Genetics of monozygotic twins reveals the impact of environmental sensitivity on psychiatric and neurodevelopmental phenotypes, 2025, Assary et al

[forestglip]

Genetics of monozygotic twins reveals the impact of environmental sensitivity on psychiatric and neurodevelopmental phenotypes

Spoiler: Authors

Elham Assary, Jonathan R. I. Coleman, Gibran Hemani, Margot P. van de Weijer, Laurence J. Howe, Teemu Palviainen, Katrina L. Grasby, Rafael Ahlskog, Marianne Nygaard, Rosa Cheesman, Kai Lim, Chandra A. Reynolds, Juan R. Ordoñana, Lucia Colodro-Conde, Scott Gordon, Juan J. Madrid-Valero, Anbupalam Thalamuthu, Jouke-Jan Hottenga, Jonas Mengel-From, Nicola J. Armstrong, Perminder S. Sachdev, Teresa Lee, Henry Brodaty, Julian N. Trollor, Margaret Wright, David Ames, Vibeke S. Catts, Antti Latvala, The Within Family Consortium, Eero Vuoksimaa, Travis Mallard, K. Paige Harden, Elliot M. Tucker-Drob, Sven Oskarsson, Christopher J. Hammond, Kaare Christensen, Mark Taylor, Sebastian Lundström, Henrik Larsson, Robert Karlsson, Nancy L. Pedersen, Karen A. Mather, Sarah E. Medland, Dorret I. Boomsma, Nicholas G. Martin, Robert Plomin, Meike Bartels, Paul Lichtenstein, Jaakko Kaprio, Thalia C. Eley, Neil M. Davies, Patricia B. Munroe & Robert Keers

Abstract
Individual sensitivity to environmental exposures may be genetically influenced. This genotype-by-environment interplay implies differences in phenotypic variance across genotypes, but these variants have proven challenging to detect. Genome-wide association studies of monozygotic twin differences are conducted through family-based variance analyses, which are more robust to the systemic biases that impact population-based methods.

We combined data from 21,792 monozygotic twins (10,896 pairs) from 11 studies to conduct one of the largest genome-wide association study meta-analyses of monozygotic phenotypic differences, in children, adolescents and adults separately, for seven psychiatric and neurodevelopmental phenotypes: attention deficit hyperactivity disorder symptoms, autistic traits, anxiety and depression symptoms, psychotic-like experiences, neuroticism and wellbeing.

The proportions of phenotypic variance explained by single-nucleotide polymorphisms in these phenotypes were estimated (h2 = 0–18%), but were imprecise. We identified 13 genome-wide significant associations (single-nucleotide polymorphisms, genes and gene sets), including genes related to stress reactivity for depression, growth factor-related genes for autistic traits and catecholamine uptake-related genes for psychotic-like experiences.

This is the largest genetic study of monozygotic twins to date by an order of magnitude, evidencing an alternative method to study the genetic architecture of environmental sensitivity. The statistical power was limited for some analyses, calling for better-powered future studies.

Link | PDF (Nature Human Behavior) [Open Access]

 

[forestglip]

Depression

Several genome-wide significant results were notable, including our finding that the PTCH1 gene was associated with variation in depression symptoms, as this gene has previously been reported to be associated with depression-related phenotypes, including neuroticism24,25, anxiety26, depression symptoms24, feeling emotionally hurt27 and sensitivity to environmental stress and adversity27.

Anxiety

The C15orf38 gene (also known as ARPIN-AP3S2) was associated with variance in anxiety symptoms in our samples from children and has previously been associated with type 2 diabetes in adults25,28 and corticotropin-releasing factor protein levels29, which are involved in regulating anxiety, mood, eating and inflammation30. Hypoglycaemia symptoms in type 2 diabetes include a rapid heartbeat, sweating and nervousness, all of which are physical sensations associated with anxiety. It is possible that certain variants in this gene impact sensitivity to the effects of diet and stressors that are involved in the variability in insulin31, unpleasant physical sensations of which may be contextualized and made sense of as worries and anxieties (for example, the two-factor model of emotions32).

Autistic traits

For autistic traits, the identified gene set included genes involved in tissue morphogenesis and healing that regulate the response to transforming growth factor beta (TGFβ1) levels and are involved in tissue repair pathways33. Growth factors serve important roles in neurodevelopment, immune function and development of the central nervous system and there is evidence that autism is associated with TGFβ1 and other growth factor-encoding genes34,35,36.

Psychotic-like experiences

For PLEs [psychotic-like experiences], the identified gene sets were related to the regulation of dopamine and catecholamine uptake. Our findings are supported by catecholamine’s involvement in the stress response and the hypothesized role of dopamine system dysregulation in the aetiology of psychosis37.

 

[Jonathan Edwards]

Can anyone explain what this abstract means? To me it is a prime example of how jargon in genetics is used to turn simple system dynamic concepts into impenetrable gibberish. There is no mention of stochastic causation either.

 

[forestglip]

Can anyone explain what this abstract means? To me it is a prime example of how jargon in genetics is used to turn simple system dynamic concepts into impenetrable gibberish. There is no mention of stochastic causation either.

I tried reading the paper, and can't understand most of it. But I think the main idea is this: they're not looking for SNPs that cause these conditions. They're looking for SNPs that cause increased variation in getting the condition (in other words, SNPs that increase the influence of environment or chance).

With monozygotic twins, their DNA is (nearly) identical, so most variation between twins should be due to non-DNA factors. Suppose you have three pairs of twins with different alleles:
Pair 1: Allele A (Neither twin has depression)
Pair 2: Allele B (Both twins have depression)
Pair 3: Allele C (One twin has depression and one twin does not have depression)

So allele C allows more influence from environment or chance on whether a person gets depression.

More from Wikipedia: Gene–environment interaction

Sometimes, sensitivity to environmental risk factors for a disease are inherited rather than the disease itself being inherited. Individuals with different genotypes are affected differently by exposure to the same environmental factors, and thus gene–environment interactions can result in different disease phenotypes. For example, sunlight exposure has a stronger influence on skin cancer risk in fair-skinned humans than in individuals with darker skin.[3]

 

[Jonathan Edwards]

More from Wikipedia: Gene–environment interaction

But this is just the basics that we are all familiar with. Apart from monogenic conditions pretty much all SNP risk associations are 'permissive' or 'dispositional' in the context of other factors. Most fall into the C situation. The first sentence in the abstract gives me the strong feeling that the authors' do not understand their subject at this level.

And there seem to be a lot of them!