Brain Matters Vol. 8 No. 2


Written by Brianna Mae Huner

investigations came to the forefront. It was initially
projected that the data collected from the HGP would
revolutionize the screening, diagnosis, and treatment of
mental illnesses. However, 20 years after this prediction was
made, the etiology of these conditions remains unclear, as
the nature of these illnesses has been found to be difficult to
discern through genetic studies.
Schizophrenia Spectrum Disorder (also known as
schizophrenia) is characterized by symptoms of three types:
positive, negative, and disorganized symptoms, with a poor
prognosis and heavy cost toward the individual, their
family, and society. Positive symptoms are referred to as
such because their symptoms add characteristics that are
not already present in normal functioning, such as
hallucinations or delusions. Negative symptoms are the
opposite, “taking away” from normative functioning, such
as avolition (lack of motivation) and diminished emotional
expression. Disorganized symptoms refer to a lack of order
and form in terms of thinking or activity, such as
disorganized speech and motor behavior (American
Psychological Association, 2022). Schizophrenia exists on a
spectrum of disorders and is believed to be at least partially
caused by genetics. The risk of developing schizophrenia is
linked to the degree of relation to a family member with
schizophrenia. As seen in Figure 1, a first degree relative to a
patient with schizophrenia would have a 3.0%
hospitalization rate for psychosis, and a second degree
relative would have a 2.2% hospitalization rate, both
compared

Genetic Research and its
Revolutionary? Contributions
to Schizophrenia Prevention

Introduction
For over a century, physicians, neurologists, psychiatrists,
biologists, and eventually geneticists have been working
hard to answer the question: what causes schizophrenia and
its related disorders? In earlier days of research, much of the
focus was placed on the treatment of such conditions, and
scientists have made great advancements in this area. For
example, in the early 19th century, it was typical to see
patients with schizophrenia exhibit catatonia, which is a
symptom characterized by a decrease in reactivity to
environmental stimuli. These patients were stuck within
these states for days or weeks. Now, catatonia is treated
with benzodiazepines, and patients can return to non-
catatonic functioning over a much shorter period of time.
Sienart et al., 2014). This pharmacological discovery has
improved the lives of schizophrenia patients dramatically
and has shifted the typical symptomology observed in this
disorder. Yet, the question remains: what causes this
disorder, and can we use that knowledge to prevent its
development in the first place? Investigations into the
etiology (or causes) of schizophrenia have proven to be less
fruitful than their treatment-based counterparts. The
knowledge that schizophrenia is at least partially genetic
motivated a surge of investigations into the human genome.
This research began with studies using molecular genetics, a
method proven to be incredibly effective in discoveries into
etiology of other genetic diseases. With the completion of
the Human Genome Project (HGP), genome-wide
investigations 59



compared to the general population hospitalization rate of
0.9% (Karlsson, 1971). This disorder can be debilitating, often
requiring full-time hospitalization and lifetime treatment.
Many patients never return to normal functioning, even
between episodes. There is also a higher risk of suicide and
early death associated with this disorder (Jobe & Harrow,
2005). The severity of such a disease, combined with its
proven genetic component, has driven large-scale research
into the etiology of schizophrenia at the order of the genes,
producing a myriad of results.

Table 1. Rates of hospitalization with functional psychosis
in relatives of psychotic index cases in Iceland.

segregation such as dominant, recessive, and X-linked
(Chial, 2008). One can follow along using genetic information
to make reasonable predictions about the phenotype, such
as hair or eye color, of an organism by simply examining
their pedigree. The diseases with causes found through
molecular genetics followed Mendelian patterns of
inheritance, such as Huntington’s disease, whose pattern of
inheritance can be observed in Figure 2. By comparing the
genes of people who both do and do not have a familial
disorder, target genes can be identified. Additionally,
disorders such as HD and ALS are caused by a single
defective gene that can be isolated and identified relatively
easily. On the contrary, mental illnesses do not follow
Mendelian patterns of inheritance. They are likely polygenic
(caused by multiple genes) and multifactorial (caused by
genetic and environmental factors, as well as interactions
between genes and environment). By using these methods of
searching and comparing target areas of the genome, there
were genes identified as possibly being involved in mental
illnesses, but the results weren’t as clear-cut as finding one
gene that causes a certain disorder.

