ArticlePDF Available

Recent Studies on Genetic and Environmental Basis of Autism



Autism is a childhood neurodevelopmental disorder that affects 1–2 in 100 children, according to recent data on the broad array of autism spectrum disorders. It is a neurodevelopmental disorder, genetic and environmental factors playing role in autism. Molecular and mechanistic basis of autism started to be enlightened. As a genetic basis of disease, glutamate gene mechanisms supposed to develop a new method for diagnosing and treatment of autism. Aim of this mini-review is to gain a general knowledge about genetic and environmental reasons of autism.
JNBS 2014 Published by Üsküdar
Year : 2014
Volume : 1
Issue Number : 3
Doi Number : 10.5455/JNBS.1408369302
Article history:
Received 18 August 2014
Received in revised form 29 August 2014
Accepted 18 September 2014
1 Üsküdar University, Health Sciences Institute, Neuroscience Master Program
2 Üsküdar University, Faculty of Engineering and Natural Sciences, Bioengineering Program.
3 Üsküdar University, Faculty of Engineering and Natural Sciences, Department of Molecular Biology and Genetics.
*Address for Correspondance: Zeynep Kalkan, Üsküdar University, Health Sciences Institute, Neuroscience Master Program Department of Psychology,
Üsküdar University, Altunizade Mh. Haluk Türksoy Sk. No:14 İstanbul, Türkiye 34662.Phone:+90 5074929287 E-mail:
The disorders are characterized by impaired social
interaction, communication andverbal communication
and language impairments, and repetitive behaviors and
interests. Autism has an increasing prevalence in recent
years. From 2007 to 2011–2012, the incidence of ASD
rose from 1.16% to 2.00% in the United States of America
(Blumberg et al., 2013).
Most researches shows that both genetic and
environmental factors play a role in the development
of ASD. High concordance of ASD among boys and girls
cannot be explained by genetic heritability alone; shared
environmental factors explain a large proportion of the
variance in liability. In addition, prenatal exposure to
organophosphates has been related to a signicant
reduction in childhood IQ.
2. Glutamate and Autism
Glutamate is a major excitatory neurotransmitter, is
highly concentrated throughout the brain and is crucial
to neuronal plasticity and the maintenance of cognitive
1. Introduction
Autism is a neurodevelopmental disorder that affects
1–2 in 100 children, according to recent data on the broad
array of autism spectrum disorders . Autism is diagnosed
when a child or adult has abnormalities in a ‘‘triad’’ of
behavioral domains: social development, communication,
and repetitive behavior/obsessive interests. Autism can
occur at any point on the IQ continuum, and IQ is a strong
predictor of outcome (Baron-Cohen et al., 2009). Unusual
social development becomes apparent early in childhood.
Autistic infants show less attention to social stimuli, smile
and look at others less often, and respond less to their
own name. Autistic toddlers differ more strikingly from
social norms; for example, they have less eye contact
and turn taking, and do not have the ability to use simple
movements to express themselves, such as the deciency
to point at things.
Autism is one of the subtypes of autism spectrum
disorders (ASD) which refers to a group of childhood
neurodevelopmental disorders with polygenic etiology.
Autism is a childhood neurodevelopmental disorder that affects 1–2 in 100 children, according to recent data on the broad array of
autism spectrum disorders. It is a neurodevelopmental disorder, genetic and environmental factors playing role in autism. Molecular
and mechanistic basis of autism started to be enlightened. As a genetic basis of disease, glutamate gene mechanisms supposed to
develop a new method for diagnosing and treatment of autism. Aim of this mini-review is to gain a general knowledge about genetic and
environmental reasons of autism.
Keywords: autism, glutamate, immune system, genetic, neurodevelopment.
Zeynep Kalkan*1, Hazal Gür2, Belkis Atasever Arslan3
Otizm, son verilere gore, 100 çocuktan 1-2 sinde görülen bir çocuklukçağı nörogelişimsel hastalığıdır.Nörogelişimsel bir hastalık olan otizmde genetik
ve çevresel faktörler rol oynar. Otizmin moleküler ve mekanistik temelleri aydınlatılmaya başlanmıştır. Hastalığın genetik altyapılarından biri olarak,
glutamat gen mekanizması, teşhis ve tedavisi için yeni bir metod geliştirilmesine olanak sağlayabilir. Bu kısa derlemenin amacı, otizmin genetik ve
çevresel nedenleri ile ilgili yapılan son çalışmalardan faydalanılarak hastalık hakkında bilgi edinmektir.
