Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity - PubMed (original) (raw)

. 2001 Jun;68(6):1514-20.

doi: 10.1086/320588. Epub 2001 May 14.

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Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity

J D Buxbaum et al. Am J Hum Genet. 2001 Jun.

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Abstract

Although there is considerable evidence for a strong genetic component to idiopathic autism, several genomewide screens for susceptibility genes have been performed with limited concordance of linked loci, reflecting either numerous genes of weak effect and/or sample heterogeneity. Because decreasing sample heterogeneity would increase the power to identify genes, the effect on evidence for linkage of restricting a sample of autism-affected relative pairs to those with delayed onset (at age >36 mo) of phrase speech (PSD, for phrase speech delay) was studied. In the second stage of a two-stage genome screen for susceptibility loci involving 95 families with two or more individuals with autism or related disorders, a maximal multipoint heterogeneity LOD score (HLOD) of 1.96 and a maximal multipoint nonparametric linkage (NPL) score of 2.39 was seen on chromosome 2q. Restricting the analysis to the subset of families (n=49) with two or more individuals having a narrow diagnosis of autism and PSD generated a maximal multipoint HLOD score of 2.99 and an NPL score of 3.32. The increased scores in the restricted sample, together with evidence for heterogeneity in the entire sample, indicate that the restricted sample comprises a population that is more genetically homogeneous, which could therefore increase the likelihood of positional cloning of susceptibility loci.

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Figures

Figure 1

Figure 1

Multipoint analyses of chromosome 2q. Multipoint LOD analyses under dominant (solid lines) and recessive (dashed lines) modes of inheritance were performed (Vieland et al. ; Durner et al. 1999), with penetrance set at 50% (Greenberg et al. 1998) and allowing for locus heterogeneity (HLOD) (Smith ; Durner and Greenberg 1992). This simple approach works well for complex traits, even if true modes of inheritance and numbers of genes contributing to the disease are not known (Vieland et al. 1992_a,_ 1993). All genotyped family members were included in the analyses, and any individual not receiving a research diagnosis of autism, borderline autism, or Asperger disorder was defined as phenotypically unknown. Disease-allele frequency was arbitrarily set at .1 for recessive inheritance and .006 for dominant inheritance. Multipoint linkage analyses using nonparametric estimates of sharing were also performed using NPL (dotted lines) with GENEHUNTER (Kruglyak et al. 1996).

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References

Electronic-Database Information

    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for autism/autistic disorder [MIM <209850>]).

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