There’s a clear sex bias in many diseases. Lupus, for instance, affects women nine times more often than it does men. Schizophrenia tends to be far more severe in males.

But what’s behind the imbalance? A new paper in Nature helps unravel why some conditions might manifest themselves more commonly, or intensely, in one sex over another. And it suggests that new therapies might be developed with these sex-based molecular disparities in mind. 

“The sex differences and vulnerabilities for some illnesses are extremely striking, and scientists have puzzled over this issue for decades,” said Steven McCarroll, director of genomic neurobiology at the Broad Institute of MIT and Harvard, who led the research. “There hasn’t always been a good biological explanation for this, even though sex has an enormous effect.”

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McCarroll’s team found that the same gene that put people at risk for schizophrenia is highly protective against lupus and Sjögren’s syndrome, another autoimmune condition. The effects of this gene, called C4, were particularly pronounced in men — which may help explain why males develop lupus and Sjögren’s syndrome far less frequently than women do.

Broadly, this suggests that genes — and the proteins they code for — may work differently, depending on a person’s sex.

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Many genes end up working as a double-edged sword. Take the genes that cause sickle cell anemia: A person with one diseased allele actually has an increased ability to fight off malaria, a parasitic illness. But a person with two copies of the sickle cell allele develop the life-threatening blood disease.

A similar phenomenon seems to be occurring with schizophrenia, lupus, and Sjögren’s: C4 seems to offer both advantages and disadvantages to its carriers.

“There’s a yin and yang effect here: The same alleles that are helpful in one organ system may generate vulnerability in another organ system,” McCarroll said. 

The C4 gene codes for the complement component 4 protein, which helps immune cells identify cellular debris, so it can be flushed from the body. It’s been implicated previously in lupus, Sjögren’s, and schizophrenia. People are able to carry several copies of the C4 gene in their chromosomes — which, in turn, allows them to produce more of the complement C4 protein. 

McCarroll’s team analyzed the genomes of 1,265 people, as well as single nucleotide polymorphism data from 6,700 people with lupus, and 11,500 controls. 

The study found that people carrying the most copies of the C4 gene — and, by extension, producing the most complement C4 protein — were seven times less likely to develop the most common form of lupus, and 16 times less likely to develop Sjögren’s syndrome. However, people with the most copies of the C4 gene were also 1.6 times more likely to develop schizophrenia. 

This inverse relationship between schizophrenia and autoimmune disease is the most intriguing aspect of the paper, said Herbert Lachman, a schizophrenia genetics researcher at Albert Einstein College of Medicine in New York. 

“This is consistent with the well-known finding that schizophrenia is less common in patients with rheumatoid arthritis,” Lachman said.

Schizophrenia — along with many other neuropsychiatric illnesses — have long been suspected to have autoimmune roots. This paper helps solidify that theory, said Belinda Lennox, a schizophrenia researcher at the University of Oxford who was not involved in the study.

When cells are injured, their innards leak into the surrounding tissues. Immune cells take note of this debris, with help from the complement C4 protein, and home in on the damage. Sometimes, the immune cells mistake this debris for an invading pathogen and attack their own tissues — which is what occurs with autoimmune diseases like lupus and Sjögren’s syndrome. 

In people who have lower levels of complement C4 protein, less cellular debris is tagged, so it lingers for a longer time — and immune cells become more confused. 

McCarroll’s study also measured the complement protein levels in the cerebrospinal fluid of 589 people, and in the blood plasma of 1,844 people. They found that women aged 20 through 50 had far fewer complement proteins than men of the same age — because the gene expression for C4 seems to dip around that age. 

This “maps very neatly into the ages of particular risk for these disorders,” said Lennox. In schizophrenia, the peak risk for men comes in their early 20s — when the complement proteins are at their highest. 

Meanwhile, lupus and Sjögren’s tend to manifest in women between the ages of 20 and 50. Early-onset versions of these diseases have been seen in women who have no complement proteins whatsoever. 

Schizophrenia, along with autoimmune disorders like lupus and Sjögren’s, are highly complex and result from more than just an overabundance or dearth of C4 genes, the researchers said. 

Hormones may be part of the equation, along with behavior. But neither provides a full explanation as to why diseases can present so differently between sexes — nor do genes specific to the X or Y chromosomes. 

This study helps illustrate how genes behave differently depending on one’s sex, and may provide insight into future treatments of these diseases, McCarroll said. 

It also provides tantalizing clues that could prove fruitful in developing new therapies for schizophrenia and autoimmune disease, said Patricio O’Donnell, executive medical director at Takeda Pharmaceuticals. The C4 complement system is an intriguing molecular pathway to target for future drug development, he said. It’d be fairly straightforward, for instance, to genotype patients to identify how many copies of the C4 gene they have — then use that information to modulate how much of a medication they’re given, he said. 

“This paper really opens the door to thinking about how gender might influence how we treat certain diseases,” O’Donnell said. 

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