Indirect Genetic Effects Research Articles

Influence of birth weight on later life cardiovascular structure, function and disease: unpacking influences from direct genetic effects versus intrauterine programming

Abstract Aims The cardinal risk factors for cardiovascular disease in adulthood are well-recognised. In addition to these, observational studies have suggested that intrauterine and early developmental factors might play a role. However, observational associations are liable to influence by residual confounding and bias. Additionally, observational and genetic studies to date have not been able to isolate the fetal versus maternal influences. Purpose We aim to explore the causal relevance of birth weight on cardiovascular disease and cardiac structure and function using Mendelian randomization (MR), and specifically investigate the role of fetal genetic effects (reflecting the direct causal influence of birth weight) versus maternal genetic effects (reflecting the influence of the intrauterine environment). Methods Uncorrelated (r2<0.001), genome-wide significant (p<5x10-8) SNPs were extracted from genome-wide association study summary statistics for gestational age-adjusted birth weight overall, and after isolating the indirect maternal versus direct fetal genetic effects. Inverse-variance weighted Mendelian randomisation (MR) was utilised for primary analyses on outcomes of atrial fibrillation, coronary artery disease, heart failure, ischaemic stroke, and 15 measures of cardiac structure and function indexed to body surface area. Multivariable MR was utilised to explore potential mediation of effects observed on cardiovascular outcomes by cardiometabolic risk factors. P-values were FDR-adjusted to account for multiple testing. Results Higher genetically-predicted birth weight was associated with higher risk of atrial fibrillation (OR 1.26 [1.15-1.39], p<0.001), but lower risk of coronary artery disease (OR 0/78 [0.71-0.86] p<0.001). These associations were driven predominantly by direct fetal genetic effects. For the association with atrial fibrillation, there was no evidence of mediation through body mass index or height. For the association with coronary artery disease, there was at least partial mediation through systolic blood pressure (Figure 1). Higher genetically-predicted birth weight was associated with a greater chamber volumes, but lower ejection fraction (Figure 2), driven by direct fetal genetic effects. Conclusion The results of this study suggest that lower birthweight is associated with higher risk of coronary artery disease, partly mediated by a higher systolic blood pressure. Conversely, a greater birth weight was associated with higher risk of atrial fibrillation, and this was not mediated by body mass index or height. Higher birth weight was also associated with greater chamber volumes and lower ejection fraction. The associations were in all cases predominantly driven by direct fetal effects, suggesting a causal relevance of birth weight itself, and not of the intrauterine environment, on later life cardiovascular disease.Figure 1Figure 2

Competition-cooperation mechanism between Escherichia coli and Staphylococcus aureus based on systems mapping.

Interspecies interactions are a crucial driving force of species evolution. The genes of each coexisting species play a pivotal role in shaping the structure and function within the community, but how to identify them at the genome-wide level has always been challenging. In this study, we embed the Lotka-Volterra ordinary differential equations in the theory of community ecology into the systems mapping model, so that this model can not only describe how the quantitative trait loci (QTL) of a species directly affects its own phenotype, but also describe the QTL of the species how to indirectly affect the phenotype of its interacting species, and how QTL from different species affects community behavior through epistatic interactions. By designing and implementing a co-culture experiment for 100 pairs of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), we mapped 244 significant QTL combinations in the interaction process of the two bacteria using this model, including 69 QTLs from E. coli and 59 QTLs from S. aureus, respectively. Through gene annotation, we obtained 57 genes in E. coli, among which the genes with higher frequency were ypdC, nrfC, yphH, acrE, dcuS, rpnE, and ptsA, while we obtained 43 genes in S. aureus, among which the genes with higher frequency were ebh, SAOUHSC_00172, capF, gdpP, orfX, bsaA, and phnE1. By dividing the overall growth into independent growth and interactive growth, we could estimate how QTLs modulate interspecific competition and cooperation. Based on the quantitative genetic model, we can obtain the direct genetic effect, indirect genetic effect, and genome-genome epistatic effect related to interspecific interaction genes, and then further mine the hub genes in the QTL networks, which will be particularly useful for inferring and predicting the genetic mechanisms of community dynamics and evolution. Systems mapping can provide a tool for studying the mechanism of competition and cooperation among bacteria in co-culture, and this framework can lay the foundation for a more comprehensive and systematic study of species interactions.

Indirect genetic effects are shaped by demographic history and ecology in Arabidopsis thaliana.

