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Testing for Genetic Interactions in Complex Disease With Distance Correlation.

Understanding epistasis (genetic interaction) may shed some light on the genomic basis of common diseases, including disorders of maximum interest due to their high socioeconomic burden, like schizophrenia. Distance correlation is an association measure that characterizes general statistical independence between random variables, not only the linear one. Here, we propose distance correlation as a novel tool for the detection of epistasis from case-control data of single-nucleotide polymorphisms. On the methodological side, we highlight the derivation of the explicit asymptotic null distribution of the test statistic. We show that this is the only way to obtain enough computational speed for the method to be used in practice, in a scenario where the resampling techniques found in the literature are impractical. Our simulations show satisfactory calibration of significance, as well as comparable or better power than existing methodology. We conclude with the application of our technique to a schizophrenia genetics dataset, obtaining biologically sound insights.

Epistasis, Genetic

wingless signaling acts through zeste-white 3, the Drosophila homolog of glycogen synthase kinase-3, to regulate engrailed and establish cell fate.

Intrasegmental patterning in the Drosophila embryo is regulated by cell-cell communication. One of the signaling pathways that operates to specify positional information throughout the segment is mediated by the wingless (wg) protein, which is the homolog of the proto-oncogene Wnt-1. The early role of wg is to stabilize engrailed (en) expression by initiating a phase of en autoregulation in the adjacent more posterior cells. Here, we report that the segment polarity gene zeste-white 3 (zw3; also known as shaggy) acts as a repressor of en autoregulation. Genetic epistasis experiments indicate that wg signaling operates by inactivating the zw3 repression of en autoactivation. In addition, we demonstrate that zw3 encodes the Drosophila homolog of mammalian glycogen synthase kinase-3.

Amino Acid Sequence

An encyclopedia of human enhancer-gene regulatory interactions.

Identifying transcriptional enhancers and their target genes is essential for understanding gene regulation and the effect of human genetic variation on disease1-6. Here we create and evaluate a resource of more than 92 million enhancer-gene regulatory interactions across 1,458 biosamples covering 369 cell types and tissues, by integrating predictive models, chromatin states, three-dimensional contacts and large-scale genetic perturbations generated by the ENCODE Consortium7. We first create a systematic benchmarking pipeline to compare predictive models, assembling a dataset of 10,356 element-gene pairs measured in CRISPR perturbation experiments, more than 30,000 fine-mapped expression quantitative trait loci and 569 fine-mapped genome-wide association study (GWAS) variants linked to a probable causal gene. Using this framework, we develop ENCODE-rE2G, a predictive model achieving state-of-the-art performance across several prediction tasks, demonstrating that iterative perturbations and supervised machine learning can build increasingly accurate predictive models of enhancer regulation. Using ENCODE-rE2G, we build an encyclopedia of enhancer-gene regulatory interactions in the human genome, revealing global properties of enhancer networks, identifying differences in regulatory complexity across genes and improving analyses linking noncoding variants to target genes and cell types for common complex diseases. By interpreting the model, we find that beyond enhancer activity and three-dimensional enhancer-promoter contacts, additional features that guide enhancer-promoter communication include promoter class and enhancer-enhancer synergy. These genome-wide maps of enhancer-gene regulatory interactions, benchmarking software, predictive models and insights about enhancer function provide a valuable resource for future studies of gene regulation and human genetics.

Humans

Epistasis and the genetic divergence of photoperiodism between populations of the pitcher-plant mosquito, Wyeomyia smithii.

Parallel crosses between each of two southern (ancestral) and one northern (derived) population of the pitcher-plant mosquito, Wyeomyia smithii, were made to determine the genetic components of population divergence in critical photoperiod, a phenological trait that measures adaptation to seasonality along a climatic gradient. Joint scaling tests were used to analyze means and variances of first- and second-generation hybrids in order to determine whether nonadditive genetic variance, especially epistatic variance, contributed to divergence in critical photoperiod. In both crosses, digenic epistatic effects were highly significant, indicating that genetic divergence cannot have resulted solely from differences in additively acting loci. For one cross that could be tested directly for such effects, higher order epistasis and/or linkage did not contribute to the divergence of critical photoperiod between the constituent populations.

