A study on Tibetans living at high altitudes identified novel risk genes for schizophrenia (SCZ) related to hypoxia, suggesting a unique genetic signature for SCZ in this population.
Highlights:
- Whole-exome sequencing of 47 SCZ cases and 53 controls in Tibetans revealed 275 potential novel risk variants and two known variants.
- One gene, C5orf42, surpassed exome-wide significance in the Tibetan cohort, linked to ciliogenesis and neural development.
- Metascape enrichment analysis indicated that novel risk genes were enriched in pathways relevant to hypoxia, neurodevelopment, and neurotransmission.
- Verification in a Han Chinese sample (279 SCZ patients, 95 controls) showed only one variant, BAI2, suggesting unique genetic risk factors in the Tibetan population.
- The findings suggest that SCZ patients living at high altitudes may have a unique genetic risk profile related to their hypoxic environment.
Source: Translational Psychiatry (2024)
Major Findings: Schizophrenia in High-Altitude Tibetans (2024)
1. Discovery of Novel Risk Variants
Whole-Exome Sequencing: Researchers conducted whole-exome sequencing on 47 Tibetans with schizophrenia (SCZ) and 53 controls, revealing 275 new potential risk variants.
Known Variants Identified: They found two known variants (12:46244485: A/G and 22:18905934: A/G) that were already documented in existing databases.
Specific Gene Highlight: The gene C5orf42, linked to neural development and ciliogenesis, was the only one to show significant associations with SCZ.
2. Genetic Pathways Relevant to Hypoxia
Hypoxia Connection: Metascape enrichment analysis indicated that the novel risk genes were significantly enriched in pathways associated with hypoxia (low oxygen levels), neurodevelopment, and neurotransmission.
Hypoxia Impact on SCZ: This suggests that living at high altitudes, where oxygen levels are lower, could influence the development of SCZ through these genetic pathways.
3. Unique Genetic Signature in High-Altitude Populations
Specific Population Study: The study focused on a unique cohort of Tibetans living at altitudes above 4500 meters, providing insights into gene-environment interactions under extreme conditions.
Gene-Environment Interactions: The findings indicate that the harsh environmental conditions, such as hypoxia, might interact with genetic factors to increase the risk of SCZ in this population.
4. Limited Replication in Other Populations
Han Chinese Verification: When researchers tried to verify these findings in a sample of Han Chinese (279 SCZ patients and 95 controls), only one gene variant, BAI2, was found in both populations.
Implication: This suggests that the genetic risk factors for SCZ in the Tibetan population might be unique due to their specific environmental conditions.
5. Importance of C5orf42 & BAI2 Genes
C5orf42 Gene: This gene, also known as ciliogenesis and planar polarity effector 1 (CPLANE1), was significantly associated with SCZ in the Tibetan sample, hinting at its importance in neural development under hypoxic conditions.
BAI2 Gene: Although only found in one Han Chinese case, BAI2 is predominantly expressed in the brain and may play a role in modulating emotional behaviors and signal transduction in the central nervous system.
6. Enrichment in Neurodevelopmental & Neurotransmission Pathways
Pathway Enrichment: The novel risk genes were found to be strongly enriched in pathways that are crucial for brain development and function, including those involved in neurotransmitter release and neuron signaling.
Potential Therapeutic Targets: Understanding these pathways could lead to new therapeutic targets for treating or preventing SCZ, especially in populations living under extreme environmental conditions.
Study Overview: Rare Genetic Variants in Tibetans Living at High Altitudes (2024)
The study aimed to identify rare genetic variants associated with schizophrenia (SCZ) in a unique cohort of Tibetans living at high altitudes, to understand gene-environment interactions under extreme conditions.
Sample
- Tibetans: 47 individuals diagnosed with SCZ and 53 healthy controls from the Ngari Prefecture in Tibet, living at an average altitude above 4500 meters.
- Han Chinese Verification Sample: 279 SCZ patients and 95 healthy controls from the general Han population in China.
Methods
- Whole-Exome Sequencing (WES): Performed on Tibetan SCZ cases and controls to identify rare and novel genetic variants. Sequencing reads aligned to the human reference genome, variants filtered for quality.
- Gene & Variant Analysis: Association analysis using various models to determine significant differences between cases and controls. Metascape enrichment analysis to identify pathways relevant to hypoxia, neurodevelopment, and neurotransmission.
- Verification in Han Chinese Sample: Selected 47 new variants identified in Tibetans for verification in the Han Chinese sample.
Limitations
- Small Sample Size: The limited number of participants, especially in the isolated Tibetan population, may yield spurious findings and limit the statistical power of the study.
- Replication Challenges: Findings in isolated populations may not generalize to other populations, making replication and broader application of the results difficult.
- Environmental Factors: The study primarily focused on genetic factors, potentially overlooking complex interactions between multiple environmental factors and SCZ.
Unique Genetic Signature & Manifestations in High-Altitude Schizophrenia
1. Genetic/Exome Signature in High Altitudes
Hypoxia-Related Genes
The study found that the genetic variants associated with schizophrenia (SCZ) in high-altitude Tibetans are enriched in pathways related to hypoxia, which is a condition of low oxygen levels.
This is significant because these individuals live at very high altitudes where oxygen levels are naturally lower.
Specific Genes Identified:
- C5orf42 (CPLANE1): This gene was notably significant in the Tibetan sample and is involved in neural development. Its association suggests that the unique environmental pressures of high altitude might affect brain development differently in this population.
