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Journal of Child Psychology and Psychiatry 53:5 (2012), pp 510–518
doi:10.1111/j.1469-7610.2011.02478.x
Annual Research Review: Impact of advances in
genetics in understanding developmental
psychopathology
Anjené M. Addington and Judith L. Rapoport
Child Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda,
MD 20892, USA
It was hoped that diagnostic guidelines for, and treatment of, child psychiatric disorders in DSM-5
would be informed by the wealth of clinical genetic research related to neurodevelopmental disorders. In
spite of remarkable advances in genetic technology, this has not been the case. Candidate gene, genome-wide association, and rare copy number variant (CNV) studies have been carried out for attentiondeficit/hyperactivity disorder (ADHD), Autism, Tourette’s Syndrome, and schizophrenia, with intriguing
results, but environmental factors, incomplete penetrance, pleiotropy, and genetic heterogeneity,
underlying any given phenotype have limited clinical translation. One promising approach may be the
use of developmental brain imaging measures as more relevant phenotypes. This is particularly important, as subtle abnormalities in timing and expression of gene pathways underlying brain development
may well link these disorders and be the ultimate target of treatments. Keywords: Developmental
psychopathology, genetics, copy number variants, pre-natal diagnosis, nosology, prevention.
Introduction
Genetic technology is advancing so quickly that this
review will probably be outdated before it goes to
press. There have been impressive advances in our
broader understanding of the genetics of psychiatric
disorders, with potential for treatment, and ultimately prevention (Geschwind, 2011), but the relevance for diagnosis of childhood onset disorders
remains unclear. This special issue on Nosology in
Developmental Psychopathology provides a welcome
opportunity to review the clinical impact of genetic
studies with prediction for the future. The focus of
this review is the implications of genetic research for
the practice of child psychiatry generally, but we
illustrate historic issues and current research trends
across an array of disorders.
Advances in genetic technology have certainly had
an impact upon research! As reviewed in this Journal in 2009 (Plomin & Davis, 2009), papers on the
genetics of developmental psychopathology have
been increasing exponentially. The number of publications have paralleled methodological advances
from linkage to genome-wide association studies
(GWAS) and copy number variants (CNVs) with
whole genome sequencing (Roach et al., 2010) and
stem cell studies (Marchetto, Winner, & Gage, 2010)
now being carried out.
For this special issue on nosology, we restrict
ourselves to the current impact on understanding
diagnosis, treatment, and/or prevention of childhood
onset disorders. Several lines of evidence make this
question of great interest. It is increasingly accepted
Conflict of interest statement: No conflicts declared.
that subtle disturbances of brain development
underlie the pathology of many mental disorders in
adults as well as in children (Lewis & Levitt, 2002;
Rapoport, Addington, Frangou, & Psych, 2005). It is
hoped and predicted that advances in developmental
brain imaging will provide intermediate phenotypes
for genetic studies (Pine, Ernst, & Leibenluft, 2010).
In addition, the dramatic advances in cytogenetic/
genomic array-based diagnosis is of particular
interest for developmental disorders, as most
molecular-based brain morphological abnormalities
are manifested in childhood (Epstein, Erickson, &
Wynshaw-Boris, 2004).
Nosology is crucial for clinical practice. While there
are no genetic guidelines planned for DSM-5, genetic
findings have implications for diagnosis and treatment, or even prevention, that are of potential clinical interest. Given the challenges in psychiatry to
identify measurable laboratory tests to diagnose
disorders as in other branches of medicine, one
anticipated outcome from the multitude of genetics
studies has been that we would elucidate more
genetically homogeneous subtypes of our current
diagnostic categories. As we will demonstrate
throughout this review, with a few rare exceptions,
this is not yet the case.
Family, twin, and adoption studies have documented high heritability of several major childhood
psychiatric disorders (Gupta & State, 2007; Lombroso, Pauls, & Leckman, 1994; Thapar, O’Donovan, &
Owen, 2005). Nonetheless, genome-wide association
studies, which examine the association between a
particular allele and a diagnosis or trait within a
population, have indicated that most common disorders (psychiatric and nonpsychiatric) are complex,
2011 The Authors. Journal of Child Psychology and Psychiatry 2011 Association for Child and Adolescent Mental Health.
Published by Blackwell Publishing, 9600 Garsington Road, Oxford OX4 2DQ, UK and 350 Main St, Malden, MA 02148, USA
doi:10.1111/j.1469-7610.2011.02478.x
involving large numbers of genes, each of small effect
(Ku, Loy, Pawitan, & Chia, 2010; Risch & Merikangas,
1996). Given the high phenotypic variability associated with the best candidate genes in psychiatry
(Wallace et al., 2010), such as disrupted in schizophrenia-1 (DISC1; Millar et al., 2000) and MECP2
(Zoghbi, 2003), or the best established CNVs, for
example 22q11 deletions (Green et al., 2009), and the
importance of environmental exposures (Hallmayer
et al., 2011), our field has little reason to expect
phenotypic specificity from a particular genetic variant. This is illustrated in Figure 1.
