Rare DNA variants in the brain-derived neurotrophic factor gene increase risk for attention-deficit hyperactivity disorder: a next-generation sequencing study

Hawi, Ziarih; Cummins, Tarrant; Tong, Janette; Arcos‐Burgos, Mauricio; Zhao, Qiongyi; Matthews, Natasha; Newman, Daniel P.; Johnson, Beth; Vance, Alasdair; Heussler, Helen; Lévy, Florence; Easteal, Simon; Wray, Naomi R.; Kenny, Elaine; Morris, Derek W.; Kent, Lindsey; Gill, Michael; Bellgrove, Mark A.

doi:10.1038/mp.2016.117

Cited by 33 publications

(21 citation statements)

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“…(50) Regulation and initiation of translation has been linked to neuropsychiatric disorders including ADHD, through the regulation of brain-derived neurotrophic factor (BDNF). (51–53) Based on the repeated association and the described functional work, we suggest the involvement of transcriptional regulation as one of the mechanisms that modulate the ADHD risk.…”

Section: Discussionmentioning

confidence: 89%

From rare Copy Number Variations to biological processes in ADHD

Harich

Voet

Klein

et al. 2019

Preprint

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AimAttention-deficit/hyperactivity disorder (ADHD) is a highly heritable psychiatric disorder. The objective of this study was to define ADHD-associated candidate genes, and their associated molecular modules and biological themes, based on the analysis of rare genetic variants.MethodsWe combined data from 11 published copy number variation (CNV) studies in 6176 individuals with ADHD and 25026 controls and prioritized genes by applying an integrative strategy based on criteria including recurrence in ADHD individuals, absence in controls, complete coverage in copy number gains, and presence in the minimal region common to overlapping CNVs, as well as on protein-protein interactions and information from cross-species genotype-phenotype annotation.ResultsWe localized 2241 eligible genes in the 1532 reported CNVs, of which we classified 432 as high-priority ADHD candidate genes. The high-priority ADHD candidate genes were significantly co-expressed in the brain. A network of 66 genes was supported by ADHD-relevant phenotypes in the cross-species database. In addition, four significantly interconnected protein modules were found among the high-priority ADHD genes. A total of 26 genes were observed across all applied bioinformatic methods. Look-up in the latest genome-wide association study for ADHD showed that among those 26, POLR3C and RBFOX1 were also supported by common genetic variants.ConclusionsIntegration of a stringent filtering procedure in CNV studies with suitable bioinformatics approaches can identify ADHD candidate genes at increased levels of credibility. Our pipeline provides additional insight in the molecular mechanisms underlying ADHD and allows prioritization of genes for functional validation in validated model organisms.

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Section: Discussionmentioning

confidence: 89%

From rare Copy Number Variations to biological processes in ADHD

Harich

Voet

Klein

et al. 2019

Preprint

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“…Although we considered only three families, we identified AAED1 as a novel ADHD candidate gene, showing that combining linkage analysis and WES can be an efficient strategy to prioritize ADHD-associated genes/variants. In contrast to previous studies focusing on pre-defined gene-sets [23,61], we performed an exome-wide search for rare variants. Additionally, we validated the association of the newly identified ADHD risk genes in an independent sample.…”

