Parental inflammatory bowel disease and autism in children: Triangulating the evidence using four complementary study designs

Aws A S Sadik, Christina Dardani*, Panagiota Pagoni, Karoline Alexandra Havdahl, Evangelia Stergiakouli , Jakob Grove, Golam M Khandaker, Sarah A Sullivan, Stanley Zammit, Hannah J Jones, George Davey Smith, Christina Dalman, Håkan Karlsson, Renee M Gardner, Dheeraj Rai

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

31 Citations (Scopus)
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Abstract

Evidence linking parental diagnoses of inflammatory bowel disease (IBD) with offspring autism is inconclusive. We conducted four complementary studies to investigate associations between parental diagnoses of IBD and offspring autism and elucidate their underlying aetiology. (1) Nationwide population-based cohort study using Swedish registers to examine associations between parental IBD diagnoses and autism diagnoses in offspring, (2) Linkage disequilibrium (LD)-score regression to estimate the genetic correlation between the phenotypes. (3) Polygenic risk score (PRS) analyses in the Avon Longitudinal Study of Parents and Children (ALSPAC) to investigate associations between maternal genetic liability to IBD and autism factor mean score in offspring. (4) Two-sample Mendelian randomization (MR) to assess bidirectional causal links between genetic liability to IBD and autism. We found evidence of an association between parental IBD diagnoses and offspring autism (maternal: OR= 1.32; 95% CI: 1.25 to 1.40; p<0.001; paternal: OR= 1.09; 95% CI: 1.02 to 1.17; p=0.012; n= 2 324 227, 52.3% male). PRS analyses in ALSPAC indicated associations between maternal PRS for IBD subtypes and a measure of broad autism phenotype, autism factor mean score, in the offspring (UC: βPRS= 0.02; 95%CI: 0.003 to 0.05; p= 0.02; R2=0.06; Crohn’s: βPRS= 0.03; 95%CI: 0.01 to 0.05; p= 0.004; R2= 0.06; n= 7348, 50.3% male). MR analyses provided evidence of a potential causal effect of genetic liability for IBD, especially ulcerative colitis, on autism (ORMR= 1.03; 95%CI: 1.01 to 1.06). Triangulating evidence from a nationwide register-based cohort study, genetic correlation, polygenic risk score analyses and MR, we found evidence of a potentially causal link between parental, particularly maternal, diagnoses and genetic liability to IBD and offspring autism. Perinatal immune system dysregulation, micronutrient malabsorption and anaemia may be implicated.
Original languageEnglish
Pages (from-to)1406-1411
Number of pages6
JournalNature Medicine
Volume28
Issue number7
Early online date2 Jun 2022
DOIs
Publication statusE-pub ahead of print - 2 Jun 2022

Bibliographical note

Funding Information:
The Medical Research Council (MRC) and the University of Bristol support the MRC Integrative Epidemiology Unit (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/5, MC_UU_00011/6; P.P., A.H., E.S., G.M.K., H.J.J., G.D.S.). G.D.S., H.J., D.R., S.S., and S.Z. are supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. C. Dardani acknowledges the support of Wellcome Trust (215379/Z/19/Z). G.M.K. acknowledges funding support from the Wellcome Trust (201486/Z/16/Z), and the MRC UK (MR/W014416/1 and MR/S037675/1). The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724, and R248-2017-2003), NIMH (1U01MH109514-01), and the Universities and University Hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Center for Integrative Sequencing, iSEQ, Aarhus University, Denmark. R.G. acknowledges funding support from the Swedish Research Council (VR2017-02900). A.H. was supported by grants from the southeastern Norway Regional Health Authority (2020022, 2018059) and the Research Council of Norway (274611, 288083). H.K. is supported by grants from the Swedish Research Council (2018-02907) and Hjärnfonden (FO2020-0019). C. Dalman acknowledges funding from the Swedish Research Council (523-2010-1052) to support the Psychiatry Sweden register linkage and for further support of studies of the role of the early life immune system in autism (2021-01306). The UK Medical Research Council and Wellcome [Grant ref: 217065/Z/19/Z] and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses.

Funding Information:
The Medical Research Council (MRC) and the University of Bristol support the MRC Integrative Epidemiology Unit (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/5, MC_UU_00011/6; P.P., A.H., E.S., G.M.K., H.J.J., G.D.S.). G.D.S., H.J., D.R., S.S., and S.Z. are supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. C. Dardani acknowledges the support of Wellcome Trust (215379/Z/19/Z). G.M.K. acknowledges funding support from the Wellcome Trust (201486/Z/16/Z), and the MRC UK (MR/W014416/1 and MR/S037675/1). The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724, and R248-2017-2003), NIMH (1U01MH109514-01), and the Universities and University Hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Center for Integrative Sequencing, iSEQ, Aarhus University, Denmark. R.G. acknowledges funding support from the Swedish Research Council (VR2017-02900). A.H. was supported by grants from the southeastern Norway Regional Health Authority (2020022, 2018059) and the Research Council of Norway (274611, 288083). H.K. is supported by grants from the Swedish Research Council (2018-02907) and Hjärnfonden (FO2020-0019). C. Dalman acknowledges funding from the Swedish Research Council (523-2010-1052) to support the Psychiatry Sweden register linkage and for further support of studies of the role of the early life immune system in autism (2021-01306). The UK Medical Research Council and Wellcome [Grant ref: 217065/Z/19/Z] and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses.

Publisher Copyright:
© 2022, The Author(s).

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