Abstract
The cell—cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.
Highlights
The gene coding for Cadherin 13 (CDH13) was found among the top hits in several genome-wide association studies (GWAS) for attention-deficit/hyperactivity disorder (ADHD) [1,2,3]
ANCOVA with age and gender as covariates showed a significant association of rs2199430 genotype with NEO-PI-R scores for the personality trait of agreeableness (F2, 871 = 5.038, p = 0.007, ηp2 = 0.011) in the adult ADHD (aADHD) group
CDH13 intron 2 SNP rs2199430 is associated with frontal cortex CDH13 expression levels [13]
Summary
The gene coding for Cadherin 13 (CDH13) was found among the top hits in several genome-wide association studies (GWAS) for attention-deficit/hyperactivity disorder (ADHD) [1,2,3]. The gene is located within the only significant region identified in a genome-wide linkage meta-analysis [4]. The greatest effect was detected for rs2199430 with an 80% increase in CDH13 expression levels in samples derived from GG allele carriers [13]. Rs2199430 is located within a 2 kb hotspot of SNPs, which are responsible for the association of CDH13 with temporal lobe volumes [14], and the minor G allele of rs2199430 was nominally associated (
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