Do men have a higher genetic variance than women?

Do men have a higher genetic variance than women?

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I've heard that with the distribution of our genome women have less variation on the bell curve than men.

Is there any basis for this? It was my understanding that women have more genetic variation than men due to having two X chromosomes and there being more variation on gene expression within the X chromosomes.

I've also seen a theory that with traits linked to genes on the X-chromosome in women being averaged across the genetic variants found on each of a woman's two X-chromosomes, this would reduce the likelihood of extreme traits (men have just one X-chromosome, precluding this averaging process).

Is there any biological possibility for men to have more genetic variation than women, and if so what would be a potential reason for it?

This question is very interesting and I would love to have a reference to an article that provides such evidence.

Decomposing your question:

  1. Is it true that there is more genetic variance among males than among females (in humans I guess)

  2. If the answer to (1) is yes then: Why is it so?

I am trying to address these two points below

1. Is it true that there is more genetic variance among males than among females ?

There are different ways of understanding your question 1. Do you want to talk about…

  • Allele richness

  • Heterozygosity

  • Polymorphism

  • Part of the genetic variance in phenotypic variance (heritability). I don't think it is what you meant though!

Therefore, the question is slightly unclear and I don't know of any paper who address any of these questions anyway. So… I don't know!

2. Assuming (1) is true, then Why is it so?

There are many possible explanations for such observation (assuming this pattern has been observed). Below I give some hypothesis I can think of.

  • There might have a higher selection (survival differential) among females than males. In a consequence, genetic variance among young females is higher than among older females. In total, genetic variance among females would be lower to that of males.

  • There might have a very high variance on the Y-chromosom but not on the X-chromosom. This might for example be a consequence of the arrest of recombination that occur on the Y-chromosom. As a consequence of this arrest of recombination, selection hardly purge deleterious mutations (see Muller's Ratchet). See Shigeta's answer for a more detailed overview of this point. See shigeta's answer for more information.

  • Males might migrate more. If one look at the sex-specific genetic variance in a population (and not on the world-wide metapopulation), this variance might be greater for the sex that migrate more because different genetic background might be brought from other neighbor populations.

  • Higher selection within mitochondria in females very early in life (in the egg for example) resulting in a decreased mitochondrial genetic variance in females. This is maybe a bit far-fetched.

  • There might have other hypotheses for species for which sex of an individual is not determined by sex-chromosomes. (see Sex Determination System)

  • Depending on what you mean in your question, I guess we might find many other hypotheses when thinking of migration, different fitness landscape (different optimum), different selection intensity.

  • We might as well think of genetic variance of gender-specific gametes (especially for haplon-diplontic species for example)

  • This evidence (assuming it has been observed) was a False Positive!

Note: @terdon provided a very good explanation (which was deleted) of why males might cause most of the genetic diversity but as @terdon and I discussed (in the comments that were also deleted) this is not an explanation for greater diversity among males. The reason is that the variation is created via mutation in the testis and the ovary. The fact that most mutations happen in males does not influence the sex-specific diversity because males sire as many male offsprings than female offsprings (so do females!).

This is an interesting question and we should probably have a statistical geneticist around, so further answers may show up better than this one. So I'm also assuming the question is: Is the rate of variation on the X,Y and autosomal chromosomes different? Also assuming XY male heterogamy as humans have - different sex chromosomes will give different results between male/female.

The main distinction being - if males absorb more mutations on X as well as Y, then it would be nigh on impossible to see this phenomenon statistically since those chromosomes get passed on to females immediately.

Its important to remember that some of the X and Y regions do recombine even in men in the pseudoautosomal regions. The Y also maintains itself with a self-recombination event in meiosis. So the message here applies to the SDR (sex determining regions) of the X and Y chromosomes - other regions are quite possibly not different than the other chromosomes.

Anyway I've found this modeling paper "Patterns of Neutral Genetic Variation on Recombining Sex Chromosomes" which estimates and compares the relative coalescence time for variations on the autosomal, X and Y regions.

