title: 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.
authors.affiliation: Program in Human Genetics, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee 37232-0615, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: McCauley
authors.forename: L M
authors.initials: LM
authors.lastname: Olson
authors.forename: M
authors.initials: M
authors.lastname: Dowd
authors.forename: T
authors.initials: T
authors.lastname: Amin
authors.forename: A
authors.initials: A
authors.lastname: Steele
authors.forename: R D
authors.initials: RD
authors.lastname: Blakely
authors.forename: S E
authors.initials: SE
authors.lastname: Folstein
authors.forename: J L
authors.initials: JL
authors.lastname: Haines
authors.forename: J S
authors.initials: JS
authors.lastname: Sutcliffe
mesh_terms: D001321:Autistic Disorder / Q000145:classification / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005192:Family Health; D005787:Gene Frequency; D008040:Genetic Linkage; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008562:Membrane Glycoproteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D018895:Microsatellite Repeats; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D050486:Serotonin Plasma Membrane Transport Proteins
chemical_list: D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D004247:DNA