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.

Figure 1. An example of parental origin determination

In blue and red are two phased haplotypes of a proband. Among other typed individuals, the closest paternal relative known to also carry the blue haplotype is R₁, a cousin, while the corresponding maternal relative is R₂. For the red haplotype, a maternal aunt (R₃) carries the haplotype, while the closest known carrier on the father side is R₄. Since R₁ is a closer than R₂ and R₃ is a closer than R₄, the blue and red haplotypes are likely paternally and maternally inherited respectively. The single-tile score (see Methods) supporting this assignment is 0.194.

Figure 2. Chromosome 11p15 locus

Markers associated with T2D (rs2334499, rs231362, rs2237892) as well as breast cancer (rs3817198), are indicated. The two regions containing clusters of imprinted genes are shaded. Location of the CTCF binding region studied (OREG0020670) and gene annotations were taken from the University of California Santa Cruz genome browser. Estimated recombination rates (from HapMap) are plotted to reflect the linkage disequilibrium structure in the region.

Figure 3. Chromosome 7q32 locus

Markers associated with T2D (rs4731702, rs972283) as well as basal cell carcinoma (rs157935), are indicated. Rs972283, reported in the DIAGRAM study is not on the Illumina chip. Data on the correlated marker rs4731702 (r² = 1, HapMap Ceu) is reported here. The region containing the known imprinted genes is shaded. Gene annotations were taken from the University of California Santa Cruz genome browser. Estimated recombination rates (from HapMap) are plotted to reflect the linkage disequilibrium structure in the region.