Neonatal genetics of gene expression reveal potential origins of autoimmune and allergic disease risk

• Published in: Nature communications 2020-07, Vol.11 (1), p.3761-3761, Article 3761
• Main Authors: Huang, Qin Qin, Tang, Howard H. F., Teo, Shu Mei, Mok, Danny, Ritchie, Scott C., Nath, Artika P., Brozynska, Marta, Salim, Agus, Bakshi, Andrew, Holt, Barbara J., Khor, Chiea Chuen, Sly, Peter D., Holt, Patrick G., Holt, Kathryn E., Inouye, Michael
• Format: Article
• Language: English
• Subjects: 13/106; 38/39; 45/22; 45/61; 631/208/199; 631/208/212/2019; Allergic diseases; Autoimmune Diseases - genetics; Autoimmune Diseases - immunology; Butyrophilins - genetics; Butyrophilins - metabolism; Cathepsin H - genetics; Cathepsin H - metabolism; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Child; Child Development - physiology; Child, Preschool; Children; Cord blood; Datasets as Topic; Disease; Fetal Blood - cytology; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Developmental - immunology; Gene mapping; Gene Regulatory Networks - immunology; Genetic Predisposition to Disease; Genetics; Genome-Wide Association Study; Health risks; Histocompatibility antigen HLA; HLA-C Antigens - genetics; HLA-C Antigens - metabolism; Humanities and Social Sciences; Humans; Hypersensitivity - genetics; Hypersensitivity - immunology; Immune system; Infant; Infant, Newborn; Lipopolysaccharides; Lymphocytes; Lymphocytes T; Mendelian Randomization Analysis; multidisciplinary; Myeloid cells; Myeloid Cells - immunology; Myeloid Cells - metabolism; Neonates; Oligonucleotide Array Sequence Analysis; Origins; Polymorphism, Single Nucleotide; Prospective Studies; Quantitative trait loci; Quantitative Trait Loci - immunology; Randomization; Science; Science (multidisciplinary); Stimulation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17477-x

Chronic immune-mediated diseases of adulthood often originate in early childhood. To investigate genetic associations between neonatal immunity and disease, we map expression quantitative trait loci (eQTLs) in resting myeloid cells and CD4 + T cells from cord blood samples, as well as in response to lipopolysaccharide (LPS) or phytohemagglutinin (PHA) stimulation, respectively. Cis -eQTLs are largely specific to cell type or stimulation, and 31% and 52% of genes with cis -eQTLs have response eQTLs (reQTLs) in myeloid cells and T cells, respectively. We identified cis regulatory factors acting as mediators of trans effects. There is extensive colocalisation between condition-specific neonatal cis -eQTLs and variants associated with immune-mediated diseases, in particular CTSH had widespread colocalisation across diseases. Mendelian randomisation shows causal neonatal gene expression effects on disease risk for BTN3A2 , HLA-C and others. Our study elucidates the genetics of gene expression in neonatal immune cells, and aetiological origins of autoimmune and allergic diseases. Some immune-mediated diseases may originate in early childhood. The authors mapped eQTLs and response eQTLs to various stimuli in neonatal myeloid cells and T cells, and revealed their potential role in immune-mediated diseases using colocalisation and Mendelian randomisation.