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• W4387497350 abstract "The Major Histocompatibility Complex (MHC) region, although a hotspot for disease association, is often excluded from further analyses, owing to both extreme variation and a complex long-range LD structure. A long line of evidence points to the involvement of the MHC region in the genetic predisposition for schizophrenia (SCZ) and its implication has been supported by strong hits from genome-wide association studies (GWAS). Here, we examine this region in detail, by integrating HLA and C4 types and examining them in tandem with common SNPs. We perform HLA (Human Leukocyte Antigen) and C4 gene imputation, as well as conditional analysis to reveal new and shared genetic associations between them. For the HLA genes, we merged the 1000 Genomes reference panel including HLA types with the Haplotype Reference Consortium (HRC) panel (European and East Asian ancestry), in order to both take advantage of a wide range of SNPs available and to be able to integrate our results with the SNPs previously reported in the PGC SCZ wave 3 analysis. We integrated the panel into the Ricopili pipeline and imputed cohorts from the PGC SCZ wave 3 set, followed by univariate association analysis. For the C4 genes, we made use of the panel from Kamitaki et al. (European only, no overlapping individuals with the HLA reference), and we followed up on the analysis by Sekar et al. (2016), with a larger number of cohorts and a larger reference panel. Association was performed at a cohort level including population covariates and the results combined in a meta-analysis. We further merged HLA and C4 results post-imputation, using the association values of common SNPs as validation, in order to reveal shared and multivariate signals. Finally, we performed conditional analysis based on stepwise regression, to further investigate the relationship and interplay between previous SCZ GWAS results in the MHC locus, with the HLA- and C4-augmented results. Univariate association analysis on HLA imputed types identified HLA_B*08 as the most strongly associated subtype (OR=0.82, p=2.2e-35), alongside a number of other associations. After conditioning on the strongest SNP (rs8321, OR=0.84, p=7.7e-39), the signal drops substantially but does not vanish (p=5.5e-05). Similarly, conditioning other HLA subtypes on HLA_B*08, leaves a number of weak signals. Imputation of the C4 genes replicated previous effects and, owing to larger sample size, has yielded smaller standard errors. Joint analysis of HLA and C4 genes, including conditional and multivariate analysis, is ongoing. Building on previous work, we integrate HLA and C4 imputation with common SNPs in the MHC, to better characterize this large and highly polymorphic region and its relationship with SCZ risk. We identify a number of new associations, which suggest discrete but intertwined genetic signals. Such HLA associations, which are negatively associated with SCZ risk, possibly span several gene subtypes that belong to different variations of the human 8.1 ancestral haplotype, known to have a protective effect on the disorder. HLA types are more likely than common SNPs to provide interpretable insights into the underlying biology. Additionally, screening for HLA and C4 types in individuals is much easier, and might prove useful for stratifying patients accordingly." @default.
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• W4387497350 date "2023-10-01" @default.
• W4387497350 modified "2023-10-18" @default.
• W4387497350 title "INSIGHTS OFFERED BY HLA AND C4 TYPE IMPUTATION IN SCHIZOPHRENIA" @default.
• W4387497350 doi "https://doi.org/10.1016/j.euroneuro.2023.08.019" @default.
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