A Common <i>CDH13</i> Variant Is Associated with Low Agreeableness and Neural Responses to Working Memory Tasks in ADHD

• Main Authors: Georg C. Ziegler, Ann-Christine Ehlis, Heike Weber, Maria Rosaria Vitale, Johanna E. M. Zöller, Hsing-Ping Ku, Miriam A. Schiele, Laura I. Kürbitz, Marcel Romanos, Paul Pauli, Raffael Kalisch, Peter Zwanzger, Katharina Domschke, Andreas J. Fallgatter, Andreas Reif, Klaus-Peter Lesch
• Format: Article
• Language: English
• Published: MDPI AG 2021-08-01
• Series: Genes
• Subjects: ADHD; <i>CDH13</i>; neurodevelopment; executive functions; working memory; Big Five
• Online Access: https://www.mdpi.com/2073-4425/12/9/1356

The cell—cell signaling gene <i>CDH13</i> is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. <i>CDH13</i> regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of <i>CDH13</i> on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the <i>CDH13</i> gene in humans is sparse. Therefore, we tested for association of a functional intronic <i>CDH13</i> 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 <i>CDH13</i> is associated with personality traits and impacts neural processing during working memory tasks. Thus, <i>CDH13</i> might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.