1. ¹Wellcome Trust Centre for Human Genetics, University of Oxford, UK
2. ²Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK
3. ³Department of Biology, University of Bologna, Bologna, Italy
4. ⁴Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan
5. ⁵Centre for Integrated Genomic Medical Research, University of Manchester, UK
6. ⁶University Department of Psychiatry, Warneford Hospital, Oxford, UK
7. ⁷Stella Maris Clinical Research Institute for Child and Adolescent Neuropsychiatry, Calambrone (Pisa), Italy

Correspondence: Professor AP Monaco, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK. Tel: 44 1865 270 004; Fax: 44 1865 280 411; E-mail: anthony.monaco@well.ox.ac.uk

⁸http://www.well.ox.ac.uk/monaco/autism/IMGSAC.shtml

Received 9 July 2008; Revised 18 September 2008; Accepted 1 October 2008; Published online 12 November 2008.

Abstract

Autism is a common, severe and highly heritable neurodevelopmental disorder. The International Molecular Genetic Study of Autism Consortium (IMGSAC) genome screen for linkage in affected sib-pair families identified a chromosome 7q susceptibility locus (AUTS1), that has subsequently shown evidence of increased sharing in several independent multiplex samples and in two meta-analyses. Taking into account the location of the MET gene under this linkage peak, and the fact that it has recently been reported to be associated with autism, the gene was further analyzed as a promising autism candidate. The gene encodes a transmembrane receptor tyrosine kinase of the hepatocyte growth factor/scatter factor (HGF/SF). MET is best known as an oncogene, but its signalling also participates in immune function, peripheral organ development and repair, and the development of the cerebral cortex and cerebellum (all of which have been observed earlier as being disregulated in individuals with autism). Here we present a family-based association analysis covering the entire MET locus. Significant results were obtained in both single locus and haplotype approaches with a single nucleotide polymorphism in intron 1 (rs38845, P<0.004) and with one intronic haplotype (AAGTG, P<0.009) in 325 multiplex IMGSAC families and 10 IMGSAC trios. Although these results failed to replicate in an independent sample of 82 Italian trios, the association itself was confirmed by a case–control analysis performed using the Italian cohort (P<0.02). The previously reported positive association of rs1858830 failed to replicate in this study. Overall, our findings provide further evidence that MET may play a role in autism susceptibility.