Historic perspective
Cytogenetic findings with respect to chromosomal
imbalance such as trisomy 21 (Lejeune, Turpin, &
Gautier, 1959) led to optimism regarding the genetics of specific behavioral syndromes (Skuse & Seigal,
2008). Utilization of classic cytogenetic techniques,
such as high resolution G-banded karyotyping
developed in the 1970s (Yunis et al., 1978), led to the
identification of many microdeletion syndromes
such as 15q11-q13 deletions responsible for PraderWilli (Butler, Meaney, & Palmer, 1986), 17p11.2
deletions associated with Smith-Magenis (Smith
et al., 1986), and 22q11 deletions causing DiGeorge
and velocardiofacial syndromes (Greenberg, Elder,
Haffner, Northrup, & Ledbetter, 1988). Over the next
decade, continued efforts led to identification of
genetic causes for Charcot-Marie Tooth and Angelman
syndromes, among others (Mefford & Eichler, 2009).
Also, fueling this optimism was the ability to detect
single genes with strong causal influence on a variety
of neurodevelopmental disorders such as Lesch–
Impact of advances in genetics
511
Nyhan syndrome, Tuberous Sclerosis, or Neurofibromatosis (Hebebrand, Scherag, Schimmelmann, &
Hinney, 2010). Nonetheless, researchers are yet to
definitively identify a causal variant for any of the
more common, non-Mendelian psychiatric disorders.
Historically, linkage studies of psychiatric
illnesses have had limited success in identifying risk
genes, with a few exceptions such as NRG1 and
DTNBP1 in schizophrenia (Stefansson et al., 2002;
Straub et al., 2002). Recently, GWAS studies have
had some success in identifying common singlenucleotide-polymorphisms (SNPs) that have small
effects on risk, but heterogeneity is a major limitation for GWAS. In spite of evidence that attentiondeficit/hyperactivity disorder (ADHD) is highly heritable, a meta-analysis of genome-wide association
studies found no significant genome-wide associations, suggesting that the effects of common risk
variants are very small (Neale et al., 2010). In contrast, linkage studies can detect a signal in a particular region that may be derived from many kinds
of susceptibility variants including common SNPs,
multiple rare variants, or CNVs which may occur in
one or more genes in a region. A recent meta-analysis of 32 linkage studies, including 3255 pedigrees
with schizophrenia and related disorders revealed
suggestive evidence for linkage on 2q, 5q, and 8p (Ng
et al., 2009). These regions had all been implicated
previously (Lewis et al., 2003). Of note, one region
that did not emerge from this analysis was the major
histocompatibility complex (MHC) region on chromosome 6, which was highlighted in a series of
recent GWAS studies (Purcell et al., 2009; Shi et al.,
2009; Stefansson et al., 2009).
Figure 1 Neuropsychiatric phenotypes associated with copy number variations (CNVs). Reprinted with permission from the American
Journal of Psychiatry (Copyright 2010), American Psychiatric Association
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Anjené M. Addington and Judith L. Rapoport
Disrupted in schizophrenia-1 is one of several
schizophrenia risk genes (albeit with variable
phenotype within the families) of current intense
research interest because of its importance in brain
development (Jaaro-Peled et al., 2009). DISC1 contains two common nonsynonymous (i.e. changes
amino acid) SNPs -Leu607Phe and Ser704Cys – that
modulate facets of DISC1 molecular functioning
important for cortical development, fronto-temporal
cortical anatomy in adults, as well as risk for diverse
psychiatric phenotypes that often emerge during
childhood and adolescence.
