Linkage and association analysis at the serotonin transporter (SLC6A4) locus in a rigid‐compulsive subset of autism

Abstract

Autism is a complex genetic neurodevelopmental disorder in which affected individuals display deficits in language, social relationships, and patterns of compulsive and stereotyped behaviors and rigidity. Linkage analysis in our dataset of 57 New England and 80 AGRE multiplex autism families reveals a multipoint heterogeneity LOD (HLOD) score of 2.74 at D17S1871 in 17q11.2. Analysis of phenotypic subsets shows an increased HLOD of 3.62 in families with compulsive behaviors and rigidity. The serotonin transporter locus (SLC6A4) maps nearby and is considered a functional candidate gene in autism and obsessive-compulsive disorder. We genotyped an insertion/deletion polymorphism in the promoter (5-HTTLPR), and seven single nucleotide polymorphisms (SNPs) across the 38-kb transcriptional unit. Transmission disequilibrium (TD) analysis reveals nominal association at a SNP in intron 5 (P = 0.02) as well as 5-HTTLPR (P = 0.01), corresponding to over-transmission of the short allele. TD analysis in the rigid-compulsive subset shows no evidence for association. Intermarker linkage disequilibrium was determined. All SNPs define a single haplotype block, while 5-HTTLPR lies 5' to this block. Three SNPs are sufficient to detect all common alleles (> or =5%) in this > 26-kb block. Analysis of haplotypes for these markers demonstrates no evidence for association to autism. These data indicate that a common allele within the coding region of SLC6A4 is not responsible for the observed linkage. However, the presence of heterogeneous disease variants within the block or the existence of a common disease-associated allele either upstream or downstream of this block is possible. In fact, such variants may well account for linkage to 17q11.2 in our families.

Neonatal serotonin depletion alters behavioral responses to spatial change and novelty

“…(Chugani et al, 1999;Chandana et al, 2005). A serotonergic (5-HT) deficit during cortical development, moreover, is compatible with reports of treatment successes using serotonin uptake blockers as well as with genetic linkage studies suggesting impairments in genes linked to proper serotonin neurotransmission (Cabelli et al, 1995;Klauck et al, 1997;Anderson et al, 2002;Veenstra-VanderWeele et al, 2002;Conroy et al, 2004;Coutinho et al, 2004;McCauley et al, 2004;Muhle et al, 2004;Murphy et al, 2004;Nabi et al, 2004;Coon et al, 2005;Mulder et al, 2005;Scott and Deneris, 2005;Whitaker-Azmitia, 2005). It is interesting in this context to note that a defective serotonergic innervation is also compatible with alterations of brainstem segmentation genes such as engrailed or Hox 2, which have been implicated in autism (Polleux and Lauder, 2004;Bartlett et al, 2005;Benayed et al, 2005).…”

Enhanced activity of human serotonin transporter variants associated with autism

“…Elucidation of the genetic variants and their biological impact offers the possibility of prenatal counselling, earlier identification of at-risk children, development of animal models and pursuit of biology-informed therapeutics. With these goals, we and others have pursued genome-wide linkage analyses of autism, identifying a strong linkage signal at 17q11.2-17q21 (Cook et al 1997;McCauley et al 2004;Stone et al 2004;Cantor et al 2005;Sutcliffe et al 2005). Although the linkage signal we obtained was already highly significant, particularly for a complex neurobehavioral disorder (HLODw5), linkage increased substantially when male-only subject families were included in the analysis (HLODw8).…”

Evaluation of CSF neurotransmitters and folate in 25 patients with Rett disorder and effects of treatment

“…They had a median age of 5.6 years (range, 4.8-11); all had a particular phenotype, with unusual motor agitation and a high number of various stereotypies. Moreover, four patients with a median age of 7 years (range 2-7) had high HVA/5-HIAA (patients 1,5,12,14).…”