28 September 2022

The Genetics Of Autism and ADHD

A new study compared the genetic profiles of people diagnosed with an autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and people diagnosed with both disorders. Both conditions are highly heritable. 

The study used large data set with 23,583 subjects (with ADHD and/or one of four subtypes of autism spectrum disorder) and 42,201 controls, apparently mostly from the national health records of Denmark and possibly also from 23andMe data. The study excluded individuals with a moderate to severe mental retardation from both its subjects and its controls.

The study finds seven genes that are associated with both disorders, and five genes that distinguish between the disorders which are also associated with educational attainment, neuroticism and regional brain volume. 

The Paper And Its Abstract
Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable neurodevelopmental conditions, with considerable overlap in their genetic etiology. We dissected their shared and distinct genetic etiology by cross-disorder analyses of large datasets. 
We identified seven loci shared by the disorders and five loci differentiating them. All five differentiating loci showed opposite allelic directions in the two disorders and significant associations with other traits, including educational attainment, neuroticism and regional brain volume. 
Integration with brain transcriptome data enabled us to identify and prioritize several significantly associated genes. The shared genomic fraction contributing to both disorders was strongly correlated with other psychiatric phenotypes, whereas the differentiating portion was correlated most strongly with cognitive traits. Additional analyses revealed that individuals diagnosed with both ASD and ADHD were double-loaded with genetic predispositions for both disorders and showed distinctive patterns of genetic association with other traits compared with the ASD-only and ADHD-only subgroups. 
These results provide insights into the biological foundation of the development of one or both conditions and of the factors driving psychopathology discriminatively toward either ADHD or ASD.
Manuel Mattheisen, et al., "Identification of shared and differentiating genetic architecture for autism spectrum disorder, attention-deficit hyperactivity disorder and case subgroups" Nat Genet (September 26, 2022). https://doi.org/10.1038/s41588-022-01171-3 (closed access).

The Data Set

The data set was apparently a national health care record system for Denmark in which there were 2,304 cases with both ADHD ad an autism spectrum disorder, 11,964 ADHD cases without an autism spectrum disorder, and 9,315 cases with an autism spectrum disorder without ADHD, although some of the data may also have been from the 23andme consumer genetic profiling company (a data set that would include me, my family, and a number of my extended family members). Also:
Controls were randomly selected from the full control cohort to roughly match a 1:4 ratio in cases and controls. . . . we excluded individuals with a moderate to severe mental retardation (ICD10: F71-F79) from both the case and control cohort.

Autism spectrum disorder cases were further categoried into four subtypes: childhood autism (cha, ICD10 F84.0); atypical autism (ata, ICD10 F84.1); Asperger’s syndrome (asp, ICD10 F84.5); and pervasive disorders, unspecified and others (pdm, ICD10 F84.8+9). 

It appears that ADHD cases were not subtyped, which is something of a shame. There is good reasons to think that the genetic basis of ADHD predominantly inattentive type (i.e. without hyperactivity), has a different genetic basis than ADHD combined type (and ADHD predominately hyperactive which probably overlaps heavily with the combined type). This level of information ought to have been available although empirically efforts to further subtype ADHD probably wouldn't have been available in the data. See, e.g, prior posts at this blog from September 8, 2012, April 3, 2012, and October 18, 2017 (Genetics of ADHD hyperactivity/impulsivity and inattention dimensions are quite different),

A Key Figure From The Paper


A figure from the closed access paper:


Fig. 2: Comparison of PRS profiles across ADHD and ASD subtypes for 15 traits and/or phenotypes that have shown significant genetic correlations with ADHD and ASD in the past.

Peer Review

The relatively new practice of disclosing comments from the peer review of the paper, provides some interesting insights although it is rather technical and difficult to evaluate without an open access manuscript to reference it to for the most part. Some notable comment state:
A serious limitation of this study is that the design relies on the common psychiatric nosology that in particular for ASD and ADHD has been problematic, surely in the past when only one of both diagnosis was allowed. Given the high comorbidity between ADHD and ASD, and among other psychiatric disorders in general, plus the fact that recent research shows that ‘genes do not respect diagnostic classifications’ (see CDG publications) I would rather see a focus on the shared genetic findings for ADHD and ASD, in aiming to find general genetic/biological vulnerabilities for trans diagnostic neurodevelopmental problems, instead of relying on a classification system that has surely proven its value in clinical practice but does not seem to guide biological underpinnings of those disorders.

and

Concerning the used sample, I would appreciate getting some more details on the assessment of comorbid ASD and ADHD in the respective cohort. While some of the individuals might have been diagnosed under DSM-IV, which did not allow a comorbid diagnosis of ADHD, I wonder if and how this was accounted for in the datasets. In light of the cited Meta-study 25-32% of ASD individuals do fulfill the criteria for ADHD. In this study, the comorbid cohort accounts for 10% of the sample (assuming they were from both the ASD and the ADHD cohorts).

The responses gave rise to a table regarding the shared risk genes:

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