The phenotype of an individual can be affected by the genes of its conspecifics through indirect genetic effects (IGEs). IGEs have been studied across different organisms including wild and domesticated animals and plants, but little is known about their genetic architecture. Here, in a large-scale intraspecific interaction experiment, we show that the contribution of IGEs to the biomass variation of Arabidopsis thaliana is comparable to values classically reported in animals. Moreover, we identify 11 loci explaining 85.1% of the variability in IGEs. We find that positive IGE alleles (that is, those with positive effects on neighbour biomass) occur both in relict accessions from southern Eurasia and in post-glacial colonizers from northern Scandinavia, and that they are likely to have two divergent origins: for nine loci, they evolved in the post-glacial colonizers independently from the relicts, while the two others were introgressed in the post-glacial colonizer from the relicts. Finally, we find that variation in IGEs probably reflects divergent adaptations to the contrasting environments of the edges and the centre of the native range of the species. These findings reveal a surprisingly tractable genetic basis of IGEs in A. thaliana that is shaped by the ecology and the demographic history of the species.

Integrative multi-omics analysis of genomic, epigenomic, and metabolomics data leads to new insights for Attention-Deficit/Hyperactivity Disorder.

The evolving field of multi-omics combines data and provides methods for simultaneous analysis across several omics levels. Here, we integrated genomics (transmitted and non-transmitted polygenic scores [PGSs]), epigenomics, and metabolomics data in a multi-omics framework to identify biomarkers for Attention-Deficit/Hyperactivity Disorder (ADHD) and investigated the connections among the three omics levels. We first trained single- and next multi-omics models to differentiate between cases and controls in 596 twins (cases = 14.8%) from the Netherlands Twin Register (NTR) demonstrating reasonable in-sample prediction through cross-validation. The multi-omics model selected 30 PGSs, 143 CpGs, and 90 metabolites. We confirmed previous associations of ADHD with glucocorticoid exposure and the transmembrane protein family TMEM, show that the DNA methylation of the MAD1L1 gene associated with ADHD has a relation with parental smoking behavior, and present novel findings including associations between indirect genetic effects and CpGs of the STAP2 gene. However, out-of-sample prediction in NTR participants (N = 258, cases = 14.3%) and in a clinical sample (N = 145, cases = 51%) did not perform well (range misclassification was [0.40, 0.57]). The results highlighted connections between omics levels, with the strongest connections between non-transmitted PGSs, CpGs, and amino acid levels and show that multi-omics designs considering interrelated omics levels can help unravel the complex biology underlying ADHD.

Trait-Specific Indirect Effects Underlie Variation in the Response of Spiders to Cannibalistic Social Partners.

AbstractIn cannibalistic species, selection to avoid conspecifics may stem from the need to avoid being eaten or to avoid competition. Individuals may thus use conspecific cues to modulate their behavior to such threats. Yet the nature of variation for such cues remains elusive. Here, we use a half-sib/full-sib design to evaluate the contribution of (indirect) genetic or environmental effects to the behavioral response of the cannibalistic wolf spider Lycosa fasciiventris (Dufour, 1835) toward conspecific cues. Spiders showed variation in relative occupancy time, activity, and velocity on patches with or without conspecific cues, but direct genetic variance was found only for occupancy time. These three traits were correlated and could be lumped in a principal component: spiders spending more time in patches with conspecific cues moved less and more slowly in those areas. Genetic and/or environmental components of carapace width and weight loss in the social partner, which may reflect the quality and/or quantity of cues produced, were significantly correlated with this principal component, with larger partners causing focal individuals to move more slowly. Therefore, environmental and genetic trait variation in social partners may maintain trait diversity in focal individuals, even in the absence of direct genetic variation.

Evolutionary rescue from climate change: male indirect genetic effects on lay-dates and their consequences for population persistence.

Changes in avian breeding phenology are among the most apparent responses to climate change in free-ranging populations. A key question is whether populations will be able to keep up with the expected rates of environmental change. There is a large body of research on the mechanisms by which avian lay-dates track temperature change and the consequences of (mal)adaptation on population persistence. Often overlooked is the role of males, which can influence the lay-date of their mate through their effect on the prelaying environment. We explore how social plasticity causing male indirect genetic effects can help or hinder population persistence when female genes underpinning lay-date and male genes influencing female's timing of reproduction both respond to climate-mediated selection. We extend quantitative genetic moving optimum models to predict the consequences of social plasticity on the maximum sustainable rate of temperature change, and evaluate our model using a combination of simulated data and empirical estimates from the literature. Our results suggest that predictions for population persistence may be biased if indirect genetic effects and cross-sex genetic correlations are not considered and that the extent of this bias depends on sex differences in how environmental change affects the optimal timing of reproduction. Our model highlights that more empirical work is needed to understand sex-specific effects of environmental change on phenology and the fitness consequences for population dynamics. While we discuss our results exclusively in the context of avian breeding phenology, the approach we take here can be generalized to many different contexts and types of social interaction.

