The importance of research on environmental factors in a highly heritable disorder
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The importance of research on environmental factors in a highly heritable disorder
Mark A. Corrales, MPP US Environmental Protection Agency
Statements are those of the author, and do not necessarily represent views or policies of the EPA
Autism One Conference May 22, 2009
Parallel Universes?
• General public • Parents & affected kids • Interest groups:
– environmental health advocacy – industries
• Researchers • Policy/ decision-makers: Lawyers, economists, policy and risk analysts, staff scientists, etc.
Getting from here to there
• If you believe national-level medical and environmental health interventions are needed… • the autism research literature is a key bottleneck.
From evidence to action
Drug development Experimental toxicology, mechanisms RCTs Behav./Educ. therapy guidelines Regulations to limit risk factors
Anecdotes, case studies Guesses, theories
Prospective epidemiology Retrospective epidemiology Ecologic More studies
studies
Better studies More types of studies
(multiple lines of evidence)
Public & scientific consensus
Is there sufficient evidence for action? Published scientific research literature on environmental factors in autism is still quite limited compared to other diseases or health effects.
Why so little research on environmental factors in autism?
• • • All autism research limited (until recently) Behavioral > molecular level (until recently) Genes > Environment: High heritability misinterpreted as “genes not environment” Toxicology and epidemiology not sufficiently integrated with autism research so far
•
Why so little research on environmental factors in autism?
• • • All autism research limited (until recently) Behavioral > molecular level (until recently) Genes > Environment: High heritability misinterpreted as “genes not environment” Toxicology and epidemiology not sufficiently integrated with autism research so far
•
Most autism science is extremely recent
As of early 2009, • Half of all the autism research literature indexed in PubMed was published in the past eight years: 2000-2008. • One third was published in just the last five years: 2004-2008.
Very Recent Explosion of Interest in Autism
In 2008:
• Newspaper articles: >3,000 headlines/ year • Scientific journal articles: >1,000 / year • New books: >150 / year
Journal articles
But so far…
• Treatment -New ASD treatments approved: 0 • Primary prevention (at national level) -Environmental standards, regulations, or other actions taken based on any potential ASD risk factors: 0
Autism Literature is Still Relatively Limited
• If you believe national-level medical and environmental health interventions are needed… • the autism research literature is a key bottleneck.
What has autism literature focused on?
Why so little research on environmental factors in autism?
• • • All autism research limited (until recently) Behavioral > molecular level (until recently) Genes > Environment: High heritability misinterpreted as “genes not environment” Toxicology and epidemiology not sufficiently integrated with autism research so far
•
Autism literature has focused on behavioral, not chemical level
• The PDD literature focused on the behavioral and cognitive levels three times as much as did biomedical literature as a whole (as % of articles). • 56% vs. only 38% of publications were indexed with chemical substances in PubMed vs. PDD literature, even recently (2000-2006).
Corrales, Ringer, & Herbert 2008 IMFAR poster #2999
Moldin vs. Lathe biological level
% of publications 1985-2007 with MeSH
Chem level
Focus on Chemicals & Drugs Level
100%
75%
50%
48%
30%
25%
0%
re n
la r
TB
Pr io n
si on
Bi po
hr
es
AD
Pe
ile
Ep
op
ep r
tis
in i
iz
Comorbid disorders at elevated prevalence in PDD according to Rzhetsky (2007)
Sc h
Rh
D
PD
D
[M H
ps
en
H
H
CP
ia
IV
D
y
]
Why so little research on environmental factors in autism?
• • • All autism research limited (until recently) Behavioral > molecular level (until recently) Genetic > Environmental studies: High heritability misinterpreted as “genes not environment” Toxicology and epidemiology not sufficiently integrated with autism research so far
•
Genetic etiology pie
A few molecular substances have dominated the literature (1985-2007)
• Approx. 2,000 unique substance terms in ASD literature, occurring 12k times in 4,000 PMIDs
– Half the substance terms appear only once. – Avg. substance is in just 6 PMIDs
• Chemicals in >100 articles each:
– MECP2 gene or protein (>400) – Serotonin (251) – Risperidone (112)
Corrales, Ringer, & Herbert 2008 IMFAR poster #2999.
