Transmission disequilibrium testing of the chromosome 15q11-q13 region in autism. American Journal of Medical Genetics

Department of Psychiatry, College of Medicine, University of Florida, Gainesville, Florida, USA.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics (Impact Factor: 3.42). 10/2008; 147B(7):1116-25. DOI: 10.1002/ajmg.b.30733
Source: PubMed


Evidence implicates the serotonin transporter gene (SLC6A4) and the 15q11-q13 genes as candidates for autism as well as restricted repetitive behavior (RRB). We conducted dense transmission disequilibrium mapping of the 15q11-q13 region with 93 single nucleotide polymorphisms (SNPs) in 86 strictly defined autism trios and tested association between SNPs and autism using the transmission disequilibrium test (TDT). As exploratory analyses, parent-of-origin effects were examined using likelihood-ratio tests (LRTs) and genotype-phenotype associations for specific RRB using the Family-Based Association Test (FBAT). Additionally, gene-gene interactions between nominally associated 15q11-q13 variants and 5-HTTLPR, the common length polymorphism of SLC6A4, were examined using conditional logistic regression (CLR). TDT revealed nominally significant transmission disequilibrium between autism and five SNPs, three of which are located within close proximity of the GABA(A) receptor subunit gene clusters. Three SNPs in the SNRPN/UBE3A region had marginal imprinting effects. FBAT for genotype-phenotype relations revealed nominally significant association between two SNPs and one ADI-R subdomain item. However, both TDT and FBAT were not statistically significant after correcting for multiple comparisons. Gene-gene interaction analyses by CLR revealed additive genetic effect models, without interaction terms, fit the data best. Lack of robust association between the 15q11-q13 SNPs and RRB phenotypes may be due to a small sample size and absence of more specific RRB measurement. Further investigation of the 15q11-q13 region with denser genotyping in a larger sample set may be necessary to determine whether this region confers risk to autism, indicated by association, or to specific autism phenotypes.

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    • "Based on literature review, we selected nine ASD-related genes (GABRA4, GABRB1, TDO2, GABRB2, GABRA2, GABRB3, GABRA5, SLC25A12, and BDNF; details in Table 2) for this study; these genes had been found to be associated with ASD symptoms (Belmonte et al., 2004; Cheng et al., 2009; Freitag, 2007; S.-J. Kim et al., 2008; Nabi et al., 2004). We selected SNPs within each ASD-related candidate region and identified them from NCBI's SNP database (dbSNP) ( "
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