Family-based association study of ITGB3 in autism spectrum disorder and its endophenotypes

The integrin- β 3 gene ( ITGB3 ), located on human chromosome 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; odds ratio (OR)=2.000), at the expense of haplotype H1, which is under-transmitted (HBAT P =0.018; OR=0.725). These two common haplotypes differ only at rs12603582 located in intron 11, which reaches a P -value of 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.