Faculty Opinions recommendation of Signatures of negative selection in the genetic architecture of human complex traits.

Author(s):  
Benjamin Neale
2018 ◽  
Vol 50 (5) ◽  
pp. 746-753 ◽  
Author(s):  
Jian Zeng ◽  
Ronald de Vlaming ◽  
Yang Wu ◽  
Matthew R. Robinson ◽  
Luke R. Lloyd-Jones ◽  
...  

2014 ◽  
Vol 23 (22) ◽  
pp. 5893-5905 ◽  
Author(s):  
Xu Zhang ◽  
Erika L. Moen ◽  
Cong Liu ◽  
Wenbo Mu ◽  
Eric R. Gamazon ◽  
...  

2018 ◽  
Author(s):  
Luke J. O’Connor ◽  
Armin P. Schoech ◽  
Farhad Hormozdiari ◽  
Steven Gazal ◽  
Nick Patterson ◽  
...  

Complex traits and common disease are highly polygenic: thousands of common variants are causal, and their effect sizes are almost always small. Polygenicity could be explained by negative selection, which constrains common-variant effect sizes and may reshape their distribution across the genome. We refer to this phenomenon as flattening, as genetic signal is flattened relative to the underlying biology. We introduce a mathematical definition of polygenicity, the effective number of associated SNPs, and a robust statistical method to estimate it. This definition of polygenicity differs from the number of causal SNPs, a standard definition; it depends strongly on SNPs with large effects. In analyses of 33 complex traits (average N=361k), we determined that common variants are ∼4x more polygenic than low-frequency variants, consistent with pervasive flattening. Moreover, functionally important regions of the genome have increased polygenicity in proportion to their increased heritability, implying that heritability enrichment reflects differences in the number of associations rather than their magnitude (which is constrained by selection). We conclude that negative selection constrains the genetic signal of biologically important regions and genes, reshaping genetic architecture.


2017 ◽  
Vol 49 (10) ◽  
pp. 1421-1427 ◽  
Author(s):  
Steven Gazal ◽  
Hilary K Finucane ◽  
Nicholas A Furlotte ◽  
Po-Ru Loh ◽  
Pier Francesco Palamara ◽  
...  

2019 ◽  
Vol 51 (8) ◽  
pp. 1295-1295
Author(s):  
Steven Gazal ◽  
Hilary K. Finucane ◽  
Nicholas A. Furlotte ◽  
Po-Ru Loh ◽  
Pier Francesco Palamara ◽  
...  

2019 ◽  
Author(s):  
Anton E. Shikov ◽  
Alexander V. Predeus ◽  
Yury A. Barbitoff

AbstractOver recent decades, genome-wide association studies (GWAS) have dramatically changed the understanding of human genetics. A recent genetic data release by UK Biobank has allowed many researchers worldwide to have comprehensive look into the genetic architecture of thousands of human phenotypes. In this study, we developed a novel statistical framework to assess phenome-wide significance and genetic pleiotropy across the human phenome based on GWAS summary statistics. We demonstrate widespread sharing of genetic architecture components between distinct groups of traits. Apart from known multiple associations inside the MHC locus, we discover high degree of pleiotropy for genes involved in immune system function, apoptosis, hemostasis cascades, as well as lipid and xenobiotic metabolism. We find several notable examples of novel pleiotropic loci (e.g., the MIR2113 microRNA broadly associated with cognition), and provide several possible mechanisms for these association signals. Our results allow for a functional phenome-wide look into the shared components of genetic architecture of human complex traits, and highlight crucial genes and pathways for their development.


2016 ◽  
Author(s):  
Steven Gazal ◽  
Hilary K. Finucane ◽  
Nicholas A Furlotte ◽  
Po-Ru Loh ◽  
Pier Francesco Palamara ◽  
...  

