Attention-deficit/hyperactivity disorder associated with KChIP1 rs1541665 in Kv channels accessory proteins

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is an early onset childhood neurodevelopmental disorder with high heritability. A number of genetic risk factors and environment factors have been implicated in the pathogenesis of ADHD. Genes encoding for subtypes of voltage-dependent K channels (Kv) and accessory proteins to these channels have been identified in genome-wide association studies (GWAS) of ADHD. We conducted a two-stage case–control study to investigate the associations between five key genes (KChIP4, KChIP1, DPP10, FHIT, and KCNC1) and the risk of developing ADHD. In the discovery stage comprising 256 cases and 372 controls, KChIP1 rs1541665 and FHIT rs3772475 were identified; they were further genotyped in the validation stage containing 328cases and 431 controls.KChIP1 rs1541665 showed significant association with a risk of ADHD at both stages, with CC vs TT odds ratio (OR) = 1.961, 95% confidence interval (CI) = 1.366–2.497, in combined analyses (P-FDR = 0.007). Moreover, we also found rs1541665 involvement in ADHD-I subtype (OR (95% CI) = 2.341(1.713, 3.282), and Hyperactive index score (P = 0.005) in combined samples.Intriguingly, gene-environmental interactions analysis consistently revealed the potential interactionsof rs1541665 collaboratingwith maternal stress pregnancy (Pmul = 0.021) and blood lead (Padd = 0.017) to modify ADHD risk. In conclusion, the current study provides evidence that genetic variants of Kv accessory proteins may contribute to the susceptibility of ADHD.Further studies with different ethnicitiesare warranted to produce definitive conclusions.

Common and Unique Genetic Background between Attention-Deficit/Hyperactivity Disorder and Excessive Body Weight

“…Classic association studies included a unique set of genes and polymorphisms selected on the basis of the results of gene prioritization studies for ADHD and/or obesity supplemented with GWAS results. Polymorphisms in the KCNIP1 (rs1541665) [64], SLC1A3 (rs1049522) [65], MTHFR (rs1801131) [66], ADRA2A (rs18005) [67] and SLC6A2 (rs5569) [68,69] genes were associated with ADHD risk, which is in line with previous reports.…”

Calcium Sensors in Neuronal Function and Dysfunction

“…The idea that KChIPs may contribute to neuronal disease first arose when calsenilin/ KChIP3 was discovered as an interactor with presenilins, and to regulate the processing of presenilins, which suggested a link to the pathogenesis of Alzheimer's disease (Buxbaum et al 1998;Jo et al 2004). KChIP1 has been implicated in changes in behavioral anxiety in knockout mice (Xia et al 2010) and a human genetic variant associated with attention deficit disorder (Yuan et al 2017). KChIPs have also been shown to be involved in pain control (Jin et al 2012;Kuo et al 2017;Tian et al 2018).…”

Genetics and epigenetics of attention deficit hyperactivity disorder

“…Выявлены ассоциации аллелей генов SLC6A4 и LPHN3 с развитием СДВГ [21]. Показана ассоциация СДВГ с генами мембранных белков: с аллелем rs1541665 гена напряжения калиевых каналов KChIP1 (potassium voltage-gated channel interacting protein 1) [22], с SNP (rs1979398, rs16880453, rs1531545, rs4074793) гена интегрин альфа-1 ITGA1 [23]. Выявлена ассоциация аллеля АС rs2069456 в гене циклинзависимой киназы 5 (Cdk5) с развитием СДВГ, более выраженная у обследованных мужского пола [24].…”