Association Study of 10 Genes Encoding Neurotrophic Factors and Their Receptors in Adult and Child Attention-Deficit/Hyperactivity Disorder

Ribasés, Marta; Hervás, Amaia; Ramos-Quiroga, Josep Antoni; Bosch, Rosa; Bielsa, Anna; Gastaminza, Xavier; Fernández-Anguiano, Mònica; Nogueira, Mariana; Gómez-Barros, Núria; Valero, Sergi; Gratacòs, Mónica; Estivill, Xavier; Casas, Miquel; Cormand, Bru; Bayés, Mònica

doi:10.1016/j.biopsych.2007.11.004

Cited by 92 publications

(75 citation statements)

References 80 publications

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“…Following this strategy, which allows capturing additional associations that might have been skipped in previous studies that focused on the overall ADHD sample, we found preliminary evidence for the involvement of FBXO33 in combined ADHD but not in the inattentive subgroup. These findings are in agreement with previous reports pointing to the validity of the DSM-IV distinction between the combined and predominantly inattentive types, support previous studies that find differential genetic components across ADHD subtypes and suggest that the combined group may represent a distinctive and more homogeneous phenotype that may facilitate the identification of genetic factors contributing to ADHD (Larsson et al, 2006;Ribases et al, 2008;Ribases et al, 2009;Todd et al, 2001). Thus, the identification of phenotypic characteristics that define subgroups of patients affected by specific sets of genes, such as clinical subtypes, may be an alternative approach to reduce genetic heterogeneity in ADHD.…”

Section: Discussionsupporting

confidence: 83%

“…Despite the fact that genetic studies have mainly focused on children, there is evidence pointing to the existence of an even stronger genetic component in adult ADHD (Biederman, 2005;Biederman and Faraone, 2005;Chang et al, 2013;Faraone et al, 2005). In addition, different lines of investigation suggest a distinct genetic load between persistent and remitting ADHD, and support the existence of specific genetic factors contributing to the stability of ADHD symptoms across life Price et al, 2005;Ribases et al, 2008). Thus, previous GWAS focused on childhood ADHD may have increased heterogeneity by including in the analysis the subset of patients in whom ADHD will remit.…”

Section: Discussionmentioning

confidence: 99%

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

Sánchez-Mora

Ramos-Quiroga

Bosch

et al. 2014

Neuropsychopharmacol

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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;

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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

Sánchez-Mora

Ramos-Quiroga

Bosch

et al. 2014

Neuropsychopharmacol

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“…TrkC is expressed throughout the brain and is most abundant in the hippocampus [Ernfors et al, 1992]. A previous molecular genetic study has implicated neurotrophic factors, especially, NT3, in ADHD risk, though not NTRK1 or NTRK3 [Ribases et al, 2008]. Additionally in the present study, one SNP within NTRK2 moderated the relationship between birth weight centile and ADHD hyperactive-impulsive symptoms at a trend level.…”

Section: Discussionsupporting

confidence: 55%

“…CNTFR encodes for ciliary neurotrophic factor receptor and is implicated in neurodevelopment and neuron survival [DeChiara et al, 1995]. In independent samples of children and adults, a three-marker CNTFR haplotype was associated with ADHD [Ribases et al, 2008]. Taken together, these findings suggest that CNTFR may be implicated in the development of ADHD.…”

Section: Discussionmentioning

confidence: 88%

“…Of the many systems implicated in the ischemiahypoxia response, dopaminergic [Levy, 1991;Swanson et al, 2007], neurotrophic [Ribases et al, 2008;Sanchez-Mora et al, 2009], angiogenic [Kim et al, 2002;Jesmin et al, 2004], kynurenine [Oades, 2011] and cytokine systems [Oades, 2011] are also implicated in the development of ADHD and related conditions. Therefore, genetic variants within these five systems were the focus of this study.…”

Section: Introductionmentioning

confidence: 99%

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Angiogenic, neurotrophic, and inflammatory system SNPs moderate the association between birth weight and ADHD symptom severity

Smith

Anastopoulos

Garrett

et al. 2014

American J of Med Genetics Pt B

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Low birth weight is associated with increased risk for AttentionDeficit/Hyperactivity Disorder (ADHD); however, the etiological underpinnings of this relationship remain unclear. This study investigated if genetic variants in angiogenic, dopaminergic, neurotrophic, kynurenine, and cytokine-related biological pathways moderate the relationship between birth weight and ADHD symptom severity. A total of 398 youth from two multi-site, family-based studies of ADHD were included in the analysis. The sample consisted of 360 ADHD probands, 21 affected siblings, and 17 unaffected siblings. A set of 164 SNPs from 31 candidate genes, representing five biological pathways, were included in our analyses. Birth weight and gestational age data were collected from a state birth registry, medical records, and parent report.Generalized Estimating Equations tested for main effects and interactions between individual SNPs and birth weight centile in predicting ADHD symptom severity. SNPs within neurotrophic (NTRK3) and cytokine genes (CNTFR) were associated with

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Developmental Twin Study of Attention Problems

Chang

Lichtenstein²,

Asherson³

et al. 2013

JAMA Psychiatry

161

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The genetic and environmental link between attention-deficit/hyperactivity disorder in childhood and the adult manifestation of the disorder is poorly understood because of a lack of longitudinal studies with crossinformant data. Objective: To explore the relative contribution of genetic and environmental influences on symptoms of attention problems from childhood to early adulthood. Design: Analysis was conducted using longitudinal structural equation modeling with multiple informants. Setting: The Swedish Twin Study of Child and Adolescent Development. Participants: One thousand four hundred eighty twin pairs were prospectively followed up from childhood to young adulthood. Main Outcome Measures: Symptoms were obtained using parent and self-ratings of the Attention Problems Scale at ages 8 to 9, 13 to 14, 16 to 17, and 19 to 20 years. Results: The best-fitting model revealed high heritability of attention problems as indexed by parent and selfratings from childhood to early adulthood (h 2 = 0.77-0.82). Genetic effects operating at age 8 to 9 years continued, explaining 41%, 34%, and 24% of the total variance at ages 13 to 14, 16 to 17, and 19 to 20 years. Moreover, new sets of genetic risk factors emerged at ages 13 to 14, 16 to 17, and 19 to 20 years. Conclusions: The shared view of self-and informantrated attention problems is highly heritable in childhood, adolescence, and early adulthood, suggesting that the previous reports of low heritability for attentiondeficit/hyperactivity disorder in adults are best explained by rater effects. Both genetic stability and genetic innovation were present throughout this developmental stage, suggesting that attention problems are a developmentally complex phenotype characterized by both continuity and change across the life span.

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Association Study of 10 Genes Encoding Neurotrophic Factors and Their Receptors in Adult and Child Attention-Deficit/Hyperactivity Disorder

Cited by 92 publications

References 80 publications

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

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

Angiogenic, neurotrophic, and inflammatory system SNPs moderate the association between birth weight and ADHD symptom severity

Developmental Twin Study of Attention Problems

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