Assessing the impact of a combined analysis of four common low-risk genetic variants on autism risk

The accumulation of multiple risk alleles markedly increases the risk of being affected, and compared with studying polymorphisms individually, it improves the identification of subgroups of individuals at greater risk. In the present study, we show that this approach can be applied to autism by specifically looking at a high-risk population of children who have siblings with autism. A two-sample study design and the generation of a genetic score using multiple independent genes were used to assess the risk of autism in a high-risk population.In both samples, odds ratios (ORs) increased significantly as a function of the number of risk alleles, with a genetic score of 8 being associated with an OR of 5.54 (95% confidence interval [CI] 2.45 to 12.49). The sensitivities and specificities for each genetic score were similar in both analyses, and the resultant area under the receiver operating characteristic curves were identical (0.59).These results suggest that the accumulation of multiple risk alleles in a genetic score is a useful strategy for assessing the risk of autism in siblings of affected individuals, and may be better than studying single polymorphisms for identifying subgroups of individuals with significantly greater risk.Autism is a heterogeneous disorder characterized by impairments in social interaction, deficits in verbal and nonverbal communication, restricted interests and repetitive behaviors [1]. Autism comprises the severe end of a group of autism spectrum disorders (ASD) [2]. The prevalence of autism is estimated at 0.2%, with males being more likely than females to have a diagnosis of autism (ratio of approximately 4:1) [3].There is compelling evidence from twin and family studies indicating a strong genetic component in autism. The average risk of recurrence of autism in siblings is approximately 10% [4] in families with one affected sibling, which is much higher than the prevalence in the general population, but much lower than would be expect