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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.

SUBMITTER: Kong A

PROVIDER: S-EPMC3746295 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Parental origin of sequence variants associated with complex diseases.

Kong Augustine A 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

Nature 20091201 7275

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 f ...[more]

PMID: 20016592

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Project description:Identifying drivers of complex traits from the noisy signals of genetic variation obtained from high-throughput genome sequencing technologies is a central challenge faced by human geneticists today. We hypothesize that the variants involved in complex diseases are likely to exhibit non-neutral evolutionary signatures. Uncovering the evolutionary history of all variants is therefore of intrinsic interest for complex disease research. However, doing so necessitates the simultaneous elucidation of the targets of natural selection and population-specific demographic history.Here we characterize the action of natural selection operating across complex disease categories, and use population genetic simulations to evaluate the expected patterns of genetic variation in large samples. We focus on populations that have experienced historical bottlenecks followed by explosive growth (consistent with many human populations), and describe the differences between evolutionarily deleterious mutations and those that are neutral.Genes associated with several complex disease categories exhibit stronger signatures of purifying selection than non-disease genes. In addition, loci identified through genome-wide association studies of complex traits also exhibit signatures consistent with being in regions recurrently targeted by purifying selection. Through simulations, we show that population bottlenecks and rapid growth enable deleterious rare variants to persist at low frequencies just as long as neutral variants, but low-frequency and common variants tend to be much younger than neutral variants. This has resulted in a large proportion of modern-day rare alleles that have a deleterious effect on function and that potentially contribute to disease susceptibility.The key question for sequencing-based association studies of complex traits is how to distinguish between deleterious and benign genetic variation. We used population genetic simulations to uncover patterns of genetic variation that distinguish these two categories, especially derived allele age, thereby providing inroads into novel methods for characterizing rare genetic variation driving complex diseases.

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Parental origin of sequence variants associated with complex diseases.

Publications

Parental origin of sequence variants associated with complex diseases.

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