Twin Research & Twin Research & Sri Lankan Twin Sri Lankan Twin

RegistryRegistry

Sisira SiribaddanaSisira Siribaddana

Why study twins?Why study twins? IIdentified individual genes account for only dentified individual genes account for only

a fraction of the familiarity of a fraction of the familiarity of complexcomplex trait traitss or diseaseor disease

There is a continued role for assessing the There is a continued role for assessing the overall role of genetic and shared familial overall role of genetic and shared familial effects through family studies. effects through family studies.

Twin and twin-family studies are a Twin and twin-family studies are a particularly powerful tool for such studies.particularly powerful tool for such studies.

Information on specific genes and specific Information on specific genes and specific environemts can be considered.environemts can be considered.

The study of geneticsThe study of genetics, medicine, medicine and behaviour is at a turning pointand behaviour is at a turning point

• Full human genome sequence was Full human genome sequence was published - a historic moment.published - a historic moment.– 3 billion base pairs in the human genome3 billion base pairs in the human genome– c 30 000 to 40 000 genesc 30 000 to 40 000 genes– code for about 70000 proteinscode for about 70000 proteins

• Thus, developments in molecular genetic Thus, developments in molecular genetic analysis render it now possible to attempt analysis render it now possible to attempt identification of liability genes in complex, identification of liability genes in complex, multifactorial traits, and to dissect out with new multifactorial traits, and to dissect out with new precision the role of genetic predisposition and precision the role of genetic predisposition and environment/life style factors in these disorders.environment/life style factors in these disorders.

Behavioral geneticists assume that any Behavioral geneticists assume that any similarities between siblings not due to similarities between siblings not due to

heredity must be due to growing up in the heredity must be due to growing up in the same home.same home.

But it isn’t the home environmentBut it isn’t the home environmentthat makes the difference.that makes the difference.

It is the environment shared by It is the environment shared by children (in) the same peer group.children (in) the same peer group.

Judith Rich Harris, 1998Judith Rich Harris, 1998

Monogenic & Monogenic & Complex Complex disordersdisorders

The majority of The majority of human diseaseshuman diseasesare complex, i.e. are complex, i.e. multiple geneticmultiple geneticand non-genetic and non-genetic causescauses

Characteristics of complex traitsCharacteristics of complex traitsTrait values areTrait values are determined determined by complex interactions by complex interactions

among numerous metabolic and physiologicalamong numerous metabolic and physiological systems, systems, as well asas well as demographic and lifestyle factorsdemographic and lifestyle factors

VVariation in a large number ofariation in a large number of genes can potentially genes can potentially influence inter-individual variationinfluence inter-individual variation of trait values of trait values

TThe impact of any one gene is likely to behe impact of any one gene is likely to be small to small to moderate in sizemoderate in size

For diseases: Monogenic diseases that mimic complex For diseases: Monogenic diseases that mimic complex diseases typically account for a small fraction of disease diseases typically account for a small fraction of disease cases (examples in breast cancer, obesity, hypertension)cases (examples in breast cancer, obesity, hypertension)

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.

FAMILY STUDYFAMILY STUDY

• Provides estimates of the degree of Provides estimates of the degree of family aggregationfamily aggregation

• Risks to siblings, parents, offspring as Risks to siblings, parents, offspring as well as to other relatives can be well as to other relatives can be estimatedestimated

• Similarity ofSimilarity of different types of relatives different types of relatives can permit modelling of genetic can permit modelling of genetic versus non-genetic familial influencesversus non-genetic familial influences

Genes or shared family Genes or shared family experiences?experiences?

• To disentangle genes and experience, To disentangle genes and experience, we study special family groups:we study special family groups:

• Either Either family members sharing family members sharing experiences but differing in shared experiences but differing in shared genes, e.g. genes, e.g. twin studies twin studies oror

• family members sharing genes, but family members sharing genes, but differing in their shared experience, differing in their shared experience, e.g. e.g. adoption studiesadoption studies

Assumptions of the classical twin studyAssumptions of the classical twin study

• Equality of environmental variances in MZ Equality of environmental variances in MZ and DZ pairsand DZ pairs

Differences may arise from:Differences may arise from:placentation and placentation and in utero in utero effects effects

Fetal programming hypothesis Fetal programming hypothesis implicationsimplications

differential parental treatmentdifferential parental treatmentzygosity determination errorszygosity determination errors

• Random matingRandom mating

The Classical Twin StudyThe Classical Twin Study

• Monozygotic (MZ) pairs are genetically Monozygotic (MZ) pairs are genetically alikealike

• Dizygotic (DZ) pairs, like siblings, share Dizygotic (DZ) pairs, like siblings, share on average half of their geneson average half of their genes

Classical Twin Method Classical Twin Method

A grater degree of similarity with respect A grater degree of similarity with respect to the presence of a disease/trait to the presence of a disease/trait (concordance*) between MZ pairs (concordance*) between MZ pairs than between DZ pairs is evidence of a than between DZ pairs is evidence of a genetic contribution to its aetiology.genetic contribution to its aetiology.

