Association of LPHN3 rs6551665 A/G polymorphism with attention deficit and hyperactivity disorder in Korean children

Hwang, In Wook; Lim, Myung Ho; Kwon, Ho Jang; Jin, Han Jun

doi:10.1016/j.gene.2015.04.033

Cited by 30 publications

(23 citation statements)

References 42 publications

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“…Future studies of genomic regions surrounding rs4860437 might reveal a cryptic mechanism. It is particularly compelling that ADGRL3 marker rs4860437, which is a major predictor variable component in the trees for SUD, is in complete LD with ADHD susceptibility markers rs6551665 and rs1947274 in Caucasians 28,30,52 , suggesting that the phenotype underpinning SUD is under the pleiotropic effect of ADGRL3 variants. Unfortunately, rs4860437 was not included in the exome chip used to genotype the MTA sample and, therefore, could not be included in the analyses for this sample.…”

Section: Discussionmentioning

confidence: 99%

ADGRL3 (LPHN3) variants predict substance use disorder

et al. 2019

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Genetic factors are strongly implicated in the susceptibility to develop externalizing syndromes such as attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder, conduct disorder, and substance use disorder (SUD). Variants in the ADGRL3 (LPHN3) gene predispose to ADHD and predict ADHD severity, disruptive behaviors comorbidity, long-term outcome, and response to treatment. In this study, we investigated whether variants within ADGRL3 are associated with SUD, a disorder that is frequently co-morbid with ADHD. 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. Our results indicate that SUD can be efficiently and robustly predicted in ADHD participants. The genetic models used remained highly efficient in predicting SUD in a large sample of individuals with severe SUD from a psychiatric institution that were not ascertained on the basis of ADHD diagnosis, thus identifying ADGRL3 as a risk gene for SUD. Recursive-partitioning analyses revealed that rs4860437 was the predominant predictive variant. This new methodological approach offers novel insights into higher order predictive interactions and offers a unique opportunity for translational application in the clinical assessment of patients at high risk for SUD.

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Section: Discussionmentioning

confidence: 99%

ADGRL3 (LPHN3) variants predict substance use disorder

et al. 2019

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“…Family-based designs are robust against population admixture and stratification, and allow conducting complex segregation analysis and linkage and association studies that would be next to impossible in case/control-based designs [32,61,62,63]. With few exceptions [64,65,66,67], recent genetic studies on ADHD have primarily focused on case/control-based designs to study genetic contributions to ADHD susceptibility [15,16,18,68,69,70].…”

Section: Discussionmentioning

confidence: 99%

“…Genetic factors are strongly implicated in the aetiology of ADHD, CD, ODD, and SUD [6,10,11,12]. In particular, common single nucleotide polymorphisms (SNPs) harboured in the Adhesion G-protein-coupled receptor L3 ( ADGRL3 , also known as Latrophilin 3 or LPHN3 ; markers rs2345039, rs6551665, and rs1947274), the Synaptosomal-associated protein of molecular weight 25 kDa ( SNAP25 ), the Fibroblast growth factor 1 ( FGF1 ), the Solute carrier family 6 (neurotransmitter transporter, noradrenalin) member 2 ( SLC6A2 ), and the Dopamine receptor D4 ( DRD4 ) genes predispose one to ADHD [6,13], as confirmed by worldwide replications [2,3,6,14,15,16,17,18,19,20,21].…”

Section: Introductionmentioning

confidence: 99%

Genetic Variation Underpinning ADHD Risk in a Caribbean Community

Puentes-Rozo

Acosta-López

Cervantes-Henríquez

et al. 2019

Cells

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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.

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“…Using cohorts of thousands of individuals from Colombia, Germany, Norway, Spain, and the United States, we found a significant homogeneous genetic effect of ADGRL3 variants predisposing to ADHD in children, adolescents, and adults, and predicting the response to stimulant medication, Ribases et al 2011;Fallgatter et al 2013). These results were independently replicated in four additional pharmacogenetic studies from Canada, Brazil, and Korea (Choudhry et al 2012;Labbe et al 2012;Bruxel et al 2015;Hwang et al 2015).…”

Section: Introductionmentioning

confidence: 71%

ADGRL 3 ( LPHN 3) variants are associated with a refined phenotype of ADHD in the MTA study

Acosta

Swanson

Stehli

et al. 2016

Mol Genet Genomic Med

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Background ADHD is the most common neuropsychiatric condition affecting individuals of all ages. Long‐term outcomes of affected individuals and association with severe comorbidities as SUD or conduct disorders are the main concern. Genetic associations have been extensively described. Multiple studies show that intronic variants harbored in the ADGRL3 (LPHN3) gene are associated with ADHD, especially associated with poor outcomes.MethodsIn this study, we evaluated this association in the Multimodal Treatment Study of children with ADHD (MTA), initiated as a 14‐month randomized clinical trial of 579 children diagnosed with DSM‐IV ADHD‐Combined Type (ADHD‐C), that transitioned to a 16‐year prospective observational follow‐up, and 289 classmates added at the 2‐year assessment to serve as a local normative comparison group (LNCG). Diagnostic evaluations at entry were based on the Diagnostic Interview Schedule for Children‐Parent (DISC‐P), which was repeated at several points over the years. For an add‐on genetic study, blood samples were collected from 232 in the MTA group and 139 in the LNCG.ResultsFor the 205 MTA participants, 14.6% retained the DISC‐P diagnosis of ADHD‐C in adolescence. For 127 LNCG participants, 88.2% remained undiagnosed by the DISC‐P. We genotyped 15 polymorphic SNP markers harbored in the ADGRL3 gene, and compared allele frequencies for the 30 cases with continued diagnosis of ADHD‐C in adolescence to the other participants. Replication of the association of rs2345039 ADGRL3 variant was observed (P value = 0.004, FDR corrected = 0.03; Odds ratio = 2.25, upper CI 1.28–3.97).ConclusionThe detection of susceptibility conferred by ADGRL3 variants in the extreme phenotype of continued diagnosis of ADHD‐C from childhood to adolescence provides additional support that the association of ADGRL3 and ADHD is not spurious. Exploring genetic effects in longitudinal cohorts, in which refined, age‐dependent phenotypes are documented, is crucial to understand the natural history of ADHD.

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Association of LPHN3 rs6551665 A/G polymorphism with attention deficit and hyperactivity disorder in Korean children

Cited by 30 publications

References 42 publications

ADGRL3 (LPHN3) variants predict substance use disorder

ADGRL3 (LPHN3) variants predict substance use disorder

Genetic Variation Underpinning ADHD Risk in a Caribbean Community

ADGRL 3 ( LPHN 3) variants are associated with a refined phenotype of ADHD in the MTA study

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