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. 2022 Aug 16;12(1):334.
doi: 10.1038/s41398-022-02068-9.

Maternal pregnancy-related infections and autism spectrum disorder-the genetic perspective

Ron Nudel  1   2 , Wesley K Thompson  2   3   4 , Anders D Børglum  2   5   6 , David M Hougaard  2   7 , Preben B Mortensen  2   8 , Thomas Werge  2   3   9 , Merete Nordentoft  1   2   9 , Michael E Benros  10   11   12
Affiliations

Maternal pregnancy-related infections and autism spectrum disorder-the genetic perspective

Ron Nudel et al. Transl Psychiatry. .

Abstract

Autism spectrum disorder (ASD) refers to a group of neurodevelopmental disorders which include deficits in behavior, social interaction and communication. ASD has a complex genetic architecture, and it is also influenced by certain environmental exposures. Both types of predisposing factors may be related to immunological mechanisms, involving, for example, immune system genes and infections. Past studies have shown an association between infections occurring during the pregnancy in the mother and increased risk of ASD in the child, an observation which has received recent support from experimental animal studies of ASD-like behavior. The aim of this study was to study the genetic contribution to this effect. We employed genetic correlation analyses across potential ASD subtypes stratified on the basis of maternal pregnancy-related infections within the iPSYCH ASD case-cohort sample, as well as a case-case GWAS. We validated the trends of the genetic correlation analyses observed in our sample using GWAS summary statistics from the PGC ASD study (excluding iPSYCH). The genetic correlation between ASD with a history of maternal pregnancy-related infections and ASD without a history of maternal infections in iPSYCH was rg = 0.3811. We obtained a similar estimate between the former and the PGC ASD phenotype (rg = 0.3997). Both estimates are lower compared to the genetic correlation between ASD without a history of maternal infections and the PGC ASD phenotype (rg = 0.6735), and between ASD with a history of maternal infections occurring only more than 2 months following childbirth and the PGC ASD phenotype (rg = 0.6293). Additionally, we observed genetic variance between the two main ASD phenotypes using summary statistics from the case-case GWAS in iPSYCH (h2cc = 0.1059), indicating genome-wide differences between the phenotypes. Our results suggest potentially different etiologies of ASD based on a history of maternal pregnancy-related infections, which may, in part, be genetic. This highlights the relevance of maternal pregnancy-related infections to genetic studies of ASD and provides new insights into the molecular underpinnings of ASD.

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Conflict of interest statement

All researchers had full independence from the funders. The authors report no biomedical financial interests or potential conflicts of interest. TW states that he has acted as a lecturer and scientific counselor to H. Lundbeck A/S.

Figures

Fig. 1
Fig. 1. Overview of the analyses in the current study.
Green boxes refer to auxiliary analyses (providing context for the main analyses and/or replicating previous findings); blue boxes refer to definitions of cases and controls for the main genetic analyses; red boxes refer to primary genetic analyses; lastly, orange boxes refer to secondary genetic (sensitivity) analyses, including analyses with internal control phenotypes and replication.
Fig. 2
Fig. 2. Manhattan plot for the case-case GWAS between ASD with a history of maternal pregnancy-related infections and ASD with no history of maternal infections.
The blue line represents the threshold for suggestive association (P = 1 × 10−5), and the red line represents the threshold for genome-wide significance (P = 5 × 10−8).
See this image and copyright information in PMC

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