Defining the autism minimum candidate gene region on chromosome 7.

Previous genetic and cytogenetic studies provide evidence that points to one or more autism susceptibility genes residing on chromosome 7q (AUTS1, 115-149 cM on the Marshfield map). However, further localization using linkage analysis has proven difficult. To overcome this problem, we examined the Collaborative Linkage Study of Autism (CLSA) data-set to identify only the families potentially linked to chromosome 7. Out of 94, 47 families were identified and 17 markers were used to generate chromosomal haplotypes. We performed recombination breakpoint analysis to determine if any portion of the chromosome was predominately shared across families. The most commonly shared region spanned a 6 cM interval between D7S501 and D7S2847. Additional markers at 1 cM intervals within this region were genotyped and association and recombination breakpoint analysis was again performed. Although no significant allelic association was found, the recombination breakpoint data points to a shared region between D7S496-D7S2418 (120-123 cM) encompassing about 4.5 Mb of genomic DNA containing over 50 genes.

Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families.

Autistic disorder is a neurodevelopmental disorder with a complex genetic etiology. Observations of maternal duplications affecting chromosome 15q11-q13 in patients with autism and evidence for linkage and linkage disequilibrium to markers in this region in chromosomally normal autism families indicate the existence of a susceptibility locus. We have screened the families of the Collaborative Linkage Study of Autism for several markers spanning a candidate region covering approximately 2 Mb and including the Angelman syndrome gene (UBE3A) and a cluster of gamma-aminobutyric acid (GABA(A)) receptor subunit genes (GABRB3, GABRA5, and GABRG3). We found significant evidence for linkage disequilibrium at marker D15S122, located at the 5' end of UBE3A. This is the first report, to our knowledge, of linkage disequilibrium at UBE3A in autism families. Characterization of null alleles detected at D15S822 in the course of genetic studies of this region showed a small (approximately 5-kb) genomic deletion, which was present at somewhat higher frequencies in autism families than in controls.

On the detection of linkage in multiple data sets: a comparison of various statistical approaches.

We contrast the pooling of multiple data sets with the compound HLOD (HLOD-C) and the posterior probability of linkage (PPL), two approaches that have been shown to have more power in the presence of genetic heterogeneity. We also propose and evaluate several multipoint extensions.

Impact of maternal depression on ratings of comorbid depression in adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVE: To assess the degree to which indirect maternal reports of comorbid major depression (MD) in adolescents with and without attention-deficit/hyperactivity disorder (ADHD) were influenced by the mother's personal history of MD. METHOD: Bivariate regression was used to model the impact of maternal depression on the direct and indirect report of MD in ADHD (n = 150) and non-ADHD (n = 123) subjects. The dependent variable (i.e., risk for MD) was modeled as a function of the main effect of ADHD, the main effect of reporter, their interaction, and higher-order interactions with maternal depression. RESULTS: There was a significant interaction between maternal depression and the effect of reporter exclusively in non-ADHD control subjects. ADHD continued to be a significant risk factor for MD independent of maternal reporting or maternal depression. CONCLUSIONS: The potential distortion of indirect interviews by depressed mothers may be stronger in community than in clinical settings and does not account for the increased risk for MD in referred adolescents with ADHD.

The importance of watching our weights: how the choice of weights for non-independent sib pairs can dramatically alter results.

Handling non-independent sib pairs in families with multiple affected sibs presents a problem in likelihood-based nonparametric linkage analyses. We contrast the more stable partial-likelihood solution in MAPMAKER/SIBS with the extremely variable partial-likelihood approach used in ASPEX, and the potential inflation of lods when the problem is ignored as in BETA.

An autosomal genomic screen for autism. Collaborative linkage study of autism.

