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Host genetic susceptibility to infectious diseases: Integration of genome-wide association, genetic network and pathway analyses

Introduction: Due to variety of factors, we are still faced with major limitations in understanding the infectious disease pathogenesis and therefore lack proper tools to effectively treat some of them. Host genetics profile is often suggested to be responsible for observed variations in disease occurrence and treatment outcomes. Objective: To use hypothesis-free approach, genome-wide association study (GWAS) with network analysis, in order to provide an insight into the role of host genetics in the complex infectious disease pathogenesis, based on the resource of isolated human populations from the 10, 001 Dalmatians biobank. Methods: We included 1, 998 participants representing isolated island populations and 1, 012 participants from mainland population. GWAS, corrected for kinship, age, sex and socioeconomic factors, with fixed effect meta- analyses was performed for 14 infection-related phenotypes. Genotypic correlations between each phenotype-associated SNPs from GWAS were used for network construction and significantly associated modules were investigated by functional enrichment analyses. We also searched for the overlap between correlated infectious phenotypes to find shared core genes and pathways. Results: Three genes reached a genome-wide significance threshold – HAPLN1 for meningitis in all cohorts, while IPMK for tuberculosis and TTC39B for hepatitis in island cohorts. Genetic network additionally revealed genes DCN and CORIN to be marginally significant for tuberculosis, DMD for hepatitis and GALNT18 for systemic infections. Pathway analysis also revealed enrichment in genes outside of the immune system that may have plausible functions in various infection-related outcomes. Conclusion: Since infectious diseases represent complex phenotypes, with usually common low- risk genetic variants in the host, network analyses showed to be a favourable post-GWAS approach to identify genes below rigid genome- wide significance threshold. Despite biological roles that seem to correspond to the imposed infectious diseases pathogenesis, some variants may be wide-spread, while others could be a result of genetic drift and isolation and possibly even local co-adaptation.

GWAS, genetic network, pathway, infectious diseases

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