Cord blood lipid correlation network profiles are associated with subsequent attention-deficit/hyperactivity disorder and autism spectrum disorder symptoms at 2 years: a prospective birth cohort study

Abstract

Background: Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are neurodevelopmental conditions with early life origins. Alterations in blood lipids have been linked to ADHD and ASD; however, prospective early life data are limited. This study examined (i) associations between the cord blood lipidome and ADHD/ASD symptoms at 2 years of age, (ii) associations between prenatal and perinatal predictors of ADHD/ASD symptoms and cord blood lipidome, and (iii) mediation by the cord blood lipidome.

Methods: From the Barwon Infant Study cohort (1074 mother-child pairs, 52.3% male children), child circulating lipid levels at birth were analysed using ultra-high-performance liquid chromatography-tandem mass spectrometry. These were clustered into lipid network modules via Weighted Gene Correlation Network Analysis. Associations between lipid modules and ADHD/ASD symptoms at 2 years, assessed with the Child Behavior Checklist, were explored via linear regression analyses. Mediation analysis identified indirect effects of prenatal and perinatal risk factors on ADHD/ASD symptoms through lipid modules.

Findings: The acylcarnitine lipid module is associated with both ADHD and ASD symptoms at 2 years of age. Risk factors of these outcomes such as low income, Apgar score, and maternal inflammation were partly mediated by higher birth acylcarnitine levels. Other cord blood lipid profiles were also associated with ADHD and ASD symptoms.

Interpretation: This study highlights that elevated cord blood birth acylcarnitine levels, either directly or as a possible marker of disrupted cell energy metabolism, are on the causal pathway of prenatal and perinatal risk factors for ADHD and ASD symptoms in early life.

Funding: The foundational work and infrastructure for the BIS was sponsored by the Murdoch Children's Research Institute, Deakin University, and Barwon Health. Subsequent funding was secured from the Minderoo Foundation, the European Union's Horizon 2020 research and innovation programme (ENDpoiNTs: No 825759), National Health and Medical Research Council of Australia (NHMRC) and Agency for Science, Technology and Research Singapore [APP1149047], The William and Vera Ellen Houston Memorial Trust Fund (via HOMER Hack), The Shepherd Foundation, The Jack Brockhoff Foundation, the Scobie & Claire McKinnon Trust, the Shane O'Brien Memorial Asthma Foundation, the Our Women Our Children's Fund Raising Committee Barwon Health, the Rotary Club of Geelong, the Ilhan Food Allergy Foundation, Geelong Medical and Hospital Benefits Association, Vanguard Investments Australia Ltd, the Percy Baxter Charitable Trust, and Perpetual Trustees.

Keywords: Acylcarnitine; Attention-deficit/hyperactivity disorder symptoms; Autism spectrum disorder symptoms; Cord blood; Fatty acids; Lipidomics.

Fig. 1

Barwon Infant Study participant flowchart. Participants included in each analysis were those with complete data on the variables of interest.

Fig. 2

Construction of modules using WGCNA. (A) The cluster dendrogram built by hierarchical clustering of the dissimilarity (1-TOM) matrix, where dissimilarity is represented by height. Each colour represents one module and grey are unclustered lipids. (B) Heatmap representation of the lipid network's topological association. Within this heatmap, each row and column represents a specific lipid feature. Pale shades indicate minimal topological association, while deeper shades of red indicate increased overlap. Darker patches on the diagonal represent modules. Lipid module assignments are displayed along the left and on top. (C) Histogram visualizes the distribution of the number and class types of lipid features in each module. Full list of lipid feature assignment can be found in Supplementary Table S2.

Fig. 3

Visualization of the Cyan, Turquoise, Brown and Magenta networks constructed from the Topological Overlay Matrix. The nodes represent individual lipid features, node and edge colour denotes module membership. The hub lipid is denoted by bold text.

Fig. 4

The association between the cord blood lipid module eigenlipids and subsequent CBCL-ADHP and CBCL-ASP outcomes at 2 years. Note: Point estimates represent adjusted mean difference in module eigenlipid (SD units with 95% CI) per unit increase in CBCL raw score with 95% CI; AC, acylcarnitine; PE, phosphatidylethanolamine; TG, triglyceride; PS, phosphatidylserine; SM, sphingomyelin; CE, cholesteryl esters; LPC, lysophosphatidylcholine; TG(o), alkyldiacylglycerol; FFA, free fatty acid; HexCer, hexosylceramide. Ranked by strength of the association across both outcomes. ¹Model adjusted for child sex, gestational age (weeks) at birth, minutes from cord blood sample collection to storage, days cord blood sample stored, maternal blood contamination and age at CBCL. p-values, Q-values, R², adjusted alpha (Benjamini–Hochberg critical value) and Akaike information criteria (AIC) can be found in Supplementary Table S3.