A profile and review of findings from the Early Markers for Autism study: unique contributions from a population-based case–control study in California

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Abstract

Background

The Early Markers for Autism (EMA) study is a population-based case–control study designed to learn more about early biologic processes involved in ASD.

Methods

Participants were drawn from Southern California births from 2000 to 2003 with archived prenatal and neonatal screening specimens. Across two phases, children with ASD ( n = 629) and intellectual disability without ASD (ID, n = 230) were ascertained from the California Department of Developmental Services (DDS), with diagnoses confirmed according to DSM-IV-TR criteria based on expert clinical review of abstracted records. General population controls (GP, n = 599) were randomly sampled from birth certificate files and matched to ASD cases by sex, birth month and year after excluding individuals with DDS records. EMA has published over 20 papers examining immune markers, endogenous hormones, environmental chemicals, and genetic factors in association with ASD and ID. This review summarizes the results across these studies, as well as the EMA study design and future directions.

Results

EMA enabled several key contributions to the literature, including the examination of biomarker levels in biospecimens prospectively collected during critical windows of neurodevelopment. Key findings from EMA include demonstration of elevated cytokine and chemokine levels in maternal mid-pregnancy serum samples in association with ASD, as well as aberrations in other immune marker levels; suggestions of increased odds of ASD with prenatal exposure to certain endocrine disrupting chemicals, though not in mixture analyses; and demonstration of maternal and fetal genetic influence on prenatal chemical, and maternal and neonatal immune marker and vitamin D levels. We also observed an overall lack of association with ASD and measured maternal and neonatal vitamin D, mercury, and brain-derived neurotrophic factor (BDNF) levels.

Limitations

Covariate and outcome data were limited to information in Vital Statistics and DDS records. As a study based in Southern California, generalizability for certain environmental exposures may be reduced.

Conclusions

Results across EMA studies support the importance of the prenatal and neonatal periods in ASD etiology, and provide evidence for the role of the maternal immune response during pregnancy. Future directions for EMA, and the field of ASD in general, include interrogation of mechanistic pathways and examination of combined effects of exposures.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13229-021-00429-7.

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Most cited references 117

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The Changing Epidemiology of Autism Spectrum Disorders

Kristen Lyall, Lisa A Croen, Julie T. Daniels … (2017)

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with lifelong impacts. Genetic and environmental factors contribute to ASD etiology, which remains incompletely understood. Research on ASD epidemiology has made significant advances in the past decade. Current prevalence is estimated to be at least 1.5% in developed countries, with recent increases primarily among those without comorbid intellectual disability. Genetic studies have identified a number of rare de novo mutations and gained footing in the areas of polygenic risk, epigenetics, and gene-by-environment interaction. Epidemiologic investigations focused on nongenetic factors have established advanced parental age and preterm birth as ASD risk factors, indicated that prenatal exposure to air pollution and short interpregnancy interval are potential risk factors, and suggested the need for further exploration of certain prenatal nutrients, metabolic conditions, and exposure to endocrine-disrupting chemicals. We discuss future challenges and goals for ASD epidemiology as well as public health implications.

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Genome-wide Association Study Identifies 27 Loci Influencing Concentrations of Circulating Cytokines and Growth Factors.

Ari Ahola-Olli, Peter Würtz, Aki Havulinna … (2017)

Circulating cytokines and growth factors are regulators of inflammation and have been implicated in autoimmune and metabolic diseases. In this genome-wide association study (GWAS) of up to 8,293 Finns we identified 27 genome-widely significant loci (p < 1.2 × 10(-9)) for one or more cytokines. Fifteen of the associated variants had expression quantitative trait loci in whole blood. We provide genetic instruments to clarify the causal roles of cytokine signaling and upstream inflammation in immune-related and other chronic diseases. We further link inflammatory markers with variants previously associated with autoimmune diseases such as Crohn disease, multiple sclerosis, and ulcerative colitis and hereby elucidate the molecular mechanisms underpinning these diseases and suggest potential drug targets.

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Genetic heritability and shared environmental factors among twin pairs with autism.

