Universität zu Köln

Martinez, Ariel F., Abe, Yu ORCID: 0000-0001-7435-1047, Hong, Sungkook, Molyneux, Kevin ORCID: 0000-0001-9126-0139, Yarnell, David, Loehr, Heiko, Driever, Wolfgang ORCID: 0000-0002-9551-9141, Acosta, Maria T., Arcos-Burgos, Mauricio ORCID: 0000-0002-8529-0574 and Muenke, Maximilian ORCID: 0000-0002-7719-6545 (2016). An Ultraconserved Brain-Specific Enhancer Within ADGRL3 (LPHN3) Underpins Attention-Deficit/Hyperactivity Disorder Susceptibility. Biol. Psychiatry, 80 (12). S. 943 - 955. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1873-2402

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Abstract

BACKGROUND: Genetic factors predispose individuals 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 noncoding 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 (similar to 207 Kb). Family-based genetic analyses of 838 individuals (372 affected and 466 unaffected patients) identified ADHD-associated single nucleotide polymorphisms harbored in some of these conserved elements. Luciferase assays and zebrafish green fluorescent protein 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 (evolutionary conserved region 47) that functions as a transcriptional enhancer. A three-variant ADHD risk haplotype in evolutionary conserved region 47, formed by rs17226398, rs56038622, and rs2271338, reduced enhancer activity by 40% in neuroblastoma and astrocytoma cells (p(Bonferroni) < .0001). This enhancer also drove green fluorescent protein expression in the zebrafish brain in a tissue-specific manner, sharing aspects of endogenous ADGRL3 expression. The rs2271338 risk allele disrupts binding of YY1 transcription factor, an important factor in the development and function of the central nervous system. Expression quantitative trait loci analysis of postmortem human brain tissues revealed an association between rs2271338 and reduced ADGRL3 expression in the thalamus. CONCLUSIONS: These results uncover the first functional evidence of common noncoding variants with potential implications for the pathology of ADHD.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Martinez, Ariel F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Abe, Yu UNSPECIFIED orcid.org/0000-0001-7435-1047 UNSPECIFIED Hong, Sungkook UNSPECIFIED UNSPECIFIED UNSPECIFIED Molyneux, Kevin UNSPECIFIED orcid.org/0000-0001-9126-0139 UNSPECIFIED Yarnell, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Loehr, Heiko UNSPECIFIED UNSPECIFIED UNSPECIFIED Driever, Wolfgang UNSPECIFIED orcid.org/0000-0002-9551-9141 UNSPECIFIED Acosta, Maria T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Arcos-Burgos, Mauricio UNSPECIFIED orcid.org/0000-0002-8529-0574 UNSPECIFIED Muenke, Maximilian UNSPECIFIED orcid.org/0000-0002-7719-6545 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-252429
DOI:	10.1016/j.biopsych.2016.06.026
Journal or Publication Title:	Biol. Psychiatry
Volume:	80
Number:	12
Page Range:	S. 943 - 955
Date:	2016
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1873-2402
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DEFICIT HYPERACTIVITY DISORDER; SUBSTANCE USE DISORDERS; YIN YANG 1; ADHD; GENE; BINDING; YY1; ASSOCIATION; EXPRESSION; ZEBRAFISH Multiple languages Neurosciences; Psychiatry Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/25242