Multivariate GWAS of psychiatric disorders and their cardinal symptoms reveal two dimensions of cross-cutting genetic liabilities

Abstract

28A single dimension of general psychopathology, p, has been hypothesized to represent a general 29 liability that spans multiple types of psychiatric disorders and non-clinical variation in psychiatric 30 symptoms across the lifespan. We conducted genome-wide association analyses of lifetime 31 symptoms of mania, psychosis, irritability in 124,952 to 208,315 individuals from UK Biobank, 32 and then applied Genomic SEM to model the genetic relationships between these psychiatric 33 symptoms and clinically-defined psychiatric disorders (schizophrenia, bipolar disorder, major 34 depressive disorder). Two dimensions of cross-cutting genetic liability emerged: general 35 vulnerability to self-reported symptoms (p self ) versus transdiagnostic vulnerability to clinically-36 diagnosed disease (p clinician ). These were only modestly correlated (r g = .344). Multivariate GWAS 37 identified 145 and 11 independent and genome-wide significant loci for p clinician and p self , 38 respectively, and improved polygenic prediction, relative to univariate GWAS, in hold-out 39 samples. Despite the severe impairments in occupational and educational functioning seen in 40 patients with schizophrenia and bipolar disorder, p self showed stronger and more pervasive genetic 41 correlations with facets of socioeconomic disadvantage (educational attainment, income, and 42 neighborhood deprivation), whereas p clinician was more strongly associated with medical disorders 43 unrelated to the brain. Genetic variance in p clinician that was unrelated to general vulnerability to 44 psychiatric symptoms was associated with less socioeconomic disadvantage, suggesting positive 45 selection biases in clinical samples used in psychiatric GWAS. These findings inform criticisms 46 of psychiatric nosology by suggesting that cross-disorder genetic liabilities identified in GWASs 47 of clinician-defined psychiatric disease are relatively distinct from genetic liabilities operating on 48 self-reported symptom variation in the general population. 49

Differences in directed functional brain connectivity related to age, sex and mental health

“…Given recent indications that psychopathology may not be explained F I G U R E 1 Principal component analysis (PCA) of mental health questionnaire from UK Biobank. We used the first two principal components as proxies of general psychopathology, referred to as "pF" and "pF 2 " by a single dimension (Mallard et al, 2019), we also included the second principal component, which explained 11.94% of the variance.…”

Differences in directed functional brain connectivity related to age, sex and mental health

“…This component related mostly to depression/anxiety items. Given recent indications that psychopathology may not be explained by a single dimension (Mallard et al, 2019), we also included the second principal component, which explained 11.94% of the variance. We refer to this component as pF 2, and this component related mostly to psychosis items.…”

Informed dimension reduction of clinically-related genome-wide association summary data characterises cross-trait axes of genetic risk

“…Our second motivation was to extract different axes underlying IMD genetic risk. Work in metabolic 31 and psychiatric 32 diseases have taken related approaches to attempt to learn composite factors underlying risk of these related diseases through deeper phenotyping of patients before testing these factors for genetic association. Alternatively, decomposition of estimated effects at 94 type 2 diabetes risk variants, together with their effects on 46 metabolic traits was used to cluster these variants into 5 groups, three focused on insulin resistance and two on beta cell function.…”