No abstract

Etiologic insights into psychopathology may be gained by using hypothesis-free methods to identify associations between genetic risk for broad psychopathology and phenotypes measured during adolescence, including both markers of child psychopathology and intermediate phenotypes such as neural structure that may link genetic risk with outcomes. We conducted a phenome-wide association study (phenotype n=1,269-1,694) of polygenic risk scores (PRS) for broad spectrum psychopathology (i.e., Compulsive, Psychotic, Neurodevelopmental, and Internalizing) in youth of PCA-selected European ancestry (n=5,556; ages 9-13) who completed the baseline and/or two-year follow-up of the ongoing Adolescent Brain Cognitive DevelopmentSM (ABCD) Study. We found that Neurodevelopmental and Internalizing PRS were significantly associated with a host of proximal as well as distal phenotypes (Neurodevelopmental: 187 and 211; Internalizing: 122 and 173 phenotypes at baseline and two-year follow-up, respectively), whereas Compulsive and Psychotic PRS showed zero and one significant associations, respectively, after Bonferroni correction. Neurodevelopmental PRS were further associated with brain structure metrics (e.g., total volume, mean right hemisphere cortical thickness), with only cortical volume indirectly linking Neurodevelopmental PRS to grades in school. Genetic variation influencing risk to psychopathology manifests broadly as behaviors, psychopathology symptoms, and related risk factors in middle childhood and early adolescence. Keywords: Phenome-wide Association Study (PheWAS), polygenic risk scores, Neurodevelopmental, Internalizing

COVID continues to be a major international public health concern, the underlying mechanisms of which are not fully understood. Recent studies suggest that COVID may cause prolonged inflammation within the central nervous system. However, the evidence so far has been limited to few small-scale case studies. To address this, this study leveraged a longitudinal dataset from the UK Biobank that included neuroimaging data prior to and following COVID testing (analytic N=416 including n=224 COVID-positive cases) and applied a novel and non-invasive Diffusion Basis Spectrum Imaging (DBSI) technique to derive putative indices of neuroinflammation (i.e., restricted fraction; DBSI-RF) for gray matter structures and white matter tracts in the brain. We hypothesized that SARS-CoV-2 infection would be associated with elevated DBSI markers of putative neuroinflammation and conducted linear regression analyses with adjustment for age, sex, race, body mass index, smoking frequency, and data acquisition interval. After multiple testing correction using false discovery rate, we found no evidence that COVID is associated with variability in neuroinflammation. Several brain regions showed nominally significant differences in DBSI-RF between COVID cases and controls including psychopathology-related regions linked that are either part of (i.e., orbitofrontal cortex) or functionally connected to the olfactory network (e.g., amygdala, caudate). It remains possible that there are acute and transitory neuroinflammatory effects associated with COVID that were not observed in our study due to potential resolution of COVID prior to the scan. Future research is warranted to examine whether neuroinflammation is associated with SARS-CoV-2 infection in a time- and/or symptom-dependent manner.

Genetic risk for Late Onset Alzheimer disease (AD) has been associated with lower cognition and smaller hippocampal volume in healthy young adults. However, it remains unclear whether these and other associations are present during childhood. Using data from 5,556 genomically-con rmed European ancestry youth who completed the baseline session of the ongoing the Adolescent Brain Cognitive Development Study SM (ABCD Study®), our phenome-wide association study estimating associations between indices of genetic risk for late-onset AD (n = 4; AD polygenic risk scores (PRS), APOE rs429358 genotype, AD PRS with the APOE region removed (AD PRS−APOE ), and an interaction between AD PRS−APOE and APOE genotype) and 1,687 psychosocial, behavioral, and neural phenotypes revealed no signi cant associations after correction for multiple testing (all ps > 0.0002; all p fdr >0.07). These data suggest that AD genetic risk may not phenotypically manifest during middle-childhood or that effects are smaller than this sample is powered to detect.

Alcohol expectancies (AEs) are associated with likelihood of alcohol initiation and subsequent alcohol use disorders. It is unclear whether genetic predisposition to alcohol use and/or related traits contributes to shaping how one expects to feel when drinking alcohol. We used the Adolescent Brain Cognitive Development study to examine associations between genetic (i.e., polygenic risk for problematic alcohol use, depression, risk-taking), familial (i.e., parent self-reported alcohol problems), and psychosocial (i.e., adverse childhood experiences, peer use and disapproval toward alcohol) factors and positive and negative AEs in alcohol-naïve children (max analytic N = 6,935). Mixed-effect regression models showed that parental education, importance of the child’s religious beliefs, adverse childhood experiences, peer disapproval of alcohol use, and polygenic liability for risk-taking were associated with positive and/or negative AEs, to varying degrees. Overall, our results suggest several familial and psychosocial predictors of AEs but little evidence of contributions from polygenic liability to problematic alcohol use or related phenotypes.