Review article 1 Genetics and major depressive disorder: clinical implications for disease risk, prognosis and treatment Chiara Fabbria, Stuart Montgomeryb, Cathryn M. Lewisa and Alessandro Serrettic 05/20/2020 on BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3XI41p+sDLxaJAfxodQioFdTux8hVN8Nb0QiuAByVd3P1vgkD/oV9Yw== by https://journals.lww.com/intclinpsychopharm from Downloaded In the post-genomic era, genetics has led to limited clinical identification of new pharmacological targets. Increase in Downloaded applications in the diagnosis and treatment of major power thanks to larger samples and methods integrating depressive disorder (MDD). Variants in genes coding genetic data with gene expression, the integration of from for cytochrome enzymes are included in guidelines for common variants and rare variants, are expected to https://journals.lww.com/intclinpsychopharm assisting in antidepressant choice and dosing, but there advance our knowledge and assist in personalized are no recommendations involving genes responsible for psychiatry. Int Clin Psychopharmacol 35: XXX–XXX antidepressant pharmacodynamics and no consensus Copyright © 2020 The Author(s). Published by Wolters applications for guiding diagnosis or prognosis. However, Kluwer Health, Inc. genetics has contributed to a better understanding of International Clinical Psychopharmacology 2020, 35:XXX–XXX MDD pathogenesis and the mechanisms of antidepressant action, also thanks to recent methodological innovations Keywords: antidepressant, exome sequencing, gene, genome-wide by association studies, major depressive disorder, polygenic BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3XI41p+sDLxaJAfxodQioFdTux8hVN8Nb0QiuAByVd3P1vgkD/oV9Yw== that overcome the challenges posed by the polygenic a architecture of these traits. Polygenic risk scores can be Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, bImperial College used to estimate the risk of disease at the individual level, School of Medicine, London, UK and cDepartment of Biomedical and which may have clinical relevance in cases with extremely Neuromotor Sciences, University of Bologna, Bologna, Italy high scores (e.g. top 1%). Genetic studies have also Correspondence to Alessandro Serretti, MD, Department of Biomedical and shed light on a wide genetic overlap between MDD and NeuroMotor Sciences, University of Bologna, Viale Carlo Pepoli 5, 40123 Bologna, Italy other psychiatric disorders. The relationships between Tel: +39 051 6584233; fax +39 051 521030; genes/pathways associated with MDD and known drug e-mail: [email protected] targets are a promising tool for drug repurposing and Received 24 August 2019 Accepted as revised 16 December 2019 Introduction These biomarkers can help in finding the biological Historically, psychiatrists always had few or no tools to underpinnings of clinical manifestations, distinguish dif- interrogate their patients’ bodies on the pathophysiology ferent dimensions within and across diagnostic catego- of their symptoms. Patterns of symptoms that often occur ries and tailor treatment prescription (Strawbridge et al., together have been classified in disorders in order to have 2017). The idea of implementing this approach has led a standard nosology that guides diagnosis and treatment. to the term precision psychiatry, which implies that each Attempts to give more space to dimensional over cate- patient has a distinctive profile of biological dysfunc- gorical classifications have mostly failed, because of the tions, which interacting with environmental factors is complexity of that kind of approach. As a matter of fact, responsible for the clinical presentation (Fernandes et al., the possible combinations of symptoms, their respective 2017). The knowledge needed to implement precision intensity and fluctuations cannot easily be captured in psychiatry is still partial, but recent rapid technological on a way that is applicable in routine clinical practice. For and methodological improvements are making it more 05/20/2020 example, 1030 unique depressive symptom profiles were and more feasible. A central part of this process is the identified in one sample only (Fried and Nesse, 2015). postgenomic revolution: the cost/time for sequencing a This represents an obstacle to personalized psychia- human genome dropped from $100 millions/several years try and leads to the delivery of relatively homogeneous in 2001 to $1000/2 days in 2017, while genome-wide com- treatments within diagnostic categories. A dimensional mon variant genotyping can be done for ~ $25–50 per approach can be more easily applied to objectively meas- subject (National