A genomewide screen for autism-spectrum disorders: evidence for a major susceptibility locus on chromosome 3q25-27

Abstract

To identify genetic loci for autism-spectrum disorders, we have performed a two-stage genomewide scan in 38 Finnish families. The detailed clinical examination of all family members revealed infantile autism, but also Asperger syndrome (AS) and developmental dysphasia, in the same set of families. The most significant evidence for linkage was found on chromosome 3q25-27, with a maximum two-point LOD score of 4.31 (Z(max )(dom)) for D3S3037, using infantile autism and AS as an affection status. Six markers flanking over a 5-cM region on 3q gave Z(max dom) >3, and a maximum parametric multipoint LOD score (MLS) of 4.81 was obtained in the vicinity of D3S3715 and D3S3037. Association, linkage disequilibrium, and haplotype analyses provided some evidence for shared ancestor alleles on this chromosomal region among affected individuals, especially in the regional subisolate. Additional potential susceptibility loci with two-point LOD scores >2 were observed on chromosomes 1q21-22 and 7q. The region on 1q21-22 overlaps with the previously reported candidate region for infantile autism and schizophrenia, whereas the region on chromosome 7q provided evidence for linkage 58 cM distally from the previously described autism susceptibility locus (AUTS1).

Figure 1

Pedigree structure for 19 families in the initial genomewide screen (stage I). Families 1 and 3 are linked genealogically and were treated as one family. Blackened symbols denote infantile autism, symbols with diagonal lines denote AS, and symbols with vertical lines denote developmental dysphasia.

Figure 2

The two-point LOD scores under homogeneity obtained from the whole genomewide screen under different diagnostic categories: diagnostic criterion 1, families with infantile autism (A);. diagnostic criterion 2, families with infantile autism and AS (B);. and diagnostic criterion 3, families with infantile autism, AS, and developmental dysphasia combined (C).

Figure 3

Parametric multipoint LOD score (MLS) analysis, which allows for heterogeneity, was performed using the SIMWALK 2.81 program in different diagnostic categories. On chromosome X, the MLS analysis was performed using the GENEHUNTER program with diagnostic criterion 3. Cat1 = diagnostic criterion 1, Cat2 = diagnostic criterion 2, and Cat3 = diagnostic criterion 3.

Figure 4

A common ancestor originating from central Finland was detected for core families 1 and 3. The shared chromosomal segment on 3q25-27 was observed in four patients with autism. Blackened symbols denote infantile autism, and symbols with vertical lines denote developmental dysphasia.

Figure 5

The observed chromosomal segment of ∼4 cM on 3q in 34 core families. Five markers were localized on the contig map of NCBI. The families are divided into two groups, according to the birthplaces of the grandparents.