Where is the Missing Heritability

We will assume that the heritability

calculations are correct, and that GWAS is
somehow not finding all the heritability"
Note that this assumption is not
necessarily true: some of the missing
heritability might be because the
heritability estimates are wrong, but many
seem to be robust"
Given this assumption, what might account
for the missing heritability?"

Currently Four Major Theories

Infinitesimal model: many variants of small
effect"
Rare allele model: many rare alleles of large
effect"
Epistasis and genotype x environment
effects: interactions with variants that differ
between individuals"
Epigenetic variation: inherited variation
underlies disease, but its epigenetic rather
than genetic variation"

Infinitesimal model
Disease is caused
by a large number
of common
variants, each of
small effect"
Disease comes
from cumulative
effects of these"
Effect sizes are so
small that you
need very large
sample sizes to
detect them"

Infinitesimal model
Evidence that suggests this: if variants each have a
small effect, they will not be purged by natural
selection, and so are expected to be present"
Variance is typically found to occur across the
genome, and animal breeders successfully use
markers across the genome to continuously improve
traits. Furthermore, model organism research
usually finds multiple variants with a range of effect
sizes"
GWAS is not powered to detect variants with small
effect sizes, so that from a distribution of effect
sizes, it can only detect the variants with the largest
effects i.e. missing heritability would be expected"

Infinitesimal model
However, lots of variants of small effects would be
expected to produce a blending (continuous
distribution) of phenotypes, rather than the
patchiness (like traits running in families) we
observe"
This model cannot explain some population disease
incidence, such as the differences in disease rates
for the same ethnic group living in different countries"
What are these variants actually doing? Is it realistic
to think that so many genes could be having an
effect on a single trait?"

Infinitesimal model
The smaller
the effect size,
the greater the
sample size
needed to
detect it"
Current
studies can
only detect
risks greater
than 20%
above average
(odds ratio
above 1.2)"

Rare alleles model

Disease is
caused by a
number of rare
variants, each of
large effect"
Disease comes
from having just
one or a few"
Effect sizes are
large, but most
individuals with
the disease have
different variants"

Rare alleles model

Disease-causing alleles are expected to be rare
because of selection against them, and this is known
to be true"
Large effect rare alleles have been found (e.g.
BRCA1 mutations) "
However, simulations show that most rare alleles
would be detected by GWAS (BRCA1), and the rates
of diseases recurrence found in families is not
consistent with only one or two alleles being involved"
Changes in disease frequencies over time (e.g.
increased incidence of heart disease) suggests more
than just one or two large-effect alleles"

Genotype x environment
These come where the effect of the genotype
is modulated by the environmental conditions"
The idea is that a certain genotype will result
in a certain phenotype only under some, but
not other, environmental conditions"
Therefore, unlike fully environmental or fully
genetic effects, the phenotype is the result of
an interaction between the genotype and
environment!

Genotype x environment
These are obviously known to occur, and
heritability measures try to exclude these"
What we mean by environment is very
broad includes the abiotic environment, the
biotic environment, and the cultural/
behavioural environment"
However, often we dont know what the
environmental effects are that interact with a
given genotype to influence a given trait"

Epistasis (genetic interactions)

The interaction between nonallelic genes at two
or more loci resulting in one gene masking the
phenotypic expression of another gene"
Therefore, the phenotypic effect of one gene
variant is dependent on the state of one or more
other gene variant"
In this case, the phenotype that arises is
dependent on the combination of variants that
an individual has the effects of the variants are
not additive"

Epistatic effects

The assumption is that these alleles contribute

additively to risk"
However, maybe one determines whether some
of the others do result in increased risk or not"

Epistatic effects

X
X

The assumption is that these alleles contribute

additively to risk"
However, maybe one determines whether some
of the others do result in increased risk or not"

Epistasis (genetic interactions)

Because variants work in combinations under
epistasis, we need to assess the effect of
combinations of variants on the risk of disease"
very large samples are required to find sufficient
individuals of each genotype combination to
measure small effects accurately, and the number of
comparisons scales exponentially with the number
of interactions, so the testing burden is enormous."
some will soon ask, as seismologists have, whether
we are trying to predict the unpredictable. [Jason
Moore, Dartmouth Medical School]"

Epistasis (genetic interactions)

But is epistasis really a major force in the
phenotypic outcome of genotype?"
Controversial some say there is little
evidence for epistasis having large effects in
human studies"
Others note that significant contributions of
epistasis have been found in model
organisms, and that it is known that usually a
number of genes interact in each biological
pathway"

Epigenetic variants
Gene activity is not only determined by the primary
DNA sequence, but also from epigenetic factors:
primarily DNA methylation and histone modifications"
Therefore changes in these epigenetic factors
without any change in the DNA can affect phenotype"
The major question is whether these epigenetic
changes are heritable (or sufficiently heritable) to
contribute to missing heritability"
DNA methylation can be heritable, but is
controversial whether it is in practice. Histone
modification is less obviously heritable"
More evidence is accumulating for the heritability of
these epigenetic marks, but its still controversial"

The concept of continuous

liability of disease
Diseases are typically considered in a binary
sense (you have them or you dont)"
However, many human traits are quantitative,
not qualitative like this (e.g. height; http://
www.nature.com/scitable/nated/topicpage/
multifactorial-inheritance-and-genetic-disease-919)"

Are we therefore mistaken in thinking that

diseases are qualitative traits are they more
likely to be quantitative?"
We know that many/all diseases have different
levels of severity for the same disease"

The concept of continuous

liability of disease
This quantitative view of disease is
sometimes called the continuous liability of
disease or the threshold model of disease"
If we accept this, then it requires a different
approach to doing GWA studies"

 In the traditional
approach, there are
likely to be controls at
nearly the same risk of
disease as the cases"
Using a quantitative
framework can avoid
this"