HERVs UNMASKED: GENETIC CLUES TO PSYCHIATRIC DISORDERS

In recent years, researchers have delved into a relatively unexplored area of genetics that holds significant clues for understanding psychiatric disorders by integrating Human Endogenous Retroviruses (HERVs), mysterious elements consisting of remnants of ancient viral DNA millions of years ago, previously considered junk DNA. These sequences multiply themselves using a copy-paste mechanism known as retrotransposition, constituting 8% of the whole genome. However, emerging evidence suggests they might play a crucial role in conditions such as schizophrenia, bipolar disorder, and major depressive disorder. While most HERVs have lost their ability to move within the genome, they can still influence the expression of nearby genes. This regulation primarily occurs through viral promoters known as long terminal repeats (LTRs), although some HERVs also retain remnants of viral genes that could have additional biological functions. Advanced technologies like Transcriptome-Wide Association Studies (TWAS), which combine RNA sequencing data with genetic information, are used to investigate how variations in HERV expression levels might influence disease risk. For a precise study of variation, retrotranscriptome association studies (rTWAS) were employed.

In this study, researchers analyzed the dorsolateral prefrontal cortex (DLPFC), a brain region implicated in psychiatric disorders. After several analyses, including conditional analyses, rTWAS fine-mapping, sensitivity analyses, co-expression network analysis, and genomic context, the researcher identified 26 HERV expressions associated with susceptibility to various psychiatric disorders. The significant HERV signals were found in the Major Histocompatibility Complex (MHC) on chromosomes ERV316A3_6p22.1b and ERV316A3_2q33.1g. Significant HERV for bipolar expression was found in MER4_20q13.13 and PRIMA41_9q34. HERVs for major depressive disorder (MMD) were located on chromosomes 1p31, 9p23, 3p21, and 14q24. For ADHD, seven expression signatures were identified, but none were HERVs. Only one expression signature was associated with autism spectrum conditions, and it was not a HERV. Interestingly, one HERV (MER4_20q13.13) was associated with both schizophrenia and bipolar disorder. Another key finding includes the biological function and the regulatory mechanism. It is found that HERVs are not randomly distributed but grouped into modules within canonical genes. It is also found that HERV can influence gene expression

Fig. 1: A summary of the retrotranscriptome-wide association study (rTWAS) approach

The meticulous methodology of the study, involving advanced RNA sequencing, precise HERV quantification, and robust statistical analysis, underscores the potential of HERVs as significant factors in psychiatric disorders. By leveraging the rich CommonMind Consortium dataset and employing sophisticated bioinformatics tools, the research provides crucial insights into the complex genetic architecture of psychiatric conditions. This comprehensive analysis framework, encompassing data normalization, SNP weight construction, rTWAS, secondary analyses, network analysis, and gene ontology interpretation, offers a detailed understanding of the genetic and transcriptomic landscape underlying psychiatric disorders. The approach enabled the integration of diverse genetic data across different populations, ensuring robust and translatable findings.

Refrence

Duarte RR, Pain O, Bendall ML, de Mulder Rougvie M, Marston JL, Selvackadunco S, Troakes C, Leung SK, Bamford RA, Mill J, O’reilly PF. Integrating human endogenous retroviruses into transcriptome-wide association studies highlights novel risk factors for major psychiatric conditions. Nature Communications. 2024 May 22;15(1):3803.

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