In any case the models in the paper says 'yes they are different and Y non-autosomal regions accumulate variants faster'. The coalescence time is the amount of time for a variation to spread into the general population on one of these 3 types of regions.

In cases where there is neutral selectional pressure "Close to the SDR, expected coalescence times are shorter on Y chromosomes and longer on X chromosomes than for autosomal sites."

Which is to say speeds for incorporating variations are Y > X > autosomal

Note that the paper goes on to say that when there are more than one competing versions of the Y chromosome in a population (which seems likely to be the case), then the spread of variations on the Y goes to a normal autosomal rate.

So its likely that this effect is small overall.

It has been documented that some Y chromosomes are very competitive though.


This post contains a logical error (see the added section on comments) and the post was deleted by its owner (@terdon). I copy-pasted this deleted post here by request of @sterid who wanted to see it.

Please do not up or down vote!

Yes, this is actually true. The following is taken from the introduction of the classic human genome paper[1]:

  • The mutation rate is about twice as high in male as in female meiosis, showing that most mutation occurs in males.

This actually makes a lot of sense from an evolutionary point of view. Primates, like many animals, are species where the male competes for the female. This means that the onus is on the male to convince the female that he is the best father for her offspring. This gives rise to some fascinating and strange behaviors:

Mutations are one of the ways that genetic diversity can be generated. Genetic diversity, in turn, makes it likely that someone or other will manage to impress the female, that some male is born faster, smarter or stronger (or whatever it is the females of his species value) than his peers. Diversity is also important as it increases the chances that a species will survive a catastrophic change in it's environment. The more random stuff you have floating around, the likelier it is that one of them will do just what it is you happen to need at the moment.

Now let's imagine a mutation whose result is a slight increase in the rate of mutation. This will cause in a net gain of diversity. As long as the increase in mutation rate is not great enough to start causing other problems, the increase in diversity will be advantageous and the mutation in question will be selected for. This is a horrible simplification, but I hope you get the general drift.

So, in humans, the males generate greater diversity but it is the females who chose which new traits are favored. In other words, men push evolution but women drive.

  1. Lander et al Nature 409, 860-921 (15 February 2001) | doi:10.1038/35057062;

Discussion between Remi.b and terdon explaining the logical issues of the post

Remi.b: t explains why men create greater genetic diversity. I think the OP was asking if it is true that, among men, the genetic variance is higher than among females. I don't this question got answered. Or maybe I didn't get the link between differential of "diversity creation" between sexes and difference in genetic variance (or diversity?) between the sexes.

terdon: @Remi.b My logic is: men have a higher rate of mutation => more mutations occur in men => men will have more differences in their DNA compared to other men. This means they will have a greater genetic diversity since the higher rate of mutation will result in a more varied group of genotypes.

Remi.b: Yes but mutations occur in the testis when reproducing. And men sire male and female offspring that both carry the same amount of mutations. Therefore the diversity should be the same. What point am I missing in your speech? The only possible explanation to me would imply differential selection early in life in male and in females. The sex that is under stronger selection has a lower genetic variance.

terdon: @Remi.b ah, you make a very good point. Looks like it is my reasoning that is missing something and not your understanding of it :). I will edit my answer as soon as I get the chance.

Men vs. Women: Our Key Physical Differences Explained

"Sexual dimorphism" is the scientific term for physical differences between males and females of a species. Many extreme examples exist: Peacocks far outclass peahens, for instance, while female anglerfish both outsize and outwit their tiny, rudimentary, parasitic male counterparts.

Unlike those animals, men and women are more physically similar than we are different. Nonetheless, there are a few key distinctions in our physiques. Some of them are designed to suit each sex for the role it plays in reproduction, while others exist to help us tell each other apart and to aid in our mutual attraction.

Male sexual orientation influenced by genes, study shows

A study of gay men in the US has found fresh evidence that male sexual orientation is influenced by genes. Scientists tested the DNA of 400 gay men and found that genes on at least two chromosomes affected whether a man was gay or straight.

A region of the X chromosome called Xq28 had some impact on men's sexual behaviour – though scientists have no idea which of the many genes in the region are involved, nor how many lie elsewhere in the genome.

