title: Human Birth Weight and Reproductive Immunology: Testing for Interactions between Maternal and Offspring KIR and HLA-C Genes.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, CA, USA.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Clark
authors.forename: Olympe
authors.initials: O
authors.lastname: Chazara
authors.forename: Eric M
authors.initials: EM
authors.lastname: Sobel
authors.forename: Håkon K
authors.initials: HK
authors.lastname: Gjessing
authors.forename: Per
authors.initials: P
authors.lastname: Magnus
authors.forename: Ashley
authors.initials: A
authors.lastname: Moffett
authors.forename: Janet S
authors.initials: JS
authors.lastname: Sinsheimer
mesh_terms: D001724:Birth Weight / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D047109:Fetal Development / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D015236:HLA-C Antigens / Q000235:genetics*; D006801:Humans; D011247:Pregnancy; D054340:Receptors, KIR / Q000235:genetics*
chemical_list: D015236:HLA-C Antigens; D054340:Receptors, KIR
keywords: Family-based association; Gene-gene interaction; HLA; Intergenerational effects; KIR; Maternal-fetal genotype interaction; Quantitative traits; The Norwegian Mother and Child Cohort (MoBa) Study; Variance components