Sex affects transcriptional associations with schizophrenia across the dorsolateral prefrontal cortex, hippocampus, and caudate nucleus

Kynon J M Benjamin; Ria Arora; Arthur S Feltrin; Geo Pertea; Hunter H Giles; Joshua M Stolz; Laura D'Ignazio; Leonardo Collado-Torres; Joo Heon Shin; William S Ulrich; Thomas M Hyde; Joel E Kleinman; Daniel R Weinberger; Apuã C M Paquola; Jennifer A Erwin

doi:10.1038/s41467-024-48048-z

Sex affects transcriptional associations with schizophrenia across the dorsolateral prefrontal cortex, hippocampus, and caudate nucleus

Nat Commun. 2024 May 10;15(1):3980. doi: 10.1038/s41467-024-48048-z.

Authors

Kynon J M Benjamin^#^{1

2

3}, Ria Arora^#^{4

5}, Arthur S Feltrin⁴, Geo Pertea⁴, Hunter H Giles^{4

6}, Joshua M Stolz⁴, Laura D'Ignazio^{4

7}, Leonardo Collado-Torres^{4

8}, Joo Heon Shin⁴, William S Ulrich⁴, Thomas M Hyde^{4

9

7}, Joel E Kleinman^{4

9}, Daniel R Weinberger^{4

9

7

6

10}, Apuã C M Paquola^{11

12}, Jennifer A Erwin^{13

14

15}

Affiliations

¹ Lieber Institute for Brain Development, Baltimore, MD, USA. KynonJade.Benjamin@libd.org.
² Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. KynonJade.Benjamin@libd.org.
³ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. KynonJade.Benjamin@libd.org.
⁴ Lieber Institute for Brain Development, Baltimore, MD, USA.
⁵ Department of Biology, Johns Hopkins University Krieger School of Arts & Sciences, Baltimore, MD, USA.
⁶ Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁷ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA.
⁹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁰ Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Lieber Institute for Brain Development, Baltimore, MD, USA. Apua.Paquola@libd.org.
¹² Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Apua.Paquola@libd.org.
¹³ Lieber Institute for Brain Development, Baltimore, MD, USA. Jennifer.Erwin@libd.org.
¹⁴ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Jennifer.Erwin@libd.org.
¹⁵ Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Jennifer.Erwin@libd.org.

^# Contributed equally.

Abstract

Schizophrenia is a complex neuropsychiatric disorder with sexually dimorphic features, including differential symptomatology, drug responsiveness, and male incidence rate. Prior large-scale transcriptome analyses for sex differences in schizophrenia have focused on the prefrontal cortex. Analyzing BrainSeq Consortium data (caudate nucleus: n = 399, dorsolateral prefrontal cortex: n = 377, and hippocampus: n = 394), we identified 831 unique genes that exhibit sex differences across brain regions, enriched for immune-related pathways. We observed X-chromosome dosage reduction in the hippocampus of male individuals with schizophrenia. Our sex interaction model revealed 148 junctions dysregulated in a sex-specific manner in schizophrenia. Sex-specific schizophrenia analysis identified dozens of differentially expressed genes, notably enriched in immune-related pathways. Finally, our sex-interacting expression quantitative trait loci analysis revealed 704 unique genes, nine associated with schizophrenia risk. These findings emphasize the importance of sex-informed analysis of sexually dimorphic traits, inform personalized therapeutic strategies in schizophrenia, and highlight the need for increased female samples for schizophrenia analyses.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Caudate Nucleus* / metabolism
Chromosomes, Human, X / genetics
Dorsolateral Prefrontal Cortex* / metabolism
Female
Gene Expression Profiling
Hippocampus* / metabolism
Humans
Male
Prefrontal Cortex / metabolism
Quantitative Trait Loci*
Schizophrenia* / genetics
Schizophrenia* / metabolism
Sex Characteristics*
Sex Factors
Transcriptome

Abstract

Publication types

MeSH terms

Grants and funding