A functional genetic link between distinct developmental language disorders.

Background: Rare mutations affecting the FOXP2 transcription factor cause a monogenic speech and language disorder. We hypothesized that neural pathways downstream of FOXP2 influence more common phenotypes, such as specific language impairment.

Methods: We performed genomic screening for regions bound by FOXP2 using chromatin immunoprecipitation, which led us to focus on one particular gene that was a strong candidate for involvement in language impairments.

Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene.

Autism is a genetically complex neurodevelopmental syndrome in which language deficits are a core feature. We describe results from two complimentary approaches used to identify risk variants on chromosome 7 that likely contribute to the etiology of autism. A two-stage association study tested 2758 SNPs across a 10 Mb 7q35 language-related autism QTL in AGRE (Autism Genetic Resource Exchange) trios and found significant association with Contactin Associated Protein-Like 2 (CNTNAP2), a strong a priori candidate.

Wnt-pathway activation during the early stage of neurodegeneration in FTDP-17 mice.

Glycogen synthase kinase-3beta (GSK-3beta), a key component of the Wnt signaling pathway, has been recognized as an important tau kinase with a potential pathogenic role in dementia. We have previously shown that GSK-3beta-induced tau-hyperphosphorylation and Wnt-activation enhance tau-induced degeneration in Drosophila. Here, we demonstrate that Wnt-activation occurs prior to 3 months of age in the JNPL3 mouse model of frontotemporal dementia (FTD).

Stratification based on language-related endophenotypes in autism: attempt to replicate reported linkage.

The identification of autism susceptibility genes has been hampered by phenotypic heterogeneity of autism, among other factors. However, the use of endophenotypes has shown preliminary success in reducing heterogeneity and identifying potential autism-related susceptibility regions. To further explore the utility of using language-related endophenotypes, we performed linkage analysis on multiplex autism families stratified according to delayed expressive speech and also assessed the extent to which parental phenotype information would aid in identifying regions of linkage.

Search for autism loci by combined analysis of Autism Genetic Resource Exchange and Finnish families.

Objective: Several genome-wide screens have been performed in autism spectrum disorders resulting in the identification of numerous putative susceptibility loci. Analyses of pooled primary data should result in an increased sample size and the different study samples have a potential to strengthen the evidence for some earlier identified loci, reveal novel loci, and even to provide information of the general significance of the locus. The objective of this study was to search for potential susceptibility loci for autism, which are supported by two independent samples.

Replication of autism linkage: fine-mapping peak at 17q21.

Autism is a heritable but genetically complex disorder characterized by deficits in language and in reciprocal social interactions, combined with repetitive and stereotypic behaviors. As with many genetically complex disorders, numerous genome scans reveal inconsistent results. A genome scan of 345 families from the Autism Genetic Resource Exchange (AGRE) (AGRE_1), gave the strongest evidence of linkage at 17q11-17q21 in families with no affected females.

Association of the serotonin transporter and receptor gene polymorphisms in neuropsychiatric symptoms in Alzheimer disease.

Background: Serotonin has been linked to neuropsychiatric symptoms in Alzheimer disease, mainly agitation/aggression, depression, and psychosis. Neuropsychiatric symptoms have been associated with polymorphisms of the promoter region (5-HTTPR ) and intron 2 of the serotonin transporter gene (5-HTTVNTR) or the 5-HT2A and 5-HT2C receptor genes in some but not all studies.

Objective: To examine the association of the serotonin promoter, transporter, and receptor genes with neuropsychiatric symptoms in patients with Alzheimer disease.

A genomewide screen of 345 families for autism-susceptibility loci.

We previously reported a genomewide scan to identify autism-susceptibility loci in 110 multiplex families, showing suggestive evidence (P <.01) for linkage to autism-spectrum disorders (ASD) on chromosomes 5, 8, 16, 19, and X and showing nominal evidence (P <.05) on several additional chromosomes (2, 3, 4, 10, 11, 12, 15, 18, and 20).

Association between human mu-opioid receptor gene polymorphism, pain tolerance, and opioid addiction.

Central to both pain responses and opioid addiction is activity at the micro -opioid receptor. To explore the role of the micro -opioid receptor gene (OPRM) in human pain tolerance and opioid addiction, we examined the relationships among OPRM genotype and experimental pain tolerance in opioid addicts in methadone treatment (n = 50) and healthy normal controls (n = 59). Pain phenotype (pain tolerant vs.

Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families.

Autism is a syndrome characterized by deficits in language and social skills and by repetitive behaviors. We hypothesized that potential quantitative trait loci (QTLs) related to component autism endophenotypes might underlie putative or significant regions of autism linkage. We performed nonparametric multipoint linkage analyses, in 152 families from the Autism Genetic Resource Exchange, focusing on three traits derived from the Autism Diagnostic Interview: "age at first word," "age at first phrase," and a composite measure of "repetitive and stereotyped behavior.