Decomposition of phenotypic heterogeneity in autism reveals underlying genetic programs

[Hoopoe]

Abstract​

Unraveling the phenotypic and genetic complexity of autism is extremely challenging yet critical for understanding the biology, inheritance, trajectory and clinical manifestations of the many forms of the condition. Using a generative mixture modeling approach, we leverage broad phenotypic data from a large cohort with matched genetics to identify robust, clinically relevant classes of autism and their patterns of core, associated and co-occurring traits, which we further validate and replicate in an independent cohort. We demonstrate that phenotypic and clinical outcomes correspond to genetic and molecular programs of common, de novo and inherited variation and further characterize distinct pathways disrupted by the sets of mutations in each class. Remarkably, we discover that class-specific differences in the developmental timing of affected genes align with clinical outcome differences. These analyses demonstrate the phenotypic complexity of children with autism, identify genetic programs underlying their heterogeneity, and suggest specific biological dysregulation patterns and mechanistic hypotheses.

Decomposition of phenotypic heterogeneity in autism reveals underlying genetic programs - Nature Genetics

Classes of autism are uncovered with a generative mixture modeling approach leveraging matched phenotypic and genetic data from a large cohort, revealing different genetic programs underlying their phenotypic and clinical traits.

www.nature.com

This seems potentially relevant to ME/CFS because they also found that in a portion of people with autism the genetic predisposition comes into play at certain stage of development. In ME/CFS we may find something similar with genetic risk factors becoming relevant during adolescence. The relevant genes could be related to brain maturation at this stage, or sex hormones.

 

[Hutan]

I've heard before that "autism" is in fact many things, each somehow meeting the core requirement of social interaction differences and repetitive or unusually focussed behaviour. I've also heard before that genetic analyses support the idea that there are many ways to that broad label of autism spectrum disorder.

This paper proposes 4 sub-types, claiming genetic variation support for the classified phenotypic variation. I think that still substantially minimises the variation within the people given the label, which, as far as I can see, can range from people with developmental delays, substantial learning difficulties and aggressive behaviour, to people with some relatively mild social interaction differences and focussed interests.

I think this variation is worth keeping in mind if DecodeME should find any genetic overlap with autism. (To be clear, I have no idea if it will. I think I have seen some claims and studies suggesting ME/CFS might be more common in people with autism).

I think the caution applies to other poorly defined conditions too e.g. depression, anxiety. If genetic overlaps with other conditions are proposed, it will be useful to look at the studies of that condition that found the overlapping genetic marker, and see what the selection criteria and approach to diagnosis might tell us.