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Human birth weight is under stabilizing selection, seeking balance between extremes of high and low, thereby reducing fetal and maternal perinatal mortality risk. Certain combinations of maternal killer immunoglobulin-like receptor (KIR) and paternally derived fetal human leuokocyte antigen-C (HLA-C) alleles were previously associated with higher risk of high and low birth weight in a study with limited sample size (n=1,316). Using recently developed methods to impute HLA and KIR haplotypes using single nucleotide polymorphism (SNP) genotype data, we tested associations of fetal HLA and maternal KIR genotypes with offspring birth weight in a large sample. We imputed KIR haplotypes using the KIR*IMP imputation software in 10,602 mother-offspring pairs of European descent from singleton pregnancies from five studies. Using mixed linear regression models to account for mothers with multiple children, we tested associations between maternal KIR A vs B haplotypes (AA, AB/BA, BB genotypes) as well as copy number of activating receptor gene KIR2DS1 (0, 1, 2 copies of the gene) in the presence of fetal HLA C1/C2 alleles, and offspring birth weight. Associations were analyzed in each cohort before performing a meta-analysis to estimate the interaction effects between maternal KIR and fetal HLA-C2 on birth weight across the entire sample. The KIR haplotypes achieved imputation accuracy estimated at >95% in most of the cohorts. No interaction effects were observed between either the maternal A vs. B haplotype or the maternal KIR2DS1 locus and fetal HLA-C. When specifically trying to replicate the previously associated combination of maternal KIR2DS1 and paternally inherited fetal HLA-C2, there was a negligible change in offspring birth weight for each additional KIR2DS1 allele and HLA-C2 of paternal origin (7g lower birth weight per allele [95% CI: -54, 40], P = 0.78). We found little evidence of association between birth weight and maternal KIR haplotypes or fetal HLA-C2 and were unable to replicate previously reported findings. Our observations reinforce the importance of replication and the use of large sample sizes in the validation of genetic associations.Author Summary Babies born with very high or low birth weights and their mothers are at a higher risk of illness and death than babies with weights close to average. Genes involved in the maternal immune system, called textquotedblleft KIR textquotedblright , and the fetal immune system, called textquotedblleft HLA-C textquotedblright , are important for early development of the placenta. Previously published research using a small sample has provided evidence for the role of interacting combinations of these genes in driving the spectrum of birth weight and maintaining the balancing selection of mother-child physiology that results in healthy birth outcomes. Here we harness recently developed methods to impute these genetic data to test associations of maternal KIR and fetal HLA with child textquoteright s birth weight in a larger sample. By examining >10,000 European ancestry mother-child pairs, we found no relationship between child textquoteright s birth weight and any of the genetic combinations we tested of KIR in the mother and HLA-C in the fetus. We show that despite biological plausibility, it is important to validate genetic associations through replication and using the largest sample sizes possible. Future research could benefit from including birth weights in the true extremes of the spectrum, using methods such as high throughput genome sequencing technologies which could provide more accurate data for these gene regions on a larger scale, and investigation in ancestrally diverse populations.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was supported by a PhD studentship granted to C.S.D by the QUEX Institute, a collaborative program between the University of Exeter and the University of Queensland. R.M.F. and R.N.B were supported by a Wellcome Senior Research Fellowship (WT220390). R.M.F. is also supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number R01HD101669. N.M.W and G.W. were supported by an Australian National Health and Medical Research Council (NHMRC) Investigator grant (APP2008723). D.M.E. is supported by an NHMRC Investigator grant (APP2017942). The contents of the published material are solely the responsibility of the authors and do not reflect the views of the NHMRC. Genotyping of the EFSOCH study samples was funded by the Wellcome Trust and Royal Society (grant 104150/Z/14/Z). The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and C.S.D, R.M.F. and D.M.E will serve as guarantors for the contents of this paper. A comprehensive list of grants funding (PDF, 330KB) is available on the ALSPAC website. This research was specifically funded by the Wellcome Trust (Grant ref: WT088806). HAPO was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Diabetes and Digestive