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Cite: Sandin, Sven, et al. “The familial risk of autism.” JAMA 311.17 (2014): 1770-1777.

My wife and I are hoping to have more children. I am pretty convinced of paternal age effect,* so aside from issues like Down Syndrome, which is due to maternal age, the risk for various behavioral issues such as autism are on the radar for us. Also, there are people in the extended pedigree who are probably on the Asperger spectrum (I probably would characterize myself as on the spectrum, but many people who have met me contend that this just isn’t a good description and so might confuse or mislead readers who only know me from the blog. It might be more accurate to say that I’m low on “agreeability”). But should I be worried?

This weekend I heard about a documentary, Mimi and Donna, which is about a 90 year old woman who has to confront letting her 60 year old daughter be institutionalized. Because of her age the woman has never been properly diagnosed, but she definitely has some sort of “intellectual disability.” Today she might have been diagnosed with autism. The film-maker is the grand-daughter of Mimi, and the niece of Donna. What she said was very interesting to me. Her brother has a son with autism, and she herself has a son with autism. As she admits, it runs in the family. Though as I stated above some of my family members exhibit behavior which might seem on the Aspergers end of the spectrum (and I do have a lot of physical scientists and engineers in my pedigree), none of them have been diagnosed autism, nor are they mentally retarded in any way.

As of now my daughter is nearly 3 years old and displays no sign of autism, and my son is young yet but makes eye contact and is socially typical (yes, I am aware of later onset). So I began to realize perhaps I should at least update my odds a bit. I may contribute de novo mutations for risk, but it seems that I don’t carry them from previous generations. I found a large Swedish study, The Familial Risk of Autism, which outlines clearly the odds conditional on affected or unaffected siblings. The figure above is from that paper, and here are the results:

Results In the sample, 14 516 children were diagnosed with ASD [Autism spectrum disorder], of whom 5689 had autistic disorder. The RRR [relative recurrence risk] and rate per 100 000 person-years for ASD among monozygotic twins was estimated to be 153.0 (95% CI, 56.7-412.8; rate, 6274 for exposed vs 27 for unexposed ); for dizygotic twins, 8.2 (95% CI, 3.7-18.1; rate, 805 for exposed vs 55 for unexposed); for full siblings, 10.3 (95% CI, 9.4-11.3; rate, 829 for exposed vs 49 for unexposed); for maternal half siblings, 3.3 (95% CI, 2.6-4.2; rate, 492 for exposed vs 94 for unexposed); for paternal half siblings, 2.9 (95% CI, 2.2-3.7; rate, 371 for exposed vs 85 for unexposed); and for cousins, 2.0 (95% CI, 1.8-2.2; rate, 155 for exposed vs 49 for unexposed). The RRR pattern was similar for autistic disorder but of slightly higher magnitude.We found support for a disease etiology including only additive genetic and nonshared environmental effects. The ASD heritability was estimated to be 0.50 (95% CI, 0.45-0.56) and the autistic disorder heritability was estimated to 0.54 (95% CI, 0.44-0.64).

I am aware that the basal risk is low. But the cumulative sum of a lot of independent low risks can be quite stressful.

* A presentation at ASHG 2014 which had huge sample sizes (~1000 trios) with whole genome sequencing convinced me that paternal age effect shouldn’t be doubted. It’s real.

 
• Category: Science • Tags: Behavior Genetcs 
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  1. My dad’s an alcoholic, my sister quit drinking at 24 because of issues, both my brothers have drinking problems–one is a full-blown alcoholic, the other not yet. My mother is a casual drinker with high tolerance. I married an alcoholic (now sober for some 28 years).

    I am, like my mother, a casual drinker with high tolerance. And my son, at 26, is doing fine and doesn’t drink much (smokes more weed than I’d like, but much less than other twentysomethings I know). I know autism’s heritability is more easily quantified than addiction’s, but I’ve always had the worry in the back of my mind, so in a small way, I know how you feel. Glad both kids are socially typical.

    (and I, too, score low on agreeability.)

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  2. There are two paternal age effects. One is the observed correlation with autism and schizophrenia, the topic of the post. The other, the topic of the footnote, is de novo mutations. They are concrete and we can quantify them. We can be sure it is a real effect, of great statistical significance. But what is its practical significance? How bad is an extra mutation? Are they the cause of the first effect?

