Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes

The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11–q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3×10−5). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3×10−4). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3×10−39), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts

Common genetic variants on 5p14.1 associate with autism spectrum disorders

Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)—two genes encoding neuronal cell-adhesion molecules—revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 × 10−8, odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 × 10−8 to 2.1 × 10−10. Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs

The Development of the Child\u27s Concept of Ecology

In recent years, the quality of our environment and its ability to continue to provide food and energy for a growing population have become topics of nearly worldwide concern. In the United States, this concern has generated a number of educational efforts in ecology extending even to the elementary school. However, these curricula appear to have been formulated with little knowledge of how the concept of ecology develops in children. This study sought to answer two questions: 1) What are the effects of the following variables on the development of the child\u27s concept of ecology: a) developmental changes across the intuitive, concrete, and formal operations stages of cognitive development as outlined by Piaget; b) sex of the child; c) place of residence (urban vs. rural)? 2) What are the major parameters of the child\u27s concept of ecology? Based on a pilot study, a semi-structured interview was constructed around seven parameters: Ecology, Biosphere, Pollution, Population, Niche, Species Interaction, and Adaption. A :five-point Likert-type rating scale was constructed to measure each of the seven parameters. Two judges each rated tape-recorded interviews of 132 children on each of the seven scales. In order to answer question one, a separate 2 x 2 x 3 analysis of variance was performed on the mean ratings for each subject on each scale. The results showed· cognitive stage as a significant main effect in the development of the concept of ecology. On all seven scales the- subjects\u27 responses became less egocentric and concrete and more general and abstract as they-moved from intuitive to formal stages..

THE DEVELOPMENT OF THE CHILD\u27S CONCEPT OF ECOLOGY

In recent years, the quality of our environment and its ability to continue to provide food and energy for a growing population have become topics of nearly worldwide concern. In the United States, this concern has generated a number of educational efforts in ecology extending even to the elementary school. However, these curricula appear to have been formulated with little knowledge of how the concept of ecology develops in children. This study sought to answer two questions: 1) What are the effects of the following variables on the development of the child\u27s concept of ecology: a) developmental changes across the intuitive, concrete, and formal operations stages of cognitive development as outlined by Piaget; b) sex of the child; c) place of residence (urban vs. rural)? 2) What are the major parameters of the child\u27s concept of ecology? Based on a pilot study, a semi-structured interview was constructed around seven parameters: Ecology, Biosphere, Pollution, Population, Niche, Species Interaction, and Adaption. A :five-point Likert-type rating scale was constructed to measure each of the seven parameters. Two judges each rated tape-recorded interviews of 132 children on each of the seven scales. In order to answer question one, a separate 2 x 2 x 3 analysis of variance was performed on the mean ratings for each subject on each scale. The results showed· cognitive stage as a significant main effect in the development of the concept of ecology. On all seven scales the- subjects\u27 responses became less egocentric and concrete and more general and abstract as they-moved from intuitive to formal stages..