Another stretch of DNA on chromosome 8 also played a role in male sexual orientation – though again the precise mechanism is unclear.

Researchers have speculated in the past that genes linked to homosexuality in men may have survived evolution because they happened to make women who carried them more fertile. This may be the case for genes in the Xq28 region, as the X chromosome is passed down to men exclusively from their mothers.

Michael Bailey, a psychologist at Northwestern University in Illinois, set out the findings at a discussion event held in conjunction with the annual meeting of the American Association for the Advancement of Science in Chicago on Thursday. "The study shows that there are genes involved in male sexual orientation," he said. The work has yet to be published, but confirms the findings of a smaller study that sparked widespread controversy in 1993, when Dean Hamer, a scientist at the US National Cancer Institute, investigated the family histories of more than 100 gay men and found homosexuality tended to be inherited. More than 10% of brothers of gay men were gay themselves, compared to around 3% of the general population. Uncles and male cousins on the mother's side had a greater than average chance of being gay, too.

The link with the mother's side of the family led Hamer to look more closely at the X chromosome. In follow-up work, he found that 33 out of 40 gay brothers inherited similar genetic markers on the Xq28 region of the X chromosome, suggesting key genes resided there.

Hamer faced a firestorm when his study was published. The fuss centred on the influences of nature and nurture on sexual orientation. But the work also raised the more dubious prospect of a prenatal test for sexual orientation. The Daily Mail headlined the story "Abortion hope after 'gay genes findings' ". Hamer warned that any attempt to develop a test for homosexuality would be "wrong, unethical and a terrible abuse of research".

The gene or genes in the Xq28 region that influence sexual orientation have a limited and variable impact. Not all of the gay men in Bailey's study inherited the same Xq28 region. The genes were neither sufficient, nor necessary, to make any of the men gay.

The flawed thinking behind a genetic test for sexual orientation is clear from studies of twins, which show that the identical twin of a gay man, who carries an exact replica of his brother's DNA, is more likely to be straight than gay. That means even a perfect genetic test that picked up every gene linked to sexual orientation would still be less effective than flipping a coin.

While genes do contribute to sexual orientation, other multiple factors play a greater role, perhaps including the levels of hormones a baby is exposed to in the womb. "Sexual orientation has nothing to do with choice," said Bailey. "We found evidence for two sets [of genes] that affect whether a man is gay or straight. But it is not completely determinative there are certainly other environmental factors involved."

Last year, before the latest results were made public, one of Bailey's colleagues, Alan Sanders, said the findings could not and should not be used to develop a test for sexual orientation.

"When people say there's a gay gene, it's an oversimplification," Sanders said. "There's more than one gene, and genetics is not the whole story. Whatever gene contributes to sexual orientation, you can think of it as much as contributing to heterosexuality as much as you can think of it contributing to homosexuality. It contributes to a variation in the trait."

Qazi Rahman, a psychologist at King's College London, said the results were valuable for further understanding the biology of sexual orientation. "This is not controversial or surprising and is nothing people should worry about. All human psychological traits are heritable, that is, they have a genetic component," he said. "Genetic factors explain 30 to 40% of the variation between people's sexual orientation. However, we don't know where these genetic factors are located in the genome. So we need to do 'gene finding' studies, like this one by Sanders, Bailey and others, to have a better idea where potential genes for sexual orientation may lie."

Rahman rejected the idea that genetics research could be used to discriminate against people on the basis of their sexual orientation. "I don't see how genetics would contribute more to the persecution, discrimination and stigmatisation of lesbian, gay, bisexual and transgender people any more than social, cultural or learning explanations. Historically, the persecution and awful treatment of LGBT groups has been because politicians, religious leaders and societies have viewed sexual orientation as 'choice' or due to poor upbringing."

Steven Rose, of the Open University, said: "What worries me is not the extent, if at all, to which our genetic, epigenetic or neural constitution and development affect our sexual preferences, but the huge moral panic and religious and political agenda which surrounds the question."

Stop laughing. I know, my initial reaction too was, “really – it took genetics to tell us that?” But this is serious….really.

