Individual common variants exert weak effects on the risk for autism spectrum disorders.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk.

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants.

Functional expressions of the aging brain.

In the conventional view, aging of the brain is associated with atrophy vascular abnormalities and loss of volume in hippocampus and amygdala. Cognitively, aging is associated with slowing of processing and memory loss. However, many studies of aging do not examine the cases to exclude demented people.

A genome-wide scan for common alleles affecting risk for autism.

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8).

Overlap between autism and specific language impairment: comparison of Autism Diagnostic Interview and Autism Diagnostic Observation Schedule scores.

Autism and specific language impairment (SLI) are developmental disorders that, although distinct by definition, have in common some features of both language and social behavior. The goal of this study was to further explore the extent to which specific clinical features of autism are seen in SLI. The children with the two disorders, matched for non-verbal IQ, were compared on the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS).

Overrepresentation of mood and anxiety disorders in adults with autism and their first-degree relatives: what does it mean?

Research indicates that relatives of individuals with autism have higher rates of affective disorders than both the general population and families of children with other developmental disabilities. In addition, individuals with autism have high rates of co-morbid mood and anxiety disorders. This study sought to identify possible reasons for these previous findings by documenting the presence of affective disorders in both probands (the individuals with autism) and their family members.

Language and reading abilities of children with autism spectrum disorders and specific language impairment and their first-degree relatives.

Autism spectrum disorder (ASD) and specific language impairment (SLI) are developmental disorders exhibiting language deficits, but it is unclear whether they arise from similar etiologies. Language impairments have been described in family members of children with ASD and SLI, but few studies have quantified them. In this study, we examined IQ, language, and reading abilities of ASD and SLI children and their first-degree relatives to address whether the language difficulties observed in some children with ASD are familial and to better understand the degree of overlap between these disorders and their broader phenotypes.

Mapping autism risk loci using genetic linkage and chromosomal rearrangements.

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families.

Communicative competence in parents of children with autism and parents of children with specific language impairment.

While the primary language deficit in autism has been thought to be pragmatic, and in specific language impairment (SLI) structural, recent research suggests phenomenological and possibly genetic overlap between the two syndromes. To compare communicative competence in parents of children with autism, SLI, and down syndrome (DS), we used a modified pragmatic rating scale (PRS-M). Videotapes of conversational interviews with 47 autism, 47 SLI, and 21 DS parents were scored blind to group membership.

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.

Etiologies of autism in a case-series from Tanzania.

Most autism has a genetic cause although post-encephalitis cases are reported. In a case-series (N = 20) from Tanzania, 14 met research criteria for autism. Three (M:F = 1:2) had normal development to age 22, 35, and 42 months, with onset of autism upon recovery from severe malaria, attended by prolonged high fever, convulsions, and in one case prolonged loss of consciousness.

Comorbid psychiatric disorders in children with autism: interview development and rates of disorders.

The Kiddie Schedule for Affective Disorders and Schizophrenia was modified for use in children and adolescents with autism by developing additional screening questions and coding options that reflect the presentation of psychiatric disorders in autism spectrum disorders. The modified instrument, the Autism Comorbidity Interview-Present and Lifetime Version (ACI-PL), was piloted and frequently diagnosed disorders, depression, ADHD, and OCD, were tested for reliability and validity. The ACI-PL provides reliable DSM diagnoses that are valid based on clinical psychiatric diagnosis and treatment history.

Atypical behaviors in children with autism and children with a history of language impairment.

The frequency, course, and inter-relationships of atypical eating, sleeping, self-injurious behavior, aggression and temper tantrums in children with autism and children with a history of language impairment (HLI), was investigated using a parent interview that was created to examine these problem behaviors. The relationships between these behaviors and language, IQ, severity of autistic symptoms and depression were also assessed. Atypical eating behavior, abnormal sleep patterns, temper tantrums, and self-injurious behavior were significantly more common in the children with autism than those with HLI.

Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors.

Autism is a spectrum of neurodevelopmental disorders with a primarily genetic etiology exhibiting deficits in (1) development of language and (2) social relationships and (3) patterns of repetitive, restricted behaviors or interests and resistance to change. Elevated platelet serotonin (5-HT) in 20%-25% of cases and efficacy of selective 5-HT reuptake inhibitors (SSRIs) in treating anxiety, depression, and repetitive behaviors points to the 5-HT transporter (5-HTT; SERT) as a strong candidate gene. Association studies involving the functional insertion/deletion polymorphism in the promoter (5-HTTLPR) and a polymorphism in intron 2 are inconclusive, possibly because of phenotypic heterogeneity.

