0e419e2452ea0e7235915254e884a32b pmc_35052433.pdf c736a65b2b106da34723014ab868d7bd1da8cd80 pmc_35052433.pdf 87296793c429bc34c2bb91b8b6533ab4450c93757a0ec89d2acd55d6c1e69062 pmc_35052433.pdf Title: Exploring the Contribution to ADHD of Genes Involved in Mendelian Disorders Presenting with Hyperactivityand/or Inattention Subject: Attention-deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder characterized by hyperactivity, impulsivity, and/or inattention, which are symptoms also observed in many rare genetic disorders. We searched for genes involved in Mendelian disorders presenting with ADHD symptoms in the Online Mendelian Inheritance in Man (OMIM) database, to curate a list of new candidate risk genes for ADHD. We explored the enrichment of functions and pathways in this gene list, and tested whether rare or common variants in these genes are associated with ADHD or with its comorbidities. We identified 139 genes, causal for 137 rare disorders, mainly related to neurodevelopmental and brain function. Most of these Mendelian disorders also present with other psychiatric traits that are often comorbid with ADHD. Using whole exome sequencing (WES) data from 668 ADHD cases, we found rare variants associated with the dimension of the severity of inattention symptoms in three genes: KIF11, WAC, and CRBN. Then, we focused on common variants and identified six genes associated with ADHD (in 19,099 cases and 34,194 controls): MANBA, UQCC2, HIVEP2, FOPX1, KANSL1, and AUH. Furthermore, HIVEP2, FOXP1, and KANSL1 were nominally associated with autism spectrum disorder (ASD) (18,382 cases and 27,969 controls), as well as HIVEP2 with anxiety (7016 cases and 14,475 controls), and FOXP1 with aggression (18,988 individuals), which is in line with the symptomatology of the rare disorders they are responsible for. In conclusion, inspecting Mendelian disorders and the genes responsible for them constitutes a valuable approach for identifying new risk genes and the mechanisms of complex disorders. Keywords: ADHD; rare mendelian disorders; genetic variants Author: Noèlia Fernàndez-Castillo, Judit Cabana-Domínguez, Djenifer B. Kappel, Bàrbara Torrico, Heike Weber, Klaus-Peter Lesch, Oscar Lao, Andreas Reif and Bru Cormand Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Fri Dec 31 11:11:21 2021 CET ModDate: Wed Jan 5 02:28:28 2022 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 12 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 635099 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- KORLVE+VnURWPalladioL Type 1 Custom yes yes no 10 0 QYTJME+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 HMELGM+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 FQZNOT+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 TWGHFX+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 36 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 40 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 44 0 KONDUX+EuphemiaUCAS-Bold Type 1C WinAnsi yes yes no 56 0 HIZBRM+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 59 0 QMDDXF+CMSY10 Type 1 Builtin yes yes no 84 0 GPJLFL+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 101 0 GPJLFN+PalatinoLinotype TrueType WinAnsi yes yes no 104 0 GPJLFP+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 107 0 WBVKDJ+URWPalladioL-BoldItal Type 1 Custom yes yes no 114 0 LWLIVD+EURM10 Type 1 Builtin yes yes no 124 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-05-27 02:51:17 CEST RepresentationInformation: pmc_35052433.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-31 12:08:18 CEST Size: 635099 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 306 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Gene Selection Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Whole-Exome Sequencing Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Rare Variant Association Analyses Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Common Variant Gene-Based Association Studies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Gene-Based Analyses and Meta-Analysis with Comorbid Conditions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: MetaXcan Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Effect on Subcortical Brain Volumes Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Children: Item: Title: Genes in Mendelian Disorders Presenting with ADHD Symptoms Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Rare Variants in the OMIM Gene List and ADHD Symptomatology in Patients Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Common Variants in the OMIM Gene List and ADHD Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Contribution to Comorbidities of the Genes Associated with ADHD Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Info: Title: Exploring the Contribution to ADHD of Genes Involved in Mendelian Disorders Presenting with Hyperactivityand/or Inattention Author: Noèlia Fernàndez-Castillo, Judit Cabana-Domínguez, Djenifer B. Kappel, Bàrbara Torrico, Heike Weber, Klaus-Peter Lesch, Oscar Lao, Andreas Reif and Bru Cormand Subject: Attention-deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder characterized by hyperactivity, impulsivity, and/or inattention, which are symptoms also observed in many rare genetic disorders. We searched for genes involved in Mendelian disorders presenting with ADHD symptoms in the Online Mendelian Inheritance in Man (OMIM) database, to curate a list of new candidate risk genes for ADHD. We explored the enrichment of functions and pathways in this gene list, and tested whether rare or common variants in these genes are associated with ADHD or with its comorbidities. We identified 139 genes, causal for 137 rare disorders, mainly related to neurodevelopmental and brain function. Most of these Mendelian disorders also present with other psychiatric traits that are often comorbid with ADHD. Using whole exome sequencing (WES) data from 668 ADHD cases, we found rare variants associated with the dimension of the severity of inattention symptoms in three genes: KIF11, WAC, and CRBN. Then, we focused on common variants and identified six genes associated with ADHD (in 19,099 cases and 34,194 controls): MANBA, UQCC2, HIVEP2, FOPX1, KANSL1, and AUH. Furthermore, HIVEP2, FOXP1, and KANSL1 were nominally associated with autism spectrum disorder (ASD) (18,382 cases and 27,969 controls), as well as HIVEP2 with anxiety (7016 cases and 14,475 controls), and FOXP1 with aggression (18,988 individuals), which is in line with the symptomatology of the rare disorders they are responsible for. In conclusion, inspecting Mendelian disorders and the genes responsible for them constitutes a valuable approach for identifying new risk genes and the mechanisms of complex disorders. 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