Brain Matters Vol. 8 2025

60

Research Method #1: Molecular Genetics
Biologists have been using the varying tools at their disposal
over time to investigate the etiology of genetic diseases,
with one of these methods being molecular genetics. This
research revealed key insights into the fields of biology,
neurology, and genetics, though it was not as comparatively
impactful in psychiatry. Molecular genetics, a field of
research that studies genes on a molecular level, focuses on
variations in DNA. Studies using this framework have shed
light on the genetic mutations behind a number of
neurological disorders, such as Huntington’s disease (HD),
Fragile X Syndrome (FXS), and Amyotrophic Lateral
Sclerosis (ALS) (Cowan et al., 2002). These discoveries
allowed for improved screening and early identification of
these conditions. However, studies using molecular genetics
to find the causes of mental illnesses gave mixed results of
small effect sizes. This difference can be explained through
the nature of these conditions, particularly within the
inheritance patterns of the disorder whose causes were
found. 
Many Americans are made aware of Mendelian patterns of
inheritance, though they may not know it by that name,
while taking high school biology, through lessons about
yellow and green peas and Punnett squares. Classic
Mendelian patterns of inheritance involve patterns of
segregation

While investigating the human genome to find associations
between certain genes and specific psychiatric disorders, a
number of loci were identified. Linkage analysis was often
used in these studies prior to the completion of the Human
Genome Project, which uses genetic markers to find areas
on the genome that are close to genes thought to cause
certain conditions (Pulst, 1999). Some well-known findings
from analyses looking into schizophrenia identified
chromosomal regions associated with the serotonin 5HT2A
receptor gene (13q14.1-32), as well as chromosomal regions
related to synapse-related genes (22q11-12) (Cowan et al.,
2002). These findings garnered interest, considering the
importance of synapses in neuronal function and
serotonin’s role in mood regulation and homeostatic roles
(Mohammad-Zadeh & Bryant, 2008). With the advent of new
techniques

Figure 1. Correa & Guimaraes (2006). Pedigree
showcasing the inheritance of Huntington's Disease (HD).



Research Method #2: Data Analysis from The
Human Genome Project 
The Human Genome Project (HGP) was a moon-shot project,
with the goal of sequencing the entire human genome, and
its completion created a new wave of data and discoveries
into the field of genetic biology. Launching in 1990 and
concluding in 2003, the HGP cost $3 billion (Gannett, 2023).
The ability to map the entire human genome created a vast
bank of data that could be utilized when researching, for
example, cancer and its treatment (Rood & Regev, 2021). It
was predicted that the discoveries resulting from the HGP
data would allow for gene-based treatments for critical
disease such as diabetes and hypertension, as well as change
the game for the treatment of mental illnesses. Some
scientists went so far as to say that the impact the HGP
would have on the field of medicine would be comparable to
the discovery of antibiotics (Torrey, 2024). Genome wide
association studies (GWAS) were conducted using the new
data, and nearly 300 single nucleotide polymorphism (SNP)
genetic loci were linked to an increased risk of the
development of schizophrenia. Such findings seemed to
signal that major breakthroughs were on the way.  
Unfortunately, much of the evidence uncovered through
GWAS did not hold up under scrutiny. Through comparisons
between studies, about half of the genomic loci associated
with schizophrenia was discovered to also be associated
with other disorders believed to be partially genetic, such as
bipolar disorder and autism (Torrey, 2024). Therefore, an
argument can be made that these loci are associated with
psychiatric disorders as a whole, rather than schizophrenia
specifically. Additionally, many of the SNPs identified were
found to have a very small effect size, and while they could
be linked to schizophrenia, they could not be linked to a
cause of schizophrenia. This bears resemblance to how a
reduction in size of the frontal lobe is associated with
depression, but it is not known if this reduction causes
depression, or is caused by depression (Joseph et al., 2025).
Despite these discouraging findings, there may be one with
promise.