Adaptation, Physiological

Evaluation of epistasis detection methods for quantitative phenotypes.

MOTIVATION: Epistasis, or genetic interaction, plays a crucial role in shaping complex traits and has been increasingly recognized for its widespread influence in genetic architectures. While epistasis detection has been extensively evaluated in case-control studies, its performance with quantitative phenotypes remains comparatively understudied. RESULTS: We identified and evaluated six epistasis detection methods applicable to quantitative trait analysis: EpiSNP, Matrix Epistasis, MIDESP, PLINK Epistasis, QMDR, and REMMA. Using the EpiGEN simulator, we generated synthetic datasets modeling four classes of pairwise SNP interactions-dominant, multiplicative, recessive, and XOR. We also assessed BOOST and MDR algorithms using discretized (case-control) versions of the same datasets. Performance varied notably by interaction type: REMMA achieved the highest overall detection rate (55%), particularly excelling with dominant interactions (100%). MDR excelled with multiplicative (57%) and XOR (69%) interactions. Meanwhile, EpiSNP attained the best performance for recessive interactions (67%). All methods except BOOST produced F1 scores below 0.05 for most interaction types. We further evaluated the methods using a real-world dataset. When applied to the Adolescent Brain Cognitive Development dataset to analyse the externalizing behavior phenotype, both PLINK Epistasis and PLINK BOOST identified SNPs within the DRD2 and DRD4 genes, consistent with previously reported genetic associations. Given the variability in tool performance across interaction types, no single method provides optimal detection across all scenarios. Leveraging multiple detection algorithms may therefore yield more comprehensive insights into epistatic effects in quantitative trait analyses. AVAILABILITY AND IMPLEMENTATION: All relevant code and simulated datasets can be found at github.com/staslist/Epistasis_Review repository.

Epistasis, Genetic

Interstrain Recombinants of Human Cytomegalovirus Reveal Complex Genetic Correlates and Epistasis Influencing Glycoprotein Display, Virion Infectivity and Spread Characteristics.

Most of the nucleotide diversity in the human cytomegalovirus (HCMV) genome is due to approximately 17 genes with 2-14 alleles each. These allelic genes are interspersed among longer stretches of highly conserved sequences with signatures of extensive recombination that would shuffle the allelic genes into a vast number of allelic haplotypes. Bacterial artificial chromosome clones derived from 3 independent clinical isolates (TB40/e (TB), TR and Merlin (ME)) display dramatic differences in the abundance of entry-mediating glycoproteins gH/gL/gO and gH/gL/UL128-131, virion infectivity and efficiency of cell-free and cell-to-cell modes of spread. Of these, TB and ME are the most phenotypically different and share only 2 of the 17 allelic genes. A set of recombinant HCMV was generated by coinfecting cells with TB and ME and restriction fragment length polymorphism (RFLP) analyses demonstrated complex crossover patterns. Most recombinants were either "TB-like" with much more gH/gL/gO than gH/gL/UL128-131, or "ME-like" with much more gH/gL/UL128-131. This correlated with a TB or ME UL128 sequence, consistent with a G/T polymorphism affecting UL128 pre-mRNA splicing. One recombinant had a gH/gL/gO:gH/gL/UL128-131 ratio of 0.8, suggesting genetic determinants beyond UL128. Virion infectivity correlated with TB versus ME-like glycoprotein display, but intragroup variability indicated additional factors and variability in spread efficiency and the contribution of cell-free and cell-to-cell spread modes indicated an influence of characteristics beyond virion infectivity. Results suggest that the relationships among these three phenotypes are not strictly causal and that all three phenotypes are genetically complex and influenced by epistasis among polymorphic loci across the genome.

Journal Article

Ethnic variation in genetic disease: possible roles of hitchhiking and epistasis.