Autism is a severe neurodevelopmental disorder defined by social and communication deficits and ritualistic-repetitive behaviors that are detectable in early childhood. The etiology of idiopathic autism is strongly genetic, and oligogenic transmission is likely. The first stage of a two-stage genomic screen for autism was carried out by the Collaborative Linkage Study of Autism on individuals affected with autism from 75 families ascertained through an affected sib-pair. The strongest multipoint results were for regions on chromosomes 13 and 7. The highest maximum multipoint heterogeneity LOD (MMLS/het) score is 3.0 at D13S800 (approximately 55 cM from the telomere) under the recessive model, with an estimated 35% of families linked to this locus. The next highest peak is an MMLS/het score of 2.3 at 19 cM, between D13S217 and D13S1229. Our third highest MMLS/het score of 2.2 is on chromosome 7 and is consistent with the International Molecular Genetic Study of Autism Consortium report of a possible susceptibility locus somewhere within 7q31-33. These regions and others will be followed up in the second stage of our study by typing additional markers in both the original and a second set of identically ascertained autism families, which are currently being collected. By comparing results across a number of studies, we expect to be able to narrow our search for autism susceptibility genes to a small number of genomic regions. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:609-615, 1999.

Predictors of cognitive test patterns in autism families.

In a case-control study of cognitive performance, tests of intelligence, reading, spelling, and pragmatic language were administered to the parents and siblings of 90 community-ascertained probands with autism (AU group) and to the parents and siblings of 40 similarly ascertained probands with trisomy 21 Down syndrome (DS group). The two samples were comparable for age and parents' education; both groups were well-educated and had above-average intelligence. AU parents scored slightly but significantly lower on the WAIS-R Full Scale and Performance IQ, on two subtests (Picture Arrangement and Picture Completion), and on the Word Attack Test (reading nonsense words) from the Woodcock-Johnson battery. There were no differences between AU and DS siblings. As in earlier studies, AU parents, more often than DS parents, reported a history of early language-related cognitive difficulties; we were not able to replicate this in siblings. AU parents who reported such difficulties scored significantly lower on Verbal IQ, spelling, and the nonsense reading test. AU parents without a history of early language-related cognitive difficulties often had a Verbal IQ that exceeded Performance IQ by more than one standard deviation. AU siblings with early language-related difficulties had similar findings: lower Verbal IQ, poorer spelling, and poorer reading scores, compared to AU siblings without such a history. Parents with a positive history also scored worse on a measure of pragmatic language,the Pragmatic Rating Scale, but not on measures of social-related components of the broader autism phenotype. We propose that cognitive differences in a subset of autism family members are manifestations of the language-related component of the broader autism phenotype, and separate from the social-related component. This is consistent with the hypothesis that there are several genes that may interact to cause autism which segregate independently and have distinguishable manifestations in family members. The hypothesis would be further supported by finding different patterns of genetic loci linked to autism in families where one or both parents has language difficulties.

Finding specific genes that cause autism: a combination of approaches will be needed to maximize power.

Although autism is clearly inherited, it may be challenging to find the genes involved: The mechanism of inheritance is unknown, families with an autistic child are usually small, parent-child pairs are rare, and a fairly large number of genes may be involved, some or all of which may have a small effect on the phenotype. We discuss several strategies for finding genes, all of which may be used in combination to find the relevant genes.

Macrocephaly in children and adults with autism.

OBJECTIVE: To explore the frequency and onset of macrocephaly in autism and its relationship to clinical features. METHOD: Head circumferences at birth, during early childhood, and at the time of examination were studied in a community-based sample of autistic children and adults. The authors investigated whether head circumference at the time of examination was associated with clinical features. RESULTS: Fourteen percent of the autistic subjects had macrocephaly: 11% of males and 24% of females. In most, the macrocephaly was not present at birth; in some it became apparent in early and middle childhood as a result of increased rate of head growth. A small relationship was noted between head circumference percentile and less severe core features of autism. Neither macrocephaly nor head circumference percentile was associated with nonverbal IQ, verbal status, seizure disorder, neurological soft signs or minor physical anomalies in the autistic subjects. CONCLUSION: Macrocephaly is common in autism and usually is not present at birth. Rates of head growth may be abnormal in early and middle childhood in some (37%) children with autism. Macrocephaly does not define a homogeneous subgroup of autistic individuals according to clinical features.

Self-mutilation and suicide attempt: distinguishing features in prisoners.