• >130 medications in >1200 PMIDs ( ~10% of articles) • 43 environmental pollutant terms (other than Hg) occur 111 times across 84 PMIDs ( <1% of articles)
– Only 36/111 refer to a specific chemical rather than class (“teratogens” or “environmental pollutants” seen up to 13 times each) – Lead and cocaine were the most common specific toxins. – No other specific toxin (except Hg) appeared in more than 4 PMIDs. 3 Hg-related terms in 91 PMIDs (<1%)
Medications vs. environmental pollutants
• 41 dietary substances in 189 PMIDs (1-2%) (e.g., gluten, folic acid) (excluding food additives) • A few potential treatments/ causes (valproic acid, oxytocin, melatonin, secretin) found in 26-91 PMIDs each. • ~20 other terms in 2-14 PMIDs each: (food additives, illegal drugs, infectious agents or allergens, nicotine, alcohol, caffeine)
Corrales, Ringer, & Herbert 2008 IMFAR poster #2999. Includes publications 1985-2007.
Environment-relevant topics understudied in ASD literature, relative to all biomedical literature
Haz subst
Hazardous Substances + Organophosph.
Chlorpyrifos Phosphoric Acid Esters Street Drugs Cadmium Asbestos Pesticides Water Pollutants, Chemical Air Pollutants Mutagens Insecticides Cyclophosphamide Organophosphorus Compounds Endotoxins Carcinogens 0.01 0.10 1.00 10.00 100.00
Rate Ratio (Rate in ASD vs all PubMed citations)
Cell types
Cell Types
Neurons
T-Lymphocytes
Killer Cells, Natural
B-Lymphocytes
Macrophages 0.01 0.10 1.00 10.00 100.00
Rate Ratio (Rate in ASD vs all PubMed citations)
Understudied in ASD vs. in 10 comorbid disorders
(1985-2007)
• IL-6: Studied 9x more often in comorbid literature than in ASD • Glucocorticoids: 52x • Anti-Inflammatory Agents: 36x • Adrenal Cortex Hormones: 17x • Thyroxine: 7x • Steroids: 7x • Herpesviridae Infections: 16x
Corrales, Ringer, & Herbert 2008 IMFAR poster #2999
Why so little research on environmental factors in autism?
Highly-cited statements on autism and environment
• “Among cognitive diseases, ASDs are the most heritable (about 80%), suggesting that they are determined largely by genes and not by the environment.”
[emphasis added] Südhof (2008) Nature
• Heritability is at least 90%.
Moldin, Rubenstein, and Hyman (2006) Journal of Neuroscience
Genes and Environment in Autism: From Pie to Venn
G AND E DO NOT FORM A PIE CHART
GENES
ENVIRONMENT
If one is trying to show population attributable fractions (PAF), the sum is not 100%. If one is trying to partition variance, GxE should be explained.
G AND E FORM A VENN DIAGRAM
G
G&E
E
G AND E not G vs. E
• “What % is genetic?”
G&E G E
– Variance studies misinterpreted as ruling out E, or as if heritability were PAF – Sum of PAFs is not 100% – A case is not G or E
• G and E are needed to explain the risk
Tuberculosis as “a genetic disease”?
• TB was thought/ known to be “a genetic disease,” because it was seen to run in families. • Later, we realized some people are genetically more susceptible to the environmental cause (infectious agent). • TB in the population is caused by the combination of G and E (“GxE”). • Many examples of GxE have been discovered (mostly in cancers & cardiovascular disease, but also PKU, depression, ADHD, etc.)
How can environment be important if heritability is so high?
• • • • GxE epiG G G (GE interaction) E (epigenetic change) E (genetic damage) E (GE correlation)
Most heritability studies assume no GxE.
I. Gene-environment interaction (GxE)
• TB example • Most heritability estimates ignore GxE • Heritability is overestimated where genes interact with shared environment.
Shared
– GxE inflates heritability estimates when environmental risk factors are shared by dizygotic twins. Looks like the impact of their genes alone, but is actually impact of GxE.
• Shared environment would include:
– Prenatal risk factors – Widespread risk factors
G x E: One genotype is more sensitive to environment
Haynes 2003 EHP
epiG
E
II. Epigenetic modifications (de novo or inherited)
• Epigenetic tags add to apparent heritability. • Epigenetic tags may be set by prenatal or other environment. • May be de novo or possibly inherited • Epigenetic tags may be amenable to change via environmental interventions (e.g. diet).
