Unraveling Neuro-Proteogenomic Landscape and Therapeutic Implications for Human Behaviors and Psychiatric Disorders.

Understanding the genetic basis of neuro-related proteins is essential for dissecting the molecular basis of human behavioral traits and the disease etiology of neuropsychiatric disorders. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 individuals for 184 neuro-related proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-related traits such as sleeping, smoking, feelings, alcohol intake, mental health, and psychiatric disorders. Integrating with established drug information, we validated 13 out of 13 matched combinations of protein targets and diseases or side effects with available drugs, while suggesting hundreds of re-purposing and new therapeutic targets. This consortium effort provides a large-scale proteogenomic resource for biomedical research on human behaviors and other neuro-related phenotypes.

Genetic mechanisms of 184 neuro-related proteins in human plasma.

Understanding the genetic basis of neuro-related proteins is essential for dissecting the disease etiology of neuropsychiatric disorders and other complex traits and diseases. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 individuals for 184 neuro-reiated proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-reiated traits as well as complex diseases such as hypertension, high cholesterol, immune-related disorders, and psychiatric disorders. Integrating with established drug information, we validated 13 combinations of protein targets and diseases or side effects with available drugs, while suggesting hundreds of re-purposing and new therapeutic targets for diseases and comorbidities. This consortium effort provides a large-scale proteogenomic resource for biomedical research.

Mendelian randomisation identifies priority groups for prophylactic EBV vaccination.

BACKGROUND: Epstein Barr virus (EBV) infects ~ 95% of the population worldwide and is known to cause adverse health outcomes such as Hodgkin's, non-Hodgkin's lymphomas, and multiple sclerosis. There is substantial interest and investment in developing infection-preventing vaccines for EBV. To effectively deploy such vaccines, it is vital that we understand the risk factors for infection. Why particular individuals do not become infected is currently unknown. The current literature, describes complex, often conflicting webs of intersecting factors-sociodemographic, clinical, genetic, environmental-, rendering causality difficult to decipher. We aimed to use Mendelian randomization (MR) to overcome the issues posed by confounding and reverse causality to determine the causal risk factors for the acquisition of EBV. METHODS: We mapped the complex evidence from the literature prior to this study factors associated with EBV serostatus (as a proxy for infection) into a causal diagram to determine putative risk factors for our study. Using data from the UK Biobank of 8422 individuals genomically deemed to be of white British ancestry between the ages of 40 and 69 at recruitment between the years 2006 and 2010, we performed a genome wide association study (GWAS) of EBV serostatus, followed by a Two Sample MR to determine which putative risk factors were causal. RESULTS: Our GWAS identified two novel loci associated with EBV serostatus. In MR analyses, we confirmed shorter time in education, an increase in number of sexual partners, and a lower age of smoking commencement, to be causal risk factors for EBV serostatus. CONCLUSIONS: Given the current interest and likelihood of a future EBV vaccine, these factors can inform vaccine development and deployment strategies by completing the puzzle of causality. Knowing these risk factors allows identification of those most likely to acquire EBV, giving insight into what age to vaccinate and who to prioritise when a vaccine is introduced.

Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.

Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.