A Pathway-Based Genetic Score for Oxidative Stress: An Indicator of Host Vulnerability to Phthalate-Associated Adverse Neurodevelopment

Samuel Tanner; Sarah Thomson; Katherine Drummond; Martin O'Hely; Christos Symeonides; Toby Mansell; Richard Saffery; Peter D Sly; Fiona Collier; David Burgner; Eva J Sugeng; Terence Dwyer; Peter Vuillermin; Anne-Louise Ponsonby; On Behalf Of The Barwon Infant Study Investigator Group

doi:10.3390/antiox11040659

A Pathway-Based Genetic Score for Oxidative Stress: An Indicator of Host Vulnerability to Phthalate-Associated Adverse Neurodevelopment

Antioxidants (Basel). 2022 Mar 29;11(4):659. doi: 10.3390/antiox11040659.

Authors

Samuel Tanner¹, Sarah Thomson¹, Katherine Drummond¹, Martin O'Hely^{2

3}, Christos Symeonides^{2

4}, Toby Mansell², Richard Saffery², Peter D Sly^{5

6}, Fiona Collier^{2

3

7}, David Burgner^{2

8}, Eva J Sugeng⁹, Terence Dwyer^{2

10}, Peter Vuillermin^{2

3

7}, Anne-Louise Ponsonby^{1

2}, On Behalf Of The Barwon Infant Study Investigator Group⁷

Affiliations

¹ Developing Brain Division, The Florey Institute for Neuroscience and Mental Health, Parkville, VIC 3052, Australia.
² Murdoch Children's Research Institute, Royal Children's Hospital, University of Melbourne, Parkville, VIC 3052, Australia.
³ School of Medicine, Deakin University, Geelong, VIC 3216, Australia.
⁴ The Minderoo Foundation, Perth, WA 6000, Australia.
⁵ Children's Health Research Centre, University of Queensland, South Brisbane, QLD 4101, Australia.
⁶ WHO Collaborating Centre for Children's Health and Environment, South Brisbane, QLD 4104, Australia.
⁷ Barwon Health, Geelong, VIC 3216, Australia.
⁸ Department of Paediatrics, University of Melbourne, Parkville, VIC 3052, Australia.
⁹ Department of Environment and Health, Vrije Universiteit, De Boelelaan 1087, 1081 HV Amsterdam, The Netherlands.
¹⁰ Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford OX3 9DU, UK.

Abstract

The developing brain is highly sensitive to environmental disturbances, and adverse exposures can act through oxidative stress. Given that oxidative stress susceptibility is determined partly by genetics, multiple studies have employed genetic scores to explore the role of oxidative stress in human disease. However, traditional approaches to genetic score construction face a range of challenges, including a lack of interpretability, bias towards the disease outcome, and often overfitting to the study they were derived on. Here, we develop an alternative strategy by first generating a genetic pathway function score for oxidative stress (gPFSox) based on the transcriptional activity levels of the oxidative stress response pathway in brain and other tissue types. Then, in the Barwon Infant Study (BIS), a population-based birth cohort (n = 1074), we show that a high gPFSox, indicating reduced ability to counter oxidative stress, is linked to higher autism spectrum disorder risk and higher parent-reported autistic traits at age 4 years, with AOR values (per 2 additional pro-oxidant alleles) of 2.10 (95% CI (1.12, 4.11); p = 0.024) and 1.42 (95% CI (1.02, 2.01); p = 0.041), respectively. Past work in BIS has reported higher prenatal phthalate exposure at 36 weeks of gestation associated with offspring autism spectrum disorder. In this study, we examine combined effects and show a consistent pattern of increased neurodevelopmental problems for individuals with both a high gPFSox and high prenatal phthalate exposure across a range of outcomes, including high gPFSox and high DEHP levels against autism spectrum disorder (attributable proportion due to interaction 0.89; 95% CI (0.62, 1.16); p < 0.0001). The results highlight the utility of this novel functional genetic score and add to the growing evidence implicating gestational phthalate exposure in adverse neurodevelopment.

Keywords: ADHD; ASD; attention-deficit hyperactivity disorder; autism; biological pathway; cognition; genetic score; neurodevelopment; oxidative stress; phthalates; plastics.