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

Summary, in 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: p_POE = 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: p_POE = 0.01; HTB p_POE = 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.

• Författare: 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
• Avdelning/ar: Translationell Muskel Forskning; Diabetes - kardiovaskulär sjukdom; EXODIAB: Excellence of Diabetes Research in Sweden; EpiHealth: Epidemiology for Health
• Publiceringsår: 2016-08
• Språk: Engelska
• Sidor: 1702-1713
• Publikation/Tidskrift/Serie: Diabetologia
• Volym: 59
• Issue: 8
• Länkar: http://dx.doi.org/10.1007/s00125-016-3973-9
• Dokumenttyp: Artikel i tidskrift
• Förlag: Springer
• Ämne: Medical Genetics; Endocrinology and Diabetes
• Nyckelord: Families; Genetic association studies; KCNQ1; Maternal effects; Methylation; Parent-of-origin; Parental transmission; THADA; Type 2 diabetes
• Status: Published
• Forskningsgrupp: Translational Muscle Research; Diabetes - Cardiovascular Disease
• ISBN/ISSN/Övrigt: ISSN: 0012-186X