ADGRL3 (LPHN3) variants predict substance use disorder

Arcos‐Burgos, Mauricio; Vélez, Jorge I.; Martinez, Ariel F.; Ribasés, Marta; Ramos‐Quiroga, Josep Antoni; Sánchez-Mora, Cristina; Richarte, Vanesa; Roncero, Carlos; Cormand, Bru; Fernàndez‐Castillo, Noèlia; Casas, Miguel; Lopera, Francisco; Piñeda, David; Palacio, Juan David; Acosta-López, Johan E.; Cervantes-Henríquez, Martha L; Sánchez-Rojas, Manuel; Puentes-Rozo, Pedro J.; Molina, Brooke S. G.; Boden, Margaret T.; Wallis, Deeann; Lidbury, Brett A.; Newman, Saul Justin; Easteal, Simon; Swanson, James M.; Patel, Hardip R.; Volkow, Nora D.; Acosta, Maria T.; Leon, José de; Mastronardi, Claudio A.; Muenke, Maximilian

doi:10.1038/s41398-019-0396-7

Cited by 29 publications

(39 citation statements)

References 87 publications

(122 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Adhesion G protein-coupled receptors (aGPCRs) are crucial regulators of diverse functions in the nervous, immune, cardiac, and musculoskeletal systems, and their dysregulation has been linked to a variety of diseases and cancers 1 , 2 . The aGPCR latrophilin 3 (ADGRL3, human homolog) was recently associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD) and substance use in human genetic studies 3 , 4 . Gene knockdown of ADGRL3 homologs in flies 5 , fish 6 , 7 , rat 8 and mouse 9 has been associated with a pan-species hyperlocomotor phenotype, as well as dysregulation of dopamine signaling.…”

Section: Introductionmentioning

confidence: 99%

G12/13 is activated by acute tethered agonist exposure in the adhesion GPCR ADGRL3

et al. 2020

View full text Add to dashboard Cite

The adhesion GPCR latrophilin 3 (ADGRL3) has been associated with increased risk of attention-deficit/hyperactivity disorder (ADHD) and substance use in human genetic studies. Knockdown in multiple species leads to hyperlocomotion and altered dopamine signaling. Thus, ADGRL3 is a potential target for treatment of neuropsychiatric disorders that involve dopamine dysfunction, but its basic signaling properties are poorly understood. Identification of adhesion GPCR signaling partners has been limited by lack of tools to acutely activate these receptors in living cells. Here, we designed a novel acute activation strategy to characterize ADGRL3 signaling by engineering a receptor construct in which we could trigger acute activation enzymatically. Using this assay, we found that ADGRL3 signals through G12/G13 and Gq, with G12/13 the most robustly activated. Gα12/13 is a new player in ADGRL3 biology, opening up unexplored roles for ADGRL3 in the brain. Our methodological advancements should be broadly useful in adhesion GPCR research.

show abstract

Section: Introductionmentioning

confidence: 99%

G12/13 is activated by acute tethered agonist exposure in the adhesion GPCR ADGRL3

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Here we evaluated the association between ADHD and intronic SNPs harboured in, among others, the SNAP25 , ADGRL3 , FGF1 , DRD4 , and SLC6A2 genes (Table S1, Supplementary Material) in 113 nuclear families ascertained from the metropolitan area of Barranquilla, Colombia. Despite that some of the genotyped markers have been reported as associated to ADHD [71], ADHD comorbidities [72,73], and ADHD endophenotypes [40], most genetic variants associated to ADHD have mainly been identified in populations with no African American background [14,15,74,75,76,77].…”

Section: Discussionmentioning

confidence: 99%

“…ADGRL3 is a member the latrophilin subfamily of G protein-coupled receptors and has already been implicated in ADHD susceptibility, predicting ADHD severity, disruptive behaviours comorbidity, long-term outcome, response to treatment, and SUD [2,3,6,14,15,16,17,18,19,20,21,74]. Animal models of ADHD have also provided convincing evidence of the critical role of ADGRL3 in shaping the hyperactive/impulsive phenotype [87,88,89,90].…”