Males are 99.9% the same when compared to other males, and females are as well when compared to other females, but males and females are only 98.5% equal to each other – outside of the X and Y chromosomes. The genetic difference between men and women is 15 times greater than between two men or two women. In fact, it’s equal to that of men and male chimpanzees. So men really are from….never mind. It’s OK to laugh now…

We’ve been taught that other than X and Y, males and females are genetically exactly the same. They aren’t.

Does this matter? Dr. David Page, Director of the Whitehead Institute and MacArthur Genius Grant winner, says it absolutely does. He has discovered that both the X and Y chromosomes function throughout the entire body, not just within the reproductive tract.

In his words, “Humane Genome, we have a problem.” Medicine and research fails to take into account this most fundamental difference. We aren’t unisex, and our bodies know this – every cell knows it at the molecular level, according to Dr. Page.

For example, some non-reproductive tract diseases appear in vastly different percentages in men and women. Autism is found in 5 times as many males as females, Lupus in 6 times as many women as men and Rheumatoid Arthritis in 5 times as many women as men. In other diseases, men and women either react differently to disease treatment, react differently to the disease itself, or both. Dr. Page explains more and suggests a way forward in this short but very informative video.

David Page, Director of the Whitehead Institute and professor of biology at MIT, has shaped modern genomics and mapped the Y chromosome. His renowned studies of the sex chromosomes have shaped modern understandings of reproductive health, fertility and sex disorders.

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These factors mentioned are mostly unconnected with statistics. For example, how many men actually die from accidents, hazardous jobs, wars, etc., in contrast to women? The only factor connected to statistics is the factor of heart disease, but even that doesn’t tell me how much I can improve my odds by adopting healthier practices. Such statistics would be quite helpful in telling me how to set priorities in terms of taking preventive measures. For instance, if 95% of the difference in longevity is due to higher incidence of heart disease, then I know I should focus most of my energies on that, and not worry so much about not going to the doctor.

While that info maybe available, and at the same time I wish things were that straight forward myself. As one who worked as a scientist I have rarely found anything regarding human behavior to be simple.

To make statements that are backed by science you must study the change of one variable at a time, however, human behaviors and the motivation behind them, especially ones that effect longevity, are far too complex to study one variable at a time.

While science tries to come as close as possible to ruling out other variables and there are brilliant strategies applied to do just that, human behavior is just too complex to actually limit most studies to one variable and that create problems with saying things with certainty.

The fact is the more complex the topic of study, the more complex saying anything definitive gets and thus the more caveats a true answer requires. This is why you should be sceptical when you hear definitive statements made that are more than general guidelines when it concerns human behavior. Often there is really no way to present data to the general public in a straight forward helpful way with out keeping it simple. This is not because scientists believe the public is less intelligent but the answers are often complex even to the expert.

Unless you address the issues were more than one variable is involved, the caveats, you would over simplifying the truth. Even my attempt to explain the limits of making more than broad general statements or general conclusions in the face of studying a subject that defies the constraint of a single variable is starting to feel too complex.

You often hear a scientist say after a big discovery that “for every question we answered we found many more questions to ask.” These questions have to do with the caveats, which are when multiple variables are at play. When this is the case cause and effect are truly unknown. One variable like men not seeking medical help is compounded by a second variable like the genetic of boys having an XY chromosome and girls having a XX chromosome. Just think how the complexity would grow more and more unwieldy as the number of variables at play increase and you suddenly see why scientists struggle to make more than general conclusions in a short news article. Saying or implying more from a study without explaining the caveats or cases where more things are at play and explaining the limitations of a study is considered both unethical as well as unscientific.

All this to say while I and most other scientists hope studies come out with info presented in ways that are directly applicable to people’s lives and presented in ways that are easier to make decisions like you requested, there are often real scientific and ethical reasons why they do not.