(e.g., see Corrales 2009 Autism File magazine)
G
E
III. Genome damaged by environment
• Environmental factors can cause DNA damage (point mutations or structural variations such as copy number variants, CNVs, due to duplications or deletions) • This initially appears to be a de novo genetic cause of autism. • If inherited by subsequent generations it appears to be an inherited genetic cause of autism. • The root cause actually would be environmental and potentially preventable, not genetic, for such cases. • Unclear if mutation or CNV rates have risen. • Signatures of mechanism may be informative (type of SNP, or NHEJ vs. NAHR, FoSTeS, etc.). ROS causes DSBs which precede NHEJ and possibly NAHR. (Wenli Gu et al., 2008 PathoGenetics)
G
E
IV. G-E correlation: Genes can affect exposure to environmental factors
• Genes that affect non-shared environmental exposures increase apparent heritability, but prevention through environmental interventions may be possible in such cases. • Non-shared exposures driven by genes are those where one DZ twin is more exposed than other, due to their genotype. • G-> Pica (tendency to put soil, etc. in mouth, causing exposure to lead, etc.) • G-> Dietary preferences (nutritional deficiency?) • G-> Preference for social interaction, eye contact, etc.
Historical trends in exposure or environmental interventions are hidden in heritability estimates if GxE exists
• Irony: If GxE is important, growing environmental exposures will increase disease prevalence, but make heritability estimates higher over time. Apparent impact of environment is reported as smaller and smaller, even though in reality it is growing. • Twin studies only examine differences attributable to environmental conditions that differ between twins, but some environmental exposures are ubiquitous. If some interventions have not been tried in the studied twins, the potential impacts of those may not be seen.
Recap: How can environment be important if heritability is so high?
I. GxE (interaction) E (epigenetic changes) E (genetic damage) E (correlation)
III. epiG V. G
VII. G
Why so little research on environmental factors in autism?
• • • All autism research limited (until recently) Behavioral > molecular level (until recently) Genes > Environment: High heritability misinterpreted as “genes not environment” Toxicology and epidemiology not sufficiently integrated with autism research so far
•
Toxicology literature and autism literature have almost no overlap
Published 1985-2007, in PubMed: – – – – Toxicology literature: 1.5 million articles Autism literature: 10 thousand Overlap: Just 690 articles… Mostly on drug toxicity, not about environmental chemicals – Perhaps 2-4% of ASD literature is on chemicals as risk factors?
See also: Herbert, Ringer, Corrales IMFAR 2008 poster #2979
Integrating autism with toxicology or epidemiology literature
One can seek potential risk factors using this logic:
ASD - Symptom - Risk Factor
AUTISM Prepulse inhibition deficit
PRENATAL INFECTION
often includes
can be caused by
ASD - Comorbidity - Risk Factor
AUTISM ADHD
PRENATAL ETS
is often comorbid with...
has as risk factor...
In this type of analysis, one identifies known risk factors for diseases that are often comorbid with or autism. The reasoning here is that prenatal environmental tobacco smoke, alcohol, lead, or PCBs might be risk factors for autism because they have been associated with ADHD.
ASD studies rarely investigate environmental risk factors
MOST STUDIES
AUTISM AUTISM AUTISM
VERY FEW
AUTISM
VERY FEW
AUTISM
Behavior or Neuropsych trait
Brain region Cell
Gene
Toxin
Much literature linking environmental toxins to autism-related features, just not to autism per se
AUTISM AUTISM
Behavior or Neuropsych Brain trait
region Cell
Biomarkers Gene
Toxins
ASD – Gene – Toxin
AUTISM
Gene Expression
Toxins
Search for Chemicals that Interact with Autism Gene Candidates
• Objective, comprehensive search for risk factors? • 142 genes (autism candidates) selected • Toxicogenomics database queried for reports of chemicals “affecting” any of these genes (e.g., gene expression changes in animal studies) • Approx. 500 chemicals were identified, for 122 genes:
– – – – xenobiotics (pollutants, pesticides, illegal drugs, etc.) medications nutrients endogenous substances
Corrales, IMFAR 2009 poster
Results: Chemicals that Interact with Autism Gene Candidates
Genes reportedly interacting with the most chemicals • PON ( >120 chemicals) • MET, PTEN, ADRB2, TH (>30 each) • MECP2, TSC2, RELN, UBE3A, GABRB3 (4-14 chemicals each) • Most other genes (1-2 chemicals so far)
Results: Chemicals that Interact with Autism Gene Candidates
Xenobiotics or related chemicals reportedly interacting with the most candidate genes • Carbon tetrachloride (33) • t-butyl peroxide (19), hydrogen peroxide (9) • Sodium arsenite (17), arsenic trioxide (8), arsenic (4), nickel sulfate (9) • LPS (11) • Paraquat (10), chlorpyrifos (4) • Benzene (7), B[a]P (7) • Ethanol (7), tobacco smoke (4) • BPA, TCDD • Progesterone & estradiol • Corticosterone • Thyroxine • Zinc • Flavonoids • Fats
Endogenous chemicals reportedly interacting with the most candidate genes Dietary
Recap and Next Steps
• Education about heritability of autism:
– – – – GxE epiG G G (interaction) E (epi-mutation) E (genetic damage) E (correlation)
• Research on environmental factors • Integrated study of E and G factors in autism (e.g. what affects MECP2 expression?) • Integration and prioritization across E findings in autism literature (zinc, hormones, ROS, cytokines, calcium, cholesterol, neurotransmitters, melatonin, vitamin D, etc.) • More integration with toxicology and epidemiology from outside the autism literature, pulling in the “autism-relevant” literature by linking autism’s features to environment.
