1. Lydia Wallace
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Analysis of Causes of Autism Spectrum Disorders in Utah
Research Review
Lydia Wallace
Abstract
Autism Spectrum Disorders (ASD) are a range of neurological development
disorders that occur in all ages, races, ethnicities, and socioeconomic groups. However,
Utah, specifically the Wasatch Front, has one of the highest rates of autism diagnosis in
the nation and the disorder is becoming increasingly prevalent in Utah’s communities.
According to the Autism Speaks foundation, 1 in 68 people in the United States are
diagnosed with autism, which has increased by over 100% in the last decade [15]. The
number of cases has increased from 1/ 2,500 in the 1980s to 1/150 in 2011 [12]. It is
believed that these disorders exist due to a combination of genetic and environmental
factors, but the exact cause is not fully understood. Currently, researchers are working on
identifying the genes responsible for the disorders by identifying genetic risk factors as
well as analyzing potential geographic, environmental, and socioeconomic influences.
Exploration of these results and analysis of the possible causes of ASD will shed some
light on the spike in ASD case diagnosis in the Wasatch Front and suggest future areas of
study.
Introduction
Autism spectrum disorders are a range of neurological disorders including autistic
disorder, aspergers disorder, childhood disintegrative disorder (CDD), Rett's disorder,
and other persuasive development disorders (PPD). These disorders are complex
disabilities affecting a child's social, behavioral and neurological development.

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Individuals with autism begin to show regress in language and/or social skills, have poor
eye contact, display repetitive speech or behaviors, and exhibit excessive disinterest in
social interactions. These kinds of disorders have an enormous impact on the lives of
those diagnosed and their families. Treatment is expensive and often inaccessible. Early
diagnosis and therapy has been found to be the most effective way to reverse the effects
of ASD. The number of ASD cases in the United States has increased from 3.3 cases to
186 ASD cases per 10,000 [3, 6] with similar trends occurring in Utah. And, though it is
highly researched, the origin of ASD remains a mystery. The current consensus among
researchers is that environmental problems before or during birth in combination with
genetic risk factors trigger a malfunction during a child’s brain development.
Molecular and Genetic Factors
Analysis of the molecular elements of autism indicates a complex genetic puzzle
with linkage across numerous genes. What is known is that ASD is highly heritable
across generations. The sibling of a child with autism is ten times more likely to develop
a level of ASD then the average individual whereas a cousin is two times more likely to
develop ASD than average [9]. It is also known that ASD is phenotypically
heterogeneous and is linked with multiple gene loci. This means that there is not just one
gene responsible for ASD. In fact, no single locus accounts for greater than 1% of the
cases [12]. When segments of the human genome are modified or mutated it can give
rise to cognitive developmental issues as well as other negative consequences. These
kinds of developmental issues are seen and studied in relation to ASD as well as other
psychiatric disorders. Genetic variation of this kind is expected and common, but rare
genetic variants occur as well. Both common and rare variants contribute to ASD

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susceptibility. Common genetic variants increase the risk of ASD modestly whereas rare
genetic variants, whether it occurs for the first time in an individual or in a closely related
individual, greatly increase the risk of ASD [12].
Since autism is highly heritable, many studies employ genome-wide association
(GWA) studies. In these studies, researchers compare and contrast genomes of affected
individuals, their families as well as unaffected controls. Researchers analyze the
genomes to identify which single-nucleotide polymorphisms (SNPs) or common genetic
variants are associated with the appearance of specific traits, diseases, and/or disorders.
Most notable of these studies is the Autism Genome Project GWA that looked at over
1,000,000 SNPs in over 2,700 families. A single significant SNP was not found but the
presence of multiple SNPs could have a weak influence on the risk of ASD [12]. This
further delineates the complexity of the genetic factors surrounding ASD.
Significant trends can be seen in cases with rare genetic variants and de novo
mutations (i.e. mutations occurring for the first time in a germ cell). Approximately 15-
22% of ASD cases have some form of rare genetic variance including cytogenetic
abnormalities (abnormalities associated with a chromosome and its development), single
gene-mutations, or copy-number variants (CNVs otherwise defined as sub-microscopic
deletions or duplications) [12]. One fascinating trend seen among studies of de novo
mutations is that several gene mutations in ASD affect the same molecular pathways in
other syndromes such as fragile X syndrome and tuberous sclerosis syndrome [12].
When these molecular pathways are tampered with, the formation and function of
synapse adversely influenced. This is important to ASD research because it begins to

