Mental illnesses, encompassing disorders like schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, and attention-deficit hyperactivity disorder, affect millions worldwide, imposing significant personal and societal burdens. Recent advances in psychiatric genetics have illuminated their heritable nature, revealing that these conditions arise from complex interactions between genetic predispositions and environmental factors. Heritability estimates range from 30-80 per cent, with disorders like schizophrenia showing up to 80 per cent genetic influence.
Dr Alok Kulkarni
Unlike Mendelian diseases, psychiatric disorders are highly polygenic, involving thousands of common genetic variants with small effects, alongside rarer variants that confer greater risk. Genome-wide association studies (GWAS) have identified hundreds of loci, but these explain only a fraction of the variance, highlighting the ‘missing heritability’ puzzle, partly resolved by gene-environment interplay and pleiotropy—where genes influence multiple traits. This shared genetic architecture underscores why disorders often co-occur, challenging traditional diagnostic boundaries and paving the way for dimensional approaches to mental health.
What renders certain individuals vulnerable to psychiatric disorders? Vulnerability stems from a multifactorial model where genetic risk accumulates across the genome. Polygenic risk scores (PRS), which aggregate the effects of numerous genetic variants, can predict susceptibility, explaining about 5-10 per cent of variance in conditions like schizophrenia. For instance, first-degree relatives of those with bipolar disorder or schizophrenia face a 6-10 times higher risk due to familial aggregation.
Rare copy number variations (CNVs) and protein-truncating genetic variants amplify this risk, particularly in neurodevelopmental disorders like autism, where they disrupt synaptic function and brain development. Environmental stressors, such as childhood adversity or urban living, interact with these genetic factors, exacerbating vulnerability. Genetic risk for schizophrenia, for example, correlates with urban relocation.
This gene-environment synergy means no single gene 'causes' a psychiatric disorder; instead, a liability threshold is crossed when cumulative genetic load meets adverse exposures, explaining why even identical twins show concordance rates below 100 per cent. Changes in genetic and epigenetic architecture profoundly alter biological functions, influencing mental illness outcomes. Genetic mutations disrupt pathways like synaptic pruning and glutamate signaling, leading to impaired neural connectivity in schizophrenia and autism.
Epigenetic modifications – such as DNA methylation and histone acetylation – act as molecular switches, mediating environmental impacts without altering DNA sequences. In depression, chronic stress induces hypermethylation of the glucocorticoid receptor gene (NR3C1), dysregulating the hypothalamic-pituitary-adrenal (HPA) axis and heightening stress susceptibility. Similarly, in schizophrenia, repressive histone marks at GABAergic genes like GAD1 reduce inhibitory neurotransmission, contributing to cortical dysfunction and symptoms like hallucinations. Bipolar disorder shares these patterns, with methylation changes at HLA genes linking to immune dysregulation and mood instability.
These alterations affect synaptic plasticity, neurotrophin signaling (e.g., BDNF), and chromatin remodelling, resulting in persistent changes to limbic circuits that govern emotion, cognition, and behavioor, thus worsening disease progression and comorbidity. Knowing which genes malfunction opens avenues for targeted treatments. While gene therapy remains experimental, animal models demonstrate efficacy.
Precision medicine leverages GWAS insights. For instance, mutations in synaptic genes could guide novel drugs targeting calcium channels or glutamate receptors. RNA-based therapies, informed by genetic mechanisms regulating behaviour, hold promise for modulating defective pathways non-invasively, but these are still very early in the therapeutic pipeline before these personalized interventions become a clinical reality.
Challenges include delivery to the brain and ethical concerns, but integrating PRS with biomarkers could personalize interventions, shifting from symptom-based to etiology-driven care. Variability in medication response among patients arises from pharmacogenomics. Genetic polymorphisms in cytochrome P450 enzymes, like CYP2D6 and CYP2C19, dictate drug metabolism phenotypes, from poor metabolizers facing toxicity to ultrarapid metabolizers experiencing inefficacy.
For antidepressants like escitalopram, poor metabolizers of CYP2C19 require dose reductions to avoid adverse effects, while CYP2D6 variants influence risperidone's antipsychotic efficacy and side effects like hyperprolactinemia. Some clinical guidelines recommend genotyping to optimize dosing, potentially reducing trial-and-error prescribing, but this is practised mostly in specialist clinics, which have the necessary expertise to interpret the complex pharmacogenomics data.
Ethnic differences exacerbate this; Asians have higher CYP2D6 intermediate metabolizer rates, affecting treatment outcomes. Non-responders often carry variants disrupting neurotransmitter pathways, explaining why only 30-50 percent achieve remission on first-line therapies. Genes regulating immune responses play a pivotal role in psychiatric disorders. GWAS implicate immune loci, such as the HLA region in schizophrenia, where complement pathway overactivity disrupts synaptic pruning. Genetic correlations link disorders to autoimmune conditions. For example, schizophrenia correlates with Crohn's disease, and bipolar disorder with celiac disease.
Decoding the genetic basis of mental illnesses offers hope for targeted therapies, from epigenetic modulators to pharmacogenomic-guided prescribing. As research diversifies cohorts and integrates multi-omics data, precision psychiatry could transform outcomes, emphasising prevention and personalised care.
Dr Alok Kulkarni is senior consultant psychiatrist at the Manas Institute of Mental Health, Hubli.
