title: Excess maternal transmission of variants in the THADA gene to offspring with type 2 diabetes.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Taken together, the data emphasise the need for genetic studies to consider from which parent an offspring has inherited a susceptibility allele.
authors.affiliation: 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.
authors.forename: Rashmi B
authors.initials: RB
authors.lastname: Prasad
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Lund University CRC, Skåne University Hospital Malmö, SE-205 02, Malmö, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Lessmark
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Lund University CRC, Skåne University Hospital Malmö, SE-205 02, Malmö, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Almgren
authors.affiliation: Heart Center Foundation, DRC, Balatonfured, Hungary.
authors.forename: Györgyi
authors.initials: G
authors.lastname: Kovacs
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Lund University CRC, Skåne University Hospital Malmö, SE-205 02, Malmö, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Hansson
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Lund University CRC, Skåne University Hospital Malmö, SE-205 02, Malmö, Sweden.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Oskolkov
authors.affiliation: Heart Center Foundation, DRC, Balatonfured, Hungary.
authors.forename: Marta
authors.initials: M
authors.lastname: Vitai
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Lund University CRC, Skåne University Hospital Malmö, SE-205 02, Malmö, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Ladenvall
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany.|IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kovacs
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Lund University CRC, Skåne University Hospital Malmö, SE-205 02, Malmö, Sweden.
authors.forename: Joao
authors.initials: J
authors.lastname: Fadista
authors.affiliation: Santa Fe Institute, Santa Fe, NM, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Lachmann
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Lund University CRC, Skåne University Hospital Malmö, SE-205 02, Malmö, Sweden.
authors.forename: Yuedan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Lund University CRC, Skåne University Hospital Malmö, SE-205 02, Malmö, Sweden.
authors.forename: Emily
authors.initials: E
authors.lastname: Sonestedt
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Lund University CRC, Skåne University Hospital Malmö, SE-205 02, Malmö, Sweden.
authors.forename: Wenny
authors.initials: W
authors.lastname: Poon
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Lund University CRC, Skåne University Hospital Malmö, SE-205 02, Malmö, Sweden.|Department of Cell Physiology and Metabolism, University Medical Center, Geneva, Switzerland.
authors.forename: Claes B
authors.initials: CB
authors.lastname: Wollheim
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Lund University CRC, Skåne University Hospital Malmö, SE-205 02, Malmö, Sweden.
authors.forename: Marju
authors.initials: M
authors.lastname: Orho-Melander
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany.|IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Stumvoll
authors.affiliation: Folkhälsan Research Centre, Helsinki, Finland.|Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Tiinamaija
authors.initials: T
authors.lastname: Tuomi
authors.affiliation: Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
authors.forename: Svante
authors.initials: S
authors.lastname: Pääbo
authors.affiliation: Heart Center Foundation, DRC, Balatonfured, Hungary.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Koranyi
authors.affiliation: 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.|Finnish Institute of Molecular Medicine (FIMM), Helsinki University, Helsinki, Finland. Leif.Groop@med.lu.se.
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
mesh_terms: D000328:Adult; D000483:Alleles; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D000072741:Maternal Inheritance / Q000235:genetics; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D009363:Neoplasm Proteins; C477698:THADA protein, human
keywords: Families; Genetic association studies; KCNQ1; Maternal effects; Methylation; Parent-of-origin; Parental transmission; THADA; Type 2 diabetes