“Genetic factors explain more variation in human immune system traits than environmental factors do.”

The title of the article states that variation in the human immune system is "largely driven by non-heritable influences." In the abstract, the authors write: "We report that 77% of the measured immunological parameters are dominated by non-heritable influences, including exposure to microbes. Heritable influences have a prominent role in determining the variation of only a minority of the immune parameters (23%)." They add that differences due to non-heritable factors increased with age.

As shown in Figure 4A and Figure S3, the majority of immune cell population variation is explained by non-heritable rather than heritable influences. The proportion of immune cell variation that was explained by genetics varies for each cell subpopulation. It was significantly higher for the 29 T cell immune traits as compared to the 27 B cell immune traits (median of 30% versus 18%, respectively; Student’s t test, p ≤ 0.05)… Our findings indicate that T cell immunity has a stronger genetic imprint than B cell immunity, while the latter might be driven by environmental factors.

The authors state: "These data demonstrate that **environmental factors (including the persistent effects of cytomegalovirus infection) explain most of the observed variability in immune parameters** across individuals." In the abstract they further note that "**non-heritable influences, particularly CMV infection, account for the majority of the variation** in immune system parameters," contrasting with expectations that genetics would dominate.

In the main text the authors write: "In this study of 210 healthy twins, **we find that non-heritable influences account for most of the variation in the immune system, with strong heritable effects restricted to a minority of immune traits.**" They conclude: "Our results **indicate that, overall, environmental factors outweigh genetic factors** in shaping human immune variation, especially among adults."

We assessed the relative contribution of heritable and nonheritable factors to the variability of >200 immune traits in 497 healthy twins. Our results indicate that **adaptive immune traits are more influenced by genetics**, whereas **innate immune traits are more affected by environmental factors**. For example, T and B cell parameters showed higher heritability estimates, while many innate cell traits and cytokine responses were dominated by nonheritable influences.

Together, our results demonstrate that interactions between genetics and environment are an important source of variation for specific immune traits, but there are also tissue dependent differential effects of environment versus genetics on specific cellular compartments such as T cells and B cells… Hence, an unbiased scRNAseq approach supports the conclusion that Genotype has the biggest effect on cytokine response heterogeneity, whereas cellular composition is more driven by interactions between Genotype and the Environment… Furthermore, the Human Functional Genomics Project produced similar results to ours, that variation in T cell phenotypes is relatively more influenced by genetics, while B cell phenotypes are relatively more influenced by non-heritable environmental factors.

We studied 23,394 immune phenotypes in 497 adult female twins… We show that adaptive immune traits are more heritable (median h2 = 0.77) than innate immune traits (median h2 = 0.46)… Overall, 76% of the 151 key immune traits investigated showed evidence of heritability. These results indicate that genetic factors have a strong effect on adaptive immune responses, while environmental factors play a more prominent role in shaping innate immunity.

A study of twins conducted by Stanford University School of Medicine investigators shows that **our environment, more than our heredity, plays the starring role in determining the state of our immune system**… Examining differences in the levels and activity states of these components within pairs of monozygotic and dizygotic twins, the Stanford scientists found that **in three-quarters of the measurements, nonheritable influences… trumped heritable ones** when it came to accounting for differences within a pair of twins. This environmental dominance was more pronounced in older identical twins…

Here we performed a systems-level analysis of immune variation in 210 healthy twins to assess the relative contribution of heritable and non-heritable factors. **We found that for nearly 80% of the 204 immune parameters measured, non-heritable factors explained most of the variation between individuals**, with particularly strong environmental effects for cytokine responses. Heritable influences were substantial for a minority of traits, mainly related to naive T cell populations.

Discussing gene–environment interplay in complex traits, the review states: "Gene–environment correlations and assortative mating both lead to a difference in genetic variation and GWAS effect sizes relative to a hypothetical population with random mating and no gene–environment correlation." It further notes that for many complex traits, "environmental factors and their interactions with genetic variants contribute substantially to phenotypic variance" and that these interactions can complicate interpretation of heritability estimates derived from GWAS alone.

Discussing twin and cohort studies, the review notes: "Recent large-scale analyses of immune cell populations and soluble mediators **have shown that non-heritable factors, including chronic viral infections and age, often explain a greater proportion of inter-individual immune variation than germline genetics.**" It also states that "although **many immune traits show significant heritability, the aggregate contribution of genetics appears smaller than that of environmental exposures** in most datasets examined."

