Can epigenetics explain the missing heritability of complex diseases?

What is the 'missing heritability' problem, and why has it been so puzzling?

For many complex diseases like asthma, inflammatory bowel disease (IBD), and leukemia, family and twin studies have long suggested a strong heritable component—meaning that genetics play a big role in who gets sick. For asthma, heritability estimates range from 35% to 90% [3]. But when scientists ran large genome-wide association studies (GWAS) looking for common genetic variants, they could only explain a tiny fraction of that predicted heritability—less than 15% for asthma [3]. This huge gap between what family studies predicted and what GWAS found is the 'missing heritability problem.' It left researchers wondering: where is the rest of the genetic risk hiding?

The answer, it turns out, is not in one place. Recent evidence shows that the missing heritability is distributed across several layers: rare genetic variants (not captured by standard GWAS), epigenetic modifications (molecular changes that alter gene activity without changing the DNA sequence), and complex interactions between genes and the environment. No single factor explains it all.

Rare genetic variants explain a much larger share of heritability than previously believed

One major reason GWAS missed so much heritability is that they were designed to find common variants (those present in more than 1-5% of the population). But a landmark 2022 study on smoking behavior used whole-genome sequencing on over 26,000 people of European ancestry and 11,700 of African ancestry, and found that rare variants—those with minor allele frequencies between 0.01% and 1%—accounted for 35% to 74% of the total heritability across four smoking traits [2]. These rare variants boosted the heritability estimates to 1.5-4 times higher than what common-variant studies had found, and they explained 60% to 100% of the heritability predicted by family-based studies [2]. This means that for smoking, the missing heritability was largely hiding in rare genetic variants, not in epigenetic marks.

Similarly, in pediatric acute myeloid leukemia (AML), a 2024 study of 365 patients found that 26.3% harbored a pathogenic or likely pathogenic germline variant in a known or 'provocative' cancer gene [1]. Many of these variants are rare in the general population. The study also found that the burden of these germline variants was significantly higher in pediatric AML (8.6%) than in B-cell acute lymphoblastic leukemia (1.9%) or T-cell ALL (2.5%), suggesting that rare inherited variants play a bigger role in some cancers than others [1].

Epigenetics acts as a bridge between environment and genes, especially for early-life exposures

While rare variants explain a lot, they don't account for everything—especially for diseases where environmental triggers are known to be important. This is where epigenetics comes in. Epigenetic changes (like DNA methylation) can be influenced by diet, stress, smoking, and the microbiome, and these changes can alter gene activity in ways that increase disease risk. For example, in inflammatory bowel disease (IBD), over 200 genetic susceptibility loci have been identified, but they explain only a small fraction of disease variance [5]. The 2023 review argues that gene-environment interactions, acting through epigenetic mechanisms, likely contribute to the missing heritability—especially from early-life factors like the microbiome, nutrition, and tobacco smoke, which can imprint disease risk during a 'window of susceptibility' in infancy [5].

The same idea applies to asthma. A 2022 review notes that vertical maternal microbiome transfer and maternal immune factors during pregnancy can influence fetal immune development, potentially programming a pro-atopic state through epigenetic mechanisms [3]. The authors call for multi-omics approaches that integrate genetic, epigenetic, and environmental data to build accurate risk profiles [3]. This is not just theoretical: in pediatric AML, network analysis revealed that the chromatin modifiers EP300 and CREBBP—proteins that regulate gene expression through epigenetic mechanisms—are central hubs of disruption, and these same hubs are also targets of somatic (non-inherited) mutations and environmental influences [1]. This suggests that epigenetic disruption can mimic or amplify genetic risk.

Environmental exposures can become 'embodied' through epigenetic changes, contributing to disease risk

A 2021 commentary on epigenomics and health disparities makes a powerful point: for most chronic diseases, the environment plays a role nearly equal to genetics [4]. The authors note that a meta-analysis of 2,748 twin studies found the contribution of environment was nearly equal to that of genetics across 17,804 human traits [4]. Epigenetic research offers a way to study how social and physical environments 'get under the skin' to affect biology. For example, studies have linked maternal anxiety and depression during pregnancy to DNA methylation changes in the glucocorticoid receptor gene (NR3C1), a key stress-regulating gene [4]. This means that a mother's stress can leave an epigenetic mark on her child that may influence later disease risk—a form of non-genetic heritability.

However, the same commentary warns that the field is still in its early stages. Many studies have small sample sizes, and results are not always replicable. For instance, associations between childhood adversity and DNA methylation of NR3C1 and FKBP5 (another stress-related gene) could not be replicated in a study of 1,000 Black women [4]. This highlights that while epigenetics is a promising mechanism, it is not a simple or universal explanation for missing heritability. The evidence is strongest when epigenetic changes are linked to specific, measurable environmental exposures (like smoking or nutrition) and when studied in large, diverse populations.

Sources used in this answer

Related research questions