Genomic insights into the overlap between psychiatric disorders: implications for research and clinical practice
Genome Medicine
Genomic insights into the overlap between psychiatric disorders: implications for research and clinical practice
Joanne L Doherty 0
Michael J Owen 0
0 The MRC Centre for Neuropsychiatric Genetics and Genomics and The Neuroscience and Mental Health Research Institute, Cardiff University , Hadyn Ellis Buildin, Maindy Road, Cardiff CF24 4HQ , UK
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Psychiatric disorders such as schizophrenia, bipolar disorder,
major depressive disorder, attention-deficit/hyperactivity
disorder and autism spectrum disorder are common and
result in significant morbidity and mortality. Although
currently classified into distinct disorder categories, they
show clinical overlap and familial co-aggregation, and share
genetic risk factors. Recent advances in psychiatric
genomics have provided insight into the potential
mechanisms underlying the overlap between these
disorders, implicating genes involved in neurodevelopment,
synaptic plasticity, learning and memory. Furthermore,
evidence from copy number variant, exome sequencing
and genome-wide association studies supports a gradient
of neurodevelopmental psychopathology indexed by
mutational load or mutational severity, and cognitive
impairment. These findings have important implications for
psychiatric research, highlighting the need for new
approaches to stratifying patients for research. They also
point the way for work aiming to advance our
understanding of the pathways from genotype to clinical
phenotype, which will be required in order to inform new
classification systems and to develop novel therapeutic
strategies.
The overlap between psychiatric disorders: challenges to current nosology
Psychiatric disorders are common in the population [
1
] and
result in considerable morbidity and mortality [
2
]. Over the
decades, psychiatric classification systems such as the
Diagnostic and Statistical Manual of Mental Disorders
(DSM) [
3
] and the International Classification of Diseases
(ICD) [
4
] have been developed and revised in order to
improve the reliability of clinical diagnosis, inform treatment
strategies and guide research. However, in the absence of
objective diagnostic tests for psychiatric disorders, such
classifications are largely descriptive and syndromic,
describing constellations of symptoms and signs that tend to occur
together. These classification systems thus define psychiatric
disorders such as schizophrenia, bipolar disorder, major
depressive disorder, attention-deficit/hyperactivity disorder
(ADHD) and autism spectrum disorder (ASD) categorically,
according to the quality and quantity of symptoms and signs
present. Treatment guidelines have been developed on the
basis of these diagnostic categories. For example,
schizophrenia is treated with antipsychotics, bipolar disorder
with mood stabilizers and antipsychotics, major
depression with antidepressants and ADHD with
psychostimulants (Table 1).
However, it is widely acknowledged that there is
substantial heterogeneity within diagnostic categories and
that the boundary between disorder and ‘normality’ is
not always clear. Furthermore, many symptoms and
signs overlap between disorder categories and patients
often present with features of more than one disorder.
In some cases, this overlap has been dealt with by
recognizing diagnostic ‘interforms’ such as schizoaffective
disorder [
11
], or by recognizing ‘comorbidity’, whereby
patients are diagnosed with more than one disorder.
Comorbidity is often obscured in research by the use of
diagnostic hierarchies or exclusions. For example, until
the publication of the most recent edition of the DSM
(DSM-5), it was not possible to co-diagnose ASD and
ADHD. However, it is estimated that 30 to 80% of children
with ASD also have ADHD [
12,13
]. Given these diagnostic
issues, it is perhaps unsurprising that neuroscientific
advances have thus far failed to identify specific risk factors
or biomarkers that map onto disorder categories on a
oneto-one basis. Indeed, there is accumulating evidence
supporting biological overlap between disorders, fuelling
investigation into the underlying mechanisms.
Advances in genomic technology have been key to this
paradigm shift in psychiatric research. These studies
provide converging evidence across a number of different
levels, supporting the hypothesis that genetic risk factors
are shared between disorders and challenging the validity
of the classification systems currently used in research
and clinical practice. The evidence suggests that
investigating pathways common across disorders may help us to
understand the etiology of psychiatric illness. This could
revolutionize our approach to the diagnosis and treatment
of these complex disorders. Here, we review recent
evidence from family and genomic studies, which support an
overlapping and complex genetic architecture for
psychiatric disorders and provide new avenues for further
investigation of underlying mechanisms.
Family studies
Twin, family and a (...truncated)