A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts.
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Middeldorp Christel M, Hammerschlag Anke R, Ouwens Klaasjan G, Groen-Blokhuis Maria M, Pourcain Beate St, Greven Corina U, Pappa Irene, Tiesler Carla M T, Ang Wei, Nolte Ilja M, Vilor-Tejedor Natalia, Bacelis Jonas, Ebejer Jane L, Zhao Huiying, Davies Gareth E, Ehli Erik A, Evans David M, Fedko Iryna O, Guxens Mònica, Hottenga Jouke-Jan, Hudziak James J, Jugessur Astanand, Kemp John P, Krapohl Eva, Martin Nicholas G, Murcia Mario, Myhre Ronny, Ormel Johan, Ring Susan M, Standl Marie, Stergiakouli Evie, Stoltenberg Camilla, Thiering Elisabeth, Timpson Nicholas J, Trzaskowski Maciej, van der Most Peter J, Wang Carol, EArly Genetics and Lifecourse Epidemiology (EAGLE) Consortium, Psychiatric Genomics Consortium ADHD Working Group, Nyholt Dale R, Medland Sarah E, Neale Benjamin, Jacobsson Bo, Sunyer Jordi, Hartman Catharina A, Whitehouse Andrew J O, Pennell Craig E, Heinrich Joachim, Plomin Robert, Smith George Davey, Tiemeier Henning, Posthuma Danielle, Boomsma Dorret I
Аннотация
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 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.
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 to improve statistical power for identifying genetic variants.