Additionally, we investigated the effect of Adgrl3-depletion at the transcriptomic level by RNA-sequencing three ADHD-relevant brain regions: prefrontal cortex (PFC), hippocampus and striatum.
The overall evidence from the literature, corroborated by our results, suggests that ADGRL3 might be involved in brain development, and genetic modifications related to it might be part of a shared vulnerability factor associated with the underlying neurobiology of neurodevelopmental disorders such as ADHD and ASD.
As the first study to comprehensively explore the role of LPHN3 in ADHD in Chinese children, our research suggests that LPHN3 gene has a significant effect on the ADHD in a Chinese population.
Using family-based, case-control, and longitudinal samples from disparate regions of the world (n = 2698), recruited either for clinical, genetic epidemiological or pharmacogenomic studies of ADHD, we assembled recursive-partitioning frameworks (classification tree analyses) with clinical, demographic, and ADGRL3 genetic information to predict SUD susceptibility.
Polymorphisms in the gene coding for the adhesion G-protein coupled receptor LPHN3 are a risk factor for attention-deficit/hyperactivity disorder (ADHD).
Latrophilin 3 (Lphn3), which is associated with ADHD in human populations and is involved in synapse structure, and its ligand fibronectin leucine rich transmembrane protein 3 (Flrt3), were downregulated in High-Active mice.
In the group composed by predominantly hyperactive/impulsive and combined presentation, the presence of LPHN3-rs6551665 G allele was related to increased ADHD risk only in individuals carrying the TTC12-rs2303380 AA genotype (p=0.026).
We report evidence of the genetic contribution of common variants to the ADHD phenotype in four genes, with the LPHN3 gene playing a particularly important role.
Interestingly, the 4q13.1 linkage peak (lod 2.34) occurred immediately upstream of the LPHN3 gene, recently reported both linked and associated with ADHD.
The results of our study further strengthen the concept of an LPHN3 risk haplotype for ADHD and support the usefulness of the endophenotype approach in psychiatric and psychological research.
As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q-11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD.
Mutations in LPHN3 are strongly associated with attention deficit hyperactivity disorder, suggesting a role for latrophilins in human cognitive function.
We found that SNPs within the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 not only to increase the risk of developing ADHD but also to increase ADHD severity.
Recently, we identified LPHN3, a novel ADHD susceptibility gene harbored in 4q, and showed that a LPHN3 common haplotype confers susceptibility to ADHD and predicts effectiveness of stimulant medication.
These results further support the LPHN3 contribution to combined type ADHD, and specifically to the persistent form of the disorder, and point at this new neuronal pathway as a common susceptibility factor for ADHD throughout the lifespan.
Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.