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

• Published in: Diabetologia Vol. 59; no. 8; pp. 1702 - 1713
• Main Authors: Prasad, Rashmi B., Lessmark, Anna, Almgren, Peter, Kovacs, Györgyi, Hansson, Ola, Oskolkov, Nikolay, Vitai, Marta, Ladenvall, Claes, Kovacs, Peter, Fadista, Joao, Lachmann, Michael, Zhou, Yuedan, Sonestedt, Emily, Poon, Wenny, Wollheim, Claes B., Orho-Melander, Marju, Stumvoll, Michael, Tuomi, Tiinamaija, Pääbo, Svante, Koranyi, Laszlo, Groop, Leif
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.08.2016; Springer Nature B.V
• Subjects: Adult; Alleles; Basic Medicine; Biobanks; Clinical Medicine; Diabetes; Diabetes Mellitus, Type 2 - genetics; Endocrinology and Diabetes; Endokrinologi och diabetes; Families; Female; Gene loci; Genetic association studies; Genetic Predisposition to Disease - genetics; Genome-Wide Association Study; Genomes; Genotype; Human Physiology; Humans; Insulin; Internal Medicine; KCNQ1; KCNQ1 Potassium Channel - genetics; Klinisk medicin; Maternal effects; Maternal Inheritance - genetics; Medical and Health Sciences; Medical Genetics; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Metabolic Diseases; Methylation; Middle Aged; Neoplasm Proteins - genetics; Parent-of-origin; Parental transmission; Polymorphism, Single Nucleotide - genetics; THADA; Type 2 diabetes; Sweden; Germany; Finland; Parental transmission; Type 2 diabetes; Maternal effects; Parent-of-origin; Genetic association studies; Families; Methylation; KCNQ1; THADA
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-016-3973-9

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.