A new study sheds light on some of the risk factors for the development of psychosis, including the potentially causative role of sexual assault.
Investigators conducted an exposome-wide association analysis on more than 155,000 individuals. Of more than 140 correlates of psychotic experiences that they identified, they narrowed it down to 36 variables, which they further explored using Mendelian randomization analysis.
On the other hand, having experienced a physical violent crime, cannabis use, and prolonged worry after embarrassment showed a pleiotropic association and appeared to be an aftereffect of psychotic experience.
“From a public health perspective, we need more investment in comprehensive strategies to prevent traumatic experiences at the population level to decrease the burden of psychosis,” senior author Sinan Gülöksüz, MD, PhD, associate professor in the department of psychiatry and neuropsychiatry, Maastricht University Medical Center, the Netherlands, said in an interview.
“From a clinical perspective, clinicians should be aware of the harmful influence of traumatic experiences on mental health and address this through interventions such as trauma-informed care,” he said.
The study was published online in.
‘Disentangling’ cause and effect
“Previous research has shown associations between psychosis and a few environmental factors, such as substance use, urbanicity, pregnancy complications, and traumatic experiences, but research has so far investigated only a few specific environmental factors by singling them out in individual studies,” Dr. Gülöksüz said.
“Yet, environment is a much more complex and interactive network that includes many factors shaping our health – where we live, what we eat, our lifestyle preferences and habits such as exercise and smoking, and our social surrounding,” he continued. “Rarely has it been possible to understand whether these environmental factors have causal roles in developing psychosis.”
To investigate the question, the researchers turned to the UK Biobank, one of the largest population-based datasets in the world. The current study focused on individuals with completed data on mental questionnaires that assessed psychotic experiences (n = 155,247; mean [SD] age, 55.94 [7.74] years; 57% female).
They began by conducting an exposome-wide association study, using logistic regression analyses with psychotic experiences as the outcome and adjusting all analyses for age and sex.
“Initially, we identified many associations between environmental factors and psychotic experiences in this large cohort,” Dr. Gülöksüz reported.
In the final multivariable model, variables associated with psychotic experiences were further analyzed using “genetically informed approaches to probe potential associations.”
The researchers utilized Mendelian randomization (MR) methodology “to disentangle cause and effect in this observational study,” Dr. Gülöksüz said. “This method reduces confounding and reverse causation in observational studies by using genetic variants that have been passed on from generation to generation randomly as instruments.”
MR analysis “has allowed us to assess whether these associations reflect potentially causal influences of environmental factors on psychotic experiences,” he added.
Well-studied and unexplored risk factors
The researchers identified 162 variables associated with psychotic experiences in the discovery dataset and were able to replicate 148. When these 148 variables were subjected to multivariable analyses, 36 were found to be statistically significantly associated with psychotic experiences. Of these variables, 28 had “significant genetic overlap” with psychotic experiences.
When the researchers conducted one-sample MR analyses, they found forward associations with three variables and reverse associations with three variables.
Forward associations were found with ever having experienced sexual assault (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.14-1.52; P = 2.67), and forward associations (with pleiotropy) were found with ever having experienced a physically violent crime and risk-taking behavior (OR, 1.25, 95% CI, 1.11-1.41; P = 3.28 and OR, 1.21, 95% CI, 1.08-1.35; P = 1.34, respectively).
“The allele scores for these 3 variables explained 0.03% to 0.23% variance of the corresponding variable” and the F statistics “ranged from 21.53 to 181.84, indicating that the results did not suffer from a weak-instrument bias,” the authors reported.
The researchers calculated an instrument based on increasing psychotic experiences risk allele scores and found that these scores explained 0.14% variance of psychotic experiences (F statistic, 19.26).
Using that calculation, they found a reverse association with having experienced a physically violent crime (OR, 1.08; 95% CI, 1.04-1.13; P = 3.92 × 10-4), cannabis use (OR, 1.11; 95% CI, 1.06-1.15; P = 2.64 × 10-6), and worrying too long after embarrassment (OR, 1.06; 95% CI, 1.03-1.10; P = 3.96 × 10-4). They then validated these associations.
The presence of all five correlates was associated with tenfold increased odds of psychotic experiences (OR, 10.63; 95% CI, 8.27-13.65, P = 1.2 × 10-114).
“Associations with psychotic experiences were found with both well-studied and unexplored multiple correlated variables,” the authors stated.
Era of ‘big data’
In a comment, Chirag Patel, PhD, associate professor of biomedical informatics at Harvard Medical School, Boston, who was not involved with the study, said he thought the study was “a nice example of a data-driven and comprehensive study of the environment coupled with attempts to triangulate evidence from genetics, made possible by biobank data.
“To guide public health policies and implementation of prevention strategies for psychosis, we need more systematic analyses and triangulate evidence with genetically informed methods to identify potentially modifiable risk factors in the era of ‘big data,’ ” he said.
“For instance, traumatic experiences contribute to poor mental and physical health, including psychosis,” Dr. Gülöksüz added.
The Kootstra Talent Fellowship, the Ophelia Research Project, and the Vidi Award from the Netherlands Scientific Organization provided funding to individual investigators. Dr. Gülöksüz and coauthors declared no relevant financial conflicts. Dr. Patel served as a reviewer on the study.
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