Sex-specific effects of Birth Weight on Longitudinal Behavioural Outcomes; a Mendelian Randomisation Approach using a polygenic scores.

Intro: It is unclear if sex differences in behaviour arising from birth weight (BW) are genuine because of the cross-sectional nature and potential confounding in previous studies. We aimed to test if sex differences associated with birth weight phenotype were reproducible using a Mendelian randomisation approach, i.e. polygenic score for birthweight across childhood and adolescence. Method: Utilising data from the Raine study we had 1484 genotyped participants with a total of 6446 child behaviour checklist assessments across childhood and adolescence. We used BW polygenic scores in linear mixed-effects models to predict parentally-assessed attention, aggression and social problems scales; we also derived estimates and significance for a sex-by-genotype interaction. We used a Bonferroni corrected significance threshold and tested robustness of the results with teacher assessments of behaviour as well as a second polygenic score. Results: We found a sex-by-genotype interaction with lower BW polygenic scores (BW-PGS) associated with increased aggression in males compared to females. These findings were consistent across various analyses, including teacher assessments. Surprisingly, a lower BW-PGS showed protective effects in females, while lower BW phenotype had detrimental effects in males with evidence of a genotype-phenotype mismatch increasing aggression problems in males only. Conclusion: This study underscores the genuine nature of behavioural sex differences arising from low BW and highlights the sex-dependent and diverging effects of environmental and genetic BW determinants. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement We would like to acknowledge the Raine Study participants and their families for their ongoing participation in the study and the Raine Study team for study co-ordination and data collection. We also thank the NHMRC for their long-term contribution to funding the study over the last 30 years. The core management of the Raine Study is funded by The University of Western Australia, Curtin University, Telethon Kids Institute, Women and Infants Research Foundation, Edith Cowan University, Murdoch University, The University of Notre Dame Australia and the Raine Medical Research Foundation. The Raine Study Gen2-14 year follow-up was sponsored by the NHMRC Program Grant 211912 and 003209. The Raine Study Gen2-17 year follow-up was sponsored by the NHMRC Program Grant 353514. DNA or GWAS data from the Gen2-17 year follow-up was sponsored by the NHMRC (Palmer et al, ID 572613; Beilin et al, ID 403981; Huang et al, ID 1059711) and the Canadian Institutes of Health Research - CIHR (Lye et al, MOP-82893). The Pawsey Supercomputing Centre provided computation resources to carry out analyses required with funding from the Australian Government and the Government of Western Australia. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Human Research Ethics Committees at the University of Western Australia, King Edward Memorial Hospital, and Princess Margaret Hospital in Perth, Australia, granted ethics approvals. Participants were eligible for analysis if they had data available on biological sex, at least one follow up behavioural assessment, and genetic data. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data sets generated during and/or analyzed during the present study are not available. The Raine Study is committed to a high level of confidentiality of the data in line with the informed consent provided by participants. Requests for data should be directed to the Raine Study Executive.