Low-frequency variant functional architectures reveal strength of negative selection across coding and non-coding annotations

et al. 2018

Preprint

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Regulatory elements, e.g. enhancers and promoters, have been widely reported to be enriched for disease and complex trait heritability. We investigated how this enrichment varies with the age of the underlying genome sequence, the conservation of regulatory function across species, and the target gene of the regulatory element. We estimated heritability enrichment by applying stratified LD score regression to summary statistics from 41 independent diseases and complex traits (average N =320K) and meta-analyzing results across traits. Enrichment of human enhancers and promoters was larger in elements with older sequence age, assessed via alignment with other species irrespective of conserved functionality: enhancer elements with ancient sequence age (older than the split between marsupial and placental mammals) were 8.8x enriched (vs. 2.5x for all enhancers; p = 3e-14), and promoter elements with ancient sequence age were 13.5x enriched (vs. 5.1x for all promoters; p = 5e-16). Enrichment of human enhancers and promoters was also larger in elements whose regulatory function was conserved across species, e.g. human enhancers that were enhancers in 5 of 9 other mammals were 4.6x enriched (p = 5e-12 vs. all enhancers). Enrichment of human promoters was larger in promoters of loss-of-function intolerant genes: 12.0x enrichment (p = 8e-15 vs. all promoters). The mean value of several measures of negative selection within these genomic annotations mirrored all of these findings. Notably, the annotations with these excess heritability enrichments were jointly significant conditional on each other and on our baseline-LD model, which includes a broad set of coding, conserved, regulatory and LD-related annotations.

Section: Discussionsupporting

confidence: 87%

“…We note several limitations of our work. First, we focused our analyses on common variants by using a 1000 Genomes LD reference panel, but future work could draw inferences about lowfrequency variants using larger reference panels 44 . Second, our main analyses were restricted to enhancers and promoters identified in liver tissue 9 .…”

Section: Discussionmentioning

confidence: 99%

Disease heritability enrichment of regulatory elements is concentrated in elements with ancient sequence age and conserved function across species

Hujoel

Gazal

et al. 2018

Preprint

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“…We compared functional enrichment between groups of related traits ( 8 brain-related, 6 bloodrelated, and 5 immune-related traits; Supplementary Figure 5). Brain-related traits had smaller functional enrichments both for heritability and for polygenicity, consistent with previous findings 17,19,22 . Smaller functional enrichment could be explained by stronger negative selection for these traits 19 , which may strongly limit the enrichment of any functional category.…”

Section: Polygenicity Of Functional Categories Across 33 Complex Traitssupporting

confidence: 91%

“…Brain-related traits had smaller functional enrichments both for heritability and for polygenicity, consistent with previous findings 17,19,22 . Smaller functional enrichment could be explained by stronger negative selection for these traits 19 , which may strongly limit the enrichment of any functional category. Stronger negative selection would also be consistent with greater genome-wide polygenicity for these traits (Table 1).…”

Section: Polygenicity Of Functional Categories Across 33 Complex Traitssupporting

confidence: 91%

“…We refer to this phenomenon as flattening, as the distribution of heritability across the genome is flattened relative to the underlying biology. Although it is widely known that negative selection constrains common-variant effect sizes on average 10,[16][17][18][19][20] , the extent to which negative selection leads to increased polygenicity is unknown.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Polygenicity of complex traits is explained by negative selection

O’Connor

Schoech

et al. 2018

Preprint

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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. strongly than % (Figure 2b). Third, $ (but not % ) is closely related to missing heritability and polygenic prediction accuracy (Methods).Ma can be defined for categories of SNPs, such as low-frequency SNPs or coding SNPs. To compare categories of different size, we divide Ma by the number of SNPs in each category. We refer to differences in per-SNP Ma simply as differences in polygenicity. We define polygenicity enrichment as the per-SNP Ma of all SNPs in a category divided by the per-SNP Ma of all SNPs; analogously, we define heritability enrichment as the per-SNP heritability of all SNPs in a category divided by the per-SNP heritability of all SNPs (similar to previous work 22 ). "All SNPs" refers to common ( ≥ 0.05) and low-frequency (0.005 ≤ < 0.05) SNPs. Enrichment can be either >1 or <1 (i.e. depletion).

Extreme Polygenicity of Complex Traits Is Explained by Negative Selection

O’Connor

Schoech

The American Journal of Human Genetics

et al. 2019

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224

248

Complex traits and common diseases are extremely polygenic, their heritability spread across thousands of loci. One possible explanation is that thousands of genes and loci have similarly important biological effects when mutated. However, we hypothesize that for most complex traits, relatively few genes and loci are critical, and negative selection-purging large-effect mutations in these regions-leaves behind common-variant associations in thousands of less critical regions instead. We refer to this phenomenon as flattening. To quantify its effects, we introduce a mathematical definition of polygenicity, the effective number of independently associated SNPs (M e), which describes how evenly the heritability of a trait is spread across the genome. We developed a method, stratified LD fourth moments regression (S-LD4M), to estimate M e , validating that it produces robust estimates in simulations. Analyzing 33 complex traits (average N ¼ 361k), we determined that heritability is spread $43 more evenly among common SNPs than among low-frequency SNPs. This difference, together with evolutionary modeling of new mutations, suggests that complex traits would be orders of magnitude less polygenic if not for the influence of negative selection. We also determined that heritability is spread more evenly within functionally important regions in proportion to their heritability enrichment; functionally important regions do not harbor common SNPs with greatly increased causal effect sizes, due to selective constraint. Our results suggest that for most complex traits, the genes and loci with the most critical biological effects often differ from those with the strongest common-variant associations.