Abstract
Mood instability is a core clinical feature of affective and psychotic disorders. In keeping with the Research Domain Criteria approach, it may be a useful construct for identifying biology that cuts across psychiatric categories. We aimed to investigate the biological validity of a simple measure of mood instability and evaluate its genetic relationship with several psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD), schizophrenia, attention deficit hyperactivity disorder (ADHD), anxiety disorder and post-traumatic stress disorder (PTSD). We conducted a genome-wide association study (GWAS) of mood instability in 53,525 cases and 60,443 controls from UK Biobank, identifying four independently associated loci (on chromosomes 8, 9, 14 and 18), and a common single-nucleotide polymorphism (SNP)-based heritability estimate of ~8%. We found a strong genetic correlation between mood instability and MDD (rg = 0.60, SE = 0.07, p = 8.95 × 10−17) and a small but significant genetic correlation with both schizophrenia (rg = 0.11, SE = 0.04, p = 0.01) and anxiety disorders (rg = 0.28, SE = 0.14, p = 0.04), although no genetic correlation with BD, ADHD or PTSD was observed. Several genes at the associated loci may have a role in mood instability, including the DCC netrin 1 receptor (DCC) gene, eukaryotic translation initiation factor 2B subunit beta (eIF2B2), placental growth factor (PGF) and protein tyrosine phosphatase, receptor type D (PTPRD). Strengths of this study include the very large sample size, but our measure of mood instability may be limited by the use of a single question. Overall, this work suggests a polygenic basis for mood instability. This simple measure can be obtained in very large samples; our findings suggest that doing so may offer the opportunity to illuminate the fundamental biology of mood regulation.
Highlights
Mood instability is a common clinical feature of affective and psychotic disorders, major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia[1]
Mood instability in MDD and BD within United Kingdom (UK) Biobank In previous work we have identified individuals within
This proportion was highest in the BD group (74.0%) followed by the three MDD groups (71.7% for recurrent severe MDD, 64.2% for recurrent moderate MDD and 43.7% for single-episode MDD)
Summary
Mood instability is a common clinical feature of affective and psychotic disorders, major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia[1] It may be relatively common in the general population, estimated to affect ~13% of individuals[2]. Mood instability may be of fundamental importance for understanding the pathophysiology of MDD and BD, as well as conditions such as borderline personality disorder, anxiety disorders, Ward et al Translational Psychiatry (2017)7:1264 attention deficit hyperactivity disorder (ADHD) and psychosis[4]. This trait is reported by 40–60% of individuals with MDD5 and is recognised as part of the prodromal stage of BD6. General population twin studies suggest that additive genetic effects account for 40% of the variance in measures of affect intensity and 25% of the variance in affective liability[8]
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