Nonlethal forms of self-injury are often discussed together with suicide attempts as though they belonged on a continuum of self-harm. Both types of self-injury are common in prisons, which have a predominantly male population; however, most studies of nonlethal self-injury have been done with female subjects. This exploratory study tested the hypothesis that prisoners who injured themselves without intending to die would differ clinically from prisoners who had attempted suicide. Inmates admitted to the prison unit of a public hospital for treatment of self-inflicted wounds or who had a history of previous self-injury were administered a standardized intake protocol by the first author, which included asking about their intent at the time they injured themselves. Patients were classified as self-mutilators or suicide attempters on the basis of intent. Fifteen patients reported that they had attempted to take their own lives, while 16 reported other reasons for harming themselves. Suicide attempt was associated with adult affective disorder 13/15 versus 2/16 mutilators); self-mutilation with a history of childhood hyperactivity (12/16 versus 1/15 suicide attempters) and a mixed dysthymia/anxiety syndrome that began in childhood or early adolescence (9/16). Prison self-mutilators and suicide attempters had very different clinical presentations and histories. The history of childhood hyperactivity in self-mutilators deserves further study in both correctional and noncorrectional populations.

Probabilistic diagnosis in linkage analysis of bipolar disorder: putting weights on the fringe.

We explored the utility of probabilistic weighting of fringe phenotypes in linkage analysis of bipolar disorder for the GAW10 chromosome 18 data. Four liability classes were assigned probabilistic weights based on the estimated probability that the case was a true bipolar. The weights were incorporated in parametric and nonparametric, single and multipoint analyses.

Assessing risk for the Tourette spectrum of disorders among first-degree relatives of probands with Tourette syndrome.

Previous studies have indicated that genetic investigations of Tourette syndrome (TS) should focus on a phenotype that includes not only TS, but chronic tics (CT) and obsessive-compulsive disorder (OCD) as well. These studies have shown that sex may play a role in determining which of the disorders in the TS spectrum is expressed in a susceptible individual. Female relatives of TS probands far more often express OCD, while male relatives more often express TS or CT. Data from the Yale Family Study of TS were used to model risk to first-degree relatives of probands with TS for a variety of TS disease phenotypes. Risk to relatives was modeled using multivariate Cox regression analysis, a method appropriate for assessing risk when there is correlation among disease onsets. This is the first known application of this method to family data. The study identified two proband characteristics that increase the risk for disease onset among both male and female relatives for all TS spectrum disorders, lending credence to the hypothesis that TS spectrum disorders share a common etiology. These were a relatively younger age-at-onset, and no experience of simple motor tics. The predictive ability of two additional factors varied by both sex and disease phenotype. These characteristics, i.e., proband onset with compulsive tics, and proband onset with range, appear to increase risk primarily in female relatives, and for the OCD part of the spectrum.

Clinical correlates of enuresis in ADHD and non-ADHD children.

Enuresis and attention deficit hyperactivity disorder (ADHD) are common childhood disorders that often co-occur. Although each has been linked to neurodevelopmental immaturity and increased risk for psychopathology, the clinical correlates of enuresis remain unclear. Subjects were 140 6-17-year-old boys with DSM-III-R ADHD and 120 non-ADHD controls. Information on enuresis and psychiatric diagnoses was obtained in a standardized manner blind to the child's clinical status. Our results show that (1) enuresis did not increase the risk for psychopathology in children with or without ADHD; (2) enuresis was not associated with psychosocial adversity or developmental immaturity; (3) enuresis was associated with increased risk for learning disability, impaired intellectual functioning, and impaired school achievement in normal control children but not in children with ADHD; and (4) the same pattern of findings was obtained after stratifying children with enuresis by primary versus secondary and by nocturnal versus diurnal subtypes. These results suggest that the clinical implications of enuresis may differ for ADHD and non-ADHD children.

Tourette's syndrome: what are the influences of gender and comorbid obsessive-compulsive disorder?

