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• W4387496945 abstract "The availability of genome-wide association studies (GWAS) allows for vast opportunity to define the genomic underpinnings of complex disorders. In the post-GWAS age it is now apparent that loci alone do not reliably predict outcomes and individual factors are a vital component in disease risk. Body mass index (BMI) is a measure with associations across psychiatric disorders: genomic and/or clinical associations exist with BMI and schizophrenia, mood disorders, substance use, and eating disorders. Genetic risk models are often blind to BMI, which may dampen the importance of loci that have dynamic function across the BMI spectrum. Disentangling the relationship between genetic risk for psychiatric conditions, genetic risk for BMI, and cellular impacts of BMI is paramount in elucidating disease mechanisms in psychiatry. We use paired whole genome and mRNA sequencing from GTEx post-mortem tissues to identify direct effects of BMI on mRNA expression (Exp ∼ BMI + PC1:20) and indirect effects of BMI on expression mediated by expression quantitative trait loci (eQTLs). BMI-eQTLs are SNPs with a Bonferroni-significant BMI*SNP interaction (Exp ∼ SNP + BMI + SNP*BMI + PC1:20). BMI-eGenes are associated eGenes of BMI-eQTL. We use bulk mRNA cellular deconvolution using CIBERSORTx and bMIND to refine associations in a cell-type specific manner. We assess the functional relevance of BMI-eGenes by comparing to “Base” BMI-blind eQTLs (Exp ∼ SNP + PC1:20) using probability of loss-of-function (pLI) scores and tissue overlap. We identify overlap with psychiatric and anthropometric GWAS loci and assess tissue enrichments using transcriptomic imputation via MultiXcan. We identified 8328 BMI-eGenes across tissues, which are most numerous in the frontal cortex (n=372), small intestine (n=362), and minor salivary gland (n=350). Genes associated directly with BMI are most numerous in subcutaneous adipose (n=211) and skeletal muscle (n=188). In the frontal cortex (BA9) the pregnane X receptor pathway is enriched (FDR=0.015), and includes CYP3A4, a known drug metabolizer. We identify a negative correlation between BMI and microglia in the hippocampus (r=-0.26, p=3.0e-4) and the NAc (r=-0.17, p=6.5e-3). In the minor salivary gland, BMI is correlated with four immune cell types and BMI-eGenes are enriched for TNF-alpha signaling (FDR=0.016). BMI-eGenes are enriched for high pLI (constrained) genes in four tissues, including two brain tissues while Base-eGenes have no high pLI enrichments. We identify overlap of BMI-eGenes and Bonferroni-significant MultiXcan-eGenes across psychiatric disorders including C4A-artery in schizophrenia and FADS1-putamen in bipolar disorder-all. BMI-eGenes have unique tissue enrichments across psychiatric traits compared to Base eGenes. Our results identify potential cellular mechanisms underlying BMI-induced dysfunction in the brain mediated by cell composition and eQTL activity. The BMI-eGenes identified are relevant across psychiatric disorders and have the power to enhance precision in transciptomic risk models. We plan to extend our analyses by employing statistical fine-mapping integrated with experimental data to refine BMI-dynamic genomic loci and probe the phenotypic consequences using phenome-wide association studies in large scale biobanks. Additionally, we will utilize partitioned heritability to characterize the contributions of BMI-eQTL toward the heritability of anthropometric, psychiatric, and immune traits." @default.
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• W4387496945 date "2023-10-01" @default.
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• W4387496945 title "W22. DISENTANGLING THE ROLES OF GENETICS AND BODY MASS INDEX ACROSS PSYCHIATRIC DISORDERS" @default.
• W4387496945 doi "https://doi.org/10.1016/j.euroneuro.2023.08.213" @default.
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