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PgmNr 54: Human single-cell transcriptomes identify cell-types and states relevant to brain disorders.

Authors:
S. Gerges 1,2,3,5; T. Singh 1,2,3; M. Goldman 1; S. Berretta 1,4; S. McCarroll 1,2,3; M. Daly 1,2,3

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Affiliations:
1) Department of Genetics, Harvard Medical School, Boston, MA.; 2) Stanley Center, Broad Institute, Cambridge, MA; 3) Analytic and Translational Genetics Unit, MGH, Boston, MA; 4) Harvard Brain Tissue Resource Center, McLean Hospital, Belmont, MA.; 5) John A. Paulson School Of Engineering And Applied Sciences, Harvard University, Cambridge, MA


Genetic studies have identified hundreds of genetic loci associated with brain-related traits. However, the fundamental neurobiology that explains how genetic etiology translates into disease manifestation remains elusive. Single-cell RNA-sequencing (RNA-seq) allows for unprecedented resolution into the cell-types most relevant to psychiatric and neurological disease etiology as well as complex traits more broadly.

Here, we combine single-cell RNA-seq of over 40,000 cells from caudate and prefrontal cortex from multiple individuals with genome-wide association study (GWAS) summary statistics and rare-variants from over 25 brain-related traits. We show that brain traits have both shared and distinctive expression signatures which map onto diverse cell-types and states in the human brain. Specifically, we use partitioned LD score regression (LDSC) to show that schizophrenia, bipolar disorder, educational attainment and IQ are most enriched in a new cell-type population known as “eccentric” spiny projection neurons (eSPN) (p=1.29e-15, p=9.83e-11, p=9.22e-10 and p=3.72e-10 respectively), as well as both “direct” (dSPN) and “indirect” (iSPN) populations in the patch and matrix compartments of the striatum (p<1e-10) and cortical pyramidal neurons (p<1e-8). Importantly, while the cell-type associations are similar, we demonstrate they are driven by different sets of genes.

We contrast this with other traits, such as neuroticism and major depressive disorder which are exclusively enriched in excitatory pyramidal neurons (p < 1.0e-05) and interneurons defined during development (p=1.23e-06), respectively. In contrast to psychiatric and cognitive traits, we show that neurological disorders such as Alzheimer’s disease and multiple sclerosis are significantly enriched in specific types of “disease-associated” microglial cell-states.

To our knowledge, this is the most in depth single-cell RNA-seq survey of the human caudate nucleus, which is associated with roles in procedural learning, and one of the most comprehensive surveys of the frontal cortex, which is associated with higher-order functions. Importantly, both regions are heavily implicated in brain disorders, and provide an atlas for further investigation of brain phenotypes. Altogether, our approach to utilizing human single-cell data allows for unprecedented resolution into the most relevant cells that contribute to disease onset using the both rare and common genetic studies of the brain.