Saira Saeed Mirza

Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis: the CARTA consortium

Objectives To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach. Design Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress. Participants Current, former and never smokers of European ancestry aged ≥16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). Primary outcome measures Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis. Results The analytic sample included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers. Conclusions Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.

Meta-analysis of genome-wide association studies of anxiety disorders

Anxiety disorders (ADs), namely generalized AD, panic disorder and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based on clinical presentation, ADs likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat–response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based ADs, we applied two phenotypic approaches: (1) comparisons between categorical AD cases and supernormal controls, and (2) quantitative phenotypic factor scores (FS) derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case–control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65 × 10−8); for FS, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86 × 10−9). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of ADs.

10-year trajectories of depressive symptoms and risk of dementia: a population-based study

BACKGROUND Late-life depressive symptoms have been extensively studied for their relationship with incident dementia, but have been typically assessed at a single timepoint. Such an approach neglects the course of depression, which, given its remitting and relapsing nature, might provide further insights into the complex association of depression with dementia. We therefore repeatedly measured depressive symptoms in a population of adults over a decade to study the subsequent risk of dementia. METHODS Our study was embedded in the Rotterdam Study, a population-based study of adults aged 55 years or older in Rotterdam (Netherlands), ongoing since 1990. The cohort is monitored continuously for major events by data linkage between the study database and general practitioners. We examined a cohort of participants who were free from dementia, but had data for depressive symptoms from at least one examination round in 1993-95, 1997-99, or 2002-04. We assessed depressive symptoms with the validated Dutch version of the Center for Epidemiology Depression Scale (CES-D) and the Hospital Anxiety and Depression Scale-Depression. We used these data to identify 11-year trajectories of depressive symptoms by latent class trajectory modelling. We screened participants for dementia at each examination round and followed up participants for 10 years for incident dementia by latent trajectory from the third examination round to 2014. We calculated hazard ratios (HR) for dementia by assigned trajectory using two Cox proportional hazards models (model 1 adjusted for age and sex only, and model 2 adjusted additionally for APOEɛ4 carrier status, educational level, body-mass index, smoking, alcohol consumption, cognitive score, use of antidepressants, and prevalent disease status at baseline). We repeated the analyses censoring for incident stroke, restricting to Alzheimers disease as an outcome, and accounting for mortality as a competing risk for dementia. FINDINGS From 1993-2004, we obtained data for depressive symptoms from at least one examination round for 3325 participants (median age: 74·88 years [IQR 70·62-80·06], 1995 [60%] women). We identified five trajectories of depressive symptoms in these 3325 individuals, characterised by maintained low CES-D scores (low; 2441 [73%]); moderately high starting scores but then remitting (decreasing; 369 [11%]); low starting scores, increasing, then remitting (remitting; 170 [5%]); low starting scores that steadily increased (increasing; 255 [8%]); and maintained high scores (high; 90 [3%]). During 26 330 person-years, 434 participants developed incident dementia. Only the trajectory with increasing depressive symptoms was associated with a higher risk of dementia compared with the low depressive symptom trajectory, using model 2 (HR 1·42, 95% CI 1·05-1·94; p=0·024). Additionally, only the increasing trajectory was associated with a higher risk of dementia compared with the low trajectory after censoring for incident stroke (1·58, 1·15-2·16; p=0·0041), restricting to Alzheimers disease as an outcome (1·44, 1·03-2·02; p=0·034), and accounting for mortality as a competing risk (1·45, 1·06-1·97; p=0·019). INTERPRETATION Risk of dementia differed with different courses of depression, which could not be captured by a single assessment of depressive symptoms. The higher risk of dementia only in the increasing trajectory suggests depression might be a prodrome of dementia. FUNDING Erasmus Medical Center; ZonMw; the Netherlands Ministry of Education Culture and Science; and the Netherlands Ministry for Health, Welfare and Sports.

New Strategy to Reduce the Global Burden of Stroke

The socioeconomic and health effect of stroke and other noncommunicable disorders (NCDs) that share many of the same risk factors with stroke, such as heart attack, dementia, and diabetes mellitus, is huge and increasing.1–4 Collectively, NCDs account for 34.5 million deaths (66% of deaths from all causes)3 and 1344 million disability-adjusted life years lost worldwide in 2010.2 The burden of NCDs is likely to burgeon given the aging of the world’s population and the epidemiological transition currently observed in many low- to middle-income countries (LMICs).5,6 In addition, there is low awareness in the population about these NCDs and their risk factors,7–10 particularly in LMICs.11 These factors, coupled with underuse of strategies for primary prevention of stroke/NCDs on an individual level and the lack of accurate data on the prevalence and effect of risk factors in different countries and populations have been implicated in the ever-increasing worldwide burden of the NCDs.12–15 Of particular concern is a significant increase in the number of young adults (aged <65 years) affected by stroke,16 and the increasing epidemic of overweight/obesity17 and diabetes mellitus worldwide.18 If these trends continue, the burden of stroke and other major NCDs will increase even faster. The increasing burden of stroke and other major NCDs provide strong support for the notion that the currently used primary prevention strategies for stroke and other major NCDs (business as usual) are not sufficiently effective. The most pertinent solution to this problem is the implementation of new, effective, widely available, and cost-effective prevention and treatment strategies to reduce the incidence and severity distribution of stroke and other major NCDs. The recent INTERSTROKE case-control study, conducted in 22 countries worldwide, provided evidence that, collectively, 10 risk factors accounted …

