TY - JOUR
T1 - Comprehensive analyses of RNA-seq and genome-wide data point to enrichment of neuronal cell type subsets in neuropsychiatric disorders
AU - Olislagers, M.
AU - Rademaker, K.
AU - Adan, R. A.H.
AU - Lin, B. D.
AU - Luykx, J. J.
N1 - Funding Information:
Funding was provided through a personal Rudolf Magnus Talent Fellowship (H150) to Jurjen Luykx and by grants of the Netherlands Organisation for Scientific Research (NWO: 024.004.012, ALWOP.137 and OCENW.KLEIN.071) to Roger Adan. The authors thank Kevin Kenna, Mark Bakker, and Nathan Skene for fruitful input on statistical analyses. The authors thank Albert Batalla Cases for comments and suggestions on the manuscript.
Publisher Copyright:
© 2021, The Author(s).
PY - 2022/2
Y1 - 2022/2
N2 - Neurological and psychiatric disorders, including 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/quantitative brain-related traits (n = 12,544,007 individuals). Single-cell transcriptomic datasets from the Karolinska Institute and 10x Genomics 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.
AB - Neurological and psychiatric disorders, including 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/quantitative brain-related traits (n = 12,544,007 individuals). Single-cell transcriptomic datasets from the Karolinska Institute and 10x Genomics 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.
KW - Animals
KW - Bipolar Disorder/genetics
KW - Genome-Wide Association Study
KW - Humans
KW - Mice
KW - Neurons
KW - RNA-Seq
KW - Schizophrenia/genetics
UR - http://www.scopus.com/inward/record.url?scp=85118298843&partnerID=8YFLogxK
U2 - 10.1038/s41380-021-01324-6
DO - 10.1038/s41380-021-01324-6
M3 - Article
C2 - 34719691
AN - SCOPUS:85118298843
SN - 1359-4184
VL - 27
SP - 947
EP - 955
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 2
ER -