Comprehensive analyses of RNA-seq and genome-wide data point to enrichment of neuronal cell type subsets in neuropsychiatric disorders

Abstract

Neurologic, psychiatric and substance use disorders share a range of symptoms, which could be the result of shared genetic background. Many genetic loci have been identified for these disorders using genome-wide association studies, but conclusive evidence about cell types wherein these loci are active is lacking. We aimed to uncover implicated brain cell types in neuropsychiatric traits and to assess consistency in results across RNA datasets and methods. We therefore comprehensively employed cell-type enrichment methods by integrating single-cell transcriptomic data from mouse brain regions with an unprecedented dataset of 42 human genome-wide association study results of neuropsychiatric, substance use and behavioral brain-related traits (n=12,544,007). Single-cell transcriptomic datasets from the Karolinska Institute and the 10x Genomics dataset were used. Cell type enrichment was determined using Linkage Disequilibrium Score Regression, Multi-marker Analysis of GenoMic Annotation, and Data-driven Expression Prioritized Integration for Complex Traits. We found the largest degree of consistency across methods for implication of pyramidal cells in schizophrenia and cognitive performance. For other phenotypes, such as bipolar disorder, two methods implicated the same cell types, i.e. medium spiny neurons and pyramidal cells. For autism spectrum disorders and anorexia nervosa, no consistency in implicated cell types was observed across methods. We found no evidence for astrocytes being consistently implicated in neuropsychiatric traits. In conclusion, we provide comprehensive evidence for a subset of neuronal cell types being consistently implicated in several, but not all psychiatric disorders, while non-neuronal cell types seem less implicated.

Editorial: Cross-disorder Genetics in Neuropsychiatry

“…These observations fuel the concept of neuropsychiatry as a field in itself (Yudofsky and Hales, 2002). In contrast to the many shared characteristics between neurological and psychiatric disorders, recent findings point to a higher degree of genetic overlap between major psychiatric disorders in comparison to neurological disorders (Brainstorm Consortium et al, 2018;Olislagers et al, 2021). "Lumping and splitting" are common phenomena in medicine overall (Lüscher, 2019) and within psychiatry (Marquand et al, 2016).…”

Decoding frontotemporal and cell type-specific vulnerabilities to neuropsychiatric disorders and psychoactive drugs

“…Our study identified additional sets of neurons (PVALB and LAMP5) as highly vulnerable cells to psychoactive drugs and show this vulnerability is specific to neurons from the TL. Integrating brain single cell with GWAS data, Olislagers et al 86 showed that neuronal cell subsets are consistently implicated in several psychiatric disorders. Our study confirms and extend these results, as we further refined the neuronal subtypes to the inhibitory sub-type (PVALB and SST) and again highlight their specificity to the TL.…”

“…Integrating brain single cell with GWAS data, Olislagers et al . 86 showed that neuronal cell subsets are consistently implicated in several psychiatric disorders. Our study confirms and extend these results, as we further refined the neuronal subtypes to the inhibitory sub-type (PVALB and SST) and again highlight their specificity to the TL.…”

“…Our study confirms and extend these results, as we further refined the neuronal subtypes to the inhibitory sub-type (PVALB and SST) and again highlight their specificity to the TL. However, differently from both 18 and 86 , in our study we jointly integrated multiple datasets: regional single cell analysis in TL/FL, GWAS data, gene expression (bulk-RNA) in brain from psychiatric disorders patients and gene response to psychoactive drugs. This allowed us to disentangle the relative contribution of genetic susceptibility and psychoactive drugs the cell type vulnerability.…”