Educational attainment, health outcomes and mortality: a within-sibship Mendelian randomization study.

Previous Mendelian randomization (MR) studies using population samples (population MR) have provided evidence for beneficial effects of educational attainment on health outcomes in adulthood. However, estimates from these studies may have been susceptible to bias from population stratification, assortative mating and indirect genetic effects due to unadjusted parental genotypes. MR using genetic association estimates derived from within-sibship models (within-sibship MR) can avoid these potential biases because genetic differences between siblings are due to random segregation at meiosis. Applying both population and within-sibship MR, we estimated the effects of genetic liability to educational attainment on body mass index (BMI), cigarette smoking, systolic blood pressure (SBP) and all-cause mortality. MR analyses used individual-level data on 72 932 siblings from UK Biobank and the Norwegian HUNT study, and summary-level data from a within-sibship Genome-wide Association Study including >140 000 individuals. Both population and within-sibship MR estimates provided evidence that educational attainment decreased BMI, cigarette smoking and SBP. Genetic variant-outcome associations attenuated in the within-sibship model, but genetic variant-educational attainment associations also attenuated to a similar extent. Thus, within-sibship and population MR estimates were largely consistent. The within-sibship MR estimate of education on mortality was imprecise but consistent with a putative effect. These results provide evidence of beneficial individual-level effects of education (or liability to education) on adulthood health, independently of potential demographic and family-level confounders.

Indirect genetic effects increase heritability estimates for male and female extra-pair reproduction.

The question of why females engage in extra-pair behaviours is long-standing in evolutionary biology. One suggestion is that these behaviours are maintained through pleiotropic effects on male extra-pair behaviors (genes controlling extra-pair reproduction are shared between sexes, but only beneficial to one sex, in this case, males). However, for this to evolve extra-pair reproduction must be both heritable and positively genetically correlated between sexes. Previous studies have suggested low heritability with no evidence for between-sex genetic correlations in extra-pair reproduction. However, these have not considered indirect genetic effects (derived from the behaviour of others, IGEs) from the social partner, the influence of the social partner's genotype on the phenotype of an individual, despite the potential of IGEs to uncover hidden heritable variation. Using data from a closed house sparrow population with a genetic pedigree spanning two decades, we tested the influence of social partner IGEs on heritable variation and genetic correlation estimates of extra-pair reproduction. We found that the inclusion of IGEs resulted in larger heritable genetic variance for both male and female extra-pair heritability. While IGEs did not change between-sex genetic correlations, we found they reduced uncertainty in those estimates. Future studies should consider the effect of IGEs on the mechanisms of sex specific extra-pair reproduction.

Direct and Indirect Genetic Effects on Aggression

BackgroundFamily members resemble each other in their propensity for aggression. In twin studies, approximately 50% of the variance in aggression can be explained by genetic influences. However, if there are genotype-environment correlation mechanisms, such as environmental manifestations of parental and sibling genotypes, genetic influences may partly reflect environmental influences. In this study, we investigated the importance of indirect polygenic score (PGS) effects on aggression. MethodsWe modeled the effect of PGSs based on 3 genome-wide association studies: early-life aggression, educational attainment, and attention-deficit/hyperactivity disorder (ADHD). The associations with aggression were tested in a within- and between-family design (37,796 measures from 7740 individuals, ages 3–86 years [mean = 14.20 years, SE = 12.03], from 3107 families, 55% female) and in a transmitted/nontransmitted PGS design (42,649 measures from 6653 individuals, ages 3–61 years [mean = 11.81 years, SE = 8.68], from 3024 families, 55% female). All participants are enrolled in the Netherlands Twin Register. ResultsWe found no evidence for contributions of indirect PGS effects on aggression in either a within- and between-family design or a transmitted/nontransmitted PGS design. Results indicate significant direct effects on aggression for the PGSs based on early-life aggression, educational attainment, and ADHD, although explained variance was low (within- and between-family: early-life aggression R2 = 0.3%, early-life ADHD R2 = 0.6%, educational attainment R2 = 0.7%; transmitted/nontransmitted PGSs: early-life aggression R2 = 0.2%, early-life ADHD R2 = 0.9%, educational attainment R2 = 0.5%). ConclusionsPGSs included in the current study had a direct (but no indirect) effect on aggression, consistent with results of previous twin and family studies. Further research involving other PGSs for aggression and related phenotypes is needed to determine whether this conclusion generalizes to overall genetic influences on aggression.

