Parental origin of sequence variants associated with complex diseases.
Parental origin of sequence variants associated with complex diseases.
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易感性变体的影响可能取决于它们是从哪个父母遗传的。虽然序列变异和人类特征之间的许多关联已经通过全基因组关联被发现，但父母起源的影响在很大程度上被忽视了。结合系谱与远程定相，我们证明，38,167冰岛人基因分型使用SNP芯片，大多数等位基因的父母的起源可以确定。然后，我们专注于与疾病相关的SNP，并且在已知印记基因的500 kb范围内。七个独立的SNP协会进行了检查。五个，乳腺癌和基底细胞癌各一个，2型糖尿病（T2 D）三个，表现出父母来源的特定关联。这些变体位于两个基因组区域，11 p15和7 q32，每个区域都有一簇印记基因。此外，在11 p15的一种新的变异rs 2334499被认为与T2 D相关，其中当父系遗传时赋予风险的等位基因在母系传播时具有保护性。我们在11 p15处发现了一个甲基化差异的CTCF结合位点，并证明了rs 2334499与该位点甲基化降低的相关性。
Effects of susceptibility variants may depend on from which parent they are inherited. While many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Combining genealogy with long range phasing, we demonstrate that for 38,167 Icelanders genotyped using SNP chips, the parental origin of most alleles can be determined. We then focused on SNPs that associate with diseases and are within 500kb of known imprinted genes. Seven independent SNP associations were examined. Five, one each with breast cancer and basal cell carcinoma, and three with type 2 diabetes (T2D), exhibit parental-origin specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, a novel variant rs2334499 at 11p15 was seen to associate with T2D where 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.
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