title: Family-based association study of ITGB3 in autism spectrum disorder and its endophenotypes.
abstract: 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.
authors.affiliation: Laboratory of Molecular Psychiatry and Neurogenetics, University Campus Bio-Medico, Rome, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Napolioni
authors.forename: Federica
authors.initials: F
authors.lastname: Lombardi
authors.forename: Roberto
authors.initials: R
authors.lastname: Sacco
authors.forename: Paolo
authors.initials: P
authors.lastname: Curatolo
authors.forename: Barbara
authors.initials: B
authors.lastname: Manzi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Alessandrelli
authors.forename: Roberto
authors.initials: R
authors.lastname: Militerni
authors.forename: Carmela
authors.initials: C
authors.lastname: Bravaccio
authors.forename: Carlo
authors.initials: C
authors.lastname: Lenti
authors.forename: Monica
authors.initials: M
authors.lastname: Saccani
authors.forename: Cindy
authors.initials: C
authors.lastname: Schneider
authors.forename: Raun
authors.initials: R
authors.lastname: Melmed
authors.forename: Tiziana
authors.initials: T
authors.lastname: Pascucci
authors.forename: Stefano
authors.initials: S
authors.lastname: Puglisi-Allegra
authors.forename: Karl-Ludvig
authors.initials: KL
authors.lastname: Reichelt
authors.forename: Francis
authors.initials: F
authors.lastname: Rousseau
authors.forename: Patricia
authors.initials: P
authors.lastname: Lewin
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Persico
mesh_terms: D000293:Adolescent; D000328:Adult; D001321:Autistic Disorder / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D058068:Endophenotypes; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007223:Infant; D039661:Integrin beta3 / Q000235:genetics*; D007438:Introns; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012044:Regression Analysis; D012701:Serotonin / Q000097:blood; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: C061248:ITGB3 protein, human; D039661:Integrin beta3; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin