<i>LPHN</i>3 and attention‐deficit/hyperactivity disorder: a susceptibility and pharmacogenetic study

Bruxel, Estela M.; Salatino-Oliveira, Angélica; Akutagava-Martins, Gláucia Chiyoko; Tovo‐Rodrigues, Luciana; Genro, Júlia Pasqualini; Zeni, Cristian Patrick; Polanczyk, Guilherme; Chazan, R; Schmitz, Marcelo; Arcos‐Burgos, Mauricio; Rohde, Luís Augusto; Hutz, Mara H.

doi:10.1111/gbb.12224

Cited by 58 publications

(42 citation statements)

References 51 publications

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“…This perspective promotes the idea of a more integrated approach to treatments of individuals with a particular diagnosis, more predictable treatment responses and better predictive side effect profiles. In fact, research relevant to this approach is presently underway (17). For example, several genes are associated with altered enzyme levels that can impact drug metabolism (18).…”

Section: Informing Treatment and Patient Managementmentioning

confidence: 99%

The Genetic Intersection of Neurodevelopmental Disorders and Shared Medical Comorbidities – Relations that Translate from Bench to Bedside

2016

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Most psychiatric disorders are considered neurodevelopmental, and the associated genes often are expressed in tissues outside of the brain. This suggests a biological relatedness with medical co-occurrences that could have broad clinical implications for diagnosis and patient management over a lifetime. A qualitative integration of public data from genetic consortia of psychiatric disorders and medical comorbidities explores the question of whether genetically associated psychiatric illnesses present with co-occurring disturbances can be used to define specific mental–physical health relations. Novel patterns of gene-disorder relations appear with approximately one-third of conservatively defined, consortia-generated candidate risk genes with multiple psychiatric diagnoses. Moreover, nearly as many genes overlap with non-psychiatric phenotypes, including cardiovascular, renal, respiratory, and metabolic disturbances. While the landscape of genetic risk will change as study populations are expanded and biological confirmations accrue, the current relationships suggest that a mostly siloed perspective of gene relatedness to one categorical psychiatric diagnosis is not clinically useful. The future holds the promise that once candidates are fully validated, genome screening and mutation identification will bring more precision for predicting the risk for complex health conditions. Our view is that as genetic data are refined, continuing to decipher a shared pattern of genetic risk for brain and peripheral organ pathophysiology is not simply an academic exercise. Rather, determining relatedness will impact predictions of multifaceted health risks, patient treatment, and management.

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Section: Informing Treatment and Patient Managementmentioning

confidence: 99%

The Genetic Intersection of Neurodevelopmental Disorders and Shared Medical Comorbidities – Relations that Translate from Bench to Bedside

2016

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“…Another ADHD candidate gene found in a large family by linkage analysis and replicated in parallel in a global casecontrol study (n = 2627 ADHD subjects, n = 2531 controls) is adhesion-G protein-coupled-receptor-L3 (ADGRL3, formerly LPHN3), a brain-specific G protein-coupled receptor with cell adhesion function [23]. ADGRL3 was confirmed as an ADHD candidate locus in two other independent casecontrol studies, by association of one haplotype in ADGRL3 [21] and single associations of several SNPs [22]. In the zebrafish model, the loss of adgrl3 leads to a reduction of dopaminergic neurons in the ventral diencephalon and a hyperactive/impulsive phenotype [23], whereas in Adgrl3knockout mice, an increase in reward motivation and activity level as well as other ADHD-analogous behaviors was observed-parallel to dysregulation of the dopamine transporter [24,25].…”

Section: Genome-wide Association Studies (Gwas)mentioning

confidence: 83%

Genetics of ADHD: What Should the Clinician Know?

Grimm

Kranz

Reif

2020

Curr Psychiatry Rep

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Purpose of Review Attention deficit hyperactivity disorder (ADHD) shows high heritability in formal genetic studies. In our review article, we provide an overview on common and rare genetic risk variants for ADHD and their link to clinical practice. Recent findings The formal heritability of ADHD is about 80% and therefore higher than most other psychiatric diseases. However, recent studies estimate the proportion of heritability based on singlenucleotide variants (SNPs) at 22%. It is a matter of debate which genetic mechanisms explain this huge difference. While frequent variants in first mega-analyses of genomewideassociation study data containing several thousand patients give the first genome-wide results, explaining only little variance, the methodologically more difficult analyses of rare variants are still in their infancy. Some rare genetic syndromes show higher prevalence for ADHD indicating a potential role for a small number of patients. In contrast, polygenic risk scores (PRS) could potentially be applied to every patient. We give an overview how PRS explain different behavioral phenotypes in ADHD and how they could be used for diagnosis and therapy prediction. Summary Knowledge about a patient's genetic makeup is not yet mandatory for ADHD therapy or diagnosis. PRS however have been introduced successfully in other areas of clinical medicine, and their application in psychiatry will begin within the next years. In order to ensure competent advice for patients, knowledge of the current state of research is useful forpsychiatrists.

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“…The identification of LPHN3 as an ADHD‐candidate gene stems from a finding in a large multigenerational pedigree in a population isolate . Consecutive association with an SNP located within LPHN3 was shown in a large replication sample of 2627 cases and in subsequent replications . The importance of this association was verified by two translational animal models.…”

Section: Molecular Genetic Studiesmentioning

confidence: 95%

Recent developments in the genetics of attention‐deficit hyperactivity disorder

Grimm

Kittel‐Schneider

Reif

2018

Psychiatry Clin Neurosci

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Attention-deficit hyperactivity disorder (ADHD) is a developmental psychiatric disorder that affects children and adults. ADHD is one of the psychiatric disorders with the strongest genetic basis according to familial, twin, and single nucleotide polymorphisms (SNP)-based epidemiological studies. In this review, we provide an update of recent insights into the genetic basis of ADHD. We discuss recent progress from genome-wide association studies (GWAS) looking at common variants as well as rare copy number variations. New analysis of gene groups, so-called functional ontologies, provide some insight into the gene networks afflicted, pointing to the role of neurodevelopmentally expressed gene networks. Bioinformatic methods, such as functional enrichment analysis and protein-protein network analysis, are used to highlight biological processes of likely relevance to the etiology of ADHD. Additionally, copy number variations seem to map on important pathways implicated in synaptic signaling and neurodevelopment. While some candidate gene associations of, for example, neurotransmitter receptors and signaling, have been replicated, they do not seem to explain significant variance in recent GWAS. We discuss insights from recent case-control SNP-GWAS that have presented the first whole-genome significant SNP in ADHD.

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

Cited by 58 publications

References 51 publications

The Genetic Intersection of Neurodevelopmental Disorders and Shared Medical Comorbidities – Relations that Translate from Bench to Bedside

The Genetic Intersection of Neurodevelopmental Disorders and Shared Medical Comorbidities – Relations that Translate from Bench to Bedside

Genetics of ADHD: What Should the Clinician Know?

Recent developments in the genetics of attention‐deficit hyperactivity disorder

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