Partitioning genetic effects on birth weight at classical human leukocyte antigen loci into indirect maternal and direct fetal components using structural equation modelling

Birth weight (BW), as a proxy for intrauterine growth, is influenced by both fetal and maternal genetic factors. Single nucleotide polymorphisms in the human leukocyte antigen (HLA) region in both maternal and fetal genomes have been robustly associated with BW in previous genetic association studies suggesting the involvement of classical HLA alleles in BW etiology. However, no study to date has partitioned the association between BW and classical HLA alleles into maternal and fetal components. We used structural equation modelling (SEM) to estimate the indirect maternal (i.e. via the intrauterine environment) and direct fetal effects of classical HLA alleles on BW. Our SEM leverages the data structure of the UK Biobank (UKB), which includes participants own BW and/or the BW of their firstborn child (in the case of UKB females). We show via simulation that our model yields asymptotically unbiased estimates of the maternal and fetal allelic effects on BW and appropriate type I error rates, in contrast to simple regression models that estimate unconditioned maternal and fetal effects. Asymptotic power calculations show that we have sufficient power to detect moderate-sized maternal or fetal allelic effects (standardized effect size [≥] 0.01) of common HLA alleles on BW in the UKB. Applying our SEM to imputed classical HLA alleles and own and offspring BW of [~]270,000 participants from the UKB replicated the previously reported association at the HLA-C locus (C*04:01, P = 2.13x10-7, C*05:01, P= 6.91x10-5, C*03:03, P= 4.53x10-3, respectively) and revealed strong evidence for maternal (HLA-A*03:01, P = 7.90x10-8; B*35:01, P = 7.78x10-5; B*39:06, P = 8.49 x10-5) and fetal allelic effects (HLA-B*39:06, P = 4.03x10-4) of non-HLA-C alleles on BW. These novel allelic associations between BW and classical HLA alleles provide insight into the immunogenetics of fetal growth in utero.