Bjella, T. | bioRxiv Science

bioRxiv2022

Multivariate genetic analysis of personality and cognitive traits reveals abundant pleiotropy and improves prediction

Personality and cognition are heritable mental traits, and their genetic determinants may be distributed across interconnected brain functions. However, previous studies have employed univariate approaches which reduce complex traits to summary measures. We applied the "pleiotropy-informed" multivariate omnibus statistical test (MOSTest) to genome-wide association studies (GWAS) of 35 item and task-level measures of neuroticism and cognition from the UK Biobank (n=336,993). We identified 431 significant genetic loci and found evidence of abundant pleiotropy across personality and cognitive domains. Functional characterisation implicated genes with significant tissue-specific expression in all tested brain tissues and enriched in brain-specific gene-sets. We conditioned independent GWAS of the Big 5 personality traits and cognition on our multivariate findings, which boosted genetic discovery in other personality traits and improved polygenic prediction. These findings advance our understanding of the polygenic architecture of complex mental traits, indicating a prominence of pleiotropic genetic effects across higher-order domains of mental function. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/481967v2_ufig1.gif" ALT="Figure 1"> View larger version (89K): org.highwire.dtl.DTLVardef@1641108org.highwire.dtl.DTLVardef@9a24eeorg.highwire.dtl.DTLVardef@1eeae99org.highwire.dtl.DTLVardef@108db7f_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2019

Cannabis use is associated with increased levels of soluble gp130 in schizophrenia but not in bipolar disorder

The complex effects of plant cannabinoids on human physiology is not yet fully understood, but include a wide spectrum of effects on immune modulation. The immune system and its inflammatory effector pathways are recently emerging as possible causative factors in psychotic disorders. The present study aimed to investigate whether self-administered cannabis use was associated with changes in circulating immune and neuroendocrine markers in schizophrenia (SCZ, n=401) and bipolar disorder patients (BD, n=242). A screening of 13 plasma markers reflecting different inflammatory pathways was performed in SCZ and BD patients after subdividing each group into cannabis user and non-user subgroups. We found that i) soluble gp130 (sgp130) concentrations were significantly elevated among cannabis users in the SCZ group (p=0.002) after multiple testing correction, but not in BD. ii) Nominally significant differences were observed in the levels of IL-1RA (p=0.0059), YKL40 (p=0.0069), CatS (p=0.013), sTNFR1 (p=0.031), and BDNF (p=0.020), where these factors exhibited higher plasma levels in cannabis user SCZ patients than in non-users. iii) These differences in systemic levels were not reflected by altered mRNA expression of genes encoding sgp130, IL-1RA, YKL40, CatS, sTNFR1, and BDNF in whole blood. In sum, our results show that cannabis self-administration is associated with markedly higher sgp130 levels in SCZ, but not in BD, and that this phenomenon is independent of the modulation of peripheral immune cells. These findings warrant further investigation into the potential neuroimmune, anti-inflammatory, and biobehavioral-cognitive effects of cannabis use in SCZ.

pharmacology and toxicology↗