Avi Reichenberg

National Health Registers and
Autism Research
Avi (Abraham) Reichenberg, PhD
• Genetic and environmental factors in autism liability.
• Finding and ruling-out environmental risk factors for
– Cross and multigenerational investigations.
– Mega registry studies.
• Building you own autism registry.
A-B-C of twin studies
A. MZ twins share 100% of
their genes
B. DZ twins share 50% of their
C. MZ/DZ ratio of a trait
reflects etiological
influences on that trait.
• Correlation between a trait
(e.g., height) between two
• MZcorr=0.5
• DZcorr=0.2
• Heritability=
Strong genetic contribution to
autism liability
Lichtenstein et al. Am J Psychiatry. 2012
A new view on autism and related
Slide: Joseph Buxbaum
Genomic architecture of ASD
Common genetic variations
(SNPs) acting together can
increase risk for ASD
Related syndromes/
Chromosomal abnormalities
Rare genetic mutations
(CNVs) alone may be
considered causative
Common variants and ASD
Devlin et al., 2012
Related syndromes
Copy-number variation and ASD
Devlin et al., 2012
Don’t forget the environment!
Lichtenstein et al. Am J Psychiatry. 2012
The new view on autism and related
conditions should also consider the
environmental space
The first (modern) register
• The population register in Sweden dates
back to the 17th century.
• Requiring the names and dates of those
born or passed away.
• Created to increase the efficiency of tax
collection and military recruitment.
• According to the population census, the
number of population in the country was
2,175,124, of whom 410,400 lived in the
territory of Finland.
• The population size was considerably lower
than expected, and the information on
population number was declared secret.
MMR vaccination and autism
Intrauterine growth
Sandin et al. 2013
SSRI and pregnancy outcome
SSRI and Autism
Folic Acid and Autism
The challenges
Self report vs. Independent observations/measurement
Advancing maternal age
Sandin et al. JAACAP 2012
Advancing paternal age
Hultman et al. Molecular Psychiatry (2011) 16, 1203-1212;
International Collaboration for Autism
Registry Epidemiology (ICARE)
• ICARE combines data from 6 population-based
registries of AD/ASD with additional demographic
and familial/perinatal data.
W Australia
US (California) – coming soon!
Registry I
Registry II
Registry III
• ~ 31,000 cases of ASD.
• ~ 20,000 cases of autism.
• ~ 3,000,000 non-cases
Schendel et al. JADD 2013
International Collaboration for Autism
Registry Epidemiology
Schendel et al. JADD 2013
International Collaboration for Autism
Registry Epidemiology
Schendel et al. JADD 2013
Federated database
Schendel et al. JADD 2013
Cross generational effects
•Medications in pregnancy
•Environmental toxins
•Impaired growth
•Preterm birth
Benjamin Franklin and Multigeneration Effects
• Ran away from home
• His son, William had problematic family
relationships with his children.
• His grandson…….
Why study multigenerational effects?
• Utilizing Quasi
Experimental Designs 
Better understanding of
confounding and causality.
D'Onofrio et al. Child Dev. 2010
Lichtenstein et al. Am J Psychiatry. 2012
Why study multigenerational effects?
• Some risk factor  disease associations
may not be limited to events in a single
The new new thing
The new new thing
Health Registry-based Triad+
• Reliable AND valid (but sometime just valid) case-identification registries
allowing for continuous follow up.
• Linkable other population based registers
Family relations
Biological materials
• Analytic infrastructure
– Epidemiologists
– Psychologists/socielogists
– Statisticians
+ Openness to collaborations
+ Access to data
Unique identification number
used by all data sources and
allowing individual linkage
International Collaboration of Autism
Registry Epidemiology (ICARE)
Multigenerational FamIlial and Environmental
Risk for Autism (MINERvA) Network
Diana Schendel
Sven Sandin
Kim Carter
Richard Francis
Theres Grønborg
Mady Hornig
Anastesia Nyman
Eric Parner
Camila Stoltenberg
Nina Gunnes
Joseph Buxbaum
Alexander Kolevzon
David Hougaard
Yudi Pawitan
Emma Frans
Christina Hultman
Micki Bresnahan
Ezra Susser
Mika Gissler
Raz Gross
Amanda Langridge
Helen Leonard
Abdre Sourander
Paul Surén
Stephen Levine
Jonathan Mill
Jakob Christensen
Mads Hollegaard
Paul Lichtenstein
Sebastian Lundstrom
Autism Speaks partner for ICARE: Michael Rosanoff
NIH partners for MINERvA: Alice Kau, Deborah
Hirtz, Cindy Lawler

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