Towards an understanding of the role of chromosome 15q11-q13 in idiopathic autism
Delahanty, Ryan James
TOWARD AN UNDERSTANDING OF THE ROLE OF CHROMOSOME 15Q11-Q13 IN IDIOPATHIC AUTISM RYAN JAMES DELAHANTY Dissertation under the direction of Dr. James S. Sutcliffe The 15q11-q13 region is a genomic interval involved in a growing number of genomic disorders. The genes in the interval are subject to imprinting and parent-of-origin expression effects. Maternal duplication of the 15q11-q13 region is the most frequent chromosomal abnormality associated with autism. Extensive work has indicated that two genes in this interval, UBE3A and GABRB3, show very strong evidence for association with autism. To examine the extent to which these genes may contribute to autism, family-based association studies of UBE3A and GABRB3 were undertaken. Here we have investigated the role of common variants of UBE3A and GABRB3 in autism as well as the an intense investigation of the association of a rare variant, P11S in GABRB3 and its role in autism. In addition, we have investigated MECP2, a gene which when defective causes Rett syndrome, and potentially regulates gene expression of UBE3A and GABRB3. e have used genetic and biochemical methods to investigate two genes in the UBE3A network, ECT2 and GCH1. Finally, we used genotype data and multiplex ligation probe amplification (MLPA) to determine if copy number variation in the form of deletions and duplications in UBE3A and GABRB3 may play a role in the etiology of autism. Our findings indicated that a common allele of MECP2 is associated with autism, which was replicated by another group. We show association with UBE3A and its associated genes ECT2 and GCH1 as well as a relationship between UBE3A and GCH1 gene and protein expression, observed in a model system, and validated in our samples, which may provide guidance and support for a role of UBE3A and its action at the synapse and potential contribution to autism. We show modest association of GABRB3 with autism and epilepsy, but find a single coding variant, P11S, maternally overtransmitted and in such cases dramatically increasing autism risk. Finally, we found little evidence for microdeletions or microduplications in UBE3A and GABRB3 to contribute to autism pathology. The work presented in this thesis expands on earlier findings with regard to the role of GABRB3 and UBE3A in autism and represents an investigation of variants in these and their related genes spanning the spectrum from common variants of modest effect to rare variants of more profound effect. The availability of new technologies to evaluate copy number variation and next generation sequencing will likely uncover a wider role for 15q11-q13 and related loci in autism. The role of more highly penetrant private mutations of this nature is suggested as an avenue for further investigation.