Section: Discussionmentioning

confidence: 99%

Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing

et al. 2018

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Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with a complex genetic background, hampering identification of underlying genetic risk factors. We hypothesized that combining linkage analysis and whole-exome sequencing (WES) in multi-generation pedigrees with multiple affected individuals can point toward novel ADHD genes. Three families with multiple ADHD-affected members (N total = 70) and apparent dominant inheritance pattern were included in this study. Genotyping was performed in 37 family members, and WES was additionally carried out in 10 of those. Linkage analysis was performed using multi-point analysis in Superlink Online SNP 1.1. From prioritized linkage regions with a LOD score ≥ 2, a total of 24 genes harboring rare variants were selected. Those genes were taken forward and were jointly analyzed in gene-set analyses of exome-chip data using the MAGMA software in an independent sample of patients with persistent ADHD and healthy controls (N = 9365). The gene-set including all 24 genes together, and particularly the gene-set from one of the three families (12 genes), were significantly associated with persistent ADHD in this sample. Among the latter, gene-wide analysis for the AAED1 gene reached significance. A rare variant (rs151326868) within AAED1 segregated with ADHD in one of the families. The analytic strategy followed here is an effective approach for identifying novel ADHD risk genes. Additionally, this study suggests that both rare and more frequent variants in multiple genes act together in contributing to ADHD risk, even in individual multi-case families.

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“…They detected four study-wide significant loci that implicated four genes known to be expressed in the brain during prenatal stages of development: NT5DC1, SEC23IP, PSD, and ZCCHC4. Hawi et al [144] found novel rare variants in the BDNF gene by sequencing 117 genes in 152 youth with ADHD and 188 controls.…”

Section: The Search For Rare Genetic Variantsmentioning

confidence: 99%

Genetics of attention deficit hyperactivity disorder

2018

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Decades of research show that genes play an vital role in the etiology of attention deficit hyperactivity disorder (ADHD) and its comorbidity with other disorders. Family, twin, and adoption studies show that ADHD runs in families. ADHD's high heritability of 74% motivated the search for ADHD susceptibility genes. Genetic linkage studies show that the effects of DNA risk variants on ADHD must, individually, be very small. Genome-wide association studies (GWAS) have implicated several genetic loci at the genome-wide level of statistical significance. These studies also show that about a third of ADHD's heritability is due to a polygenic component comprising many common variants each having small effects. From studies of copy number variants we have also learned that the rare insertions or deletions account for part of ADHD's heritability. These findings have implicated new biological pathways that may eventually have implications for treatment development.Attention deficit hyperactivity disorder (ADHD) is a childhood-onset condition with impairing symptoms of inattention, impulsivity, and hyperactivity. Decades of research have documented and replicated key facts about the disorder (for a review, see ref.[1]). It occurs in about 5% of children with little geographic or cross-cultural variation in prevalence and often co-occurs with other conditions, including mood, anxiety, conduct, learning, and substance use disorders. Longitudinal studies show that two-thirds of ADHD youth will continue to have impairing symptoms of ADHD in adulthood. People with ADHD are at risk for a wide range of functional impairments: school failure, peer rejection, injuries due to accidents, criminal behavior, occupational failure, divorce, suicide, and premature death. Although many details of ADHD's pathophysiology are unknown, neuropsychological and neuroimaging studies implicate brain circuits regulating executive functioning, reward processing, timing, and temporal information processing.This article reviews data about the role that genes play in the etiology of ADHD from two perspectives. Family, twin, and adoption studies provide a firm foundation for asserting that genes are involved in the etiology of ADHD. The view from molecular genetics provides a basis for understanding mechanisms whereby genes affect biological pathways that lead to ADHD. Family, twin and adoption studies of ADHDEvidence for heritability from family, adoption, and twin studies A study of 894 ADHD probands and 1135 of their siblings aged 5-17 years old found a ninefold increased risk of ADHD in siblings of ADHD probands compared with siblings of controls [2]. Adoption studies suggest that the familial factors of ADHD are attributable to genetic factors rather than shared environmental factors [3,4] with the most recent one reporting rates of ADHD to be greater among biological relatives of non-adopted ADHD children than adoptive relatives of adopted ADHD children. The adoptive relatives had a risk for ADHD like the risk in relatives of control childr...

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Rare DNA variants in the brain-derived neurotrophic factor gene increase risk for attention-deficit hyperactivity disorder: a next-generation sequencing study

Cited by 33 publications

References 44 publications

From rare Copy Number Variations to biological processes in ADHD

From rare Copy Number Variations to biological processes in ADHD

Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing

Genetics of attention deficit hyperactivity disorder

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