Genome-wide and Ordered-Subset linkage analyses provide support for autism loci on 17q and 19p with evidence of phenotypic and interlocus genetic correlates.

Jacob L Mccauley,Chun Li,Kimberly Gainer,Lan Jiang,Genea Crockett,Susan E Folstein,James S Sutcliffe,Jonathan L Haines,Lana M Olson

doi:10.1186/1471-2350-6-1

Jacob L Mccauley, Chun Li + Show 7 more

Open Access

https://doi.org/10.1186/1471-2350-6-1

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Abstract

BackgroundAutism is a neurobehavioral spectrum of phenotypes characterized by deficits in the development of language and social relationships and patterns of repetitive, rigid and compulsive behaviors. Twin and family studies point to a significant genetic etiology, and several groups have performed genomic linkage screens to identify susceptibility loci.MethodsWe performed a genome-wide linkage screen in 158 combined Tufts, Vanderbilt and AGRE (Autism Genetics Research Exchange) multiplex autism families using parametric and nonparametric methods with a categorical autism diagnosis to identify loci of main effect. Hypothesizing interdependence of genetic risk factors prompted us to perform exploratory studies applying the Ordered-Subset Analysis (OSA) approach using LOD scores as the trait covariate for ranking families. We employed OSA to test for interlocus correlations between loci with LOD scores ≥1.5, and empirically determined significance of linkage in optimal OSA subsets using permutation testing. Exploring phenotypic correlates as the basis for linkage increases involved comparison of mean scores for quantitative trait-based subsets of autism between optimal subsets and the remaining families.ResultsA genome-wide screen for autism loci identified the best evidence for linkage to 17q11.2 and 19p13, with maximum multipoint heterogeneity LOD scores of 2.9 and 2.6, respectively. Suggestive linkage (LOD scores ≥1.5) at other loci included 3p, 6q, 7q, 12p, and 16p. OSA revealed positive correlations of linkage between the 19p locus and 17q, between 19p and 6q, and between 7q and 5p. While potential phenotypic correlates for these findings were not identified for the chromosome 7/5 combination, differences indicating more rapid achievement of "developmental milestones" was apparent in the chromosome 19 OSA-defined subsets for 17q and 6q. OSA was used to test the hypothesis that 19p linkage involved more rapid achievement of these milestones and it revealed significantly increased LOD* scores at 19p13.ConclusionsOur results further support 19p13 as harboring an autism susceptibility locus, confirm other linkage findings at 17q11.2, and demonstrate the need to analyze more discreet trait-based subsets of complex phenotypes to improve ability to detect genetic effects.

Highlights

Autism is a neurobehavioral spectrum of phenotypes characterized by deficits in the development of language and social relationships and patterns of repetitive, rigid and compulsive behaviors
Families were recruited through three sites: (a) 71 families from the Tufts/NEMC site, (b) 2 families from the Vanderbilt University site, and (c) the remainder of families (85) were chosen from the Autism Genetics Resource Exchange (AGRE) repository based on our own recruitment criteria
For instances of empirically significant increases in evidence for linkage, we explored the nature of the genetic correlation to ask whether it reflected clinical correlations in the respective subsets

Summary

Introduction

Autism is a neurobehavioral spectrum of phenotypes characterized by deficits in the development of language and social relationships and patterns of repetitive, rigid and compulsive behaviors. Autism (OMIM # 209850) is a neurobehavioral disorder involving deficits in language and social abilities and patterns of repetitive behaviors, restricted interests and resistance to change. The most recent estimate of population prevalence for the broader autism spectrum indicates a rate of 34/10,000 (~1/300) [1], with a male: female ratio of 4:1 [2,3]. Twin studies show a concordance of 60% among monozygotic (MZ) twins and 0% among dizygotic (DZ) pairs for classic autism, but this increases to 92% for MZ pairs and 10% for DZ pairs when a broader phenotype of related social and language abnormalities is included [4,5]. While the data do not strongly endorse any one model for inheritance, twin and family studies support a multilocus etiology with as many as 10–20 loci (reviewed in [9,10,11])

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