Genomic insights into the overlap between psychiatric disorders: implications for research and clinical practice

Genome Medicine, Apr 2014

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.

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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 - 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)


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Joanne L Doherty, Michael J Owen. Genomic insights into the overlap between psychiatric disorders: implications for research and clinical practice, Genome Medicine, 2014, pp. 29, Volume 6, Issue 4, DOI: 10.1186/gm546