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A potential association of RNF219-AS1 with ADHD: Evidence from categorical analysis of clinical phenotypes and from quantitative exploration of executive function and white matter microstructure endophenotypes |
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| Authors: | Guang-Hui Fu Wai Chen Hai-Mei Li Yu-Feng Wang Lu Liu Qiu-Jin Qian |
| Affiliation: | 1. Peking University Sixth Hospital/Institute of Mental Health, Beijing, China;2. Mental Health Service, Fiona Stanley Hospital, Perth, Australia Graduate School of Education, The University of Western Australia, Perth, Australia School of Medicine, The University of Notre Dame Australia, Fremantle, Australia School of Psychology, Murdoch University, Perth, Australia;3. Peking University Sixth Hospital/Institute of Mental Health, Beijing, China National Clinical Research Center for Mental Disorders & The Key Laboratory of Mental Health, Ministry of Health (Peking University, Beijing, China |
| Abstract: | AimsAttention‐deficit/hyperactivity disorder (ADHD) is a neuropsychiatric disorder of substantial heritability, yet emerging evidence suggests that key risk variants might reside in the noncoding regions of the genome. Our study explored the association of lncRNAs (long noncoding RNAs) with ADHD as represented at three different phenotypic levels guided by the Research Domain Criteria (RDoC) framework: (i) ADHD caseness and symptom dimension, (ii) executive functions as functional endophenotype, and (iii) potential genetic influence on white matter architecture as brain structural endophenotype.MethodsGenotype data of 107 tag single nucleotide polymorphisms (SNP) from 10 candidate lncRNAs were analyzed in 1040 children with ADHD and 630 controls of Chinese Han descent. Executive functions including inhibition and set‐shifting were assessed by STROOP and trail making tests, respectively. Imaging genetic analyses were performed in a subgroup of 33 children with ADHD and 55 controls using fractional anisotropy (FA).ResultsOne SNP rs3908461 polymorphism in RNF219‐AS1 was found to be significantly associated with ADHD caseness: with C‐allele detected as the risk genotype in the allelic model (P = 8.607E‐05) and dominant genotypic model (P = 9.628E‐05). Nominal genotypic effects on inhibition (p = 0.020) and set‐shifting (p = 0.046) were detected. While no direct effect on ADHD core symptoms was detected, mediation analysis suggested that SNP rs3908461 potentially exerted an indirect effect through inhibition function [B = 0.21 (SE = 0.12), 95% CI = 0.02‐0.49]. Imaging genetic analyses detected significant associations between rs3908461 genotypes and FA values in corpus callosum, left superior longitudinal fasciculus, left posterior limb of internal capsule, left posterior thalamic radiate (include optic radiation), and the left anterior corona radiate (P FWE corrected < 0.05).ConclusionOur present study examined the potential roles of lncRNA in genetic etiological of ADHD and provided preliminary evidence in support of the potential RNF219‐AS1 involvement in the pathophysiology of ADHD in line with the RDoC framework. |
| Keywords: | ADHD inhibition lncRNA RNF219-AS1 white matter microstructure |