Joachim Hallmayer, Sue Cleveland, Andrea Torres … (2011)

Autism is considered the most heritable of neurodevelopmental disorders, mainly because of the large difference in concordance rates between monozygotic and dizygotic twins. To provide rigorous quantitative estimates of genetic heritability of autism and the effects of shared environment. Twin pairs with at least 1 twin with an autism spectrum disorder (ASD) born between 1987 and 2004 were identified through the California Department of Developmental Services. Structured diagnostic assessments (Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule) were completed on 192 twin pairs. Concordance rates were calculated and parametric models were fitted for 2 definitions, 1 narrow (strict autism) and 1 broad (ASD). For strict autism, probandwise concordance for male twins was 0.58 for 40 monozygotic pairs (95% confidence interval [CI], 0.42-0.74) and 0.21 for 31 dizygotic pairs (95% CI, 0.09-0.43); for female twins, the concordance was 0.60 for 7 monozygotic pairs (95% CI, 0.28-0.90) and 0.27 for 10 dizygotic pairs (95% CI, 0.09-0.69). For ASD, the probandwise concordance for male twins was 0.77 for 45 monozygotic pairs (95% CI, 0.65-0.86) and 0.31 for 45 dizygotic pairs (95% CI, 0.16-0.46); for female twins, the concordance was 0.50 for 9 monozygotic pairs (95% CI, 0.16-0.84) and 0.36 for 13 dizygotic pairs (95% CI, 0.11-0.60). A large proportion of the variance in liability can be explained by shared environmental factors (55%; 95% CI, 9%-81% for autism and 58%; 95% CI, 30%-80% for ASD) in addition to moderate genetic heritability (37%; 95% CI, 8%-84% for autism and 38%; 95% CI, 14%-67% for ASD). Susceptibility to ASD has moderate genetic heritability and a substantial shared twin environmental component.

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Author and article information

Contributors

Kristen Lyall:

ORCID: http://orcid.org/0000-0002-4633-0799

kld98@drexel.edu

Journal

Journal ID (nlm-ta): Mol Autism

Journal ID (iso-abbrev): Mol Autism

Title: Molecular Autism

Publisher: BioMed Central (London )

ISSN (Electronic): 2040-2392

Publication date (Electronic): 18 March 2021

Publication date PMC-release: 18 March 2021

Publication date Collection: 2021

Volume: 12

Electronic Location Identifier: 24

Affiliations

[1 ]GRID grid.166341.7, ISNI 0000 0001 2181 3113, A.J. Drexel Autism Institute, , Drexel University, ; Suite 560, 3020 Market St, Philadelphia, PA 19104 USA

[2 ]GRID grid.280062.e, ISNI 0000 0000 9957 7758, Division of Research, , Kaiser Permanente Northern California, ; Oakland, CA USA

[3 ]GRID grid.236815.b, ISNI 0000 0004 0442 6631, Environmental Health Investigations Branch, , California Department of Public Health, ; Richmond, CA USA

[4 ]GRID grid.266102.1, ISNI 0000 0001 2297 6811, University of California, ; San Francisco, San Francisco, CA USA

[5 ]GRID grid.21107.35, ISNI 0000 0001 2171 9311, School of Medicine, , Johns Hopkins University, ; Baltimore, MD USA

[6 ]GRID grid.21107.35, ISNI 0000 0001 2171 9311, Department of Mental Health, , Johns Hopkins University, ; Baltimore, MD USA

[7 ]GRID grid.27860.3b, ISNI 0000 0004 1936 9684, UC Davis MIND Institute, , University of California, Davis, ; Davis, CA USA

Author information

Kristen Lyall http://orcid.org/0000-0002-4633-0799

Article

Publisher ID: 429

DOI: 10.1186/s13229-021-00429-7

PMC ID: 7977191

PubMed ID: 33736683

SO-VID: 43320513-4b77-4b92-a6b5-63e1b451ddd1

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 30 November 2020

Date accepted : 23 February 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: R01-ES016669

Award Recipient : Lisa A. Croen

Funded by: FundRef http://dx.doi.org/10.13039/100005188, Tobacco-Related Disease Research Program;

Award ID: 8RT-0115

Award Recipient : Martin Kharrazi

Custom metadata

ScienceOpen disciplines: Neurosciences

Keywords: autism,risk factors,immune response,early markers for autism

Data availability:

ScienceOpen disciplines: Neurosciences

Keywords: autism, risk factors, immune response, early markers for autism

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A profile and review of findings from the Early Markers for Autism study: unique contributions from a population-based case–control study in California

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Abstract

Background

Methods

Results

Limitations

Conclusions

Supplementary Information

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Most cited references 117

The Changing Epidemiology of Autism Spectrum Disorders

Genome-wide Association Study Identifies 27 Loci Influencing Concentrations of Circulating Cytokines and Growth Factors.

Genetic heritability and shared environmental factors among twin pairs with autism.

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