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bridge a gap between other genetically inherited diseases as well as other psychiatric
disorders and opens windows to other overlapping areas of study.
The most significant CNVs and SNPs are those that alter genes that encode for
Shank2, Shank3, SAPAP2 from the GKAP/SAPAP family of Shank interacting proteins.
These proteins are major components in the excitatory glutamatergic synapses which, are
vital for brain function [12]. Overall it has been established that ASD is a complex
combination of genetic variants and mutations that are highly heritable across
generations. These genetic variations, in combination with environmental factors, put an
individual at risk for ASD.
Environmental Factors
The genetic factors, while important, are not the only component of ASD.
According to a study done in California in 2011 and a similar study done in Denmark in
2013, approximately 50% of the risk was traced to environmental factors whereas
approximately 50% was associated with genetics [9]. There are many prospective
environmental factors that could contribute to development of ASD. The role of these
factors is still debated because an “environment” can have extreme variations from place
to place. Despite this debate, a series of possible common environmental influences have
been narrowed to include complications during pregnancy and/or exposure to chemicals
during prenatal and perinatal stages of development.
Potential environmental factors include advanced parental age, breech
presentation, maternal weight gain, maternal fever during pregnancy, chemical and
pollutant exposures including hazardous air pollutants, heavy metals and pesticides, and
early exposure to prescription medications such as valproic acid, thalidomide and

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selective serotonin reuptake inhibitors [2, 3]. Geggal points out that heavy-metal
pesticides, air pollutants and other toxins surround people more than ever before [9]. It’s
rational to infer that these toxins have an adverse effect on our bodies.
The increasing prevalence of ASD indicates that there has to be an influencing
factor causing this steep influx of cases. Some groups argue that the increase in cases is
purely due to increased awareness and better diagnosis strategies but there is a consensus
among researchers that growing awareness is simply not a strong enough explanation for
the almost exponential growth rate of ASD diagnosis. Many researchers argue that
environmental factors are the culprit. Since ASD is a developmental disorder and can be
diagnosed as early as 14 months, the prenatal and perinatal window of development is a
considerable area of research [10]. If a fetus was exposed to all or some of the
environmental factors listed above it could interrupt the proper development pathway of
the human brain [10]. Any changes to the genomic sequence or molecular pathways
during this developmental window could cause substantial changes to the developing
cells which causes a domino effect of problems as the brain develops. Many of the
environmental factors are interrelated and cause changes on the molecular level. For
instance, it was found that both immune system interferences and differing zinc
homeostasis might affect synaptic transmission in an individual with ASD [10].
The culmination of these studies indicates that environmental factors are related
to complications before or during birth. These complications disrupt a molecular
pathway thereby altering the development of the brain.

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Discussion: How do Environmental and Genetic factors relate to each
Other?
In order to discuss the significance of the growing rate of ASD diagnosis in the
Wasatch Front, we must first consider how the genetic and environmental factors relate.
Indeed, the key to finding the cause for ASD is understanding the correlation between the
genetic and environmental factors. Andreas Grabrucker of the Neurocenter of Ulm
University stated, “Many symptoms are observed and many significant associations of
environmental as well as genetic factors were found. What is missing so far is a
hypothesis, unifying all those different factors” [10]. It can be definitively stated that
ASD is caused by a combination of genetic and environmental factors.
There is strong evidence for the interrelatedness of genetic and environmental
factors. For example, in order for the central nervous system to develop correctly, the
immune system must be responding properly [12]. An irregularity in the immuoresponse,
whether triggered by errors in the genetic makeup or exposure of toxins from the
environment, during this precise period of brain development fosters an unfavorable
environment for the fetus. This triggers errors in the developmental pathway thereby
modifying the growth of the brain. An individual will have high risk for ASD if they
have specific genetic variants and mutations caused by certain SNPs or CNVs. These
genetic variations cause errors in the genetic makeup of the individual, which means
there will be a ripple effect of issues as the body develops. If the genetic information
contains errors, cells will not grow and/or function correctly, which also triggers errors in
the developmental pathway linking the genetic and environmental factors contributing to
ASD.