One promising approach may be the use of developmental brain imaging measures as more relevant
phenotypes (Pine et al., 2010). In a recent study,
Raznahan et al. (Raznahan et al., 2010) related
DISC1 genotype at Leu607Phe and Ser704Cys to
cortical thickness (CT) in a large sample of healthy
children and adolescents, aged 9–22, on whom
magnetic resonance imaging brain scans had been
acquired longitudinally. Rate of cortical thinning
varied with DISC1 genotype. Specifically, the rate of
cortical thinning was attenuated in Phe-Carrier
compared with Leu-Homozygous groups (in bilateral
superior frontal and left angular gyri) and accelerated in Ser-Homozygous compared with Cys-Carrier
groups (in left anterior cingulate and temporal
cortices). Both SNPs additively predicted fixed
differences in right lateral temporal cortex, which
were maximal between Phe-Carrier/Ser-Homozygous (thinnest) versus Leu-Homozygous/Cys-Carrier (thickest) groups. These findings suggest that
these SNPs influence risk for diverse phenotypes, in
concert with other genetic and environmental factors, by impacting on the early maturation of frontotemporal cortices and support a theme that subtle
variations in structural and functional brain development will provide a frame for integrating diverse
genetic findings.
Childhood onset disorders are not only caused in
part by many genes of small effect but also, based on
studies of schizophrenia and bipolar disorder, it is
likely that a large proportion of the heritable risk is
due to the interaction or combinations of hundreds
or thousands of common variants, none of which
contributes an individually measurable effect to risk
(Craddock et al., 2008; Purcell et al., 2009). To date,
there are few genes that have been replicated using
linkage or GWAS for autism spectrum disorder,
ADHD, or nonsyndromal mental retardation.
There is building evidence that some alleles are
shared across psychiatric disorders (e.g., schizophrenia and bipolar disorder), and that there may be
some very broad specificity for common alleles with
respect to general disease category (e.g., psychiatric–
nonpsychiatric); (Purcell et al., 2009; Williams et al.,
2010). The small effect size of common alleles, and
the prior probability that any chosen candidate gene
or allele will be associated with a given phenotype is
extremely low, and results with existing genome-
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wide techniques have been weak or inconsistent for
other child psychiatric disorders such as obsessivecompulsive disorder and tourette syndrome (Grados,
2010), as well as autism (State, 2010).
Copy number variants
Rapid advances in molecular genetic technology,
particularly in DNA microarray technology, have
greatly enhanced our ability to detect submicroscopic copy number variations (Beaudet & Belmont,
2008). These technologies, coupled with the dramatic decline in cost for running microarrays, have
lead to a flurry of reports describing novel genomic
syndromes over the past several years. CNVs are
typically defined as a DNA segment of at least 1 kb in
size, for which copy number differences have been
observed in the comparison of two or more genomes.
In addition to the somewhat surprising findings that
many healthy individuals carry large segments of
DNA that are either missing a copy or have gained an
extra copy (Iafrate et al., 2004; Sebat et al., 2004),
many specific regions have now clearly been associated with several neurodevelopmental phenotypes.
There has been increasing interest in the rare variant
(CNV) approach in child psychiatry.
The overlap across broad diagnostic categories,
inheritance from a healthy relative (phenotypic
heterogeneity/incomplete penetrance), and the convergence of multiple genetic etiologies on some basic
syndromes (genetic heterogeneity) provide major
insights about the biology of mental illness. Reports
from multiple investigators of recurrent microdeletion of 16p11.2 in up to 1% of autistic patients
(Weiss et al., 2008) has now been extended to
include individuals with intellectual deficiency, language disorder, and schizophrenia (Mefford & Eichler, 2009). Intriguingly, while both duplications and
deletions at 16p11 occur within autism (Weiss et al.,
2008), duplications are more selectively associated
with schizophrenia with differing associated head
size/brain imaging measures (Mccarthy et al.,
2009). The best known CNV in psychiatry, which
confers a very high risk for psychopathology, is the
deletion at 22q11 that has now been associated with
language delay, psychosis, bipolar disorder, autism,
and obsessive-compulsive disorder (OCD; Green
et al., 2009).
