Transcript Twin Research & Sri Lankan Twin Registry Sisira Siribaddana Why study twins?  Identified individual genes account for only a fraction of the familiarity of.

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 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
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
Pattern of inheritance
Gene mapping
Huntington's
disease
Rare autosomal dominant
dynamic 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 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 hypothesesII
• 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
BW
 same maternal
environment
 MZ: same genes
 DZ versus MZ:
Genes influencing
prenatal and adult
life
BW
genes
Adult
life
Adult
life
Other Differences
100 pairs of spontaneous twins
DZ (70)
MZ
Dichorionic
Dichorionic
Monochorionic
Monochorionic
diamniotic
diamniotic
diamniotic
monoamniotic
10/30
19/30
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