Section: Discussionmentioning

confidence: 99%

Genetic Variation Underpinning ADHD Risk in a Caribbean Community

Puentes-Rozo

Acosta-López

Cervantes-Henríquez

et al. 2019

Cells

Self Cite

View full text Add to dashboard Cite

Attention Deficit Hyperactivity Disorder (ADHD) is a highly heritable and prevalent neurodevelopmental disorder that frequently persists into adulthood. Strong evidence from genetic studies indicates that single nucleotide polymorphisms (SNPs) harboured in the ADGRL3 (LPHN3), SNAP25, FGF1, DRD4, and SLC6A2 genes are associated with ADHD. We genotyped 26 SNPs harboured in genes previously reported to be associated with ADHD and evaluated their potential association in 386 individuals belonging to 113 nuclear families from a Caribbean community in Barranquilla, Colombia, using family-based association tests. SNPs rs362990-SNAP25 (T allele; p = 2.46 × 10−4), rs2282794-FGF1 (A allele; p = 1.33 × 10−2), rs2122642-ADGRL3 (C allele, p = 3.5 × 10−2), and ADGRL3 haplotype CCC (markers rs1565902-rs10001410-rs2122642, OR = 1.74, Ppermuted = 0.021) were significantly associated with ADHD. Our results confirm the susceptibility to ADHD conferred by SNAP25, FGF1, and ADGRL3 variants in a community with a significant African American component, and provide evidence supporting the existence of specific patterns of genetic stratification underpinning the susceptibility to ADHD. Knowledge of population genetics is crucial to define risk and predict susceptibility to disease.

show abstract

“…ADHD diagnosis was assessed in all individuals using behavioral [54][55][56] and psychopathological interviews, which include the structured Diagnostic Interview for Children and Adults (DICA) version IV [57]. This interview (1) considers the A criterion of the DSM-IV, (2) utilizes a systematic approach to collect clinical information about ADHD symptoms exhibited by an individual using a binary classification (0 = absent; 1 = present) system, and (3) has been extensively used by our group and others in genetic studies of ADHD [27,49,52,53,[58][59][60]. ADHD symptom data were collected during the clinical assessment stage, where 11 schools were visited (seven of medium socio-economic stratum).…”

Section: Subjectsmentioning

confidence: 99%

ADGRL3, FGF1 and DRD4: Linkage and Association with Working Memory and Perceptual Organization Candidate Endophenotypes in ADHD

et al. 2021

Self Cite

View full text Add to dashboard Cite

Attention deficit hyperactivity disorder (ADHD) is a highly heritable neurobehavioral disorder that affects children worldwide, with detrimental long-term consequences in affected individuals. ADHD-affected patients display visual–motor and visuospatial abilities and skills that depart from those exhibited by non-affected individuals and struggle with perceptual organization, which might partially explain impulsive responses. Endophenotypes (quantifiable or dimensional constructs that are closely related to the root cause of the disease) might provide a more powerful and objective framework for dissecting the underlying neurobiology of ADHD than that of categories offered by the syndromic classification. In here, we explore the potential presence of the linkage and association of single-nucleotide polymorphisms (SNPs), harbored in genes implicated in the etiology of ADHD (ADGRL3, DRD4, and FGF1), with cognitive endophenotypes related to working memory and perceptual organization in 113 nuclear families. These families were ascertained from a geographical area of the Caribbean coast, in the north of Colombia, where the community is characterized by its ethnic diversity and differential gene pool. We found a significant association and linkage of markers ADGRL3-rs1565902, DRD4-rs916457 and FGF1-rs2282794 to neuropsychological tasks outlining working memory and perceptual organization such as performance in the digits forward and backward, arithmetic, similarities, the completion of figures and the assembly of objects. Our results provide strong support to understand ADHD as a combination of working memory and perceptual organization deficits and highlight the importance of the genetic background shaping the neurobiology, clinical complexity, and physiopathology of ADHD. Further, this study supplements new information regarding an ethnically diverse community with a vast African American contribution, where ADHD studies are scarce.

show abstract

ADGRL3 (LPHN3) variants predict substance use disorder

Cited by 29 publications

References 87 publications

G12/13 is activated by acute tethered agonist exposure in the adhesion GPCR ADGRL3

G12/13 is activated by acute tethered agonist exposure in the adhesion GPCR ADGRL3

Genetic Variation Underpinning ADHD Risk in a Caribbean Community

ADGRL3, FGF1 and DRD4: Linkage and Association with Working Memory and Perceptual Organization Candidate Endophenotypes in ADHD

Contact Info

Product

Resources

About