Linkage and Association Analysis at the Serotonin Transporter (SLC6A4) Locus in a Rigid-Compulsive Subset of Autism

J. L. McCauley, L. M. Olson, M. Dowd, T. Amin, A. Steele, R. D. Blakely, S. E. Folstein, J. L. Haines, J. S. Sutcliffe

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119 Scopus citations


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 (≥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.

Original languageEnglish (US)
Pages (from-to)104-112
Number of pages9
JournalAmerican Journal of Medical Genetics - Neuropsychiatric Genetics
Volume127 B
Issue number1
StatePublished - May 15 2004


  • Autism
  • Haplotype
  • Linkage disequilibrium
  • Phenotypic subsetting

ASJC Scopus subject areas

  • Genetics(clinical)
  • Neuropsychology and Physiological Psychology
  • Neuroscience(all)


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