    Here is a paper that claims that the effect is tiny, that the substantive age effect (for schizophrenia) is not causal. It finds that for a fixed father, younger children do not have elevated risk; that the age of the father at the birth of the first child is just as predictive as the age of the father at the birth of the child in question. Presumably the correlation is caused by the proto-schizophrenic father not reproducing till late in life.

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    • Replies: @JayMan
    And here's an even better paper out of Sweden that looked within families and found a paternal age effect for all sorts of mental disorders. This one looked within families, and found that later borns do indeed have higher incidences of certain disorders.

    http://twitter.com/JayMan471/statuses/472123171764961280

  3. Sean says:

    Unless your wife has a rather ‘matter of fact’ personality or is interested in abstruse technical subjects I wouldn’t think you particularly have much to worry about, relatively speaking. While you can come across as being oddly forthright, you are very quick to pick up on people slighting you, which suggests good social cognition.

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  4. Immigrant from former USSR [AKA "Florida Resident"] says:

    Mr. Khan:
    Please be more superstitious to chat about your family (gratuitous comment.)
    I doubt my family info is interesting to anybody, so I refrain from discussing it.

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  5. JayMan says: • Website
    @Douglas Knight
    There are two paternal age effects. One is the observed correlation with autism and schizophrenia, the topic of the post. The other, the topic of the footnote, is de novo mutations. They are concrete and we can quantify them. We can be sure it is a real effect, of great statistical significance. But what is its practical significance? How bad is an extra mutation? Are they the cause of the first effect?

    Here is a paper that claims that the effect is tiny, that the substantive age effect (for schizophrenia) is not causal. It finds that for a fixed father, younger children do not have elevated risk; that the age of the father at the birth of the first child is just as predictive as the age of the father at the birth of the child in question. Presumably the correlation is caused by the proto-schizophrenic father not reproducing till late in life.

    And here’s an even better paper out of Sweden that looked within families and found a paternal age effect for all sorts of mental disorders. This one looked within families, and found that later borns do indeed have higher incidences of certain disorders.

    Read More
  6. People have accused me of time to time (most notably my older brother) of having Aspergers. While there are certainly elements of my cognition which aren’t neurotypical (I have a very low emotional affect, have always been interested in esoteric knowledge fields like taxonomy, and needed to learn the rules of socialization via trial and error and reading in books, rather than picking them up organically) from what I understand you need to have some aspect of ritualized/repetitive behavior to be considered to be on the spectrum, and I completely lack such behaviors.

    That said, as my daughter has gotten older, it’s been a bizarre experience for me, insofar as unlike me, she does not seem “strange” in any fundamental fashion. I mean, she’s clearly an intelligent child, and picks up on things rather quickly, but she doesn’t display any of the weird passion for knowledge I did at her age. By the time I was five I was already binge-watching nature shows, and memorizing the binomials of dinosaurs, while she’s pretty content to just watch Strawberry Shortcake on Netflix. It has made me wonder how much of my neurology is actually genetic versus literally the result of pathology (my mother had gestational diabetes, and by the time I was born my blood sugar level was only 13).

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  7. Jay, what makes that paper better?

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    • Replies: @JayMan
    The Peterson et al paper "adjusted" their results both for maternal age and urbanicity, both of which likely attenuated their results. Doing a simple within-family study is better, as that controls for inherited confounders coming from the parents.
  8. Is there any reason to find autism particularly scary?

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    • Replies: @Sean
    Aspergers is to the cognitive elite and what schizophrenia is to the underclass. It proly is a excess of a certain style of cognition. Men are from Mars and all that. Un-erased maternal markers on the X may feminize male Asperger’s cases.
  9. Sean says:
    @CupOfCanada
    Is there any reason to find autism particularly scary?

    Aspergers is to the cognitive elite and what schizophrenia is to the underclass. It proly is a excess of a certain style of cognition. Men are from Mars and all that. Un-erased maternal markers on the X may feminize male Asperger’s cases.