- BAI2: Found in both the Tibetan and Han Chinese samples, this gene is linked to brain function and emotional regulation. However, in Tibetans, it showed a different variant, indicating a unique genetic adaptation to their environment.
2. Manifestations in Schizophrenia
Gene-Environment Interaction: The high-altitude environment, characterized by hypoxia, likely interacts with these unique genetic variants, potentially altering the way schizophrenia manifests in these individuals.
Neurodevelopment & Neurotransmission: The genetic pathways affected in high-altitude schizophrenia involve neurodevelopment (how the brain develops) and neurotransmission (how brain cells communicate). Variants in these pathways might lead to differences in brain structure and function compared to conventional schizophrenia.
Potential Symptoms: While core symptoms of SCZ like hallucinations, delusions, and cognitive impairment remain, the high-altitude population might experience these symptoms differently or with varying intensity due to the interplay between their genetic makeup and the environmental stress of hypoxia.
3. Differences from Standard Schizophrenia
Genetic Variants: Conventional schizophrenia studies typically identify common genetic variants influencing susceptibility, but the Tibetan study found rare variants specific to their unique environment.
Environmental Influence: The role of hypoxia in high-altitude schizophrenia suggests that environmental factors might play a more pronounced role in the disease’s development and progression compared to more typical settings.
Adaptations: The identified genetic adaptations might mean that Tibetans have developed certain protective or risk factors unique to their high-altitude lifestyle, which are not seen in other populations.
4. Understanding the Differences
Tailored Interventions: Recognizing these unique genetic signatures can help in developing targeted treatments that consider the specific environmental and genetic context of high-altitude populations.
Broader Insights: Studying such unique populations enhances our overall understanding of schizophrenia, revealing how different environments can shape the genetic risk and manifestation of the disorder. This can lead to more personalized approaches in managing and treating schizophrenia across diverse populations.
Why Whole Exome Sequencing is Helpful in Schizophrenia and Psychiatric Disorders
1. Focus on Coding Regions
High Impact Variants: Whole exome sequencing (WES) targets the exons, which are the coding regions of the genome. These regions contain the instructions for building proteins, and mutations here are more likely to have significant effects on biological functions and contribute to diseases like schizophrenia.
Disease-Associated Mutations: Most known disease-causing mutations are located in the exons. By focusing on these regions, WES is efficient in identifying mutations that directly impact protein function, which is crucial for understanding the molecular basis of psychiatric disorders.
2. Cost-Effective & Efficient
Economic Advantage: Compared to whole genome sequencing (WGS), WES is less expensive, making it more accessible for large-scale studies. This cost-effectiveness allows researchers to study larger cohorts, increasing the statistical power of the findings.
Data Management: WES generates less data than WGS, which simplifies data analysis and reduces the computational resources needed. This efficiency makes WES a practical choice for initial genetic studies in complex disorders like schizophrenia.
3. Identification of Rare Variants
Rare & Novel Variants: WES is particularly useful for detecting rare genetic variants that might be missed by other methods. In psychiatric disorders like schizophrenia, where common variants only explain a part of the genetic risk, identifying rare mutations can provide critical insights into the disease’s etiology.
Novel Gene Discovery: By sequencing the exomes of individuals with schizophrenia, researchers can discover new genes and pathways involved in the disorder, contributing to a deeper understanding of its genetic architecture.
4. Insights into Pathways & Mechanisms
Biological Pathways: The variants identified through WES can be linked to specific biological pathways and processes, such as neurodevelopment, neurotransmission, and synaptic function, which are often disrupted in psychiatric disorders. This helps in elucidating the underlying mechanisms of diseases like schizophrenia.
Gene-Environment Interactions: WES can reveal how genetic variants interact with environmental factors, offering a comprehensive view of the factors contributing to psychiatric disorders. This is particularly relevant in studies involving unique populations or specific environmental conditions.
5. Clinical Applications & Personalized Medicine
Diagnostic Tool: WES can be used as a diagnostic tool to identify pathogenic mutations in patients with psychiatric disorders, aiding in accurate diagnosis and classification of these conditions.
Personalized Treatment: Understanding the specific genetic variants associated with an individual’s psychiatric disorder can lead to personalized treatment strategies. For instance, targeted therapies can be developed to address the unique genetic profile of each patient, improving treatment efficacy and outcomes.
Conclusion: High Altitude Tibetans & Genetic Risk for Schizophrenia
The study on schizophrenia in high-altitude Tibetans has revealed unique genetic risk factors that are enriched in pathways associated with hypoxia, neurodevelopment, and neurotransmission.
Whole-exome sequencing identified 275 novel risk variants and highlighted specific genes like C5orf42 and BAI2, suggesting a distinct genetic signature in this population.
These findings underscore the importance of considering environmental factors, such as hypoxia, in understanding the genetic underpinnings of schizophrenia.
The study also demonstrated the value of examining isolated populations to uncover rare variants that may not be present or significant in more diverse groups.
While verification in the Han Chinese sample was limited, the unique genetic adaptations observed in Tibetans provide new insights into the interplay between genes and environment in schizophrenia.
This research paves the way for further studies to explore these genetic mechanisms and develop targeted interventions for populations living under extreme environmental conditions.
References
- Study: Whole-exome sequencing of individuals from an isolated population under extreme conditions implicates rare risk variants of schizophrenia (2024)
- Authors: Lei Chen et al.