Several studies indicate some shared susceptibility genes across schizophrenia and bipolar disorder
(Moskvina et al., 2009; O’Donovan et al., 2008a;
Purcell et al., 2009), although this does not appear
to carry over for CNVs (Grozeva et al., 2007). An
increased rate of rare de novo CNVs observed in
autism and schizophrenia has been reported (Sebat
et al., 2007; Stone et al., 2008; Xu et al., 2008),
although other reports indicate that rare CNVs are
often inherited from a healthy parent and therefore
represent a partial risk rather than a highly penetrant etiologic factor (Walsh et al., 2008; Weiss et al.,
2011 The Authors. Journal of Child Psychology and Psychiatry 2011 Association for Child and Adolescent Mental Health.
doi:10.1111/j.1469-7610.2011.02478.x
2008). More studies are needed to see which pattern
is more typical. The association of the same rare
CNVs with autism and schizophrenia is even more
clear (Rapoport, Chavez, Greenstein, Addington, &
Gogtay, 2009), as well as with epilepsy and mental
retardation (O’Donovan, Kirov, & Owen, 2008b),
possibly autism and Selective Mutism (State, 2011)
leads to further erosion of phenotypic specificity in
psychiatric genetics. We are left with the still vague
model that any particular clinical diagnosis is
determined by other yet to be discovered genetic,
epigenetic, and environmental modifiers.
Identification of intermediate phenotypes closer to
the biologic action of the genes would be extremely
useful. Both childhood onset schizophrenia and
autism have been shown to have abnormal brain
development with premature increase in brain size
for autism and premature cortical ‘pruning’ for
schizophrenia (Rapoport et al., 2009), leading to a
model that the underlying phenotype may involve
dysregulation of genes affecting the timing rather
than the pattern of cortical development. Crespi and
others also have modeled the overlap between autism and schizophrenia (Crespi, Stead, & Elliot, 2010;
Mccarthy et al., 2009), which suggests that timing
and/or pattern of early brain development should be
explored in genetics studies.
Future technologies E.G. whole genome
sequencing and induced pluripotent stem cells
A myriad of new technologies will undoubtedly reveal
many more novel rare syndromic disorders, particularly as the resolution and accuracy improves as
the reality of whole genome sequencing becomes
common practice. Currently, deep resequencing of
candidate genes has revealed several de novo, likely
pathogenic variants in patients with autism and
schizophrenia. Examples in autism include the
X-linked neuroligins, NLGN3 and NLGN4 (Jamain
et al., 2003; Laumonnier et al., 2004), SHANK3 on
22q13.3 (Durand et al., 2007; Gauthier et al., 2009;
Moessner et al., 2007), and CNTNAP2 on 7q35
(Bakkaloglu et al., 2008). Similarly, novel variants
have been discovered in patients with schizophrenia
in SHANK3 (Gauthier et al., 2010), KIF17 (Tarabeux
et al., 2010), and UPF3B (Addington et al., 2011). In
general, searches for deleterious de novo variants in
candidate genes has not revealed as much as anticipated or hoped (Delorme et al., 2010; Dwyer et al.,
2010; Piton et al., 2010). Inevitably, results from
whole genome sequencing studies will produce an
abundance of new candidate variants. The ultimate
challenge will be to determine the functionality of
these variants and how they interact with other
genetic and environmental factors.
Human-induced pluripotent stem cells (hiPSCs) is
an emerging technology that has the appeal of being
able to create neurons (or other cell of choice) from
cultured fibroblasts, thus providing access to the
Impact of advances in genetics
513
currently unattainable brain tissue we so desperately need to study. The goal of this strategy is to
develop neurons and glial cells from patient samples
to characterize their gene expression patterns, morphological properties, and physiologic abnormalities. These experiments will allow us to correlate
patterns of protein expression and changes in cellular behaviors associated with the genetic and
behavioral differences observed in specific patients.
Clustering of neuronal phenotypes, together with
information about symptoms in humans carrying
specific mutations, will help us determine whether
different forms of neurodevelopmental psychopathology arise from defects in distinct signaling
pathways. This is a very new area of research with
methodologies still being improved, but there is tremendous potential for diagnostic and treatment
applications, as recently indicated for autism
(Voineagu et al., 2011).
Prenatal diagnosis – prevention
With the introduction of array comparative genomic
hybridization (CGH) and SNP microarrays, diagnostic testing is readily available. Remarkably, the focus
has shifted such that both phenotype-first and
genotype-first approaches are in wide use. These
techniques allow for broad screening of patient
populations that largely (though not completely)
replace classic cytogenetic testing. This has major
implications for both prenatal screening and diagnostic testing. There is already change in the timing
of risk assessment at some clinical sites.
While the risk of any one neurodevelopmental
disorder will be very small, large scale populationbased studies that ascertain subjects across a wide
range of phenotypes will provide better information
about the prediction of risk for developing any
undesirable pathology from a given chromosomal
anomaly. To date, the most compelling abnormality
warranting genetic counseling is the 22q11 deletion,
for which there is a high likelihood (albeit nonspecific) of developmental pathology. Any genetic testing
will be controversial, either because of lack of sufficient scientific basis for clinical usefulness (Mitchell
et al., 2010) or because of more general ethical
concerns (Munger, Gill, Ormond, & Kirschner,
2007), and will remain a very personal decision.
