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ASPartOfMe
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23 Jun 2022, 9:49 am

Common inherited variants tied to autism show sex bias in families

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Females are resistant to the influences of common, inherited genetic variants linked to autism, a new family study suggests. The findings lend support to the ‘female protective effect,’ a popular theory that proposes that people with two X chromosomes are somehow shielded from the condition.

Autism is challenging to diagnose in girls and women, but genetics also plays a role in this skewed ratio: Autistic girls and women carry more rare, de novo variants linked to the condition — such as large disruptions in the genome and small insertions or deletions — than boys and men do, previous studies show.

The new work focuses on sex differences among common, inherited variants tied to the condition because “this was more of an area of ambiguity,” says Elise Robinson, assistant professor of epidemiology at Harvard University, who led the new research. Part of the problem, Robinson says, has been that sex differences in autism’s presentation and genetic architecture make comparisons of common variants challenging, yielding inconsistent findings.

Robinson and her colleagues used several different strategies to account for some of these differences. They assessed people with intellectual disability (ID) separately from those with autism because ID is more common in autistic females than males, which may skew results. The team also investigated the genetic load of common variants tied to autism in children with the condition as well in as their unaffected parents. Assessing parents enabled the team to get around issues related to diagnostic bias, Robinson says.

Siblings of females with autism alone are more likely to have autism than are siblings of males with the condition, the researchers found. Mothers of people with autism also carry a higher genetic load than fathers do, the team reported in June in Cell Genomics

The findings provide “strong support for the female protective effect model” and may further motivate researchers to understand the mechanisms that underlie it, says Donna Werling, assistant professor of genetics at the University of Wisconsin-Madison, who was not involved in the research. “If we understand those mechanisms, then we have potential to better understand the biology of autism,” she says.

he new work drew on data for 1,707 siblings of autistic females without ID and 6,270 siblings of autistic males without ID from iPSYCH, a collection of medical and genetic information from more than 1.47 million people born in Denmark.

Siblings of autistic females are seven times as likely to have an autism diagnosis as age- and sex-matched people from the general population in Denmark, whereas siblings of males are four times as likely, the researchers found. Given that siblings share a large proportion of their genetics, the findings suggest that females carry more autism-linked variants than males do. Siblings of people with ID alone, in contrast, are more likely to be diagnosed with ID than are people in the general population, but the likelihood does not differ by sex.

In another analysis, Robinson and her colleagues examined polygenic risk scores — sums of common variants tied to autism — for 7,628 people with the condition, 13,362 of their unaffected parents and 18,862 people from the general population. The data came from the Simons Simplex Collection, SPARK and the UK Biobank. (The Simons Simplex Collection and SPARK are funded by the Simons Foundation, Spectrum’s parent organization.)

Polygenic risk scores do not differ by sex in the general population, but mothers of children with autism have significantly higher scores than fathers do, the analysis shows. The extent to which unaffected children inherit autism-linked common genetic variants from their parents may also differ by sex, according to preliminary evidence: 1,611 unaffected female siblings’ polygenic risk scores are roughly the average of their parents’ scores, as expected by chance, but 1,519 unaffected male siblings’ scores are lower than the parental average, suggesting that they inherit fewer of the variants than expected.

“People have been looking for the female protective effect for a long time and mostly not finding it, but it looks like they got it in terms of higher thresholds for females in both mothers and siblings of females,” says Catherine Lord, distinguished professor of psychiatry and education at the University of California in Los Angeles, who was not involved in the study.

Levels of polygenic transmission vary according to sex among people with autism too, the team also found. But the presence of disruptive de novo mutations modifies the genetic load filled by common, inherited variants. Generally, autistic children over-inherit common variants tied to the condition from their parents. Females without de novo mutations in autism-linked genes have nearly three times the levels of over-inheritance than males with de novo mutations, the new study shows.

Anlingering question in the field is the extent to which diagnostic bias or genetics account for autism’s sex ratio. “

Robinson and her colleagues point out in the new study that their findings do not provide insight into mechanisms: Females may be protected from autism or males may be sensitive to it — or both. Also, genetic influences tied to autism are linked to other attributes in the general population, such as higher educational attainment and reasoning ability. Understanding the balance between factors that provide benefits and those that increase the likelihood of having difficulties is important not only in autism but across human variability, she says.


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SharonB
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23 Jun 2022, 5:17 pm

Hmmm. Well, my family bucks that theory. Autism in most the women and girls, none in the men or boys (including my own children). So I am more Autistic than my male peer and paid less? Crap.



IsabellaLinton
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23 Jun 2022, 6:04 pm

Somehow I don't understand the article.
I'm not sure what they're saying.

Brief summary please?

I feel way more autistic than any of the autistic men I know.
Is that what it's saying?



Lady Strange
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23 Jun 2022, 6:34 pm

IsabellaLinton wrote:
Somehow I don't understand the article.
I'm not sure what they're saying.

Brief summary please?

I feel way more autistic than any of the autistic men I know.
Is that what it's saying?


Yeah I am also having trouble figuring out what it is saying.



Joe90
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23 Jun 2022, 6:53 pm

I never understand articles. I don't know why they don't just get to the point of what they're trying to say, instead of all these names, figures and research locations.


