Abstract
Background: Genes related to cell adhesion pathway have been implicated in the genetic architecture of attention-deficit/hyperactivity disorder (ADHD). Cell adhesion molecule 1, encoded by CADM1 gene, is a protein which facilitates cell adhesion, highly expressed in the human prefrontal lobe. This study aimed to evaluate the association of CADM1 genotype with ADHD, executive function, and regional brain functions. Methods: The genotype data of 10-tag single nucleotide polymorphisms of CADM1 for 1,040 children and adolescents with ADHD and 963 controls were used for case–control association analyses. Stroop color–word interference test, Rey–Osterrieth complex figure test, and trail making test were conducted to assess “inhibition,” “working memory,” and “set-shifting,” respectively. A subsample (35 ADHD versus 56 controls) participated in the nested imaging genetic study. Resting-state functional magnetic resonance images were acquired, and the mean amplitude of low-frequency fluctuations (mALFF) were captured. Results: Nominal significant genotypic effect of rs10891819 in “ADHD-alone” subgroup was detected (P = 0.008) with TT genotype as protective. The results did not survive multiple testing correction. No direct genetic effect was found for performance on executive function tasks. In the imaging genetic study for the “ADHD-whole” sample, rs10891819 genotype was significantly associated with altered mALFF in the right superior frontal gyrus (rSFG, peak t = 3.85, corrected P < 0.05). Specifically, the mALFFs in T-allele carriers were consistently higher than GG carriers in ADHD and control groups. Endophenotypic correlation analyses indicated a significant negative correlation between “word interference time” in Stroop (shorter “word interference time” indexing better inhibitory function) and mALFF in the rSFG (r = -0.29, P = 0.006). Finally, mediation analysis confirmed significant indirect effects from “rs10891819 genotype (T-allele carriers)” via “mALFF (rSFG)” to “inhibition (“word interference time”)” (Sobelz = -2.47; B = -2.61, 95% confidence interval -0.48 to -4.72; P = 0.009). Conclusions: Our study offered preliminary evidence to implicate the roles of CADM1 in relation to prefrontal brain activities, inhibition function, and ADHD, indicating a potential “gene–brain–behavior” relationship of the CADM1 gene. Future studies with larger samples may specifically test these hypotheses generated by our exploratory findings.
Highlights
Attention-deficit/hyperactivity disorder (ADHD)—characterized by developmentally inappropriate levels of inattention, hyperactivity, and impulsivity—is one of the most common childhood neurodevelopmental disorders with an estimated worldwide prevalence of 5% (American PsychiatricAssociation, 2013)
In the “ADHD-alone” subsample, the genotypic distribution of rs10891819 was different from the controls at the nominal levels of significance in both additive model (P = 0.008) and the recessive model with TT genotype as protective [odds ratio = 0.48, P = 0.012] (Table 3)
The results showed a negative correlation between mean amplitude of lowfrequency fluctuation (mALFF) in the right superior frontal gyrus (rSFG) and “word interference time” in the STROOP test (r = -0.29, P = 0.006, Figure 2A), indicating higher mALFF levels correlated with better performance in this inhibition task
Summary
Attention-deficit/hyperactivity disorder (ADHD)—characterized by developmentally inappropriate levels of inattention, hyperactivity, and impulsivity—is one of the most common childhood neurodevelopmental disorders with an estimated worldwide prevalence of 5% (American PsychiatricAssociation, 2013). The Research Domain Criteria (RDoC), proposed by the National Institute of Mental Health, offer a different theoretical framework to re-orientate research approach, in particular, redirect the primary focus from diagnostic categories of ADHD to the functioning of specific domains (i.e., along the continuum from genes to molecules, cells, brain circuitry, cognitive endophenotypes, and behaviors) that are presumed to underlie the clinical manifestations (Musser and Raiker, 2019). In addition to the candidate association approach, this present study attempts to apply the RDoC approach to explore different investigative avenues to detect associations between genes (putative functional molecules), brain activities, cognitive endophenotypes, and ADHD behaviors, within the context of cell adhesion molecule 1 (CADM1) gene. This study aimed to evaluate the association of CADM1 genotype with ADHD, executive function, and regional brain functions
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