Dataset Information

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

ABSTRACT: The aims of this study were 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.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 of age) 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.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.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 to improve statistical power for identifying genetic variants.

SUBMITTER: Middeldorp CM

PROVIDER: S-EPMC5068552 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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

Middeldorp Christel M CM Hammerschlag Anke R AR Ouwens Klaasjan G KG Groen-Blokhuis Maria M MM Pourcain Beate St BS Greven Corina U CU Pappa Irene I Tiesler Carla M T CMT Ang Wei W Nolte Ilja M IM Vilor-Tejedor Natalia N Bacelis Jonas J Ebejer Jane L JL Zhao Huiying H Davies Gareth E GE Ehli Erik A EA Evans David M DM Fedko Iryna O IO Guxens Mònica M Hottenga Jouke-Jan JJ Hudziak James J JJ Jugessur Astanand A Kemp John P JP Krapohl Eva E Martin Nicholas G NG Murcia Mario M Myhre Ronny R Ormel Johan J Ring Susan M SM Standl Marie M Stergiakouli Evie E Stoltenberg Camilla C Thiering Elisabeth E Timpson Nicholas J NJ Trzaskowski Maciej M van der Most Peter J PJ Wang Carol C Nyholt Dale R DR Medland Sarah E SE Neale Benjamin B Jacobsson Bo B Sunyer Jordi J Hartman Catharina A CA Whitehouse Andrew J O AJO Pennell Craig E CE Heinrich Joachim J Plomin Robert R Plomin Robert R Smith George Davey GD Tiemeier Henning H Posthuma Danielle D Boomsma Dorret I DI

Journal of the American Academy of Child and Adolescent Psychiatry 20160805 10

<h4>Objective</h4>The aims of this study were 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.<h4>Method</h4>Within the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium, genome-wide single nucleotide polymorphisms (SNPs) and ADHD symptom scores were available for ...[more]

PMID: 27663945

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Project description:BACKGROUND:Previous studies have reported associations between attention-deficit/hyperactivity disorder symptoms and DNA methylation in children. We report the first epigenome-wide association study meta-analysis of adult attention-deficit/hyperactivity disorder symptoms, based on peripheral blood DNA methylation (Infinium HumanMethylation450K array) in three population-based adult cohorts. METHODS:An epigenome-wide association study was performed in the Netherlands Twin Register (N = 2258, mean age 37 years), Dunedin Multidisciplinary Health and Development Study (N = 800, age 38 years), and Environmental Risk Longitudinal Twin Study (N = 1631, age 18 years), and results were combined through meta-analysis (total sample size N = 4689). Region-based analyses accounting for the correlation between nearby methylation sites were also performed. RESULTS:One epigenome-wide significant differentially methylated position was detected in the Dunedin study, but meta-analysis did not detect differentially methylated positions that were robustly associated across cohorts. In region-based analyses, six significant differentially methylation regions (DMRs) were identified in the Netherlands Twin Register, 19 in the Dunedin study, and none in the Environmental Risk Longitudinal Twin Study. Of these DMRs, 92% were associated with methylation quantitative trait loci, and 68% showed moderate to large blood-brain correlations for DNA methylation levels. DMRs included six nonoverlapping DMRs (three in the Netherlands Twin Register, three in the Dunedin study) in the major histocompatibility complex, which were associated with expression of genes in the major histocompatibility complex, including C4A and C4B, previously implicated in schizophrenia. CONCLUSIONS:Our findings point at new candidate loci involved in immune and neuronal functions that await further replication. Our work also illustrates the need for further research to examine to what extent epigenetic associations with psychiatric traits depend on characteristics such as age, comorbidities, exposures, and genetic background.

Project description:BackgroundFor the diagnosis of attention-deficit/hyperactivity disorder (ADHD), the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) proposes that adherence to six symptoms in either group (inattention and hyperactivity/impulsivity) will lead to the diagnosis of one of three presentations of the disorder. Underlying this diagnostic algorithm is the assumption that the 18 symptoms have equal relevance for the diagnosis of ADHD, all are equally severe, and all have the same power to detect the presence of the disorder in all its degrees of severity, without considering the possibility of using marker symptoms. However, several studies have suggested that ADHD symptoms differ in both their power to discriminate the presence of the disorder and the degree of severity they represent. The aim of the present study was to replicate the results of previous research by evaluating the discriminative capacity and relative severity of ADHD symptoms, as well as to extend the investigation of this topic to Spanish-speaking Latin American samples.MethodsThe properties of ADHD symptoms rated by the parents of 474 Chilean children were analyzed. Symptom parameters were estimated using the graded response model.ResultsThe results suggest that symptoms of ADHD differ substantially in both the accuracy with which they reflect the presence of the disorder, and their relative severity. Symptoms "easily distracted by extraneous stimuli" and "have difficulty sustaining attention in tasks" (inattention) and "is on the go, acting as if driven by motor" (hyperactivity/impulsivity) were the most informative, and those with relatively lower severity thresholds.DiscussionThe fact that symptoms differ substantially in the probability of being observed conditionally to the trait level suggests the need to refine the diagnostic process by weighting the severity of the symptom, and even to assess the possibility of defining ADHD marker symptoms, as has been done in other disorders.

Dataset Information

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

Publications

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

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