The association between type 2 diabetes and attention- deficit/hyperactivity disorder: A systematic review, meta-analysis, and population-based sibling study

Attention deficit hyperactivity disorder; Cardiovascular risk factors; Type 2 diabetesTrastorno por déficit de atención con hiperactividad; Factores de riesgo cardiovascular; Diabetes tipo 2Trastorn per dèficit d'atenció amb hiperactivitat; Factors de risc cardiovascular; Diabetis tipus 2We conducted a systematic review and a meta-analysis to quantitatively summarize evidence on the association between attention-deficit/hyperactivity disorder (ADHD) and type 2 diabetes (T2D). Moreover, a register-based sibling study was conducted to simultaneously control for confounding factors. A systematic search identified four eligible observational studies (N = 5738,287). The meta-analysis showed that individuals with ADHD have a more than doubled risk of T2D when considering adjusted estimates (OR=2.29 [1.48–3.55], d=0.46). Results from the register-based Swedish data showed a significant association between ADHD and T2D (HR=2.35 [2.14–2.58]), with substance use disorder, depression, and anxiety being the main drivers of the association, and cardiovascular and familiar risk playing a smaller role. While results from the meta-analysis provide evidence for an increased risk of T2D in individuals with ADHD, the register-based analyses show that the association between ADHD and T2D is largely explained by psychiatric comorbidities. Pending further evidence of causal association, our findings suggest that early identification and treatment of ADHD comorbidities might greatly reduce the risk of developing T2D in individuals with ADHD.The project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 965381. This report reflects only the author’s view, and the European Union is not responsible for any use that may be made of the information it contains. Henrik Larsson acknowledges financial support from the Swedish Research Council (2018-02599) and the Swedish Brain Foundation (FO2021-0115). Zheng Chang acknowledges financial support from the Swedish Council for Health, Working Life and Welfare (2019-00176). Ebba Du Rietz was supported by grant PD20-0036 from the Swedish Society for Medical Research (SSMF), Funds from the Strategic Research Program in Epidemiology at Karolinska Institutet, Fredrik & Ingrid Thurings Stiftelse and Fonden för Psykisk Hälsa

Genetic association study of childhood aggression across raters, instruments, and age

Genòmica; Comportament humàGenómica; Comportamiento humanoGenomics; Human behaviourChildhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E–06), PCDH7 (P = 2.0E–06), and IPO13 (P = 2.5E–06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range |rg|: 0.19–1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~−0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range |rg|: 0.46–0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.We very warmly thank all participants, their parents, and teachers for making this study possible. The project was supported by the “Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies” project (ACTION). ACTION received funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement no 602768. Cohort-specific acknowledgements and funding information may be found in the Supplementary text

Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder

TDAH; Genoma; Estudios de asociación ampliaADHD; Genome; Wide association studiesTDAH; Genoma; Estudis d'associació ampleAttention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10−10, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h2SNP = 0.34) when compared to ADHD without DBDs (h2SNP = 0.20), high genetic correlations between ADHD + DBDs and aggressive (rg = 0.81) and anti-social behaviors (rg = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior

Brain structural and functional substrates of ADGRL3 (latrophilin 3) haplotype in attention-deficit/hyperactivity disorder

TDAH; Genotipatge; Imatges per ressonància magnèticaTDAH; Genotipado; Imagen de resonancia magnéticaADHD; Genotyping; Magnetic resonance imagingPrevious studies have shown that the gene encoding the adhesion G protein-coupled receptor L3 (ADGRL3; formerly latrophilin 3, LPHN3) is associated with Attention-Deficit/Hyperactivity Disorder (ADHD). Conversely, no studies have investigated the anatomical or functional brain substrates of ADGRL3 risk variants. We examined here whether individuals with different ADGRL3 haplotypes, including both patients with ADHD and healthy controls, showed differences in brain anatomy and function. We recruited and genotyped adult patients with combined type ADHD and healthy controls to achieve a sample balanced for age, sex, premorbid IQ, and three ADGRL3 haplotype groups (risk, protective, and others). The final sample (n = 128) underwent structural and functional brain imaging (voxel-based morphometry and n-back working memory fMRI). We analyzed the brain structural and functional effects of ADHD, haplotypes, and their interaction, covarying for age, sex, and medication. Individuals (patients or controls) with the protective haplotype showed strong, widespread hypo-activation in the frontal cortex extending to inferior temporal and fusiform gyri. Individuals (patients or controls) with the risk haplotype also showed hypo-activation, more focused in the right temporal cortex. Patients showed parietal hyper-activation. Disorder-haplotype interactions, as well as structural findings, were not statistically significant. To sum up, both protective and risk ADGRL3 haplotypes are associated with substantial brain hypo-activation during working memory tasks, stressing this gene’s relevance in cognitive brain function. Conversely, we did not find brain effects of the interactions between adult ADHD and ADGRL3 haplotypes.This work was supported by several grants from the Plan Nacional de I+D+i and co-funded by the Instituto de Salud Carlos III-Subdirección General de Evaluación y Fomento de la Investigación and the European Regional Development Fund (FEDER): Research Project Grant (PI11/01629, PI11/01766, PI16/01505, PI17/00289, PI18/01788, PI19/00394, PI19/00721, and PI19/01224), Miguel Servet Research Contracts (CP09/00119 and CPII15/00023 to MR, CP10/00596 to EP-C and CP14/00041 and CPII19/00009 to JR), Sara Borrell contract (CD15/00199 to CSM), PFIS contract (FI20/00047 to LF), mobility grant (MV16/00039 to CSM), Pla Estratègic de Recerca i Innovació en Salut (PERIS); Generalitat de Catalunya (MENTAL-Cat; SLT006/17/287) and the Agència de Gestió d’Ajuts Universitaris i de Recerca-AGAUR, Catalonian Government (2009SGR211 and 2017SGR1461). The funding organizations played no role in the study design, data collection and analysis, or manuscript approval

Changes in the Mental Health of Children and Adolescents during the COVID-19 Lockdown : Associated Factors and Life Conditions

This study investigated the psychological impact of the coronavirus disease 2019 (COVID-19) among youth by analyzing their emotional/behavioral problems before and during the long-lasting lockdown in Spain. For that purpose, 699 parents with children aged 6-17 and 552 adolescents aged 12-17, who completed the parent and adolescent version of the Strengths and Difficulties Questionnaire at the beginning of 2019, responded to a survey from 26 May to 15 June 2020 that assessed psychological well-being and life conditions during quarantine (i.e., sociodemographic characteristics, situation before the lockdown, physical environment and accompaniment during the lockdown, COVID-related variables). According to both parent- and self-reports, children and youth experienced a significant worsening in emotional symptoms, conduct problems, hyperactivity/inattention, peer problems, and total difficulties subscales. Findings also suggested that impairment was mainly associated with variables related to the child's situation prior to home quarantine, the quality and quantity of the child's social networks during the lockdown, the daily routines the child followed, the concerns the child had about health, and the presence of economic and learning problems caused by the COVID-19. Thus, the present investigation emphasizes the need for carefully monitoring the mental health of younger people, provides guidance for the development of interventions that mitigate some of the psychological difficulties faced in a situation of confinement, and highlights the importance of paying special attention to high-risk group