Unmasking Etiologies of MDD

Major depressive disorder (MDD) – a global health challenge, is a leading cause of disability worldwide. MDD is a complex condition that stems from intrinsic biological, psychological, and social factors and is characterized by debilitating symptoms that severely impact daily functioning and the patient’s quality of life.

Over the past decade, genetic research using genome-wide association studies (GWAS) has made significant advances in psychiatric genetics. Recently, scientists have identified 178 genetic risk loci and over 200 candidate genes linked to MDD. Although monumental, this success poses a critical dilemma—most of the identified genetic signals may not be specific to MDD. This raises an important awareness challenge; genetic researchers are now highlighting why current methods risk misinterpreting the fundamental biological roots of depression.

Understanding MDD's Heterogeneity

Major Depressive Disorder is an umbrella term, and the condition encompasses diverse psychological impairments. Moreover, MDD refers to a highly heterogeneous group of disorders. Hence, an MDD diagnosis mandates the evidence of at least two weeks of clinically significant depressed mood or anhedonia (loss of interest/pleasure), along with four additional symptoms relating to the physical axis (like sleep or appetite disturbance), psychomotor changes, cognitive problems, or thoughts of death/suicide.

Additionally, the severity, clinical features, trajectory, and presentation of MDD vary widely. For instance, two patients being diagnosed with MDD—one may experience a persistently low mood, and the other may mostly show marked loss of interest/pleasure. That is, MDD may define two symptoms that reflect different underlying etiologies. Furthermore, about 75% of patients diagnosed with MDD meet criteria for at least one additional psychiatric disorder.

Notably, familial and twin studies consistently show that MDD is moderately heritable, with estimates ranging from 30-50%. Studies suggest that certain subtypes, such as recurrent MDD and early-onset MDD, exhibit higher heritability estimates compared to single-episode illnesses or cases identified in community samples.

Minimal Phenotyping and Gene Mapping

The recent surge in genetic discoveries, including the identification of 178 loci, was made possible by recruiting enormous cohorts (analyzing data from over 1.2 million participants in the largest study from 2021). To recruit studies on this vast scale, genetic researchers largely relied on "minimal phenotyping" strategies. These inexpensive and simple methods typically do not assess the complete diagnostic criteria required by established systems like the DSM (Diagnostic and Statistical Manual of Mental Disorders) or ICD (International Classification of Diseases). This entails using electronic health record (EHR) diagnosis codes, or relying on short surveys or single questions, such as asking if a person was ever "diagnosed with clinical depression" or "seen a general practitioner for nerves, anxiety, tension or depression".

The consequence of relying on minimal phenotyping is a loss of specificity in the genetic signal. Experts estimate that more than half of the cases identified using a single-item assessment are likely false positives. Even with short, two-to-three-item questionnaires, only four out of ten participants who score positive are actually depressed.

Therefore, much of the genetic signal identified using these broad approaches is not attributable to the specific clinical syndrome of MDD but, rather, to a vulnerability to general low mood or negative affect, a trait best termed dysphoria.

Non-Specific Genetic Risk

When genetic loci are identified using minimal phenotyping definitions of depression, they are often found to be non-specific, indexing traits beyond MDD. One clear example is the personality trait neuroticism.

High neuroticism scores are strongly associated with an increased risk for MDD. When loci are mapped via minimal phenotyping definitions, they contribute significantly to neuroticism. In fact, studies using minimal phenotyping have found a strong genetic correlation (rg) between MDD and neuroticism, ranging from 0.70 to 0.75. If researchers only characterize these non-specific loci, any corresponding treatments designed for MDD would likely also affect the personality trait of neuroticism.

This lack of specificity highlights a difference in heritability estimates based on diagnostic rigor. The SNP-based heritability (h2SNP) for minimal phenotyping definitions of MDD is lower than for well-defined cases. For instance, the heritability of severe recurrent depression is estimated to be around 25%, compared to less than 10% for symptom-based depression.

Core MDD Biology

While minimal phenotyping tends to reveal genetic signals related to general dysphoria and neurodevelopmental functions, studies focusing on severely defined cases, particularly those using the "gold standard" of structured interviews by clinically experienced interviewers, offer distinct biological clues.

The genetic component unique to MDD, which relates to the severe episodic shifts of mood and associated neurovegetative and cognitive changes, remains inaccessible to broad minimal phenotyping approaches.

In more rigorously defined samples, such as women with recurrent MDD meeting structured interview criteria, two genome-wide significant loci were identified and replicated. Candidate genes identified from these severe cohorts are enriched in mitochondrial function. Conversely, genes implicated by GWAS of dysphoria are enriched in neurodevelopmental functions. For example, the latter studies identified many genes associated with regulating gene transcription, neurodevelopment, and neuronal function, such as NEGR1 (neuronal growth regulator 1) and OLFM4 (olfactomedin 4).

In addition, MDD is profoundly influenced by environmental triggers. The effect of both genes and the environment, especially stressful life events (SLEs) and childhood trauma, is crucial and often interacts. Many candidate genes proven in genes and environmental (GxE) interactions, such as CRHR1 (corticotropin-releasing hormone receptor 1) and FKBP5 (FK506-binding protein 51), are connected directly to the activity of the Hypothalamus-Pituitary-Adrenal (HPA) axis, suggesting they help identify groups with altered stress sensitivity.

Conclusion

Major depressive disorder is a complex illness that occurs from multiple causes and due to interactions of environmental triggers with the individual’s genetic make-up. While large-scale genetic studies have uncovered hundreds of possible links, many of these signals are not specific to depression itself but to broader traits such as low mood or stress sensitivity. This means that the science is still evolving, and the interpretation of findings largely depends on the clinical findings.

Further, MDD shows heterogenous symptoms and this diversity makes it difficult to ascertain the exact biological causes. Thus, personalized approaches to diagnosis and treatment are essential and clinical expertise of the physician is valuable. Combining detailed clinical evaluations with careful genetic research can aid in improving diagnostic accuracy in this group of disorders.