Objectives: To focus on the emerging role of common genetic variants and how the identification and the combination of risk-associated common variants in ASDs can lead to identification of siblings of children with ASD who are at higher risk of autism.
Methods: Two sets of multiplex families were used: an “exploratory population” consisted of 544 families from the Autism Genetic Resource Exchange repository (AGRE, www.agre.org) and a “replication population” consisted of 668 families from the University of Pennsylvania combined with a different subset from the AGRE repository. SNPs associated with an increased risk of autism were identified by performing gender-based genome-wide association (GWA) studies on the “exploratory population”. SNPs associated with autism were prioritized using relevant biological and functional data for genes where SNPs were located. The ability of highly prioritized SNPs to maintain their association with autism was determined in both “exploratory” and “replication populations” through a reproducibility index estimated using a resampling approach. A gender-specific genetic score, the sum of individual risk-associated alleles, was then constructed. The ability of these gender-specific genetic scores to discriminate siblings with or without ASD was evaluated in the “exploratory population” and in the “replication population”.
Results: Thirty eight SNPs were found to maintain their association with autism following reproducibility studies. Genetic scores (GS) were constructed for 1,974 children with autism and 584 unaffected siblings. In males GS of 23 was associated with an 90% specificity (95%CI:86-94), a 30% sensitivity (95%CI:27-41), and a 51% (95%CI:45-55) positive predictive value (PPV). In females, a GS of 28 was associated with a 81% specificity (95%CI:75-85), a 50% sensitivity (95%CI:45-56), and a 22% PPV (95%CI:18-26).
Conclusions: Our findings demonstrate that a combination of multiple risk-associated common variants in a gender-specific genetic score allows for the identification of siblings of children with ASD who have a significantly higher risk of developing autism.