Case-Control Genome-Wide Association Study of Persistent Attention-Deficit Hyperactivity Disorder Identifies FBXO33 as a Novel Susceptibility Gene for the Disorder.

Sánchez-Mora C1, Ramos-Quiroga JA2, Bosch R3, Corrales M4, Garcia-Martinez I5, Nogueira M4, Pagerols M5, Palomar G4, Richarte V4, Vidal R4, Arias-Vasquez A6, Bustamante M7, Forns J8, Gross-Lesch S9, Guxens M8, Hinney A10, Hoogman M11, Jacob C9, Jacobsen KK12, Kan C13, Kiemeney L14, Kittel-Schneider S9, Klein M11, Onnink M15, Rivero O16, Zayats T12, Buitelaar J17, Faraone SV18, Franke B15, Haavik J12, Johansson S12, Lesch KP16, Reif A9,Sunyer J8, Bayés M19, Casas M2, Cormand B20, Ribasés M1.

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Abstract

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high heritability. At least 30% of patients diagnosed in childhood continue to suffer ADHD during adulthood and genetic risk factors may play an essential role in the persistence of the disorder throughout lifespan. To date, Genome-Wide Association Studies (GWAS) of ADHD have been completed in seven independent datasets, six of which were pediatric samples and one on persistent ADHD using a DNA-pooling strategy, but none of them reported genome-wide significant associations. In an attempt to unravel novel genes for the persistence of ADHD into adulthood, we conducted the first two-stage GWAS in adults with ADHD. The discovery sample included 607 ADHD cases and 584 controls. Top signals were subsequently tested for replication in three independent follow-up samples of 2,104 ADHD patients and 1,901 controls. None of the findings exceeded the genome-wide threshold for significance (PGC<5e-08), but we found evidence for the involvement of the FBXO33 gene in combined ADHD in the discovery sample (P=9.02e-07) and in the joint analysis of both stages (P=9.7e-03). Additional evidence for a FBXO33 role in ADHD was found through gene-wise and pathway enrichment analyses in our genomic study. Risk alleles were associated with lower FBXO33 expression in lymphoblastoid cell lines and with reduced frontal grey matter volume in a sample of 1,300 adult subjects. Our findings point for the first time at the ubiquitination machinery as a new disease mechanism for adult ADHD and establish a rationale for searching for additional risk variants in ubiquitination-related genes.Neuropsychopharmacology accepted article preview online, 06 October 2014. doi:10.1038/npp.2014.267.