Chapter 4: Genetics and Epigenetics—Innate Susceptibility and Gene-Environment Interaction

Four-Level Interaction Framework Positioning: This chapter corresponds to the genetic mutation layer—the first layer of the Four-Level Interaction Framework. Genetic variations (SNPs, CNVs, de novo mutations) provide the "innate susceptibility" for psychiatric disorders, but genes are not destiny—they interact with environmental factors through epigenetic mechanisms, collectively determining whether an individual develops the disorder.

Chapter 2 introduced the basic concepts of genes. Building upon that, this chapter delves into three key questions: How do genetic variations affect the risk of psychiatric disorders? How do environmental factors regulate gene expression without altering the DNA sequence (epigenetics)? How do genes and the environment interact to shape mental health?

Before exploring how genetics and the environment shape us, it is necessary to first clarify a fundamental psychological concept: Temperament. In psychology, temperament does not refer to what is colloquially called "grace" or "charm," but specifically to those innate psychodynamic characteristics that are primarily determined by genetic and physiological factors. It is a relatively stable personality disposition that manifests early in an individual's life, serving as the "biological foundation" of personality, so to speak. Temperament determines the speed, intensity, and flexibility of our mental activities. Understanding the innate nature of temperament helps us better comprehend how genetics sets the stage for mental health.

4.1 Genetics: The Inheritance of Life, and a Prelude to Destiny

Genetics studies how life is inherited and varied. Everyone inherits a unique genome from their parents, which determines basic characteristics and pre-sets a "susceptibility" to certain diseases.

• Genes and Heritable Traits: Genes influence the expression of various traits by encoding proteins—eye color, blood type, height, and even certain behavioral tendencies are all influenced by genes. Psychiatric disorders are also heritable; individuals with a family history of illness face a relatively higher risk.
• Polygenic Inheritance: Most complex traits and disorders, including psychiatric disorders, are not determined by a single gene, but are the result of the combined action of minor variations in multiple genes. The contribution of each individual gene might be negligible, but their accumulation, fueled by environmental factors, determines the final outcome.
• Heritability: Heritability is a statistical concept that measures what proportion of the variation in a certain trait or disease within a specific population and environment can be attributed to genetic factors. The heritability of schizophrenia is approximately 80%, bipolar disorder is 70%–80%, and major depressive disorder is 40%–50%. This means that while genes play a crucial role in the occurrence of psychiatric disorders, they are not the sole factor.

4.2 Epigenetics: The "Switch" of Gene Expression, and the Imprint of the Environment

Epigenetics studies how gene expression is regulated without changing the DNA sequence itself. Epigenetic modifications act like "switches" for genes, determining whether a gene is expressed or silenced, thereby affecting cellular functions and individual traits.

• Primary Mechanisms:
  • DNA Methylation: One of the most common epigenetic modifications. It involves adding methyl groups to specific locations on DNA molecules, typically leading to gene silencing.
  • Histone Modification: Inside the nucleus, DNA winds around histones to form chromatin. Chemical modifications of histones (such as acetylation and methylation) can alter chromatin structure, thereby affecting gene accessibility and expression.
  • Non-coding RNA: Certain RNA molecules that do not encode proteins (such as microRNAs) regulate gene expression by binding to mRNA or directly acting on chromatin.
• Environmental Imprints: Epigenetic modifications serve as an important bridge for gene-environment interactions. Environmental factors (diet, stress, toxin exposure, childhood trauma, etc.) can induce long-lasting epigenetic modifications early in life or even during adulthood. These modifications affect brain development, neural circuit function, and stress response systems, thereby increasing the risk of psychiatric disorders. For instance, childhood adversity can increase the risk of depression and anxiety in adulthood by altering the methylation patterns of stress-response genes.
• Reversibility and Transgenerational Inheritance: Unlike the relative stability of DNA sequences, epigenetic modifications are reversible to some extent, meaning that interventions (such as environmental enrichment or pharmacological treatment) could potentially alter adverse epigenetic imprints. Furthermore, some epigenetic modifications can even be inherited across generations, affecting the health of offspring.

4.3 Gene-Environment Interaction: The Intertwining of Nature and Nurture

The debate over "nature versus nurture" has a long history in life sciences. Today, we know that it is a complex and dynamic interaction between genes and the environment. Gene-environment interaction (GxE) refers to how individuals with a specific genotype react differently to a particular environmental exposure compared to individuals with other genotypes exposed to the same environment.

• Susceptibility and Triggers: Genes can make a person particularly "sensitive" to certain environmental factors, and specific environmental exposure can then become the "trigger" for the onset of a disorder. For example, individuals carrying a certain genetic variant may have a significantly elevated risk of developing depression after experiencing major life stress events.
• Protection and Resilience: Not all gene-environment interactions are negative. Certain genotypes may enable individuals to exhibit greater resilience in adverse environments, regulating stress responses more effectively.
• Implications for Psychiatric Disorders: The GxE model explains why not everyone carrying risk genes becomes ill, and why different individuals have different outcomes under the same adverse environment. This underscores the need to simultaneously consider genetic background and environmental factors in the prevention and treatment of psychiatric disorders.