Thank you
APPENDIX/ ADDITIONAL SLIDES
Population Attributable Fraction (PAF)
What fraction of today’s cases would be avoided if this risk factor were not present?
2.0 1.5 1.0 0.5 0.0 e (unexposed) E (exposed) Extra risk Baseline Risk
News articles
Books with autism in title
Autism funding, trials, research
• NIH research funding per DALY (disease adjusted life year) (FY03-08):
– $150 for mental health – $1,100 for cancer – $2,800 for infectious diseases in the U.S.
• Federal grants for autism research (as of mid-2007):
– behaviors (almost 40% of grants) – genetics (30-40% of grants)
• Autism research published 1985-2007:
– 20% on diagnosis – 10% on therapy – 1% on prevention
• 63 autism-related active intervention trials as of early 2008:
– Almost 75% (47 clinical trials) on medications – 14% (9) on behavioral therapy – 10% (6) on dietary therapy or supplements
The importance of research on environmental factors in a highly heritable disorder
Mark A. Corrales, MPP US Environmental Protection Agency
Statements are those of the author, and do not necessarily represent views or policies of the EPA
Autism One Conference May 22, 2009
Parallel Universes?
• General public • Parents & affected kids • Interest groups:
– environmental health advocacy – industries
• Researchers • Policy/ decision-makers: Lawyers, economists, policy and risk analysts, staff scientists, etc.
Getting from here to there
• If you believe national-level medical and environmental health interventions are needed… • the autism research literature is a key bottleneck.
From evidence to action
Drug development Experimental toxicology, mechanisms RCTs Behav./Educ. therapy guidelines Regulations to limit risk factors
Anecdotes, case studies Guesses, theories
Prospective epidemiology Retrospective epidemiology Ecologic More studies
studies
Better studies More types of studies
(multiple lines of evidence)
Public & scientific consensus
Is there sufficient evidence for action? Published scientific research literature on environmental factors in autism is still quite limited compared to other diseases or health effects.
Why so little research on environmental factors in autism?
• • • All autism research limited (until recently) Behavioral > molecular level (until recently) Genes > Environment: High heritability misinterpreted as “genes not environment” Toxicology and epidemiology not sufficiently integrated with autism research so far
•
Why so little research on environmental factors in autism?
• • • All autism research limited (until recently) Behavioral > molecular level (until recently) Genes > Environment: High heritability misinterpreted as “genes not environment” Toxicology and epidemiology not sufficiently integrated with autism research so far
•
Most autism science is extremely recent
As of early 2009, • Half of all the autism research literature indexed in PubMed was published in the past eight years: 2000-2008. • One third was published in just the last five years: 2004-2008.
Very Recent Explosion of Interest in Autism
In 2008:
• Newspaper articles: >3,000 headlines/ year • Scientific journal articles: >1,000 / year • New books: >150 / year
Journal articles
But so far…
• Treatment -New ASD treatments approved: 0 • Primary prevention (at national level) -Environmental standards, regulations, or other actions taken based on any potential ASD risk factors: 0
Autism Literature is Still Relatively Limited
• If you believe national-level medical and environmental health interventions are needed… • the autism research literature is a key bottleneck.