How affection differs among twins

For this research, 464 pairs of adult twins were studied. The twins varied greatly in age (18-84 years old), and about half were fraternal, with the other half being identical. Twins are often used for “nature versus nurture” studies because, though usually raised in the same household and exposed to the same experiences in adolescence, only identical twins share the exact same genetics. In comparison, from a genetic perspective, fraternal twins are about as similar as any other pair of siblings.

Each participating twin rated how strongly they agreed with a series of statements about affectionate behavior. Then, responses among pairs of twins were compared to one another.

Now, if genetics don’t influence affection at all, that would mean that both fraternal and identical twins would have largely the same answers. That’s not what happened, at least regarding female twin pairs. Identical female twins gave much more identical answers than fraternal female twins. This is a strong piece of evidence that at least some aspect of affection is determined via genetics among women.

Why is affection a genetic trait for women and not men? Floyd and his team don’t have a concrete answer to that question yet. But they did note that men are generally less affectionate than women.

“When we measure people’s tendency to be affectionate and to receive affection from other people, almost without exception we find that women score higher than men,” Floyd comments. “The trait of being affectionate may be more adaptive for women in an evolutionary sense. There is some speculation that affectionate behavior is more health supportive for women than it is for men, and that it helps women to manage the effects of stress more than it does for men. That may be partly why women are more likely than men to inherit the tendency to behave that way rather than that tendency simply being a product of their environment.”


David De Lossy/Photodisc/Getty Images

Testosterone enables men to develop larger skeletal muscles as well as larger hearts. Men also have a larger proportion of Type 2 muscle fibers, which generate power, strength and speed. Testosterone also increases the production of red blood cells, which absorb oxygen, giving men an even greater aerobic advantage, reports "New York Times" writer Gina Kolata, in an interview with Dr. Mark Tarnopolsky, an exercise researcher at McMaster University in Ontario.

Why Do Women Tend to Have Higher Body Fat Percentage than Men?

While it is obviously not true in all cases, women generally have more percent body fat than men.

There are many reasons why women have more body fat than men. One is biological. Body fat content is 25% for women at normal size compared to 15% for men. All other things being equal, such as age and exercise levels, women require fewer calories per pound of body weight daily than do men. Female hormones make it easier to convert fat into food. Women more often do the cooking in the households. Finally, in fat-prone women, birth control pills cause the body to produce increased amounts of fat and water. Estrogen alone will cause increased deposition of fat. Anyone on the pill needs to decrease caloric intake by at least 10% in order to maintain the same weight.

After 40, the key to weight loss is fat calorie control and increased exercise.

Weight loss in the 50's and 60's is slow. However, when needed, it so markedly improves overall health status as well as the way a person feels and looks that it is well worth the effort.

The scientific reasons why men are more violent than women

Worldwide statistics show that men are responsible for the vast majority of violence globally.

But what causes men to commit horrible acts, while women rarely do the same? And can anything be done to change this pattern of violence?

The aggression divide

It’s important to note that although there is a clear delineation by sex when it comes to violent crime, men are certainly not destined to be killing machines. Most men are not violent, and we also have plenty of examples of women committing atrocious crimes.

Nevertheless, a clear sex difference has been documented cross-culturally in the way men and women display aggression.

Men are far more likely to express their aggression directly: through physical violence or verbal abuse. Women are more likely to be indirectly aggressive: to focus on damaging someone’s social standing or spreading rumors to hurt someone’s reputation.

This points to a very clear reason why men are overrepresented in violent crime statistics: male aggression is almost always in a form that is criminalized.

However, noting this difference doesn’t tell us why men act out violently. For this, we have to look at the research on complex biological and environmental factors impacting male violence.


No other hormone has such a bad reputation as testosterone — responsible for horny, sweaty teens and grumpy, risk-taking adults. However, many of the effects of this little hormone are commonly misunderstood.

You have three main life stages of experiencing testosterone as a male. Firstly, before birth the hormone helps generate the male sex organs, then — at puberty — it kicks those organs into gear. Finally, once matured, circulating testosterone plays a role in stimulating sperm production and sexual arousal.

The role of circulating testosterone in relation to aggression and violence is complicated.

Testosterone spikes when men are in competitive or challenging situations with other men, however only among men with a history of violence do we see this boost in hormones result in violence.

