumference and rates of macrocephaly are increased in autism, a high degree of variability is present, underscoring the complex clinical heterogeneity of the disorder. The wide distribution of head circumference in autism has major implications for genetic, neuroimaging, and other neurobiological research.

Early Regression in Social Communication in Autism Spectrum Disorders: A CPEA Study

In a multisite study of 351 children with autism spectrum disorders, 21 children with developmental delays, and 31 children with typical development, this study used caregiver interviews (i.e., the Autism Diagnostic Interview-Revised) at the time of entry into other research projects and follow-up telephone interviews designed for this project to describe the childrens early acquisition and loss of social-communication milestones. Children who had used words spontaneously and meaningfully and then stopped talking were described by their caregivers as showing more gestures, greater participation in social games, and better receptive language before the loss and fewer of these skills after the loss than other children with autism spectrum disorders. A significant minority of children with autism without word loss showed a very similar pattern of loss of social-communication skills, a pattern not observed in the children with developmental delays or typical development.

Genetics of essential hypertension

Blood pressure is a complex quantitative trait that is determined by multiple environmental and genetic factors. Although some simple Mendelian forms of high blood pressure have been described, essential hypertension is characterized by a complex mode of inheritance. Based on recent advances in molecular biology and statistical genetics, it has become feasible to search for chromosome regions that may contain genes contributing to the pathogenesis of hypertension in humans. For example, recent linkage and association studies have raised the possibility that a blood pressure regulatory locus may exist in or near the angiotensinogen gene on chromosome 1. Detailed genetic experiments in animal models of hypertension may help to guide further clinical studies and lead to an improved understanding of gene action in the pathogenesis of essential hypertension.

Mitochondrial Dysfunction in Autistic Patients with 15q Inverted Duplication

Two autistic children with a chromosome 15q11‐q13 inverted duplication are presented. Both had uneventful perinatal courses, normal electroencephalogram and magnetic resonance imaging scans, moderate motor delay, lethargy, severe hypotonia, and modest lactic acidosis. Both had muscle mitochondrial enzyme assays that showed a pronounced mitochondrial hyperproliferation and a partial respiratory chain block most parsimoniously placed at the level of complex III, suggesting candidate gene loci for autism within the critical region may affect pathways influencing mitochondrial function. Ann Neurol 2003;53:801–804

Association between amygdala volume and anxiety level : Magnetic resonance imaging (MRI) study in autistic children

Our objective was to evaluate brain-behavior relationships between amygdala volume and anxious/depressed scores on the Child Behavior Checklist in a well-characterized population of autistic children. Volumes for the amygdala, hippocampus, and whole brain were obtained from three-dimensional magnetic resonance images (MRIs) captured from 42 children who met the criteria for autistic disorder. Anxious/depressed symptoms were assessed in these children by the Anxious/Depressed subscale of the Child Behavior Checklist. To investigate the association between anxious/depressed scores on the Child Behavior Checklist and amygdala volume, data were analyzed using linear regression methods with Pearson correlation coefficients. A multivariate model was used to adjust for potential covariates associated with amygdala volume, including age at MRI and total brain size. We found that anxious/depressed symptoms were significantly correlated with increased total amygdala volume (r = .386, P = .012) and right amygdala volume (r = .469, P = .002). The correlation between anxious/depressed symptoms and left amygdala volume did not reach statistical significance (r = .249, P = .112). Child Behavior Checklist anxious/depressed scores were found to be a significant predictor of amygdala total (P = .014) and right amygdala (P = .002) volumes. In conclusion, we have identified a significant brain-behavior relationship between amygdala volume and anxious/depressed scores on the Child Behavior Checklist in our autistic cohort. This specific relationship has not been reported in autism. However, the existing literature on human psychiatry and behavior supports our reported evidence for a neurobiologic relationship between symptoms of anxiety and depression with amygdala structure and function. Our results highlight the importance of characterizing comorbid psychiatric symptomatology in autism. The abundance of inconsistent findings in the published literature on autism might reflect differences between study populations regarding age at MRI, level of impairment within autistic subjects, and underlying anxiety level in the selected study groups.

Gene mapping studies with the syndrome of autism

The UCLA Registry for Genetic Studies of Autism had collected data on 308 families by February 1, 1983. A subsample of 46 families withat least two affected children was analyzed for evidence of a Mendelian mode of inheritance. The data were consistent with an autosomal recessive mode of inheritance (Ritvo, E. R., Spence, M. A., Freeman, B. J. Mason-Brothers, A., Mo. A., and Marazita, M. L., 1985, American Journal of Psychiatry, in press). Thirty-four of these families were subjected to gene linkage analyses with 30 standard phenotypic gene markers. There is no evidence of linkage between the purported autism locus and HLA, either from analysis of HLA haplotype sharing or fromlod scores. In addition, close linkage with autism, i.e., ≤5% recombination, could be excluded for 19 of the other autosomal genetic markers. The largest positivelod score, 1.04, was with haptoglobin (HP), at recombination frequencies of 10% in males and 50% in females. Normal C-and Q-banded chromosome polymorphisms were evaluated for association with autism and as additional linkage markers.