THE GENETICS OF AUTISM/PDD: AN INVESTIGATION OF SEROTONIN, NOREPINEPHRINE AND DOPAMINE TRANSPORTER GENES IN THE ETIOLOGY OF AUTISM AND THE RELATED PERVASIVE DISORDERS

Abstract

<p>Autism is a pervasive developmental disorder (PDD) characterized by behavioral abnormalities which include: lack of social relationships, delayed or deviant language development, motor stereotypes and preoccupation with repetitive movements or activities. Twin and family studies have suggested that a strong genetic component exists for this condition, however, attempts to identify the genes involved have failed. Current investigations into the etiology and pathophysiology of many neuropsychiatric disorders implicate the involvement of neurotransmitter systems. Previous studies from this laboratory have identified possible maternal effect loci that in conjunction with alleles of fetal susceptibility genes could explain many of the complex features of the etiology and genetics of autism/PDD.</p> <p>This study involves the analysis of monoamine (biogenic amine) transport systems in relation to autism. Markers linked to and with in the serotonin, norepinephrine and dopamine transporter genes were used for assessing concordance or allele sharing among affected sib pairs and allele and genotype distributions among first-degree relatives and affected children. The presence of linkage with autism was observed for all three candidate genes. Significant levels of identity by descent (IBD) allele sharing were observed among affected sibling pairs for the serotonin transporter (Mean statistic; t2=2.27, p<0.05), dopamine transporter (t2=1.20, p<0.05) and norepinephrine transporter (t2=164, p<0.05). A separate analysis of each microsatellite locus revealed a trend towards increased maternal concordance. Symmetry between transmitted and non-transmitted alleles was noted at microsatellite and VNTR loci when transmission disequilibrium of alleles was analyzed. Application of the transmission disequilibrium test (TDT) to STin2/5HTTLPR haplotypes demonstrated association to the 12 copy (304 bp) allele of STin2 and the long variant of the functional polymorphism, 5HTTLPR. Mothers of two affected children showed STin2 (SERT intronic VNTR) genotype frequency differences when compared to female controls (%2= 20.97, d.f.=l 1, p=0.0099). Significant differences between parental allele frequencies and population-based control frequencies tested for all microsatellite loci were observed. Correlation between those sib pairs sharing two alleles IBD for SERT loci and mothers with a del/del genotype at the DβH locus (associated with low serum DβH) supports the interaction between this locus and the maternal effect genes. Susceptibility, conferred by biogenic amine transporters, SERT, NET and DAT1, is supported by linkage and allelic association observed for all three genes. Correlation between concordance for SERT markers and maternal genotype at the DPH locus lends support to a maternal effect / fetal susceptibility model of autism. The presence of a possible parent-of-origin effect is also indicated by the presence of increased maternal concordance at microsatellite loci linked to SERT, NET and DAT1.</p>