Mutations in sphingolipid metabolism genes are associated with ADHD
| Autor: | Henriquez-Henriquez, Marcela, Acosta, Maria T, Martinez, Ariel F, Vélez, Jorge I, Lopera, Francisco, Pineda, David, Palacio, Juan D, Quiroga, Teresa, Worgall, Tilla S, Deckelbaum, Richard J, Mastronardi, Claudio, Molina, Brooke SG, MTA Cooperative Group, Arcos-Burgos, Mauricio, Muenke, Maximilian |
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| Rok vydání: | 2020 |
| Předmět: |
Adult
medicine.medical_specialty Clinical Sciences Biology Predictive markers Polymorphism Single Nucleotide Article lcsh:RC321-571 Cellular and Molecular Neuroscience Neurodevelopmental disorder Clinical Research Genetic variation medicine Genetics ADHD Attention deficit hyperactivity disorder Humans 2.1 Biological and endogenous factors Psychology Genetic Predisposition to Disease Clinical genetics Allele Polymorphism Aetiology MTA Cooperative Group Child lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Gene Biological Psychiatry Pediatric Sphingolipids Human Genome Single Nucleotide medicine.disease Attention Deficit Hyperactivity Disorder (ADHD) Brain Disorders Psychiatry and Mental health Sphingomyelin Phosphodiesterase Mental Health Attention Deficit Disorder with Hyperactivity Expression quantitative trait loci Cohort Mutation Public Health and Health Services Attention Deficit Disorder (ADD) Medical genetics |
| Zdroj: | Translational psychiatry, vol 10, iss 1 Translational Psychiatry Translational Psychiatry, Vol 10, Iss 1, Pp 1-13 (2020) |
| Popis: | Attention deficit hyperactivity disorder (ADHD) is the most prevalent neurodevelopmental disorder in children, with genetic factors accounting for 75–80% of the phenotypic variance. Recent studies have suggested that ADHD patients might present with atypical central myelination that can persist into adulthood. Given the essential role of sphingolipids in myelin formation and maintenance, we explored genetic variation in sphingolipid metabolism genes for association with ADHD risk. Whole-exome genotyping was performed in three independent cohorts from disparate regions of the world, for a total of 1520 genotyped subjects. Cohort 1 (MTA (Multimodal Treatment study of children with ADHD) sample, 371 subjects) was analyzed as the discovery cohort, while cohorts 2 (Paisa sample, 298 subjects) and 3 (US sample, 851 subjects) were used for replication. A set of 58 genes was manually curated based on their roles in sphingolipid metabolism. A targeted exploration for association between ADHD and 137 markers encoding for common and rare potentially functional allelic variants in this set of genes was performed in the screening cohort. Single- and multi-locus additive, dominant and recessive linear mixed-effect models were used. During discovery, we found statistically significant associations between ADHD and variants in eight genes (GALC, CERS6, SMPD1, SMPDL3B, CERS2, FADS3, ELOVL5, and CERK). Successful local replication for associations with variants in GALC, SMPD1, and CERS6 was demonstrated in both replication cohorts. Variants rs35785620, rs143078230, rs398607, and rs1805078, associated with ADHD in the discovery or replication cohorts, correspond to missense mutations with predicted deleterious effects. Expression quantitative trait loci analysis revealed an association between rs398607 and increased GALC expression in the cerebellum. |
| Databáze: | OpenAIRE |
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