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. Many associations between gene sequence variants and human traits have been discovered in genome-wide association studies (GWAS), but most of these studies treat maternal and paternal alleles as interchangeable, so little is known about how the parental origin of sequence variants influences phenotypes. A new GWAS technique that combines genealogy and long-range phasing can determine the parental origin of most alleles, as shown in a survey of genotypes from over 38,000 Icelandic individuals. Five single-nucleotide variations previously shown to be associated with complex diseases — one with breast cancer, one with base-cell carcinoma and three with type 2 diabetes — are found to be dependent on parental origin. A new variant that is protective when maternally transmitted is second only to that of the gene TCF7L2 variant in contributing to diabetes risk when transmitted paternally. The effect of sequence variants on phenotypes may depend on parental origin. Here, a method is developed that takes parental origin — the impact of which, to date, has largely been ignored — into account in genome-wide association studies. For 38,167 Icelanders genotyped, the parental origin of most alleles is determined; furthermore, a number of variants are found that show associations specific to parental origin, including three with type 2 diabetes.

Parental origin of sequence variants associated with complex diseases