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Aspie1
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23 Jun 2022, 7:47 pm

I think the OP's quote suggests that autism is sex-linked.

Background:
Women have XX chromosomes, while men have XY chromosomes. And autism is carried on the X chromosome.

So... when a woman is carrying autism on one of her X chromosomes, it's almost always canceled out by her second, unaffected X chromosome. So unless both X chromosomes carry the autism gene, a woman won't have it. Men, on the other hand, have only one X chromosome; their Y chromosome can't carry much, as it's smaller and weaker. So, when a man's X chromosome carries autism, he's guaranteed to have it, along with the misery it inflicts, as there's nothing on the Y chromosome to cancel it out with.

Did I interpret things correctly? :?:



Last edited by Aspie1 on 23 Jun 2022, 7:53 pm, edited 1 time in total.

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23 Jun 2022, 7:53 pm

What it's trying to say, albeit badly:

Ok, for the vast majority of genetic traits, you have 2 relevant genes. One gene is on a chromosome you got from your mom, and one gene is on the equivalent chromosome you got from your dad.

For example, you might have a blue-eye gene from your dad, and a brown-eye gene from your mom.

Think of genes as like pairs of shoes. Right shoe came from your mom, left shoe from your dad. These "pairs" don't have to match.

Sometimes people get a defective or wonky gene that doesn't work very well. In fact, pretty much everyone has some wonky genes. But because you have two versions of each gene, one from each parent, chances are good that even if one of your genes is messed up, its partner gene is just fine. Your body uses the good gene and ignores the bad gene.

There is one big exception to this general rule: the last pair of chromosomes, pair 23, is a little bit different in 50% of the population: men.

Women have two x-shaped chromosomes at pair 23. Men have one x and one y. The y, of course, makes men *men*.

If a woman has a problem gene on one of her pair-number-23 chromosomes, there's a good chance that she'll have a perfectly good gene on the other side of the pair.

By contrast, if a man has a bad gene on x-chromosome #23, well, he's out of luck. That gene doesn't have a corresponding gene over on the y chromosome. The y chromosome does different stuff. It has to, otherwise we wouldn't get men.

The same is true for any wonky genes on the y chromosome--the corresponding gene on the x can't make up for it.

This is most likely why all sorts of unfortunate problems like mental retardation strike boys more often than girls: the two x chromosomes create a protective effect.

In this study, they looked at girls vs boys with autism and found that the girls had, on average, more wonky genes than the boys.

The study authors speculate that the effects of a few bad genes show up strongly in boys due to their xy chromosomes not canceling out the bad effects, while girls with only a few bad genes do better because of their protective xx configuration. It takes more genetic damage before girls show symptoms, so the girls who *do* show symptoms have more wonky genes. And since they have more of these genes, their family members also tend to have more of these genetic variants.



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23 Jun 2022, 8:14 pm

Thank you.
That makes sense.
I didn't bother reading it more than once, so I'm thankful you did! :twisted:

I was just referred for genetic testing regarding wonky family genes, so this is interesting.

I wonder how Fragile X factors in? I know that can occur for boys or girls, though.



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24 Jun 2022, 11:51 am

"Wimmin autists less like evil space monsters than mens autists cuz crommosones don't work so good. So wimmin autists not has problems at all and if they say they do they stoopid evil whiny b!tches" There. The End. :roll:



Joe90
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24 Jun 2022, 12:18 pm

Quote:
I wonder how Fragile X factors in? I know that can occur for boys or girls, though.


With Fragile-X, usually boys are affected more severely than girls. Some girls with it can even lead normal lives, while most boys with it often have severe developmental disability.

I know quite a lot about Fragile-X syndrome because I have a friend with it. FXS is probably the closest other developmental disorder to autism, as lack of certain social skills (such as misunderstanding body language and not making eye contact) are symptoms of FXS. They can have sensory issues too.

I often mention FXS here but nobody seems to notice.


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IsabellaLinton
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24 Jun 2022, 7:50 pm

Joe90 wrote:
Quote:
I wonder how Fragile X factors in? I know that can occur for boys or girls, though.


With Fragile-X, usually boys are affected more severely than girls. Some girls with it can even lead normal lives, while most boys with it often have severe developmental disability.

I know quite a lot about Fragile-X syndrome because I have a friend with it. FXS is probably the closest other developmental disorder to autism, as lack of certain social skills (such as misunderstanding body language and not making eye contact) are symptoms of FXS. They can have sensory issues too.

I often mention FXS here but nobody seems to notice.


I had heard of it all my life but didn't really know what it was until the last few months.
I've done quite a bit of reading about it as well.
I was surprised it affects boys more severely because the "X" makes it sound like a female mutation.

I might find out that I'm Fragile-X but I don't think so.
Some of the descriptors didn't match up.

I think all the genetic abnormalities are really interesting.



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24 Jun 2022, 7:57 pm

Wow interesting, thank you for explaining it in easier to understand terms! I wonder if females have more of this protective effect because biologically speaking females carry the offspring, thus wanting higher chances of survival (optimal chance) for females to ensure the better continuation of the species.