The high incidence of some genetic diseases in certain ethnic groups is important in planning of medical genetic programs. Simple interaction models predict that at least some lethal recessive alleles will have "hitchhiked" to increased frequencies because of linkage to genes whose alleles have been favored by selection for other reasons in certain populations. In the absence of linkage or epistasis with a gene favored by selection, heterozygote advantage for a recessive lethal may produce the same phenomenon. In the hitchhiking model (linkage), the increase in the gene frequency is temporary, but the length of time that the increased gene frequency is at least double the base frequency may be quite long. Changes in gene frequency for the unlinked epistatic model result in a new equilibrium with a possibly higher gene frequency. The most likely chromosomal regions in which hitchhiked lethal recessives would be found are in the vicinity of genes whose allelic frequencies vary substantially among human racial groups (e.g., Gm, Rh, Duffy, lactose tolerance, or HL-A). There will be a hitchhiking effect if recombination distance is less than the selective advantage. The closer the linkage of two loci, the easier hitchhiking effects will be to detect. Hitchhiking is suggested by nonrandom association of the recessive disease and one of the selected markers, as in the case of Gm and cystic fibrosis. However, there is so far insufficient evidence of linkage between them. More pedigree information is necessary than is now available.

Alleles

Bayesian inference of fitness landscapes via tree-structured branching processes.

MOTIVATION: The complex dynamics of cancer evolution, driven by mutation and selection, underlies the molecular heterogeneity observed in tumors. The evolutionary histories of tumors of different patients can be encoded as mutation trees and reconstructed in high resolution from single-cell sequencing data, offering crucial insights for studying fitness effects of and epistasis among mutations. Existing models, however, either fail to separate mutation and selection or neglect the evolutionary histories encoded by the tumor phylogenetic trees. RESULTS: We introduce FiTree, a tree-structured multi-type branching process model with epistatic fitness parameterization and a Bayesian inference scheme to learn fitness landscapes from single-cell tumor mutation trees. Through simulations, we demonstrate that FiTree outperforms state-of-the-art methods in inferring the fitness landscape underlying tumor evolution. Applying FiTree to a single-cell acute myeloid leukemia dataset, we identify epistatic fitness effects consistent with known biological findings and quantify uncertainty in predicting future mutational events. The new model unifies probabilistic graphical models of cancer progression with population genetics, offering a principled framework for understanding tumor evolution and informing therapeutic strategies. AVAILABILITY AND IMPLEMENTATION: The Python package FiTree and the analysis workflows are available at https://github.com/cbg-ethz/FiTree.

Bayes Theorem

IBAS: Interaction-bridged association studies discovering novel genes underlying complex traits.

Genetic contributions to complex traits are often mediated through coordinated gene-gene interaction networks, yet most existing association frameworks focus on marginal single-gene effects and overlook higher-order dependency structures. Direct modeling of interactions remains challenging due to combinatorial complexity and statistical instability. We introduce Interaction-Bridged Association Study (IBAS), a general framework that incorporates pathway-level interaction patterns into genotype-phenotype association analysis without explicitly enumerating interactions. IBAS leverages transcriptomic reference data to construct low-dimensional representations of pathway activity, which guide SNP-weighting and gene-level association testing within a kernel-based framework. In perturbation-based simulations, IBAS demonstrates improved stability and reproducibility compared to conventional TWAS and gene-based methods, while maintaining well-calibrated Type I error under phenotype permutation. Application to the WTCCC datasets identifies both known and novel genes across multiple complex diseases, including candidates with modest marginal effects missed by standard approaches. These findings are supported by replication in an independent cohort, and analyses across multiple reference tissues revealing both shared and tissue-specific signals. Overall, IBAS provides a statistically robust and computationally tractable framework for incorporating interaction effects into association mapping, extending beyond the single-gene paradigm and enabling more comprehensive characterization of complex trait. IBAS is available on GitHub at: https://github.com/QingrunZhangLab/IBAS.

Polymorphism, Single Nucleotide

The emergence of putative epistatic mutations and iSNVs in SARS-CoV-2 XBB.1.16 variants linked with alteration in immunogenic determinants.

