Background Pharmacogenetic studies aiming to personalize the treatment of depression are based on the assumption that response to antidepressants is a heritable trait, but there is no compelling ...evidence to support this. Methods We estimate the contribution of common genetic variation to antidepressant response with Genome-Wide Complex Trait Analysis in a combined sample of 2799 antidepressant-treated subjects with major depressive disorder and genome-wide genotype data. Results We find that common genetic variants explain 42% (SE = .180, p = .009) of individual differences in antidepressant response. Conclusions These results suggest that response to antidepressants is a complex trait with substantial contribution from a large number of common genetic variants of small effect.
Anxiety disorders are leading contributors to the global disease burden, highly prevalent across the lifespan and associated with substantially increased morbidity and early mortality.
The aim of ...this study was to examine age-related changes across a wide range of physiological measures in middle-aged and older adults with a lifetime history of anxiety disorders compared with healthy controls.
The UK Biobank study recruited >500 000 adults, aged 37-73, between 2006 and 2010. We used generalised additive models to estimate non-linear associations between age and hand-grip strength, cardiovascular function, body composition, lung function and heel bone mineral density in a case group and in a control group.
The main data-set included 332 078 adults (mean age 56.37 years; 52.65% females). In both sexes, individuals with anxiety disorders had a lower hand-grip strength and lower blood pressure, whereas their pulse rate and body composition measures were higher than in the healthy control group. Case-control group differences were larger when considering individuals with chronic and/or severe anxiety disorders, and differences in body composition were modulated by depression comorbidity status. Differences in age-related physiological changes between females in the anxiety disorder case group and healthy controls were most evident for blood pressure, pulse rate and body composition, whereas this was the case in males for hand-grip strength, blood pressure and body composition. Most differences in physiological measures between the case and control groups decreased with increasing age.
Findings in individuals with a lifetime history of anxiety disorders differed from a healthy control group across multiple physiological measures, with some evidence of case-control group differences by age. The differences observed varied by chronicity/severity and depression comorbidity.
•Advanced statistical modelling techniques were used to examine age-related changes in 15 physiological measures in individuals with bipolar disorder.•Bipolar disorder cases differed from healthy ...controls in hand-grip strength, blood pressure, pulse rate and multiple measures of body composition.•Case-control differences in age-related physiological changes were most evident for cardiovascular function (in both sexes) and body composition (in females).•Targeted screening for cardiovascular and metabolic health in middle age is warranted to potentially mitigate excess mortality.
Individuals with bipolar disorder have a reduced life expectancy and may experience accelerated biological ageing. In individuals with bipolar disorder and healthy controls, we examined differences in age-related changes in physiology.
UK Biobank recruited more than 500,000 participants, aged 37–73, between 2006 and 2010. Generalised additive models were used to examine associations between age and grip strength, cardiovascular function, body composition, lung function and heel bone mineral density.
The main dataset included 271,118 adults (mean age = 56.04 years; 49.60% females). We found statistically significant differences between cases and controls for grip strength, blood pressure, pulse rate and body composition, with standardised mean differences of up to -0.24 (95% CI -0.28 to -0.19). Evidence of differences in lung function, heel bone mineral density or arterial stiffness was limited. Case-control differences were most evident for age-related changes in cardiovascular function (both sexes) and body composition (females). Differences did not uniformly narrow or widen with age and differed by sex. For example, the difference in systolic blood pressure between male cases and controls was -1.3 mmHg at age 50 and widened to -4.7 mmHg at age 65. Diastolic blood pressure in female cases was 1.2 mmHg higher at age 40 and -1.2 mmHg lower at age 65.
Analyses did not distinguish between bipolar disorder subtypes. Results may not generalise to other age groups.
Differences between bipolar disorder cases and controls were most evident for cardiovascular and body composition measures. Targeted screening for cardiovascular and metabolic health in middle age is warranted to potentially mitigate excess mortality.