*Proband- wise concordance*Proband- wise concordance

*Pair-wise concordance*Pair-wise concordance

Classical Twin MethodClassical Twin Method

StrengthsStrengths

Scope unlimited in terms of diversity of Scope unlimited in terms of diversity of application and research designs. application and research designs.

Useful to compare the relative contribution Useful to compare the relative contribution of genes and environment (social & of genes and environment (social & developmental) developmental)

Unite divers disciplines to form multi Unite divers disciplines to form multi disciplinary collaborationsdisciplinary collaborations

Classical Twin MethodClassical Twin Method

Weakness/criticismWeakness/criticism

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

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

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

Genes, developmental history and Genes, developmental history and environment as determinants of healthenvironment as determinants of health

Testing of epidemiological causal Testing of epidemiological causal hypotheseshypotheses

• An association between an observed exposure, such as An association between an observed exposure, such as smoking, and disease outcome, such as depression, may be smoking, and disease outcome, such as depression, may be causal or due to factors common to both (confounding).causal or due to factors common to both (confounding).

• Confounding factors may be unknown or unmeasurable Confounding factors may be unknown or unmeasurable

• It may also not be logistically possible or ethical to test the It may also not be logistically possible or ethical to test the association experimentally in an intervention study/ RCTassociation experimentally in an intervention study/ RCT

• Twin pairs discordant for outcome or disease are a design Twin pairs discordant for outcome or disease are a design for testing the causal hypothesisfor testing the causal hypothesis

Testing of epidemiological Testing of epidemiological causal hypothesescausal hypothesesIIII

• Differences between MZ cotwins in a pair are due to Differences between MZ cotwins in a pair are due to environmental causes (in the very broadest sense)environmental causes (in the very broadest sense) somatic mutations and other genetic changes somatic mutations and other genetic changes

during developmentduring development prenatal and birth order effects prenatal and birth order effects differential treatment in childhooddifferential treatment in childhood different exposures ( occupational, lifestyle)different exposures ( occupational, lifestyle)

Provides evidence for potential interventionsProvides evidence for potential interventions

Testing of epidemiological Testing of epidemiological causal hypothesescausal hypotheses

• Exposure/disease discordant Exposure/disease discordant DZ pairs are fully matched on DZ pairs are fully matched on early childhood effects, and early childhood effects, and partially on genetic factors partially on genetic factors

• Studies of exposure discordant Studies of exposure discordant twin pairs have increased twin pairs have increased power compared to unmatched power compared to unmatched case-control series, depending case-control series, depending on the degree of familiality of on the degree of familiality of the exposurethe exposure

AA role for twin studies in the future?role for twin studies in the future? It is being increasingly recognized that identified It is being increasingly recognized that identified

individual genes accounts for only a fraction of the individual genes accounts for only a fraction of the familiality of a trait or disease, and there is a familiality of a trait or disease, and there is a continued role for assessing the overall role of continued role for assessing the overall role of genetic and shared familial effects through family genetic and shared familial effects through family studies. studies.

Twin and twin-family studies are a particularly Twin and twin-family studies are a particularly powerful tool for such studies.powerful tool for such studies.

Multiple measurements of risk factors and morbidity Multiple measurements of risk factors and morbidity over time should be an integral part of all such over time should be an integral part of all such studies, which permit an assessment of the studies, which permit an assessment of the developmental dynamics of disease risk and the developmental dynamics of disease risk and the unfolding of behavioural risk factors from childhood unfolding of behavioural risk factors from childhood through adolescence into adulthood.through adolescence into adulthood.

