The Quantitative-MFG Test

A Linear Mixed Effect Model to Detect Maternal-Offspring Gene Interactions

Michelle M. Clark, John Blangero, Thomas D. Dyer, Eric M. Sobel, Janet S. Sinsheimer

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Maternal-offspring gene interactions, aka maternal-fetal genotype (MFG) incompatibilities, are neglected in complex diseases and quantitative trait studies. They are implicated in birth to adult onset diseases but there are limited ways to investigate their influence on quantitative traits. We present the quantitative-MFG (QMFG) test, a linear mixed model where maternal and offspring genotypes are fixed effects and residual correlations between family members are random effects. The QMFG handles families of any size, common or general scenarios of MFG incompatibility, and additional covariates. We develop likelihood ratio tests (LRTs) and rapid score tests and show they provide correct inference. In addition, the LRT's alternative model provides unbiased parameter estimates. We show that testing the association of SNPs by fitting a standard model, which only considers the offspring genotypes, has very low power or can lead to incorrect conclusions. We also show that offspring genetic effects are missed if the MFG modeling assumptions are too restrictive. With genome-wide association study data from the San Antonio Family Heart Study, we demonstrate that the QMFG score test is an effective and rapid screening tool. The QMFG test therefore has important potential to identify pathways of complex diseases for which the genetic etiology remains to be discovered.

Original languageEnglish (US)
Pages (from-to)63-80
Number of pages18
JournalAnnals of Human Genetics
Volume80
Issue number1
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Fingerprint

Genotype
Mothers
Genes
Inborn Genetic Diseases
Genome-Wide Association Study
Single Nucleotide Polymorphism
Linear Models
Parturition

Keywords

  • Family-based association
  • Gene-gene interaction
  • Intergenerational effects
  • Maternal-fetal genotype incompatibility
  • Measured genotype analysis
  • Pedigree GWAS
  • Quantitative traits
  • Score test
  • Variance components

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

The Quantitative-MFG Test : A Linear Mixed Effect Model to Detect Maternal-Offspring Gene Interactions. / Clark, Michelle M.; Blangero, John; Dyer, Thomas D.; Sobel, Eric M.; Sinsheimer, Janet S.

In: Annals of Human Genetics, Vol. 80, No. 1, 01.01.2016, p. 63-80.

Research output: Contribution to journalArticle

Clark, Michelle M. ; Blangero, John ; Dyer, Thomas D. ; Sobel, Eric M. ; Sinsheimer, Janet S. / The Quantitative-MFG Test : A Linear Mixed Effect Model to Detect Maternal-Offspring Gene Interactions. In: Annals of Human Genetics. 2016 ; Vol. 80, No. 1. pp. 63-80.
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