title: Parental origin of sequence variants associated with complex diseases.
abstract: Effects of susceptibility variants may depend on from which parent they are inherited. Although many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Here we show that for 38,167 Icelanders genotyped using single nucleotide polymorphism (SNP) chips, the parental origin of most alleles can be determined. For this we used a combination of genealogy and long-range phasing. We then focused on SNPs that associate with diseases and are within 500 kilobases of known imprinted genes. Seven independent SNP associations were examined. Five-one with breast cancer, one with basal-cell carcinoma and three with type 2 diabetes-have parental-origin-specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, we observed a novel association between the SNP rs2334499 at 11p15 and type 2 diabetes. Here the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF-binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site.
authors.affiliation: deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland. kong@decode.is
authors.forename: Augustine
authors.initials: A
authors.lastname: Kong
authors.forename: Valgerdur
authors.initials: V
authors.lastname: Steinthorsdottir
authors.forename: Gisli
authors.initials: G
authors.lastname: Masson
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.forename: Patrick
authors.initials: P
authors.lastname: Sulem
authors.forename: Soren
authors.initials: S
authors.lastname: Besenbacher
authors.forename: Aslaug
authors.initials: A
authors.lastname: Jonasdottir
authors.forename: Asgeir
authors.initials: A
authors.lastname: Sigurdsson
authors.forename: Kari Th
authors.initials: KT
authors.lastname: Kristinsson
authors.forename: Adalbjorg
authors.initials: A
authors.lastname: Jonasdottir
authors.forename: Michael L
authors.initials: ML
authors.lastname: Frigge
authors.forename: Arnaldur
authors.initials: A
authors.lastname: Gylfason
authors.forename: Pall I
authors.initials: PI
authors.lastname: Olason
authors.forename: Sigurjon A
authors.initials: SA
authors.lastname: Gudjonsson
authors.forename: Sverrir
authors.initials: S
authors.lastname: Sverrisson
authors.forename: Simon N
authors.initials: SN
authors.lastname: Stacey
authors.forename: Bardur
authors.initials: B
authors.lastname: Sigurgeirsson
authors.forename: Kristrun R
authors.initials: KR
authors.lastname: Benediktsdottir
authors.forename: Helgi
authors.initials: H
authors.lastname: Sigurdsson
authors.forename: Thorvaldur
authors.initials: T
authors.lastname: Jonsson
authors.forename: Rafn
authors.initials: R
authors.lastname: Benediktsson
authors.forename: Jon H
authors.initials: JH
authors.lastname: Olafsson
authors.forename: Oskar Th
authors.initials: OT
authors.lastname: Johannsson
authors.forename: Astradur B
authors.initials: AB
authors.lastname: Hreidarsson
authors.forename: Gunnar
authors.initials: G
authors.lastname: Sigurdsson
authors.forename: Anne C
authors.initials: AC
authors.lastname: Ferguson-Smith
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gudbjartsson
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
mesh_terms: D000483:Alleles; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics; D000076246:CCCTC-Binding Factor; D002280:Basal Cell Carcinoma / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005220:Fathers; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D018392:Genomic Imprinting / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D007055:Iceland; D008297:Male; D009035:Mothers; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D012097:Repressor Proteins