Cross-disorder Genetics in Neuropsychiatry

Although severe neuropsychiatric disorders have been known to run in families for more than a century, the etiology of the disorders are still poorly understood. For neurological disorders, some diseases are considered oligogenic and monogenic while others are likely more polygenic, where the genetic risk is defined by a large number of alleles across the whole genome. For psychiatric disorders, large-scale genomic research in the past decades has provided insights into their genetic architecture: it is now well established that the genetic architecture of psychiatric disorders is highly polygenic. Although most risk loci influencing neuropsychiatric disorders, biological, and behavioral traits are yet to be identified, a considerable number of rare and common variant loci are shown to be pleiotropic and influence more than one neuropsychiatric disorder. In addition, other mental and somatic traits such as personality traits, cognitive function, brain imaging measures, cardiovascular traits, and BMI share risk loci with neuropsychiatric diseases. The degree of shared genetic influences across neuropsychiatric disorders provides opportunities and challenges for the field of psychiatric genetics. Hence, a better understanding of cross-disorder genetics can transform mental health research.

In line with their high degree of shared clinical characteristics and earlier twin- and family studies, (neuro)psychiatric disorders show a substantial degree of shared genetic influences. The etiologies are not as distinct as presented by the existing categorical diagnostic guidelines. The degree of genetic correlations across neuropsychiatric disorders suggests a common psychopathological base, despite additional ‘unique’ genetic ‘specifiers’ differentiating between disorders. Thus, research into cross-disorder genetics may inform the development of new classification systems and new concepts about etiology of disease. Overlapping genetic mechanisms and discovery of shared pathobiological mechanisms may also inform the development of new and effective cross-disorder treatments. As more common and rare variant loci are expected to be identified for (neuro)psychiatric disorders in the coming years, the variance explained and predictive validity of polygenic risk scores could improve, and become clinically meaningful. However, the substantial genetic overlap between psychiatric disorders and the abovementioned traits may make it challenging to develop prediction tools and help differentiate disorders as defined by the current classification systems. In addition, we expect that more refined and effective methods designed for polygenic phenotypes will help disentangle the genetic underpinnings of neuropsychiatric disorders. Besides classical genetic approaches, emerging omics and multiomics approaches have reiterated the finding of overlapping omics phenotypes for different neuropsychiatric diseases. Yet, they may also aid in further elucidating the findings from classical genetics approaches.

In this Research Topic, we encourage the research community to contribute with original articles, perspectives, methodological papers, or reviews about the increasingly important field of cross-disorder genetics. Topics may be related to a broad array of traits and disorders with relevance to neuroscience, e.g.
• neuropsychiatric disorders, including both neurological and psychiatric disorders and disorders with overarching symptoms, such as Huntington’s disease;
• behavioral traits; or
• quantifiable measures, such as EEG, blood, cerebrospinal fluid and MRI measurements.