PARADIGM SHIFTS IN BIOMEDICAL RESEARCHPARADIGM SHIFTS IN BIOMEDICAL RESEARCH

Structural genomics   

Functional genomicsGenomics

  Proteomics

Map-based gene discovery

  

Sequence-based gene discovery

Monogenic disorders

  

Multifactorial disorders

Specific DNA diagnosis

  

Monitoring of susceptibility

Analysis of one gene

  

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

Gene action   

Gene regulation

Etiology (specific mutation)

 

Pathogenesis (mechanism)

One species   

Several species

Adverse pre-natal environment could be Adverse pre-natal environment could be important in several important diseases in important in several important diseases in childhood.childhood.

Adult disease may be due to sub-optimal Adult disease may be due to sub-optimal development during fetal life.development during fetal life.

Originated from the observation of the Originated from the observation of the association between increased prevalence association between increased prevalence of hypertension, NIDDM, cardiovascular of hypertension, NIDDM, cardiovascular disease with low birth weightdisease with low birth weight

Barker HypothesisBarker Hypothesis (fetal origin hypothesis- fetal programming) (fetal origin hypothesis- fetal programming)

Maternal

environment

Maternal

environment

Twin approachTwin approachMaternal environmentMaternal environment

Adult life

Adult life

Adult life

Adult life

Twin approachTwin approachfetoplacental environmentfetoplacental environment

same maternal environment

intra-pair birth weight difference: 250 g

MZ: same genes

DZ versus MZ: Genes influencing

prenatal and adult life

Adult life

Adult life

Adult life

BWBW BW

genes

Other DifferencesOther Differences

DZ (70) MZDZ (70) MZ

Dichorionic Monochorionic MonochorionicDichorionic Monochorionic Monochorionic

diamniotic diamniotic monoamnioticdiamniotic diamniotic monoamniotic

10/30 19/30 1/30 10/30 19/30 1/30

(6-separated-4fused)(6-separated-4fused)

DichorionicDichorionic

diamnioticdiamniotic

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

100 pairs of spontaneous twins100 pairs of spontaneous twins

Solutions to minimise Solutions to minimise weaknessesweaknesses

At the design stage At the design stage

Include pre-natal factors as co-variables Include pre-natal factors as co-variables

ex-placentation, birth weightex-placentation, birth weight

Twins Vs Singletons Twins Vs Singletons

(sibs and family)(sibs and family)

MZ DZMZ DZ

Reared together reared apart Reared together reared apartReared together reared apart Reared together reared apart

(Adoption studies)(Adoption studies)

Advances in twin approach Advances in twin approach

Different aspects of twin researchDifferent aspects of twin research

Zygosity Zygosity

placentation, US scans, Genetic markers, placentation, US scans, Genetic markers, questionnaires questionnaires

Biology of twining and obstetrics aspectsBiology of twining and obstetrics aspects

Twin studies on traitsTwin studies on traits

Twin studies on specific illnessesTwin studies on specific illnesses

Social and educational Social and educational

Strategies to recruit twins for studiesStrategies to recruit twins for studies

• Clinical case seriesClinical case series

• Volunteers - healthy or disease linkedVolunteers - healthy or disease linked

• Register linked- birth or disease registersRegister linked- birth or disease registers

• Community basedCommunity based

Volunteer twin studiesVolunteer twin studies

AdvantagesAdvantages

No requirement for twin registerNo requirement for twin register

Higher response to surveys or testsHigher response to surveys or tests

Flexibility in case definitionFlexibility in case definition

DisadvantagesDisadvantages

Bias towards concordant pairsBias towards concordant pairs

Unrepresentative prevalence figuresUnrepresentative prevalence figures

Zygosity may be incompletely confirmedZygosity may be incompletely confirmed

Population based twin registersPopulation based twin registers

AdvantagesAdvantages

More representative prevalence figuresMore representative prevalence figures

No inherent bias towards concordant pairsNo inherent bias towards concordant pairs

Flexibility in case definitionFlexibility in case definition

DisadvantagesDisadvantages

Often difficult to set up and maintainOften difficult to set up and maintain

Incomplete response may bias prevalenceIncomplete response may bias prevalence

Zygosity may be incompletely confirmedZygosity may be incompletely confirmed

Record linked to routine dataRecord linked to routine data

AdvantagesAdvantages

Highly efficient if availableHighly efficient if available

Usually representativeUsually representative

Comparison of twins v singletonsComparison of twins v singletons

DisadvantagesDisadvantages

Ascertainment may be incompleteAscertainment may be incomplete

Not immune to biases in concordanceNot immune to biases in concordance

Inflexible case definitionInflexible case definition