Human Birth Weight and Reproductive Immunology: Testing for Interactions between Maternal and Offspring KIR and HLA-C
Michelle M Clark1, Olympe Chazara, Eric M Sobel
1Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, CA, USA.
Background/Aims:
Maternal and offspring cell contact at the site of placentation presents a plausible setting for maternal-fetal genotype (MFG) interactions affecting fetal growth. We test hypotheses regarding killer cell immunoglobulin-like receptor (KIR) and HLA-C MFG effects on human birth weight by extending the quantitative MFG (QMFG) test.
Methods:
Until recently, association testing for MFG interactions had limited applications. To improve the ability to test for these interactions, we developed the extended QMFG test, a linear mixed-effect model that can use multi-locus genotype data from families.
Results:
We demonstrate the extended QMFG test's statistical properties. We also show that if an offspring-only model is fit when MFG effects exist, associations can be missed or misattributed. Furthermore, imprecisely modeling the effects of both KIR and HLA-C could result in a failure to replicate if these loci's allele frequencies differ among populations. To further illustrate the extended QMFG test's advantages, we apply the extended QMFG test to a UK cohort study and the Norwegian Mother and Child Cohort (MoBa) study.
Conclusion:
We find a significant KIR-HLA-C interaction effect on birth weight. More generally, the QMFG test can detect genetic associations that may be missed by standard genome-wide association studies for quantitative traits.
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