The SARS-CoV-2 XBB variants have been proposed to evolve towards immune evasion against vaccination or natural infection, which may contribute to higher transmissibility. The XBB.1.16 independently emerged due to accumulation of two important substitutions, E180V and T478R in the spike protein. Its pseudoviral infectivity and evasion of humoral immunity were similar to XBB.1 and XBB.1.5. In March 2023, XBB.1.16 had outcompeted other dominant XBB variants in India, which indicate a potential growth advantage. Here, intra-host single nucleotide variations (iSNV) and mutations were screened in SARS-CoV-2 genomes in closely related individuals at two time points: at symptoms onset, and during recovery. The prominence of putative epistatic iSNVs (E180V, G184V, G252V, D253G, and P521S/T) in XBB.1.16 variants were detected during the recovery phase. E180V exhibits mutational constellations with the G252V and P521T in a subset of samples, and this pattern was also detected in contemporary SARS-CoV-2 genomes. Higher order protein structural predictions suggested that the putative epistatic interactions among E180V, G184V, and G252V, D253G may be associated with S protein folding and structural stability. This study involving genomics and computational analyses highlights the potential role of these putative epistatic interactions in immune evasion, which may have contributed to dominance of XBB variants.

Humans

Renal albumin excretion: twin studies identify influences of heredity, environment, and adrenergic pathway polymorphism.

Albumin excretion marks early glomerular injury in hypertension. This study investigated heritability of albumin excretion in twin pairs and its genetic determination by adrenergic pathway polymorphism. Genetic associations used single nucleotide polymorphisms at adrenergic pathway loci spanning catecholamine biosynthesis, storage, catabolism, receptor action, and postreceptor signal transduction. We studied 134 single nucleotide polymorphisms at 46 loci for a total of >51,000 genotypes. Albumin excretion heritability was 45.2+/-7.4% (P=2x10(-7)), and the phenotype aggregated significantly with adrenergic, renal, metabolic, and hemodynamic traits. In the adrenergic system, excretions of both norepinephrine and epinephrine correlated with albumin. In the kidney, albumin excretion correlated with glomerular and tubular traits (Na(+) and K(+) excretion; fractional excretion of Na(+) and Li(+)). Albumin excretion shared genetic determination (genetic covariance) with epinephrine excretion, and environmental determination with glomerular filtration rate and electrolyte intake/excretion. Albumin excretion associated with polymorphisms at multiple points in the adrenergic pathway: catecholamine biosynthesis (tyrosine hydroxylase), catabolism (monoamine oxidase A), storage/release (chromogranin A), receptor target (dopamine D1 receptor), and postreceptor signal transduction (sorting nexin 13 and rho kinase). Epistasis (gene-by-gene interaction) occurred between alleles at rho kinase, tyrosine hydroxylase, chromogranin A, and sorting nexin 13. Dopamine D1 receptor polymorphism showed pleiotropic effects on both albumin and dopamine excretion. These studies establish new roles for heredity and environment in albumin excretion. Urinary excretions of albumin and catecholamines are highly heritable, and their parallel suggests adrenergic mediation of early glomerular permeability alterations. Albumin excretion is influenced by multiple adrenergic pathway genes and is, thus, polygenic. Such functional links between adrenergic activity and glomerular injury suggest novel approaches to its prediction, prevention, diagnosis, and treatment.

Adolescent

QTL mapping for seed vigor-related traits under artificial aging in common wheat in two introgression line (IL) populations.

