Documente Academic
Documente Profesional
Documente Cultură
RCTs Behav./Educ.
Experimental
therapy
toxicology,
guidelines
mechanisms
Prospective
epidemiology Regulations
Retrospective to limit risk
epidemiology factors
Ecologic
Anecdotes, studies
More studies
case studies
Better studies
Guesses,
theories More types of studies
(multiple lines of evidence)
Chem level
100%
75%
MeSH
48%
50%
30%
25%
0%
n
CP
ia
r
IV
TB
]
n
on
D
y
la
H
re
ps
io
H
en
[M
si
po
Pr
AD
Pe
ile
es
hr
D
Bi
Ep
op
r
tis
PD
ep
i
iz
in
D
h
Rh
Sc
Chlorpyrifos
Phosphoric Acid Esters
Street Drugs
Cadmium
Asbestos
Pesticides
Water Pollutants, Chemical
Air Pollutants
Mutagens
Insecticides
Cyclophosphamide
Organophosphorus Compounds
Endotoxins
Carcinogens
Neurons
T-Lymphocytes
B-Lymphocytes
Macrophages
GENES
ENVIRONMENT
G&E
G E
G AND E
G&E
not G vs. E G E
• “What % is genetic?”
– 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 (GE interaction)
Most heritability studies assume no GxE.
• G E (genetic damage)
• G E (GE correlation)
I. Gene-environment
interaction (GxE)
• TB example
• Most heritability estimates ignore GxE Shared
V. G E (genetic damage)
VII. G E (correlation)
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:
Prepulse
AUTISM PRENATAL
inhibition INFECTION
deficit
often
can be
includes
caused by
ASD - Comorbidity - Risk Factor
AUTISM PRENATAL
ADHD ETS
is often
has as
comorbid
risk factor...
with...
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 VERY VERY
STUDIES FEW FEW
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 • PON
reportedly interacting with ( >120 chemicals)
the most 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 • Carbon tetrachloride (33)
chemicals • t-butyl peroxide (19), hydrogen peroxide (9)
reportedly interacting with • Sodium arsenite (17), arsenic trioxide (8),
the most candidate genes arsenic (4), nickel sulfate (9)
• LPS (11)
• Paraquat (10), chlorpyrifos (4)
• Benzene (7), B[a]P (7)
• Ethanol (7), tobacco smoke (4)
• BPA, TCDD
1.5
Extra risk
Risk
1.0
Baseline
0.5
0.0
e (unexposed) E (exposed)
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