Cizek, P. | Search bioRxiv

bioRxiv2019

From rare Copy Number Variations to biological processes in ADHD

AimAttention-deficit/hyperactivity disorder (ADHD) is a highly heritable psychiatric disorder. The objective of this study was to define ADHD-associated candidate genes, and their associated molecular modules and biological themes, based on the analysis of rare genetic variants.\n\nMethodsWe combined data from 11 published copy number variation (CNV) studies in 6176 individuals with ADHD and 25026 controls and prioritized genes by applying an integrative strategy based on criteria including recurrence in ADHD individuals, absence in controls, complete coverage in copy number gains, and presence in the minimal region common to overlapping CNVs, as well as on protein-protein interactions and information from cross-species genotype-phenotype annotation.\n\nResultsWe localized 2241 eligible genes in the 1532 reported CNVs, of which we classified 432 as high-priority ADHD candidate genes. The high-priority ADHD candidate genes were significantly co-expressed in the brain. A network of 66 genes was supported by ADHD-relevant phenotypes in the cross-species database. In addition, four significantly interconnected protein modules were found among the high-priority ADHD genes. A total of 26 genes were observed across all applied bioinformatic methods. Look-up in the latest genome-wide association study for ADHD showed that among those 26, POLR3C and RBFOX1 were also supported by common genetic variants.\n\nConclusionsIntegration of a stringent filtering procedure in CNV studies with suitable bioinformatics approaches can identify ADHD candidate genes at increased levels of credibility. Our pipeline provides additional insight in the molecular mechanisms underlying ADHD and allows prioritization of genes for functional validation in validated model organisms.

genetics↗

bioRxiv2018

Integrative cross-species analyses identify deficits in habituation learning as a widely affected mechanism in Autism

BackgroundAlthough habituation is one of the most ancient and fundamental forms of learning, its regulators and relevance for human disease are poorly understood.\n\nMethodsWe manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and tested these models in light-off jump habituation. We dissected neuronal substrates underlying the identified habituation deficits and integrated genotype-phenotype annotations, gene ontologies and interaction networks to determine the clinical features and molecular processes that are associated with habituation deficits.\n\nResultsWe identified more than 100 genes required for habituation learning. For the vast majority of these, 93 genes, a role in habituation learning was previously unknown. These genes characterize ID disorders with overgrowth/macrocephaly and comorbid ASD. Moreover, ASD individuals from the Simons Simplex Collection carrying disruptive de novo mutations in these genes exhibit increased rates of specific aberrant behaviors including stereotypic speech, hyperactivity and irritability. At the molecular level, ID genes required for normal habituation are enriched in synaptic function and converge on Ras-MAPK signaling. Both increased Ras-MAPK signaling in GABAergic and decreased Ras-MAPK signaling in cholinergic neurons specifically inhibit the adaptive habituation response.\n\nConclusionsOur work demonstrates the relevance of habituation learning to autism, identifies an unprecedented number of novel habituation players, supports an emerging role for inhibitory neurons in habituation and reveals an opposing, circuit-level-based mechanism for Ras-MAPK signaling. This establishes habituation as a possible, widely applicable target for pharmacologic intervention in ID/ASD.

neuroscience↗