602
Behavior Genes
than just within particular families. The
simplest and most commonly used study
design is to compare allelic frequency
between affected cases and controls. It
has long been known that association can
detect those genes that account for as little
as 1% of the variance in a trait. However,
association only occurs either if the marker
itself contributes to the trait or disorder
or if a gene contributing to the trait or
disorder is so close to the marker locus
that there is linkage disequilibrium (LD).
LD is the phenomenon whereby alleles at
adjacent loci are found in a combination
that is undisturbed over many generations
of potential crossing-over.
One of the difFculties in interpreting
association studies is that recent admix-
tures of populations can bring about
stratiFcation. This occurs when two eth-
nic groups have different frequencies of
a disease and the trait that is being stud-
ied and also have different frequencies
of marker alleles. Consequently, in mixed
populations from these groups, there may
be a spurious association unless cases and
controls are carefully matched for ethnic-
ity. To overcome the need to carry out
case control matching, which may be dif-
Fcult in some highly admixed populations
where there has been much immigration,
one can use family based methods with
‘‘internal controls.’’ ±or example, in the
transmission disequilibrium test (TDT),
trios consisting of an affected offspring
and both parents are studied. At least
one parent needs to be heterozygous at
the marker locus. It is then possible to
test the frequency of affected offspring
to whom a particular allele is transmit-
ted, with the frequency of those who do
not receive that allele. That is, the un-
transmitted marker alleles are effectively
the ‘‘controls’’ while the transmitted al-
leles are the ‘‘case alleles.’’ A signiFcant
distortion of the chance expectation of
transmission of alleles is easily tested by
a simple statistic called the
McNemar
χ
2
where a signiFcant result indicates that
LD is present. The principles of TDT are
shown in ±ig. 8.
The drawback of allelic association stud-
iesistha
tLDcanon
lybede
tec
tedove
r
very short distances and hence many thou-
sands, not hundreds, of markers would be
needed to carry out a whole genome scan.
There is currently considerable debate over
the approximate number of markers that
would be required to carry out a genome
scan using LD. One controversial sugges-
tion based on simulations suggests that
this might be as many as 500 000 mark-
ers. However, some empirical studies have
shown that in moderately outbred popula-
tions, LD can be detected over distances
up to 1 cM. Although LD is not evenly
distributed across the genome, this would
mean that a few thousand markers would
probably be sufFcient for an initial screen
of the genome. Even so, until recently,
a genome scan using this number of
markers was not feasible, but now the avail-
ability of very dense marker maps based on
single nucleotide polymorphisms (SNPs)
AA
AB
AB
Allele
Father
Mother
Transmitted
A
B
Non transmitted
A
A
Fig. 8
Transmission/Disequilibrium Test (TDT).
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