Abstract
The CDH13 gene codes for T-cadherin, a GPI-anchored protein with cell adhesion properties that is highly expressed in the brain and cardiovascular system. Previous studies have suggested that CDH13 may be a promising candidate gene for Attention Deficit/Hyperactivity Disorder (ADHD). The aims of this study were to identify, functionally characterize, and estimate the frequency of coding CDH13 variants in adult ADHD patients and controls. We performed sequencing of the CDH13 gene in 169 Norwegian adult ADHD patients and 63 controls and genotyping of the identified variants in 641 patients and 668 controls. Native and green fluorescent protein tagged wild type and variant CDH13 proteins were expressed and studied in CHO and HEK293 cells, respectively. Sequencing identified seven rare missense CDH13 variants, one of which was novel. By genotyping, we found a cumulative frequency of these rare variants of 2.9% in controls and 3.2% in ADHD patients, implying that much larger samples are needed to obtain adequate power to study the genetic association between ADHD and rare CDH13 variants. Protein expression and localization studies in CHO cells and HEK293 cells showed that the wild type and mutant proteins were processed according to the canonical processing of GPI-anchored proteins. Although some of the mutations were predicted to severely affect protein secondary structure and stability, no significant differences were observed between the expression levels and distribution of the wild type and mutant proteins in either HEK293 or CHO cells. This is the first study where the frequency of coding CDH13 variants in patients and controls is reported and also where the functional properties of these variants are examined. Further investigations are needed to conclude whether CDH13 is involved in the pathogenesis of ADHD or other conditions.
Highlights
IntroductionMajor advances have been made in our understanding of the genetic underpinning of human disorders
During the past decade, major advances have been made in our understanding of the genetic underpinning of human disorders
One of the most reproducible associations with Attention Deficit/Hyperactivity Disorder (ADHD) was found for markers at the CDH13 locus, that were ranked among the top results in four of the primary genome wide association (GWA) studies and the meta-analyses of these studies, as well as a meta-analysis of five linkage scans [4,12]
Summary
Major advances have been made in our understanding of the genetic underpinning of human disorders. As more susceptibility genes are discovered for psychiatric disorders, it has become clear that many of these genes are expressed in the brain and contribute to mental dysfunction, but are involved in more general biological mechanisms and may contribute to a range of different disorders and phenotypes This is illustrated in the search for ADHD susceptibility genes. Seven independent GWA studies in ADHD have been performed on different child and adult ADHD samples [4,5,6,7,8,9,10,11] These studies did not identify any genes that were consistently associated with ADHD at a genome-wide level of significance, markers in certain genes were found to be strongly associated with ADHD in multiple studies. CDH13 has been implicated in related psychiatric phenotypes such as methamphetamine and alcohol dependence, and depressive symptoms [13,14,15]
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