Disease Heritability Enrichment of Regulatory Elements Is Concentrated in Elements with Ancient Sequence Age and Conserved Function across Species

11 12 Background: Nearly all Eurasians have ~2% Neanderthal ancestry due to several events of 13 inbreeding between anatomically modern humans and archaic hominins. Previous studies 14 characterizing the legacy of Neanderthal ancestry in modern Eurasians have identified 15 examples of both adaptive and deleterious effects of admixture. However, we lack a 16 comprehensive understanding of the genome-wide influence of Neanderthal introgression on 17 modern human diseases and traits. 18 Results: We integrate recent maps of Neanderthal ancestry with well-powered association 19 studies for more than 400 diverse traits to estimate heritability enrichment patterns in regions of 20 the human genome tolerant of Neanderthal ancestry and in introgressed Neanderthal variants 21 themselves. First, we find that variants in regions tolerant of Neanderthal ancestry are depleted 22 131We find three exceptions to this complex trait heritability depletion; sunburn (1.16x, P = 132 0.3), skin color (1.21x, P = 0.4), and tanning (1.25x, P = 0.4) are not depleted among regions 133 that retain Neanderthal ancestry (Fig. 1B). These three traits are genetically correlated with 134 magnitudes between r = 0.55 and 0.86. Several previous hypotheses suggest that the 135 introgression of Neanderthal alleles related to hair and skin pigmentation could have provided 136 non-African AMHs with adaptive benefits as they moved to higher latitudes. 3,4,17,18 The 137 exceptions to the overall depletion we observe for skin traits suggest that regions of the human 138 genome involved in skin pigmentation were more tolerant of Neanderthal introgression than 139 regions of the genome associated with other traits. 140 141

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“…Statistical significance is estimated by LDSC by using a block jacknife across adjacent variants in 200 equally-sized blocks. 36,41…”

Section: Methodsmentioning

confidence: 99%

Quantifying the contribution of Neanderthal introgression to the heritability of complex traits

McArthur

Rinker

Capra

2020

Preprint

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“…If θ = 0, we recover the univariate models introduced in Bulik-Sullivan et al [4]. If θ = 1 we obtain the stratified models that are most commonly used in more recent work [5, 6, 7, 11, 10].…”

Section: Methodsmentioning

confidence: 99%

Assumptions about frequency-dependent architectures of complex traits bias measures of functional enrichment

Zabad

Ragsdale

Sun

et al. 2020

Preprint

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Linkage-Disequilibrium Score Regression (LDSC) is a popular framework for analyzing GWAS summary statistics that allows for estimating SNP heritability, confounding, and functional enrichment of genetic variants with different annotations. Recent work has highlighted the influence of implicit and explicit assumptions of the model on the biological interpretation of the results. In this work, we explored a formulation of LDSC that replaces the r2 measure of LD with a recently-proposed unbiased estimator of the D2 statistic. In addition to modest statistical difference across estimators, this derivation highlighted implicit and unrealistic assumptions about the relationship between allele frequency, effect size, and annotation status. We carry out a systematic comparison of alternative LDSC formulations by applying them to summary statistics from 47 GWAS traits. Our results show that commonly used models likely underestimate functional enrichment. These results highlight the importance of calibrating the LDSC model to achieve a more robust understanding of polygenic traits.

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“…The heritability enrichment is defined as the proportion of heritability explained by SNPs in the annotation divided by the proportion of SNPs in the annotation. Standard effect size , which quantifies the effects unique to the annotation, is the proportionate change in per-SNP heritability associated with a one standard deviation increase in the value of the annotation, conditional on other annotations in the baseline v2.1 model 82 .…”

Section: Methodsmentioning

confidence: 99%

Genome-wide association study of musical beat synchronization demonstrates high polygenicity

Niarchou

Gustavson

Sathirapongsasuti

et al. 2019

Preprint

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30 †Joint supervision 31 32 2 33Abstract 34 35While timing and rhythm-related phenotypes are heritable, the human genome 36 variations underlying these traits are not yet well-understood. We conducted a genome-37 wide association study to identify common genetic variants associated with a self-38 reported musical rhythm phenotype in 606,825 individuals. Rhythm exhibited a highly 39 polygenic architecture with sixty-eight loci reaching genome-wide significance 40 (p<5x10 -8 ) and SNP-based heritability of 13%-16%. Polygenic scores for rhythm 41 predicted the presence of musician-related keywords in the BioVU electronic health 42 record biobank. Genetic associations with rhythm were enriched for genes expressed in 43 brain tissues. Genetic correlation analyses revealed shared genetic architecture with 44 several traits relevant to cognition, emotion, health, and circadian rhythms, paving the 45 way to a better understanding of the neurobiological pathways of musicality. 46 47 48 49 50We conducted a genome-wide association study (GWAS) to identify common 73 genetic variants associated with a self-reported musical rhythm phenotype, i.e. "Can 74 you clap in time with a musical beat?", collected from 606,825 individuals participating in 75 research with the personal genetics company 23andMe, Inc. We then validated this self-76 reported phenotype in a separate internet-based behavioural study conducted in 724 77 individuals and found that it was significantly correlated with rhythm perception (Online 78 Methods). In the GWAS, a total of 68 independent SNPs surpassed the threshold for 79 genome-wide significance (p<5x10 -08 ). In addition to determining which genes were 80 implicated by these variants, we estimated how much of the total phenotypic variance 81 could be explained by all variation across the genome (i.e., SNP-based heritability). We 82 then further explored this heritability to test the hypothesis that variants associated with 83 rhythm were enriched among genes expressed in brain compared to genes expressed 84 in other tissues (e.g., muscle, adipose, etc.), and furthermore enriched in genes 85 expressed in neurons compared to other brain cell types (e.g., oligodendrocyte, 86 astrocyte). 87Using an independent sample of 67,441 genotyped individuals from the 88 Vanderbilt University Medical Center biobank, BioVU, we tested whether a cumulative 89 sum of the genetic effects for rhythm detected in our GWAS (i.e., rhythm polygenic 90 score), was significantly associated with an indication of musician status in the 91 electronic health record (EHR). Because little is yet known about the relationship of the 92 genomics of rhythm to other traits, we also performed exploratory genetic correlation 93 analysis including 764 complex traits for which a well-powered GWAS has been 94 performed and deposited in LDHub 16 . Finally, we evaluated the contribution to rhythm 95 deviation increase in the rhythm discrimination test). In the remainder of the paper, the 122 "rhythm" trait in our study refers to the self-reported b...

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Disease Heritability Enrichment of Regulatory Elements Is Concentrated in Elements with Ancient Sequence Age and Conserved Function across Species

Cited by 80 publications

References 69 publications

Quantifying the contribution of Neanderthal introgression to the heritability of complex traits

Quantifying the contribution of Neanderthal introgression to the heritability of complex traits

Assumptions about frequency-dependent architectures of complex traits bias measures of functional enrichment

Genome-wide association study of musical beat synchronization demonstrates high polygenicity

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