Mutations in sphingolipid metabolism genes are associated with ADHD

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dc.contributor.authorHenriquez-Henriquez, Marcela
dc.contributor.authorAcosta, Maria T.
dc.contributor.authorMartinez, Ariel F.
dc.contributor.authorVelez, Jorge, I
dc.contributor.authorLopera, Francisco
dc.contributor.authorPineda, David
dc.contributor.authorPalacio, Juan D.
dc.contributor.authorQuiroga, Teresa
dc.contributor.authorWorgall, Tilla S.
dc.contributor.authorDeckelbaum, Richard J.
dc.contributor.authorMastronardi, Claudio
dc.contributor.authorMolina, Brooke S. G.
dc.contributor.authorArcos-Burgos, Mauricio
dc.contributor.authorMuenke, Maximilian
dc.date.accessioned2025-01-23T19:49:41Z
dc.date.available2025-01-23T19:49:41Z
dc.date.issued2020
dc.description.abstractAttention 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, andCERK). Successful local replication for associations with variants inGALC,SMPD1, andCERS6was 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 increasedGALCexpression in the cerebellum.
dc.fuente.origenWOS
dc.identifier.doi10.1038/s41398-020-00881-8
dc.identifier.issn2158-3188
dc.identifier.urihttps://doi.org/10.1038/s41398-020-00881-8
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/100513
dc.identifier.wosidWOS:000553431800004
dc.issue.numero1
dc.language.isoen
dc.revistaTranslational psychiatry
dc.rightsacceso restringido
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleMutations in sphingolipid metabolism genes are associated with ADHD
dc.typeartículo
dc.volumen10
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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