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 = 2.3x10(-5)). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3x10(-4)). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3x10(-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.

In utero Exposure to ß-2-Adrenergic Receptor Agonist Drugs and Risk for Autism Spectrum Disorders.

OBJECTIVES: The purpose of this study was to investigate associations between use of ß-2-adrenergic receptor (B2AR) agonist drugs during pregnancy and risk for autism spectrum disorders (ASD). METHODS: A case-control study was conducted by using Denmark's health and population registers. Among children born between 1997 and 2006, 5200 cases with ASD admission diagnoses and 52 000 controls without ASD were identified and individually matched on month and year of birth. Conditional logistic regression models were used to estimate odds ratios (OR) and confidence intervals (CI) for any B2AR agonist exposure during pregnancy, preconception, and by trimester. RESULTS: In total, 3.7% of cases and 2.9% of controls were exposed to B2ARs during pregnancy. Use of B2ARs during pregnancy was associated with increased risk of ASD, even after adjustment for maternal asthma and other covariates (OR: 1.3, 95% CI: 1.1-1.5). The elevated risk was observed with use of B2AR during preconception (OR: 1.3, 95% CI: 1.0-1.6), first trimester (OR: 1.3, 95% CI: 1.1-1.5), second trimester (OR: 1.5, 95% CI: 1.1-1.7), and the third trimester (OR: 1.4, 95% CI: 1.1-1.7). There was some evidence that longer B2AR within-pregnancy use was associated with the increased risk. CONCLUSIONS: B2AR agonist exposure during pregnancy may be associated with an increased risk for ASD. If the effect is real, any intervention must be balanced against benefits of indicated medication use by pregnant women.

In utero exposure to selective serotonin reuptake inhibitors and risk for autism spectrum disorder.

We investigated whether there is an association between increased risk for autism spectrum disorders (ASD) and selective serotonin reuptake inhibitors (SSRIs) used during pregnancy. This study used Denmark's health and population registers to obtain information regarding prescription drugs, ASD diagnosis, and health and socioeconomic status. There were 1.5 % of cases and 0.7 % of controls exposed to SSRIs during the pregnancy period, and higher effect estimates observed with longer use. We found evidence that in utero exposure to SSRIs increases a child's risk associated with ASD. These results, while adding to the limited knowledge on prenatal pharmacological exposures as potential ASD risk factors, need to be balanced against the benefits of indicated medication use by pregnant mothers.