BACKGROUND: Seed vigor recognized as a quantitative trait is of particular importance for agricultural production. However, limited knowledge is available for understanding genetic basis of wheat seed vigor. METHODS: The aim of this study was to identify quantitative trait loci (QTL) responsible for 10 seed vigor-related traits representing multiple aspects of seed-vigor dynamics during artificial aging with 6 different treatment times (0, 24, 36, 48, 60, and 72 h) under controlled conditions (48 °C, 95% humidity, and dark). The mapping populations were two wheat introgression lines (IL-1 and IL-2) derived from recipient parent (Lumai 14) and donor parent (Shaanhan 8675 or Jing 411). RESULTS: A total of 26 additive QTLs and 72 pairs of epistatic QTLs were detected for wheat seed-vigor traits. Importantly, chromosomes 1B and 7B contained several co-located QTLs, and chromosome 2A had a QTL-rich region near the marker Xwmc667, indicating that these QTLs may affect wheat seed vigor with pleiotropic effects. Furthermore, several possible consistent QTLs (hot-spot regions) were examined by comparison analysis of QTLs detected in this study and reported previously. Finally, a set of candidate genes for wheat seed vigor were predicted to be involved in transcription regulation, carbohydrate and lipid metabolism. CONCLUSION: The present findings lay new insights into the mechanism underlying wheat seed vigor, providing valuable information for wheat genetic improvement especially marker-assisted breeding to increase seed vigor and consequently achieve high grain yield despite of further investigation required.

Triticum

Two-locus models of disease.

Most complex diseases have not been amenable to genetic analysis under the assumption of single locus or multifactorial models. Consequently, interest has turned to the consideration of the properties of oligogenic models. i.e., genetic models involving a small number of genes. Nine two-locus models of disease, representing both epistatic and heterogeneous genetic models, are investigated: three models of heterogeneity and six models of epistatis. For each model we derive formulas for the recurrence risk to various classes of relatives in terms of penetrances and gene frequencies. We also develop formulas for the components of variance for the epistatic models in terms of the same genetic parameters. The range of penetrances and the associated gene frequencies that predict a predetermined value for the population prevalence and recurrence risk to the sibling of proband are calculated for various rates of the prevalence and risk to sibs. It is found that for many of these genetic models, there is a very limited range of penetrances that fit a particular set of assumed risks. Estimated population prevalence and risks to sibs and monozygotic twins for bipolar and schizophrenia illness are used to test for compatibility with expected values for recurrence risks under these models.

Bipolar Disorder

RAD25 (SSL2), the yeast homolog of the human xeroderma pigmentosum group B DNA repair gene, is essential for viability.

Xeroderma pigmentosum (XP) patients are extremely sensitive to ultraviolet (UV) light and suffer from a high incidence of skin cancers, due to a defect in nucleotide excision repair. The disease is genetically heterogeneous, and seven complementation groups, A-G, have been identified. Homologs of human excision repair genes ERCC1, XPDC/ERCC2, and XPAC have been identified in the yeast Saccharomyces cerevisiae. Since no homolog of human XPBC/ERCC3 existed among the known yeast genes, we cloned the yeast homolog by using XPBC cDNA as a hybridization probe. The yeast homolog, RAD25 (SSL2), encodes a protein of 843 amino acids (M(r) 95,356). The RAD25 (SSL2)- and XPBC-encoded proteins share 55% identical and 72% conserved amino acid residues, and the two proteins resemble one another in containing the conserved DNA helicase sequence motifs. A nonsense mutation at codon 799 that deletes the 45 C-terminal amino acid residues in RAD25 (SSL2) confers UV sensitivity. This mutation shows epistasis with genes in the excision repair group, whereas a synergistic increase in UV sensitivity occurs when it is combined with mutations in genes in other DNA repair pathways, indicating that RAD25 (SSL2) functions in excision repair but not in other repair pathways. We also show that RAD25 (SSL2) is an essential gene. A mutation of the Lys392 residue to arginine in the conserved Walker type A nucleotide-binding motif is lethal, suggesting an essential role of the putative RAD25 (SSL2) ATPase/DNA helicase activity in viability.

Amino Acid Sequence

Genetic control of phosphorus assimilation in Neurospora crassa: dose-dependent dominance and recessiveness in constitutive mutants.

