Psychiatric Genetics and Phenotypes

Psychiatric Genetic Mapping Challenges

• Disappointment in psychiatric genetic mapping studies has led to scrutiny on defining and assessing phenotypes.
• Current studies largely depend on categorical disease diagnoses from the DSM-5 classification.
• Two main criticisms of the diagnostic classification system:
  • Psychiatric diagnoses are often based on subjective clinical evaluations, complicating the ascertainment of affected individuals.
  • Even with clear diagnoses, individuals with the same disorder may exhibit diverse, nonoverlapping symptoms, reflecting different underlying causes (etiologies).

Shift to Continuous Trait Mapping

• Concerns regarding diagnosis-based phenotyping have increased interest in mapping heritable traits with continuous variation.
• Continuous measures relevant to psychiatric disorders may include:
  • Biochemical levels (e.g., neurotransmitter metabolites, hormone levels).
  • Cognitive assessments and personality tests.
  • Brain structure and function imaging.
  • Biophysical markers like evoked potentials.
  • Molecular techniques including gene expression profiling.

Categorical Phenotyping

• DSM diagnoses remain the most prevalent categorical phenotypes in psychiatric studies.
• Some studies focus on singular DSM diagnoses, whereas others encompass a range of diagnoses, especially for disorders thought to be part of a single spectrum (e.g., mood disorders).
• Key methods for standardizing diagnostic criteria:
  • Utilizing experienced clinicians and training them on specific diagnostic tools.
  • Implementing a "best estimate" approach using comprehensive information such as interviews and medical records.
  • Consensus diagnosis, where multiple diagnosticians review and agree on diagnoses to ensure accuracy.

Sample Selection and Phenotype Redefinition

• Effective studies leverage genetic epidemiology data to select affected individuals.
• Disorders may exhibit varying Mendelian inheritance patterns, suggesting the need to identify significant loci for genes influencing the phenotype.
• Enhancing the mapping process can involve narrowing the phenotype definition; for example:
  • Alzheimer’s studies benefitted from focusing on individuals with early-onset cases (before age 65), which followed an autosomal dominant inheritance.
• Other criteria for refining phenotypes can include ethnic background, age of onset, treatment responses, symptom severity, or comorbid disorders.

Broadening vs. Narrowing the Phenotype

• Although narrowing the phenotype can improve genetic defect discovery chances, it may decrease study power due to fewer eligible affected individuals.
• Suggestion arises that broadening the phenotype might be beneficial for certain complex diseases to include additional phenotypes within a disease spectrum, enhancing the statistical power for gene mapping.