This is consistent with other studies, which show that among men known for their aggressive behavior, testosterone has a clear effect in provoking hostility and violence, an effect that has also been documented in women.

However, the effect of a testosterone boost is not consistent across the male population, with studies showing a myriad of responses in men in response to testosterone in a competitive environment: some aggressive, some caring. Clearly, testosterone is no silver bullet to understanding male violence.

Other theories focus on the role of the testosterone exposure before birth, noting the masculinization of the fetus’s brain. However, such hypotheses are notoriously difficult to test and there are no good studies showing whether this model holds water.

Ultimately, biology provides a partial but ultimately incomplete picture of why men commit violence.


So if biology isn’t the whole answer, what about social norms?

The American Psychological Association recently issued guidelines that caution against the impact of “traditional masculinity ideology” on mental well-being. This ideology was defined as “upholding the values of anti-femininity, achievement, avoidance of the appearance of weakness, adventure, risk and violence.”

Some of these values are not inherently harmful but can be when not properly balanced or when given undue emphasis in the daily lives of men.

Although the APA guidelines are not without their critics, it has been well documented that certain patterns of male violence — particularly against women and gender non-conforming men — are strongly correlated with a belief in strict gender roles.

When men hold onto a fairly narrow view of what it is to be a man, challenges to this masculine identity — such as when a partner who doesn’t wish to play the housewife or a gay man who doesn’t act as a man “should” — can lead to feelings of intense anger, ultimately resulting in violence.

We also know that some features of masculinity — stoicism, toughness and self-sufficiency — can be a barrier for men with mental health issues or troubles with aggression seeking treatment.

The result is that some men, because of their limited view of masculinity, are far more likely to act violently toward the vulnerable and to fail to seek help when they need it.


The aggression divide is complicated by the predisposition of men to certain mental disorders, in particular, anti-social personality disorder (ASPD), which is defined by a pervasive and persistent disregard for morals, social norms and the rights and feelings of others.

It is not a mental illness, but a set of characteristics that correlate strongly with violence, risk-taking and crime. Symptoms of ASPD include being callous and unemotional, immorality, deviancy, deception, irritability, aggression, impulsivity and recklessness.

There are many factors involved in developing ASPD but sex is clearly one of the key ones, with men three times more likely to have the disorder than women. It’s unclear how ASPD develops or why men are more likely to have the disorder, but studies indicate a complex set of genetic and environmental interactions.

Ultimately, the sex difference found in ASPD diagnoses probably doesn’t explain all forms of male violence — but it does give a good indication of why the worst of the worst offenders are likely to be male.

Advocating change

If some men reading this article are offended by the findings above, there is something that can be done about it.

Although biological predispositions are difficult to change, many key factors in male violence, including traditional masculinity ideology, can be challenged and changed for the better.

Moreover, recognizing that violence is largely a male problem allows society to orient its efforts toward catching potentially violent males early and to attempt to change the risk factors that cause such shameful gender statistics.

Only by looking honestly at the causes of male violence can we hope to decrease the rate of violent crime in the community.


Intersexual selection has been proposed as an important force in shaping a number of morphological traits that differ between human populations and/or between the sexes. Important to these accounts is the source of mate preferences for such traits, but this has not been investigated. In a large sample of twins, we assess forced-choice, dichotomous mate preferences for height, skin colour, hair colour and length, chest hair, facial hair, and breast size. Across the traits, identical twins reported more similar preferences than nonidentical twins, suggesting genetic effects. However, the relative magnitude of estimated genetic and environmental effects differed greatly and significantly between different trait preferences, with heritability estimates ranging from zero to 57%.

Citation: Verweij KJH, Burri AV, Zietsch BP (2012) Evidence for Genetic Variation in Human Mate Preferences for Sexually Dimorphic Physical Traits. PLoS ONE 7(11): e49294.