What has autism literature focused on?
Why so little research on environmental factors in autism?
• • • All autism research limited (until recently) Behavioral > molecular level (until recently) Genes > Environment: High heritability misinterpreted as “genes not environment” Toxicology and epidemiology not sufficiently integrated with autism research so far
•
Autism literature has focused on behavioral, not chemical level
• The PDD literature focused on the behavioral and cognitive levels three times as much as did biomedical literature as a whole (as % of articles). • 56% vs. only 38% of publications were indexed with chemical substances in PubMed vs. PDD literature, even recently (2000-2006).
Corrales, Ringer, & Herbert 2008 IMFAR poster #2999
Moldin vs. Lathe biological level
% of publications 1985-2007 with MeSH
Chem level
Focus on Chemicals & Drugs Level
100%
75%
50%
48%
30%
25%
0%
re n
la r
TB
Pr io n
si on
Bi po
hr
es
AD
Pe
ile
Ep
op
ep r
tis
in i
iz
Comorbid disorders at elevated prevalence in PDD according to Rzhetsky (2007)
Sc h
Rh
D
PD
D
[M H
ps
en
H
H
CP
ia
IV
D
y
]
Why so little research on environmental factors in autism?
• • • All autism research limited (until recently) Behavioral > molecular level (until recently) Genetic > Environmental studies: High heritability misinterpreted as “genes not environment” Toxicology and epidemiology not sufficiently integrated with autism research so far
•
Genetic etiology pie
A few molecular substances have dominated the literature (1985-2007)
• Approx. 2,000 unique substance terms in ASD literature, occurring 12k times in 4,000 PMIDs
– Half the substance terms appear only once. – Avg. substance is in just 6 PMIDs
• Chemicals in >100 articles each:
– MECP2 gene or protein (>400) – Serotonin (251) – Risperidone (112)
Corrales, Ringer, & Herbert 2008 IMFAR poster #2999.
• >130 medications in >1200 PMIDs ( ~10% of articles) • 43 environmental pollutant terms (other than Hg) occur 111 times across 84 PMIDs ( <1% of articles)
– Only 36/111 refer to a specific chemical rather than class (“teratogens” or “environmental pollutants” seen up to 13 times each) – Lead and cocaine were the most common specific toxins. – No other specific toxin (except Hg) appeared in more than 4 PMIDs. 3 Hg-related terms in 91 PMIDs (<1%)
Medications vs. environmental pollutants
• 41 dietary substances in 189 PMIDs (1-2%) (e.g., gluten, folic acid) (excluding food additives) • A few potential treatments/ causes (valproic acid, oxytocin, melatonin, secretin) found in 26-91 PMIDs each. • ~20 other terms in 2-14 PMIDs each: (food additives, illegal drugs, infectious agents or allergens, nicotine, alcohol, caffeine)
Corrales, Ringer, & Herbert 2008 IMFAR poster #2999. Includes publications 1985-2007.
Environment-relevant topics understudied in ASD literature, relative to all biomedical literature
Haz subst
Hazardous Substances + Organophosph.
Chlorpyrifos Phosphoric Acid Esters Street Drugs Cadmium Asbestos Pesticides Water Pollutants, Chemical Air Pollutants Mutagens Insecticides Cyclophosphamide Organophosphorus Compounds Endotoxins Carcinogens 0.01 0.10 1.00 10.00 100.00
Rate Ratio (Rate in ASD vs all PubMed citations)
Cell types
Cell Types
Neurons
T-Lymphocytes
Killer Cells, Natural
B-Lymphocytes
Macrophages 0.01 0.10 1.00 10.00 100.00
Rate Ratio (Rate in ASD vs all PubMed citations)
Understudied in ASD vs. in 10 comorbid disorders
(1985-2007)
• IL-6: Studied 9x more often in comorbid literature than in ASD • Glucocorticoids: 52x • Anti-Inflammatory Agents: 36x • Adrenal Cortex Hormones: 17x • Thyroxine: 7x • Steroids: 7x • Herpesviridae Infections: 16x
Corrales, Ringer, & Herbert 2008 IMFAR poster #2999
Why so little research on environmental factors in autism?
Highly-cited statements on autism and environment
• “Among cognitive diseases, ASDs are the most heritable (about 80%), suggesting that they are determined largely by genes and not by the environment.”
