Association of DISC1 with autism and Asperger syndrome.

The DISC1 gene at 1q42 has generated considerable interest in various psychiatric diseases, since a balanced translocation interrupting the gene was found to cosegregate with schizophrenia and related mental illnesses in a large Scottish pedigree. To date, linkage and association findings to this locus have been replicated in several study samples ascertained for psychotic disorders. However, the biological function of DISC1 in neuronal development would suggest a potential role for this gene also in other, early onset neuropsychiatric disorders. Here we have addressed the allelic diversity of the DISC1, DISC2 and TRAX genes, clustered in 1q42, in Finnish families ascertained for infantile autism (97 families, n(affected)=138) and Asperger syndrome (29 families, n(affected)=143). We established association between autism and a DISC1 intragenic microsatellite (D1S2709; P=0.004). In addition, evidence for association to Asperger syndrome was observed with an intragenic single nucleotide polymorphism (SNP) of DISC1 (rs1322784; P=0.0058), as well as with a three-SNP haplotype (P=0.0013) overlapping the HEP3 haplotype, that was previously observed to associate with schizophrenia in Finnish families. The strongest associations were obtained with broad diagnostic categories for both disorders and with affected males only, in agreement with the previous sex-dependent effects reported for DISC1. These results would further support the involvement of DISC1 gene also in the etiopathogenesis of early onset neuropsychiatric disorders.

Independent replication and initial fine mapping of 3p21-24 in Asperger syndrome.

BACKGROUND: Asperger syndrome is characterised by abnormalities in social interaction as well as repetitive and stereotyped behaviours and interests. The trait is thought to display complex inheritance, but in a subset of families the inheritance resembles the autosomal dominant model. Linkage to 3p14-24 has recently been reported in Asperger syndrome in Finnish families with a maximum multipoint NPL(all) of 3.32 at D3S2432. METHODS: We have replicated linkage findings to 3p21-24 in 12 new extended Asperger syndrome families. Linkage analyses were performed separately for the 12 new families, and linkage and association analyses were also performed jointly with data from the original genome-wide screen. RESULTS: Best two point and multipoint logarithm of the odds (LOD) scores in analyses of both data sets were obtained at D3S2432 (NPL(all) = 3.83) with both subsets of families contributing to linkage. Association analysis of the combined data set produced a trend towards association with D3S2432 and D3S1619. CONCLUSIONS: This study further validates 3q21-24 as a candidate region for Asperger syndrome.

A heterogeneity-based genome search meta-analysis for autism-spectrum disorders.

Autism and autism-spectrum disorders exhibit high heritability, although specific susceptibility genes still remain largely elusive. We performed a heterogeneity-based genome search meta-analysis (HEGESMA) of nine genome scans on autism or autism-spectrum disorders. Each genome scan was separated in 30 cM bins and the maximum linkage statistic from each bin was ranked. Significance for each bin's average rank and for between-scan heterogeneity (dis-similarity in the average ranks) was obtained through Monte Carlo tests. For autism, data from 771 affected sibpairs were synthesized across six separate genome scans. Region 7q22-q32 reached genome-wide significance both in weighted and unweighted analyses, with evidence for significantly low between-scan heterogeneity. The flanking chromosomal region 7q32-qter reached the less stringent threshold of suggestive significance, with no evidence for low between-scan heterogeneity. For autism-spectrum disorders (634 affected sibpairs from five separate scans), no chromosomal region reached genome-wide significance. However, suggestive significance was reached for the chromosomal regions 17p11.2-q12 and 10p12-q11.1 in weighted analyses. There was evidence for significantly high between-scan heterogeneity for the former region. The meta-analysis suggests that the 7q22-q32 region should be further scrutinized for autism susceptibility genes, while autism-spectrum disorders seem to have quite diverse linkage signals across scans, possibly suggesting genetic heterogeneity across subsyndromes and subpopulations.

Genome-wide scan for loci of Asperger syndrome.

Asperger syndrome (AS), characterised by inadequate social interaction, lack of empathy and a dependence of routines and rituals, is classified as belonging to the autism spectrum disorders (DSM-IV and ICD-10). Although the prevalence of AS has been estimated to range from 0.3 up to 48.4 per 10 000, the phenotype still remains relatively unrecognised by clinicians. Several reports, including the original description by Hans Asperger (1944), have suggested that AS has a strong genetic component. Here, we have performed a genome-wide scan on Finnish families ascertained for AS with a strictly defined phenotype. In the initial scan, Z(max)>1.5 was observed on nine chromosomal regions, 1q21-22, 3p14-24, 3q25-27, 4p14, 4q32, 6p25, 6q16, 13q31-33 and 18p11. In the fine mapping stage, the highest two-point LOD scores were observed on chromosomes 1q21-22 (D1S484, Z(max dom)=3.58), 3p14-24 (D3S2432, Z(max dom)=2.50) and 13q31-33 (D13S793, Z(max dom)=1.59). The loci on 1q21-22 and 3p14-24 overlap with previously published autism susceptibility loci, and the loci on 1q21-22 and 13q31-33 overlap with the reported schizophrenia susceptibility loci. The present study is the first genome-wide screen in AS and therefore replication data sets are needed to evaluate further the significance of the AS-loci identified here.

Evidence for allelic association on chromosome 3q25-27 in families with autism spectrum disorders originating from a subisolate of Finland.

Recent molecular studies on autism and related disorders have supported a multilocus etiology for the disease spectrum. To maximize genetic and cultural homogeneity, we have focused our molecular studies to families originating from a subisolate of Central Finland. Genealogical studies enabled the identification of a megapedigree comprising of 12 core families with autism and Asperger syndrome (AS). We analyzed two chromosomal regions on Iq and 3q showing highest lod scores in our genome-wide scan, as well as the AUTS1 locus on chromosome 7q. For markers on 3q25-27, more significant association was observed in families from subisolate compared to families from the rest of Finland. In contrast, no clear evidence for association on AUTS1 locus was obtained. The wide interval showing association, in particular, on chromosome 3q suggests a locus for autism spectrum of disorders on this chromosomal region.