1. Avi (Abraham) Reichenberg, PhD
National Health Registers and Autism Research
Avi (Abraham) Reichenberg, PhD

2. 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.

3. A-B-C of twin studies A-B-C Example:
MZ twins share 100% of their genes
DZ twins share 50% of their genes
MZ/DZ ratio of a trait reflects etiological influences on that trait.
Correlation between a trait (e.g., height) between two twins:
MZcorr=0.5
DZcorr=0.2
Heritability=
2X(MZcorr-DZcorr)=0.6

4. Strong genetic contribution to autism liability
Lichtenstein et al. Am J Psychiatry. 2012

5. A new view on autism and related conditions
Before
After
Slide: Joseph Buxbaum

6. 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

7. Common variants and ASD
Devlin et al., 2012

8. Related syndromes

9. Copy-number variation and ASD
Devlin et al., 2012

10. Don’t forget the environment!
Lichtenstein et al. Am J Psychiatry. 2012

11. The new view on autism and related conditions should also consider the environmental space

12. 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.

13. MMR vaccination and autism

14. Intrauterine growth
Sandin et al. 2013

15. SSRI and pregnancy outcome

16. SSRI and Autism

17. Folic Acid and Autism

18. The challenges
Self report vs. Independent observations/measurement

19. Advancing maternal age
Sandin et al. JAACAP 2012

20. Advancing paternal age
Hultman et al. Molecular Psychiatry (2011) 16, ;
doi: /mp

21. 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

22. International Collaboration for Autism Registry Epidemiology
Schendel et al. JADD 2013

23. International Collaboration for Autism Registry Epidemiology
Schendel et al. JADD 2013

24. Federated database
Schendel et al. JADD 2013

25. Cross generational effects
Medications in pregnancy
Environmental toxins
Impaired growth
Preterm birth

26. Benjamin Franklin and Multigeneration Effects
Ran away from home
His son, William had problematic family relationships with his children.
His grandson…….

27. 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

28. Why study multigenerational effects?
Some risk factor  disease associations may not be limited to events in a single generation.

29. The new new thing

30. The new new thing

31. 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

32. Acknowledgments
International 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