Excess maternal transmission of variants in the THADA gene to offspring with type 2 diabetes

Research output: Contribution to journalArticle

Abstract

Aims/hypothesis: Genome-wide association studies (GWAS) have identified more than 65 genetic loci associated with risk of type 2 diabetes. However, the contribution of distorted parental transmission of alleles to risk of type 2 diabetes has been mostly unexplored. Our goal was therefore to search for parent-of-origin effects (POE) among type 2 diabetes loci in families. Methods: Families from the Botnia study (n = 4,211, 1,083 families) were genotyped for 72 single-nucleotide polymorphisms (SNPs) associated with type 2 diabetes and assessed for POE on type 2 diabetes. The family-based Hungarian Transdanubian Biobank (HTB) (n = 1,463, >135 families) was used to replicate SNPs showing POE. Association of type 2 diabetes loci within families was also tested. Results: Three loci showed nominal POE, including the previously reported variants in KCNQ1, for type 2 diabetes in families from Botnia (rs2237895: pPOE = 0.037), which can be considered positive controls. The strongest POE was seen for rs7578597 SNP in the THADA gene, showing excess transmission of the maternal risk allele T to diabetic offspring (Botnia: pPOE = 0.01; HTB pPOE = 0.045). These data are consistent with previous evidence of allelic imbalance for expression in islets, suggesting that the THADA gene can be imprinted in a POE-specific fashion. Five CpG sites, including those flanking rs7578597, showed differential methylation between diabetic and non-diabetic donor islets. Conclusions/interpretation: Taken together, the data emphasise the need for genetic studies to consider from which parent an offspring has inherited a susceptibility allele.

Details

Authors
  • Anna Lessmark
  • Peter Almgren
  • Györgyi Kovacs
  • Nikolay Oskolkov
  • Marta Vitai
  • Claes Ladenvall
  • Peter Kovacs
  • Joao Fadista
  • Michael Lachmann
  • Yuedan Zhou
  • Wenny Poon
  • Michael Stumvoll
  • Tiinamaija Tuomi
  • Svante Pääbo
  • Laszlo Koranyi
Organisations
External organisations
  • Heart Center Foundation
  • Leipzig University
  • Santa Fe Institute
  • Folkhälsan
  • Helsinki University Central Hospital
  • Max Planck Institute for Evolutionary Anthropology
  • Institute for Molecular Medicine Finland (FIMM)
  • Skåne University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
  • Endocrinology and Diabetes

Keywords

  • Families, Genetic association studies, KCNQ1, Maternal effects, Methylation, Parent-of-origin, Parental transmission, THADA, Type 2 diabetes
Original languageEnglish
Pages (from-to)1702-1713
Number of pages12
JournalDiabetologia
Volume59
Issue number8
Publication statusPublished - 2016 Aug
Publication categoryResearch
Peer-reviewedYes