Wednesday, August 3, 2022

Environmental factors play a greater role in the etiology of psychotic experiences than genetic factors: some groups of individuals with seemingly low genetic risk for psychotic experience may develop them if exposed to high levels of environmental risk

Taylor MJ, Freeman D, Lundström S, Larsson H, Ronald A. Heritability of Psychotic Experiences in Adolescents and Interaction With Environmental Risk. JAMA Psychiatry. Published online August 03, 2022. doi:10.1001/jamapsychiatry.2022.1947

Key Points

Question  Are psychotic experiences less heritable for adolescents who experience more environmental risk factors?

Findings  In a twin study of 4855 twin pairs aged 16 years from the UK, the relative importance of genetic influences on certain psychotic experiences diminished with more exposure to environmental risk factors. A similar pattern of results was observed in an independent sample from Sweden (N = 8568 pairs).

Meaning  These results suggest gene-by-environment interactions in relation to psychotic experiences; some groups of individuals with seemingly low genetic risk for psychotic experience may develop them if exposed to high levels of environmental risk, in a similar manner to clinical observations in relation to schizophrenia.


Importance  Genetic risk factors are known to play a role in the etiology of psychotic experiences in the general population. Little is known about whether these risk factors interact with environmental risks for psychotic experiences.

Objective  To assess etiological heterogeneity and exposure to environmental risks associated with psychotic experiences in adolescence using the twin design.

Design, Setting, and Participants  This twin study, conducted from December 1, 2014, to August 31, 2020, included a UK-based sample of twin pairs aged 16 years. This investigation evaluated the extent to which the genetic variance underlying psychotic experiences and the magnitude of the heritability of psychotic experiences was moderated by exposure to 5 environmental risk factors (bullying, dependent life events, cannabis use, tobacco use, and low birth weight). Psychotic experiences were assessed by 5 self-reported measures and 1 parent-reported measure. Participants’ exposure to environmental risks was assessed at birth and age 12 to 16 years. Structural equation models were used to assess differences in the variance in and heritability of psychotic experiences across these exposures, while controlling for gene-environment correlation effects. Analyses were repeated in an independent Swedish sample. Data analyses were performed from September 1, 2018, to August 31, 2020.

Main Outcomes and Measures  Primary outcome measures were exposure to environmental factors, as measured by a composite score, and psychotic experiences.

Results  A total of 4855 twin pairs (1926 female same-sex pairs, 1397 male same-sex pairs, and 1532 opposite-sex pairs) were included from the Twins Early Development Study (TEDS), and 6435 twin pairs (2358 female same-sex pairs, 1861 male same-sex pairs, and 2216 opposite-sex pairs) were included from the Child and Adolescent Twin Study in Sweden (CATSS). Mean age of twins from TEDS was 16.5 years. Mean age of twins from CATSS was 18.6 years. More exposure to environmental risk factors was associated with having more psychotic experiences. The relative contribution of genetic influences to psychotic experiences was lower with increasing environmental exposure for paranoia (44%; 95% CI, 33%-53% to 38%; 95% CI, 14%-58%), cognitive disorganization (47%; 95% CI, 38%-51% to 32%; 95% CI, 11%-45%), grandiosity (41%; 95% CI, 29%-52% to 32%; 95% CI, 9%-48%), and anhedonia (49%; 95% CI, 42%-53% to 37%; 95% CI, 15%-54%). This pattern was replicated for the measure of psychotic experiences in the independent Swedish replication sample. The heritability of hallucinations and parent-rated negative symptoms remained relatively constant.

Conclusions and Relevance  Findings of this twin study suggest that environmental factors play a greater role in the etiology of psychotic experiences than genetic factors. The relative importance of environmental factors is even higher among individuals exposed to environmental risks for psychotic experiences, highlighting the importance of a diathesis-stress or bioecological framework for understanding adolescent psychotic experiences.


In this cohort study, we tested whether the heritability of adolescent psychotic experiences changes with exposure to environmental risks associated with psychotic experiences. Results suggest a gene-by-environment interaction for paranoia, hallucinations, cognitive disorganization, grandiosity, and anhedonia. The findings were replicated in an independent Swedish sample, thus lending robustness to our results. Our study thus suggests differences in heritability of certain psychotic experiences that may be associated with environmental exposures.

