Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, London, UK
Correspondence: Philip J. Asherson, Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK
Declaration of interest None. Funding detailed in Acknowledgements.
See editorial, pp.
9394, this issue.
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ABSTRACT |
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Aims To review the role of molecular genetics studies in childhood behavioural and developmental traits.
Method Molecular approaches to complex disorders are reviewed, with examples from autism, reading disability and attention-deficit hyperactivity disorder (ADHD).
Results The most robust finding in ADHD is the association of a variable number tandem repeat polymorphism in exon 3 of the DRD4 gene. Other replicated associations with ADHD are outlined in the text. In autism, there is a replicated linkage finding on chromosome 7. Linkage studies in reading disability have confirmed a locus on chromosome 6 and strongly suggest one on chromosome 15.
Conclusions In the next 5-10 years susceptibility genes for these disorders will be established. Describing their relationship to biological and behavioural function will be a far greater challenge.
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INTRODUCTION |
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COMBINING QUANTITATIVE GENETIC AND MOLECULAR GENETIC APPROACHES |
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One of the key issues for those engaged in molecular genetic studies is the identification of heritable phenotypes. Traditional diagnostic categories are useful in practice, but their validity in terms of their underlying aetiology is uncertain. Nevertheless, the general approach so far has been to use categorical criteria based on definitions such as those in DSM-IV (American Psychiatric Association, 1994) or ICD-10 (World Health Organization, 1992).
Alternative approaches aimed at identifying quantitative trait loci (QTLs) can be applied whenever a behavioural or developmental trait is continuously distributed throughout the population. These approaches may be particularly applicable to child psychopathology, since with few exceptions, behavioural disorders of childhood can be conceptualised as extremes on continuously distributed dimensions. Many of the conditions encountered in childhood seem to have close parallels in normal variations in human behaviour. Questions therefore arise about the relationship between quantitative dimensions of behaviour and extreme diagnostic categories, and whether genes that exert an influence across a normal range of behaviour also exert their influence at the pathological extremes.
Quantitative genetic studies using twin samples have approached this issue by considering the relationship between diagnostic categories or cut-offs on dimensional scores in twin probands and quantitative scores in their twin partners (DeFries & Fulker, 1985, 1988). A simple multiple regression procedure is used to test the hypothesis that quantitative trait scores of twin partners (co-twins) should be more similar to those of the probands for identical co-twins compared with non-identical co-twins. Using this approach, mild learning difficulties (Plomin et al, 1991), hyperactivity and spelling disability (Stevenson et al, 1993) appear to represent extremes of continuously distributed traits, whereas severe learning difficulties (Plomin et al, 1991) and early language delay (Dale et al, 1998) appear to be distinct disorders.
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STRATEGIES FOR MOLECULAR GENETIC RESEARCH |
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Linkage analysis using multiply affected families
Early genetic studies of common behavioural disorders such as schizophrenia
and bipolar disorder were based on the assumption of single-gene inheritance.
Large, multiply affected families were identified, and this appeared to show
Mendelian inheritance. In some cases results using this approach suggested the
identification of rare familial forms segregating single genes of major
effect. For example, there are three independent reports of linkage between
markers on chromosome 4p near to the dopamine D5 receptor gene, and bipolar
and schizo-affective disorder (Blackwood
et al, 1996; Asherson
et al, 1998; Ewald
et al, 1998).
However, analyses of such families using traditional linkage approaches have in general been unsuccessful and are unlikely to identify genetic risk factors for common forms of these disorders. As a result, more recent linkage studies of behavioural phenotypes have focused on using sibling pairs and small nuclear families rather than multiplex pedigrees (reviewed by Craddock & Owen, 1996; Risch, 2000).
