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Diabetologia. 2016 Aug;59(8):1702-13. doi: 10.1007/s00125-016-3973-9. Epub 2016 May 7.

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

Author information

1
Lund University Diabetes Centre, Department of Clinical Sciences, Lund University CRC, Skåne University Hospital Malmö, SE-205 02, Malmö, Sweden. Rashmi.Prasad@med.lu.se.
2
Lund University Diabetes Centre, Department of Clinical Sciences, Lund University CRC, Skåne University Hospital Malmö, SE-205 02, Malmö, Sweden.
3
Heart Center Foundation, DRC, Balatonfured, Hungary.
4
Department of Medicine, University of Leipzig, Leipzig, Germany.
5
IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.
6
Santa Fe Institute, Santa Fe, NM, USA.
7
Department of Cell Physiology and Metabolism, University Medical Center, Geneva, Switzerland.
8
Folkhälsan Research Centre, Helsinki, Finland.
9
Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
10
Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
11
Lund University Diabetes Centre, Department of Clinical Sciences, Lund University CRC, Skåne University Hospital Malmö, SE-205 02, Malmö, Sweden. Leif.Groop@med.lu.se.
12
Finnish Institute of Molecular Medicine (FIMM), Helsinki University, Helsinki, Finland. Leif.Groop@med.lu.se.

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: 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.

KEYWORDS:

Families; Genetic association studies; KCNQ1; Maternal effects; Methylation; Parent-of-origin; Parental transmission; THADA; Type 2 diabetes

PMID:
27155871
DOI:
10.1007/s00125-016-3973-9
[Indexed for MEDLINE]

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