Parental inflammatory bowel disease and autism in children

Abstract

Evidence linking parental inflammatory bowel disease (IBD) with autism in children is inconclusive. We conducted four complementary studies to investigate associations between parental IBD and autism in children, and elucidated their underlying etiology. Conducting a nationwide population-based cohort study using Swedish registers, we found evidence of associations between parental diagnoses of IBD and autism in children. Polygenic risk score analyses of the Avon Longitudinal Study of Parents and Children suggested associations between maternal genetic liability to IBD and autistic traits in children. Two-sample Mendelian randomization analyses provided evidence of a potential causal effect of genetic liability to IBD, especially ulcerative colitis, on autism. Linkage disequilibrium score regression did not indicate a genetic correlation between IBD and autism. Triangulating evidence from these four complementary approaches, we found evidence of a potential causal link between parental, particularly maternal, IBD and autism in children. Perinatal immune dysregulation, micronutrient malabsorption and anemia may be implicated.

Fig. 1. Summary of studies conducted, aiming at investigating the links between parental diagnoses of IBD and offspring autism in children and elucidating their underlying etiology.

Manhattan plot icons adapted from a previous publication.

Extended Data Fig. 1. Study sample derivation for the Swedish cohort study.

a, Children born before 1987 were excluded from the study population. b, Individuals were excluded stepwise with the criteria aligned to a previous study (reference ). c, Individuals without information from the MBR were excluded. d, Children with diagnoses of autism or IDs and genetic or metabolic conditions documented in the MBR that were known to cause neurodevelopmental disorders (NDDs), as the NDDs may be attributable to the condition. e, Those whose biological fathers were unknown were excluded. f, Those whose biological mothers or fathers lacked data on place of birth, age at delivery, education level, psychiatric history, or family income quintile were excluded.

Extended Data Fig. 2. Prevalence and overlap in diagnoses among the mothers included in the present study.

Overall prevalences of Crohn’s, UC, and other IBD diagnoses are shown in terms of mothers diagnosed (j) as well as children born to those mothers and followed up for autism in Study 1 (index persons, i). Overlap in the diagnoses is only shown for index persons included in the study, to align with values in Table 2 in the main text, though the extent of overlap is virtually identical if mothers or index persons are displayed. For example, of the 7,000 mothers diagnosed with Crohn’s, 1984 (28.4%) were also diagnosed with colitis, and the analogous proportion of children is 28.0% (3,466/12,390).

Extended Data Fig. 3. Prevalence and overlap in diagnoses among the fathers included in the present study.

Overall prevalences of Crohn’s, UC, and other IBD diagnoses are shown in terms of fathers diagnosed (j) as well as children born to those mothers and followed up for autism in Study 1 (index persons, i). Overlap in the diagnoses is only shown for index persons included in the study, to align with values in Table 2 in the main text, though the extent of overlap is virtually identical if fathers or index persons are displayed. For example, of the 6,244 fathers diagnosed with Crohn’s, 1,925 (30.8%) were also diagnosed with colitis, and the analogous proportion of children is 30.3% (3,414/11,274).

Extended Data Fig. 4. Study sample derivation and characteristics for the PRS analyses in ALSPAC.

^aAlthough initial ALSPAC recruitment resulted in 13,988 children who were alive at 1 year of age, when the children were approximately 7 years old, the initial sample was bolstered with eligible children who did not join the study initially. 913 children were additionally enrolled during three phases of recruitment. This resulted in 14,901 children alive at 1 year of age. Detailed information can be found at references^{–,– b}Details on QC process can be found in Methods. ^cConsent for biological samples has been collected in accordance with the Human Tissue Act (2004).

Extended Data Fig. 5. Associations between maternal polygenic risk score for IBD, UC, Crohn’s, and autism factor mean score in the children, at 13 P-value thresholds for PRS generation.

n = 7,348 mother–child pairs. Data are presented as beta coefficients and 95% CIs. Calculated by linear regression of the mothers’ PRS for IBD, UC, or Crohn’s on the standardized autism factor mean score in the children, adjusted for child’s sex and the first ten principal components of the ALSPAC genotype data.

Extended Data Fig. 6. Associations between children’s polygenic risk score for IBD, UC, Crohn’s, and autism factor mean score, at 13 P-value thresholds for PRS generation.

n = 7,503 children. Data are presented as beta coefficients and 95% CIs. Calculated by linear regression of the children’s PRS for IBD, UC, or Crohn’s on the standardized autism factor mean score in the children, adjusted for child’s sex and the first ten principal components of the ALSPAC genotype data.

Extended Data Fig. 7. Genetic instrument extraction process for the MR analyses investigating the causal links between genetic liability to autism and IBD, UC, and Crohn’s.

Between phenotype pairs, GWAS summary data were restricted to a common set of SNPs and then clumped in PLINK 1.90 using the 1000 Genomes phase 3 European ancestry reference panel, and an r² = 0.01, within a 10,000 Kb window. Among the independent variants, instruments were defined using a genome-wide significance threshold of P ≤ 5×10⁻⁸. The only exception was autism, as only two independent and genome-wide significant variants were identified. We therefore relaxed the P-value threshold to 5 × 10⁻⁷ to improve statistical power, as used previously).

Extended Data Fig. 8. Genetic instrument extraction process for the MR analyses investigating the causal links between genetic liability to autism without ID (iPSYCH subsample) and IBD, UC, and Crohn’s.

Between phenotype pairs, GWAS summary data were restricted to a common set of SNPs and then clumped in PLINK 1.90 using the 1000 Genomes phase 3 European ancestry reference panel, and an r² = 0.01, within a 10,000 Kb window. Among the independent variants, instruments were defined using a genome-wide significance threshold of P ≤ 5 × 10⁻⁸. The only exception was autism, as only two independent and genome-wide significant variants were identified. We therefore relaxed the P-value threshold to 5 × 10⁻⁷ to improve statistical power, as used previously.

Extended Data Fig. 9. Ascertainment of outcomes and exposures from the National Patient Register (NPR).

a, Diagnostic codes for ascertainment of outcomes and exposures. b, Frequency of IBD diagnoses, by year, in NPR for study cohort mothers from 1987 to 2010. c, Frequency of IBD diagnoses, by year, in NPR for study cohort fathers from 1987 to 2010. ICD-9: International Classification of Diseases – ninth edition; ICD-10: International Classification of Diseases – tenth edition.