OBJECTIVE: To explore the influence of gender and comorbid obsessive-compulsive disorder (OCD) on the phenomenology of Tourette's syndrome (TS). METHOD: TS proband groups defined by gender and comorbid OCD status were compared on a variety of sociodemographic variables, clinical characteristics, and perinatal complications. RESULTS: Compared to females, males more often onset with rage and had ever experienced any form of simple tics. Females onset with compulsive tics more often than males. Probands with comorbid OCD were more likely than those without OCD to onset with complex tics. Delivery complications, especially forceps deliveries, were associated with being male and with having OCD. Fetal exposure to relatively high levels of coffee, cigarettes, or alcohol predicted OCD in TS probands. Diagnosis of TS occurred at later ages among females than among males. Males and females displayed different age distributions. CONCLUSIONS: Males and females tend to experience different kinds of symptoms at onset. However, the overall experience of TS appears to be similar for both groups. Perinatal brain injury is implicated in the etiology of TS in some boys. Early brain injury may cause or exacerbate the development of OCD in some TS sufferers.

Gender and mortality in schizophrenia: do women act like men?

The effect of gender on mortality was explored for a sample of DSM-III diagnosed schizophrenics followed for up to 42 years. The data for 332 cases and 304 matched normal controls were from the retrospective cohort family studies, the Iowa 500 and non-500. Survival analysis and Cox regression models were used to test the effects of gender, illness status and their interaction on the risks for natural and unnatural deaths. The control men experienced significantly more unnatural deaths than the control women, which was not found for schizophrenic men and women. The unnatural death rate among schizophrenic women was similar to the rate for schizophrenic and control men, and significantly higher than for control women during the early phase of the illness. Findings suggest that some factors that predict suicide may be similar for schizophrenic women and men.

The role of gender in identifying subtypes of schizophrenia: a latent class analytic approach.

Past literature suggests that schizophrenic men and women may be at different risks for developing different subtypes of schizophrenia. This hypothesis was tested using data from the well-known retrospective cohort family studies, the Iowa 500 and the Iowa non-500. The sample consisted of 171 male and 161 female DSM-III schizophrenic patients and 713 of their first-degree relatives. First, bivariate tests for gender differences were conducted regarding family morbidity, age of onset, premorbid history, season of birth, and expression of deficit and affective symptoms. Restricted maximum likelihood latent class analysis was then used to test whether there was a subgroup of schizophrenic men who were more likely to have a low familial risk for schizophrenia or schizophrenia spectrum disorders, deficit symptoms, poor premorbid history, and birth in the winter months, suggesting possible early environmental insults, compared to schizophrenic women. Results showed that although men were more likely to meet these criteria, women also met them, thus suggesting gender differences in the prevalence of the subtype. Schizophrenic women were more likely to express a form of the illness characterized by dysphoria, persecutory delusions, and a higher family morbidity risk for schizophrenia than schizophrenic men. Results for spectrum disorders among relatives were equivocal with regard to gender.

Use and abuse of controlled substances by pharmacists and pharmacy students.

The use of controlled substances by samples of pharmacists and pharmacy students in one New England state was surveyed. A questionnaire was sent in November 1984 to a sample of 510 pharmacists randomly selected from the membership list of the state's pharmaceutical association and to a sample of 470 students from the state's pharmacy schools; 76% and 67% of the eligible pharmacists and students responded, respectively. The questionnaire elicited information about the respondents' use of controlled substances for self-treatment and recreation, as well as the instrumental use of stimulants to enhance performance. Almost half of the pharmacists (46%) and two thirds of the students (62%) reported using a controlled substance at some time without a prescription; 19% and 41%, respectively, used one within the past year. Whereas students used the drugs most often for recreation (57% ever, 36% currently), use by pharmacists was more equally divided among self-treatment (29% ever, 13% currently), recreation (29% ever, 9% currently), and instrumental purposes (21% ever). The drugs most often used were marijuana, stimulants (especially cocaine by students), tranquilizers, and opiates. Drug use was generally limited in amount, but 18% of the pharmacists and 35% of the students who ever used a drug either became dependent or were at risk of drug abuse. Current drug use was most strongly associated with age, non-attendance at religious services, student access, year in school, and citizenship. The findings of this study suggest the need for continued development of impaired pharmacist committees and drug abuse prevention programs for pharmacists and pharmacy students.