Relationship Between Sex Biases in Gene Expression and Sex Biases in Autism and Alzheimer's Disease

Overview

Journal Biol Sex Differ

Publisher Biomed Central

Specialties Biology
Physiology

Date 2024 Jun 6

PMID 38844994

Authors

Stuart B Fass

Bernard Mulvey

Rebecca Chase

Wei Yang

Din Selmanovic

Sneha M Chaturvedi

Eric Tycksen

Lauren A Weiss

Joseph D Dougherty

Affiliations

Soon will be listed here.

Abstract

Background: Sex differences in the brain may play an important role in sex-differential prevalence of neuropsychiatric conditions.

Methods: In order to understand the transcriptional basis of sex differences, we analyzed multiple, large-scale, human postmortem brain RNA-Seq datasets using both within-region and pan-regional frameworks.

Results: We find evidence of sex-biased transcription in many autosomal genes, some of which provide evidence for pathways and cell population differences between chromosomally male and female individuals. These analyses also highlight regional differences in the extent of sex-differential gene expression. We observe an increase in specific neuronal transcripts in male brains and an increase in immune and glial function-related transcripts in female brains. Integration with single-nucleus data suggests this corresponds to sex differences in cellular states rather than cell abundance. Integration with case-control gene expression studies suggests a female molecular predisposition towards Alzheimer's disease, a female-biased disease. Autism, a male-biased diagnosis, does not exhibit a male predisposition pattern in our analysis.

Conclusion: Overall, these analyses highlight mechanisms by which sex differences may interact with sex-biased conditions in the brain. Furthermore, we provide region-specific analyses of sex differences in brain gene expression to enable additional studies at the interface of gene expression and diagnostic differences.

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References

Kissel L, Werling D . Neural Transcriptomic Analysis of Sex Differences in Autism Spectrum Disorder: Current Insights and Future Directions. Biol Psychiatry. 2021; 91(1):53-60. DOI: 10.1016/j.biopsych.2020.11.023. View

Labonte B, Engmann O, Purushothaman I, Menard C, Wang J, Tan C . Sex-specific transcriptional signatures in human depression. Nat Med. 2017; 23(9):1102-1111. PMC: 5734943. DOI: 10.1038/nm.4386. View

Trabzuni D, Ramasamy A, Imran S, Walker R, Smith C, Weale M . Widespread sex differences in gene expression and splicing in the adult human brain. Nat Commun. 2013; 4:2771. PMC: 3868224. DOI: 10.1038/ncomms3771. View

Lopes-Ramos C, Chen C, Kuijjer M, Paulson J, Sonawane A, Fagny M . Sex Differences in Gene Expression and Regulatory Networks across 29 Human Tissues. Cell Rep. 2020; 31(12):107795. PMC: 7898458. DOI: 10.1016/j.celrep.2020.107795. View

Fish E . The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol. 2008; 8(9):737-44. PMC: 7097214. DOI: 10.1038/nri2394. View

Marcus S, Young E, Kerber K, Kornstein S, Farabaugh A, Mitchell J . Gender differences in depression: findings from the STAR*D study. J Affect Disord. 2005; 87(2-3):141-50. DOI: 10.1016/j.jad.2004.09.008. View

Liu R, Holik A, Su S, Jansz N, Chen K, Leong H . Why weight? Modelling sample and observational level variability improves power in RNA-seq analyses. Nucleic Acids Res. 2015; 43(15):e97. PMC: 4551905. DOI: 10.1093/nar/gkv412. View

Fu J, Satterstrom F, Peng M, Brand H, Collins R, Dong S . Rare coding variation provides insight into the genetic architecture and phenotypic context of autism. Nat Genet. 2022; 54(9):1320-1331. PMC: 9653013. DOI: 10.1038/s41588-022-01104-0. View

Seney M, Huo Z, Cahill K, French L, Puralewski R, Zhang J . Opposite Molecular Signatures of Depression in Men and Women. Biol Psychiatry. 2018; 84(1):18-27. PMC: 6014892. DOI: 10.1016/j.biopsych.2018.01.017. View

10.

Gandal M, Haney J, Wamsley B, Yap C, Parhami S, Emani P . Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD. Nature. 2022; 611(7936):532-539. PMC: 9668748. DOI: 10.1038/s41586-022-05377-7. View

11.

Bellenguez C, Kucukali F, Jansen I, Kleineidam L, Moreno-Grau S, Amin N . New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet. 2022; 54(4):412-436. PMC: 9005347. DOI: 10.1038/s41588-022-01024-z. View

12.

Ouwenga R, Dougherty J . Fmrp targets or not: long, highly brain-expressed genes tend to be implicated in autism and brain disorders. Mol Autism. 2015; 6:16. PMC: 4363463. DOI: 10.1186/s13229-015-0008-1. View

13.

Colombo G, Cubero R, Kanari L, Venturino A, Schulz R, Scolamiero M . A tool for mapping microglial morphology, morphOMICs, reveals brain-region and sex-dependent phenotypes. Nat Neurosci. 2022; 25(10):1379-1393. PMC: 9534764. DOI: 10.1038/s41593-022-01167-6. View

14.

Sandberg R, Yasuda R, Pankratz D, Carter T, Del Rio J, Wodicka L . Regional and strain-specific gene expression mapping in the adult mouse brain. Proc Natl Acad Sci U S A. 2000; 97(20):11038-43. PMC: 27144. DOI: 10.1073/pnas.97.20.11038. View

15.

Hodge R, Bakken T, Miller J, Smith K, Barkan E, Graybuck L . Conserved cell types with divergent features in human versus mouse cortex. Nature. 2019; 573(7772):61-68. PMC: 6919571. DOI: 10.1038/s41586-019-1506-7. View

16.

Fairweather D, Frisancho-Kiss S, Rose N . Sex differences in autoimmune disease from a pathological perspective. Am J Pathol. 2008; 173(3):600-9. PMC: 2527069. DOI: 10.2353/ajpath.2008.071008. View

17.

Fagerberg L, Hallstrom B, Oksvold P, Kampf C, Djureinovic D, Odeberg J . Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. 2013; 13(2):397-406. PMC: 3916642. DOI: 10.1074/mcp.M113.035600. View

18.

Werling D, Parikshak N, Geschwind D . Gene expression in human brain implicates sexually dimorphic pathways in autism spectrum disorders. Nat Commun. 2016; 7:10717. PMC: 4762891. DOI: 10.1038/ncomms10717. View

19.

Hartl C, Ramaswami G, Pembroke W, Muller S, Pintacuda G, Saha A . Coexpression network architecture reveals the brain-wide and multiregional basis of disease susceptibility. Nat Neurosci. 2021; 24(9):1313-1323. PMC: 10263365. DOI: 10.1038/s41593-021-00887-5. View

20.

Fan H, Chen L, Qu X, Ren C, Wu X, Dong F . Transplanted miR-219-overexpressing oligodendrocyte precursor cells promoted remyelination and improved functional recovery in a chronic demyelinated model. Sci Rep. 2017; 7:41407. PMC: 5286453. DOI: 10.1038/srep41407. View