Genome-wide and Ordered-Subset linkage analyses provide support for autism loci on 17q and 19p with evidence of phenotypic and interlocus genetic correlates.

Background: Autism is a neurobehavioral spectrum of phenotypes characterized by deficits in the development of language and social relationships and patterns of repetitive, rigid and compulsive behaviors. Twin and family studies point to a significant genetic etiology, and several groups have performed genomic linkage screens to identify susceptibility loci.

Methods: We performed a genome-wide linkage screen in 158 combined Tufts, Vanderbilt and AGRE (Autism Genetics Research Exchange) multiplex autism families using parametric and nonparametric methods with a categorical autism diagnosis to identify loci of main effect.

A linkage disequilibrium map of the 1-Mb 15q12 GABA(A) receptor subunit cluster and association to autism.

Autism is a complex genetic neuropsychiatric condition characterized by deficits in social interaction and language and patterns of repetitive or stereotyped behaviors and restricted interests. Chromosome 15q11.2-q13 is a candidate region for autism susceptibility based on observations of chromosomal duplications in a small percentage of affected individuals and findings of linkage and association.

Examination of NRCAM, LRRN3, KIAA0716, and LAMB1 as autism candidate genes.

Background: A substantial body of research supports a genetic involvement in autism. Furthermore, results from various genomic screens implicate a region on chromosome 7q31 as harboring an autism susceptibility variant. We previously narrowed this 34 cM region to a 3 cM critical region (located between D7S496 and D7S2418) using the Collaborative Linkage Study of Autism (CLSA) chromosome 7 linked families.

How might genetic mechanisms operate in autism?

Twin and family studies provide strong evidence that autism has a largely genetic aetiology. The pattern of familial aggregation suggests that in individual families, a small number of genes act together to cause the phenotype. However, it is unlikely that the same genes act in all families.

A principal components analysis of the Autism Diagnostic Interview-Revised.

Objective: To develop factors based on the Autism Diagnostic Interview-Revised (ADI-R) that index separate components of the autism phenotype that are genetically relevant and validated against standard measures of the constructs.

Method: ADIs and ADI-Rs of 292 individuals with autism were subjected to a principal components analysis using VARCLUS. The resulting variable clusters were validated against standard measures.

Exploratory subsetting of autism families based on savant skills improves evidence of genetic linkage to 15q11-q13.

Objective: Autism displays a remarkably high heritability but a complex genetic etiology. One approach to identifying susceptibility loci under these conditions is to define more homogeneous subsets of families on the basis of genetically relevant phenotypic or biological characteristics that vary from case to case.

Method: The authors performed a principal components analysis, using items from the Autism Diagnostic Interview, which resulted in six clusters of variables, five of which showed significant sib-sib correlation.

Autism-related language, personality, and cognition in people with absolute pitch: results of a preliminary study.

Reports of a relatively high prevalence of absolute pitch (AP) in autistic disorder suggest that AP is associated with some of the distinctive cognitive and social characteristics seen in autism spectrum disorders. Accordingly we examined cognition, personality, social behavior, and language in 13 musicians with strictly defined AP (APS) and 33 musician controls (MC) without AP using standardized interviews and tests previously applied to identify the broad autism phenotype seen in the relatives of autistic probands. These included the Pragmatic Rating Scale (PRS) (social aspects of language) the Personality Assessment Schedule (PAS) (rigidity, aloofness, anxiety/worry, hypersensitivity), and WAIS performance subtests (PIQ).

Diagnostic reliability of bipolar II disorder.

Background: Although the diagnostic reliability of major depression and mania has been well established, that of hypomania and bipolar II (BPII) disorder has not. This remains an important issue for clinicians, especially for those undertaking genetic studies of BP disorder since bipolar I (BPI) and BPII disorders often cluster in the same families. We have assessed our diagnostic reliability of BP disorders, recurrent unipolar disorder, and their constituent episodes (major depression, mania, and hypomania) using interview and best-estimate diagnostic procedures used in a genetic study of families with BPI disorder.