Conditional indirect genetic effects of caregivers on brood in the clonal raider ant.

Caregivers shape the rearing environment of their young. Consequently, offspring traits are influenced by the genes of their caregivers via indirect genetic effects (IGEs). However, the extent to which IGEs are modulated by environmental factors, other than the genotype of social partners (i.e., intergenomic epistasis), remains an open question. Here we investigate how brood are influenced by the genotype of their caregivers in the clonal raider ant, Ooceraea biroi, a species in which the genotype, age and number of both caregivers and brood can be experimentally controlled. First, we used four clonal lines to establish colonies that differed only in the genotype of caregivers and measured effects on foraging activity, as well as IGEs on brood phenotypes. In a second experiment, we tested whether these IGEs are conditional on the age and number of caregivers. We found that caregiver genotype affected the feeding and foraging activity of colonies, and influenced the rate of development, survival, body size, and caste fate of brood. Caregiver genotype interacted with other factors to influence the rate of development and survival of brood, demonstrating that IGEs can be conditional. Thus, we provide an empirical example of phenotypes being influenced by IGE-by-environment interactions beyond intergenomic epistasis, highlighting that IGEs of caregivers/parents are alterable by factors other than their brood's/offspring's genotype.

Genetic variance and indirect genetic effects for affiliative social behavior in a wild primate.

Affiliative social behaviors are linked to fitness components in multiple species. However, the role of genetic variance in shaping such behaviors remains largely unknown, limiting our understanding of how affiliative behaviors can respond to natural selection. Here, we employed the "animal model" to estimate environmental and genetic sources of variance and covariance in grooming behavior in the well-studied Amboseli wild baboon population. We found that the tendency for a female baboon to groom others ("grooming given") is heritable (h2 = 0.22 ± 0.048), and that several environmental variables-including dominance rank and the availability of kin as grooming partners-contribute to variance in this grooming behavior. We also detected small but measurable variance due to the indirect genetic effect of partner identity on the amount of grooming given within dyadic grooming partnerships. The indirect and direct genetic effects for grooming given were positively correlated (r = 0.74 ± 0.09). Our results provide insight into the evolvability of affiliative behavior in wild animals, including the possibility for correlations between direct and indirect genetic effects to accelerate the response to selection. As such they provide novel information about the genetic architecture of social behavior in nature, with important implications for the evolution of cooperation and reciprocity.

Polygenic score: An anchor holding the whole life course.

Polygenic score: An anchor holding the whole life course.

Maternal depression and the polygenic p factor: A family perspective on direct and indirect effects

Within-family studies typically assess indirect genetic effects of parents on children, however social support theory points to a critical role of partners and children on women's depression. To address this research gap and account for the high heterogeneity of depression, we calculated a general psychiatric factor using eleven major psychiatric polygenic scores (polygenic p), in up to 25,000 parent-offspring trios from the Norwegian Mother, Father and Child Cohort Study (MoBa). Multilevel modeling of trio polygenic p was used to distinguish direct and indirect genetic effects on mothers depression during pregnancy (gestational age 17 and 30 weeks), infancy (6 months, 18 months) and early childhood (3 years, 5 years, and 8 years). We found mothers polygenic p predicts their depression symptoms (b = 0.092; 95 % CI [0.087,0.098]), outperforming prediction using a single major depressive disorder polygenic score (b = 0.070, 95 % CI [0.066,0.075]). Jointly modeling trio polygenic p revealed indirect genetic effects of fathers (b = 0.022, 95 % CI [0.014,0.030]) and children (b = 0.021, 95 % CI [0.010,0.037]) on mothers' depression. Our results support the generalizability of polygenic effects across mental health and highlight the role of close family members on women's depression.

Do environmental effects indexed by parental genetic variation influence common psychiatric symptoms in childhood?

