An Ultraconserved Brain-Specific Enhancer Within ADGRL3 (LPHN3) Underpins Attention-Deficit/Hyperactivity Disorder Susceptibility

A.F. Martinez, Y. Abe, S. Hong, K. Molyneux, D. Yarnell, H. Löhr, W. Driever, M.T. Acosta, M. Arcos-Burgos, M. Muenke

Resultado de la investigación: Contribución a RevistaArtículo

15 Citas (Scopus)

Resumen

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 (~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 (pBonferroni < .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. © 2016
Idioma originalEnglish (US)
Páginas (desde-hasta)943-954
Número de páginas12
PublicaciónBiological Psychiatry
Volumen80
N.º12
DOI
EstadoPublished - dic 15 2016

Huella dactilar

Attention Deficit Disorder with Hyperactivity
Brain
Green Fluorescent Proteins
YY1 Transcription Factor
Zebrafish Proteins
Alleles
Gene Transfer Techniques
Quantitative Trait Loci
Astrocytoma
Zebrafish
Luciferases
Thalamus
Neuroblastoma
Computer Simulation
Haplotypes
Genes
Single Nucleotide Polymorphism
Transcription Factors
Central Nervous System
Pathology

Citar esto

Martinez, A.F. ; Abe, Y. ; Hong, S. ; Molyneux, K. ; Yarnell, D. ; Löhr, H. ; Driever, W. ; Acosta, M.T. ; Arcos-Burgos, M. ; Muenke, M. / An Ultraconserved Brain-Specific Enhancer Within ADGRL3 (LPHN3) Underpins Attention-Deficit/Hyperactivity Disorder Susceptibility. En: Biological Psychiatry. 2016 ; Vol. 80, N.º 12. pp. 943-954.
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title = "An Ultraconserved Brain-Specific Enhancer Within ADGRL3 (LPHN3) Underpins Attention-Deficit/Hyperactivity Disorder Susceptibility",
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 (~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 (pBonferroni < .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. {\circledC} 2016",
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Martinez, AF, Abe, Y, Hong, S, Molyneux, K, Yarnell, D, Löhr, H, Driever, W, Acosta, MT, Arcos-Burgos, M & Muenke, M 2016, 'An Ultraconserved Brain-Specific Enhancer Within ADGRL3 (LPHN3) Underpins Attention-Deficit/Hyperactivity Disorder Susceptibility', Biological Psychiatry, vol. 80, n.º 12, pp. 943-954. https://doi.org/10.1016/j.biopsych.2016.06.026

An Ultraconserved Brain-Specific Enhancer Within ADGRL3 (LPHN3) Underpins Attention-Deficit/Hyperactivity Disorder Susceptibility. / Martinez, A.F.; Abe, Y.; Hong, S.; Molyneux, K.; Yarnell, D.; Löhr, H.; Driever, W.; Acosta, M.T.; Arcos-Burgos, M.; Muenke, M.

En: Biological Psychiatry, Vol. 80, N.º 12, 15.12.2016, p. 943-954.

Resultado de la investigación: Contribución a RevistaArtículo

TY - JOUR

T1 - An Ultraconserved Brain-Specific Enhancer Within ADGRL3 (LPHN3) Underpins Attention-Deficit/Hyperactivity Disorder Susceptibility

AU - Martinez, A.F.

AU - Abe, Y.

AU - Hong, S.

AU - Molyneux, K.

AU - Yarnell, D.

AU - Löhr, H.

AU - Driever, W.

AU - Acosta, M.T.

AU - Arcos-Burgos, M.

AU - Muenke, M.

N1 - Cited By :5 Export Date: 4 April 2018 CODEN: BIPCB

PY - 2016/12/15

Y1 - 2016/12/15

N2 - 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 (~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 (pBonferroni < .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. © 2016

AB - 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 (~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 (pBonferroni < .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. © 2016

U2 - 10.1016/j.biopsych.2016.06.026

DO - 10.1016/j.biopsych.2016.06.026

M3 - Article

VL - 80

SP - 943

EP - 954

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

IS - 12

ER -