Anahtar Kelimeler: otizm, glutamate, immune system, genetik, nörogelişim
JNBS 2014 Published by Üsküdar
functioning. However, excess glutamate has been shown
to be a potent neurotoxin that leads to neuronal cell
death (Manev et al., 1989) and is deemed to play a role in
the pathophysiology of some neuropsychiatric disorders
(Sheldon et al., 2007). Recently, a hyperglutamatergic
hypothesis of autism was proposed (Blaylock et al.,
2009) based on evidence of hyperglutamatergia in the
brain of individuals with autism. For instance, in a study,
levels of GAD 65 kDa and GAD 67 kDa proteins, both of
which are involved in converting glutamate to GABA, are
reduced in the brains of individuals with autism, resulting
in increased levels of glutamate in the brain substrate
(Fatemi et al, 2002). In addition, in another study that
contains neuroimaging magnetic resonance spectroscopy
has demonstrated that individuals with ASD have
signicantly higher concentrations of glutamate in the
amygdala- hippocampal region than do healthy controls
(Page et al., 2006). The high level of plasma glutamate
level especially in children with normal IQ is supposed
to be biomarker to diagnose autism (Shimmura et al.,
2011). Higher glutamate level is not limited to plasma,
and some studies conrmed its higher level in some brain
regions (amygdala-hippocampal regions) of patients with
autism compared to the controls (Page et al., 2006).
Most psychiatric and neurodevelopmental disorders
(PNDD) have a strong heritable component (Sullivan et al.,
2012). Twin studies have proved that neurodevelopmental
disorders, such as (ASD) (Posthuma et al., 2013).
Glutamate receptors (GluRs) mediate excitatory synaptic
transmission and plasticity in the brain (Traynelis et al.,
2010). Glutamate receptors encode GRIK2, GRIN3B
and GRIA3 genes which are related to ASD. In addition,
anomalies in regions on chromosomes six and seven,
encoding Glu receptors, have been related to ASD (Yang
et al., 2013). Abnormalities in the glutamatergic system
might therefore be implied in ASD. Indeed, epileptic
seizures which have been related to excitatory Glu and
decreased GABA, are common in ASD (Ballaban et al.,
3. Effects of environmental factors against autism
In addition to genetic basis of glutamate level,
environmental components also play role increased
glutamate level children with autism. Many children
with autism are picky eaters. They do not like a variety
of different foods. Eating problems are risk factors for
nutritional deciencies. Some of these children do not like
to try new foods and have food selectivity (Kral et al.,
Last ndings support that many children with autism
suffer from amino acids metabolism impairment.
Nearly, all the studies reported higher levels of plasma
glutamate in children with autism than those of the
controls. Hyperglutamatergic state causes excitotoxicity
and neurodegeneration (Sheldon et al., 2007). Moreover,
this increased glutamate level is compatible with the
ndings that the level of proteins involved in transforming
glutamate to GABA is decreased. A study compared
plasma level of 25 amino acids between high-functioning
autism children and the healthy controls. The study
showed that only the levels of glutamate and glutamine
were different between the two groups. While the level
of glutamate was increased, the level of glutamine was
decreased (Shimmura et al., 2011).
4. Immunologic system and autism
There is increasing evidence supporting that an immune
insult during pregnancy can have a signicant effect on
the developing fetus (Brown, 2012). For over 30 years,
epidemiological research has continued to nd associations
between maternal infection and increased risk of autism
(Atladottir et al., 2010). A recent large case-control
population based study revealed an increased risk of
developing autism spectrum disorder (ASD) with maternal
fever, which was attenuated if pregnant mothers used a
fever reducing agent (Zerbo et al., 2013). In addition,
reports highlight associations between risk of having a
child with autism and increased levels of inammatory
mediators in both the maternal sera and amniotic uid.
