Abstract
BackgroundAttention-Deficit Hyperactivity Disorder (ADHD) is a complex neurodevelopmental disorder (NDD) which may significantly impact on the affected individual’s life. ADHD is acknowledged to have a high heritability component (70–80%). Recently, a meta-analysis of GWAS (Genome Wide Association Studies) has demonstrated the association of several independent loci. Our main aim here, is to apply PASCAL (pathway scoring algorithm), a new gene-based analysis (GBA) method, to the summary statistics obtained in this meta-analysis. PASCAL will take into account the linkage disequilibrium (LD) across genomic regions in a different way than the most commonly employed GBA methods (MAGMA or VEGAS (Versatile Gene-based Association Study)). In addition to PASCAL analysis a gene network and an enrichment analysis for KEGG and GO terms were carried out. Moreover, GENE2FUNC tool was employed to create gene expression heatmaps and to carry out a (DEG) (Differentially Expressed Gene) analysis using GTEX v7 and BrainSpan data.ResultsPASCAL results have revealed the association of new loci with ADHD and it has also highlighted other genes previously reported by MAGMA analysis. PASCAL was able to discover new associations at a gene level for ADHD: FEZF1 (p-value: 2.2 × 10− 7) and FEZF1-AS1 (p-value: 4.58 × 10− 7). In addition, PASCAL has been able to highlight association of other genes that share the same LD block with some previously reported ADHD susceptibility genes. Gene network analysis has revealed several interactors with the associated ADHD genes and different GO and KEGG terms have been associated. In addition, GENE2FUNC has demonstrated the existence of several up and down regulated expression clusters when the associated genes and their interactors were considered.ConclusionsPASCAL has been revealed as an efficient tool to extract additional information from previous GWAS using their summary statistics. This study has identified novel ADHD associated genes that were not previously reported when other GBA methods were employed. Moreover, a biological insight into the biological function of the ADHD associated genes across brain regions and neurodevelopmental stages is provided.
Highlights
Attention-Deficit Hyperactivity Disorder (ADHD) is a complex neurodevelopmental disorder (NDD) which may significantly impact on the affected individual’s life
Polygenic liability models has pointed towards a model in which both, single-nucleotide polymorphisms (SNPs) and rare copy number variants (CNVs) are involved in ADHD genetics For these reasons, it is considered that common variation. explains a substantial fraction of ADHD heritability [5,6,7]
Gene-based-analysis gene-based analysis (GBA) of ADHD done with summary statistics from European meta-analysis has revealed association of 19 loci surpassing the required Bonferroni threshold (2.26 × 10− 6)
Summary
Attention-Deficit Hyperactivity Disorder (ADHD) is a complex neurodevelopmental disorder (NDD) which may significantly impact on the affected individual’s life. PASCAL will take into account the linkage disequilibrium (LD) across genomic regions in a different way than the most commonly employed GBA methods (MAGMA or VEGAS (Versatile Gene-based Association Study)). Different genetic approaches were employed to search for ADHD susceptibility genes [3, 4]. Early ADHD (GWAS) have failed to detect robust signals surpassing the established significance threshold (5 × 10 − 8). This could be possibly due to the lack of standardized phenotyping protocols and the need of a larger number of cases and controls that allow the detection of common variants with an small effect [8]. None of the findings from these early GWAS were genome-wide significant, some interesting loci were highlighted: CDH13, SLC9A9, NOS1 and CNR1 [9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
