John C DeFries
The following article appeared
in Nature Reviews Neuroscience 3, 767 -780 (October, 2002). Below
is the preface and a summary of key points. To download the pdf
of the full article, click here
GENETIC DISSECTION OF A COMPLEX COGNITIVE TRAIT
Simon E. Fisher & John C. DeFries
Developmental dyslexia, a specific impairment
of reading ability despite adequate intelligence and educational
opportunity, is one of the most frequent childhood disorders.
Since the first documented cases at the beginning of the last
century, it has become increasingly apparent that the reading
problems of people with dyslexia form part of a heritable neurobiological
syndrome. As for most cognitive and behavioural traits, phenotypic
definition is fraught with difficulties and the genetic basis
is complex, making the isolation of genetic risk factors a formidable
challenge. Against such a background, it is notable that several
recent studies have reported the localization of genes that
influence dyslexia and other language-related traits. These
investigations exploit novel research approaches that are relevant
to many areas of human neurogenetics.
Despite decades of multidisciplinary investigation, the
biological basis of dyslexia — a specific impairment
of reading ability — remains obscure. But a series
of recent studies has emphasized the contribution of genetic
factors to this disorder.
Dyslexia runs in families, and studies of monozygotic
and dizygotic twins have provided valuable insights into
the heritability of the condition. Methods developed for
these studies have also aided in the genetic mapping of
this reading disability.
For several reasons, the genetic analysis of dyslexia
is complex. For example, there is no straightforward correspondence
between genotype and phenotype, and phenotypic variations
can depend on the developmental stage of the subject.
Similarly, there is a lack of consensus on the definition
of dyslexia, and on whether it is a single trait or a
cluster of traits with distinct aetiologies.
Successful localization of genes that influence dyslexia
has been aided by innovations in three areas. First, methods
have been developed for mapping genes that contribute
to quantitative variability in reading performance. Second,
researchers are dissecting the phenotypic profile into
distinct but related components for genetic study. Third,
it is now possible to scan all chromosomes of the genome
when searching for genes that influence complex traits
such as dyslexia.
Targeted linkage studies of dyslexia have provided strong
evidence that two chromosomal regions — 15q21 and
6p21 — are involved in this syndrome. Similarly,
genome-wide scans have identified further regions on chromosomes
2, 3 and 18 that seem to be linked to dyslexia in multiple
independent sets of families.
Although the linkage results highlight chromosomal regions
that are involved in dyslexia susceptibility, finding
individual genes that are affected remains a daunting
task. So far, no specific dyslexia gene has been identified,
but studies of speech and language deficits have found
a gene — FOXP2 — that is responsible for a
rare form of the disorder.