Human Genome Research Institute, urable quantitative parameters, such as blood protein 2018). This has made possible the genotyping of large levels, neuroimaging brain measures, or genetic variants. samples with major depressive disorder (MDD), as well as other psychiatric disorders and healthy controls, and This is an open-access article distributed under the terms of the Creative testing the influence of genetic variants on the risk of dis- Commons Attribution-Non Commercial-No Derivatives License 4.0 (CC-BY- ease and treatment response (Howard et al., 2019). The NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially existing literature shows that genetic variants explain without permission from the journal. very small variance individually and the cumulative effect 0268-1315 Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. DOI: 10.1097/YIC.0000000000000305 Copyright © 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 2 International Clinical Psychopharmacology 2020, Vol 35 No 3 of many variants (hundreds or thousands) is responsible Genomics Consortium, 2013; Network and Pathway for the genetic susceptibility to these traits (Zhang et al., Analysis Subgroup of Psychiatric Genomics Consortium, 2018). Specific analysis approaches have been applied 2015; Amare et al., 2019). Clinically, severe MDD patients to capture this polygenic architecture, such as pathway may show symptoms relatively rare in this disorder and analysis and polygenic risk scores (PRS). These meth- more typical of schizophrenia and other neurodevelop- odologies have provided promising results in identifying mental disorders, such as early onset, cognitive deficits, the genetic contribution to MDD and antidepressant social difficulties and psychotic symptoms, and higher response, which have rapidly expanding clinical applica- risk of childhood attention deficit hyperactivity disorder tions, and they can have an important potential in con- (ADHD) diagnosis (e.g. 6.3% in early onset vs. 0.9% in tributing to the development of new drugs for depression later onset MDD cases) (Rice et al., 2019). Some of these or drug repositioning, as discussed in the next paragraphs. symptoms are relatively common in MDD, for exam- ple cognitive and psychosocial deficits were described Pathway analysis: insights into the biological in 30–50% of patients in partial or complete remission mechanisms of depression (Lam et al., 2014), but they are distributed on a contin- The analysis of genetic pathways instead of individual uum, and clinically it is not straightforward to identify a genetic variants as unit of analysis is a way to unravel the threshold for distinguishing patients having high risk of complexity of MDD pathogenesis and the corresponding a negative prognosis (e.g. incomplete functional recovery mechanisms mediating antidepressant response. Genetic between episodes and high disease recurrence). Genetics pathways are groups of genes functionally related among may help in reaching this objective, through the identi- each other, which mediate a distinct cellular or molec- fication of genetic risk factors in specific genomic areas ular process or reflect interactions among proteins or (genes or pathways) or general genetic risk factors (e.g. molecules. by using PRS). For example, higher PRS for schizophre- nia or ADHD was associated with the risk of early onset Pathway analysis led to the identification of several bio- MDD, psychotic symptoms and social communication logical mechanisms that mediate depression and anti- difficulties (Rice et al., 2019). At treatment level, patients depressant action. These can be grouped in some main sharing more genetic risk factors with schizophrenia may clusters: axonal development, neuron differentiation and have higher risk of poor treatment response, as demon- morphogenesis, neural-plasticity, excitatory neurotrans- strated in bipolar disorder [International Consortium on mission, cytokines, immune response and regulation Lithium Genetics (ConLi+Gen) et al., 2018], and possi- of gene expression (Zeng et al., 2017; Wray et al., 2018; bly need treatment with drugs having alternative mech- Howard et al., 2018; Fabbri et al., 2019a). anisms of action. These findings suggest that part of the genetic predispo- Despite a probable neurodevelopmental component sition to depression manifests during brain development, in a subgroup of cases, genetic studies provided quite as exemplified by the involvement of the NETRIN1 convincing evidence that MDD pathogenesis and anti- signaling pathway. Key proteins of this pathway affect depressant action mostly involve modifications of neu- axon guidance,