Amplification is the primary mode of gene-by-sex interaction in complex human traits

Zhu, Carrie; Ming, Matthew J.; Cole, Jared M.; Edge, Michael D.; Kirkpatrick, Mark; Harpak, Arbel

doi:10.1016/j.xgen.2023.100297

Cited by 23 publications

(25 citation statements)

References 83 publications

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“…2D). These results are in line with previous work suggesting that SPs, like other anthropometric traits, have clear differences in the magnitude of sex-specific effects when compared with other quantitative traits in the UKB ( 42 ).…”

Section: Resultssupporting

confidence: 93%

“…To test for pervasive differences in the magnitude of genetic effects, we performed sex-specific GWASs of all the skeletal traits and evaluated these polygenic scores in both sexes in a hold-out dataset ( 30 ). This method had recently been applied to examine sex-specific effects in biobank traits ( 42 ). Across all SPs that we tested, polygenic scores had a significantly larger standardized effect size (standardized in males and females separately) in males compared with females (Student’s t test p < 1 × 10 −3 for all comparisons) (Fig.…”

Section: Resultsmentioning

confidence: 99%

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The genetic architecture and evolution of the human skeletal form

Kun

Javan

Smith

et al. 2023

Science

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The human skeletal form underlies bipedalism, but the genetic basis of skeletal proportions (SPs) is not well characterized. We applied deep-learning models to 31,221 x-rays from the UK Biobank to extract a comprehensive set of SPs, which were associated with 145 independent loci genome-wide. Structural equation modeling suggested that limb proportions exhibited strong genetic sharing but were independent of width and torso proportions. Polygenic score analysis identified specific associations between osteoarthritis and hip and knee SPs. In contrast to other traits, SP loci were enriched in human accelerated regions and in regulatory elements of genes that are differentially expressed between humans and great apes. Combined, our work identifies specific genetic variants that affect the skeletal form and ties a major evolutionary facet of human anatomical change to pathogenesis.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

The genetic architecture and evolution of the human skeletal form

Kun

Javan

Smith

et al. 2023

Science

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“…Here, both the additive and cis -interaction effects are simulated in the same way as previously described where, for the two groups of interacting variants, 10% of SNPs were selected to be in group #1 and we chose ±10 kb windows to assign SNPs to group #2. To create G × E effects, we follow a simulation strategy implemented by Zhu et al 65 and split our sample population in half to emulate two subsets of individuals coming from different environments. We randomly draw the effect sizes for the first environment from a standard Gaussian distribution which we denote as γ 1 .…”

Section: Methodsmentioning

confidence: 99%

“…These interact with the group #2 SNPs which are selected to be variants within a ± 100 kilobase (kb) window around each SNP in group #1. G × E effects were simulated using an amplification model 65 (see Materials and Methods) where we split the sample population in half to emulate two subsets of individuals coming from different environments. We randomly draw variant effect sizes for the first environment from a standard Gaussian distribution.…”

Section: Figures and Tablesmentioning

confidence: 99%

Discovering non-additive heritability using additive GWAS summary statistics

Darnell

Smith

Ramachandran

et al. 2022

Preprint

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The inflation of test statistics in genome-wide association (GWA) studies due to confounding factors such as cryptic relatedness, population stratification, and spurious non-zero genetic effects driven by linkage disequilibrium (LD) has been well characterized in the literature. The key theoretical contribution of this work is that epistasis (i.e., the interaction between multiple loci and/or genes) can also lead to bias in GWA summary statistics. To address this challenge, we develop marginal epistatic LD score regression and the accompanying software package MELD: an extended framework which takes in GWA test statistics and accurately partitions true additive genetic variation from non-additive genetic variation, as well as other biases. By re-analyzing 25 well-studied quantitative phenotypes from 349,468 individuals of European ancestry in the UK Biobank and up to 159,095 individuals in BioBank Japan, we illustrate that nonlinear effects are a significant source of signal in reported GWA summary statistics and provide evidence that epistasis is more widespread in human phenotypes than previously reported. Of the 25 complex traits we analyzed in the UK Biobank, 23 phenotypes have a significant amount of epistatic confounding captured within additive variation, including height, urate level, and cholesterol levels. The MELD software and its application to these biobanks represent a significant step towards resolving the true contribution of epistasis to human complex traits.

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“…In addition, the relative importance of different types of GxE (e.g., locus-specific GxE, genome-wide effects of E on genetic variance, genome-wide effects of E on both genetic and environmental variance) is currently unclear. Studies of GxSex interaction face similar challenges 19–24 .…”

Section: Introductionmentioning

confidence: 99%

Distinct explanations underlie gene-environment interactions in the UK Biobank

Durvasula,

Price

2023

Preprint

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The role of gene-environment (GxE) interaction in disease and complex trait architectures is widely hypothesized, but currently unknown. Here, we apply three statistical approaches to quantify and distinguish three different types of GxE interaction for a given disease/trait and E variable. First, we detect locus-specific GxE interaction by testing for genetic correlation (rg) < 1 across E bins. Second, we detect genome-wide effects of the E variable on genetic variance by leveraging polygenic risk scores (PRS) to test for significant PRSxE in a regression of phenotypes on PRS, E, and PRSxE, together with differences in SNP-heritability across E bins. Third, we detect genome-wide proportional amplification of genetic and environmental effects as a function of the E variable by testing for significant PRSxE with no differences in SNP-heritability across E bins. Simulations show that these approaches achieve high sensitivity and specificity in distinguishing these three GxE scenarios. We applied our framework to 33 UK Biobank diseases/traits (average N=325K) and 10 E variables spanning lifestyle, diet, and other environmental exposures. First, we identified 19 trait-E pairs with rg significantly < 1 (FDR<5%) (average rg=0.95); for example, white blood cell count had rg=0.95 (s.e. 0.01) between smokers and non-smokers. Second, we identified 28 trait-E pairs with significant PRSxE and significant SNP-heritability differences across E bins; for example, type 2 diabetes had a significant PRSxE for alcohol consumption (P=1e-13) with 4.2x larger SNP-heritability in the largest versus smallest quintiles of alcohol consumption (P<1e-16). Third, we identified 15 trait-E pairs with significant PRSxE with no SNP-heritability differences across E bins; for example, triglyceride levels had a significant PRSxE effect for composite diet score (P=4e-5) with no SNP-heritability differences. Analyses using biological sex as the E variable produced additional significant findings in each of the three scenarios. Overall, we infer a substantial contribution of GxE and GxSex effects to disease and complex trait variance.

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Amplification is the primary mode of gene-by-sex interaction in complex human traits

Cited by 23 publications

References 83 publications

The genetic architecture and evolution of the human skeletal form

The genetic architecture and evolution of the human skeletal form

Discovering non-additive heritability using additive GWAS summary statistics

Distinct explanations underlie gene-environment interactions in the UK Biobank

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