Vista Equipo: An Ultraconserved brain-specific enhancer within ADGRL3 (LPHN3) underpins attention-deficit/hyperactivity disorder susceptibility

An Ultraconserved brain-specific enhancer within ADGRL3 (LPHN3) underpins attention-deficit/hyperactivity disorder susceptibility

BACKGROUND—Genetic factors predispose to attention deficit/hyperactivity disorder (ADHD). Previous studies have reported linkage and association to ADHD of gene variants within ADGRL3. In this study, we functionally analyzed non-coding variants in this gene as likely pathological contributors. METHO...

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Autores Principales:	Martinez, Ariel F., Abe, Yu, Hong, Sungkook, Molyneux, Kevin, Yarnell, David, Löhr, Heiko, Driever, Wolfgang, Acosta, Maria T., Arcos-Burgos, Mauricio, Muenke, Maximilian
Formato:	Artículo (Article)
Lenguaje:	Inglés (English)
Publicado:	Society of Biological Psychiatry 2016
Materias:	ADHD Genetics ADGRL3 LPHN3 Latrophilin Cis-acting regulatory element Enhancer Evolutionary conserved regions Zebrafish
Acceso en línea:	https://repository.urosario.edu.co/handle/10336/26069 https://doi.org/10.1016/j.biopsych.2016.06.026

