Pathway analysis in attention deficit hyperactivity disorder: An ensemble approach

Mooney, Michael A.; McWeeney, Shannon K.; Faraone, Stephen V.; Hinney, Anke; Hebebrand, Johannes; Nigg, Joel T.; Wilmot, Beth

doi:10.1002/ajmg.b.32446

Cited by 42 publications

(32 citation statements)

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“…Animal studies have shown that it acts as a ligand for PlexinA1, which is involved in critical steps of neuronal development in the spinal cord 29 and cardiac development 30,31 . This finding is consistent with prior research implicating neurite outgrowth dysregulation in ADHD 24,32 , and highlighting it as potential neural mediator of genetic risk for ADHD. This should be tested in future studies by applying imaging genetics mediation models 33 or Mendelian randomization approaches 34 .…”

Section: Discussionsupporting

confidence: 91%

Genetic markers of ADHD-related variations in intracranial volume

Klein

Walters

Demontis

et al. 2017

Preprint

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Word count main text: 3,002 /4000Word count online methods: 2,777/3,000References: 47 (without methods)/50 4 ABSTRACT Attention-Deficit/Hyperactivity Disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex pathophysiology, where genetic risk is hypothesized to be mediated by alterations in structure and function of diverse brain networks. We tested one aspect of this hypothesis by investigating the genetic overlap between ADHD (n=55,374) and (mainly subcortical) brain volumes (n=11,221-24,704), using the largest publicly available studies. At the level of common variant genetic architecture, we discovered a significant negative genetic correlation between ADHD and intracranial volume (ICV). Meta-analysis of individual variants found significant loci associated with both ADHD risk and ICV; additional loci were identified for ADHD and amygdala, caudate nucleus, and putamen volumes. Gene-set analysis in the ADHD-ICV meta-analytic data showed significant association with variation in neurite outgrowth-related genes. In summary, our results suggest new hypotheses about biological mechanisms involved in ADHD etiology and highlight the need to study additional brain parameters. Abstract length: 147 words

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Section: Discussionsupporting

confidence: 91%

Genetic markers of ADHD-related variations in intracranial volume

Klein

Walters

Demontis

et al. 2017

Preprint

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“…Examination of the "molecular landscape" derived from the top findings from these initial GWAS studies along with other data concluded that genes regulating directed neurite outgrowth were strongly implicated in the etiology of ADHD [90]. Pathway and gene set analyses of GWAS data implicated pathways involved in the regulation of neurotransmitter release, neurite outgrowth and axon guidance as contributors to the etiology of ADHD [91][92][93].…”

Section: Genome-wide Significant Common 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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“…It is well‐known that ADHD has a strong genetic loading as shown by several studies reporting increased ADHD rates and co‐morbid psychiatric symptoms in ADHD children's parents in comparison with healthy controls (Okan Ibiloglu et al., ). Genetic ADHD background has been only partially explored: recent pathway analyses demonstrated that different mechanisms are involved in the pathogenesis of ADHD including neurotransmitter release dysregulation, and abnormalities in neurite outgrowth and axon guidance (Mooney, McWeeney, Faraone, Hinney & Hebebrand, ). As well as genetics, it is well‐known that some environmental habits, such as smoking during pregnancy, alcohol consumption and lead exposure all increase the risk of ADHD onset (Jaspers et al., ; Koshy, Delpisheh & Brabin, ; Melchior et al., ; Pineda et al., ).…”

Section: Introductionmentioning

confidence: 99%