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

View ORCID ProfileQin Qin Huang, Howard H. F. Tang, Shu Mei Teo, View ORCID ProfileScott C. Ritchie, View ORCID ProfileArtika P. Nath, Marta Brozynska, Agus Salim, Andrew Bakshi, Barbara J. Holt, Danny Mok, Chiea Chuen Khor, Peter D. Sly, Patrick G. Holt, Kathryn E. Holt, Michael Inouye
doi: https://doi.org/10.1101/683086
Qin Qin Huang
Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, AustraliaDepartment of Clinical Pathology, University of Melbourne, Parkville, Victoria 3010, Australia
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  • For correspondence: qinqin.huang@baker.edu.au minouye@baker.edu.au mi336@medschl.cam.ac.uk
Howard H. F. Tang
Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, AustraliaSchool of BioSciences, The University of Melbourne, Parkville, Victoria 3010, Australia
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Shu Mei Teo
Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, AustraliaCambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, United Kingdom
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Scott C. Ritchie
Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, AustraliaCambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, United Kingdom
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Artika P. Nath
Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, AustraliaCambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, United Kingdom
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Marta Brozynska
Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, AustraliaCambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, United Kingdom
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Agus Salim
Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, AustraliaDepartment of Mathematics and Statistics, School of Engineering and Mathematical Sciences, La Trobe University, Bundoora, Victoria 3086, Australia
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Andrew Bakshi
Monash Biomedicine Discovery Institute, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia
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Barbara J. Holt
Telethon Kids Institute, The University of Western Australia, Perth, Western Australia 6009, Australia
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Danny Mok
Telethon Kids Institute, The University of Western Australia, Perth, Western Australia 6009, Australia
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Chiea Chuen Khor
Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore 138672, Singapore
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Peter D. Sly
Child Health Research Centre, The University of Queensland, Brisbane, Queensland 4101, Australia
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Patrick G. Holt
Telethon Kids Institute, The University of Western Australia, Perth, Western Australia 6009, AustraliaChild Health Research Centre, The University of Queensland, Brisbane, Queensland 4101, Australia
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Kathryn E. Holt
Department of Infectious Diseases, Central Clinical School, Monash University, Melbourne, Victoria 3004, AustraliaThe London School of Hygiene and Tropical Medicine, London WC1E 7TH, United Kingdom
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Michael Inouye
Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, AustraliaDepartment of Clinical Pathology, University of Melbourne, Parkville, Victoria 3010, AustraliaCambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, United KingdomThe Alan Turing Institute, London, United Kingdom
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  • For correspondence: qinqin.huang@baker.edu.au minouye@baker.edu.au mi336@medschl.cam.ac.uk
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Abstract

Chronic immune-mediated diseases of adulthood often originate in early childhood. To investigate genetic associations between neonatal immunity and disease, we collected cord blood samples from a birth cohort and mapped expression quantitative trait loci (eQTLs) in resting monocytes and CD4+ T cells as well as in response to lipopolysaccharide (LPS) or phytohemagglutinin (PHA) stimulation, respectively. Cis-eQTLs were largely specific to cell type or stimulation, and response eQTLs were identified for 31% of genes with cis-eQTLs (eGenes) in monocytes and 52% of eGenes in CD4+ T cells. We identified trans-eQTLs and mapped cis regulatory factors which act as mediators of trans effects. There was extensive colocalisation of causal variants for cell type- and stimulation-specific neonatal cis-eQTLs and those of autoimmune and allergic diseases, in particular CTSH (Cathepsin H) which showed widespread colocalisation across diseases. Mendelian randomisation showed causal neonatal gene transcription effects on disease risk for BTN3A2, HLA-C and many other genes. Our study elucidates the genetics of gene expression in neonatal conditions and cell types as well as the aetiological origins of autoimmune and allergic diseases.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted June 27, 2019.
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Neonatal genetics of gene expression reveal the origins of autoimmune and allergic disease risk
Qin Qin Huang, Howard H. F. Tang, Shu Mei Teo, Scott C. Ritchie, Artika P. Nath, Marta Brozynska, Agus Salim, Andrew Bakshi, Barbara J. Holt, Danny Mok, Chiea Chuen Khor, Peter D. Sly, Patrick G. Holt, Kathryn E. Holt, Michael Inouye
bioRxiv 683086; doi: https://doi.org/10.1101/683086
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Neonatal genetics of gene expression reveal the origins of autoimmune and allergic disease risk
Qin Qin Huang, Howard H. F. Tang, Shu Mei Teo, Scott C. Ritchie, Artika P. Nath, Marta Brozynska, Agus Salim, Andrew Bakshi, Barbara J. Holt, Danny Mok, Chiea Chuen Khor, Peter D. Sly, Patrick G. Holt, Kathryn E. Holt, Michael Inouye
bioRxiv 683086; doi: https://doi.org/10.1101/683086

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