Editor: Alexandre Roulin, University of Lausanne, Switzerland

Received: August 21, 2012 Accepted: October 8, 2012 Published: November 14, 2012

Copyright: © 2012 Verweij et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: Funding provided by the Wellcome Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Researchers pinpoint genes behind sex biases in autoimmune disorders, schizophrenia

Some diseases exhibit a clear sex bias, occurring more often, hitting harder or eliciting different symptoms in men or women.

For instance, the autoimmune conditions lupus and Sjögren's syndrome affect nine times more women than men, while schizophrenia affects more men and tends to cause more severe symptoms in men than in women.

Likewise, early reports suggest that despite similar rates of infection, men are dying from COVID-19 more often than women, as happened during previous outbreaks of the related diseases SARS and MERS.

For decades, scientists have tried to pinpoint why some diseases have an unexpected sex bias. Behavior can play a role, but that explains only a piece of the puzzle. Hormones are commonly invoked, but how exactly they contribute to the disparity is unclear. As for genes, few, if any, answers have been found on the X and Y sex chromosomes for most diseases.

Now, work led by researchers in the Blavatnik Institute at Harvard Medical School and at the Broad Institute of MIT and Harvard provides a clear genetic explanation behind the sex bias observed in some of these diseases.

The team's findings, reported May 11 in Nature, suggest that greater abundance of an immune-related protein in men protects against lupus and Sjögren's but heightens vulnerability to schizophrenia.

The protein, called complement component 4 (C4) and produced by the C4 gene, tags cellular debris for prompt removal by immune cells.

Credit: Harvard Medical School

  • Regardless of sex, natural variation in the number and type of C4 genes contained in people's DNA constitutes the largest common genetic risk factor for developing these three diseases. People with the most C4 genes were seven times less likely to develop systemic lupus erythematosus, an autoimmune condition that can range from mild to life-threatening, and 16 times less likely to develop primary Sjögren's syndrome, a systemic autoimmune syndrome characterized by dry eyes and dry mouth, than those with the fewest C4 genes. Conversely, those with the most C4 genes were 1.6 times more likely to develop the neuropsychiatric condition schizophrenia.
  • Even in people with similar complement gene profiles, the genes produce more protein in men than in women, further skewing disease susceptibility and protection.

"Sex acts as a lens that magnifies the effects of genetic variation," said the study's first author, Nolan Kamitaki, research associate in genetics in the lab of Steven McCarroll at HMS and the Broad.

"We all know about illnesses that either women or men get a lot more, but we've had no idea why," said Steven McCarroll, the Dorothy and Milton Flier Professor of Biomedical Science and Genetics at HMS and director of genomic neurobiology at the Stanley Center for Psychiatric Research at the Broad. "This work is exciting because it gives us one of our first handles on the biology."

McCarroll is co-senior author of the study with Timothy Vyse of King's College London.

Although C4 variation appears to contribute powerfully to disease risk, it is only one among many genetic and environmental factors that influence disease development.

The study's results are informing the ongoing development of drugs that modulate the complement system, the authors said.

"For example, researchers will need to make sure that drugs that tone down the complement system do not unintentionally increase risk for autoimmune disease," said McCarroll. "Scientists will also need to consider the possibility that such drugs may be differentially helpful in male and female patients."

On a broader level, the work offers a more solid foundation for understanding sex variation in disease than has been available before.

"It's helpful to be able to think about sex-biased disease biology in terms of specific molecules, beyond vague references to 'hormones,'" McCarroll said. "We now realize that the complement system shapes vulnerability for a wide variety of illnesses."

In 2016, researchers led by Aswin Sekar, a former McCarroll lab member who is a co-author of the new study, made international headlines when they revealed that specific C4 gene variants underlie the largest common genetic risk factor for developing schizophrenia.

The new work suggests that C4 genes confer both an advantage and disadvantage to carriers, much as the gene variant that causes sickle cell disease also protects people against malaria.

"C4 gene variants come with this yin and yang of heightened and reduced vulnerability in different organ systems," said McCarroll.

The findings, when combined with insights from earlier work, offer insights into what may be happening at the molecular level.