Linkage analysis using affected sibling pairs
Pairs of siblings affected with the same disorder are presumed to share
susceptibility genes inherited from the same parent. This hypothesis can be
tested by ascertaining a series of affected sibling pairs and genotyping the
sample with markers spread evenly throughout the genome. Where affected
siblings share parental alleles more often than by chance alone, this
indicates linkage between a susceptibility gene and the marker alleles. These
studies can be robust in the sense that diagnostic criteria can be specified
in an attempt to reduce genetic and aetiological heterogeneity, and no
assumptions are required about the underlying mode of inheritance. The major
limitation is the power of the technique, so that large numbers of affected
pairs are needed to detect genes of moderate to small effect.
A measure frequently used to evaluate the power of affected sibling pair
linkage is the ratio of the risk to the sibling of an affected proband and
population prevalence, a parameter known as s. Low
s values may be due to a variety of factors such as
polygenic transmission, genetic heterogeneity, phenocopies and low penetrance,
which may require unfeasibly large sample sizes to overcome. Disorders such as
autism may be more amenable to this approach since the estimated
s is very large (100-200), well within the theoretical
resolution of linkage strategies. On the other hand, disorders such as ADHD
have an estimated
s somewhere between 2 and 5 (Biederman
et al, 1990,
1992). Indeed, if more than
one gene causes ADHD, then the
value for any single gene (the
gene-specific
or
g) must be very low.
Association strategies
Association studies compare the frequencies of marker alleles in a group of
affected individuals with those in a sample of control subjects without the
disorder or drawn from the general population. A statistically significant
difference suggests either tight linkage, resulting in linkage disequilibrium
between a marker allele and the susceptibility locus, or that the marker
allele itself confers susceptibility to disorder. Linkage disequilibrium (LD)
describes the phenomenon where two loci are so close together on a chromosome
that they are not separated by recombination events over many generations.
Loci linked together in such a way reflect fragments of ancestral chromosomes
that remain intact despite many meiotic events over multiple generations and
therefore appear to be associated even in individuals from different
families.
The power of association to detect genes of small effect is well known.
Risch & Merikangas (1996),
using stringent criteria that took into account the large number of loci
required to screen the entire genome, estimated that a sample of 340 unrelated
cases would detect association with a susceptibility gene with a frequency of
0.5 and gene-specific of 2.0. In comparison, 2498 affected sibling
pairs would be required to detect the same gene by linkage analysis. Despite
this, the usefulness of the approach has been limited by the fact that
thousands of markers are required to perform a whole genome search. For this
reason association approaches are still in their infancy and in most cases
have only been applied to the analysis of a few candidate genes. Fortunately,
the development of a new-generation high-density marker map and the technology
to screen these in large numbers is under way, so that LD mapping strategies
are fast becoming the focus of current interest in the study of complex
disorders (Chakravati, 1999;
Kruglyak & Nickerson,
2001).
Association studies in behavioural disorders have unfortunately thrown up a number of contradictory results (for example, see O'Donovan & Owen, 1999). This has been in part because of the problems of diagnosis and comparability of patient populations from different centres, and inadequate sample sizes in many studies. A confounding factor in casecontrol studies is the selection of control subjects, which can result in stratification effects. The solution to this problem is to sample both parents of affected probands and use the non-transmitted parental alleles as control genotypes (haplotype relative risk analysis; Falk & Rubinstein, 1987), or look for increased transmission of a specific allele from heterozygote parents (transmission disequilibrium test; Spielman & Ewens, 1996).
Quantitative trait loci mapping
An alternative approach to mapping genes for disorders using categorical
criteria is the analysis of traits that are continuously distributed in the
population (Plomin et al,
1994,
2000). Such quantitative
traits are influenced by the action and co-action of multiple genes or QTLs.
Developmental traits such as general cognitive ability (g) and
reading ability, and behavioural traits such as hyperactivity, may be better
perceived in this way. In QTL linkage, the difference in trait values,
measured on a dimensional scale for pairs of siblings, is squared and examined
as a function of the number of shared parental alleles
(Haseman & Elston, 1972;
Kruglyak & Lander, 1995).
