Friday, May 21, 2010
Franklin Hall B Level 4 (Philadelphia Marriott Downtown)
11:00 AM
Background: Autism is a common neurodevelopmental disorder that is characterized by deficits in reciprocal social interaction, communication and patterns of repetitive behaviors and restricted interests. Twin and family studies indicate high heritability, but evidence supports a highly complex architecture for the underlying genetic etiology. Serotonin dysregulation has long been implicated in autism, and rare autism-associated variants in the serotonin transporter (SERT; gene symbol: SLC6A4) lead to gains of function involving increased activity and abnormal regulation. In autism families, these SERT variants result in more severe rigid-compulsive behaviors, but one has also been observed in multiple pedigrees with obsessive compulsive disorder (OCD). Selective serotonin reuptake inhibitors (SSRIs) that selectively target SERT are a key front-line therapy for OCD. Thus, SERT variants and SSRI treatment efficacy highlight a shared etiology between autism and OCD involving serotonin regulation via SERT.
Objectives: We are pursuing related hypotheses that genes and/or pathways related to SERT regulation and SSRI-responsive OCD behaviors harbor autism susceptibility alleles.
Methods: In this study, we tested these hypotheses following a rare variant susceptibility model. We sequenced exons for two loci, DLGAP3 and ADAMTS6, in unrelated autism probands and controls. DLGAP3 is also known as SAPAP3 (SAP90/PSD95-associated protein 3), and mutations have been described in cases of OCD and trichotillomania, and a mouse knock-out shows analogous behaviors that are responsive to treatment with SSRIs. ADAMTS6 encodes a disintegrin and metalloproteinase with thrombospondin motifs 6, and this locus was identified using the SCAN database (www.scandb.org) based on SNPs within this locus that significantly predict variation of SLC6A4 gene expression in lymphoblastoid cell lines. Exonic sequences for these two genes were sequenced in a pilot sample of 200 cases and 200 controls.
Results: Preliminary sequence analysis of DLGAP3 shows similar numbers of synonymous and nonsynonymous variants between cases and controls. In contrast, analysis of ADAMTS6 for rare variants revealed 8 nonsynonymous and 4 synonymous variants in cases vs 3 nonsynonymous and 1 synonymous variants in controls, suggesting a greater burden of rare, transcribed variants in ADAMTS6 in individuals with autism.
Conclusions: We conclude that further studies of rare variation are warranted for ADAMTS6, while for DLGAP3, rare variants do not seem to be a significant contributor to autism risk.
Objectives: We are pursuing related hypotheses that genes and/or pathways related to SERT regulation and SSRI-responsive OCD behaviors harbor autism susceptibility alleles.
Methods: In this study, we tested these hypotheses following a rare variant susceptibility model. We sequenced exons for two loci, DLGAP3 and ADAMTS6, in unrelated autism probands and controls. DLGAP3 is also known as SAPAP3 (SAP90/PSD95-associated protein 3), and mutations have been described in cases of OCD and trichotillomania, and a mouse knock-out shows analogous behaviors that are responsive to treatment with SSRIs. ADAMTS6 encodes a disintegrin and metalloproteinase with thrombospondin motifs 6, and this locus was identified using the SCAN database (www.scandb.org) based on SNPs within this locus that significantly predict variation of SLC6A4 gene expression in lymphoblastoid cell lines. Exonic sequences for these two genes were sequenced in a pilot sample of 200 cases and 200 controls.
Results: Preliminary sequence analysis of DLGAP3 shows similar numbers of synonymous and nonsynonymous variants between cases and controls. In contrast, analysis of ADAMTS6 for rare variants revealed 8 nonsynonymous and 4 synonymous variants in cases vs 3 nonsynonymous and 1 synonymous variants in controls, suggesting a greater burden of rare, transcribed variants in ADAMTS6 in individuals with autism.
Conclusions: We conclude that further studies of rare variation are warranted for ADAMTS6, while for DLGAP3, rare variants do not seem to be a significant contributor to autism risk.