The X Chromosome's Influences on the Human Brain

Overview

Journal Sci Adv

Date 2025 Jan 24

PMID 39854466

Authors

Zhiwen Jiang

Patrick F Sullivan

Tengfei Li

Bingxin Zhao

Xifeng Wang

Tianyou Luo

Shuai Huang

Peter Y Guan

Jie Chen

Yue Yang

Jason L Stein

Yun Li

Dajiang Liu

Lei Sun

Hongtu Zhu

Affiliations

Soon will be listed here.

Abstract

Genes on the X chromosome are extensively expressed in the human brain. However, little is known for the X chromosome's impact on the brain anatomy, microstructure, and functional networks. We examined 1045 complex brain imaging traits from 38,529 participants in the UK Biobank. We unveiled potential autosome-X chromosome interactions while proposing an atlas outlining dosage compensation for brain imaging traits. Through extensive association studies, we identified 72 genome-wide significant trait-locus pairs (including 29 new associations) that share genetic architectures with brain-related disorders, notably schizophrenia. Furthermore, we found unique sex-specific associations and assessed variations in genetic effects between sexes. Our research offers critical insights into the X chromosome's role in the human brain, underscoring its contribution to the differences observed in brain structure and functionality between sexes.

References

Hofer E, Roshchupkin G, Adams H, Knol M, Lin H, Li S . Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults. Nat Commun. 2020; 11(1):4796. PMC: 7508833. DOI: 10.1038/s41467-020-18367-y. View

Tedja M, Wojciechowski R, Hysi P, Eriksson N, Furlotte N, Verhoeven V . Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error. Nat Genet. 2018; 50(6):834-848. PMC: 5980758. DOI: 10.1038/s41588-018-0127-7. View

Trubetskoy V, Pardinas A, Qi T, Panagiotaropoulou G, Awasthi S, Bigdeli T . Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. 2022; 604(7906):502-508. PMC: 9392466. DOI: 10.1038/s41586-022-04434-5. View

Satterthwaite T, Wolf D, Roalf D, Ruparel K, Erus G, Vandekar S . Linked Sex Differences in Cognition and Functional Connectivity in Youth. Cereb Cortex. 2014; 25(9):2383-94. PMC: 4537416. DOI: 10.1093/cercor/bhu036. View

Zhu Z, Zhang F, Hu H, Bakshi A, Robinson M, Powell J . Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat Genet. 2016; 48(5):481-7. DOI: 10.1038/ng.3538. View

Sacchet M, Livermore E, Iglesias J, Glover G, Gotlib I . Subcortical volumes differentiate Major Depressive Disorder, Bipolar Disorder, and remitted Major Depressive Disorder. J Psychiatr Res. 2015; 68:91-8. PMC: 11887997. DOI: 10.1016/j.jpsychires.2015.06.002. View

Wade T, Gordon S, Medland S, Bulik C, Heath A, Montgomery G . Genetic variants associated with disordered eating. Int J Eat Disord. 2013; 46(6):594-608. PMC: 3775874. DOI: 10.1002/eat.22133. View

Gayen S, Maclary E, Buttigieg E, Hinten M, Kalantry S . A Primary Role for the Tsix lncRNA in Maintaining Random X-Chromosome Inactivation. Cell Rep. 2015; 11(8):1251-65. PMC: 4449283. DOI: 10.1016/j.celrep.2015.04.039. View

Tukiainen T, Villani A, Yen A, Rivas M, Marshall J, Satija R . Landscape of X chromosome inactivation across human tissues. Nature. 2017; 550(7675):244-248. PMC: 5685192. DOI: 10.1038/nature24265. View

10.

Luciano M, Davies G, Summers K, Hill W, Hayward C, Liewald D . The influence of X chromosome variants on trait neuroticism. Mol Psychiatry. 2019; 26(2):483-491. PMC: 7850965. DOI: 10.1038/s41380-019-0388-2. View

11.

Sng L, Thomson P, Trabzuni D . Genome-wide human brain eQTLs: In-depth analysis and insights using the UKBEC dataset. Sci Rep. 2019; 9(1):19201. PMC: 6915738. DOI: 10.1038/s41598-019-55590-0. View

12.

Hong D, Reiss A . Cognitive and neurological aspects of sex chromosome aneuploidies. Lancet Neurol. 2014; 13(3):306-18. DOI: 10.1016/S1474-4422(13)70302-8. View

13.

Ancelin M, Carriere I, Artero S, Maller J, Meslin C, Ritchie K . Lifetime major depression and grey-matter volume. J Psychiatry Neurosci. 2018; 44(1):45-53. PMC: 6306287. DOI: 10.1503/jpn.180026. View

14.

de Leeuw C, Mooij J, Heskes T, Posthuma D . MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput Biol. 2015; 11(4):e1004219. PMC: 4401657. DOI: 10.1371/journal.pcbi.1004219. View

15.

Sherman B, Hao M, Qiu J, Jiao X, Baseler M, Lane H . DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res. 2022; 50(W1):W216-W221. PMC: 9252805. DOI: 10.1093/nar/gkac194. View

16.

Engreitz J, Pandya-Jones A, McDonel P, Shishkin A, Sirokman K, Surka C . The Xist lncRNA exploits three-dimensional genome architecture to spread across the X chromosome. Science. 2013; 341(6147):1237973. PMC: 3778663. DOI: 10.1126/science.1237973. View

17.

Yao X, Glessner J, Li J, Qi X, Hou X, Zhu C . Integrative analysis of genome-wide association studies identifies novel loci associated with neuropsychiatric disorders. Transl Psychiatry. 2021; 11(1):69. PMC: 7820351. DOI: 10.1038/s41398-020-01195-5. View

18.

Shanmugan S, Seidlitz J, Cui Z, Adebimpe A, Bassett D, Bertolero M . Sex differences in the functional topography of association networks in youth. Proc Natl Acad Sci U S A. 2022; 119(33):e2110416119. PMC: 9388107. DOI: 10.1073/pnas.2110416119. View

19.

Schwartz C, Louie R, Toutain A, Skinner C, Friez M, Stevenson R . X-Linked intellectual disability update 2022. Am J Med Genet A. 2022; 191(1):144-159. DOI: 10.1002/ajmg.a.63008. View

20.

Ballout R, Dickerson C, Wick M, Al-Sweel N, Openshaw A, Srivastava S . Int22h1/Int22h2-mediated Xq28 duplication syndrome: de novo duplications, prenatal diagnoses, and additional phenotypic features. Hum Mutat. 2020; 41(7):1238-1249. PMC: 7292747. DOI: 10.1002/humu.24009. View