An alternative approach selects one sibling from the top few per cent
(diagnosed cases) and regresses the phenotypic score of the other sibling onto
the number of shared parental alleles
(Fulker et al, 1995;
Fulker & Cherney, 1996). Considerable additional power can be gained by
the use of phenotypically discordant as well concordant sibling pairs and the
selection of siblings within the top and bottom deciles
(Risch & Zhang, 1995; Purcell et al, 2001).
Furthermore, both concordant and discordant siblings provide a powerful
resource for QTL association mapping as well as linkage, using variance
component approaches (Fulker et
al, 1999).
Genetic maps and high-throughput genotyping
Investigators working before DNA markers became readily accessible were
restricted to the use of classic genetic markers such as red
blood cell antigens (ABO, MNS and Rh) and the human leucocyte antigens (HLA).
The use of DNA markers began with the discovery of techniques for measuring
variation within genomic DNA. Modern maps were introduced following the
discovery that within non-coding regions of genomic DNA there are simple
sequence repeats (SSRs) of short (two to four) nucleotide sequences
(Weber & May, 1990). The
usefulness of these markers lies in the ease with which they can be typed,
following introduction of the polymerase chain reaction (PCR) and the use of
efficient gel electrophoresis systems that allow multiple SSRs to be analysed
together. Newer machines using capillaries instead of conventional slab gels
enable the processing of 6000-18 000 individual genotypes on one machine in a
day. This rate of production is adequate for genome-wide linkage, but for
association mapping a much closer grid of markers is required, so that even
more rapid methods are needed.
New approaches to very rapid genotyping
New approaches that are expected to have far-reaching consequences for
mapping genes in complex disorders depend upon the detection of
single-nucleotide polymorphisms (Anon.,
1999; Craig et al,
2000). Single-nucleotide polymorphisms (SNPs) consist mainly of
single base substitutions and are the most frequent type of variation in the
human genome. The SNP Consortium and International Human Genome Sequencing
Consortium have identified and mapped 1.42 million SNPs, which are distributed
throughout the human genome at an average density of one SNP every 1900 base
pairs (International SNP Map Working
Group, 2001). Further developments aim at screening gene sequences
directly, so that instead of searching for associations with anonymous
markers, genome scans will be able to focus on variation within genes that
affects protein sequence and expression, or lies very close to such functional
variants. So far 60 000 of the identified SNPs fall within protein coding
sequences and 85% of coding regions are within 5000 base pairs of the nearest
SNP. It has been estimated that a systematic approach to cataloguing all the
variation that may be relevant to human behaviour would involve around 10 000
genes, an achievable goal within the next few years. Such polymorphisms will
then be available for use in behavioural genetics association studies.
In parallel with the identification of SNPs, methods are under development for efficient SNP genotyping (see Landegren et al, 1998, for review). The approaches which have gained widest publicity are the development of DNA micro-arrays, commonly referred to as DNA chips (Lander, 1999), and, more recently, matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDITOF; Griffin et al, 1999). The impact of these technologies on gene mapping is likely to be profound, since it will be possible to screen very large samples for linkage and association with extremely dense marker maps, greatly increasing the power to detect genes of small effect in complex disorders.
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MOLECULAR GENETIC STUDIES OF CHILDHOOD BEHAVIOURAL AND DEVELOPMENTAL TRAITS |
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Molecular studies of autism
Autism is a pervasive developmental disorder with onset by 3 years of age
and is defined by the presence of a triad of social and communication
impairments with restricted, repetitive or stereotyped behaviours. The
disorder is interesting from a genetic perspective because, unlike most
complex disorders, it is relatively rare and has a high degree of familiality.
Nevertheless, it shows a complex mode of inheritance best explained by the
action of several genes. Familial clustering is high, with an estimated
s of about 100, calculated from a population prevalence of
around 2-4 per 10 000 and a risk to siblings of around 3%. Such clustering may
be the result of shared environmental factors, but findings from twin studies
provide overwhelming evidence for the importance of genetic influences:
monozygotic (MZ) concordance rates are 60-90%, compared with less than 5% in
dizygotic (DZ) twins, giving an estimated broad heritability of over 90%
(reviewed by Rutter et al,
1999a,b).