Treatment-resistant depression (TRD) is a major contributor to the disability caused by major depressive disorder (MDD). Primary care electronic health records provide an easily accessible approach ...to investigate TRD clinical and genetic characteristics. MDD defined from primary care records in UK Biobank (UKB) and EXCEED studies was compared with other measures of depression and tested for association with MDD polygenic risk score (PRS). Using prescribing records, TRD was defined from at least two switches between antidepressant drugs, each prescribed for at least 6 weeks. Clinical-demographic characteristics, SNP-based heritability (h
) and genetic overlap with psychiatric and non-psychiatric traits were compared in TRD and non-TRD MDD cases. In 230,096 and 8926 UKB and EXCEED participants with primary care data, respectively, the prevalence of MDD was 8.7% and 14.2%, of which 13.2% and 13.5% was TRD, respectively. In both cohorts, MDD defined from primary care records was strongly associated with MDD PRS, and in UKB it showed overlap of 71-88% with other MDD definitions. In UKB, TRD vs healthy controls and non-TRD vs healthy controls h
was comparable (0.25 SE = 0.04 and 0.19 SE = 0.02, respectively). TRD vs non-TRD was positively associated with the PRS of attention deficit hyperactivity disorder, with lower socio-economic status, obesity, higher neuroticism and other unfavourable clinical characteristics. This study demonstrated that MDD and TRD can be reliably defined using primary care records and provides the first large scale population assessment of the genetic, clinical and demographic characteristics of TRD.
The association between urbanicity and risk of schizophrenia is well established. The incidence of schizophrenia has been observed to increase in line with rising levels of urbanicity, as measured in ...terms of population size or density. This association is expressed as Incidence Rate Ratio (IRR), and the results are usually presented by comparing the most urban with the most rural environment. In this study, we undertook to express the effect of urbanicity on the risk of schizophrenia in a linear form and to perform a meta-analysis of all available evidence. We first employed a simple regression analysis of log (IRR) as given in each study on the urbanicity category, assuming a uniform distribution and a linear association. In order to obtain more accurate estimates, we developed a more sophisticated method that generates individual data points with simulation from the summary data presented in the original studies, and then fits a logistic regression model. The estimates from each study were combined with meta-analysis. Despite the challenges that arise from differences between studies as regards to the number and relative size of urbanicity levels, a linear association was observed between the logarithm of the odds of risk for schizophrenia and urbanicity. The risk for schizophrenia at the most urban environment was estimated to be 2.37 times higher than in the most rural environment. The same effect was found when studies measuring the risk for nonaffective psychosis were included.
The authors investigated the pathways (genetic, environmental, lifestyle, medical) leading to inflammation in major depressive disorder using C-reactive protein (CRP), genetic, and phenotypic data ...from the UK Biobank.
This was a case-control study of 26,894 participants with a lifetime diagnosis of major depressive disorder from the Composite International Diagnostic Interview and 59,001 control subjects who reported no mental disorder and had not reported taking any antidepressant medication. Linear regression models of log CRP level were fitted to regress out the effects of age, sex, body mass index (BMI), and smoking and to test whether the polygenic risk score (PRS) for major depression was associated with log CRP level and whether the association between log CRP level and major depression remained after adjusting for early-life trauma, socioeconomic status, and self-reported health status.
CRP levels were significantly higher in patients with depression relative to control subjects (2.4 mg/L compared with 2.1 mg/L, respectively), and more case than control subjects had CRP levels >3 mg/L (21.2% compared with 16.8%, respectively), indicating low-grade inflammation. The PRS for depression was positively and significantly associated with log CRP levels, but this association was no longer significant after adjustment for BMI and smoking. The association between depression and increased log CRP level was substantially reduced, but still remained significant, after adjustment for the aforementioned clinical and sociodemographic factors.
The data indicate that the "genetic" contribution to increased inflammation in depression is due to regulation of eating and smoking habits rather than an "autoimmune" genetic predisposition. Moreover, the association between depression and increased inflammation even after full adjustment indicates either the presence of yet unknown or unmeasured psychosocial and clinical confounding factors or that a core biological association between depression and increased inflammation exists independently from confounders.
•Living with a spouse or partner was associated with reduced odds of lifetime depression.•No evidence of an association between having two children and lifetime depression.•Having three or more ...children was associated with higher odds of lifetime depression.•Associations were similar across age groups, the sexes, neighbourhood deprivation and genetic predisposition.•Mendelian randomisation analyses indicate a causal effect of number of children on depression.