[emphasis added] Südhof (2008) Nature
• Heritability is at least 90%.
Moldin, Rubenstein, and Hyman (2006) Journal of Neuroscience
Genes and Environment in Autism: From Pie to Venn
G AND E DO NOT FORM A PIE CHART
GENES
ENVIRONMENT
If one is trying to show population attributable fractions (PAF), the sum is not 100%. If one is trying to partition variance, GxE should be explained.
G AND E FORM A VENN DIAGRAM
G
G&E
E
G AND E not G vs. E
• “What % is genetic?”
G&E G E
– Variance studies misinterpreted as ruling out E, or as if heritability were PAF – Sum of PAFs is not 100% – A case is not G or E
• G and E are needed to explain the risk
Tuberculosis as “a genetic disease”?
• TB was thought/ known to be “a genetic disease,” because it was seen to run in families. • Later, we realized some people are genetically more susceptible to the environmental cause (infectious agent). • TB in the population is caused by the combination of G and E (“GxE”). • Many examples of GxE have been discovered (mostly in cancers & cardiovascular disease, but also PKU, depression, ADHD, etc.)
How can environment be important if heritability is so high?
• • • • GxE epiG G G (GE interaction) E (epigenetic change) E (genetic damage) E (GE correlation)
Most heritability studies assume no GxE.
I. Gene-environment interaction (GxE)
• TB example • Most heritability estimates ignore GxE • Heritability is overestimated where genes interact with shared environment.
Shared
– GxE inflates heritability estimates when environmental risk factors are shared by dizygotic twins. Looks like the impact of their genes alone, but is actually impact of GxE.
• Shared environment would include:
– Prenatal risk factors – Widespread risk factors
G x E: One genotype is more sensitive to environment
Haynes 2003 EHP
epiG
E
II. Epigenetic modifications (de novo or inherited)
• Epigenetic tags add to apparent heritability. • Epigenetic tags may be set by prenatal or other environment. • May be de novo or possibly inherited • Epigenetic tags may be amenable to change via environmental interventions (e.g. diet).
(e.g., see Corrales 2009 Autism File magazine)
G
E
III. Genome damaged by environment
• Environmental factors can cause DNA damage (point mutations or structural variations such as copy number variants, CNVs, due to duplications or deletions) • This initially appears to be a de novo genetic cause of autism. • If inherited by subsequent generations it appears to be an inherited genetic cause of autism. • The root cause actually would be environmental and potentially preventable, not genetic, for such cases. • Unclear if mutation or CNV rates have risen. • Signatures of mechanism may be informative (type of SNP, or NHEJ vs. NAHR, FoSTeS, etc.). ROS causes DSBs which precede NHEJ and possibly NAHR. (Wenli Gu et al., 2008 PathoGenetics)
G
E
IV. G-E correlation: Genes can affect exposure to environmental factors
• Genes that affect non-shared environmental exposures increase apparent heritability, but prevention through environmental interventions may be possible in such cases. • Non-shared exposures driven by genes are those where one DZ twin is more exposed than other, due to their genotype. • G-> Pica (tendency to put soil, etc. in mouth, causing exposure to lead, etc.) • G-> Dietary preferences (nutritional deficiency?) • G-> Preference for social interaction, eye contact, etc.
Historical trends in exposure or environmental interventions are hidden in heritability estimates if GxE exists
• Irony: If GxE is important, growing environmental exposures will increase disease prevalence, but make heritability estimates higher over time. Apparent impact of environment is reported as smaller and smaller, even though in reality it is growing. • Twin studies only examine differences attributable to environmental conditions that differ between twins, but some environmental exposures are ubiquitous. If some interventions have not been tried in the studied twins, the potential impacts of those may not be seen.
Recap: How can environment be important if heritability is so high?
I. GxE (interaction) E (epigenetic changes) E (genetic damage) E (correlation)
III. epiG V. G
VII. G
Why so little research on environmental factors in autism?
• • • All autism research limited (until recently) Behavioral > molecular level (until recently) Genes > Environment: High heritability misinterpreted as “genes not environment” Toxicology and epidemiology not sufficiently integrated with autism research so far
•
Toxicology literature and autism literature have almost no overlap
Published 1985-2007, in PubMed: – – – – Toxicology literature: 1.5 million articles Autism literature: 10 thousand Overlap: Just 690 articles… Mostly on drug toxicity, not about environmental chemicals – Perhaps 2-4% of ASD literature is on chemicals as risk factors?