Twin studies also suggest that traditional diagnostic boundaries are far too
restricted, since a higher MZ:DZ concordance ratio is found using a broad
autistic phenotype, consisting of a combination of cognitive and social
deficits similar to autism but in milder form
(Bailey et al,
1998).
In the light of these findings it is not surprising that there has been a concerted effort to pursue genetic linkage studies using affected sibling pairs. This was first achieved by the International Molecular Genetic Study of Autism Consortium, which brought together groups from across Europe and the USA. In large collaborative projects the reliability of clinical assessments and subsequent diagnosis across multiple groups is always a key issue, especially with behavioural phenotypes, which are difficult to measure accurately and are generally quantitative rather than qualitative. However, this was facilitated by the adoption by all participating groups of the same assessment instruments: the Autism Diagnostic Interview (ADI; Le Couteur et al, 1989) and the Autism Diagnostic Observation Schedule (ADOS; Lord et al, 1989). A public information resource and DNA data-bank known as the Autism Genetic Resource Exchange has been established (http://www.agre.org).
The first report of a full genome linkage screen for autism identified
three chromosomal regions showing evidence suggestive of linkage. The most
significant of these was on the long arm of chromosome 7, which gave rise to a
gene-specific of 5.0
(International Molecular Genetic Study of
Autism Consortium, 1998). Consistent evidence for the chromosome 7
locus and another locus on chromosome 2 has come from several published and
unpublished data-sets (Barrett et
al, 1999; Phillipe et
al, 1999; Risch et
al, 1999; Auranen et
al, 2000; reviewed by
Lamb et al, 2000). If
the identified genetic loci acted in a simple additive fashion they would
contribute less than 10% to the overall
s value of around
100, suggesting that there must be multiple genes of very small effect or
perhaps more likely important genegene and
geneenvironment interactions. The next step is to identify the genes
themselves, by genotyping dense maps of SSR and SNP markers to refine the
linkage regions and search for associations with particular genes and
functional variants.
Molecular studies of reading disability
Familial transmission of reading disability has been recognised for a long
time and twin studies demonstrate a substantial heritable component, estimated
to be between 50% and 70% (DeFries et
al, 1987; Gillis et
al, 1992; Alarcon et
al, 1998). Furthermore, twin studies suggest that the QTL
perspective, which views genetic factors involved in reading disability as the
same as those contributing to the quantitative dimension of the disability, is
valid and should inform the design of molecular genetic studies. In fact,
molecular studies of reading disability began in 1983 using traditional
linkage approaches, giving suggestive but inconclusive results on chromosomes
6 and 15 (Smith et al,
1983; Bisgaard et al,
1987; Gross-Glenn et
al, 1991; Rabin et
al, 1993).
Cardon et al (1994) were the first to apply a QTL approach to linkage mapping. This was achieved by deriving a continuous measure of reading ability from a battery of psychometric tests used to test the siblings of probands with reading disability. They found considerable evidence for a gene in the chromosome 6 region implicated earlier, with a moderate to strong influence on reading ability. Further evidence for the chromosome 6 and chromosome 15 loci came from an analysis of six large families (Grigorenko et al, 1997), which found that these loci were linked to two distinct reading-related phenotypes: phonological awareness with chromosome 6, and single-word reading with chromosome 15. Final confirmation for the chromosome 6 locus has come from two linkage studies (Fisher et al, 1999; Gayan et al, 1999). Since then, association mapping with simple sequence repeat markers has been used to screen the chromosome 6 and 15 linkage regions. Association was detected with chromosome 15 markers in two series of probands giving an overall significance value of P=0.000 000 08 (Morris et al, 2000). Current work is focused on identifying the specific genes involved.
