30 / 2026-03-10 10:34:24

Deciphering the genetic dark matters of neuropsychiatric disorders

noncoding variants; structural variants; tandem repeats; rare variants

前沿论坛 > 基因组学与医药健康

The genetics underlying neuropsychiatric disorders are far from being fully understood, which hinders the development of successful therapeutic procedures. Our recent efforts focus on deciphering the genetic dark matters of neuropsychiatric disorders, through developing omics-integration methods to identify and interpret disease-relevant rare and noncoding variants. First, for identifying rare deleterious SNVs from whole-genome sequence data when the cohort size is limited, we have designed a hybrid framework, taking advantage of the statistical power of SKAT-O while integrating it with disease-specific variant prioritization. Applying this framework, we have identified 11 disease-relevant genes based on a medium size Chinese cohort for Alzheimer's disease, mostly driven by East-Asian specific rare SNVs. One of the rare SNVs, RABEP1 p.R845W, was found to induce endocytosis dysregulation and exacerbate toxic amyloid β accumulation, supporting its involvement in the mechanisms of Alzheimer's disease. Second, we developed Intrepid-plus, integrating tissue-specific regulatory activities with 3D chromatin conformations, to identify regulatory target genes for GWAS noncoding SNVs across multiple tissue types. Applying this method to 14 neuropsychiatric disorders, we found that the regulatory target genes in the brain tend to enrich in nervous system development related processes, those in the non-brain tissues are inclined to interfere with synapse and neuroinflammation related processes. Through tissue-specific gene regulatory networks, we then constructed disorder similarity networks in two brain and three non-brain tissues, highlighting both known disorder clusters and unexpected disorder clusters (e.g. Parkinson’s disease is consistently grouped with psychiatric disorders). We showcase the potential pharmaceutical applications of the small bowel and its disorder clusters, illustrated by the known drug targets NR1I3 and NFACT1, and their small bowel-specific regulatory modules. Third, we have developed SVJudge, for scoring the pathogenicity of noncoding structural variants through integrating multi-omics regulatory information, that outperformed state-of-the-art methods. Last but not the least, we leveraged long-read sequencing and identified tandem repeat expansions as s significant genetic contributor for Schizophrenia, and dissected their regulatory impact through a whole-genome scanning of transcriptional factor (TF) binding activities, demonstrating that many of the tandem repeat expansions affect the binding of TF-target genes that are therapeutically relevant to Schizophrenia. In summary, our work has expanded the toolbox for identifying and interpreting the hidden genetic matters of neuropsychiatric disorders, especially for medium-sized cohorts. Our findings may broaden the understanding of the population-specific genetic mechanisms and promote the development of effective therapeutic interventions for these disorders.