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1.  A Pharmacogenetic Study of Escitalopram in Autism Spectrum Disorders 
Scientific Abstract
To determine the effect of serotonin transporter polymorphism promoter region (5-HTTPLR) genotypic variation (low, intermediate, and high expression groups) on response to escitalopram treatment of children and adolescents with Autism Spectrum Disorders (ASDs).
The study used a forced titration, open label design, with genotype blind until study completion. Participants were children and adolescents aged 4 to 17 years of age with a confirmed ASD (Autistic Disorder, Asperger’s Disorder, or Pervasive Developmental Disorder, Not Otherwise Specified).
There was an interaction between genotype group and time on the Aberrant Behavior Checklist Irritability Subscale (primary outcome variable) (linear MMLE = −4.84, Z = −2.89, SE = 1.67, p = 0.004). Examination of baseline to last-observation carried forward scores revealed that a genotype grouping based on a previous study of platelet 5-HT uptake revealed less response in the genotype group that had S/S genotype for 5-HTTLPR and did not have a diplotype in intron 1 previously shown to be associated with increased platelet 5-HT uptake.
This genotype-blind, prospective pharmacogenetic study found the group of subjects with associated with the lowest platelet 5-HT uptake from previous study had the smallest reduction in ABC-Irritability scores after open label treatment with escitalopram. Replication is necessary to confirm these findings.
Lay Abstract
Many children with Autism Spectrum Disorders have problems with anxiety, obsessions, compulsions, and insisting that things stay the same. When other interventions are not adequately helping the child deal with these difficulties, sometimes medication is considered a treatment option.
Serotonin is inactivated when it is taken back into nerve cells by a protein called the serotonin transporter. Escitalopram blocks this protein. We wanted to know if variation in the gene that produces the protein target for escitalopram would be related to response to this treatment.
PMCID: PMC2937270  PMID: 20020537
autistic disorder; escitalopram; pharmacogenetics; open label; drug treatment
2.  Common genetic variants on 5p14.1 associate with autism spectrum disorders 
Nature  2009;459(7246):528-533.
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.
PMCID: PMC2943511  PMID: 19404256
3.  Autism genome-wide copy number variation reveals ubiquitin and neuronal genes 
Nature  2009;459(7246):569-573.
Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins1–4. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs5–9. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with ~550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10−3). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10−3). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10−6). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.
PMCID: PMC2925224  PMID: 19404257
4.  Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes 
PLoS Genetics  2009;5(6):e1000536.
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.
Author Summary
Autism spectrum disorders (ASDs) are common neurodevelopmental syndromes with a strong genetic component. ASDs are characterized by disturbances in social behavior, impaired verbal and nonverbal communication, as well as repetitive behaviors and/or a restricted range of interests. To identify 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. To enrich for variants most likely to interfere with gene function, we restricted our analyses to deletions and gains encompassing exons. Of the many genomic regions highlighted, 27 were seen to harbor rare variants in cases and not controls, both in the first phase of our analysis, and also in an independent replication cohort comprised of 859 cases and 1,051 controls. More work in a larger number of individuals will be required to determine which of the rare alleles highlighted here are indeed related to the ASDs and how they act to shape risk.
PMCID: PMC2695001  PMID: 19557195

Results 1-4 (4)