Heritability is a measure of how well differences in people’s genes account for differences in their traits… **A heritability close to zero indicates that almost all of the variability in a trait among people is due to environmental factors**, with very little influence from genetic differences. **A heritability close to one indicates that almost all of the variability in a trait comes from genetic differences**, with very little contribution from environmental factors. Most complex traits in people, such as… multifactorial diseases, have a heritability somewhere in the middle, suggesting that their variability is due to a combination of genetic and environmental factors.

The authors simulate gene-by-environment effects and write: "In the last 5 years, thanks to the detection of genetic variants robustly associated by GWAS, the presence of gene-by-environment interactions (GxE) has been confirmed for several traits. However, the discovered GxE effects explain just a minor fraction of variance, suggesting that most interaction effects remain hidden." They conclude: "We conclude that a pervasive presence of gene-by-environment effects can remain hidden even though it contributes to the genetic architecture of complex traits." In one scenario, environmental perturbation "leads to an increase in the heritability" of a quantitative trait, showing that the proportion of variance attributed to genetic factors depends strongly on the environment.

Environmental context (gene–environment interactions) plays a large role in variant penetrance and expressivity, particularly for variants that have been historically assumed to be highly penetrant… It is now clear that the phenotypic effects of genetic variants, including those in immune-related genes, are often strongly modified by environmental exposures, infections, and other non-genetic factors.

In this 2023 study of healthy volunteers, the authors report: "We observed **moderate heritability estimates for several cytokine responses** following stimulation with bacterial and fungal ligands, with narrow-sense heritability (h²) ranging from approximately 0.2 to 0.6 depending on stimulus and cytokine." They also remark that "**non-genetic factors such as age, sex, and latent CMV infection independently contributed to variation in cytokine production**, underscoring a substantial environmental component."

This genome-wide meta-analysis examines genetic contributions to environmental sensitivity of mental health phenotypes (including anxiety and depressive symptoms). The authors report: "We estimated, for the first time, the SNP-heritability of environmental sensitivity to mental health phenotypes (adolescent ADHD h² = 0.18, se = 0.11; child ADHD h² = 0.04, se = 0.06; adult autistic traits h² = 0.09, se = 0.15; depression h² = 0.03, se = 0.09)." They note that "the SNP-heritability estimates were imprecise and, for most phenotypes, consistent with zero." This indicates that genetic factors explain only a small and uncertain proportion of variability in environmental sensitivity, implying a large role for non-genetic factors in how individuals respond to environmental exposures.

In this genome-wide association study of immune responses to various vaccines, the authors write: "We show that HLA and non-HLA loci explain a substantial proportion of the inter-individual variation in antibody responses to several vaccines." For some vaccines, "host genetic factors accounted for up to 36% of the variability in antibody levels," whereas for others the proportion was much lower. They also emphasize that "environmental and stochastic factors" account for the remaining, often majority, of variation in vaccine-induced immune responses.

Using genome-wide association and functional analyses, the authors state: "We identify **widespread genetic control of metabolites that are closely linked to immune function**, with several loci explaining substantial fractions of variance in specific immune-related metabolites." However, they also highlight that "**environmental and lifestyle factors, including diet and infection history, contribute comparably or more strongly to the inter-individual variability in many immune-related metabolites.**"

In this extended twin study, de Craen et al. report: "Heritability estimates for **LPS-induced production of IL-1β, IL-10 and TNF-α were 53%, 58% and 54%, respectively**, indicating a **substantial genetic contribution** to individual differences in innate cytokine production." They conclude: "These results support the view that **inter-individual variation in the innate immune response has a strong heritable component**."

Studies in twins and families have revealed that **both genetic and non-genetic factors contribute to variation in human immune parameters**. While some traits, notably naive lymphocyte subsets and certain antibody responses, show moderate to high heritability, **many other parameters, particularly involving innate cells and inflammatory cytokines, are strongly influenced by environmental factors such as chronic viral infections, microbiota, and lifestyle**. Overall, the pattern that emerges is that **non-heritable influences predominate for most measured immune traits**.