id	ir-10336-26069
recordtype	dspace
spelling	ir-10336-260692020-08-06T16:21:56Z An Ultraconserved brain-specific enhancer within ADGRL3 (LPHN3) underpins attention-deficit/hyperactivity disorder susceptibility Un potenciador específico del cerebro ultraconservado dentro de ADGRL3 (LPHN3) apuntala la susceptibilidad al trastorno por déficit de atención / hiperactividad Martinez, Ariel F. Abe, Yu Hong, Sungkook Molyneux, Kevin Yarnell, David Löhr, Heiko Driever, Wolfgang Acosta, Maria T. Arcos-Burgos, Mauricio Muenke, Maximilian ADHD Genetics ADGRL3 LPHN3 Latrophilin Cis-acting regulatory element Enhancer Evolutionary conserved regions Zebrafish BACKGROUND—Genetic factors predispose to attention deficit/hyperactivity disorder (ADHD). Previous studies have reported linkage and association to ADHD of gene variants within ADGRL3. In this study, we functionally analyzed non-coding variants in this gene as likely pathological contributors. METHODS—In silico, in vitro and in vivo approaches were used to identify and characterize evolutionary conserved elements within the ADGRL3 linkage region (~207 Kb). Family-based genetic analyses on 838 individuals (372 affected and 466 unaffected) identified ADHD-associated SNPs harbored in some of these conserved elements. Luciferase assays and zebrafish GFP transgenesis tested conserved elements for transcriptional enhancer activity. Electromobility shift assays were used to verify transcription factor binding disruption by ADHD risk alleles. RESULTS—An ultraconserved element was discovered (ECR47) that functions as a transcriptional enhancer. A three-variant ADHD risk haplotype in ECR47, formed by rs17226398, rs56038622 and rs2271338, reduced enhancer activity by 40% in neuroblastoma and astrocytoma cells (PBonferroni<0.0001). This enhancer also drove GFP expression in the zebrafish brain in a tissue-specific manner, sharing aspects of endogenous ADGRL3 expression. The rs2271338 risk allele disrupts binding of YY1, an important factor in the development and function of the central nervous system. Expression quantitative trait loci analysis of post-mortem human brain tissues revealed an association between rs2271338 and reduced ADGRL3 expression in the thalamus. 2016-12-15 2020-08-06T16:20:35Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion ISSN: 0006-3223 EISSN: 1873-2402 https://repository.urosario.edu.co/handle/10336/26069 https://doi.org/10.1016/j.biopsych.2016.06.026 eng info:eu-repo/semantics/openAccess application/pdf Society of Biological Psychiatry Elsevier Biological Psychiatry
institution	EdocUR - Universidad del Rosario
collection	DSpace
language	Inglés (English)
topic	ADHD Genetics ADGRL3 LPHN3 Latrophilin Cis-acting regulatory element Enhancer Evolutionary conserved regions Zebrafish
spellingShingle	ADHD Genetics ADGRL3 LPHN3 Latrophilin Cis-acting regulatory element Enhancer Evolutionary conserved regions Zebrafish Martinez, Ariel F. Abe, Yu Hong, Sungkook Molyneux, Kevin Yarnell, David Löhr, Heiko Driever, Wolfgang Acosta, Maria T. Arcos-Burgos, Mauricio Muenke, Maximilian An Ultraconserved brain-specific enhancer within ADGRL3 (LPHN3) underpins attention-deficit/hyperactivity disorder susceptibility
description	BACKGROUND—Genetic factors predispose to attention deficit/hyperactivity disorder (ADHD). Previous studies have reported linkage and association to ADHD of gene variants within ADGRL3. In this study, we functionally analyzed non-coding variants in this gene as likely pathological contributors. METHODS—In silico, in vitro and in vivo approaches were used to identify and characterize evolutionary conserved elements within the ADGRL3 linkage region (~207 Kb). Family-based genetic analyses on 838 individuals (372 affected and 466 unaffected) identified ADHD-associated SNPs harbored in some of these conserved elements. Luciferase assays and zebrafish GFP transgenesis tested conserved elements for transcriptional enhancer activity. Electromobility shift assays were used to verify transcription factor binding disruption by ADHD risk alleles. RESULTS—An ultraconserved element was discovered (ECR47) that functions as a transcriptional enhancer. A three-variant ADHD risk haplotype in ECR47, formed by rs17226398, rs56038622 and rs2271338, reduced enhancer activity by 40% in neuroblastoma and astrocytoma cells (PBonferroni<0.0001). This enhancer also drove GFP expression in the zebrafish brain in a tissue-specific manner, sharing aspects of endogenous ADGRL3 expression. The rs2271338 risk allele disrupts binding of YY1, an important factor in the development and function of the central nervous system. Expression quantitative trait loci analysis of post-mortem human brain tissues revealed an association between rs2271338 and reduced ADGRL3 expression in the thalamus.
format	Artículo (Article)
author	Martinez, Ariel F. Abe, Yu Hong, Sungkook Molyneux, Kevin Yarnell, David Löhr, Heiko Driever, Wolfgang Acosta, Maria T. Arcos-Burgos, Mauricio Muenke, Maximilian
author_facet	Martinez, Ariel F. Abe, Yu Hong, Sungkook Molyneux, Kevin Yarnell, David Löhr, Heiko Driever, Wolfgang Acosta, Maria T. Arcos-Burgos, Mauricio Muenke, Maximilian
author_sort	Martinez, Ariel F.
title	An Ultraconserved brain-specific enhancer within ADGRL3 (LPHN3) underpins attention-deficit/hyperactivity disorder susceptibility
title_short	An Ultraconserved brain-specific enhancer within ADGRL3 (LPHN3) underpins attention-deficit/hyperactivity disorder susceptibility
title_full	An Ultraconserved brain-specific enhancer within ADGRL3 (LPHN3) underpins attention-deficit/hyperactivity disorder susceptibility
title_fullStr	An Ultraconserved brain-specific enhancer within ADGRL3 (LPHN3) underpins attention-deficit/hyperactivity disorder susceptibility
title_full_unstemmed	An Ultraconserved brain-specific enhancer within ADGRL3 (LPHN3) underpins attention-deficit/hyperactivity disorder susceptibility
title_sort	ultraconserved brain-specific enhancer within adgrl3 (lphn3) underpins attention-deficit/hyperactivity disorder susceptibility
publisher	Society of Biological Psychiatry
publishDate	2016
url	https://repository.urosario.edu.co/handle/10336/26069 https://doi.org/10.1016/j.biopsych.2016.06.026
_version_	1674805773687848960
score	12,131701

An Ultraconserved brain-specific enhancer within ADGRL3 (LPHN3) underpins attention-deficit/hyperactivity disorder susceptibility

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