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

Abstract

The integrin-b 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 P¼0.038). Haplotype H3 is largely over-transmitted to the affected offspring and doubles the risk of an ASD diagnosis (HBAT P¼0.005; odds ratio (OR)¼2.000), at the expense of haplotype H1, which is undertransmitted (HBAT P¼0.018; OR¼0.725). 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 (P¼0.008). 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, P¼0.001; multiple regression analysis, P¼0.010). 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. INTRODUCTIONAutism spectrum disorder (ASD) is a complex neurodevelopmental disorder, characterized by different levels of impairment in social interaction and communication, by stereotypies and rigid patterns of behavior, and disease onset before 3 years of age (OMIM 209850). 1 ASD is believed to primarily stem from genetic factors, based on the observation of 60-92% concordance rates in monozygotic twins vs 0-10% in dizygotic twins, with heritability estimated at or above 90%. 2,3 The cause underlying autism in the majority of patients remains unknown, although several known medical conditions account for B10% of cases. 4 ASD, similar to many other complex human disorders, does not show a simple inheritance pattern, as it may involve multiple common variants, each conveying a modest effect in epistatic interaction, rare variants with high penetrance, or perhaps more likely the coincidence of a rare variant acting upon a genetic background rendered vulnerable by a set of common variants. 2-5 Accordingly, familial aggregation of 'endophenotypes' , heritable quantitative traits distributed continuously among ASD patients and first-degree relatives, can promote the search of genetic susceptibility factors in ASD.

Autism genetics: Methodological issues and experimental design

“…Another vulnerability gene, MET, was identified by Campbell and Levitt collaborating with our group for the genetic studies involved in this project [80,81]. In addition, we have identified other new vulnerability genes and confirmed associations initially reported in other samples for several genes, including ADA [82], APOE [83], HOXA1 [84,85], ITG-B3 [86], PON1 [87], PRKCB1 [88], SLC6A4 [89,90], SLC-25A12 [91].…”

Integrin β3 Haploinsufficiency Modulates Serotonin Transport and Antidepressant-Sensitive Behavior in Mice

“…Evidence documenting the association of ITGB3 with whole blood 5-HT levels, replicated by multiple laboratories (Weiss Integrin β3 modulates CNS SERT function in mice M Mazalouskas et al , 2006a, 2006bCoutinho et al, 2007;Cross et al, 2008;Napolioni et al, 2011) led us to examine whether haploinsufficiency in the integrin β3 gene modulates SERT function in the CNS. In contrast to studies in platelets, disruption of a single Itgb3 allele in mice was sufficient to dramatically diminish 5-HT uptake by SERT in raphe synaptosomes, indicating that serotonergic signaling in the CNS is more sensitive to alterations in integrin β3 subunit expression (Carneiro et al, 2008).…”

Is there a redundancy of β3 and other platelet receptors in the brain and central nervous system?

“…Intriguingly, the ITGB3 gene that encodes 3 was identified both as a quantitative trait locus for serotonin blood levels and as a candidate gene for autism spectrum disorder (ASD) either alone or in interaction with allelic variants of the serotonin transporter (SERT) gene (SLC6A4) [9]. ITGB3 and SLC6A4 expression is correlated in platelets and brain both in humans and in mice [10].…”

“…ITGB3 and SLC6A4 expression is correlated in platelets and brain both in humans and in mice [10]. Specific SNPs within ITGB3 have also been linked to a high frequency of spontaneous abortions, preterm delivery, and obstetric complications both in autistic individuals and in the general population [9][10][11][12]. Deletion of 3 in mice resulted in diminished SERT activity in platelets and increased fetal mortality [13].…”