Mutants called nuc-1c, constitutive for alkaline phosphatase synthesis, were isolated and mapped very close to nuc-1 mutants in which this enzyme is not expressed. nuc-1 is epistatic to nuc-1c. nuc-1c acts only if it is cis to normal nuc-1 function. The preparation of partial diploids heterozygous for various nuc-1 alleles is described; nuc-1c is dominant to nuc-1+, which in turn is dominant to nuc-1. In heterocaryons with nuc-1+, nuc-1c is dominant when it is present in high proportion, but essentially recessive if it is present in low proportions. In heterocaryons with nuc-1, nuc-1c is again dominant when present in high proportions, but in low proportions it "complements" to give essentially normal repressibility. A model of regulation consistent with these findings is presented.

Alkaline Phosphatase

GiGCN: a network-based framework for uncovering synthetic lethal and viable genetic interactions.

Genetic interactions (GIs) underpin the functional connectivity of genes and pathways, and are important for dissecting genotype-phenotype relationships and identifying therapeutic targets for diseases. However, the scale of the human genome restricts systematic experimental interrogation of GIs. Existing computational tools focus on predicting synthetic lethality (SL) and synthetic viability (SV), the two primary forms of GIs, yet their accuracy and biological interpretability are compromised by inadequate modeling of the molecular mechanisms behind positive and negative interactions, as well as the limitation of negative samples. To overcome these challenges, we developed Genetic Interaction Graph Convolutional Network (GiGCN), a signed network modeling framework for the joint identification of gene pairs with SL and SV. We built a high-confidence signed genetic network by integrating verified GIs, and non-interacting gene pairs, together with gene semantic similarity derived from biological processes. By leveraging disentangled subspace decomposition, this framework separately models distinct functional dimensions within gene networks, enabling robust representation of context-dependent regulatory relationships and accurate discrimination of SL and SV events. Benchmark experiments demonstrate that GiGCN outperforms state-of-the-art approaches (area under receiver operating-characteristic curve: 0.978, and area under precision-recall curve: 0.944). Further analyses reveal biologically meaningful insights, including known and novel SL interactions centered on the oncogene MYC Proto-Oncogene (MYC), as well as SV interactions linked to autophagy and mitophagy pathways. This study provides a robust and interpretable network-based strategy for systematically exploring GIs. The GiGCN framework not only improves the precision of SL and SV prediction, but also offers mechanistic insights into gene functional relationships, thereby supporting the discovery of actionable therapeutic targets for cancer and other human diseases.

Humans

Representation of Nonepistatic selection models and analysis of multilocus Hardy-Weinberg Equilibrium configurations.

The paper develops conditions for the existence and the stability of central equilibria emanating from selection recombination interaction with generalized nonepistatic selection forms operating in multilocus multiallele systems. The selection structure admits a natural representation as simple sums of Kronecker products based on a common set of marginal selection components. A flexible parametrization of the recombination process is introduced leading to a canonical derivation of the transformation equations connecting gamete frequency states over successive generations. Conditions for the existence and stability of multilocus Hardy-Weinberg (H.W.) type equilibria are elaborated for the classical nonepistatic models (multiplicative and additive viability effects across loci) as well as for generalized nonepistatic selection expressions. It is established that the range of recombination distributions maintaining a stable H.W. polymorphic equilibrium is confined to loose linkage in the pure multiplicative case, but is not restricted in the additive model. In the bisexual case we ascertain for the generalized nonepistatic model the stability conditions of a common H.W polymorphism.

Alleles

Three additional genes involved in pyrimidine dimer removal in Saccharomyces cerevisiae: RAD7, RAD14 and MMS19.

The ability to remove ultraviolet (UV)-induced pyrimidine dimers from the nuclear DNA of yeast was examined in two radiation-sensitive (rad) mutants and one methyl methanesulfonate-sensitive (mms) mutant of the yeast Saccharomyces cerevisiae. The susceptibility of DNA from irradiated cells to nicking by an endonuclease activity prepared from crude extracts of Micrococcus luteus was used to measure the presence of dimers in DNA. The rad7, rad14 and mms19 mutants were found to be defective in their ability to remove UV-induced dimers from nuclear DNA. All three mutants belong to the same epistatic group as the other mutants involved in excision-repair. All three mutants show enhanced UV-induced mutations. The rad14 mutant also shows epistatic interactions with genes in the other two UV repair pathways.

DNA Repair