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  10. Is there any reason to find autism particularly scary?

    the majority of individuals diagnosed with ASD are mentally retarded. a substantial minority can’t talk, and engage in antisocial behavior like not controlling bowel movements into adulthood.

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    • Replies: @seebs
    I think you have a selection bias here. I spend a lot of time talking to adults. I run into a ridiculous number of adults who are diagnosable-with-ASD, but never got diagnosed because they weren't sufficiently badly impaired to get studied to try to find out what's wrong with them.

    So what we're saying is that if you check every single person with severe developmental impairment for autism, and almost never check anyone else for autism, you'll find that "a majority" of the autistics you identify are severely impaired. But that's pretty meaningless.

    I also note that one of my friends is one of the autistics who can't talk. She's a highly-paid software engineer who writes as fluently as I do.
  11. Muse says:

    I believe ASD is best thought of as a social impairment. Smart kids (kids of smart guys like you) that end up on the spectrum are often diagnosed with High Functioning Autism or what the DSM may still refer to PDDNOS (Pervasive Developmental Disorder Not Otherwise Specified). These kids are quirky, socially awkward, but can often find a place in the world for themselves as adults. They grow up, get educated and get jobs. They just might be unusually interested in the behavior of ants, or the impact of alleles on human traits.

    Early diagnosis, early intervention (money helps) and good parenting make all the difference in the world.

    I have found having children, even though they are flawed, to be one of the more rewarding things I have done in my life.

    That being said, all reproduction is a crap shoot.

    In the end, they wont live, but then again who does?

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  12. the majority of individuals diagnosed with ASD are mentally retarded. a substantial minority can’t talk, and engage in antisocial behavior like not controlling bowel movements into adulthood.

    Do we know how much of the variation in the manifestation ASD is environmental? For example, would your child be most likely to fall on the same part of the spectrum as your family members with autism do?

    While intellectual disability may often be comorbid with ASD, I think it’s worth keeping in mind that severe intellectual disability only affects 16% of people with ASD. I’d think you’d be pretty well positioned to find the best possible therapies for any of your children whatever challenges they might have.

    I think the more important question though is how important is it to be neurotypical and/or smart in order to live a fulfilling life?

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  13. People are terrible at noticing Apsergers in high-IQ adults who are trying not to show it, so I wouldn’t say what your friends think says much, unless they’ve known you from childhood.

    We can and do substitute active thought for the instincts normals have, if we care to.

    Not that I want to speculate on whether you are or aren’t.

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  14. JayMan says: • Website
    @Douglas Knight
    Jay, what makes that paper better?

    The Peterson et al paper “adjusted” their results both for maternal age and urbanicity, both of which likely attenuated their results. Doing a simple within-family study is better, as that controls for inherited confounders coming from the parents.

    Read More
  15. Jay, both studies adjusted for maternal age. Why do you use scare quotes?

    Why would adjusting for urbanicity attentuate an age effect? Aren’t age and urbanicity negatively correlated risk factors, so adjusting for one should increase the effect of the other?

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    • Replies: @JayMan

    Why would adjusting for urbanicity attentuate an age effect?
     
    The urban effect is the result of genetic sorting (people with a genetic liability to schizophrenia tend to live in cities, as per recent research out of Sweden). Therefore, adjusting for it will attenuate your relationship.
  16. dan says:

    I am pretty clueless about most of the issues raised here, but regarding the “paternal aging effect”, i believe there’s something you can do.

    That is, you can have a sample of your reproductive material frozen (liquid nitrogen temperatures) for potential usage later. This is proven technology.

    If it were a “maternal aging effect” then of course everything would be much more difficult because of the invasive nature of the procedure to get the material, so it wouldn’t be such an easy insurance policy. But not so for paternity.

    And along those lines, you might also consider having the umbilical cord of your next child preserved. Some parents do this, on the chance that it may be useful for later stem cell therapy (also, at some point down the road when the technology is more fully developed).

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  17. Do you know this paper? http://www.pnas.org/content/111/42/15161.abstract
    They find a different pattern for low IQ autism (more de novos) than for high IQ autism (more familial) and basically predict different genetic architectures for these different “autisms”.
    I don’t know if that makes you worry more or less, probably less, since the risks are then probably not necessarily additive. OTOH you’re more worried about intellectual disability than high-functioning autism anyway.

