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

Author:
  • Rashmi B. Prasad
  • Anna Lessmark
  • Peter Almgren
  • Györgyi Kovacs
  • Ola Hansson
  • Nikolay Oskolkov
  • Marta Vitai
  • Claes Ladenvall
  • Peter Kovacs
  • Joao Fadista
  • Michael Lachmann
  • Yuedan Zhou
  • Emily Sonestedt
  • Wenny Poon
  • Claes B. Wollheim
  • Marju Orho-Melander
  • Michael Stumvoll
  • Tiinamaija Tuomi
  • Svante Pääbo
  • Laszlo Koranyi
  • Leif Groop
Publishing year: 2016-08
Language: English
Pages: 1702-1713
Publication/Series: Diabetologia
Volume: 59
Issue: 8
Document type: Journal article
Publisher: Springer

Abstract english

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.

Keywords

  • Medical Genetics
  • Endocrinology and Diabetes
  • Families
  • Genetic association studies
  • KCNQ1
  • Maternal effects
  • Methylation
  • Parent-of-origin
  • Parental transmission
  • THADA
  • Type 2 diabetes

Other

Published
  • Genomics, Diabetes and Endocrinology
  • Diabetes - Cardiovascular Disease
  • ISSN: 0012-186X
Emily Sonestedt
E-mail: emily [dot] sonestedt [at] med [dot] lu [dot] se

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