A change in the region of the genome known as the Major
Histocompatibility Complex presents strong evidence of an
association with schizophrenia, potentially revealing a link
between the disorder and the immune system. The Major
Histocompatibility Complex (MHC), located on chromosome
6, is associated with the regulation of immune functions, as
well as many infectious diseases and autoimmune disorders
(Abualros et al., 2021). A GWAS revealed an association
between a small alteration in this area and the development
of schizophrenia (Caseras et al., 2024). While this finding
may initially seem confusing, it does connect some previous
findings and hypotheses about schizophrenia. The presence
of some infectious diseases during pregnancy, such as
influenza, though new evidence reveals that more research
is needed in this area (Fung et al., 2022), and Toxoplasma
gondii (Yang et al., 2024), are known to slightly increase the
risk of the child developing schizophrenia. The MHC’s
association to autoimmune disorders could also shed light
onto the hypothesis that differences in the functions of
microglia (the “brain’s immune system”) could explain some
of the symptoms of schizophrenia, as it is hypothesized that
essential synapses could be erroneously tagged for
consumption by microglia as a part of the brain’s synaptic
pruning process used to clear unused and unneeded
synapses (Li et al., 2023). This incorrect deletion of synapses
could explain the cognitive and disorganized issues often
associated with schizophrenia, as vital neuronal pathways
could be disrupted. Unfortunately, this finding only had a
polygenic risk score, which gives an estimate of an
individual’s genetic risk for developing a specific trait, to
explain less than 10% of the variation in liability for the
disease (Andreassen et al., 2023). While these findings are
promising, they are far from the revolution that was
predicted.

Genetic Research and its Revolutionary? Contributions to Schizophrenia Prevention

One can follow along using
genetic information to make

reasonable predictions about the
phenotype, such as hair or eye

color, of an organism by simply
examining their pedigree.

61

techniques and technology, it was believed that we would be
able to find clearer answers in these areas and their
connection to schizophrenia. 

Future Directions
Despite the lack of definitive findings through genetic
studies, there may still be something to be gleaned from this
data. The results of the HGP still have hopes of finding
significant results, as researchers hope to use newly
introduced machine learning functions to aid in their
search. They are also making efforts to factor in potential
epigenetic changes caused by environmental factors and
gene x environment interactions, or perhaps the solution
lies in something that hasn’t been considered yet.
It is possible that the flaw in this system is the question
itself. It is widely accepted that there is no single or primary
cause of many mental disorders, and it is possible that these
disorders are the result of multiple different pathways. To
explain this, we may look toward an example in the medical
world: obesity, and its association with Leptin and Leptin
genes. Leptin is a hormone that signals satiety, telling the
body when it should stop eating. Leptin receptor deficiency
is a rare genetic disorder which causes a mutation in the
Leptin gene that results in an inability for the body to
produce Leptin. Without a satiety signal, the body’s ability
to regulate eating is compromised, and the subject becomes
obese



obese. However, when this subject is treated with Leptin
supplements, their food intake regulation ability is restored,
and they return to a normal weight. In this case, this
mutation causes obesity. But not all cases can be explained
this way. Leptin treatment only works on obese patients
who have this mutation, and if they do not, the treatment
produces little effect (Milan et al., 2021). Obesity has multiple
causes, and treatment must be derived based on the specific
cause. Could a similar approach be applied to schizophrenia,
where different treatments could be used for different
causes? Could we pinpoint these different causes?
One of the most important traits needed in research is
curiosity. While many may be discouraged by the lack of
major breakthroughs in the genetic research of
schizophrenia and other psychiatric disorders, others may
see this as eye-opening, and an invitation to think
nontraditionally about these findings. While it was
originally believed that genetic research such as molecular
genetics, linkage analysis, genome wide association studies,
and more would be the key to understanding the etiology of
schizophrenia, this was found to be inaccurate, but that
doesn’t mean that all hope is lost. All that is needed is a new
question to be asked.

About the Author
Brianna Mae is a Junior at the University of Illinois majoring in
Clinical/Community Psychology. She became involved in Brain Matters to gain
more experience researching and writing about the current research in
Neuroscience. When she is not writing for Brain Matters, she is also involved in
Dr. Kwapil's Project on Life Experiences Lab, and is the Treasurer for the
Psychology Research and Community Club (PRACC). Brianna Mae is hoping to
pursue a PhD in Clinical Neuropsychology and conduct research about the
neurological basis behind different clinical disorders. 