Parental genes may indirectly influence offspring psychiatric outcomes through the environment that parents create for their children. These indirect genetic effects, also known as genetic nurture, could explain individual differences in common internalising and externalising psychiatric symptoms during childhood. Advanced statistical genetic methods leverage data from families to estimate the overall contribution of parental genetic nurture effects. This study included up to 10,499 children, 5990 mother–child pairs, and 6,222 father–child pairs from the Norwegian Mother Father and Child Study. Genome-based restricted maximum likelihood (GREML) models were applied using software packages GCTA and M-GCTA to estimate variance in maternally reported depressive, disruptive, and attention-deficit hyperactivity disorder (ADHD) symptoms in 8-year-olds that was explained by direct offspring genetic effects and maternal or paternal genetic nurture. There was no strong evidence of genetic nurture in this sample, although a suggestive paternal genetic nurture effect on offspring depressive symptoms (variance explained (V) = 0.098, standard error (SE) = 0.057) and a suggestive maternal genetic nurture effect on ADHD symptoms (V = 0.084, SE = 0.058) was observed. The results indicate that parental genetic nurture effects could be of some relevance in explaining individual differences in childhood psychiatric symptoms. However, robustly estimating their contribution is a challenge for researchers given the current paucity of large-scale samples of genotyped families with information on childhood psychiatric outcomes.

Dyslipidemia and Risk of Preeclampsia: A Multiancestry Mendelian Randomization Study.

Preeclampsia is a leading cause of maternal morbidity, and dyslipidemia has been associated with preeclampsia in observational studies. We use Mendelian randomization analyses to estimate the association between lipid levels, their pharmacological targets, and the risk of preeclampsia in 4 ancestry groups. We extracted uncorrelated (R2<0.001) single-nucleotide polymorphisms strongly associated (P<5×10-8) with LDL-C (low-density lipoprotein cholesterol), HDL-C (high-density lipoprotein cholesterol), and triglycerides from genome-wide association studies of European, admixed African, Latino, and East Asian ancestry participants. Genetic associations with risk of preeclampsia were extracted from studies of the same ancestry groups. Inverse-variance weighted analyses were performed separately for each ancestry group before they were meta-analyzed. Sensitivity analyses were conducted to evaluate bias due to genetic pleiotropy, demography, and indirect genetic effects. The meta-analysis across 4 ancestry groups included 1.5 million subjects with lipid measurements, 7425 subjects with preeclampsia, and 239 290 without preeclampsia. Increasing HDL-C was associated with reduced risk of preeclampsia (odds ratio, 0.84 [95% CI, 0.74-0.94]; P=0.004; per SD increase in HDL-C), which was consistent across sensitivity analyses. We also observed cholesteryl ester transfer protein inhibition-a drug target that increases HDL-C-may have a protective effect. We observed no consistent effect of LDL-C or triglycerides on the risk of preeclampsia. We observed a protective effect of elevated HDL-C on risk of preeclampsia. Our findings align with the lack of effect in trials of LDL-C modifying drugs but suggest that HDL-C may be a new target for screening and intervention.

Indirect genetic effects for social network structure in Drosophila melanogaster.

The position an individual holds in a social network is dependent on both its direct and indirect social interactions. Because social network position is dependent on the actions and interactions of conspecifics, it is likely that the genotypic composition of individuals within a social group impacts individuals' network positions. However, we know very little about whether social network positions have a genetic basis, and even less about how the genotypic makeup of a social group impacts network positions and structure. With ample evidence indicating that network positions influence various fitness metrics, studying how direct and indirect genetic effects shape network positions is crucial for furthering our understanding of how the social environment can respond to selection and evolve. Using replicate genotypes of Drosophila melanogaster fruit flies, we created social groups that varied in their genotypic makeup. Social groups were videoed, and networks were generated using motion-tracking software. We found that both an individual's own genotype and the genotypes of conspecifics in its social group affect its position within a social network. These findings provide an early example of how indirect genetic effects and social network theory can be linked, and shed new light on how quantitative genetic variation shapes the structure of social groups. This article is part of a discussion meeting issue 'Collective behaviour through time'.

Why we need families in genomic research on developmental psychopathology.

