Genetic and epigenetic analyses of panic disorder in the post-GWAS era
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PSYCHIATRY AND PRECLINICAL PSYCHIATRIC STUDIES - REVIEW ARTICLE
Genetic and epigenetic analyses of panic disorder in the post‑GWAS era Yoshiro Morimoto1,2 · Shinji Ono3 · Naohiro Kurotaki4 · Akira Imamura2 · Hiroki Ozawa1,2 Received: 29 January 2020 / Accepted: 3 May 2020 © The Author(s) 2020
Abstract Panic disorder (PD) is a common and debilitating neuropsychiatric disorder characterized by panic attacks coupled with excessive anxiety. Both genetic factors and environmental factors play an important role in PD pathogenesis and response to treatment. However, PD is clinically heterogeneous and genetically complex, and the exact genetic or environmental causes of this disorder remain unclear. Various approaches for detecting disease-causing genes have recently been made available. In particular, genome-wide association studies (GWAS) have attracted attention for the identification of disease-associated loci of multifactorial disorders. This review introduces GWAS of PD, followed by a discussion about the limitations of GWAS and the major challenges facing geneticists in the post-GWAS era. Alternative strategies to address these challenges are then proposed, such as epigenome-wide association studies (EWAS) and rare variant association studies (RVAS) using next-generation sequencing. To date, however, few reports have described these analyses, and the evidence remains insufficient to confidently identify or exclude rare variants or epigenetic changes in PD. Further analyses are therefore required, using sample sizes in the tens of thousands, extensive functional annotations, and highly targeted hypothesis testing. Keywords Panic disorder · Genome-wide association studies (GWAS) · Missing heritability · Next-generation sequencing (NGS) · Rare variant association study (RVAS) · Epigenome-wide association study (EWAS)
Introduction Panic disorder (PD) is an anxiety disorder characterized by recurrent and unexpected panic attacks, subsequent anticipatory anxiety, and phobic avoidance. Approximately, 10–20% of patients with PD are refractory, with severe and chronic symptoms that seriously affect their quality of life (Markowitz et al. 1989). PD has a high incidence rate, with a lifetime prevalence of 1–3%, and is a disorder frequently observed in clinical practice (Wittchen et al. 2011). Several genetic and * Yoshiro Morimoto y‑morimoto@nagasaki‑u.ac.jp 1
Department of Neuropsychiatry, Unit of Translation Medicine, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto 1‑7‑1, Nagasaki 852‑8501, Japan
2
Child and Adolescent Psychiatry Community Partnership Unit, Nagasaki University Hospital, Nagasaki, Japan
3
Aino-Ariake Hospital, Unzen, Nagasaki, Japan
4
Department of Clinical Psychology, Faculty of Medicine, Kagawa University, Kagawa, Japan
epidemiological studies, including family and twin studies, have shown that genetic factors play an important role in the pathogenesis of PD. First-degree relatives of a proband with PD are at a sixfold risk of developing this disease (Goldstein et
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