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Mutations in sphingolipid metabolism genes are associated with ADHD.

ABSTRACT: 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.

SUBMITTER: Henriquez-Henriquez M

PROVIDER: S-EPMC7359313 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Mutations in sphingolipid metabolism genes are associated with ADHD.

Henriquez-Henriquez Marcela M Acosta Maria T MT Martinez Ariel F AF Vélez Jorge I JI Lopera Francisco F Pineda David D Palacio Juan D JD Quiroga Teresa T Worgall Tilla S TS Deckelbaum Richard J RJ Mastronardi Claudio C Molina Brooke S G BSG Arcos-Burgos Mauricio M Muenke Maximilian M

Translational psychiatry 20200713 1

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 ge ...[more]

PMID: 32661301

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Project description:Background Inflammation and immune cell infiltration in infarcted myocardial tissue are critical to myocardial infarction (MI) prognosis, and alterations in sphingolipid metabolism (SM) have been shown to potentially influence the inflammatory response and induce cardioprotection, but the underlying mechanisms are unclear. We therefore performed bioinformatics analysis to screen for key genes of SM in MI immune cells. Methods Three matrix files including GSE61145, GSE23294, and GSE71906 were downloaded from the Gene Expression Omnibus (GEO) database. GSE61145 was a human peripheral blood database, and GSE23294 and GSE71906 were 2 mouse myocardial tissue databases. R and annotation packages were used to screen for differentially-expressed genes (DEGs). Datasets of human and mouse cardiac tissues were downloaded from the GEO database for subsequent validation. The downloaded platform and matrix files were processed using R language and annotation packages. Key targets and enrichment pathways were identified using Gene Ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The Wilcoxon test was performed on the genes involved in SM pathways in neutrophils. Results A total of 261 DEGs were obtained from human peripheral blood datasets, among which 101 were immune-related. GO analysis revealed that neutrophil activation, T cell activation, and T cell differentiation were significantly enriched in the immune-related DEGs. Three types of immune cells were identified in infarcted myocardial tissues. In addition, 194 DEGs were obtained from mouse myocardial tissue data, among which 6 SM-related genes (Asah1, Degs1, Neu1, Sptlc2, Sphk1, and Gba2) were significantly associated with MI. Evaluation of the relationships between these DEGs and neutrophils showed that the expression of the Sptlc2 gene was significantly upregulated in neutrophils of the MI group, while the expression levels of the Asah1 and Degs1 genes were downregulated. Conclusions We identified 3 SM-related genes that were highly associated with neutrophils in MI, which may advance our understanding of SM in immune cells after MI.

Project description:Sphingolipid metabolism is dysregulated in type 2 diabetes mellitus (T2DM); however, the focus of previous studies was mostly limited to ceramide (Cer), and only few studies have investigated other metabolites, including sphingosine-1 phosphate (So1P). The present study aimed to examine the involvement of 8 major sphingolipid metabolites, including Cer, glucosyl ceramide (GluCer), lactosyl ceramide (LacCer), sphingomyelin (SM), sphinganine (Sa), So1P, sphingosine (So) and sphinganine-1-phosphate (Sa1P), during the progression of T2DM, and to evaluate the ability of serum sphingolipids to predict cases of diabetes with an elevated risk of cardiovascular complications. Blood samples were obtained from 245 participants who were divided into 3 groups: Healthy controls, pre-diabetes (pre-DM) and diagnosed diabetes. The 8 major sphingolipid metabolites were measured by high-performance liquid chromatography-tandem mass spectrometry and blood parameters were determined by routine laboratory assays for all subjects. Among the sphingolipid metabolites, So1P was associated with sex and lean mass index, but not with the body mass index. So1P was highest in healthy controls and gradually decreased when the disease proceeded to pre-DM and T2DM. GluCer, SM, Sa and So decreased in pre-DM and rose again in T2DM, graphically exhibiting a 'U' shape change during the progression of diabetes. So1P and Sa were identified to be significantly associated with cardiovascular complications by multivariate logistic regression analysis. Receiver operating characteristic curve analysis also suggested that So1P and Sa were able to indicate cardiovascular complications in diabetic patients. Pre-DM and diabetes were significantly associated with decreased So1P, SM, Sa and So, compared with the healthy controls. So1P was correlated with the progression of T2DM, and was a predictor of an elevated risk of cardiovascular complications among T2DM patients, along with Sa. The present study was registered with ClinicalTrials.gov (no. NCT02826759; April 2016).

Project description:The development of nonalcoholic fatty liver disease (NAFLD) has been reported to be caused by sphingolipid family inducing insulin resistance, mitochondrial dysfunction, and inflammation, which can be regulated by multiple sphingolipid metabolic pathways. This study aimed to explore the molecular mechanism of crucial sphingolipid metabolism related genes (SMRGs) in NAFLD. Firstly, the datasets (GSE48452, GSE126848, and GSE63067) from the Gene Expression Omnibus database and sphingolipid metabolism genes (SMGs) from previous research were collected for this study. The differentially expressed genes (DEGs) between different NAFLD and controls were acquired through "limma," and the SMRGs were authenticated via weighted gene co-expression network analysis (WGCNA). After overlapping the DEGs and SMRGs, the causality between the intersection genes (DE-SMRGs) and NAFLD was explored to sort out the candidate biomarkers by Mendelian randomization (MR) study. The receiver operating characteristic (ROC) curves of candidate biomarkers in GSE48452 and GSE126848 were yielded to determine the biomarkers, followed by the nomogram construction and enrichment analysis. Finally, the immune infiltration analysis, the prediction of transcription factors (TFs) and drugs targeting biomarkers were put into effect. A total of 23 DE-SMRGs were acquired based on the differential analysis and weighted gene co-expression network analysis (WGCNA), of which 3 DE-SMRGs (CD37, CXCL9 and IL7R) were picked out for follow-up analysis through univariate and multivariate MR analysis. The values of area under ROC curve of CD37 and CXCL9 were >0.7 in GSE48452 and GSE126848, thereby being regarded as biomarkers, which were mainly enriched in amino acid metabolism. With respect to the Spearman analysis between immune cells and biomarkers, CD37 and CXCL9 were significantly positively associated with M1 macrophages (P < .001), whose proportion was observably higher in NAFLD patients compared with controls. At last, TFs (ZNF460 and ZNF384) of CD37 and CXCL9 and a total of 79 chemical drugs targeting CD37 and CXCL9 were predicted. This study mined the pivotal SMRGs, CD37 and CXCL9, and systematically explored the mechanism of action of both biomarkers based on the public databases, which could tender a fresh reference for the clinical diagnosis and therapy of NAFLD.

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Mutations in sphingolipid metabolism genes are associated with ADHD.

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Mutations in sphingolipid metabolism genes are associated with ADHD.

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