Treatment
Pharmacogenetics studies investigate genetic associations of drug response, and there are some clear
examples of success in all of medicine (Feero, Guttmacher, & Collins, 2010). While there have been a
variety of studies relating risk genes to response to
stimulant drugs (Polanczyk et al., 2005), these have
had little practical relevance, but may be useful in
understanding the physiologic response to stimulants. Other predictive studies in pediatric psycho-
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Anjené M. Addington and Judith L. Rapoport
pharmacology have not been realized and remain
impractical.
In the 1960s, the basic laboratory work by Seymour Kaufman on phenylketonuria (PKU), a metabolic disorder that can lead to progressive mental
retardation, brain damage, and seizures if left
untreated, led to a preventive dietary treatment
consisting of restricted phenylalanine intake, particularly during infancy and childhood (Friedman,
Kaufman, & Kang, 1972; Kaufman, 1983; Kaufman
et al., 1978). Since that time, no understanding of
the mechanisms of syndromic neurodevelopmental
disorders has led to prevention or successful symptom reversal. Nevertheless, the steady discovery of
monogenic disorders and the resulting creation of
mouse models for these disorders have led to treatment research in some syndromal childhood onset
conditions. The best illustrations would be the
ongoing treatment research in Fragile X syndrome
(FXS).
Mutations in the FMR1 (fragile X mental retardation) gene can cause a variety of disabilities,
including cognitive deficits, attention-deficit/hyperactivity disorder, autism, and other socio-emotional
problems. In addition, individuals with the full
mutation form distinct difficulties, including primary
ovarian insufficiency, neuropathy, and the fragile
X-associated tremor/ataxia syndrome (which is also
sometimes seen in older premutation carriers). The
cause of FXS is decreased or absent levels of fragile X
mental retardation proteins (FMRP) that are typically
caused by full mutation (>200 CGG repeats) of FMR1
gene. Therefore, multigenerational family involvement is commonly encountered when a proband is
identified with a FMR1 mutation.
Fragile X mental retardation proteins is a RNA
binding protein that modulates dendritic maturation
and synaptic plasticity through the inhibition of
group 1 mGluR-mediated dendritic protein synthesis
(Bagni & Greenough, 2005). Studies of metabotropic
glutamate receptor 5 (mGluR5) pathway antagonists
in multiple animal models of FXS have demonstrated
benefits in reducing seizures, improving behavior,
and enhancing cognition and correction of plasticity
phenotypes. While most of the work is currently
focusing on mGluR5, which is expressed most highly
in the hippocampus, neocortex, and striatum, some
work is also ongoing with mGluR1 which is
expressed primarily in the cerebellum. The work in
rodents showed a role for mGLuRs in regulating
inhibitory and excitatory balance with anticonvulsant properties of mGluR5 antagonists. Human FXS
patients have cognitive impairment, and often seizure disorder (Bear, 2005).
The ‘mGLuR Theory’ of FXS is now being tested
directly, and preclinical research suggests potential
efficacy for anxiety, convulsions, pain, and migraine. Neuropharm Group plc recently reported
results of a single dose trail with the selective
mGLuR5 antagonist, fenobam, in 12 subjects. Sin-
J Child Psychol Psychiatry 2012; 53(5): 510–8
gle doses of 150 mg were well tolerated with anecdotal reports of some efficacy (Berry-Kravis et al.,
2009). As a result of pharmacologic problems,
fenobam is not likely to be followed up for fragile X.
However, phase II trials of novel mGluR5 antagonists are in progress for individuals with FXS (BerryKravis et al., 2009; Dolen, Carpenter, Ocain, &
Bear, 2010). While there are no detailed reports
available yet, Novartis has just completed its phase
II double blind trials (Harris, 2010), and Roche has
recently initiated a similar trial with another novel
mGluR5 agent. Lithium, also an indirect downregulator, or mGluR, was found helpful as an add-on
treatment for 15 young males with FXS (BerryKravis et al., 2008). Finally, Seaside Therapeutics
initiated a trial of a GABA-B receptor agonist (which
inhibits glutamatergic signaling), but no data are
available yet.
