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.

Details

Title
Mutations in sphingolipid metabolism genes are associated with ADHD
Author
Henriquez-Henriquez Marcela 1 ; Acosta, Maria T 2 ; Martinez, Ariel F 2   VIAFID ORCID Logo  ; Vélez, Jorge I 3   VIAFID ORCID Logo  ; Lopera, Francisco 4 ; Pineda, David 4   VIAFID ORCID Logo  ; Palacio, Juan D 4   VIAFID ORCID Logo  ; Quiroga, Teresa 5 ; Worgall, Tilla S 6 ; Deckelbaum, Richard J 7 ; Mastronardi Claudio 8 ; Molina, Brooke S, G 9   VIAFID ORCID Logo  ; Vitiello Benedetto 10 ; Severe, Joanne B 11 ; Jensen, Peter S 12 ; Eugene, Arnold L 13 ; Hoagwood Kimberly 14 ; Richters, John 15 ; Vereen, Donald R 16 ; Hinshaw, Stephen P 17 ; Elliott, Glen R 18 ; Wells, Karen C 19 ; Epstein, Jeffery N 20 ; Murray, Desiree W 21 ; Keith, Conners C 19 ; March, John 19 ; Swanson, James 22 ; Wigal, Timothy 23 ; Cantwell, Dennis P 24 ; Abikoff, Howard B 25 ; Hechtman Lily 26 ; Greenhill, Laurence L 27 ; Newcorn, Jeffrey H 28 ; Hoza Betsy 29 ; Pelham, William E 30 ; Gibbons, Robert D 31 ; Marcus, Sue 32 ; Hur Kwan 33 ; Kraemer, Helena C 34 ; Hanley, Thomas 35 ; Stern, Karen 36 ; Arcos-Burgos Mauricio 37   VIAFID ORCID Logo  ; Muenke Maximilian 2   VIAFID ORCID Logo 

1  Pontificia Universidad Católica de Chile, Department of Clinical Laboratories, School of Medicine, Santiago, Chile (GRID:grid.7870.8) (ISNI:0000 0001 2157 0406); ELSA Clinical Laboratories (IntegraMedica, part of Bupa), Santiago de Chile, Chile (GRID:grid.7870.8) 
2  National Institutes of Health, Medical Genetics Branch, National Human Genome Research Institute, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165) 
3  Universidad del Norte, Barranquilla, Colombia (GRID:grid.412188.6) (ISNI:0000 0004 0486 8632) 
4  University of Antioquia, Neuroscience Research Group, Medellin, Colombia (GRID:grid.412881.6) (ISNI:0000 0000 8882 5269) 
5  Pontificia Universidad Católica de Chile, Department of Clinical Laboratories, School of Medicine, Santiago, Chile (GRID:grid.7870.8) (ISNI:0000 0001 2157 0406) 
6  Columbia University, Department of Pathology and Cell Biology, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729) 
7  Columbia University, Department of Pediatrics, Institute of Human Nutrition, College of Physicians and Surgeons, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729) 
8  Universidad del Rosario, Neuroscience Group (NeurUROS), Institute of Translational Medicine, School of Medicine and Health Sciences, School of Medicine and Health Sciences, Bogotá, Colombia (GRID:grid.412191.e) (ISNI:0000 0001 2205 5940) 
9  University of Pittsburgh, Departments of Psychiatry, Psychology, and Pediatrics, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000) 
10  National Institute of Mental Health, National Institutes of Health, Child & Adolescent Treatment and Preventive Interventions Research Branch, Bethesda, USA (GRID:grid.416868.5) (ISNI:0000 0004 0464 0574) 
11  National Institute of Mental Health, National Institutes of Health, Division of Services and Intervention Research, Bethesda, USA (GRID:grid.416868.5) (ISNI:0000 0004 0464 0574) 
12  The REACH Institute, New York, USA (GRID:grid.416868.5); Mayo Clinic, Department of Psychiatry and Psychology, Rochester, USA (GRID:grid.66875.3a) (ISNI:0000 0004 0459 167X) 
13  The Ohio State University, Center for Psychiatry and Behavioral Health, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943) 
14  Columbia University, Department of Child Psychiatry, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729) 
15  National Institutes of Health, National Institute of Nursing Research, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165) 
16  National Institutes of Health, National Institute of Drug Abuse, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165) 
17  University of California Berkeley, The Institute of Human Development, Berkeley, USA (GRID:grid.47840.3f) (ISNI:0000 0001 2181 7878); University of California San Francisco, Department of Psychiatry, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
18  University of California San Francisco, Department of Psychiatry, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811); Children’s Health Council, Palo Alto, USA (GRID:grid.492978.9) (ISNI:0000 0004 0623 8124) 
19  Duke University School of Medicine, Department of Psychiatry and Behavioral Sciences, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961) 
20  Duke University School of Medicine, Department of Psychiatry and Behavioral Sciences, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961); Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, Cincinnati, USA (GRID:grid.239573.9) (ISNI:0000 0000 9025 8099) 
21  Duke University, The Sanford School of Public Policy, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961); University of North Carolina at Chapel Hill, Frank Porter Graham Child Development Institute, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208) 
22  University of California, Irvine School of Medicine, Department of Pediatrics, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243) 
23  University of California, Irvine School of Medicine, Department of Pediatrics, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243); Avida Inc., Newport Beach, USA (GRID:grid.266093.8) 
24  University of California, Los Angeles School of Medicine, Department of Psychiatry and Behavioral Sciences, Neuropsychiatric Institute, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718) 
25  New York University Grossman School of Medicine, Department of Child and Adolescent Psychiatry, New York, USA (GRID:grid.137628.9) (ISNI:0000 0004 1936 8753) 
26  McGill University, Division of Child Psychiatry, Montreal Children’s Hospital, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649) 
27  Columbia University, Division of Child and Adolescent Psychiatry, Department of Psychiatry, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729) 
28  Icahn School of Medicine at Mount Sinai, Department of Psychiatry, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
29  University of Pittsburgh, Departments of Psychiatry, Psychology, and Pediatrics, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000); University of Vermont, Department of Psychological Science, Burlington, USA (GRID:grid.59062.38) (ISNI:0000 0004 1936 7689) 
30  University of Pittsburgh, Departments of Psychiatry, Psychology, and Pediatrics, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000); Florida International University, Department of Psychology, Miami, USA (GRID:grid.65456.34) (ISNI:0000 0001 2110 1845) 
31  The University of Chicago, Departments of Medicine, Public Health Sciences and Comparative Human Development, Chicago, USA (GRID:grid.170205.1) (ISNI:0000 0004 1936 7822) 
32  Icahn School of Medicine at Mount Sinai, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
33  University of Illinois at Chicago, Department of Psychiatry, Chicago, USA (GRID:grid.185648.6) (ISNI:0000 0001 2175 0319) 
34  Stanford University, Department: Psychiatry and Behavioral Sciences, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
35  US Department of Education, Office of Special Education Programs, Washington, USA (GRID:grid.419881.d) (ISNI:0000 0001 2176 2483) 
36  US Department of Justice, Office of Juvenile Justice and Delinquency Prevention, Washington, USA (GRID:grid.423379.8) (ISNI:0000 0001 2197 809X) 
37  Universidad de Antioquia, Grupo de Investigación en Psiquiatría (GIPSI), Departamento de Psiquiatría, Instituto de Investigaciones Me´dicas, Facultad de Medicina, Medelli´n, Colombia (GRID:grid.412881.6) (ISNI:0000 0000 8882 5269) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
21583188
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41398-020-00881-8
ProQuest document ID
2487258025
Copyright
© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.