PXD066283

PXD066283 is an original dataset announced via ProteomeXchange.

Title	Rare coding genetic variants confer high risk of ADHD, implicate neuronal biology, and impact socioeconomic outcomes
Description	Attention deficit hyperactivity disorder (ADHD) is a childhood onset neurodevelopmental disorder with a large genetic risk component. It affects around 5% of children and 2.5% of adults and is associated with a range of severe outcomes. Here we identify three genes (MAP1A, ANO8, ANK2, P < 3.07e-6) implicated in ADHD by rare coding variants from exome sequencing of 8,895 individuals with ADHD and 53,780 controls. Rare deleterious variants in the three genes confer substantial risk for ADHD (odds ratios 5.55 - 15.13) and explain 5.2% of the overall rare variant heritability of ADHD, which was estimated to 2.5%. Protein-protein interaction networks of the three identified genes were enriched for rare variant risk of other neurodevelopmental disorders, and enrichment analyses pointed towards involvement of the networks in cytoskeleton organization, synapse function, and RNA processing. The top associated rare variant risk genes showed an increased mean expression across both pre- and postnatal brain developmental stages, with enrichment in several neuronal cell types including GABAergic and dopaminergic neurons, as well as among genes expressed in axons and in ion channel diseases. Rare protein-truncating variants were associated with lower socioeconomic status and lower education in individuals with ADHD, both before and after excluding individuals with co-occurring intellectual disability (ID). In line with this we identified a decrease in 2.25 intelligence quotient (IQ) points per rare deleterious variant in a German sample of adults with ADHD (N = 962). Individuals with both ADHD and ID showed increased load of rare variant risk overall, while individuals with other psychiatric comorbidities demonstrated increased load only for specific neurodevelopmental disorder gene sets. This suggests that psychiatric comorbidity (other than ID) in ADHD primarily is driven by rare variants in specific genes, rather than a general increased load across constrained genes.
HostingRepository	MassIVE
AnnounceDate	2025-11-13
AnnouncementXML	Submission_2025-11-13_10:23:10.614.xml
DigitalObjectIdentifier
ReviewLevel	Non peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Lage Lab
SpeciesList	scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606;
ModificationList	Carbamidomethyl; Methyl; Oxidation
Instrument	LTQ Orbitrap Velos Pro; Orbitrap Exploris 480; Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-17 11:26:30	ID requested
⏵ 1	2025-11-13 10:23:11	announced

no publication

submitter keyword: IP-MS, protein-protein interaction, human induced neurons, attention deficit hyperactivity disorder, DatasetType:Proteomics

Kasper Lage
contact affiliation	Broad Institute of MIT and Harvard
contact email	klhansen@broadinstitute.org
lab head
Lage Lab
contact affiliation	Broad Institute of MIT and Harvard
contact email	klagelab@gmail.com
dataset submitter

MassIVE dataset URI

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