1. Human Birth Weight and Reproductive Immunology: Testing for Interactions between Maternal and Offspring KIR and HLA-C Genes
- Author
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Clark, Michelle M, Chazara, Olympe, Sobel, Eric M, Gjessing, Håkon K, Magnus, Per, Moffett, Ashley, and Sinsheimer, Janet S
- Subjects
Genetics ,Pediatric ,Clinical Research ,Perinatal Period - Conditions Originating in Perinatal Period ,2.1 Biological and endogenous factors ,Aetiology ,Reproductive health and childbirth ,Birth Weight ,Cohort Studies ,Female ,Fetal Development ,Genome-Wide Association Study ,Genotype ,HLA-C Antigens ,Humans ,Pregnancy ,Receptors ,KIR ,Maternal-fetal genotype interaction ,KIR ,HLA ,Gene-gene interaction ,Family-based association ,Quantitative traits ,Variance components ,Intergenerational effects ,The Norwegian Mother and Child Cohort (MoBa) Study ,Genetics & Heredity - Abstract
Background/aimsMaternal 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.MethodsUntil 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.ResultsWe 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.ConclusionWe 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.
- Published
- 2016