6. Corrêa, B.B., Xavier, M. & Guimarães, (2006). J. Association of
Huntington's disease and schizophrenia-like psychosis in a
Huntington's disease pedigree. Clin Pract Epidemiol Ment
Health 2(1). https://doi.org/10.1186/1745-0179-2-1
7. Cowan, W. M. et al. (2002). The Human Genome Project and
Its Impact on Psychiatry. Annual Review of Neuroscience, 25.
doi: 10.1146/annurev.neuro.25.112701.142853
8. Fung et al. (2022). Neuropsychiatric outcomes in offspring
after fetal exposure to maternal influenza infection during
pregnancy: A systematic review. Reproductive Toxicology. 113.
https://doi.org/10.1016/j.reprotox.2022.09.002
9. Gannet, L. (2023). The Human Genome Project. The Stanford
Encyclopedia of Philosophy. Metaphysics Research Lab,
Standford University. 
10. Gottesman, I. I. (1991). Schizophrenia genesis: The origins of
madness. W H Freeman/Times Books/ Henry Holt & Co.
10. Jobe, T. H., & Harrow, M. (2005). Long-term Outcome of
Patients with Schizophrenia: A Review. The Canadian Journal
of Psychiatry. 50(14).
https://doi.org/10.1177/070674370505001403
11. Joseph et al. (2025). Structural brain changes and
neuroticism in late-life depression: a neural basis for
depression subtypes. International Psychogeriatrics. 33(5).
https://doi.org/10.1017/S1041610221000284
12. Karlsson, J. L. (1971). Rates of the schizophrenic genotype in
relatives of psychotic persons. Hereditas. 69(2).
https://doi.org/10.1111/j.1601-5223.1971.tb02437.x
13. Li, J. et al. (2023). New insight in the cross-talk between
microglia and schizophrenia: From the perspective of
neurodevelopment. Frontiers in Psychiatry. 14.
DOI=10.3389/fpsyt.2023.1126632
14. Milan et al. (2021). Leptin and Obesity: Role and Clinical
Implication. Frontiers in Endocrinology. 12.
DOI=10.3389/fendo.2021.585887
15. Pulst, S. M. (1999). Genetic Linkage Analysis. Arch Neurol.
56(6) doi:10.1001/archneur.56.6.667 
16. Sienart et al. (2014). A Clinical Review of the Treatment of
Catatonia. Frontiers in Psychiatry. 5.
DOI.org/10.3389/fpsyt.2014.00181
17. Torrey, E. F. (2024). Did the human genome project affect
research on Schizophrenia?, Psychiatry Research, 333.
https://doi.org/10.1016/j.psychres.2023.115691.
18. Yang et al. (2024). Toxoplasma gondii infection positively
associated with schizophrenia: Evidences from UK Biobank
cohort and case-controlled studies. Journal of Psychiatric
Research. 175. https://doi.org/10.1016/j.jpsychires.2024.05.025

Brain Matters Vol. 8 2025

62

References
1. Abualrous et al. (2021). Major histocompatibility complex
(MHC) class I and class II proteins: impact of polymorphism on
antigen presentation. Current Opinion in Immunology. 70.
https://doi.org/10.1016/j.coi.2021.04.009
2. American Psychological Association, (2022). Schizophrenia
Spectrum and Other Psychotic Disorders. Diagnostic and
Statistical Manual of Mental Disorders.
https://doi.org/10.1176/appi.books.9780890425787.x02_Schizop
hrenia_Spectrum
3. Andreassen et al. (2023). New insights from the last decade of
research in psychiatric genetics: discoveries, challenges and
clinical implications. World Psychiatry. 22(1).
https://doi.org/10.1002/wps.21034
4. Caseras et al. (2024). Common risk alleles for schizophrenia
within the major histocompatibility complex predict white
matter microstructure. Translational Psychiatry. 14(194).
https://doi.org/10.1038/s41398-024-02910-2
5. Chial, H. (2008). Mendelian genetics: Patterns of inheritance
and single-gene disorders. Nature Education 1(1)

https://doi.org/10.1186/1745-0179-2-1
https://doi.org/10.1016/j.reprotox.2022.09.002
https://doi.org/10.1177/070674370505001403
https://doi.org/10.1017/S1041610221000284
https://doi.org/10.1111/j.1601-5223.1971.tb02437.x
https://doi.org/10.1016/j.psychres.2023.115691
https://doi.org/10.1016/j.jpsychires.2024.05.025
https://doi.org/10.1016/j.coi.2021.04.009
https://doi.org/10.1176/appi.books.9780890425787.x02_Schizophrenia_Spectrum
https://doi.org/10.1176/appi.books.9780890425787.x02_Schizophrenia_Spectrum
https://doi.org/10.1002/wps.21034
https://doi.org/10.1038/s41398-024-02910-2


63