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Discussion: How do Genetic and Environmental factors relate to the
Wasatch Front?
As stated above, the Wasatch Front (Salt Lake County, Davis County, Utah
County) has one of the highest rates of autism diagnosis in the nation. In Utah, 1 in 54
children are diagnosed with ASD [6]. Some have argued that this number has increased
over the last few decades purely because of increased awareness among parents and
educators. However, the rate of the increasing cases is too significant to be simply
attributed to increased awareness alone. As stated before, 1 in 68 people in the United
States are diagnosed with autism, which has increased over a 100% in the last decade
[15]. So, what is it about the Wasatch Front area that has caused such a high ASD
diagnosis rate? The answer may be found using spatial analysis.
University of Utah researcher Amanda V. Bakian and her colleagues used spatial
analysis to identify ASD geographical hotspots and cross-referenced these hotspots with
differences in children’s race/ethnicity, maternal age, paternal age, maternal education,
and paternal education between ASD cases and controls. After surveillance of Utah,
Davis, and Salt Lake counties five ASD hotspots were identified: four within Salt Lake
county and one within Davis county [3]. The research indicates that children living in the
hotspots had a risk of ASD three times greater than that of children living in other parts
of the surveillance area [3].
Bakain found significant linkage between socioeconomic status, residence of
birth, and risk of ASD. This connection indicates that those in a higher socioeconomic
status had a high risk of ASD either because (1) patients had more opportunities for
diagnosis or (2) they are more likely to be exposed to negative environmental factors due
to their residency. Diagnosed individuals were mainly White, Non-Hispanic populations.

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This data could likely be skewed because of residential segregation, but other U.S.
studies have shown that on average Hispanic populations have reduced risk of ASD.
The surveillance region contains ambient air pollution, high altitude and agricultural
pesticides, which are all possible sources for exposure to environmental toxins but more
research would need to be conducted to confirm these as risk factors [3].
In another study, also completed at the University of Utah, researchers conducted
a genome-wide linkage study on families within Utah with ASD susceptible genes to
create a large-scale pedigree to compare genetic variation across generations and identify
significant chromosomes [1]. The genome-wide linkage scan of 70 families ranging from
large (6-9 generations), medium (4-5 generations), and small (2-3 generations). Several
linkage peaks were found the most significant occurring on chromosome 15. This is
consistent with other researchers indicating and area for further, more specific genetic
research.
Based on Bakain’s spatial analysis, there are several areas along the Wasatch
Front where children are more like to be diagnosed with ASD. These areas are all
densely populated, urban areas in close proximity to highways and industrial factories
that could cause exposure to air pollutants. According to the Utah Division of Air
Quality (DAQ), on December 14, 2009, Provo, Salt Lake City, and Logan Utah/Idaho
areas were not in compliance with federal health air quality standards. However,
according to the Utah DAQ 2012 Annual Report, Utah’s air quality has been in
compliance with federal standards and has been steadily decreasing since 2009.
Comparing the Utah DAQ data with Bakain’s ASD hotspots, we can conclude that the
Wasatch front has the most polluted air relative to the rest of the state, which may

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contribute to the higher rate of ASD diagnosis. However, more research needs to be done
to definitively identify air pollutants and their relation to ASD diagnosis before it can be
identified as a major factor in Wasatch Front ASD cases.
One area of genetic research to be considered is the possibility the Founder’s
Effect has on the Wasatch Front population. Defined as a relative loss of genetic
variation when a new population is established by a select group of individuals from a
larger population, the founder’s effect can be a possible explanation for prevalence of a
genetic disease [11]. Growing prevalence of a genetic disease among White, Non-
Hispanic individuals living in Salt Lake and Davis counties could be explained by the
Founders Effect. The Wasatch Front area was predominantly colonized by the Mormon
pioneers and, although pedigree analysis indicates minimal amounts of inbreeding in the
Mormon pioneer population [11], Utah Mormons still tend to marry those raised close to
their own residential area. This relatively limited initial gene pool could explain the
increased frequency of ASD. If particular SNPs and CNVs were present in the founders
or arose through the pedigree of an affected individual it could lead to some answers
about the origins of ASD and it’s high prevalence among Wasatch Front families.
Although highly researched, there are still many questions to be answered
concerning the cause of ASD. Overall it has been established that ASD is a complex
combination of genetic variants and mutations that are highly heritable across
generations. These genetic variations, in combination with environmental factors, put an
individual at risk for ASD. Exposure to negative environmental factors during the
prenatal/perinatal brain developmental window, linked with specific SNPs and CNVs,
will put an individual at risk. Environmental factors such as chemical and pollutant

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exposures including hazardous air pollutants and heavy metals and pesticides during
pregnancy couls all adversely affect an exposed fetus [2, 3].
Even though genes associated with ASD are highly complex and have linkage
across multiple gene loci, there are genetic candidates up for further study.
Environmental factors can be narrowed as well. By applying spatial analysis to identify
ASD hotspots in other locations and cross referencing them with documented pollutant
levels perhaps a more conclusive environmental factor could be identified. Another
suggested area of research would be to look at family and community pedigrees to
determine if Founders Effect could be contributing to the prevalence of ASD cases in
certain areas. To reiterate Grabrucker’s statement, the answer lies on hypotheses that are
based on the convergence between genetic and environmental factors.

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