Parental origin of sequence variants associated with complex diseases.
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.
Kong
Augustine
A
deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland. kong@decode.is
Steinthorsdottir
Valgerdur
V
Masson
Gisli
G
Thorleifsson
Gudmar
G
Sulem
Patrick
P
Besenbacher
Soren
S
Jonasdottir
Aslaug
A
Sigurdsson
Asgeir
A
Kristinsson
Kari Th
KT
Jonasdottir
Adalbjorg
A
Frigge
Michael L
ML
Gylfason
Arnaldur
A
Olason
Pall I
PI
Gudjonsson
Sigurjon A
SA
Sverrisson
Sverrir
S
Stacey
Simon N
SN
Sigurgeirsson
Bardur
B
Benediktsdottir
Kristrun R
KR
Sigurdsson
Helgi
H
Jonsson
Thorvaldur
T
Benediktsson
Rafn
R
Olafsson
Jon H
JH
Johannsson
Oskar Th
OT
Hreidarsson
Astradur B
AB
Sigurdsson
Gunnar
G
Ferguson-Smith
Anne C
AC
Gudbjartsson
Daniel F
DF
Thorsteinsdottir
Unnur
U
Stefansson
Kari
K
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
D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D012097:Repressor Proteins