See also: Herbert, Ringer, Corrales IMFAR 2008 poster #2979
Integrating autism with toxicology or epidemiology literature
One can seek potential risk factors using this logic:
ASD - Symptom - Risk Factor
AUTISM Prepulse inhibition deficit
PRENATAL INFECTION
often includes
can be caused by
ASD - Comorbidity - Risk Factor
AUTISM ADHD
PRENATAL ETS
is often comorbid with...
has as risk factor...
In this type of analysis, one identifies known risk factors for diseases that are often comorbid with or autism. The reasoning here is that prenatal environmental tobacco smoke, alcohol, lead, or PCBs might be risk factors for autism because they have been associated with ADHD.
ASD studies rarely investigate environmental risk factors
MOST STUDIES
AUTISM AUTISM AUTISM
VERY FEW
AUTISM
VERY FEW
AUTISM
Behavior or Neuropsych trait
Brain region Cell
Gene
Toxin
Much literature linking environmental toxins to autism-related features, just not to autism per se
AUTISM AUTISM
Behavior or Neuropsych Brain trait
region Cell
Biomarkers Gene
Toxins
ASD – Gene – Toxin
AUTISM
Gene Expression
Toxins
Search for Chemicals that Interact with Autism Gene Candidates
• Objective, comprehensive search for risk factors? • 142 genes (autism candidates) selected • Toxicogenomics database queried for reports of chemicals “affecting” any of these genes (e.g., gene expression changes in animal studies) • Approx. 500 chemicals were identified, for 122 genes:
– – – – xenobiotics (pollutants, pesticides, illegal drugs, etc.) medications nutrients endogenous substances
Corrales, IMFAR 2009 poster
Results: Chemicals that Interact with Autism Gene Candidates
Genes reportedly interacting with the most chemicals • PON ( >120 chemicals) • MET, PTEN, ADRB2, TH (>30 each) • MECP2, TSC2, RELN, UBE3A, GABRB3 (4-14 chemicals each) • Most other genes (1-2 chemicals so far)
Results: Chemicals that Interact with Autism Gene Candidates
Xenobiotics or related chemicals reportedly interacting with the most candidate genes • Carbon tetrachloride (33) • t-butyl peroxide (19), hydrogen peroxide (9) • Sodium arsenite (17), arsenic trioxide (8), arsenic (4), nickel sulfate (9) • LPS (11) • Paraquat (10), chlorpyrifos (4) • Benzene (7), B[a]P (7) • Ethanol (7), tobacco smoke (4) • BPA, TCDD • Progesterone & estradiol • Corticosterone • Thyroxine • Zinc • Flavonoids • Fats
Endogenous chemicals reportedly interacting with the most candidate genes Dietary
Recap and Next Steps
• Education about heritability of autism:
– – – – GxE epiG G G (interaction) E (epi-mutation) E (genetic damage) E (correlation)
• Research on environmental factors • Integrated study of E and G factors in autism (e.g. what affects MECP2 expression?) • Integration and prioritization across E findings in autism literature (zinc, hormones, ROS, cytokines, calcium, cholesterol, neurotransmitters, melatonin, vitamin D, etc.) • More integration with toxicology and epidemiology from outside the autism literature, pulling in the “autism-relevant” literature by linking autism’s features to environment.
Thank you
APPENDIX/ ADDITIONAL SLIDES
Population Attributable Fraction (PAF)
What fraction of today’s cases would be avoided if this risk factor were not present?
2.0 1.5 1.0 0.5 0.0 e (unexposed) E (exposed) Extra risk Baseline Risk
News articles
Books with autism in title
Autism funding, trials, research
• NIH research funding per DALY (disease adjusted life year) (FY03-08):
– $150 for mental health – $1,100 for cancer – $2,800 for infectious diseases in the U.S.
• Federal grants for autism research (as of mid-2007):
– behaviors (almost 40% of grants) – genetics (30-40% of grants)
• Autism research published 1985-2007:
– 20% on diagnosis – 10% on therapy – 1% on prevention
• 63 autism-related active intervention trials as of early 2008:
– Almost 75% (47 clinical trials) on medications – 14% (9) on behavioral therapy – 10% (6) on dietary therapy or supplements
