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

Prasad, Rashmi B. LU ; Lessmark, Anna LU ; Almgren, Peter LU ; Kovacs, Györgyi ; Hansson, Ola LU orcid ; Oskolkov, Nikolay LU ; Vitai, Marta ; Ladenvall, Claes LU ; Kovacs, Peter and Fadista, Joao LU , et al. (2016) In Diabetologia 59(8). p.1702-1713
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Families, Genetic association studies, KCNQ1, Maternal effects, Methylation, Parent-of-origin, Parental transmission, THADA, Type 2 diabetes
in
Diabetologia
volume
59
issue
8
pages
12 pages
publisher
Springer
external identifiers
  • scopus:84966354983
  • pmid:27155871
  • wos:000379158800017
ISSN
0012-186X
DOI
10.1007/s00125-016-3973-9
language
English
LU publication?
yes
id
c1025a06-42c0-4a27-9d31-95f6714973a4
date added to LUP
2016-05-31 14:54:37
date last changed
2024-04-19 03:52:09
@article{c1025a06-42c0-4a27-9d31-95f6714973a4,
  abstract     = {{<p>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, &gt;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<sub>POE</sub> = 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<sub>POE</sub> = 0.01; HTB p<sub>POE</sub> = 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.</p>}},
  author       = {{Prasad, Rashmi B. and Lessmark, Anna and Almgren, Peter and Kovacs, Györgyi and Hansson, Ola and Oskolkov, Nikolay and Vitai, Marta and Ladenvall, Claes and Kovacs, Peter and Fadista, Joao and Lachmann, Michael and Zhou, Yuedan and Sonestedt, Emily and Poon, Wenny and Wollheim, Claes B. and Orho-Melander, Marju and Stumvoll, Michael and Tuomi, Tiinamaija and Pääbo, Svante and Koranyi, Laszlo and Groop, Leif}},
  issn         = {{0012-186X}},
  keywords     = {{Families; Genetic association studies; KCNQ1; Maternal effects; Methylation; Parent-of-origin; Parental transmission; THADA; Type 2 diabetes}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{1702--1713}},
  publisher    = {{Springer}},
  series       = {{Diabetologia}},
  title        = {{Excess maternal transmission of variants in the THADA gene to offspring with type 2 diabetes}},
  url          = {{http://dx.doi.org/10.1007/s00125-016-3973-9}},
  doi          = {{10.1007/s00125-016-3973-9}},
  volume       = {{59}},
  year         = {{2016}},
}