Fundamental questions about the roles of genes, environments, and their interplay in developmental psychopathology have traditionally been the domain of twin and family studies. More recently, the rapidly growing availability of large genomic datasets, composed of unrelated individuals, has generated novel insights. However, there are major stumbling blocks. Only a small fraction of the total genetic influence on childhood psychopathology estimated from family data is captured with measured DNA. Moreover, genetic influence identified using DNA is often confounded with indirect genetic effects of relatives, population stratification and assortative mating. The goal of this paper is to review how combining DNA-based genomic research with family-based quantitative genetics helps to address key issues in genomics and push knowledge further. We focus on three approaches to obtaining more accurate and novel genomic findings on the developmental aetiology of psychopathology: (a) using knowledge from twin and family studies, (b) triangulating with twin and family studies, and (c) integrating data and methods with twin and family studies. We support the movement towards family-based genomic research, and show that developmental psychologists are particularly well-placed to contribute hypotheses, analysis tools, and data.

Decomposing heritability and genetic covariance by direct and indirect effect paths.

Estimation of heritability and genetic covariance is crucial for quantifying and understanding complex trait genetic architecture and is employed in almost all recent genome-wide association studies (GWAS). However, many existing approaches for heritability estimation and almost all methods for estimating genetic correlation ignore the presence of indirect genetic effects, i.e., genotype-phenotype associations confounded by the parental genome and family environment, and may thus lead to incorrect interpretation especially for human sociobehavioral phenotypes. In this work, we introduce a statistical framework to decompose heritability and genetic covariance into multiple components representing direct and indirect effect paths. Applied to five traits in UK Biobank, we found substantial involvement of indirect genetic components in shared genetic architecture across traits. These results demonstrate the effectiveness of our approach and highlight the importance of accounting for indirect effects in variance component analysis of complex traits.

Direct and indirect genetic effects of a social supergene.

Indirect genetic effects describe phenotypic variation that results from differences in the genotypic composition of social partners. Such effects represent heritable sources of environmental variation in eusocial organisms because individuals are typically reared by their siblings. In the fire ant Solenopsis invicta, a social supergene exhibits striking indirect genetic effects on worker regulation of colony queen number, such that the genotypic composition of workers at the supergene determines whether colonies contain a single or multiple queens. We assessed the direct and indirect genetic effects of this supergene on gene expression in brains and abdominal tissues from laboratory-reared workers and compared these with previously published data from field-collected prereproductive queens. We found that direct genetic effects caused larger gene expression changes and were more consistent across tissue types and castes than indirect genetic effects. Indirect genetic effects influenced the expression of many loci but were generally restricted to the abdominal tissues. Further, indirect genetic effects were only detected when the genotypic composition of social partners differed throughout the development and adult life of focal workers, and were often only significant with relatively lenient statistical cutoffs. Our study provides insight into direct and indirect genetic effects of a social supergene on gene regulatory dynamics across tissues and castes in a complex society.

Disentangling the causal relationship between rabbit growth and cecal microbiota through structural equation models

BackgroundThe effect of the cecal microbiome on growth of rabbits that were fed under different regimes has been studied previously. However, the term “effect” carries a causal meaning that can be confounded because of potential genetic associations between the microbiome and production traits. Structural equation models (SEM) can help disentangle such a complex interplay by decomposing the effect on a production trait into direct host genetics effects and indirect host genetic effects that are exerted through microbiota effects. These indirect effects can be estimated via structural coefficients that measure the effect of the microbiota on growth while the effects of the host genetics are kept constant. In this study, we applied the SEM approach to infer causal relationships between the cecal microbiota and growth of rabbits fed under ad libitum (ADGAL) or restricted feeding (ADGR).ResultsWe identified structural coefficients that are statistically different from 0 for 138 of the 946 operational taxonomic units (OTU) analyzed. However, only 15 and 38 of these 138 OTU had an effect greater than 0.2 phenotypic standard deviations (SD) on ADGAL and ADGR, respectively. Many of these OTU had a negative effect on both traits. The largest effects on ADGR were exerted by an OTU that is taxonomically assigned to the Desulfovibrio genus (− 1.929 g/d, CSS-normalized OTU units) and by an OTU that belongs to the Ruminococcaceae family (1.859 g/d, CSS-normalized OTU units). For ADGAL, the largest effect was from OTU that belong to the S24-7 family (− 1.907 g/d, CSS-normalized OTU units). In general, OTU that had a substantial effect had low to moderate estimates of heritability.ConclusionsDisentangling how direct and indirect effects act on production traits is relevant to fully describe the processes of mediation but also to understand how these traits change before considering the application of an external intervention aimed at changing a given microbial composition by blocking/promoting the presence of a particular microorganism.