Sex Differences in the Heritability of Autism
Genes play a larger role in the development of autism in males than females
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A new paper by Sven Sandin and colleagues in JAMA Psychiatry explores sex differences in the heritability of autism. In this post, I’d like to share two graphs and a table from the paper, which capture its main findings and ideas.
The first graph shows: (a) the cumulative incidence of autism diagnoses for males and females from birth to age 20, and (b) the cumulative incidence of autism diagnoses for three age cohorts. The key findings are, first, that more males than females are diagnosed with autism, and second, that autism diagnoses are becoming more and more common. (See this earlier post for discussion of why this might be.)
The second graph shows four models of how the genetic risk for autism might be distributed among males and females. The options are: (a) no sex difference in genetic risk; (b) a higher average risk in males than females, and thus more males than females with autism; (c) no sex difference in the average risk but higher variance in risk among males, and thus more males than females with autism; and (d) a higher average risk in males and higher male risk variance, and thus again more males than females with autism.
Finally, the table below delivers the central message of the paper, namely that the heritability of autism is higher for males than females (87% vs. 76%). To be clear, autism is largely genetic for both sexes. However, non-genetic factors play a somewhat larger role in autism in females than they do in males.
Here’s an excerpt from the paper discussing these findings and their implications. Notice the impressive sample size, and the fact that the family home seems to play no role in the development of autism (“there was no support for shared environmental contributions”).
In this cohort study including 1 047 649 Swedish children, 12 226 (1.17%) received a diagnosis of autism spectrum disorder; heritability was estimated at 87.0% for males and 75.7% for females, a statistically significant difference…
To our knowledge, this cohort study is the first large family- and population-based study estimating the sex-specific associations of genetic and noninherited factors with ASD liability… [W]e demonstrated a modest, but statistically significant, difference in heritability between sexes… [T]here was no support for shared environmental contributions, and the narrow-sense heritability in the overall population was estimated at approximately 80.0%, with the remaining 20.0% explained by individual-specific effects.
Our results indicate that a relatively larger portion of ASD diagnoses can be explained by additive genetic sources in males relative to females. It is also possible that females are less impacted by additive genetic sources, or are particularly vulnerable to other risk sources.
These other risk sources (referred to as residual risk in our models rather than the potentially misleading environmental term) could theoretically arise from (1) classic environmental factors found in the built environment, (2) differences in the cultural environment leading to ascertainment or diagnosis differences, (3) genetic sources not inherited additively (eg, de novo variants), or (4) deficits in the model or its assumptions, such as interactions among genetic risk factors or genes and environment (eg, toxins, pollution, and maternal effects like type 1 diabetes or rheumatoid arthritis). Additional clinical behavioral factors should also be considered, such as female-typical autism presentation (ie, female autism phenotype) or de novo variants and variation from rare variants not inherited additively or gene-environmental interactions…
The skewed sex ratio in ASD may, partly, be explained by differences in genetic variance between sexes. This discovery opens up new avenues for further research aimed at gaining a deeper understanding of the prevalence of ASD.
The paper is titled “Examining Sex Differences in Autism Heritability.” You can read it here.
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There didn’t seem to a control for paternal age of conception; the recent work by Friston and others on the mechanisms of Autism and Psychosis would lead me to hypothesize that it’s not just heritable in an ordinary genetic way, but in an epigenetic way. Autism spectrum induces late paternal age at conception which in turn creates more key mutations which produce more profound autism spectra.
Similarly, there’s the fraternal birth-order gay male hypothesis. For women who have many pregnancies with male fetuses, they can grow immunoreactive to - a y linked protein - NLGN4Y - which modifies testosterone produced by the fetus.
I think the genetics part is not so straightforward. I'm.much more curious that maternal environment, gets so modified. it's not just the genes themselves.