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Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder

Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism... A functional promoter variant of the gene encoding the MET receptor tyrosine kinase alters SP1 and SUB1 transcription factor binding, and is associated with autism spectrum disorder (ASD). Recent analyses of postmortem cerebral cortex from ASD patients revealed altered expression of MET protein and three transcripts encoding proteins that regulate MET signaling, hepatocyte growth factor (HGF), urokinase plasminogen activator receptor (PLAUR) and plasminogen activator inhibitor‐1 (SERPINE1). To address potential risk conferred by multiple genes in the MET signaling pathway, we screened all exons and 5′ promoter regions for variants in the five genes encoding proteins that regulate MET expression and activity. Identified variants were genotyped in 664 families (2,712 individuals including 1,228 with ASD) and 312 unrelated controls. Replicating our initial findings, family‐based association test (FBAT) analyses demonstrated that the MET promoter variant rs1858830 C allele was associated with ASD in 101 new families (P=0.033). Two other genes in the MET signaling pathway also may confer risk. A haplotype of the SERPINE1 gene exhibited significant association. In addition, the PLAUR promoter variant rs344781 T allele was associated with ASD by both FBAT (P=0.006) and case–control analyses (P=0.007). The PLAUR promoter rs344781 relative risk was 1.93 (95% confidence interval (CI): 1.12–3.31) for genotype TT and 2.42 (95% CI: 1.38–4.25) for genotype CT compared to genotype CC. Gene–gene interaction analyses suggested a significant interaction between MET and PLAUR. These data further support our hypothesis that genetic susceptibility impacting multiple components of the MET signaling pathway contributes to ASD risk. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Autism Research Wiley

Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorder

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References (33)

Publisher
Wiley
Copyright
Copyright © 2008, International Society for Autism Research, Wiley‐Liss, Inc.
ISSN
1939-3792
eISSN
1939-3806
DOI
10.1002/aur.27
pmid
19360663
Publisher site
See Article on Publisher Site

Abstract

A functional promoter variant of the gene encoding the MET receptor tyrosine kinase alters SP1 and SUB1 transcription factor binding, and is associated with autism spectrum disorder (ASD). Recent analyses of postmortem cerebral cortex from ASD patients revealed altered expression of MET protein and three transcripts encoding proteins that regulate MET signaling, hepatocyte growth factor (HGF), urokinase plasminogen activator receptor (PLAUR) and plasminogen activator inhibitor‐1 (SERPINE1). To address potential risk conferred by multiple genes in the MET signaling pathway, we screened all exons and 5′ promoter regions for variants in the five genes encoding proteins that regulate MET expression and activity. Identified variants were genotyped in 664 families (2,712 individuals including 1,228 with ASD) and 312 unrelated controls. Replicating our initial findings, family‐based association test (FBAT) analyses demonstrated that the MET promoter variant rs1858830 C allele was associated with ASD in 101 new families (P=0.033). Two other genes in the MET signaling pathway also may confer risk. A haplotype of the SERPINE1 gene exhibited significant association. In addition, the PLAUR promoter variant rs344781 T allele was associated with ASD by both FBAT (P=0.006) and case–control analyses (P=0.007). The PLAUR promoter rs344781 relative risk was 1.93 (95% confidence interval (CI): 1.12–3.31) for genotype TT and 2.42 (95% CI: 1.38–4.25) for genotype CT compared to genotype CC. Gene–gene interaction analyses suggested a significant interaction between MET and PLAUR. These data further support our hypothesis that genetic susceptibility impacting multiple components of the MET signaling pathway contributes to ASD risk.

Journal

Autism ResearchWiley

Published: Jun 1, 2008

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