Cargando…
Properties and Modeling of GWAS when Complex Disease Risk Is Due to Non-Complementing, Deleterious Mutations in Genes of Large Effect
Current genome-wide association studies (GWAS) have high power to detect intermediate frequency SNPs making modest contributions to complex disease, but they are underpowered to detect rare alleles of large effect (RALE). This has led to speculation that the bulk of variation for most complex diseas...
Autores principales: | , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578756/ https://www.ncbi.nlm.nih.gov/pubmed/23437004 http://dx.doi.org/10.1371/journal.pgen.1003258 |
_version_ | 1782260032415465472 |
---|---|
author | Thornton, Kevin R. Foran, Andrew J. Long, Anthony D. |
author_facet | Thornton, Kevin R. Foran, Andrew J. Long, Anthony D. |
author_sort | Thornton, Kevin R. |
collection | PubMed |
description | Current genome-wide association studies (GWAS) have high power to detect intermediate frequency SNPs making modest contributions to complex disease, but they are underpowered to detect rare alleles of large effect (RALE). This has led to speculation that the bulk of variation for most complex diseases is due to RALE. One concern with existing models of RALE is that they do not make explicit assumptions about the evolution of a phenotype and its molecular basis. Rather, much of the existing literature relies on arbitrary mapping of phenotypes onto genotypes obtained either from standard population-genetic simulation tools or from non-genetic models. We introduce a novel simulation of a 100-kilobase gene region, based on the standard definition of a gene, in which mutations are unconditionally deleterious, are continuously arising, have partially recessive and non-complementing effects on phenotype (analogous to what is widely observed for most Mendelian disorders), and are interspersed with neutral markers that can be genotyped. Genes evolving according to this model exhibit a characteristic GWAS signature consisting of an excess of marginally significant markers. Existing tests for an excess burden of rare alleles in cases have low power while a simple new statistic has high power to identify disease genes evolving under our model. The structure of linkage disequilibrium between causative mutations and significantly associated markers under our model differs fundamentally from that seen when rare causative markers are assumed to be neutral. Rather than tagging single haplotypes bearing a large number of rare causative alleles, we find that significant SNPs in a GWAS tend to tag single causative mutations of small effect relative to other mutations in the same gene. Our results emphasize the importance of evaluating the power to detect associations under models that are genetically and evolutionarily motivated. |
format | Online Article Text |
id | pubmed-3578756 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-35787562013-02-22 Properties and Modeling of GWAS when Complex Disease Risk Is Due to Non-Complementing, Deleterious Mutations in Genes of Large Effect Thornton, Kevin R. Foran, Andrew J. Long, Anthony D. PLoS Genet Research Article Current genome-wide association studies (GWAS) have high power to detect intermediate frequency SNPs making modest contributions to complex disease, but they are underpowered to detect rare alleles of large effect (RALE). This has led to speculation that the bulk of variation for most complex diseases is due to RALE. One concern with existing models of RALE is that they do not make explicit assumptions about the evolution of a phenotype and its molecular basis. Rather, much of the existing literature relies on arbitrary mapping of phenotypes onto genotypes obtained either from standard population-genetic simulation tools or from non-genetic models. We introduce a novel simulation of a 100-kilobase gene region, based on the standard definition of a gene, in which mutations are unconditionally deleterious, are continuously arising, have partially recessive and non-complementing effects on phenotype (analogous to what is widely observed for most Mendelian disorders), and are interspersed with neutral markers that can be genotyped. Genes evolving according to this model exhibit a characteristic GWAS signature consisting of an excess of marginally significant markers. Existing tests for an excess burden of rare alleles in cases have low power while a simple new statistic has high power to identify disease genes evolving under our model. The structure of linkage disequilibrium between causative mutations and significantly associated markers under our model differs fundamentally from that seen when rare causative markers are assumed to be neutral. Rather than tagging single haplotypes bearing a large number of rare causative alleles, we find that significant SNPs in a GWAS tend to tag single causative mutations of small effect relative to other mutations in the same gene. Our results emphasize the importance of evaluating the power to detect associations under models that are genetically and evolutionarily motivated. Public Library of Science 2013-02-21 /pmc/articles/PMC3578756/ /pubmed/23437004 http://dx.doi.org/10.1371/journal.pgen.1003258 Text en © 2013 Thornton et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Thornton, Kevin R. Foran, Andrew J. Long, Anthony D. Properties and Modeling of GWAS when Complex Disease Risk Is Due to Non-Complementing, Deleterious Mutations in Genes of Large Effect |
title | Properties and Modeling of GWAS when Complex Disease Risk Is Due to Non-Complementing, Deleterious Mutations in Genes of Large Effect |
title_full | Properties and Modeling of GWAS when Complex Disease Risk Is Due to Non-Complementing, Deleterious Mutations in Genes of Large Effect |
title_fullStr | Properties and Modeling of GWAS when Complex Disease Risk Is Due to Non-Complementing, Deleterious Mutations in Genes of Large Effect |
title_full_unstemmed | Properties and Modeling of GWAS when Complex Disease Risk Is Due to Non-Complementing, Deleterious Mutations in Genes of Large Effect |
title_short | Properties and Modeling of GWAS when Complex Disease Risk Is Due to Non-Complementing, Deleterious Mutations in Genes of Large Effect |
title_sort | properties and modeling of gwas when complex disease risk is due to non-complementing, deleterious mutations in genes of large effect |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578756/ https://www.ncbi.nlm.nih.gov/pubmed/23437004 http://dx.doi.org/10.1371/journal.pgen.1003258 |
work_keys_str_mv | AT thorntonkevinr propertiesandmodelingofgwaswhencomplexdiseaseriskisduetononcomplementingdeleteriousmutationsingenesoflargeeffect AT foranandrewj propertiesandmodelingofgwaswhencomplexdiseaseriskisduetononcomplementingdeleteriousmutationsingenesoflargeeffect AT longanthonyd propertiesandmodelingofgwaswhencomplexdiseaseriskisduetononcomplementingdeleteriousmutationsingenesoflargeeffect |