Genetic basis of autism spectrum disorders; molecular genetics; statistical genetics; epigenetics, neuropsychiatric genetics; phenotypic dissection of complex genetic disorders (autism, anxiety, major depression, obsessive-compulsive disorder, and other related conditions)
Autism is a neurodevelopmental disorder affecting approximately 1 per 500 children. The broader autism spectrum of pervasive developmental disorders may have a current prevalene as high as 1 in 150. Autism exhibits a complex genetic etiology with significant clinical and locus heterogeneity. Alleles at up to twenty genes may combine in some unknown way to produce the overall risk for development of this disorder in any one individual or family.
Our web site on autism and ongoing studies is at http://autismgenes.org
We are dissecting the genetics of autism using a combination of molecular and statistical genetic approaches, informed by the altered physiology and neurodevelopment observed in patients. We are using state of the art methods to identify genetic effects using linkage and allelic association analyses, as well as testing for potential for gene-gene or epigenetic effects that may play a role in disease susceptibility. Additionally, we are dissecting the autism phenotype by using genetically-relevant traits that represent subphenotypes of this clinically variable disorder. Quantitative traits may be particularly useful in identifying loci that contribute to specific aspects of the phenotype rather than the phenotype overall.
Several candidate regions are the focus of ongoing study. One such interval in chromosome 15q11-q13 has been implicated in autism-spectrum phenotypes based on observations of chromosomal duplications leading to increased gene copy for this region. Potential maternal-specificity of the duplication origin and increasing severity of phenotype with increasing gene copy imply involvement of genomic imprinting and gene dosage effects. This chromosomal region harbors genes involved in two other neurobehavioral phenotypes (Prader-Willi syndrome and Angelman syndrome), which exhibit opposite patterns of genomic imprinting and features in common with autism. Candidate gene and linkage studies have yielded evidence for involvement of this region in susceptibility for development of autism in families without chromosomal abnormalities. Functional candidate genes in the relevant 15q11-q13 interval include a cluster of gamma-aminobutyric acid (GABA) receptor subunits (beta3, alpha5 and gamma3), the E6-AP ubiquitin-protein ligase (UBE3A) gene, also responsible for Angelman syndrome. This region is also a prime candidate for involvement of some epigenetic phenomenon that will be difficult to identify using standard approaches.
Other candidate regions we are studying include chromosomes 17q11 and 19p. These and other regions were detected by genomic linkage in autism families and all contain genes which are thought to be highly relevant to the known neurobiology of autism. A notable example is the serotonin transporter gene (SLC6A4), which maps to 17q11.2 and has long been considered an excellent functional candidate gene in autism and other neuropsychiatric disorders. Finally, we are pursuing candidate genes in neuronal systems thought to be important in autism, including serotonin, glutamate, and several others. Our approach is to examine genes and intervals using a combination of genetic linkage and high-resolution allelic association studies in autism families and through direct screening for disease-specific mutations. As disease-associated alleles are identified, we will identify the specific susceptibility variant and determine how it affects gene expression or protein function using various in vitro and in vivo (e.g. mouse models) strategies.