If any of these approaches prove to be clinically
successful, it will be among the first useful clinical
treatment applications of molecular genetics to child
psychiatry. Based on the varied phenotype, however,
even if successful, mGluR5 treatment is unlikely to
narrow phenotypic definition.
Conclusions
In spite of the limitations that have been stressed
throughout this review, there remains optimism
about the ultimate application of molecular genetics
for diagnosis and treatment of psychiatric disorders.
No short-term application is anticipated. The path
from gene discovery to treatment has been arduous,
even for nonpsychiatric conditions such as cystic
fibrosis. If risk can be calculated across disorders,
the most immediate application of molecular genetics findings is the possibility of prevention of some
disorders such as autism, intellectual disability, and
very early onset schizophrenia, through prenatal
genetic testing (Handyside, 2010). Clinical studies of
each rare variant or point mutation site could provide additive benefit, reaching an overall level of
possible prevention of up to 10% of nuclear autism
when chip technology allows each individual syndrome screening to be carried out simultaneously
(Miller et al., 2009; Shen et al., 2010). The low cost
will permit a very large number of genomic regions to
be queried (Lu et al., 2008; Van Den Veyver et al.,
2009). Nonetheless, this is likely to remain a highly
controversial area until these broader risk ratios are
known and adequate genetic counseling can be
implemented (Bassett, Scherer, & Brzustowicz,
2010).
Diagnostically, the data suggest that for the most
part, phenotypic correlates will be very broad cutting
across various neurodevelopmental, psychiatric and
neurologic disorders. There is very great likelihood of
a significantly impairing psychiatric disorder with a
22q11 deletion, for example, even though the risk of
any one of five different disorders does not exceed
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25%. Environmental effects have been underestimated (Hallmayer et al., 2011), and are also likely to
be non-specific (Peen, Schoevers, Beekman, &
Dekker, 2010).
There is a certain irony in the strong genetic link
between autism and schizophrenia. Kanner originally thought that autism might be subsumed under
schizophrenia (Kanner, 1943, 1962), but later
changed his mind in light of reports by Rutter indicating that these were separate disorders (Rutter,
1972a,b). The now established genetic links between
these diagnoses is of no immediate use to the practicing clinician. We, and others, have suggested that
the field may eventually be unified by identification
of abnormalities in timing or pattern of brain development at critical periods (Crespi et al.; Rapoport
et al., 2009; Shaw et al., 2007; State, 2011). Current
research on Huntington’s disorder shows abnormal
brain developmental trajectories decades before
onset of illness, suggesting patterns of early brain
growth as targets for treatment development (Paulsen
et al., 2010). As Bilguvar and others recently
outlined, the advent of next generation sequencing
together with evidence that mutations in a single gene
or locus can effect divergent neurodevelopmental
outcomes bring promise for future research (Bilguvar
et al., 2010). For example, identification of a rare risk
variant with varied developmental outcomes will allow studies of relatively small samples having considerable phenotypic heterogeneity.
Impact of advances in genetics
515
Psychiatric nosology has been neither demeaned
nor aided by progress in genetic research. Clinical
descriptive diagnosis remains essential for clinical
prediction and treatment. These genetic results
ultimately may be useful in understanding broad
underlying biologic risk, perhaps explaining diagnostic comorbidity, and even leading to conceptually
new treatments targeting, for example, a more general normalization of brain development. The true
role of molecular genetics in psychiatric (and other)
disorders will be a major focus of health research for
a long time to come.
Acknowledgements
This review article was invited by the journal, for which
the principal author has been offered a small honorarium payment towards personal expenses.
This manuscript is based on material funded by the
NIH.
The authors have declared that they have no competing or potential conflicts of interest.
Correspondence to
Judith L. Rapoport, 10 Center Dr., Room 3N202,
Bethesda, MD 20892, USA; Tel: 301-435-4501; Email:
[email protected]
Key points
• The last two decades of genetic research neither denigrates nor informs DSM-5 Psychiatric Classification.
• Linkage and GWAS studies have diminished the optimism for genetic diagnosis of child psychiatric disorders
• Studies of rare variants, particularly rare copy number variants have been more encouraging, but their rarity,
varied penetrance, pleiotropy, as well as genetic and phenotypic heterogeneity of psychiatric syndromes limits
the usefulness and understanding of these findings.
• There remains optimism that next generation sequencing, coupled with advances in measurement of brain
development will enable greater in-depth long-term understanding of the genetic influence in psychiatric
disorders.
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Published online: 8 November 2011
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