T72. DECODING THE PLEIOTROPY OF SCHIZOPHRENIA AND MULTIPLE SCLEROSIS AT THE HLA LOCUS

Neuropsychiatric genetics increasingly highlights the existence of shared genetic liability, heritability, and environmental risk factors, across neurological and psychiatric disorders. Notably, schizophrenia (SCZ) and multiple sclerosis (MS) share genetic and epidemiological risk factors, prodromal (e.g. sleep disturbances, headaches) and clinical symptoms (e.g. cognitive impairment, depression, anxiety), and are associated with considerable impairment worldwide. MS is a chronic neurological and autoimmune disorder – where the immune system mistakenly attacks myelin in the central nervous system. SCZ is a chronic mental health disorder and while the exact mechanism driving impairment is unknown, epidemiological and clinical evidence implicate dysregulation of the immune system. There is significant pleiotropy (shared genetic risk) between SCZ and MS, especially at the major histocompatibility complex (MHC). The MHC encodes molecules involved in antigen presentation, inflammation, and innate and adaptive immune responses. Human leukocyte antigen (HLA) haplotypes and complement component 4 genes within the MHC are also associated with risk for SCZ and MS. Risk variants regulating gene expression (eQTLs) can show substantial cell-type specificity and may interact with biological sex, aging, and immune response. While HLA-QTLs have recently been shown to have cell-type and cell-state (reactive vs. stable) specific affects in immune cells (i.e. myeloid, B, and T-cells), cell-type specific regulation of this region has not been explored in the brain despite numerous associations across neuropsychiatric traits. Technically challenging to explore, the MHC locus was historically excluded from post-GWAS analysis, but improvements in HLA imputation and alignment now allow for functional exploration of this complex locus. Using the Common Minds Consortium dorsolateral prefrontal cortex (DLPFC) (n=980; 0-89+yrs) and brainScope (n=388; 2-89+yrs) single-cell prefrontal cortex (PFC) post-mortem datasets, that have genotype-paired gene expression, we perform sex-stratified, cell-type specific, and trans-ancestral eQTL analysis for variants in the extended MHC locus (chr6:25000000 – 38000000). By performing accurate HLA-genotype imputation with cross-ancestry reference panels (CookHLA/SNP2HLA) and calculating accurate HLA gene expression based on high confidence cross-ancestry reference panels (HLApers/scHLAPers), we will accurately perform HLA-eQTL analysis in brain tissue. Following identification of HLA-QTLs, colocalization and transcriptomic imputation (S-PrediXcan) with the most recent SCZ and MS GWAS will identify context-specific gene targets in the MHC. Uniquely, genetic susceptibly for MS is enriched in genes expressed by microglia, while risk for SCZ is shared mainly between interneurons and pyramidal neurons. Preponderance of risk in specific cell types suggest them as initial drivers of disorder etiology, which then have cascading non-cell-autonomous effects, whereby altered function ultimately leads to clinical phenotypes (late-stage MS and SCZ reflect some changes in all major brain cell types, albeit to varying degrees). We hypothesis that cell-type specificity of HLA-QTLs will show greater colocalization with MS in microglia and with SCZ in neurons. We further anticipate HLA-karyotypic sex interaction effects, given the higher incidence of MS in females and the role of estrogen in immune signaling. Disclosure: Yale University, Consultant, Icahn School of Medicine at Mount Sinai, Employee