These increased inammatory markers, interleukins (IL)-
4, IL-5, and interferon (IFN)-γ. (Abdallah et al., 2012),
supporting a relationship between maternal immune
activation (MIA), aberrant fetal neurodevelopment, and
risk for neurodevelopmental disorders such as autism.
Also inammatory markers are playing role in another
neurological disorders such as panic disorder. A supporting
study has shownIL-12and IFN-γ were signicantly lower in
panic disorder group when compared to the controls and
IFN-γ values were signicant predictors of the presence of
panic disorder (Tukel et al., 2012).
5. Conclusion
Autism is not only result from genetic factors but
also environmental factors play signicant role in the
development of autism. From the beginning of individual’s
existence all factors can be effective. There are many
questions waiting to be answered about autism. Is it an
untreatable genetic destiny? Is there a chance to diagnose
autism before childhood?
It is still nebulous the underlying mechanisms of autism.
With understanding the role of molecular and mechanistic
basis of autism more details will be enlightened about
disease. Glutamate mechanism is only one of the
molecular reasons of autism. All knowledge in this area,
throw a new light on developing new genetic treatment
Abdallah, M.W., Larsen, N., Grove, J., Norgaard-Pedersen, B., Thorsen, P.,
Mortensen, E.L., Hougaard, D.M., (2012). Amniotic uid chemokines and
autism spectrum disorders: an exploratory study utilizing a danish historic
birth cohort. Brain Behav. Immun. 26, 170–176.
Atladottir, H.O., Thorsen, P., Ostergaard, L., Schendel, D.E., Lemcke,
S., Abdallah, M., Parner, E.T., (2010). Maternal infection requiring
hospitalization during pregnancy and autism spectrum disorders. J. Autism
Dev. Disord. 40, 1423– 1430.
Brown, A.S., 2012. Epidemiologic studies of exposure to prenatal infection
and risk of schizophrenia and autism. Dev. Neurobiol. 72, 1272–1276.
Ballaban-Gil, K., Tuchman, R. (2000) Epilepsy and epileptiform EEG:
Association with autism and language disorders. Ment. Retard. Dev. Disabil.
Res. Rev. 6, 300–308.
JNBS 2014 Published by Üsküdar University
Baron-Cohen, S., Scott, F.J., Allison, C., Williams, J., Bolton, P., (2009).
Prevalence of autism-spectrum conditions: UK school-based population
study. Br J Psychiatry.194, 500–509.
Blumberg, S.J.; Bramlett, M.D.; Kogan, M.D.; Schieve, L.A.; Jones,
J.R.; Lu, M.C., (2013). Changes in prevalence of parent-reported autism
spectrum disorder in school-aged U.S. Children: 2007 to 2011–2012. Natl.
Health Stat. Rep.
Fatemi, S.H. (2008). The hyperglutamatergic hypothesis of autism.
Progress in Neuro-Psychopharmacology and Biological Psychiatry. 32 (3),
Fatemi, S.H., Halt, A.R., Stary, J.M., Kanodia, R., Schulz, S.C. (2002).
Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic
parietal and cerebellar cortices. Biol Psychiatry. 52. 805–810.
Kral T. V., Eriksen W. T., Souders M. C., Pinto-Martin J. A. (2013). Eating
behaviors, diet quality, and gastrointestinal symptoms in children with
autism spectrum disorders: a brief review. Journal of Pediatric Nursing.
Manev, H., Favaron, M., Guidotti, A., Costa, E. (1989) Delayed increase of
Ca2+ inux elicited by glutamate: role in neuronal death. Mol Pharmacol
36, 106–112.
Page, L.A., Daly, E., Schmitz, N. (2006). In vivo resonance spectroscopy
study of amygdala-hippocampal and parietal regions in autism, American
Journal of Psychiatry, 163 (12), 2189–2192.
Posthuma, D., Polderman T.J.C. (2013). What have we learned from
recent twin studies about the etiology of neurodevelopmental disorders?.
Curr Opin Neurol 26, 111-121.
Sheldon, A.L., Robinson, M.B.(2007). The role of glutamatetransporters
in neurodegenerative diseases and potential opportunities for intervention.
Neurochemistry International, 51 (6-7), 333–355.
