Edwin H. Cook

A genomewide screen for autism: Strong evidence for linkage to chromosomes 2q, 7q, and 16p

Autism is characterized by impairments in reciprocal communication and social interaction and by repetitive and stereotyped patterns of activities and interests. Evidence for a strong underlying genetic predisposition comes from twin and family studies, although susceptibility genes have not yet been identified. A whole-genome screen for linkage, using 83 sib pairs with autism, has been completed, and 119 markers have been genotyped in 13 candidate regions in a further 69 sib pairs. The addition of new families and markers provides further support for previous reports of linkages on chromosomes 7q and 16p. Two new regions of linkage have also been identified on chromosomes 2q and 17q. The most significant finding was a multipoint maximum LOD score (MLS) of 3.74 at marker D2S2188 on chromosome 2; this MLS increased to 4.80 when only sib pairs fulfilling strict diagnostic criteria were included. The susceptibility region on chromosome 7 was the next most significant, generating a multipoint MLS of 3.20 at marker D7S477. Chromosome 16 generated a multipoint MLS of 2.93 at D16S3102, whereas chromosome 17 generated a multipoint MLS of 2.34 at HTTINT2. With the addition of new families, there was no increased allele sharing at a number of other loci originally showing some evidence of linkage. These results support the continuing collection of multiplex sib-pair families to identify autism-susceptibility genes.

The phenotypic manifestations of rare genic CNVs in autism spectrum disorder.

Significant evidence exists for the association between copy number variants (CNVs) and Autism Spectrum Disorder (ASD); however, most of this work has focused solely on the diagnosis of ASD. There is limited understanding of the impact of CNVs on the ‘sub-phenotypes’ of ASD. The objective of this paper is to evaluate associations between CNVs in differentially brain expressed (DBE) genes or genes previously implicated in ASD/intellectual disability (ASD/ID) and specific sub-phenotypes of ASD. The sample consisted of 1590 cases of European ancestry from the Autism Genome Project (AGP) with a diagnosis of an ASD and at least one rare CNV impacting any gene and a core set of phenotypic measures, including symptom severity, language impairments, seizures, gait disturbances, intelligence quotient (IQ) and adaptive function, as well as paternal and maternal age. Classification analyses using a non-parametric recursive partitioning method (random forests) were employed to define sets of phenotypic characteristics that best classify the CNV-defined groups. There was substantial variation in the classification accuracy of the two sets of genes. The best variables for classification were verbal IQ for the ASD/ID genes, paternal age at birth for the DBE genes and adaptive function for de novo CNVs. CNVs in the ASD/ID list were primarily associated with communication and language domains, whereas CNVs in DBE genes were related to broader manifestations of adaptive function. To our knowledge, this is the first study to examine the associations between sub-phenotypes and CNVs genome-wide in ASD. This work highlights the importance of examining the diverse sub-phenotypic manifestations of CNVs in ASD, including the specific features, comorbid conditions and clinical correlates of ASD that comprise underlying characteristics of the disorder.

A haplotype-based framework for group-wise transmission/disequilibrium tests for rare variant association analysis

MOTIVATIONnA major focus of current sequencing studies for human genetics is to identify rare variants associated with complex diseases. Aside from reduced power of detecting associated rare variants, controlling for population stratification is particularly challenging for rare variants. Transmission/disequilibrium tests (TDT) based on family designs are robust to population stratification and admixture, and therefore provide an effective approach to rare variant association studies to eliminate spurious associations. To increase power of rare variant association analysis, gene-based collapsing methods become standard approaches for analyzing rare variants. Existing methods that extend this strategy to rare variants in families usually combine TDT statistics at individual variants and therefore lack the flexibility of incorporating other genetic models.nnnRESULTSnIn this study, we describe a haplotype-based framework for group-wise TDT (gTDT) that is flexible to encompass a variety of genetic models such as additive, dominant and compound heterozygous (CH) (i.e. recessive) models as well as other complex interactions. Unlike existing methods, gTDT constructs haplotypes by transmission when possible and inherently takes into account the linkage disequilibrium among variants. Through extensive simulations we showed that type I error was correctly controlled for rare variants under all models investigated, and this remained true in the presence of population stratification. Under a variety of genetic models, gTDT showed increased power compared with the single marker TDT. Application of gTDT to an autism exome sequencing data of 118 trios identified potentially interesting candidate genes with CH rare variants.nnnAVAILABILITY AND IMPLEMENTATIONnWe implemented gTDT in C++ and the source code and the detailed usage are available on the authors website (https://medschool.vanderbilt.edu/cgg).nnnCONTACTnbingshan.li@vanderbilt.edu or wei.chen@chp.edunnnSUPPLEMENTARY INFORMATIONnSupplementary data are available at Bioinformatics online.

Serotonin Transporter Genotype and Seasonal Variation in Serotonin Function

Nielsen and colleagues (1998) have provided important data on the relationship between cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and serotonin transporter (HTT 5 SLC6A4) promoter genotype. They found a trend for higher CSF 5-HIAA levels in subjects with the l/l genotype than in subjects with the l/s and s/s genotypes. They also noted a trend for seasonal variation in CSF 5-HIAA levels in those with the l/l genotype, which appears consistent with our findings on blood serotonin (5HT) levels (Hanna et al 1998). In contrast to a previous report on normal controls (Brewerton et al. 1987), they did not observe a seasonal pattern in CSF 5-HIAA levels in their sample of unrelated Finnish alcoholics and controls. As they suggest, their lack of replication of our results may be due to differences in subject characteristics and serotonergic measures. Further work may determine whether serotonin transporter (5-HTT) activity has a stronger influence on blood 5-HT content than on CSF 5-HIAA levels. The question of whether the l/l genotype, in particular, is associated with seasonal variation in the 5-HTT may be resolved with further studies of the 5-HTT in both platelet and brain (Little et al. 1998). The advantage of repeat measures of platelet 5-HTT binding or function is that they could be used to assess intra-individual variation over time.

Drosophila melanogaster : a novel animal model for the behavioral characterization of autism-associated mutations in the dopamine transporter gene

Drosophila melanogaster : a novel animal model for the behavioral characterization of autism-associated mutations in the dopamine transporter gene