Serotonin transporter (5-HTT) and ?-aminobutyric acid receptor subunit ?3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families

Abstract

Previous studies have suggested that the serotonin transporter (5-HTT) gene and the gamma-aminobutyric acid receptor subunit beta3 (GABRB3) gene, or other genes in the 15q11-q13 region, are possibly involved in susceptibility to autism. To test this hypothesis we performed an association study on the collection of families from the International Molecular Genetic Study of Autism (IMGSA) Consortium, using the transmission disequilibrium test. Two polymorphisms in the 5-HTT gene (a functional insertion-deletion polymorphism in the promoter and a variable number tandem repeat in the second intron) were examined in 90 families comprising 174 affected individuals. Furthermore, seven microsatellite markers spanning the 15q11-q13 region were studied in 94 families with 182 affected individuals. No significant evidence of association or linkage was found at any of the markers tested, indicating that the 5-HTT and the GABRB3 genes are unlikely to play a major role in the aetiology of autism in our family data set.

Mutations in the ribosomal protein gene RPL10 suggest a novel modulating disease mechanism for autism

“…37 Association of 5-HTT with autism has been revealed in several but not all study groups worldwide. 19,49,50 In conclusion, it is intriguing that several rare cases of autism present with mutations in genes, all of which are hypothesized to modulate synaptic plasticity in the hippocampus. It remains to be elucidated if these and other genetic factors are contributing -via this or other pathways -to the development of aberrant neural central nervous system connections noticed in autism.…”

The genetics of autistic disorders and its clinical relevance: a review of the literature

“…210 Two studies 211,212 found evidence for association of a microsatellite located in intron 3 of the GABRB3 gene (GABRB3 155CA-2), whereas four other studies could not replicate this finding in samples of similar size and power. [213][214][215][216] Only nominal significant associations of different haplotypes, SNPs or microsatellites located in or around the GABRB3 and the GABRG3 gene have been found in three further studies. 215,[217][218][219] The largest study to date assessing GABA receptor subunit genes found evidence for association of a single SNP in the GABRA4 gene on chromosome 4p with AD, and for interaction effects of this variant with a SNP in the GABRB1 gene on chromosome 4p.…”

“…234,235 Some studies did not replicate these findings. 214,[236][237][238][239][240][241][242][243] Three studies have assessed the effects of the 5HTTLPR on whole-blood serotonin (5-HT) or platelet 5-HT parameters in AD. 236,237,244 One study 244 did find an increased rate of platelet-5-HT uptake in II genotypes compared to sl and ss.…”

Serotonin transporter gene promoter variants do not explain the hyperserotoninemia in autistic children

“…5,6 Our prior study described a lack of association between 5-HTT gene promoter alleles and autistic disorder in 46 Italian and 44 Caucasian-American complete trios. 6 We have subsequently collected 65 additional complete Italian trios with autistic probands, surprisingly displaying a significant preferential transmission of the L allele to affected offspring, with 78 transmissions and 63 nontransmissions of the L allele in autistics (HHRR 2 = 3.90, 1 df, 2-tail P Ͻ 0.05) vs 38 transmissions and 40 non-transmissions in unaffected sibs from the same families (autistics vs unaffected sibs: HHRR 2 = 5.82, 1 df, 2-tail P Ͻ 0.05).…”