The World Federation of ADHD International Consensus Statement: 208 Evidence-based Conclusions about the Disorder

Background:
Diverse behaviour problems in childhood correlate phenotypically, suggesting a general dimension of psychopathology that has been called the p factor. The shared genetic architecture between childhood psychopathology traits also supports a genetic p. This study systematically investigates the manifestation of this common dimension across self‐, parent‐ and teacher‐rated measures in childhood and adolescence. /

Methods:
The sample included 7,026 twin pairs from the Twins Early Development Study (TEDS). First, we employed multivariate twin models to estimate common genetic and environmental influences on p based on diverse measures of behaviour problems rated by children, parents and teachers at ages 7, 9, 12 and 16 (depressive traits, emotional problems, peer problems, autism traits, hyperactivity, antisocial behaviour, conduct problems and psychopathic tendencies). Second, to assess the stability of genetic and environmental influences on p across time, we conducted longitudinal twin modelling of the first phenotypic principal components of childhood psychopathological measures across each of the four ages. Third, we created a genetic p factor in 7,026 unrelated genotyped individuals based on eight polygenic scores for psychiatric disorders to estimate how a general polygenic predisposition to mostly adult psychiatric disorders relates to childhood p. /

Results:
Behaviour problems were consistently correlated phenotypically and genetically across ages and raters. The p factor is substantially heritable (50%–60%) and manifests consistently across diverse ages and raters. However, residual variation in the common factor models indicates unique contributions as well. Genetic correlations of p components across childhood and adolescence suggest stability over time (49%–78%). A polygenic general psychopathology factor derived from studies of psychiatric disorders consistently predicted a general phenotypic p factor across development (0.3%–0.9%). /

Conclusions:
Diverse forms of psychopathology generally load on a common p factor, which is highly heritable. There are substantial genetic influences on the stability of p across childhood. Our analyses indicate genetic overlap between general risk for psychiatric disorders in adulthood and p in childhood, even as young as age 7. The p factor has far‐reaching implications for genomic research and, eventually, for diagnosis and treatment of behaviour problems. /

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jcpp.13113

The p factor: genetic analyses support a general dimension of psychopathology in childhood and adolescence.

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate–related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Defining the role of common variation in the genomic and biological architecture of adult human height

Epidemiological studies demonstrate an association between asthma and mental health disorders, although little is known about the shared genetics and causality of this association. Thus, we aim to investigate shared genetic and the causal link between asthma and mental health disorders. We conducted a large-scale genome-wide cross-trait association study to investigate genetic overlap between asthma from UK Biobank and 8 mental health disorders from Psychiatric Genomics Consortium, including: attention deficit hyperactivity disorder (ADHD), anxiety disorder (ANX), autism spectrum disorder, bipolar disorder, eating disorder, major depressive disorder (MDD), posttraumatic stress disorder, and schizophrenia, with a sample size of 7556 to 446 032. In the single trait genome-wide association analysis, we replicated 130 and discovered 31 novel independent loci that are associated with asthma. We identified that ADHD, ANX and MDD have strong genetic correlation with asthma at the genome-wide level. Cross-trait meta-analysis identified 7 loci jointly associated with asthma and ADHD, 1 loci with asthma and ANX and 10 loci with asthma and MDD. Functional analysis revealed that the identified variants regulated gene expression in major tissues belonging to exocrine/endocrine, digestive, respiratory and hemic/immune system. Mendelian randomisation analyses suggested that ADHD and MDD (including 6.7% samples overlap with asthma) might increase the risk of asthma. This large-scale genome-wide cross-trait analysis identified shared genetics and potential causal links between asthma and three mental health disorders (ADHD, ANX, and MDD). Such shared genetics implicate potential new biological functions that are in common among them.

https://erj.ersjournals.com/content/erj/54/6/1901507.full.pdf

Shared Genetics of Asthma and Mental Health Disorders: A Large-Scale Genome-Wide Cross-Trait Analysis

Validity and utility of Hierarchical Taxonomy of Psychopathology (HiTOP): III. Emotional dysfunction superspectrum

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed a meta-analysis of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders identifying three groups of inter-related disorders. We detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning in the second trimester prenatally, and play prominent roles in a suite of neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

/pdf/genome-wide-meta-analysis-identifies-genomic-relationships-nrxo8cn8bv.pdf

Gelernter J

Papers

Genome wide meta-analysis identifies genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders