Are minor alleles more likely to be risk alleles?

Abstract Background Genome-wide association studies (GWASs) have revealed relationships between over 57,000 genetic variants and diseases. However, unlike Mendelian diseases, complex diseases arise from the interplay of multiple genetic and environmental factors. Natural selection has led to a high...

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Main Authors: Takashi Kido, Weronika Sikora-Wohlfeld, Minae Kawashima, Shinichi Kikuchi, Naoyuki Kamatani, Anil Patwardhan, Richard Chen, Marina Sirota, Keiichi Kodama, Dexter Hadley, Atul J. Butte
Format: Article
Language:English
Published: BMC 2018-01-01
Series:BMC Medical Genomics
Subjects:
Online Access:http://link.springer.com/article/10.1186/s12920-018-0322-5
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spelling doaj-16d4a69f91764aed8a10ed5a6a8133ff2021-04-02T06:28:13ZengBMCBMC Medical Genomics1755-87942018-01-0111111110.1186/s12920-018-0322-5Are minor alleles more likely to be risk alleles?Takashi Kido0Weronika Sikora-Wohlfeld1Minae Kawashima2Shinichi Kikuchi3Naoyuki Kamatani4Anil Patwardhan5Richard Chen6Marina Sirota7Keiichi Kodama8Dexter Hadley9Atul J. Butte10Rikengenesis Co., Ltd.Division of Systems Medicine, Department of Pediatrics, Stanford UniversityDepartment of Human Genetics, Graduate School of Medicine, The University of TokyoAI System Department, DeNA, Inc.StaGen Inc.Personalis, Inc.Personalis, Inc.Institute for Computational Health Sciences, University of CaliforniaInstitute for Computational Health Sciences, University of CaliforniaInstitute for Computational Health Sciences, University of CaliforniaInstitute for Computational Health Sciences, University of CaliforniaAbstract Background Genome-wide association studies (GWASs) have revealed relationships between over 57,000 genetic variants and diseases. However, unlike Mendelian diseases, complex diseases arise from the interplay of multiple genetic and environmental factors. Natural selection has led to a high tendency of risk alleles to be enriched in minor alleles in Mendelian diseases. Therefore, an allele that was previously advantageous or neutral may later become harmful, making it a risk allele. Methods Using data in the NHGRI-EBI Catalog and the VARIMED database, we investigated whether (1) GWASs more easily detect risk alleles and (2) facilitate evolutionary insights by comparing risk allele frequencies of different diseases. We conducted computer simulations of P-values for association tests when major and minor alleles were risk alleles. We compared the expected proportion of SNVs whose risk alleles were minor alleles with the observed proportion. Results Our statistical results revealed that risk alleles were enriched in minor alleles, especially for variants with low minor allele frequencies (MAFs < 0.1). Our computer simulations revealed that > 50% risk alleles were minor alleles because of the larger difference in the power of GWASs to differentiate between minor and major alleles, especially with low MAFs or when the number of controls exceeds the number of cases. However, the observed ratios between minor and major alleles in low MAFs (< 0.1) were much larger than the expected ratios of GWAS’s power imbalance, especially for diseases whose average risk allele frequencies were low, such as myopia, sudden cardiac arrest, and systemic lupus erythematosus. Conclusions Minor alleles are more likely to be risk alleles in the published GWASs on complex diseases. One reason is that minor alleles are more easily detected as risk alleles in GWASs. Even when correcting for the GWAS’s power imbalance, minor alleles are more likely to be risk alleles, especially in some diseases whose average risk allele frequencies are low. These analyses serve as a starting point for future studies on quantifying the degree of negative natural selection in various complex diseases.http://link.springer.com/article/10.1186/s12920-018-0322-5GWASsComplex diseasesMinor allelesRisk allelesNegative natural selection
collection DOAJ
language English
format Article
sources DOAJ
author Takashi Kido
Weronika Sikora-Wohlfeld
Minae Kawashima
Shinichi Kikuchi
Naoyuki Kamatani
Anil Patwardhan
Richard Chen
Marina Sirota
Keiichi Kodama
Dexter Hadley
Atul J. Butte
spellingShingle Takashi Kido
Weronika Sikora-Wohlfeld
Minae Kawashima
Shinichi Kikuchi
Naoyuki Kamatani
Anil Patwardhan
Richard Chen
Marina Sirota
Keiichi Kodama
Dexter Hadley
Atul J. Butte
Are minor alleles more likely to be risk alleles?
BMC Medical Genomics
GWASs
Complex diseases
Minor alleles
Risk alleles
Negative natural selection
author_facet Takashi Kido
Weronika Sikora-Wohlfeld
Minae Kawashima
Shinichi Kikuchi
Naoyuki Kamatani
Anil Patwardhan
Richard Chen
Marina Sirota
Keiichi Kodama
Dexter Hadley
Atul J. Butte
author_sort Takashi Kido
title Are minor alleles more likely to be risk alleles?
title_short Are minor alleles more likely to be risk alleles?
title_full Are minor alleles more likely to be risk alleles?
title_fullStr Are minor alleles more likely to be risk alleles?
title_full_unstemmed Are minor alleles more likely to be risk alleles?
title_sort are minor alleles more likely to be risk alleles?
publisher BMC
series BMC Medical Genomics
issn 1755-8794
publishDate 2018-01-01
description Abstract Background Genome-wide association studies (GWASs) have revealed relationships between over 57,000 genetic variants and diseases. However, unlike Mendelian diseases, complex diseases arise from the interplay of multiple genetic and environmental factors. Natural selection has led to a high tendency of risk alleles to be enriched in minor alleles in Mendelian diseases. Therefore, an allele that was previously advantageous or neutral may later become harmful, making it a risk allele. Methods Using data in the NHGRI-EBI Catalog and the VARIMED database, we investigated whether (1) GWASs more easily detect risk alleles and (2) facilitate evolutionary insights by comparing risk allele frequencies of different diseases. We conducted computer simulations of P-values for association tests when major and minor alleles were risk alleles. We compared the expected proportion of SNVs whose risk alleles were minor alleles with the observed proportion. Results Our statistical results revealed that risk alleles were enriched in minor alleles, especially for variants with low minor allele frequencies (MAFs < 0.1). Our computer simulations revealed that > 50% risk alleles were minor alleles because of the larger difference in the power of GWASs to differentiate between minor and major alleles, especially with low MAFs or when the number of controls exceeds the number of cases. However, the observed ratios between minor and major alleles in low MAFs (< 0.1) were much larger than the expected ratios of GWAS’s power imbalance, especially for diseases whose average risk allele frequencies were low, such as myopia, sudden cardiac arrest, and systemic lupus erythematosus. Conclusions Minor alleles are more likely to be risk alleles in the published GWASs on complex diseases. One reason is that minor alleles are more easily detected as risk alleles in GWASs. Even when correcting for the GWAS’s power imbalance, minor alleles are more likely to be risk alleles, especially in some diseases whose average risk allele frequencies are low. These analyses serve as a starting point for future studies on quantifying the degree of negative natural selection in various complex diseases.
topic GWASs
Complex diseases
Minor alleles
Risk alleles
Negative natural selection
url http://link.springer.com/article/10.1186/s12920-018-0322-5
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