Shimmura C., Suda S., Tsuchiya K. J., Hashimoto K., Ohno K., Matsuzaki
H., Iwata K., Matsumoto K., Wakuda T., Kameno Y., Suzuki K., Tsujii M.,
Nakamura K., Takei N., Mori N. (2011). Alteration of Plasma Glutamate
and Glutamine Levels in Children with High-Functioning Autism. Plos One.
6, 1-6.
Sullivan, P.F., Daly, M.J., O’Donovan M. (2012). Genetic architectures of
psychiatric disorders: the emerging picture and its implications. Nature
reviews. 13, 537–55.
Traynelis, S.F., Wollmuth, L.P., McBain, C.J., Menniti, F.S., Vance, K.M.,
Ogden, K.K., Hansen, K.B., Yuan, H., Myers, S.J., Dingledine, R. (2010).
Glutamate receptor ion channels: structure, regulation, and function.
Pharmacol Rev. 62, 405-496.
Tükel, R., Arslan, B.A., Ertekin, B.A., Ertekin, E., Oaz, S., Ergen, A.,
Kuruca, S.E., İsbir, T., (2012). Decreased IFN-γ and IL-12 levels in panic
disorder. Journal of Psychosomatic Research. 73, 63-67.
Volkmar, F., Chawarska, K., Klin, A. (2005). Autism in infancy and early
childhood. Annu Rev Psychol. 56, 315–336.
Yang, Y., Pan, C. (2013). Role of metabotropic glutamate receptor 7 in
autism spectrum disorders: A pilot study. Life Sci. 92, 149–153.
Zerbo, O., Iosif, A.M., Walker, C., Ozonoff, S., Hansen, R.L., Hertz-Picciotto,
I., (2013). Is maternal inuenza or fever during pregnancy associated with
autism or developmental delays? Results from the CHARGE (CHildhood
Autism Risks from Genetics and Environment) study. J. Autism Dev. Disord.
43, 25–33.
Autism is one of the most common subtypes of autism spectrum disorder (ASD). Recent studies suggested a relationship between immune-dependent coding genes and ASD, indicating that long term neuroimmunological anomalies affect brain development and synaptic transmission among neural networks. Furthermore, various studies focused on biomarker potential of TNF-α in autism. Ionotropic receptors are also studied as potential marker for autism since altered gene expression levels are observed in autistic patients. GRID2 is a candidate ionotropic receptor which is involved glutamate transfer. In this study, to propose TNF- α dependent cellular processes involved in autism aetiology in relation to GRID2 we performed a bioinformatic network analysis and identified potential pathways and genes that are involved in TNF-α induced changes at GRID2 receptor levels. As a result, we ascertained the GRID2 receptor gene as a candidate gene and further studied the association between GRID2 expression levels and TNF-induced neurodegeneration. Our bioinformatic analyses and experimental results revealed that TNF-α regulates GRID2 gene expression by activating Cdc42 and GOPC genes. Moreover, increased TNF-α levels leads to increase of caspase-3 protein levels triggering neuronal apoptosis leading to neuronal deficiency, which is one of the major symptoms of autism. The study is the first to show the role of TNF-α in regulation of GRID2 gene expression and its signalling pathway. As a result, GRID2 gene can be a suppressor in TNF-induced neurodegeneration which may help to understand the main factors leading to autism.
Full-text available
The relative influence of genes and environment on the liability to neurodevelopmental disorders (NDDs) can be investigated using a twin design. This review highlights the results of the most recent twin studies of NDDs. Recent twin studies have confirmed that NDDs show moderate-to-high heritability, and that from an etiological viewpoint both autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are best regarded as the extremes on a continuous liability distribution. Both ASD and ADHD show high heritability in childhood and a substantial drop in heritability in adulthood, which is likely explained by the use of different assessment strategies in childhood versus adulthood, or by a complex mechanism of gene-by-environment interaction. NDDs show substantial comorbidity among each other, and with other mental health problems, which is partly because of a shared genetic etiology between different disorders. The findings of twin studies implicate substantial heritability of NDDs, and warrant large-scale molecular genetic studies for such traits.
