Case-control genome-wide association study of persistent attention-deficit hyperactivity disorder identifies FBXO33 as a novel susceptibility gene for the disorder

Cristina Sánchez-Mora, Josep A Ramos-Quiroga, Rosa Bosch, Montse Corrales, Iris Garcia-Martínez, Mariana Nogueira, Mireia Pagerols, Gloria Palomar, Vanesa Richarte, Raquel Vidal, Alejandro Arias-Vasquez, Mariona Bustamante, Joan Forns, Silke Gross-Lesch, Monica Guxens, Anke Hinney, Martine Hoogman, Christian Jacob, Kaya K Jacobsen, Cornelis C KanLambertus Kiemeney, Sarah Kittel-Schneider, Marieke Klein, Marten Onnink, Olga Rivero, Tetyana Zayats, Jan Buitelaar, Stephen V Faraone, Barbara Franke, Jan Haavik, Stefan Johansson, Klaus-Peter Lesch, Andreas Reif, Jordi Sunyer, Mònica Bayés, Miguel Casas, Bru Cormand, Marta Ribasés*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high heritability. At least 30% of patients diagnosed in childhood continue to suffer from 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 2104 ADHD patients and 1901 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 (F-box only protein 33) 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 gray matter volume in a sample of 1300 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.

Original languageEnglish
Pages (from-to)915-26
Number of pages12
Issue number4
Publication statusPublished - Mar 2015


  • Adolescent
  • Adult
  • Aged
  • Attention Deficit Disorder with Hyperactivity
  • Case-Control Studies
  • Child
  • F-Box Proteins
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Young Adult

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