Family-based association study of ITGB3 in Autism Spectrum Disorder and its endophenotypes.

Antonio M Persico (1) , Valerio Napolioni (1) , Federica Lombardi (1) , Roberto Sacco (1) , Paolo Curatolo (1) , Barbara Manzi (1) , Riccardo Alessandrelli (1) , Roberto Militerni (1) , Carmela Bravaccio (1) , Carlo Lenti (1) , Monica Saccani (1) , Cindy Schneider (1) , Raun Melmed (1) , Tiziana Pascucci (1) , Stefano Puglisi-Allegra (1) , Karl-Ludvig Reichelt (1) , Francis Rousseau (1) , Patricia Lewin (1)

1 Molecular Psychiatry & Neurogenetics

The integrin beta 3 gene (ITGB3), located on human chr. 17q21.3, was previously identified as a quantitative trait locus (QTL) for 5-HT blood levels and has been implicated as a candidate gene for Autism Spectrum Disorder (ASD). We performed a family-based association study in 281 simplex and 12 multiplex Caucasian families. ITGB3 haplotypes are significantly associated with autism (HBAT, global P=0.038). Haplotype H3 is largely over-transmitted to the affected offspring and doubles the risk of an ASD diagnosis (HBAT P=0.005; O.R.=2.000), at the expense of haplotype H1 which is under-transmitted (HBAT P=0.018; O.R.=0.725). These two common haplotypes differ only at rs12603582 located in intron 11, which reaches a P=0.072 in single-marker FBAT analyses. Interestingly, rs12603582 is strongly associated with pre-term delivery in our ASD patients (P=0.008). On the other hand, it is SNP rs2317385, located at the 5' end of the gene, that significantly affects 5-HT blood levels (Mann-Whitney U test, P=0.001; multiple regression analysis, P=0.010). No gene-gene interaction between ITGB3 and SLC6A4 has been detected. In conclusion, we identify a significant association between a common ITGB3 haplotype and ASD. Distinct markers, located toward the 5' and 3' ends of the gene, seemingly modulate 5-HT blood levels and autism liability, respectively. Our results also raise interest into ITGB3 influences on feto-maternal immune interactions in autism.

Mots clés: Autism; Integrin beta 3; SLC6A4

Antonio M Persico, Valerio Napolioni, Federica Lombardi, Roberto Sacco, Paolo Curatolo, et al.. Family-based association study of ITGB3 in Autism Spectrum Disorder and its endophenotypes.. European Journal of Human Genetics, 2010, ⟨10.1038/ejhg.2010.180⟩. ⟨hal-00593670⟩