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

Qin Qin Huang; Howard H F Tang; Shu Mei Teo; Danny Mok; Scott C Ritchie; Artika P Nath; Marta Brozynska; Agus Salim; Andrew Bakshi; Barbara J Holt; Chiea Chuen Khor; Peter D Sly; Patrick G Holt; Kathryn E Holt; Michael Inouye

doi:10.1038/s41467-020-17477-x

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

Nat Commun. 2020 Jul 28;11(1):3761. doi: 10.1038/s41467-020-17477-x.

Authors

Qin Qin Huang^{1

2

3}, Howard H F Tang^{4

5}, Shu Mei Teo^{4

6}, Danny Mok⁷, Scott C Ritchie^{4

6

8

9}, Artika P Nath^{4

6}, Marta Brozynska^{4

6}, Agus Salim^{10

11

12}, Andrew Bakshi¹³, Barbara J Holt⁷, Chiea Chuen Khor^{14

15

16}, Peter D Sly¹⁷, Patrick G Holt^{7

17}, Kathryn E Holt^{18

19}, Michael Inouye^{20

21

22

23

24

25

26

27}

Affiliations

¹ Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, VIC, 3004, Australia. qh1@sanger.ac.uk.
² Department of Clinical Pathology, University of Melbourne, Parkville, VIC, 3010, Australia. qh1@sanger.ac.uk.
³ Department of Human Genetics, Wellcome Sanger Institute, Cambridge, UK. qh1@sanger.ac.uk.
⁴ Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, VIC, 3004, Australia.
⁵ School of BioSciences, The University of Melbourne, Parkville, VIC, 3010, Australia.
⁶ Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
⁷ Telethon Kids Institute, The University of Western Australia, Perth, WA, 6009, Australia.
⁸ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁹ National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, UK.
¹⁰ Baker Heart and Diabetes Institute, Melbourne, VIC, 3004, Australia.
¹¹ School of Mathematics and Statistics, The University of Melbourne, Parkville, VIC, 3010, Australia.
¹² Melbourne School of Population and Global Health, Carlton, VIC, 3053, Australia.
¹³ Monash Biomedicine Discovery Institute, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia.
¹⁴ Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, 138672, Singapore.
¹⁵ Singapore Eye Research Institute, Singapore, Singapore.
¹⁶ Duke-NUS Medical School, Singapore, Singapore.
¹⁷ Child Health Research Centre, The University of Queensland, Brisbane, QLD, 4101, Australia.
¹⁸ Department of Infectious Diseases, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia.
¹⁹ The London School of Hygiene and Tropical Medicine, London, WC1E 7TH, UK.
²⁰ Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, VIC, 3004, Australia. minouye@baker.edu.au.
²¹ Department of Clinical Pathology, University of Melbourne, Parkville, VIC, 3010, Australia. minouye@baker.edu.au.
²² Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK. minouye@baker.edu.au.
²³ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. minouye@baker.edu.au.
²⁴ National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, UK. minouye@baker.edu.au.
²⁵ The Alan Turing Institute, London, UK. minouye@baker.edu.au.
²⁶ British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK. minouye@baker.edu.au.
²⁷ Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK. minouye@baker.edu.au.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autoimmune Diseases / genetics*
Autoimmune Diseases / immunology
Butyrophilins / genetics
Butyrophilins / metabolism
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
Cathepsin H / genetics
Cathepsin H / metabolism
Child
Child Development / physiology*
Child, Preschool
Datasets as Topic
Fetal Blood / cytology
Gene Expression Profiling
Gene Expression Regulation, Developmental / immunology*
Gene Regulatory Networks / immunology
Genetic Predisposition to Disease
Genome-Wide Association Study
HLA-C Antigens / genetics
HLA-C Antigens / metabolism
Humans
Hypersensitivity / genetics*
Hypersensitivity / immunology
Infant
Infant, Newborn
Mendelian Randomization Analysis
Myeloid Cells / immunology
Myeloid Cells / metabolism
Oligonucleotide Array Sequence Analysis
Polymorphism, Single Nucleotide
Prospective Studies
Quantitative Trait Loci / immunology*

Substances

BTN3A2 protein, human
Butyrophilins
HLA-C Antigens
CTSH protein, human
Cathepsin H

Abstract

Publication types

MeSH terms

Substances

Grants and funding