Maternal Inheritance of a Promoter Variant in the Imprinted PHLDA2 Gene Significantly Increases Birth Weight

Am J Hum Genet. 2012 Apr 6;90(4):715-9. doi: 10.1016/j.ajhg.2012.02.021. Epub 2012 Mar 22.


Birth weight is an important indicator of both perinatal and adult health, but little is known about the genetic factors contributing to its variability. Intrauterine growth restriction is a leading cause of perinatal morbidity and mortality and is also associated with adult disease. A significant correlation has been reported between lower birth weight and increased expression of the maternal PHLDA2 allele in term placenta (the normal imprinting pattern was maintained). However, a mechanism that explains the transcriptional regulation of PHLDA2 on in utero growth has yet to be described. In this study, we sequenced the PHLDA2 promoter region in 263 fetal DNA samples to identify polymorphic variants. We used a luciferase reporter assay to identify in the PHLDA2 promoter a 15 bp repeat sequence (RS1) variant that significantly reduces PHLDA2-promoter efficiency. RS1 genotyping was then performed in three independent white European normal birth cohorts. Meta-analysis of all three (total n = 9,433) showed that maternal inheritance of RS1 resulted in a significant 93 g increase in birth weight (p = 0.01; 95% confidence interval [CI] = 22-163). Moreover, when the mother was homozygous for RS1, the influence on birth weight was 155 g (p = 0.04; 95% CI = 9-300), which is a similar magnitude to the reduction in birth weight caused by maternal smoking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Base Sequence
  • Birth Weight / genetics*
  • European Continental Ancestry Group / genetics
  • Female
  • Fetus / metabolism*
  • Genetic Variation
  • Genomic Imprinting*
  • Humans
  • Infant, Low Birth Weight
  • Infant, Newborn
  • Male
  • Molecular Sequence Data
  • Nuclear Proteins / genetics*
  • Promoter Regions, Genetic*
  • Repetitive Sequences, Nucleic Acid / genetics


  • Nuclear Proteins
  • TSSC3 protein