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  18. JayMan says: • Website
    @Douglas Knight
    Jay, both studies adjusted for maternal age. Why do you use scare quotes?

    Why would adjusting for urbanicity attentuate an age effect? Aren't age and urbanicity negatively correlated risk factors, so adjusting for one should increase the effect of the other?

    Why would adjusting for urbanicity attentuate an age effect?

    The urban effect is the result of genetic sorting (people with a genetic liability to schizophrenia tend to live in cities, as per recent research out of Sweden). Therefore, adjusting for it will attenuate your relationship.

    Read More
  19. Having kids has always been a crapshoot, you hope for the best and let the chips fall where they may. To get the most favorable odds, you need to select a mate, who is not a carrier of any deleterious genes you are also a carrier for, but that’s hard, as you can only judge based on meeting his/her immediate family and various oral reports on family history. Then even if you find a mate with a perfectly complementary genetic background to yours, you can’t figure in de novo mutations…

    This is all about to change, as with the advances in Gene Editing, using technologies like CRISPR/Cas9 we should soon be able to correct any deleterious mutation (aka SNPs) and “fix” these kinds of thing, either pre-implantation in the lab or in the fetus. We should be even able to correct them in children and even adults, to some extent.

    Once that point has been reached, we will undoubtedly then start to not just fix bad stuff, but enhance normal stuff, and even engineer new stuff… that’s when the fun starts!

    BTW, I am the father of a kid, who just turned 6 yo, who has an ASD diagnosis, and yes he is an extra burden to care for, and school, but I’m not too worried about his future academically, as he can always fall back on his good looks ;)

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  20. as he can always fall back on his good looks

    yes. he takes after his mom….

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  21. Jay, that’s nonsense. There are two genetic propensities under consideration, somatic and gametic. Only somatic propensity can affect the father’s urbanicity and age of childbirth. De novo germline mutations cannot cause urbanicity. Thus Peterson’s adjustments can attenuate the effect Peterson claims, not the effect D’Onofrio claims.

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  22. seebs says:
    @Razib Khan
    Is there any reason to find autism particularly scary?


    the majority of individuals diagnosed with ASD are mentally retarded. a substantial minority can't talk, and engage in antisocial behavior like not controlling bowel movements into adulthood.

    I think you have a selection bias here. I spend a lot of time talking to adults. I run into a ridiculous number of adults who are diagnosable-with-ASD, but never got diagnosed because they weren’t sufficiently badly impaired to get studied to try to find out what’s wrong with them.

    So what we’re saying is that if you check every single person with severe developmental impairment for autism, and almost never check anyone else for autism, you’ll find that “a majority” of the autistics you identify are severely impaired. But that’s pretty meaningless.

    I also note that one of my friends is one of the autistics who can’t talk. She’s a highly-paid software engineer who writes as fluently as I do.

    Read More
  23. I also note that one of my friends is one of the autistics who can’t talk. She’s a highly-paid software engineer who writes as fluently as I do.

    what did you say about selection bias? most people who can’t talk are retarded. not mutes.

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  24. “yes. he takes after his mom….”

    LOL …

    Funny thing about heredity, I am the tallest of a short family at 6′ 1″, while my wife is the shortest of a tall family at 5′ 7″. It now looks like our son will only be around 5′ 10″ – 6′ tall – based on various calculators, so who contributed the short genes?

    On my wife’s side, he has one 18 yo male first cousin who is 6′ 7″, and 3 younger male first cousins who are 13-15, who are 5′ 11″ – 6′ 2″… so look like they are all going to be taller than 6′ 4″ eventually.

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  25. A thing that is curious in these discutions “I have strong traits of [X]“/”I suspect that I have [X]” is that the internet is full of people claiming to have Asperger (or at leat strong AS traits) and almost zero people claiming to have Schizoid Personality Disorder (a condition with very similar symptoms and probably more common – around 1% of the population against 0.2-0.3% in AS).

    I suspect that the cause could be the exotism of the word “Asperger” – the name itself has an “eccentric genius” sounding, remembering the German-speaking mad scientists in the movies of the 50/60s.

    Read More

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