Full-text available
We analyzed data from case groups of 538 children with autism spectrum disorders (ASD) and 163 with developmental delays (DD), and from 421 typically developing controls to assess associations with maternal influenza or fever during pregnancy. Exposure information was obtained by telephone interviews, and outcomes were clinically confirmed. Though neither ASD nor DD was associated with influenza, both were associated with maternal fever during pregnancy: OR's (odds ratios) were 2.12 (95 % CI 1.17, 3.84) and 2.50 (95 % CI 1.20, 5.20) respectively. However, the fever-associated ASD risk was attenuated among mothers who reported taking antipyretic medications (OR = 1.30, 95 % CI 0.59, 2.84), but remained elevated for those who did not (OR = 2.55, 95 % CI 1.30, 4.99).
Full-text available
It has recently been hypothesized that hyperglutamatergia in the brain is involved in the pathophysiology of autism. However, there is no conclusive evidence of the validity of this hypothesis. As peripheral glutamate/glutamine levels have been reported to be correlated with those of the central nervous system, the authors examined whether the levels of 25 amino acids, including glutamate and glutamine, in the platelet-poor plasma of drug-naïve, male children with high-functioning autism (HFA) would be altered compared with those of normal controls. Plasma levels of 25 amino acids in male children (N = 23) with HFA and normally developed healthy male controls (N = 22) were determined using high-performance liquid chromatography. Multiple testing was allowed for in the analyses. Compared with the normal control group, the HFA group had higher levels of plasma glutamate and lower levels of plasma glutamine. No significant group difference was found in the remaining 23 amino acids. The effect size (Cohen's d) for glutamate and glutamine was large: 1.13 and 1.36, respectively. Using discriminant analysis with logistic regression, the two values of plasma glutamate and glutamine were shown to well-differentiate the HFA group from the control group; the rate of correct classification was 91%. The present study suggests that plasma glutamate and glutamine levels can serve as a diagnostic tool for the early detection of autism, especially normal IQ autism. These findings indicate that glutamatergic abnormalities in the brain may be associated with the pathobiology of autism.
Objectives: This report presents data on the prevalence of diagnosed autism spectrum disorder (ASD) as reported by parents of school-aged children (ages 6-17 years) in 2011-2012. Prevalence changes from 2007 to 2011-2012 were evaluated using cohort analyses that examine the consistency in the 2007 and 2011-2012 estimates for children whose diagnoses could have been reported in both surveys (i.e., those born in 1994-2005 and diagnosed in or before 2007). Data sources: Data were drawn from the 2007 and 2011-2012 National Survey of Children's Health (NSCH), which are independent nationally representative telephone surveys of households with children. The surveys were conducted by the Centers for Disease Control and Prevention's National Center for Health Statistics with funding and direction from the Health Resources and Services Administration's Maternal and Child Health Bureau. Results: The prevalence of parent-reported ASD among children aged 6-17 was 2.00% in 2011-2012, a significant increase from 2007 (1.16%). The magnitude of the increase was greatest for boys and for adolescents aged 14-17. Cohort analyses revealed consistent estimates of both the prevalence of parent-reported ASD and autism severity ratings over time. Children who were first diagnosed in or after 2008 accounted for much of the observed prevalence increase among school-aged children (those aged 6-17). School-aged children diagnosed in or after 2008 were more likely to have milder ASD and less likely to have severe ASD than those diagnosed in or before 2007. Conclusions: The results of the cohort analyses increase confidence that differential survey measurement error over time was not a major contributor to observed changes in the prevalence of parent-reported ASD. Rather, much of the prevalence increase from 2007 to 2011-2012 for school-aged children was the result of diagnoses of children with previously unrecognized ASD.
Children with autism spectrum disorders (ASD) and their caregivers face unique challenges in the children's daily eating routines and food intake patterns. The aim of this brief review is to describe eating behaviors of children with ASD, including increased food neophobia and food selectivity, and review findings on children's diet quality, and gastrointestinal (GI) symptoms. Advancing knowledge about the interrelationships between these nutrition-related domains in children with ASD is expected to have important implications for clinical nursing practice and caregiver care.
