Signatures of negative selection in the genetic architecture of human complex traits

We develop a Bayesian mixed linear model that simultaneously estimates single-nucleotide polymorphism (SNP)-based heritability, polygenicity (proportion of SNPs with nonzero effects), and the relationship between SNP effect size and minor allele frequency for complex traits in conventionally unrelat...

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Vydáno v:Nature genetics Ročník 50; číslo 5; s. 746 - 753
Hlavní autoři: Zeng, Jian, de Vlaming, Ronald, Wu, Yang, Robinson, Matthew R., Lloyd-Jones, Luke R., Yengo, Loic, Yap, Chloe X., Xue, Angli, Sidorenko, Julia, McRae, Allan F., Powell, Joseph E., Montgomery, Grant W., Metspalu, Andres, Esko, Tonu, Gibson, Greg, Wray, Naomi R., Visscher, Peter M., Yang, Jian
Médium: Journal Article
Jazyk:angličtina
Vydáno: New York Nature Publishing Group US 01.05.2018
Nature Publishing Group
Témata:
38
45
45/43
631/208/205/2138
631/208/457
Agriculture
Alleles
Analysis
Animal Genetics and Genomics
Anthropometry
Architecture
Bayes Theorem
Bayesian analysis
Biomedical and Life Sciences
Biomedicine
Cancer Research
Computer simulation
Consortia
Evolution
Evolution (Biology)
Gene expression
Gene frequency
Gene Frequency - genetics
Gene Function
Genetic aspects
Genetic diversity
Genetic polymorphisms
Genetic variance
Genome-Wide Association Study - methods
Genomes
Genomics
Genotype
Genotype & phenotype
Heritability
Human Genetics
Humans
Linear Models
Methods
Models, Genetic
Multifactorial Inheritance - genetics
Mutation
Natural selection
Negative selection
Parameter estimation
Phenotype
Phenotypic variations
Polymorphism
Polymorphism, Single Nucleotide - genetics
Quantitative Trait, Heritable
Selection, Genetic - genetics
Signatures
Single nucleotide polymorphisms
Single-nucleotide polymorphism
Type 2 diabetes
United Kingdom > UK
ISSN:1061-4036, 1546-1718, 1546-1718
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Popis
Shrnutí:We develop a Bayesian mixed linear model that simultaneously estimates single-nucleotide polymorphism (SNP)-based heritability, polygenicity (proportion of SNPs with nonzero effects), and the relationship between SNP effect size and minor allele frequency for complex traits in conventionally unrelated individuals using genome-wide SNP data. We apply the method to 28 complex traits in the UK Biobank data ( N  = 126,752) and show that on average, 6% of SNPs have nonzero effects, which in total explain 22% of phenotypic variance. We detect significant ( P  < 0.05/28) signatures of natural selection in the genetic architecture of 23 traits, including reproductive, cardiovascular, and anthropometric traits, as well as educational attainment. The significant estimates of the relationship between effect size and minor allele frequency in complex traits are consistent with a model of negative (or purifying) selection, as confirmed by forward simulation. We conclude that negative selection acts pervasively on the genetic variants associated with human complex traits. BayesS estimates SNP-based heritability, polygenicity, and the relationship between effect size and minor allele frequency using genome-wide SNP data. Applying BayesS to UK Biobank data identifies signatures of natural selection for 23 complex traits.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1061-4036
1546-1718
1546-1718
DOI:10.1038/s41588-018-0101-4