Discovery of the first genome-wide significant risk loci for ADHD

Demontis, Ditte; Walters, Raymond; Martin, Joanna; Mattheisen, Manuel; Als, Thomas Damm; Agerbo, Esben; Belliveau, Rich; Bybjerg‐Grauholm, Jonas; Bækvad-Hansen, Marie; Cerrato, Felecia; Chambert, Kimberly; Churchhouse, Claire; DuMont, Ashley L.; Eriksson, Nicholas; Gandal, Michael J.; Goldstein, Jacqueline I.; Grove, Jakob; Hansen, Christine; Hauberg, Mads E.; Hollegaard, Mads V.; Howrigan, Daniel P.; Huang, Hailiang; Maller, Julian; Moran, Jennifer L.; Pallesen, Jonatan; Palmer, Duncan S.; Pedersen, Carsten Bøcker; Poterba, Timothy; Poulsen, Jesper Buchhave; Ripke, Stephan; Robinson, Elise; Satterstrom, F. Kyle; Stevens, Christine; Turley, Patrick; Won, Hyejung; Andreassen, Ole A.; Burton, Christie L.; Boomsma, Dorret I.; Cormand, Bru; Dalsgaard, Søren; Franke, Barbara; Gelernter, Joel; Geschwind, Daniel H.; Hákonarson, Hákon; Haavik, Jan; Kranzler, Henry R.; Kuntsi, Jonna; Langley, Kate; Lesch, Klaus‐Peter; Middeldorp, Christel M.; Reif, Andreas; Rohde, Luís Augusto; Roussos, Panos; Schachar, Russell; Sklar, Pamela; Sonuga‐Barke, Edmund; Sullivan, Patrick F.; Thapar, Anita; Tung, Joyce Y.; Waldman, Irwin D.; Nordentoft, Merete; Hougaard, David M.; Werge, Thomas; Mors, Ole; Mortensen, Preben Bo; Daly, Mark J.; Faraone, Stephen V.; Børglum, Anders D.; Neale, Benjamin M.

doi:10.1101/145581

Cited by 177 publications

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“…As described by Demontis et al [94], other genes implicated by the genome-wide significant loci have relevant biological roles. DUSP6 regulates neurotransmitter homeostasis by affecting dopamine levels in the synapses.…”

Section: Genome-wide Significant Common Variantsmentioning

confidence: 91%

“…For methodologic details about the studies contributing data to this meta-analysis, see Demontis et al [94]. Twelve loci achieved genome-wide significance.…”

Section: Genome-wide Significant Common Variantsmentioning

confidence: 99%

“…When Demontis et al [94] correlated ADHD's polygenic risk with 220 disorders and traits, many highly significant correlations emerged. Figure 3 shows some of the most significant of these correlations (each passing the Bonferroni significance threshold).…”

Section: Common Variant Adhd As a Polygenic Disordermentioning

confidence: 99%

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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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Section: Genome-wide Significant Common Variantsmentioning

confidence: 91%

“…For methodologic details about the studies contributing data to this meta-analysis, see Demontis et al [94]. Twelve loci achieved genome-wide significance.…”

Section: Genome-wide Significant Common Variantsmentioning

confidence: 99%

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Genetics of attention deficit hyperactivity disorder

2018

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“…The most interesting results were obtained when we combined cocaine dependence with ADHD. We found significant association with two new genes: AMIGO3 and BSN (combined P=4.24e-07 and 5.13e-07, respectively), and also with 19 of the 20 genes previously identified in a gene-based analysis performed as part of the ADHD meta-analysis by Demontis et al (2017). Four of these 19 associations increased significance by at least one order of magnitude in the combined analysis (TIE1, CDH8, ELOVL1 and CCDC24) ( Table S7).…”

Section: Gene-based Meta-analysis With Comorbid Conditionsmentioning

confidence: 60%

Genome-wide association meta-analysis of cocaine dependence: Shared genetics with comorbid conditions

Cabana‐Domínguez

Shivalikanjli

Fernàndez‐Castillo

et al. 2018

Preprint

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Cocaine dependence is a complex neuropsychiatric disorder that is highly comorbid with other psychiatric traits. Association studies suggest that common genetic variants contribute substantially to cocaine dependence susceptibility. Also, increasing evidence supports the role of shared genetic risk factors in the lifetime co-occurrence of psychiatric traits and cocaine dependence. Here we performed a genome-wide association study (GWAS) meta-analysis of cocaine dependence using four different dbGaP datasets (2,085 cases and 4,293 controls).Although no genome-wide significant hits were found in the SNP-based analysis, the gene-based analysis identified HIST1H2BD as significantly associated with cocaine-dependence (10% FDR).This gene is located in a region on chromosome 6 enriched in histone-related genes, previously associated with schizophrenia. The top SNPs of this region, rs806973 and rs56401801 (P=3.14e-06 and 3.44e-06, respectively), are eQTLs for different genes in multiple brain areas.Furthermore, we performed LD Score regression (LDSC) analysis with comorbid conditions and found significant genetic correlations between cocaine dependence and ADHD, SCZ, MDD and risk-taking behavior. We also found, through polygenic risk score (PRS)

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“…Genome-wide association studies (GWAS) have so far been successful in identifying multiple common genetic risk variants for adult-onset disorders such as schizophrenia,9 bipolar disorder,10 depression11 and many physical illnesses such as diabetes 12. GWAS of childhood neurodevelopmental disorders had somewhat lagged behind, not least because of the difficulty accumulating large samples of patients with these disorders although genome-wide significant findings have now emerged for both ADHD13 and ASD 14. Such findings are being used to investigate the biology and epidemiology of these disorders.…”

mentioning

confidence: 99%