Avi (Abraham) Reichenberg, PhD

National Health Registers and Autism Research

Outline

• Genetic and environmental factors in autism liability.

• Finding and ruling-out environmental risk factors for autism: – Cross and multigenerational investigations.– Mega registry studies.

• Building you own autism registry.

A-B-C of twin studies

A-B-CA. MZ twins share 100% of

their genesB. DZ twins share 50% of their

genesC. MZ/DZ ratio of a trait

reflects etiological influences on that trait.

Example:• Correlation between a trait

(e.g., height) between two twins:

• MZcorr=0.5

• DZcorr=0.2• Heritability= 2X(MZcorr-DZcorr)=0.6

Strong genetic contribution to autism liability

Lichtenstein et al. Am J Psychiatry. 2012

A new view on autism and related conditions

Before After

Slide: Joseph Buxbaum

Genomic architecture of ASDCommon 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;doi:10.1038/mp.2010.121

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.– Sweden– Norway– Denmark– Finland– Israel– W Australia– US (California) – coming soon!

• ~ 31,000 cases of ASD.• ~ 20,000 cases of autism. • ~ 3,000,000 non-cases

Registry I

•Demographic

Registry II

•Mental health

Registry III

•Pregnancy information

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. 2010Lichtenstein et al. Am J Psychiatry. 2012

Why study multigenerational effects?• Some risk factor disease associations

may not be limited to events in a single generation.

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– Service– Health– Demographics– Family relations– Biological materials

• Analytic infrastructure– Epidemiologists– Psychologists/socielogists– Statisticians

+ Openness to collaborations+ Access to data

Cases

Other registers Analytics

Unique identification number used by all data sources and allowing individual linkage

AcknowledgmentsInternational Collaboration of Autism Multigenerational FamIlial and Environmental Registry Epidemiology (ICARE) Risk for Autism (MINERvA) Network

• Diana Schendel Christina Hultman• Sven Sandin Micki Bresnahan• Kim Carter Ezra Susser• Richard Francis Mika Gissler• Theres Grønborg Raz Gross• Mady Hornig Amanda Langridge • Anastesia Nyman Helen Leonard• Eric Parner Abdre Sourander• Camila Stoltenberg Paul Surén• Nina Gunnes Stephen Levine• Joseph Buxbaum Jonathan Mill• Alexander Kolevzon Jakob Christensen• David Hougaard Mads Hollegaard• Yudi Pawitan Paul Lichtenstein• Emma Frans Sebastian Lundstrom

• Autism Speaks partner for ICARE: Michael Rosanoff NIH partners for MINERvA: Alice Kau, Deborah Hirtz, Cindy Lawler