Twin Research & Sri Lankan Twin Registry

1. Twin Research & Sri Lankan Twin Registry Sisira Siribaddana

2. Why study twins? • Identified individual genes account for only a fraction of the familiarity of complex traits or disease • There is a continued role for assessing the overall role of genetic and shared familial effects through family studies. • Twin and twin-family studies are a particularly powerful tool for such studies. • Information on specific genes and specific environemts can be considered.

3. The study of genetics, medicine and behaviour is at a turning point • Full human genome sequence was published - a historic moment. • 3 billion base pairs in the human genome • c 30 000 to 40 000 genes • code for about 70000 proteins • Thus, developments in molecular genetic analysis render it now possible to attempt identification of liability genes in complex, multifactorial traits, and to dissect out with new precision the role of genetic predisposition and environment/life style factors in these disorders.

4. Behavioral geneticists assume that any similarities between siblings not due to heredity must be due to growing up in the same home. But it isn’t the home environment that makes the difference. It is the environment shared by children (in) the same peer group. Judith Rich Harris, 1998

5. Monogenic & Complex disorders The majority of human diseases are complex, i.e. multiple genetic and non-genetic causes

6. Characteristics of complex traits • Trait values aredetermined by complex interactions among numerous metabolic and physiologicalsystems, as well asdemographic and lifestyle factors • Variation in a large number ofgenes can potentially influence inter-individual variation of trait values • The impact of any one gene is likely to besmall to moderate in size • For diseases: Monogenic diseases that mimic complex diseases typically account for a small fraction of disease cases (examples in breast cancer, obesity, hypertension)

7. GENETIC BASIS OF SELECTED BEHAVIORAL DISORDERS AND TRAITS (adapted from McGuffin et al, Science 2001) Behavioral trait Pattern of inheritance Gene mapping Huntington's disease Rare autosomal dominantdynamic mutation Gene identified (huntingtin) with unstable trinucleotide repeat. Early onset Alzheimer's disease Rare autosomal dominant Three distinct genes identified (presenilins 1 and 2, and amyloid precursor protein). Late onset Alzheimer's disease Common complex Increased risk with apolipoprotein e4 allele. Attention deficit, hyperactivity disorder Common complex Three contributory loci in the dopamine system, DRD4, DAT1 and DRD5; DRD4 best replicated. Dyslexia Common complex Two contributory loci suggested on chromosomes 6 and 15; findings replicated. Schizophrenia Common complex Numerous reported linkages but no consensus; a few promising candidate genes include 5-HT2A and CHRNA7. Aggression Common complex Mutation reported in X-linked MAO A gene in one family.

8. FAMILY STUDY • Provides estimates of the degree of family aggregation • Risks to siblings, parents, offspring as well as to other relatives can be estimated • Similarity of different types of relatives can permit modelling of genetic versus non-genetic familial influences

9. Genes or shared family experiences? • To disentangle genes and experience, we study special family groups: • Either family members sharing experiences but differing in shared genes, e.g. twin studies or • family members sharing genes, but differing in their shared experience, e.g. adoption studies

10. Assumptions of the classical twin study • Equality of environmental variances in MZ and DZ pairs Differences may arise from: • placentation and in utero effects • Fetal programming hypothesis implications • differential parental treatment • zygosity determination errors • Random mating

11. The Classical Twin Study • Monozygotic (MZ) pairs are genetically alike • Dizygotic (DZ) pairs, like siblings, share on average half of their genes

12. Classical Twin Method A grater degree of similarity with respect to the presence of a disease/trait (concordance*) between MZ pairs than between DZ pairs is evidence of a genetic contribution to its aetiology. *Proband- wise concordance *Pair-wise concordance

13. Classical Twin Method Strengths Scope unlimited in terms of diversity of application and research designs. Useful to compare the relative contribution of genes and environment (social & developmental) Unite divers disciplines to form multi disciplinary collaborations

14. Classical Twin Method Weakness/criticism Equal environmental assumption- the assumption that DZ provide adequate control on the environmental (pre-natal and post natal) differences within MZ pairs.