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A More Precise Understanding of "Susceptibility":

In the context of psychiatric disorders, a more precise expression of the term "susceptibility" should be the "propensity for episodes." An individual may carry extremely high psychiatric risks at the genetic, neurostructural, or even neurotransmitter metabolic levels; however, if they live in a social environment that serves as a specific "comfort zone" where the "socio-environmental triggers" for psychiatric episodes are minimal, they may not necessarily experience an episode, even with high physiological and genetic risks. Thus, the genetic susceptibility of psychiatric disorders should be understood as genetic susceptibility to episode onset.

4.4 Disease-Specific Manifestations of Genetic Susceptibility to Episodes

4.4.1 Bipolar Disorder: The Psychiatric Disorder with the Highest Heritability

Bipolar disorder is one of the disorders with the highest heritability among all psychiatric disorders, with heritability reaching 60%–85%.

• Family Aggregation: Having a first-degree relative with bipolar disorder increases one's own risk by approximately 10-fold.
• Polygenic Architecture: A large-scale GWAS study in 2025 identified nearly 300 genetic loci and 36 unique genes most likely to be associated.
• Key Risk Genes: CACNA1C (encoding a voltage-gated calcium channel subunit) and ANK3 (encoding ankyrin-G) are closely linked to neuronal excitability, synaptic function, and cytoskeletal stability.
• Genetic Overlap: Bipolar disorder shares risk genes with schizophrenia and major depressive disorder (Cross-Disorder Group of the Psychiatric Genomics Consortium, 2019, Cell).
• Subtype Differences: Bipolar I has a heavier genetic load and shows greater genetic overlap with schizophrenia.

Gene-Environment Interaction in Bipolar Disorder: Individuals carrying risk genes have a significantly higher risk of onset after experiencing major life stress events compared to non-carriers. Epigenetic mechanisms provide a molecular-level explanation for this interaction.

Clinical Implications: For patients diagnosed with bipolar disorder, genetic factors are the most critical causal factors, making healthy reproduction and parenting a serious consideration.

4.4.2 Major Depressive Disorder (MDD): Moderate Heritability, High Environmental Interaction

The heritability of depression is approximately 40%, lower than that of bipolar disorder, meaning environmental factors carry greater weight in the onset of depression.

• Polygenic Architecture: GWAS has identified hundreds of risk loci, revealing gene enrichment related to postsynaptic density and receptor clustering.
• 5-HTTLPR Polymorphism: The most famous GxE study showed that individuals carrying the short allele have a significantly higher risk of depression after experiencing life stress compared to carriers of the long allele (Caspi et al., 2003, Science).

4.4.3 Schizophrenia: The Psychiatric Illness with the Highest Heritability

The heritability of schizophrenia is as high as around 80%.

• High Genetic Risk: If one parent has the illness, the risk for their offspring is about 10%.
• Polygenic Disease: Involves the combined effects of minor variations across multiple genes.
• CNVs and Rare Variants: 22q11.2 deletion is an important risk factor for schizophrenia; though rare, it has a large effect size.
• Genetic Overlap with Bipolar Disorder: Shares some risk genes, but differs in patterns of neurodevelopmental abnormalities.

4.4.4 Eating Disorders (Anorexia Nervosa)

The heritability of anorexia nervosa is approximately 50%–60%.

• Family Aggregation: Individuals with a family history of eating disorders have a significantly increased risk of developing the illness.
• Association with Metabolic Genes: Recent GWAS studies have found associations between anorexia nervosa and metabolism-related genes, suggesting that it is not only a psychiatric disorder but also involves genetic abnormalities in metabolic regulation.

4.4.5 Substance Use Disorders (Including Alcohol)

The genetic contribution to substance use disorders is approximately 40%–60%.

• Reward System Genes: Polymorphisms in dopamine receptor genes (DRD2, DRD4) are associated with susceptibility to addiction.
• Metabolic Enzyme Genes: Genetic variations in alcohol-metabolizing enzymes (ADH, ALDH) affect the risk of alcohol dependence—this is precisely the genetic basis of the "Asian flush" phenomenon in East Asian populations, and it also serves as a protective factor.
• Shared Genetics Across Substances: The susceptibility to addiction for different substances shares a common genetic basis.

4.4.6 Summary of Heritability Across Disorders

Psychiatric Disorder	Heritability	Core Genetic Features	Key Risk Genes/Variants
Schizophrenia	~80%	Polygenic + CNVs	22q11.2 deletion, DRD2, etc.
Bipolar Disorder	60%–85%	Polygenic, one of the highest heritabilities	CACNA1C, ANK3
Anorexia Nervosa	50%–60%	Polygenic + metabolic genes	Metabolism-related genes
Alcohol Use Disorder	50%–60%	Reward system + metabolic enzymes	ADH, ALDH, DRD2
Substance Use Disorder	40%–60%	Reward system polygenic	DRD2, DRD4
Major Depressive Disorder (MDD)	~40%	Polygenic, high environmental interaction	5-HTTLPR, postsynaptic density genes

Key Insight: The higher the heritability, the greater the weight of biological interventions (pharmacotherapy, neuromodulation); the lower the heritability, the greater the weight of socio-environmental interventions (psychotherapy, social support). However, this by no means implies that disorders with high heritability do not need social support, or that disorders with low heritability do not require pharmacotherapy—the Four-Level Interaction Framework demands that we pay attention to all levels simultaneously.