Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental behavioral disorder, affecting about 5.3% of children and adolescents worldwide. It frequently persists into adulthood and can have serious life-long health consequences. Affected individuals are at increased risk for significant socioeconomic disadvantages, such as poor educational achievement, low income, underemployment, legal problems, and impaired social relationships. In addition, ADHD increases the risk of co-morbid disruptive disorders, such as oppositional defiant disorder (ODD), conduct disorder (CD) and substance use disorder (SUD). Over the last two decades, our research has made significant contributions to the genetics of ADHD. We collected families clustering ADHD and associated comorbidities from disparate regions around the world. Using genome-wide data, we found evidence of linkage of ADHD to chromosomes 4q13.2, 5q33.3, 8q11.23, 11q22, and 17p11.93. Linkage and association analyses revealed co-segregation between ADHD and disruptive behaviors linking genetics to the natural history of the disease. The Mendelian co-segregation of ADHD with these genomic regions and their high genotypic penetrance identify them as major loci predisposing to ADHD. Fine mapping of the region at 4q13.2 identified variants in the adhesion G protein-coupled receptor L3 gene (ADGRL3, also known as latrophilin 3 or LPHN3) that predispose to ADHD. ADGRL3 encodes a member of the latrophilin subfamily of adhesion G-protein coupled receptors and is highly expressed in brain regions implicated in the dopaminergic and noradrenergic systems. ADGRL3 endogenous ligand has been identified as FLRT3, a postsynaptic membrane protein involved in axon guidance and neuronal cell migration during embryonic development. Mouse and zebrafish knockout models support ADGRL3 implication in ADHD pathophysiology. We and others have found a significant homogeneous genetic effect of ADGRL3 variants predisposing to ADHD in children, adolescents, and adults using cohorts of thousands of individuals from Colombia, Germany, Norway, Spain, South Korea, Brazil, U.S., and Canada. To the best of our knowledge, ADGRL3 this is the most replicated gene associated with ADHD. As a measure of the epidemiological impact, the population attributable risk of ADGRL3 susceptibility variants has been estimated at 8.99 (95% confidence interval = 3.90-14.12), which means that the incidence of ADHD would be reduced by 9% if we were able to control for the effect of this gene. We have reported evidence of a genetic interaction between ADGRL3 variants and a haplotype in chromosome 11q. This negative epistasis doubles the risks of developing ADHD, worsens ADHD severity, and predicts the response to stimulant medication. The haplotype at 11q encompasses the NCAM1 gene, which encodes a surface molecule with a fundamental role in neural development; DRD2, which has been previously associated with ADHD; and TTC12 and ANKK1, two relatively unknown genes associated with co-morbid disruptive symptoms. More recently, we identified a non-coding, three-marker ADGRL3 risk haplotype associated with ADHD, disruptive disorders and neuropsychological endophenotypes. This haplotype is harbored at a highly conserved sequence that functions as a brain specific transcriptional enhancer. Functional analysis of risk allele substitutions in this enhancer demonstrated disruption of YY1 repressor binding site, an important neurodevelopmental transcription factor. We have now concluded an investigation supporting a main role for ADGRL3 in the development of SUD. SUD and addiction represent a global public health problem of substantial socioeconomic implications. The World Health Organization estimates a worldwide prevalence of at least two billion alcohol users, one billion tobacco users and almost 185 million illicit drug users. The close association between ADHD and SUD, as summarized by family, twin, and genome-wide linkage and association studies, suggests that genetic factors play a crucial role in shaping the susceptibility to both ADHD and SUD. While ADGRL3 has been extensively studied in association with ADHD and disruptive behaviors (in the context of ADHD), a direct link between ADGRL3 and SUD had not been investigated. In this manuscript, we provide evidence supporting a possible functional role for ADGRL3 in modulating drug seeking behavior. We speculate that ADGRL3 variants may underlie a differential genetic susceptibility SUD and that a timely diagnosis and treatment of ADHD with stimulant medication might reduce the occurrence and/or severity of SUD. Confirmation of such hypothesis would have substantial public health implications. Another study concluded this year involves a possible involvement of sphingolipid metabolism in the development of ADHD. Based on data suggesting that ADHD patients might present with atypical central myelination and given the essential role of sphingolipids in myelin formation and maintenance, we interrogated sphingolipid metabolism gene variants for a possible association with ADHD. We found statistically significant associations between ADHD and variants in GALC, CERS6, SMPD1, SMPDL3B, CERS2, FADS3, ELOLV5 and CERK genes. Variants in GALC, SMPD1 and CERS6 were successfully replicated in additional ADHD cohorts.
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