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An Ultraconserved Brain-specific Enhancer within ADGRL3 (LPHN3) Underpins the Susceptibility to Attention Deficit/Hyperactivity Disorder Open Access

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Genetic factors predispose to attention deficit/hyperactivity disorder (ADHD), the most frequently diagnosed neurodevelopmental condition in school-age children worldwide. Previous studies have reported genetic variants predisposing to ADHD and disruptive behaviors in a region of the ADGRL3 (LPHN3) gene. This genetic association has been replicated in at least 10 ADHD cohorts from distinct regions and ethnicities worldwide, making ADGRL3 the most consistently and positively replicated gene associated with this condition.Using in silico, in vitro and in vivo approaches, I identified an ultraconserved DNA element within ADGRL3 that functions as a brain transcriptional enhancer. This enhancer, named ECR47, harbors a common three-marker ADHD risk haplotype formed by polymorphisms rs17226398, rs56038622, and rs2271338 in complete linkage disequilibrium. This risk haplotype showed a significant association with a multivariate phenotype composed of ADHD, disruptive behaviors, substance use, and neuropsychological endophenotypes in extended multigenerational families from a genetic isolate. I was able to demonstrate that this risk haplotype reduces enhancer activity by approximately 40% in rat neuroblastoma and human astrocytoma cells (PBonferroni < 0.0001). Also, zebrafish transgenesis revealed a tissue-specific pattern of GFP expression driven by ECR47 that shared many aspects of endogenous adgrl3.1 mRNA expression. The risk allele of one particular polymorphism in ECR47, rs2271338, disrupts binding of Ying and Yang 1 (YY1), a ubiquitously expressed transcription factor crucial for 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.These results uncover the first evidence of non-coding common genetic variation with potential functional implications for the pathology of ADHD. A better understanding of ADHD pathogenetics will help in the development of reliable molecular diagnostic tools and new interventions (both pharmacological and non-pharmacological) for this condition.

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