X chromosome plays large role in human brain structures, functions and health
February 19, 2025
Genes on the X chromosome – one of two sex chromosomes in humans – that are expressed in our cells have a significant impact on our brain development and function, according to new research led by the UNC Gillings School of Global Public Health.
The research shows that many of these effects, which can vary depending on a person’s sex, are responsible for brain structures and functions. Some are even linked to brain disorders like schizophrenia and autism spectrum disorder, as well as cognitive ability. Findings in the study could be valuable in developing future treatment strategies for these disorders that are personalized based on genetics.
Zhiwen Owen Jiang
Published in Science Advances, the study was led by Zhiwen (Owen) Jiang, a doctoral student in the Gillings School’s Department of Biostatistics. Jiang collaborated with fellow researchers in the UNC School of Medicine and the Biostatistics and Imaging Genomics Analysis Lab’s Statistics and Signal group (BIG-S2), led by Professor of Biostatistics Hongtu Zhu, PhD.
“We were surprised by the substantial visible sex differences in the brain structures and functions,” said Jiang, “and the clear difference between males and females in how much X-linked genes contribute to traits and in the specific genetic locations involved.”
The study, which examined 1,045 brain imaging traits extracted from more than 38,000 brain scans in the UK Biobank study, first investigated the pattern of dosage compensation (DC) across imaging traits. DC is the process to balance the expression of X chromosome genes in male and female sexes. Because males typically have XY chromosomes and females have XX chromosomes, one of the X chromosomes is randomly inactivated, or silenced, in females to ensure they don’t have twice as many X-linked genes, which could lead to health issues.
By default, most traits are affected by silenced genes, but Jiang said the team was more interested in those affected by non-silenced genes. Researchers found that 78% of traits were majorly affected by silenced genes. While all cortical volume and surface area traits followed this pattern, around half of cortical thickness traits were primarily affected by non-silenced genes. In brain functions, traits related to the primary and secondary visual networks and the default mode network were more likely affected by non-silenced genes.
They identified 72 trait-locus pairs that were associated with brain imaging traits, and of those pairs, 29 had not previously been identified. Through eQTL mapping and Mendelian randomization analysis, they prioritized five genes – AM3A, PJA1, TMLHE, PLXNA3 and ZNF275 – which impact brain structures and functions, schizophrenia, autism, and educational attainment.
The team found that one genomic region, Xq28, was overly represented in association signals, and this region has connections with various intellectual and developmental disabilities.
They also found that the X chromosome accounted for approximately twice as much brain variation in males than females. Similarly, four times more genetic associations were identified in males. This suggests that DC might reduce the X chromosome’s influences on the brain for females or that the effects were through other complex mechanisms, like epigenetics, that were not evaluated by the current study.
“Since the X chromosome is closely related to intelligence, understanding how it shapes sex differences in the brain could lead to more personalized treatments,” Jiang explained. “These findings may help develop targeted interventions for neurological and psychiatric conditions that differ between males and females. Additionally, this research could inform public health strategies by highlighting the need for sex-specific approaches in brain-related disorders.”
Jiang said that the research team plans to investigate the impact of the X chromosome on other organs in the future.
Contact the UNC Gillings School of Global Public Health communications team at sphcomm@unc.edu.