Molecular studies of ADHD
Attention-deficit hyperactivity disorder is characterised by a persistent
pattern of overactivity, inattention and impulsivity which is pervasive across
social situations and accompanied by substantial social impairments. The
disorder is common, occurring in 2-5% of children, affecting boys 2-3 times
more frequently than girls, and is one of the major causes of childhood
behavioural problems (Taylor et
al, 1996). Hyperactivity is known to aggregate within
families (Cantwell, 1972;
Biederman et al, 1990,
1992) and twin studies have
consistently shown it to be among the most highly heritable behaviours in
childhood (reviewed in Thapar et
al, 1999). Although ADHD is diagnosed using operational
criteria to define diagnostic categories, measures of hyperactivity are
continuously distributed in the general population. Recent twin studies have
used dimensional rating scales, with clinical cut-offs applied when diagnostic
categories were required. These studies all show high heritabilities
regardless of where these cut-offs had been made and regardless of whether
diagnostic or continuous criteria had been applied. This suggests strongly
that a dimensional perspective on hyperactivity is a valid and powerful
approach to the identification of QTLs and should be considered complementary
to the study of defined clinical types. Despite this, most studies to date
have applied categorical definitions based on current DSM definitions of
ADHD.
Molecular genetic studies in ADHD began by focusing on candidate genes within the dopamine system, based on a priori hypotheses from neurochemical and neuropharmacological research. Replicated associations have been reported with variations in genes for the dopamine receptors 4 (DRD4) and 5 (DRD5) and the dopamine transporter (DAT1) (Collier et al, 2000). The most robust of these findings is the association between ADHD and the 7-repeat of a 48 bp sequence within the coding region of DRD4, which is commonly repeated two, three, four or seven times (reviewed by Mill et al, 2001). A recent meta-analysis of seven casecontrol and fourteen within-family studies of this association, including both published and unpublished data, supports this finding, with odds ratios of 1.8, P=4 x 10-8 and 1.3, P=2 x 10-2, respectively (Faraone et al, 2001).
An interesting feature of the DRD4 data is the wide range of
sampling procedures giving rise to positive findings. Swanson et al
(1998) used a highly selected
group of children who all responded to methylphenidate and had the combined
subtype of ADHD without significant comorbidity. This contrasts greatly with
the studies by Rowe et al
(1998), who assessed children
attending a behavioural clinic and applied diagnostic criteria following
completion of DSMIV rating scales, and Smalley et al
(1998), who applied broader
DSMIIIR and DSMIV criteria following diagnostic
interview. An alternative approach adopted by Curran et al
(2001a) was to take a
QTL perspective in which ADHD was conceptualised as the extreme of a normally
distributed trait. In this study, they examined the relationship of the
DRD4 polymorphism in a sample of children selected from the general
population on the basis of high and low scores on five ADHD items of the
Strengths and Difficulties Questionnaire as rated by the parents, and found a
significant association with high-scoring individuals (2=8.63,
P=0.003; odds ratio 2.09).
The DAT1 findings are of particular interest since stimulant drugs
interact directly with the transporter protein. To date, there have been nine
published association studies of ADHD with a 480 bp allele of a variable
number tandem repeat (VNTR) polymorphism in the 3'-untranslated region
of the gene: five support an association and four do not (summarised by
Curran et al,
2001b). Meta-analysis of these data is consistent with a
very small main effect for the 480 bp allele and is not yet convincing
(2=3.45, P=0.06, OR=1.15). However, there is
significant evidence of heterogeneity between the combined data-sets
(
2=22.64, d.f.=8, P=0.004), suggesting that the
studies may divide into two groups: those in which the associated
DAT1 allele has a main effect and those in which the allele does not.
In this case, failure to replicate the association in some studies may result
from variation in the strength of the genetic influence in different
populations. The cause of such heterogeneity remains unknown and requires
further investigation.
Finally, association and linkage to a marker near to DRD5 has been reported by several groups (Daly et al, 1999; Barr et al, 2000; Tahir et al, 2000).
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THE FUTURE |
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication January 17, 2000. Revision received April 5, 2000. Accepted for publication April 5, 2000.
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