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

Abstract

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 (P GC o5e À 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 ¼ 9.02e À 07) and in the joint analysis of both stages (P ¼ 9.7e À 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. Neuropsychopharmacology (2015) 40, 915-926;

Gene-wide Association Study Reveals RNF122 Ubiquitin Ligase as a Novel Susceptibility Gene for Attention Deficit Hyperactivity Disorder

“…However, some genes highlighted in the previous single-marker GWAS were found among top genes surpassing the follow-up significance threshold in the present gene-wide analyses ( FBXO33 , PEX19 , COPA and KCNG4 ) 12 .…”

“…The quantile–quantile plot showed no departure from the expected P-values distribution, with a genomic control inflation factor of λ = 1.031 12 .…”

Genetics of attention deficit hyperactivity disorder

“…The initial GWAS of ADHD [76][77][78][79][80][81][82][83][84][85][86] did not discover any DNA variants that achieved genome-wide significance, even when most of these samples were combined in metaanalysis having a sample size of 2064 trios (two parents and an ADHD child), 896 ADHD patients, and 2455 controls [87]. That study did find statistical significance for a group of candidate genes previously nominated by members of the International Multisite ADHD Genetics (IMAGE) project [88].…”

“…PARK2 regulates the cell's ubiquitin-proteasome system which helps dispose damaged, misshapen, and excess proteins. Two other genes involved in this pathway (FBXO33 and RNF122) had been implicated in other studies [84,129]. A study of adult ADHD did not find a significant effect for large CNVs, but did find a significant effect for small CNVs [126].…”

SLC2A3 single‐nucleotide polymorphism and duplication influence cognitive processing and population‐specific risk for attention‐deficit/hyperactivity disorder

“…ADHD is a common, early onset and enduring neurodevelopmental disorder and persistence into adulthood is associated with considerable risk for comorbidity, such as depression, eating, and substance use disorders as well as failure in psychosocial adaptation (Geissler & Lesch, ). Although substantial heritability of ADHD is documented, with estimates of ~80%, genome‐wide screenings and cross‐disorder approaches have pinpointed only a few ADHD‐related genes (Elia et al., ; Jarick et al., ; Lee et al., ; Neale et al., ; Sanchez‐Mora et al., ; The Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium, ; Williams et al., ). In a recent copy number variant (CNV) association analysis in patients with ADHD, we identified a duplication on chromosome 12p13.31 inherited from an ADHD‐affected mother (Lesch et al., ).…”