and Kidney Diseases (R01-HD34242 and R01-HD34243); the National Center for Research Resources (M01-RR00048 and M01-RR00080); and the American Diabetes Association. Genotyping of the HAPO study samples was funded by Wellcome Trust and Royal Society grant 104150/Z/14/Z. BiB data used in this research were funded by the Wellcome Trust (WT101597MA), a joint grant from the UK Medical Research Council (MRC) and UK Economic and Social Science Research Council (ESRC) (MR/N024397/1) and the National Institute for Health Research (NIHR) under its Applied Research Collaboration for Yorkshire and Humber (NIHR200166) and the Clinical Research Network (CRN). This project utilised high-performance computing funded by the UK Medical Research Council (MRC) Clinical Research Infrastructure Initiative (award number MR/M008924/1). This study was supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. This research was funded in part, by the Wellcome Trust (Grant number: WT220390). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The UK Biobank has approval from the North West Multi-Centre Research Ethics Committee (MREC) as a Research Tissue Bank (RTB) approval. Participants provided written informed consent. Ethical approval for the Exeter Family Study of Childhood Health was given by the North and East Devon (UK) Local Research Ethics Committee (approval number 1104), and informed consent was obtained from the parents of the newborns. Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004). Study participants have the right to withdraw their consent for elements of the study or from the study entirely. Full details of the ALSPAC consent procedures are available on the study website (http://www.bristol.ac.uk/alspac/researchers/research-ethics/). Ethics approval was obtained for the main platform study and all of the individual sub-studies from the Bradford Research Ethics Committee.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.YesI 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).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesThe genetic and phenotype datasets generated by UK Biobank used in the current study are available via the UK Biobank data access process (see http://www.ukbiobank.ac.uk/register-apply/). Detailed information about the genetic data available from UK Biobank is available at http://www.ukbiobank.ac.uk/scientists-3/genetic-data/ and http://biobank.ctsu.ox.ac.uk/crystal/label.cgi?id=100314. The exact number of samples with genetic data currently available in UK Biobank may differ slightly from those described in this paper. Summary statistics from EFSOCH are available on request. Researchers interested in accessing the data are expected to send a reasonable request by sending an email to the Exeter Clinical Research Facility at crfatexeter.ac.uk. For access to the HAPO data used in this study, please contact Dr Rachel Freathy (r.freathyatexeter.ac.uk) and Prof. William Lowe Jr (wloweatnorthwestern.edu). The website describing the study and other data available is https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000096.v4.p1 The ALSPAC data management plan describes in detail the policy regarding data sharing, which is through a system of managed open access. The data used in this study are linked to ALSPAC project number B2388. To request access to the data included in this paper and all other existing ALSPAC data: (i) Please read the ALSPAC access policy, which describes the process of accessing the data and samples in detail and outlines the costs associated with doing so, (ii) you may also find it useful to browse the fully searchable ALSPAC research proposals database, which lists all research projects that have been approved since April 2011, and (iii) please submit your research proposal for consideration by the ALSPAC Executive Committee. You will receive a response within 10 working days to advise you whether your proposal has been approved. If you have any questions about accessing data, please email alspac-data@bristol.ac.uk. Please note that the study website contains details of all the data that is available through a fully searchable data dictionary and variable search tool: http://www.bristol.ac.uk/alspac/researchers/our-data/. Scientists are encouraged and able to use BiB data. Data requests are made to the BiB executive using the form available from the study website http://www.borninbradford.nhs.uk (please click on Science and Research to access the form). Guidance for researchers and collaborators, the study protocol and the data collection schedule are all available via the website. All requests are carefully considered and accepted where possible. http://www.ukbiobank.ac.uk/register-apply/ http://www.ukbiobank.ac.uk/scientists-3/genetic-data/ http://biobank.ctsu.ox.ac.uk/crystal/label.cgi?id=100314 https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000096.v4.p1 http://www.bristol.ac.uk/alspac/researchers/our-data/ http://www.borninbradford.nhs.uk