AbstractRecent work has hinted at the linkage disequilibrium (LD) dependent architecture of human complex traits, where SNPs with low levels of LD (LLD) have larger per-SNP heritability after conditioning on their minor allele frequency (MAF). However, this has not been formally assessed, quantified or biologically interpreted. Here, we analyzed summary statistics from 56 complex diseases and traits (average N = 101,401) by extending stratified LD score regression to continuous annotations. We determined that SNPs with low LLD have significantly larger per-SNP heritability. Roughly half of the LLD signal can be explained by functional annotations that are negatively correlated with LLD, such as DNase I hypersensitivity sites (DHS). The remaining signal is largely driven by our finding that common variants that are more recent tend to have lower LLD and to explain more heritability (P = 2.38 × 10−104); the youngest 20% of common SNPs explain 3.9x more heritability than the oldest 20%, consistent with the action of negative selection. We also inferred jointly significant effects of other LD-related annotations and confirmed via forward simulations that these annotations jointly predict deleterious effects. Our results are consistent with the action of negative selection on deleterious variants that affect complex traits, complementing efforts to learn about negative selection by analyzing much smaller rare variant data sets.


Author(s):  
Marina de Miguel ◽  
Isabel Rodríguez-Quilón ◽  
Myriam Heuertz ◽  
Agathe Hurel ◽  
Delphine Grivet ◽  
...  

AbstractA decade of association studies in multiple organisms suggests that most complex traits are polygenic; that is, they have a genetic architecture determined by numerous loci distributed across the genome, each with small effect-size. Thus, determining the degree of polygenicity and its variation across traits, environments and years is useful to understand the genetic basis of phenotypic variation. In this study, we applied multilocus approaches to estimate the degree of polygenicity of fitness-related traits in a long-lived plant (Pinus pinaster Ait., maritime pine) and to analyze how polygenicity changes across environments and years. To do so, we evaluated five categories of fitness-related traits (survival, height, phenology-related, functional, and biotic-stress response traits) in a clonal common garden network, planted in contrasted environments (over 12,500 trees). First, most of the analyzed traits showed evidence of local adaptation based on QST-FST comparisons. Second, we observed a remarkably stable degree of polygenicity, averaging 6% (range of 0-27%), across traits, environments and years. As previously suggested for humans, some of these traits showed also evidence of negative selection, which could explain, at least partially, the high degree of polygenicity. The observed genetic architecture of fitness-related traits in maritime pine supports the polygenic adaptation model. Because polygenic adaptation can occur rapidly, our study suggests that current predictions on the capacity of natural forest tree populations to adapt to new environments should be revised, which is of special relevance in the current context of climate change.


2017 ◽  
Author(s):  
Jian Zeng ◽  
Ronald de Vlaming ◽  
Yang Wu ◽  
Matthew R Robinson ◽  
Luke Lloyd-Jones ◽  
...  

AbstractEstimation of the joint distribution of effect size and minor allele frequency (MAF) for genetic variants is important for understanding the genetic basis of complex trait variation and can be used to detect signature of natural selection. We develop a Bayesian mixed linear model that simultaneously estimates SNP-based heritability, polygenicity (i.e. the proportion of SNPs with nonzero effects) and the relationship between effect size and MAF 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 across 28 traits, 6% of SNPs have nonzero effects, which in total explain 22% of phenotypic variance. We detect significant (p < 0.05/28 =1.8×10−3) signatures of natural selection for 23 out of 28 traits including reproductive, cardiovascular, and anthropometric traits, as well as educational attainment. We further apply the method to 27,869 gene expression traits (N = 1,748), and identify 30 genes that show significant (p < 2.3×10−6) evidence of natural selection. All the significant estimates of the relationship between effect size and MAF in either complex traits or gene expression traits are consistent with a model of negative selection, as confirmed by forward simulation. We conclude that natural selection acts pervasively on human complex traits shaping genetic variation in the form of negative selection.


2019 ◽  
Vol 29 ◽  
pp. S1282
Author(s):  
Kyoko Watanabe ◽  
Sven Stringer ◽  
Tinca Polderman ◽  
Danielle Posthuma

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