LPHN3 and attention‐deficit/hyperactivity disorder: interaction with maternal stress during pregnancy

Choudhry, Zia; Sengupta, Sarojini M.; Grizenko, Natalie; Fortier, Marie-Ève; Thakur, Geeta; Bellingham, Johanne; Joober, Ridha

doi:10.1111/j.1469-7610.2012.02551.x

Cited by 54 publications

(28 citation statements)

References 62 publications

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“…The G allele at rs6551665, which is included in the GT haplotype, was associated with ADHD in four different populations even after heterogeneity tests and multiple testing corrections were performed (Arcos-Burgos et al 2010). Nevertheless, the A allele of this same SNP (rs6551665) was significantly overtransmitted to ADHD probands in a group with mild or minimal maternal stress during pregnancy (Choudhry et al 2012).…”

Section: Discussionmentioning

confidence: 94%

“…Choudhry et al (2012) examined the role of SNPs in LPHN3 in relation to MPH response, taking into account maternal smoking and stress during pregnancy. Analyses of rs6551665, rs1947274 and rs6858066 SNPs showed that the GCA haplotype was associated with symptom improvement (Choudhry et al 2012).…”

Section: Received 16 March 2015 Revised 28 April 2015 Accepted For mentioning

confidence: 99%

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LPHN3 and attention‐deficit/hyperactivity disorder: a susceptibility and pharmacogenetic study

Bruxel

Salatino-Oliveira

Akutagava-Martins

et al. 2015

Genes Brain and Behavior

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Latrophilin 3 (LPHN3) is a brain-specific member of the G-protein coupled receptor family associated to both attention-deficit/hyperactivity disorder (ADHD) genetic susceptibility and methylphenidate (MPH) pharmacogenetics. Interactions of LPHN3 variants with variants harbored in the 11q chromosome improve the prediction of ADHD development and medication response. The aim of this study was to evaluate the role of LPHN3 variants in childhood ADHD susceptibility and treatment response in a naturalistic clinical cohort. The association between LPHN3 and ADHD was evaluated in 523 children and adolescents with ADHD and 132 controls. In the pharmacogenetic study, 172 children with ADHD were investigated. The primary outcome measure was the parent-rated Swanson, Nolan and Pelham Scale -version IV applied at baseline, first and third months of treatment with MPH. The results reported herein suggest the CGC haplotype derived from single nucleotide polymorphisms (SNPs) rs6813183, rs1355368 and rs734644 as an ADHD risk haplotype (P = 0.02, OR = 1.46). Although non-significant after multiple testing correction, its interaction with the 11q chromosome SNP rs965560 slightly increases risk (P = 0.03, OR = 1.55). Homozygous individuals for the CGC haplotype showed faster response to MPH treatment as a significant interaction effect between CGC haplotype and treatment over time was observed (P < 0.001). Homozygous individuals for the GT haplotype derived from SNPs rs6551665 and rs1947275 showed a nominally significant interaction with treatment over time (P = 0.04). Our findings replicate previous findings reporting that LPHN3 confers ADHD susceptibility, and moderates MPH treatment response in children and adolescents with ADHD.

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Section: Discussionmentioning

confidence: 94%

Section: Received 16 March 2015 Revised 28 April 2015 Accepted For mentioning

confidence: 99%

LPHN3 and attention‐deficit/hyperactivity disorder: a susceptibility and pharmacogenetic study

Bruxel

Salatino-Oliveira

Akutagava-Martins

et al. 2015

Genes Brain and Behavior

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“…Notably, Li et al (31) have demonstrated that the PKA-dependent NF-κB signaling pathway is a novel target for drug action in asthma therapy. In addition, evidence indicated that latrophilin receptors are associated with heterogeneous behavioral disorder (32), which is also a novel target in asthma (14,33). In the present study, the changes in inflammation factor levels and the mechanism underlying the rhLPHN3 Ab-mediated signaling pathway were analyzed in patients with pediatric asthma.…”

Section: Discussionmentioning

confidence: 95%

Clinical efficacy of recombinant human latrophilin 3 antibody in the treatment of pediatric asthma

