High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility.

Autism spectrum disorders are a group of highly heritable neurodevelopmental disorders with a complex genetic etiology. The International Molecular Genetic Study of Autism Consortium previously identified linkage loci on chromosomes 7 and 2, termed AUTS1 and AUTS5, respectively. In this study, we performed a high-density association analysis in AUTS1 and AUTS5, testing more than 3000 single nucleotide polymorphisms (SNPs) in all known genes in each region, as well as SNPs in non-genic highly conserved sequences. SNP genotype data were also used to investigate copy number variation within these regions. The study sample consisted of 127 and 126 families, showing linkage to the AUTS1 and AUTS5 regions, respectively, and 188 gender-matched controls. Further investigation of the strongest association results was conducted in an independent European family sample containing 390 affected individuals. Association and copy number variant analysis highlighted several genes that warrant further investigation, including IMMP2L and DOCK4 on chromosome 7. Evidence for the involvement of DOCK4 in autism susceptibility was supported by independent replication of association at rs2217262 and the finding of a deletion segregating in a sib-pair family.

Analysis of IMGSAC autism susceptibility loci: evidence for sex limited and parent of origin specific effects.

BACKGROUND AND METHODS: Autism is a severe neurodevelopmental disorder, which has a complex genetic predisposition. The ratio of males to females affected by autism is approximately 4:1, suggesting that sex specific factors are involved in its development. We reported previously the results of a genomewide screen for autism susceptibility loci in 83 affected sibling pairs (ASP), and follow up analysis in 152 ASP. Here, we report analysis of an expanded sample of 219 ASP, using sex and parent of origin linkage modelling at loci on chromosomes 2, 7, 9, 15, and 16. RESULTS: The results suggest that linkage to chromosomes 7q and 16p is contributed largely by the male-male ASP (MLS = 2.55 v 0.12, and MLS = 2.48 v 0.00, for the 145 male-male and 74 male-female/female-female ASP on chromosomes 7 and 16 respectively). Conversely linkage to chromosome 15q appears to be attributable to the male-female/female-female ASP (MLS = 2.62 v 0.00, for non-male and male-male ASP respectively). On chromosomes 2 and 9, all ASP contribute to linkage. These data, supported by permutation, suggest a possible sex limited effect of susceptibility loci on chromosomes 7, 15, and 16. Parent of origin linkage modelling indicates two distinct regions of paternal and maternal identity by descent sharing on chromosome 7 (paternal MLS = 1.46 at approximately 112 cM, and maternal MLS = 1.83 at approximately 135 cM; corresponding maternal and paternal MLS = 0.53 and 0.28 respectively), and maternal specific sharing on chromosome 9 (maternal MLS = 1.99 at approximately 30 cM; paternal MLS = 0.02). CONCLUSION: These data support the possibility of two discrete loci underlying linkage of autism to chromosome 7, and implicate possible parent of origin specific effects in the aetiology of autism.

Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene.

The results from several genome scans indicate that chromosome 2q21-q33 is likely to contain an autism susceptibility locus. We studied the potential contribution of nine positional and functional candidate genes: TBR-1; GAD1; DLX1; DLX2; cAMP-GEFII; CHN1; ATF2; HOXD1 and NEUROD1. Screening these genes for DNA variants and association analysis using intragenic single nucleotide polymorphisms did not provide evidence for a major role in the aetiology of autism. Four rare nonsynonymous variants were identified, however, in the cAMP-GEFII gene. These variants were present in five families, where they segregate with the autistic phenotype, and were not observed in control individuals. The significance of these variants is unclear, as their low frequency in IMGSAC families does not account for the relatively strong linkage signal at the 2q locus. Further studies are needed to clarify the contribution of cAMP-GEFII gene variants to autism susceptibility.

Strategies for autism candidate gene analysis.

The identification of autism susceptibility genes has moved a step closer over the last four years with the completion of eight whole genome screens for linkage. Several overlapping areas of linkage have been reported, most notably on chromosomes 7q22-31 and 2q32. These regions of replicated linkage provide a focus to search for candidate genes whose normal functions in neurodevelopment are altered to increase the risk for autism. Strategies that aim to narrow further the rather broad size of these linkage regions, such as high density single nucleotide polymorphism (SNP)-based association studies, currently suffer from practical and statistical limitations. Alternatively, positional candidate genes can be screened for deleterious variants in autistic individuals selected from large samples such as those collected by the International Molecular Genetic Study of Autism Consortium (IMGSAC). Targeted genotyping of candidate gene variants in this large multiplex family sample will then be performed to confirm association with autism.

Genetic clues to the biological basis of autism.

Autism, the prototypical pervasive developmental disorder, is characterized by impaired communication and social interaction, and by repetitive interests and behaviours. The core disorder probably affects around 5:10 000 individuals, of whom some three-quarters are male. Onset is in the first three years of life, and the disorder is associated with lifelong disabilities. Because of the clear evidence that idiopathic autism has a strong genetic basis, many groups are undertaking whole genome screens to identify susceptibility loci. We review the first results, and briefly consider the implications of molecular genetic findings for future research, diagnosis and management.

The relationship between the multidimensional health locus of control and the performance of subjects on a preventive periodontal programme.

Criteria have been defined to quantify a personality characteristic-termed locus of control. The criterion at one extreme of this range was referred to as external, indicating a belief that health was determined by a variety of other factors such as powerful other individuals or by chance. The criterion at the other extreme was termed internal, indicating a belief that health might be modified by the behaviour pattern of the individual. Locus of control scales have been used to relate psychological factors to physical disease, and the response of patients to disease. The aim of the present study was to investigate whether locus of control could be used to anticipate the response of subjects to a plaque control programme. A study was carried out on 14 males and 46 females to investigate the relationship between the multidimensional health locus of control (MHLC) and the response of a group of office workers to a plaque control programme. It was found that there was significant correlation between the external MHLC dimension of powerful others and improvement in some of the clinical criteria; a similar result was found for the internal dimension of the MHLC. In contrast, there was minimal correlation between the external dimension of the MHLC termed chance and the clinical results. It was concluded that subjects who perceive their susceptibility to disease being influenced by powerful external factors or who believe that susceptibility can be controlled by their own actions, respond more positively to a plaque control regime than those subjects who consider that susceptibility to disease is an event of chance.