Myriam Haltalli, Alina Miedzik, Liisa Peltola, Odeliya Dadoun
What is heritability? How and why should the heritability of a human
trait be assessed before trying to find the genetic loci involved?
The concept of heritability summarizes how much of the variation in a trait is
due to genetic factors. This term tends to be used with reference to the
resemblance of offspring and parents. It is defined as a ratio of variances,
specifically as the proportion of total variance in a population for a particular
measurement, taken at a particular time or age, that is attributable to variation
in additive genetic (narrow sense heritability h2) or total genetic (broad sense
heritability H2) values. The factors that contribute to the variation are genetics,
environment and random chance. High heritability suggests a strong
resemblance of a specific trait between parents and offspring, whereas low
heritability suggests low resemblance.
Broad sense heritability looks at the proportion of variation due to genetic
values that may include effects due to dominance and epistasis. It is defined
as H2 = VG/VP, where VG is the variation in genetic values and VP is
phenotypic variation. Narrow sense heritability only considers the proportion
of genetic variation due to additive genetic values – the sum of the average
effects of all the alleles the individual carries. This is defined as h2 = VA/VP,
where VA stands for the additive genetic values.
A difficulty with estimating heritability is that we are aware of genetic and
environmental variation, but we may not always be able to assess these
directly. However it is still possible still to estimate the relative effects of both
genes and environment on phenotype by assessing the empirical data
available on the observed and expected resemblance between relatives.
Conventionally, heritability was estimated from simple, balanced designs such
as the correlation of full or half siblings, the correlation of offspring and
parental phenotypes and the difference in the correlation of monozygotic (MZ)
and dizygotic (DZ) twin pairs. Generally, experimental models for studying
complex multifactorial human diseases can be viewed as unethical and the
long life span of humans creates another challenge. Twin studies, however,
takes advantage of the naturally occurring phenomenon of MZ and DZ twins,
providing a ready made experimental design.
Heritability can be estimated by comparing resemblance in phenotypic traits in
pairs of MZ and DZ twins using the ACE model. This method examines how
much phenotypic variation is due to genetic effects and how much is due to
environment by dividing it into three components: additive genetics (A),
common environment (C) and unique environment (E). MZ twins are derived
from a single fertilized egg and therefore inherit identical genetic material.
They are also generally brought up in the same environment and family thus
any differences between the individuals in an MZ pair would be due to their
respective unique environments. The following equation is used to calculate
correlation (r) between MZ twin pairs: rmz = A + C.
DZ twins raised in the same family also share a common environment but
only share half of their genetic material. Any differences between the
Myriam Haltalli, Alina Miedzik, Liisa Peltola, Odeliya Dadoun
individuals in a pair would be due to genetics as well as their unique
environments. This equation illustrates the correlation between DZ twins: rdz =
½A + C. A correlation of zero indicates no resemblance within a twin pair and
a correlation of 1 suggests the individuals in a twin pair are the same –
considering a particular trait. The difference between correlations of MZ and
DZ twins allows us to calculate the occurrence of heritability for a particular
trait. We can calculate the A, C and E values as follows:
A = 2 (rmz – rdz)
C = rmz – A
E = 1 – rmz
This can be illustrated using an example. Here we consider number of moles
and smoking.
Number of moles
Smoking
r MZ
0.4
0.9
r DZ
0.2
0.7
We can calculate the heritability of moles as follows:
A = 2 (rmz – rdz) = 2(0.4 - 0.2) = 2 x 0.2= 0.4 (40%)
This demonstrates that the proportion of the variance affected by genetic
factors is 40% of the total correlation. We can do the same for smoking:
A = 2 (0.9 - 0.7) = 2 x 0.2 = 0.4 (40%)
We can also calculate how much is due to common environment and unique
environment.
Number of Moles:
C = rmz – A = 0.4 - 0.4 = 0
E = 1 – rmz = 1 - 0.4 = 0.6 (60%)
Smoking:
C = 0.9 - 0.4 = 0.5 (50%)
E = 1 - 0.9 = 0.1 (10%)
These results show us that the heritability of moles is 40% but none of this is
due to the common environment of the twins. The heritability of smoking is
also 40%, however this time there is a 50% contribution from the common
environment.
The ACE method gives us a value for heritability (h2). Genome Wide
Association Studies (GWAS) can also be used to provide us with information
about the heritability of a trait. This approach involves rapidly scanning
markers across complete genomes to find genetic variations associated with a
Myriam Haltalli, Alina Miedzik, Liisa Peltola, Odeliya Dadoun
particular trait. Since the completion of the Human Genome Project and the
International HapMap Project, researchers have been provided with tools,
such as databases, to make it possible to find genetic contributions to specific
traits and diseases. GWAS surveys genomes for single nucleotide
polymorphisms (SNPs) that occur frequently in a group with a particular trait.
This method allows us to identify and focus on particular genetic loci involved
in causing the trait. Although GWAS does turn up a lot of variants linked to a
trait, it has been found that the individual and cumulative effects are very
small and not enough to explain previous estimates of heritability – the
‘missing heritability’. A disadvantage of this method is the fact that a lot of
genotyping is required.
Linkage mapping can also be used to identify the variants that cause
particular traits in humans. This method localizes genes based on the coinheritance of genetic markers and phenotypes in families over several
generations. This has been successful in finding genes for rare, Mendelian,
monogenic diseases for which there is a strong familial risk. However, when
looking at complex diseases that involve variants at several loci, linkage
studies can only provide information about those with the strongest influence.
It is important to assess the heritability of a trait using twin studies and GWAS
before proceeding to look for genetic loci involved, as this will indicate how
likely it is that you will be able to find the genetic loci in the first place. If
environmental factors are affecting the trait more than genetics, it would be
advisable to avoid wasting valuable resources and time and consider using
techniques such as linkage disequilibrium studies which would allow you to
determine how the trait is transferred between generations.
References:
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Boomsma, D.,Busjahn, J.,Peltonen, L. (2002). Classical twin studies
and beyond. Nature, 3, 872-882
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Smith, M. and O'brien, S. (2005) Mapping by admixture linkage
equilibrium: advances, limitations and guidelines. Nature, p.1-11
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Wray, N. & Visscher, P. (2008) Estimating trait heritability. Nature
Education 1(1)
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Visscher, P. et al. (2008) Heritability in the genomics era - concepts
and misconceptions. Nature, 9 p.255 – 266
Myriam Haltalli, Alina Miedzik, Liisa Peltola, Odeliya Dadoun