A "line item" approach to the identification of genes involved in polygenic behavioral disorders: the adrenergic alpha2A (ADRA2A) gene.

The usual approach for using single base pair polymorphisms (SNPs) for the investigation of the genetics of behavioral disorders is to examine a single diagnostic syndrome or personality trait based on variables relating to a cluster of behavioral symptoms. However, since some of these variables may address behaviors that are associated with one allele while others are associated with the other allele, the overall association may be non-significant and significant sub-syndromal associations may be missed. Thus, we have reversed the process in a technique we term a "line item" approach. As a test of the technique we have examined the association between genotypes of a C- > G-1291 Msp I promotor SNP of the ADRA2A gene and 390 individual symptoms from a structured review of DSM-IV criteria for twelve different groups of symptoms. We examined 334 individuals consisting of controls and subjects with Tourette syndrome (TS). Based on the mean scores for each genotype, those symptoms that were individually significant at alpha < or = 0.05 fell into three major groups by mode of inheritance: allele 1 codominant (11 > 12 > 22), allele 2 codominant (22 > 12 > 11), and negative heterosis (12 < 11, 22). Within each mode of inheritance group, the number of symptoms that were significant for the twelve symptom clusters was compared by chi-square analysis. This showed that symptoms were drawn from the diagnostic groups in a significantly non-random fashion. Thus, the allele 1 codominant symptoms came from the anxiety, affective, schizoid, and somatization diagnostic groups (internalizing symptoms) (chi(2) = 80.0, d.f. = 11, P < or = 0.0000001), while the allele 2 codominant symptoms came from the ADHD and oppositional defiant/conduct disorder diagnostic groups (externalizing symptoms) (chi(2) = 81.0, d.f. = 11, P < or = 0.0000001). The questions that fell in the negative heterosis type of inheritance were not significantly associated with specific diagnostic groups (P = 0.87). These results showed that the ADRA2A gene was associated with symptoms of autonomic, sympathetic dysfunction from different diagnostic groups. The advantages of the "line item" approach include (a) the identification of the symptoms associated with each allele, (b) the identification of symptom clusters independent of DSM diagnoses, (c) the elucidation of heterosis and other mode of inheritance effects, (d) the distinction between an association with a primary disorder versus a comorbid disorder, (e) the identification of associations with sub-syndromal symptom clusters that do meet full DSM-IV criteria, and (f) the identification of symptom clusters across databases.