Twin Research & Sri Lankan Twin Registry

Sisira Siribaddana

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.

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.

Behavioral geneticists assume that any similarities between siblings not due to heredity must be due to growing up in the same home.

But it isnt the home environment that makes the difference. It is the environment shared by children (in) the same peer group.
Judith Rich Harris, 1998

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

Characteristics of complex traits

Trait values are determined by complex

interactions among numerous metabolic and physiological systems, as well as demographic and lifestyle factors Variation in a large number of genes can potentially influence inter-individual variation of trait values The impact of any one gene is likely to be small 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)

GENETIC BASIS OF SELECTED BEHAVIORAL DISORDERS AND TRAITS

(adapted from McGuffin et al, Science 2001)

Behavioral trait
Huntington's disease Early onset Alzheimer's disease Late onset Alzheimer's disease
Attention deficit, hyperactivity disorder

Pattern of inheritance
Rare autosomal dominant dynamic mutation Rare autosomal dominant Common complex Common complex Common complex Common complex

Gene mapping
Gene identified (huntingtin) with unstable trinucleotide repeat. Three distinct genes identified (presenilins 1 and 2, and amyloid precursor protein). Increased risk with apolipoprotein e4 allele. Three contributory loci in the dopamine system, DRD4, DAT1 and DRD5; DRD4 best replicated. Two contributory loci suggested on chromosomes 6 and 15; findings replicated. Numerous reported linkages but no consensus; a few promising candidate genes include 5-HT2A and CHRNA7. Mutation reported in X-linked MAO A gene in one family.

Dyslexia Schizophrenia

Aggression

Common complex

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

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

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

The Classical Twin Study

Monozygotic (MZ) pairs are genetically alike Dizygotic (DZ) pairs, like siblings, share on average half of their genes

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

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

Classical Twin Method

Weakness/criticism

Equal environmental assumptionthe assumption that DZ provide adequate control on the environmental (pre-natal and post natal) differences within MZ pairs.

Discordance for smoking in MZ pairs

(picture in BMJ Oct.6,2001 issue)

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

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

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

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

A role 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.

PARADIGM SHIFTS IN BIOMEDICAL RESEARCH

Structural genomics
Genomics Map-based gene discovery Monogenic disorders Specific DNA diagnosis Analysis of one gene Gene action Etiology (specific mutation) One species

Functional genomics
Proteomics Sequence-based gene discovery Multifactorial disorders

Monitoring of susceptibility

Analysis of multiple genes in gene families, pathways, or systems

Gene regulation Pathogenesis (mechanism) Several species

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

Twin approach
Maternal environment
Maternal Maternal

environment

environment

Adult life

Adult life

Adult life

Adult life

Twin approach
fetoplacental environment
intra-pair birth weight difference: 250 g same maternal environment MZ: same genes genes BW

BW

DZ versus MZ: Genes influencing prenatal and adult life

Adult life

Adult life

Other Differences
100 pairs of spontaneous twins

DZ (70)

MZ

Dichorionic diamniotic

Dichorionic diamniotic 10/30

Monochorionic diamniotic 19/30

Monochorionic monoamniotic 1/30

(6-separated-4fused)

MZ may be treated alike, dress alike, share a special micro environment

Solutions to minimise weaknesses

At the design stage Include pre-natal factors as co-variables

ex-placentation, birth weight

Advances in twin approach

Twins Vs Singletons (sibs and family)

MZ

DZ

Reared together reared apart Reared together reared apart

(Adoption studies)

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

Strategies to recruit twins for studies Clinical case series

Volunteers - healthy or disease linked

Register linked- birth or disease registers

Community based

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

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

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