Aims: The presence of genetic variants for autism spectrum disorders (ASDs) was investigated for the metabotropic glutamate receptor 7 (GRM7) gene in a case-control study. Main methods: Employing Affymetrix SNP microarrays, 297 single nucleotide polymorphisms (SNPs) covering the GRM7 gene were selected and analyzed in ASD patients (n=22), non-ASD patients [n=14, including seven patients with development delay (DD)/mental retardation (MR), four patients with language delay (LD), and three patients with attention deficit hyperactivity disorder (ADHD)] and normal control subjects (n=18). Key findings: Twenty-one statistically significant SNPs with different inheritance models (recessive, dominant and allele) were demonstrated in three groups (ASDs vs. combined controls, ASDs vs. normal controls, ASDs vs. non-ASD patients). Associations of rs779867 and rs6782011 with ASDs were significant in all three groups and independent associations of rs779867 and rs6782011 with ASDs were found in the ASD vs. combined controls group, which are in modest linkage disequilibrium (D'>0.5). Further haplotype analysis showed that rs6782011/rs779867 (T-C) was statistically significantly related to ASDs in both the ASD vs. combined controls and ASD vs. normal controls groups (bootstrap P value=0.013, permutation P value=0.013 for the former group and bootstrap P value=0.002, permutation P value=0.020 for the latter). Significance: These findings support a role for genetic variants within the GRM7 gene in 3p26.1 in ASDs.
Psychiatric disorders are among the most intractable enigmas in medicine. In the past 5 years, there has been unprecedented progress on the genetics of many of these conditions. In this Review, we discuss the genetics of nine cardinal psychiatric disorders (namely, Alzheimer's disease, attention-deficit hyperactivity disorder, alcohol dependence, anorexia nervosa, autism spectrum disorder, bipolar disorder, major depressive disorder, nicotine dependence and schizophrenia). Empirical approaches have yielded new hypotheses about aetiology and now provide data on the often debated genetic architectures of these conditions, which have implications for future research strategies. Further study using a balanced portfolio of methods to assess multiple forms of genetic variation is likely to yield many additional new findings.
In this review, we provide a synopsis of work on the epidemiologic evidence for prenatal infection in the etiology of schizophrenia and autism. In birth cohort studies conducted by our group and others, in utero exposure to infectious agents, prospectively obtained after biomarker assays of archived maternal sera and by obstetric records was related to an increased risk of schizophrenia. Thus far, it has been demonstrated that prenatal exposure to influenza, increased toxoplasma antibody, genital-reproductive infections, rubella, and other pathogens are associated with schizophrenia. Anomalies of the immune system, including enhanced maternal cytokine levels, are also related to schizophrenia. Some evidence also suggests that maternal infection and immune dysfunction may be associated with autism. Although replication is required, these findings suggest that public health interventions targeting infectious exposures have the potential for preventing cases of schizophrenia and autism. Moreover, this work has stimulated translational research on the neurobiological and genetic determinants of these conditions. © 2012 Wiley Periodicals, Inc. Develop Neurobiol, 2012.
Elevated levels of chemokines have been reported in plasma and brain tissue of individuals with Autism Spectrum Disorders (ASD). The aim of this study was to examine chemokine levels in amniotic fluid (AF) samples of individuals diagnosed with ASD and their controls. A Danish Historic Birth Cohort (HBC) kept at Statens Serum Institute, Copenhagen was utilized. Using data from Danish nation-wide health registers, a case-control study design of 414 cases and 820 controls was adopted. Levels of MCP-1, MIP-1α and RANTES were analyzed using Luminex xMAP technology. Case-control differences were assessed as dichotomized at below the 10th percentile or above the 90th percentile cut-off points derived from the control biomarker distributions (logistic regression) or continuous measures (tobit regression). AF volume for 331 cases and 698 controls was sufficient for Luminex analysis. Including all individuals in the cohort yielded no significant differences in chemokine levels in cases versus controls. Logistic regression analyses, performed on individuals diagnosed using ICD-10 only, showed increased risk for ASD with elevated MCP-1 (elevated 90th percentile adjusted OR: 2.32 [95% CI: 1.17-4.61]) compared to controls. An increased risk for infantile autism with elevated MCP-1 was also found (adjusted OR: 2.28 [95% CI: 1.16-4.48]). Elevated levels of MCP-1 may decipher an etiologic immunologic dysfunction or play rather an indirect role in the pathophysiology of ASD. Further studies to confirm its role and to identify the potential pathways through which MCP-1 may contribute to the development of ASD are necessary.