Single Nucleotide Polymorphism Heritability of Behavior Problems in Childhood: Genome-Wide Complex Trait Analysis

Pappa, Irene; Fedko, Iryna O.; Mileva‐Seitz, Viara R.; Hottenga, Jouke‐Jan; Bakermans‐Kranenburg, Marian J.; Bartels, Meike; Beijsterveldt, Catharina E. M. van; Jaddoe, Vincent W.V.; Middeldorp, Christel M.; Rippe, Ralph C. A.; Rivadeneira, Fernando; Tiemeier, Henning; Verhulst, Frank C.; IJzendoorn, Marinus H. van; Boomsma, Dorret I.

doi:10.1016/j.jaac.2015.06.004

Cited by 46 publications

(39 citation statements)

References 58 publications

(53 reference statements)

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“…Following Yang et al,13 we estimated that the PGC ADHD subgroup GWA meta-analysis of 5,621 cases and 13,589 controls had 8% more power than the current study, and yet no significant results were found despite the SNP heritability estimated at 28% in this sample. 11 Several other studies also found evidence for polygenicity of ADHD,6–9,49 with the exception of one study 10. The range of the SNP heritability estimates for the symptom scores in the current study (Table 2) seems quite large.…”

Section: Discussionsupporting

confidence: 47%

A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts

Middeldorp

Hammerschlag

Ouwens

et al. 2016

Journal of the American Academy of Child & Adolescent Psych

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118

117

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Objective To elucidate the influence of common genetic variants on childhood attention-deficit/hyperactivity disorder (ADHD) symptoms, to identify genetic variants that explain its high heritability, and to investigate the genetic overlap of ADHD symptom scores with ADHD diagnosis. Method Within the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium, genome-wide single nucleotide polymorphisms (SNPs) and ADHD symptom scores were available for 17,666 children (< 13 years) from nine population-based cohorts. SNP-based heritability was estimated in data from the three largest cohorts. Meta-analysis based on genome-wide association (GWA) analyses with SNPs was followed by gene-based association tests, and the overlap in results with a meta-analysis in the Psychiatric Genomics Consortium (PGC) case-control ADHD study was investigated. Results SNP-based heritability ranged from 5% to 34%, indicating that variation in common genetic variants influences ADHD symptom scores. The meta-analysis did not detect genome-wide significant SNPs, but three genes, lying close to each other with SNPs in high linkage disequilibrium (LD), showed a gene-wide significant association (p values between 1.46×10-6 and 2.66×10-6). One gene, WASL, is involved in neuronal development. Both SNP- and gene-based analyses indicated overlap with the PGC meta-analysis results with the genetic correlation estimated at 0.96. Conclusion The SNP-based heritability for ADHD symptom scores indicates a polygenic architecture and genes involved in neurite outgrowth are possibly involved. Continuous and dichotomous measures of ADHD appear to assess a genetically common phenotype. A next step is to combine data from population-based and case-control cohorts in genetic association studies to increase sample size and improve statistical power for identifying genetic variants.

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Section: Discussionsupporting

confidence: 47%

A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts

Middeldorp

Hammerschlag

Ouwens

et al. 2016

Journal of the American Academy of Child & Adolescent Psych

Self Cite

118

117

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“…Two studies have assessed the contribution of measured genetic variants for a general psychopathology dimension. One study estimated the SNPheritability as 18% for maternal ratings of total problems on the Child Behavior Checklist, which measures internalizing, externalizing, and attention problems [35]. Similarly, another study estimated the SNP heritability as 38% for a general psychopathology factor derived from childhood psychopathology symptoms assessed by multiple raters [36].…”

Section: Psychiatric Comorbiditymentioning

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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“…31 Based on such findings it has been suggested that comorbidity across psychiatric disorder and traits may be attributed to a general psychopathology factor underpinned by common genetic variants. 29,32 Two studies have assessed the contribution of measured genetic variants for a general psychopathology dimension; Pappa et al (2015) reported a significant SNPheritability (h 2 snp =0.18, SE=0.10) for maternal ratings of total problems on the Child Behavior Checklist (CBCL), which measures internalizing, externalizing and attention problems. 33 Similarly, Neumann et al (2016) reported a 38% SNP heritability (h 2 snp =0.38,SE=0.16) for a general psychopathology factor derived from childhood psychopathology symptoms assessed by multiple raters.…”

Section: Introductionmentioning

confidence: 99%

“…29,32 Two studies have assessed the contribution of measured genetic variants for a general psychopathology dimension; Pappa et al (2015) reported a significant SNPheritability (h 2 snp =0.18, SE=0.10) for maternal ratings of total problems on the Child Behavior Checklist (CBCL), which measures internalizing, externalizing and attention problems. 33 Similarly, Neumann et al (2016) reported a 38% SNP heritability (h 2 snp =0.38,SE=0.16) for a general psychopathology factor derived from childhood psychopathology symptoms assessed by multiple raters. 34 These findings suggest that the co-occurrence of neurodevelopmental, externalizing and emotional symptoms in childhood is, at least in part, due to shared common risk variants.…”

Section: Introductionmentioning

confidence: 99%

The contribution of common genetic risk variants for ADHD to a general factor of childhood psychopathology

Brikell

Larsson

et al. 2017

Preprint

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Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder, with common genetic risk variants implicated in the clinical diagnosis and symptoms of ADHD.However, given evidence of comorbidity and genetic overlap across neurodevelopmental and externalizing conditions, it remains unclear whether these genetic risk variants are ADHDspecific. The aim of this study was to evaluate the associations between ADHD genetic risks and related neurodevelopmental and externalizing conditions, and to quantify the extent to which any such associations can be attributed to a general genetic liability towards psychopathology. We derived ADHD polygenic risk scores (PRS) for 13,460 children aged 9 and 12 years from the Child and Adolescent Twin Study in Sweden, using results from an independent meta-analysis of genome-wide association studies of ADHD diagnosis and symptoms. Associations between ADHD PRS, a latent general psychopathology factor, and six latent neurodevelopmental and externalizing factors were estimated using structural equation modelling. ADHD PRS were statistically significantly associated with elevated levels of inattention, hyperactivity/impulsivity, autistic traits, learning difficulties, oppositional-defiant, and conduct problems (standardized regression coefficients=0.07-0.12). Only the association with specific hyperactivity/impulsivity remained significant after accounting for a general psychopathology factor, on which all symptoms loaded positively (standardized mean loading=0.61, range=0.32-0.91). ADHD PRS simultaneously explained 1% (p-value<0.001) of the variance in the general psychopathology factor and 0.50% (p-value<0.001) in the specific hyperactivity/impulsivity factor. Our results suggest that common genetic risk variants associated with ADHD have largely general pleiotropic effects on neurodevelopmental and externalizing traits in the general population, in addition to a specific association with hyperactivity/impulsivity symptoms.

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Single Nucleotide Polymorphism Heritability of Behavior Problems in Childhood: Genome-Wide Complex Trait Analysis

Cited by 46 publications

References 58 publications

A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts

A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts

Genetics of attention deficit hyperactivity disorder

The contribution of common genetic risk variants for ADHD to a general factor of childhood psychopathology

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