We examined associations between family status (living with a spouse or partner and number of children) and lifetime depression.
We used data from the UK Biobank, a large prospective study of middle-aged and older adults. Lifetime depression was assessed as part of a follow-up mental health questionnaire. Logistic regression was used to estimate associations between family status and depression. We included extensive adjustment for social, demographic and other potential confounders, including depression polygenic risk scores.
52,078 participants (mean age = 63.6, SD = 7.6; 52% female) were included in our analyses. Living with a spouse or partner was associated with substantially lower odds of lifetime depression (OR = 0.67, 95% CI 0.62-0.74). Compared to individuals without children, we found higher odds of lifetime depression for parents of one child (OR = 1.17, 95% CI 1.07-1.27) and parents of three (OR = 1.11, 95% CI 1.03-1.20) or four or more children (OR = 1.27, 95% CI 1.14-1.42). Amongst those not cohabiting, having any number of children was associated with higher odds of lifetime depression. Our results were consistent across age groups, the sexes, neighbourhood deprivation and genetic risk for depression. Exploratory Mendelian randomisation analyses suggested a causal effect of number of children on lifetime depression.
Our data did not allow distinguishing between non-marital and marital cohabitation. Results may not generalise to all ages or populations.
Living with a spouse or partner was strongly associated with reduced odds of depression. Having one or three or more children was associated with increased odds of depression, especially in individuals not living with a spouse or partner.
Stroke is the second leading cause of death with substantial unmet therapeutic needs. To identify potential stroke therapeutic targets, we estimate the causal effects of 308 plasma proteins on stroke ...outcomes in a two-sample Mendelian randomization framework and assess mediation effects by stroke risk factors. We find associations between genetically predicted plasma levels of six proteins and stroke (P ≤ 1.62 × 10
). The genetic associations with stroke colocalize (Posterior Probability >0.7) with the genetic associations of four proteins (TFPI, TMPRSS5, CD6, CD40). Mendelian randomization supports atrial fibrillation, body mass index, smoking, blood pressure, white matter hyperintensities and type 2 diabetes as stroke risk factors (P ≤ 0.0071). Body mass index, white matter hyperintensity and atrial fibrillation appear to mediate the TFPI, IL6RA, TMPRSS5 associations with stroke. Furthermore, thirty-six proteins are associated with one or more of these risk factors using Mendelian randomization. Our results highlight causal pathways and potential therapeutic targets for stroke.
The UK Biobank (UKB) is a resource that includes detailed health-related data on about 500,000 individuals and is available to the research community. However, several obstacles limit immediate ...analysis of the data: data files vary in format, may be very large, and have numerical codes for column names.
ukbtools removes all the upfront data wrangling required to get a single dataset for statistical analysis. All associated data files are merged into a single dataset with descriptive column names. The package also provides tools to assist in quality control by exploring the primary demographics of subsets of participants; query of disease diagnoses for one or more individuals, and estimating disease frequency relative to a reference variable; and to retrieve genetic metadata.
Having a dataset with meaningful variable names, a set of UKB-specific exploratory data analysis tools, disease query functions, and a set of helper functions to explore and write genetic metadata to file, will rapidly enable UKB users to undertake their research.
Individuals with a mental health disorder appear to be at increased risk of medical illness.
To examine rates of medical illnesses in patients with bipolar disorder (n = 1720) and to examine the ...clinical course of the bipolar illness according to lifetime medical illness burden.
Participants recruited within the UK were asked about the lifetime occurrence of 20 medical illnesses, interviewed using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and diagnosed according to DSM-IV criteria.
We found significantly increased rates of several medical illnesses in our bipolar sample. A high medical illness burden was associated with a history of anxiety disorder, rapid cycling mood episodes, suicide attempts and mood episodes with a typically acute onset.
Bipolar disorder is associated with high rates of medical illness. This comorbidity needs to be taken into account by services in order to improve outcomes for patients with bipolar disorder and also in research investigating the aetiology of affective disorder where shared biological pathways may play a role.
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