When cells are injured, whether from a sunburn or infection, they leak their contents into the surrounding tissue. Cells from the adaptive immune system, which specialize in recognizing unfamiliar molecules around distressed cells, spot debris from the cell nuclei. If these immune cells mistake the flotsam for an invading pathogen, they may instigate an attack against material that isn't foreign at all—the essence of autoimmunity.

Researchers believe that complement proteins help tag these leaked molecules as trash so they're quickly removed by other cells, before the adaptive immune system pays too much attention to them. In people with lower levels of complement proteins, however, the uncollected debris lingers longer, and adaptive immune cells may become confused into acting as if the debris is itself the cause of problem.

As part of the new study, Kamitaki and colleagues measured complement protein levels in the cerebrospinal fluid of 589 people and blood plasma of 1,844 people. They found that samples from women aged 20 through 50 had significantly fewer complement proteins—including not only C4 but also C3, which activates C4—than samples from men of the same age.

That's the same age range in which lupus, Sjögren's and schizophrenia vulnerabilities differ by sex, Kamitaki said.

The results align with previous observations by other groups that severe early-onset lupus is sometimes associated with a complete lack of complement proteins, that lupus flare-ups can be linked to drops in complement protein levels and that a common gene variant associated with lupus affects the C3 receptor.

"There were all these medical hints," said McCarroll. "Human genetics helps put those hints together."

The bulk of the findings arose from analyses of whole genomes from 1,265 people along with single nucleotide polymorphism (SNP) data from 6,700 people with lupus and 11,500 controls.

C4 genes and proteins come in two types, C4A and C4B. The researchers found that having more copies of the C4A gene and higher levels of C4A proteins was associated with greater protection against lupus and Sjögren's, while C4B genes had a significant but more modest effect. On the other hand, C4A was linked with increased risk of schizophrenia, while C4B had no effect on that illness.

In men, common combinations of C4A and C4B produced a 14-fold range of risk for lupus and 31-fold range of risk for Sjögren's, compared to only 6-fold and 15-fold ranges in women, respectively.

The researchers didn't expect the genes' effects to be so strong.

"Large genetic effects tend to come from rare variants, while common gene variants generally have small effects," said McCarroll. "The C4 gene variants are common, yet they are very impactful in lupus and Sjögren's."

Still, complement genes don't tell the full story of lupus, Sjögren's or schizophrenia risk, none of which are caused entirely by genetics.

"The complement system contributes to the sex bias, but it's only one of probably many genetic and environmental contributors," said Kamitaki.

Answers from diversity

Complement genes and another family of immune-related genes, called human leukocyte antigen or HLA genes, are interspersed throughout the same complex stretch of the human genome. HLA variants have been shown to raise risk of developing other autoimmune diseases, including type 1 diabetes, celiac disease and rheumatoid arthritis, and researchers had long believed that something similar was happening with lupus and Sjögren's.

The culprit, however, remained stubbornly hard to pin down, because specific variants in HLA genes and C4 genes always seemed to appear together in the same people.

Kamitaki and colleagues overcame this hurdle by analyzing DNA from a cohort of several thousand African American research participants. The participants' DNA contained many more recombinations between complement and HLA genes, allowing the researchers to finally tease apart the genes' contributions.

"It became quite clear which gene was responsible," said McCarroll. "That was a real gift to science from African American research participants. The question had been unsolved for decades."

The discovery provides further proof that the field of genetics would benefit from diversifying the populations it studies, McCarroll said.

"It will really help for genetics to expand more strongly beyond European ancestries and learn from genetic variation and ancestries all over the world," he said.

C4 variation could contribute to sex-based vulnerabilities in other diseases not yet analyzed, the authors said. It's not yet clear whether C4 pertains to the sex bias seen in COVID-19.

"We don't know the mechanism yet for why men seem to get sicker from COVID-19," said McCarroll. "Complement molecules are potentially important in any immune or inflammatory condition, and in COVID-19, it seems the immune response can be part of a downward spiral in some patients. But we don't know the key details yet."

It also remains to be seen how the differing effects of complement genes apply to people with intersex traits, also known as disorders or differences of sex development, who don't always fit textbook genetic or biological definitions of male and female.