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Genome-wide analysis in UK Biobank identifies four loci associated with mood instability and genetic correlation with major depressive disorder, anxiety disorder and schizophrenia.

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 (r g?=?0.60, SE?=?0.07, p?=?8.95?×?10-17) and a small but significant genetic correlation with both schizophrenia (r g?=?0.11, SE?=?0.04, p?=?0.01) and anxiety disorders (r g?=?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.

SUBMITTER: Ward J

PROVIDER: S-EPMC5802589 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Genome-wide analysis in UK Biobank identifies four loci associated with mood instability and genetic correlation with major depressive disorder, anxiety disorder and schizophrenia.

Ward Joey J Strawbridge Rona J RJ Bailey Mark E S MES Graham Nicholas N Ferguson Amy A Lyall Donald M DM Cullen Breda B Pidgeon Laura M LM Cavanagh Jonathan J Mackay Daniel F DF Pell Jill P JP O'Donovan Michael M Escott-Price Valentina V Smith Daniel J DJ

Translational psychiatry 20171130 11

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 hyperact ...[more]

PMID: 29187730

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Project description:BACKGROUND.:Cognitive impairment associated with lifetime major depressive disorder (MDD) is well-supported by meta-analytic studies, but population-based estimates remain scarce. Previous UK Biobank studies have only shown limited evidence of cognitive differences related to probable MDD. Using updated cognitive and clinical assessments in UK Biobank, this study investigated population-level differences in cognitive functioning associated with lifetime MDD. METHODS.:Associations between lifetime MDD and cognition (performance on six tasks and general cognitive functioning [g-factor]) were investigated in UK Biobank (N-range 7,457-14,836, age 45-81 years, 52% female), adjusting for demographics, education, and lifestyle. Lifetime MDD classifications were based on the Composite International Diagnostic Interview. Within the lifetime MDD group, we additionally investigated relationships between cognition and (a) recurrence, (b) current symptoms, (c) severity of psychosocial impairment (while symptomatic), and (d) concurrent psychotropic medication use. RESULTS.:Lifetime MDD was robustly associated with a lower g-factor (? = -0.10, PFDR = 4.7 × 10-5), with impairments in attention, processing speed, and executive functioning (? ? 0.06). Clinical characteristics revealed differential profiles of cognitive impairment among case individuals; those who reported severe psychosocial impairment and use of psychotropic medication performed worse on cognitive tests. Severe psychosocial impairment and reasoning showed the strongest association (? = -0.18, PFDR = 7.5 × 10-5). CONCLUSIONS.:Findings describe small but robust associations between lifetime MDD and lower cognitive performance within a population-based sample. Overall effects were of modest effect size, suggesting limited clinical relevance. However, deficits within specific cognitive domains were more pronounced in relation to clinical characteristics, particularly severe psychosocial impairment.

Dataset Information

Genome-wide analysis in UK Biobank identifies four loci associated with mood instability and genetic correlation with major depressive disorder, anxiety disorder and schizophrenia.

Publications

Genome-wide analysis in UK Biobank identifies four loci associated with mood instability and genetic correlation with major depressive disorder, anxiety disorder and schizophrenia.

Similar Datasets

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