15. Discordance for smoking in MZ pairs(picture in BMJ Oct.6,2001 issue)

16. Genes, developmental history and environment as determinants of health In complex disease a person's susceptibility genotype and environmental history combine to establish present health status, and the genotype's norm of reaction determines future health trajectory

17. Testing of epidemiological causal hypotheses • An association between an observed exposure, such as smoking, and disease outcome, such as depression, may be causal or due to factors common to both (confounding). • Confounding factors may be unknown or unmeasurable • It may also not be logistically possible or ethical to test the association experimentally in an intervention study/ RCT • Twin pairs discordant for outcome or disease are a design for testing the causal hypothesis

18. Testing of epidemiological causal hypotheses II • Differences between MZ cotwins in a pair are due to environmental causes (in the very broadest sense) • somatic mutations and other genetic changes during development • prenatal and birth order effects • differential treatment in childhood • different exposures ( occupational, lifestyle) • Provides evidence for potential interventions

19. Testing of epidemiological causal hypotheses • Exposure/disease discordant DZ pairs are fully matched on early childhood effects, and partially on genetic factors • Studies of exposure discordant twin pairs have increased power compared to unmatched case-control series, depending on the degree of familiality of the exposure

20. Arole for twin studies in the future? • It is being increasingly recognized that identified individual genes accounts for only a fraction of the familiality of a trait or disease, and there is a continued role for assessing the overall role of genetic and shared familial effects through family studies. • Twin and twin-family studies are a particularly powerful tool for such studies. • Multiple measurements of risk factors and morbidity over time should be an integral part of all such studies, which permit an assessment of the developmental dynamics of disease risk and the unfolding of behavioural risk factors from childhood through adolescence into adulthood.

21. PARADIGM SHIFTS IN BIOMEDICAL RESEARCH Functional genomics Structural genomics Genomics Proteomics Map-based gene discovery Sequence-based gene discovery Monogenic disorders Multifactorial disorders Specific DNA diagnosis Monitoring of susceptibility Analysis of multiple genes in gene families, pathways, or systems Analysis of one gene Gene action Gene regulation Etiology (specific mutation) Pathogenesis (mechanism) One species Several species

22. Barker Hypothesis (fetal origin hypothesis- fetal programming) Adverse pre-natal environment could be important in several important diseases in childhood. Adult disease may be due to sub-optimal development during fetal life. Originated from the observation of the association between increased prevalence of hypertension, NIDDM, cardiovascular disease with low birth weight

23. Maternal environment Maternal environment Adult life Adult life Adult life Adult life Twin approachMaternal environment

24. genes Adult life Adult life Adult life Twin approachfetoplacental environment • intra-pair birth weight difference:  250 g • same maternal environment BW BW BW • MZ: same genes • DZ versus MZ: Genes influencing prenatal and adult life

25. Other Differences 100 pairs of spontaneous twins DZ (70) MZ Dichorionic diamniotic Dichorionic Monochorionic Monochorionic diamniotic diamniotic monoamniotic 10/30 19/30 1/30 (6-separated-4fused) MZ may be treated alike, dress alike, share a special micro environment

26. Solutions to minimise weaknesses At the design stage Include pre-natal factors as co-variables ex-placentation, birth weight

27. Advances in twin approach Twins Vs Singletons (sibs and family) MZ DZ Reared together reared apart Reared together reared apart (Adoption studies)

28. Different aspects of twin research Zygosity placentation, US scans, Genetic markers, questionnaires Biology of twining and obstetrics aspects Twin studies on traits Twin studies on specific illnesses Social and educational

29. Strategies to recruit twins for studies • Clinical case series • Volunteers - healthy or disease linked • Register linked- birth or disease registers • Community based

30. Volunteer twin studies Advantages No requirement for twin register Higher response to surveys or tests Flexibility in case definition Disadvantages Bias towards concordant pairs Unrepresentative prevalence figures Zygosity may be incompletely confirmed

31. Population based twin registers Advantages More representative prevalence figures No inherent bias towards concordant pairs Flexibility in case definition Disadvantages Often difficult to set up and maintain Incomplete response may bias prevalence Zygosity may be incompletely confirmed

32. Record linked to routine data Advantages Highly efficient if available Usually representative Comparison of twins v singletons Disadvantages Ascertainment may be incomplete Not immune to biases in concordance Inflexible case definition