Archival ReportAn Ultraconserved Brain-Specific Enhancer Within ADGRL3 (LPHN3) Underpins Attention-Deficit/Hyperactivity Disorder Susceptibility
Section snippets
Subjects
Individuals with and without ADHD were ascertained from the metropolitan area of Medellin (Antioquia, Colombia). The Paisa community is considered a genetic isolate of Caucasian descent with low admixture with Amerindian and Negroid ethnicities (21). The cohort consisted of 14 multigenerational families and 125 nuclear families for a total of 838 individuals (372 affected and 466 unaffected individuals; 335 children and adolescents [3–16 years of age] and 503 adults [≥17 years of age]). The
Identification of Potential Enhancer Elements Within ADGRL3
Using the ECR Browser, we identified highly conserved elements harbored in the ADGRL3 MCR. Although it is currently well established that the intergenome comparisons of distant species (e.g., humans and fish) are powerful in identifying critical distant regulatory elements, only 5% of the genes in the human genome contain a human/fugu noncoding ECR in their genomic neighborhood (30, 31, 32). For that reason, an analysis with species more closely related to humans than fish is required to
Discussion
Few molecular studies have attempted to explain the molecular effects of ADHD-associated genetic variants. Studies on dopamine transporter (DAT1) (37, 38, 39, 40), tryptophan hydroxylase 2 (TPH2) (41, 42), and T-cadherin (CDH13) (43) have examined the functional properties of rare missense mutations of moderate and large effects, but these findings fail to explain the higher incidence of ADHD and larger phenotypic variance observed in populations. Instead, the common disease/common variant
Acknowledgments and Disclosures
This work was supported by intramural resources from the National Human Genome Research Institute of the U.S. National Institutes of Health.
We thank Paul Kruszka, M.D., for his detailed revision of the manuscript and helpful comments.
This study used the computational capabilities of a demo license to Genomatix Software (Munich, Germany).
The authors report no biomedical financial interests or potential conflicts of interest.
References (90)
- et al.
Attention-deficit/hyperactivity disorder and comorbid disruptive behavior disorders: Evidence of pleiotropy and new susceptibility loci
Biol Psychiatry
(2007) - et al.
Molecular genetics of attention-deficit/hyperactivity disorder
Biol Psychiatry
(2005) - et al.
Influence of a latrophilin 3 (LPHN3) risk haplotype on event-related potential measures of cognitive response control in attention-deficit hyperactivity disorder (ADHD)
Eur Neuropsychopharmacol
(2013) - et al.
Association of LPHN3 rs6551665 a/g polymorphism with attention deficit and hyperactivity disorder in Korean children
Gene
(2015) - et al.
Attention-deficit/hyperactivity disorder in a population isolate: Linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11
Am J Hum Genet
(2004) - et al.
Attention-deficit/hyperactivity disorder and comorbidities in 18 Paisa Colombian multigenerational families
J Am Acad Child Adolesc Psychiatry
(2004) - et al.
Interpreting mammalian evolution using fugu genome comparisons
Genomics
(2004) - et al.
Brain development and ADHD
Clin Psychol Rev
(2006) - et al.
Flrt proteins are endogenous latrophilin ligands and regulate excitatory synapse development
Neuron
(2012) - et al.
Initial characterization of mice null for Lphn3, a gene implicated in ADHD and addiction
Brain Res
(2012)
Adolescent substance use in the multimodal treatment study of attention-deficit/hyperactivity disorder (ADHD) (MTA) as a function of childhood ADHD, random assignment to childhood treatments, and subsequent medication
J Am Acad Child Adolesc Psychiatry
Early-age clinical and developmental features associated to substance use disorders in attention-deficit/hyperactivity disorder in adults
Compr Psychiatry
The role of neuropsychologic tests in the diagnosis of attention deficit hyperactivity disorder
Pediatr Neurol
The mystery and magic of glia: A perspective on their roles in health and disease
Neuron
Brn-5 is a divergent POU domain factor highly expressed in layer IV of the neocortex
J Biol Chem
Molecular programming of stem cells into mesodiencephalic dopaminergic neurons
Trends Neurosci
YY1 regulates the neural crest-associated slug gene in xenopus laevis
J Biol Chem
Yin Yang 1, a vertebrate polycomb group gene, regulates antero-posterior neural patterning
Biochem Biophys Res Commun
Psychotogenic drugs and delirium pathogenesis: The central role of the thalamus
Med Hypotheses
Thalamic shape and connectivity abnormalities in children with attention-deficit/hyperactivity disorder
Psychiatry Res
Abnormal resting-state functional connectivity patterns of the putamen in medication-naive children with attention deficit hyperactivity disorder
Brain Res
Structural brain imaging of attention-deficit/hyperactivity disorder
Biol Psychiatry
Characterizing cognition in ADHD: Beyond executive dysfunction
Trends Cogn Sci
Attention-deficit/hyperactivity disorder
Nat Rev Dis Primers
Trends in the parent-report of health care provider-diagnosed and medicated attention-deficit/hyperactivity disorder: United States, 2003-2011
J Am Acad Child Adolesc Psychiatry
Increasing prevalence of parent-reported attention-deficit/hyperactivity disorder among children—United States, 2003 and 2007
MMWR Morb Mortal Wkly Rep
Diagnostic and Statistical Manual of Mental Disorders
Attention deficit hyperactivity disorder: A worldwide concern
J Nerv Ment Dis
Genetics of attention-deficit/hyperactivity disorder: Current findings and future directions
Expert Rev Neurother
A common genetic network underlies substance use disorders and disruptive or externalizing disorders
Hum Genet
Contribution of LPHN3 to the genetic susceptibility to ADHD in adulthood: A replication study
Genes Brain Behav
A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication
Mol Psychiatry
A two-locus genetic interaction between LPHN3 and 11q predicts ADHD severity and long-term outcome
Transl Psychiatry
A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD
Mol Psychiatry
LPHN3 and attention-deficit/hyperactivity disorder: Interaction with maternal stress during pregnancy
J Child Psychol Psychiatry
Refining psychiatric phenotypes for response to treatment: Contribution of LPHN3 in ADHD
Am J Med Genet B Neuropsychiatr Genet
LPHN3 and attention-deficit/hyperactivity disorder: A susceptibility and pharmacogenetic study
Genes Brain Behav
Association of SNAP-25, SLC6A2, and LPHN3 with OROS methylphenidate treatment response in attention-deficit/hyperactivity disorder
Clin Neuropharmacol
Screening of human Lphn3 for variants with a potential impact on ADHD susceptibility
Am J Med Genet B Neuropsychiatr Genet
Polymorphisms and phyletic relationships of the Paisa community from Antioquia (Colombia)
Gene Geogr
Potential cognitive endophenotypes in multigenerational families: Segregating ADHD from a genetic isolate
Atten Defic Hyperact Disord
ECR Browser: A tool for visualizing and accessing data from comparisons of multiple vertebrate genomes
Nucleic Acids Res
Mapping and analysis of chromatin state dynamics in nine human cell types
Nature
Discovery and characterization of chromatin states for systematic annotation of the human genome
Nat Biotechnol
Factorbook.Org: A wiki-based database for transcription factor-binding data generated by the encode consortium
Nucleic Acids Res
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HL is currently affiliated with the Institute for Developmental Biology, Cologne University, Cologne, Germany.