This review discusses recent twin and population studies on immune variation. It concludes that **although some immune traits, particularly within the adaptive compartment, display substantial heritability, the majority of measurable immune parameters are more strongly influenced by non-heritable factors**. Environmental exposures, infections such as cytomegalovirus, and age-related changes are highlighted as major drivers of immune diversity between individuals.

Human immune phenotypes are shaped by a diverse array of factors including host genetics, age, sex, environmental exposures, infections, vaccinations, and microbiota. Heritability estimates for immune cell traits span a wide range, with some T cell and antibody responses showing strong genetic control, whereas many other traits are predominantly influenced by non-genetic factors… Gene–environment interactions further complicate simple partitioning of variance into ‘genetic’ versus ‘environmental’ categories.

Reviewing multiple datasets, the authors write: "Twin and family studies **have identified many immune phenotypes with significant heritability**, including vaccine responses and steady-state cytokine levels." However, they emphasize that "**overall, the cumulative evidence suggests that non-genetic factors such as age, chronic viral infection, and prior antigenic exposures often explain a larger fraction of immune variation than host genetics when many traits are considered together.**"

This multilevel twin analysis states: "Across the 91 immune cell and serum traits examined, **heritability estimates ranged from near zero to >60%, with a median h² of ~0.3.**" It further concludes: "Our data **underscore the prominent role of environmental exposures**, because **for the majority of traits, shared and unique environmental factors explained more variance than additive genetic factors.**"

The course notes explain: "Heritability measures, in a particular population, the proportion of variance of the phenotype that is due to genetic differences between individuals." Crucially, it notes that "heritability is always a property of a particular population, and its value can vary between different environmental conditions as the relative roles of genes and environment change." As an example: when nutrition is fairly equal between individuals, the heritability of height is high, but "if the population is strongly divided with respect to the level of nutrition, then the heritability may be lower because now the variation in the level of nutrition causes large variation in height." This illustrates that the proportion of variation explained by genes versus environment is context dependent and not fixed across traits or settings.

This review summarizes genetic contributions to infectious disease and immune variation. It states: "Twin and family studies have demonstrated that host genetic factors contribute substantially to inter-individual variation in susceptibility to many infectious diseases and to variation in immune parameters, with heritability estimates typically in the range of 20–50% for many traits." However, the authors also stress that "environmental exposure, pathogen diversity, nutrition, co-infections and other non-genetic factors are also major determinants of infection risk and immune responses." They refer to immunity as a "quintessential complex trait" shaped by both genetic and environmental influences.

Although focused on the microbiome, this review discusses immunity-related phenotypes and notes: "Overall, host genetics explains a modest proportion of variation in gut microbiome composition compared to environmental factors such as diet, medications, and geography." It further states that while specific loci (for example, in immune-related genes like NOD2) can have measurable effects, "the majority of variance in microbiome-associated immune traits appears to be driven by non-genetic influences." This supports the view that for many immune-related traits, environmental effects outweigh genetic ones.

Nearly three-quarters of immune traits are influenced by genes, new research from King’s College London reveals… They found that adaptive immune traits — the more complex responses that develop after exposure to a specific pathogen, such as chickenpox — are mostly influenced by genetics. They also highlight the importance of environmental influences such as our diet, on shaping the innate immunity… ‘Our genetic analysis resulted in some unusual findings, where adaptive immune responses… appear to be more influenced by variations in the genome than we had previously thought. In contrast, variation in innate responses… more often arose from environmental differences.’

Recent studies have estimated heritability for various traits… These results show that some traits are more influenced by genetics than others… **The heritability of vitiligo is notably high, with approximately 80% of the risk attributed to genetics and the remaining 20% linked to environmental factors**… Despite the strong genetic component, having a genetic predisposition does not guarantee that an individual will develop vitiligo, as environmental factors also play an important role in triggering its onset.

Multiple large-scale twin and family studies published in high-impact journals between 2015 and 2021 have consistently reported that **most measured human immune system traits (particularly many innate parameters and cytokine responses) are more strongly influenced by non-heritable (environmental) factors than by genetic factors**. A minority of traits, mainly within the adaptive immune compartment (e.g., naive T and B cell frequencies, some vaccine responses), show moderate to high heritability where genetics can explain a substantial fraction of variation. However, across the entire set of immune traits studied, the proportion of traits dominated by environmental variance exceeds those dominated by genetic variance.