Liu¹,

Zhang²,

Liu³

2017

Exp Ther Med

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Abstract. Pediatric asthma is a chronic pulmonary inflammatory disease featuring hypersecretion of mucus and inflammation in the airway, resulting in dysfunction of the airway smooth muscle. Previous evidence demonstrated that latrophilins, a novel family of receptors, present a beneficial effect on airway smooth muscle cells. In the present study, the therapeutic effects of recombinant human latrophilin 3 (rhLPHN3) antibody (Ab) in patients with pediatric asthma were investigated, and the molecular mechanism underlying the function of LPHN3 in the treatment of asthma in clinical practice was examined. A total of 342 pediatric asthma cases were recruited and randomly divided into three groups, receiving treatment with rhLPHN3 Ab (n=134), salbutamol (n=108) or montelukast (n=100) by nasal aerosolization. Each group received the respective clinically tested dose for 16 weeks. Inflammatory factors interleukin (IL)-10, IL-17, IL-4, matrix metallopeptidase-9 (MMP-9), interferon-γ (IFN-γ) and transforming growth factor-β (TGF-β) levels in peripheral blood mononuclear cells were analyzed prior to and post treatment. The clinical outcomes revealed that pathological alterations were significantly improved following treatment with rhLPHN3 Ab for patients with pediatric asthma when compared with those receiving salbutamol and montelukast. It was also observed that rhLPHN3 Ab downregulated the plasma concentration levels of IL-10, IL-17, IL-4 and MMP-9, and upregulated IFN-γ and TGF-β levels in the three groups. In addition, clinical data demonstrated that rhLPHN3 Ab significantly promoted E-selectin and mucin 5AC expression, as well as improved the activation of nuclear factor (NF)-κB p65 DNA binding activity and the phosphorylation levels of protein kinase A. Furthermore, rhLPHN3 Ab markedly improved adhesion and proliferation of airway smooth muscle cells, which led to promotion of the contraction of these cells.In conclusion, these clinical data suggest that rhLPHN3 Ab serves an important role in the inhibition of inflammatory mediators through downregulation of NF-κB signaling pathway, which contributes to airway remodeling and bronchodilation in patients with pediatric asthma.

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“…ADGRL3 common variants predispose to ADHD, modulate brain metabolism, and predict ADHD severity and comorbidity with disruptive symptoms and substance use disorder (11, 13, 15, 16), When combined with other risk factors, ADGRL3 risk variants improve the prediction of ADHD severity, dysfunctional comorbidity, long-term outcome, and response to treatment with stimulant medication (10-16). Recent work from our group also showed genetic linkage and association of ADGRL3 variants to neuropsychological endophenotypes, providing a more powerful framework for ADHD clinical classification and for the identification of causative genetic variation (44).…”

Section: Discussionmentioning

confidence: 99%

An Ultraconserved Brain-Specific Enhancer Within ADGRL3 (LPHN3) Underpins Attention-Deficit/Hyperactivity Disorder Susceptibility

Martinez

Abe

Hong

et al. 2016

Biological Psychiatry

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BACKGROUND Genetic factors predispose to attention deficit/hyperactivity disorder (ADHD). Previous studies have reported linkage and association to ADHD of gene variants within ADGRL3. In this study, we functionally analyzed non-coding variants in this gene as likely pathological contributors. METHODS In silico, in vitro and in vivo approaches were used to identify and characterize evolutionary conserved elements within the ADGRL3 linkage region (~207 Kb). Family-based genetic analyses on 838 individuals (372 affected and 466 unaffected) identified ADHD-associated SNPs harbored in some of these conserved elements. Luciferase assays and zebrafish GFP transgenesis tested conserved elements for transcriptional enhancer activity. Electromobility shift assays were used to verify transcription factor binding disruption by ADHD risk alleles. RESULTS An ultraconserved element was discovered (ECR47) that functions as a transcriptional enhancer. A three-variant ADHD risk haplotype in ECR47, formed by rs17226398, rs56038622 and rs2271338, reduced enhancer activity by 40% in neuroblastoma and astrocytoma cells (PBonferroni<0.0001). This enhancer also drove GFP expression in the zebrafish brain in a tissue-specific manner, sharing aspects of endogenous ADGRL3 expression. The rs2271338 risk allele disrupts binding of YY1, an important factor in the development and function of the central nervous system. Expression quantitative trait loci analysis of post-mortem human brain tissues revealed an association between rs2271338 and reduced ADGRL3 expression in the thalamus. CONCLUSIONS These results uncover the first functional evidence of common non-coding variants with potential implications for the pathology of ADHD.

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LPHN3 and attention‐deficit/hyperactivity disorder: interaction with maternal stress during pregnancy

Abstract: These results provide evidence for the interaction between a genetic and environmental factor independently shown to be associated with ADHD. If confirmed in independent large studies, they may present a step forward in unraveling the complex etiology of ADHD.

Cited by 54 publications

References 62 publications

LPHN3 and attention‐deficit/hyperactivity disorder: a susceptibility and pharmacogenetic study

LPHN3 and attention‐deficit/hyperactivity disorder: a susceptibility and pharmacogenetic study

Clinical efficacy of recombinant human latrophilin 3 antibody in the treatment of pediatric asthma

An Ultraconserved Brain-Specific Enhancer Within ADGRL3 (LPHN3) Underpins Attention-Deficit/Hyperactivity Disorder Susceptibility

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