Specifically, there was an observed reduction in heritability of psychotic experiences in the presence of environmental exposures. These results are consistent with a bioecological framework, which would predict that more favorable environments would lead to higher heritability.20Our results run contrary to a diathesis-stress pathway to psychotic experiences, which would predict that environmental risks trigger a genetic susceptibility to a given disorder and would thus lead to higher heritability of a phenotype in the presence of environmental risks.20

It is also important to put our results in the context of prior studies of gene-by-environment interaction in relation to psychotic experiences. One study33 reported that the association between environmental risks and psychotic experiences increased among individuals with a family history of psychosis. Although this finding also supports gene-by-environment interaction, the results are somewhat different than what would be expected from our analyses because our analyses suggest that genetic factors were less salient in the presence of environmental exposures. Moreover, other studies34,35 have found no evidence of gene-by-environment interaction for psychotic experiences. Methodological differences may underlie these discrepancies. First, family history is not the same as genetic influence because family history includes a combination of genetic and shared environmental factors. Second, we focused on a composite exposure score comprising 5 environmental factors; prior studies have focused on more specific factors, including childhood physical abuse35 and trauma.34 Third, we focused on 6 specific psychotic experiences here, whereas prior studies used single measures. Finally, it is important to note that prior studies focus specifically on the interaction between genetic risk for psychotic experiences based on family history, by contrast with the current study that used the twin design. In our study, we tested whether heritability differed dependent on exposure to environmental risks. Heritability is a population statistic, and as such, an approach based on calculating heritability is somewhat different from an approach based on using family history as a proxy for individual genetic risk.

On a clinical level, it is first important to clarify that we focused on a young sample, who were aged 16 or 18 years. Many of these individuals will be too young to have been diagnosed with a psychotic disorder, but it is known that psychotic experiences in this age group can lead to severe clinical conditions in some individuals. Nonetheless, clinically it is often noted that many individuals with schizophrenia do not have a family history of schizophrenia. Indeed, although the relative risk for schizophrenia is increased among relatives of individuals diagnosed with schizophrenia, most relatives of individuals with schizophrenia do not develop schizophrenia.36 Our results extend these observations to adolescent psychotic experiences and indicate that they may develop in a variety of contexts. Specifically, our results suggest that psychotic experiences may be prevalent in populations with a high degree of exposure to environmental risks associated with psychotic experiences. Indeed, there is substantial conjecture that psychotic experiences can be reached through multiple pathways, such as pathways that are more based on genetic propensity and others that are more down to environmental risks; however, to our knowledge, this is one of the first studies to provide replicable empirical findings on this topic.

The previously mentioned arguments should be tempered, however, for certain types of psychotic experiences. Although we observed that the heritability differed according to environmental exposure for some psychotic experiences, the heritability was more consistent for hallucinations and negative symptoms. This is important from a clinical perspective, given that negative symptoms are thought to be particularly predictive of subsequent mental illness. As such, these results lend further weight to the argument that the etiology of psychotic experiences may differ according to specific subtypes of psychotic experience.8

Strengths and Limitations

Strengths of our study included the use of 2 representative, population-based samples in different countries. In 1 sample, we measured 6 different specific psychotic experiences, enabling us to consider gene-by-environment interactions for different psychotic experiences. There were several limitations, however. Although we employed data from both the UK and Sweden, we still only focused on 2 European countries. Many of our exposures may differ in prevalence across the world, and it would therefore be useful to assess whether similar results emerge in countries with more environmental variability than the UK and Sweden. Our measures of tobacco and cannabis use were more brief than our other measures. Future studies should use more detailed measures. We also created a composite score that involved counting the number of exposures each participant had undergone, which included summing exposures that may have different etiologies or mechanisms underlying their association with psychotic experiences. Further, although our model has controlled for gene environment correlation, we recognize that birth weight is a complex phenotype influenced by parent and child genetics and prenatal environment.

It is further important to be aware that the environmental composite is not identical across TEDS and CATSS. The life events scale, for example, includes items about increasing numbers of quarrels with parents in CATSS, which are not covered in TEDS. Percentile-based cutoffs were used to define low birth weight; birth weight was lower in TEDS than CATSS on average, and therefore, this led to heavier twins being captured in CATSS. Exclusion criteria also differed between samples; individuals with extreme obstetric complications were excluded from TEDS but not CATSS. The fact that we observed similar results between CATSS and TEDS gives us confidence that these differences did not strongly influence our results; however, they should nevertheless be interpreted with these differences in measure in mind. Finally, twins are generally born lighter than singletons. We included birth weight as an exposure here, and hence, individuals with very low birth weight may have been overrepresented in our sample. However, studying birth weight in twins here is unlikely to create any issues for generalizability for 2 reasons. First, our modeling analyses were focused on variance rather than mean differences. Second, twins were compared with twins in the design (not singletons); as such, modest mean differences between singletons and twins in birth weight did not affect the findings.

No comments:

Post a Comment