Depressive symptoms predict incident dementia during short- but not long-term follow-up period

Whether depression is a long‐term risk factor for dementia or represents a dementia prodrome is unclear. Therefore, we examined the relationship between depressive symptoms and dementia during short and long follow‐up in a population‐based cohort.

GENOME‐WIDE ASSOCIATION STUDY (GWAS) AND GENOME‐WIDE BY ENVIRONMENT INTERACTION STUDY (GWEIS) OF DEPRESSIVE SYMPTOMS IN AFRICAN AMERICAN AND HISPANIC/LATINA WOMEN

Genome‐wide association studies (GWAS) have made little progress in identifying variants linked to depression. We hypothesized that examining depressive symptoms and considering gene–environment interaction (GxE) might improve efficiency for gene discovery. We therefore conducted a GWAS and genome‐wide by environment interaction study (GWEIS) of depressive symptoms.

Meta-analysis of genome-wide association studies of anxiety disorders (vol 21, pg 1391, 2016)

Correction to: Molecular Psychiatry (2015); advance online publication 12 January 2016; doi:10.1038/mp.2015.197 Following publication of the above article, the authors noticed that the fifteenth author’s name was presented incorrectly. The author’s name should have appeared as S Van der Auwera. The publisher regrets the error.

The N-terminal pro B-type natriuretic peptide, and risk of dementia and cognitive decline: A 10-year follow-up Study in the general population

Background The N-terminal pro B-type natriuretic peptide (NT-proBNP) has a well-documented prognostic value for cardiovascular disease (CVD) and higher levels are associated with cognitive-dysfunction in patients with CVD. However, how NT-proBNP relates to incident dementia and cognitive-decline in community-dwelling persons is unknown. Methods Between 1997 and 2001, serum NT-proBNP was measured in 6040 participants (mean age 69 years, 57% women) free of heart-failure and dementia from the Rotterdam Study. Participants were continuously followed-up for incident dementia until 2012, for 56 616 person-years. Cognition was assessed at baseline and reassessed between 2002 and 2006 by Letter-Digit-Substitution-task, Stroop test and Word-Fluency test. Associations of NT-proBNP with dementia (555 cases), Alzheimers disease (357 cases) and vascular dementia (32 cases) were assessed linearly, and in quartiles using Cox regression. Associations of NT-proBNP with cognitive-decline were assessed using multiple linear regression. All analyses were repeated after excluding patients with CVD. Results Higher NT-proBNP was associated with a higher risk of dementia, even after excluding patients with CVD and adjusting for cardiovascular risk factors, HR per SD 1.27 (95% CI 1.13 to 1.44). Associations were particularly strong for vascular dementia, HR per SD 2.04 (95% CI 1.18 to 3.55), but also for Alzheimers disease when comparing the second and third quartile with first. Higher NT-proBNP was cross-sectionally associated with poorer performance in multiple cognitive tests but longitudinally only in Letter-Digit-Substitution-task. Conclusions NT-proBNP reflecting subclinical CVD is associated with dementia, particularly vascular dementia. NT-proBNP can be a useful marker of imminent cognitive-decline and dementia in absence of clinical CVD.

Positive affect is not associated with incidence of cardiovascular disease: A population-based study of older persons

INTRODUCTION The relationship between positive psychological well-being (PPWB) and cardiovascular disease (CVD) is inconsistent across different CVD outcomes and for different PPWB constructs, such as positive affect. In addition, the relationship between PPWB and CVD as a composite measure is rarely assessed. OBJECTIVE To assess whether positive affect is protective of incident CVD. METHOD Positive affect was assessed in two cohorts between 1993 and 2001 in Rotterdam using relevant questions from the Center for Epidemiological Studies Depression (CES-D) scale and the Hospital Anxiety and Depression Scale (HADS; in a sub-sample) in 6349 non-demented, CVD-free, consenting adults, aged 55+years. Composite CVD was defined as stroke, heart failure and coronary heart disease, which were continuously monitored through medical records until 1st April 2010. RESULTS There were 1480 (23.3%) first time CVD events during follow-up (11.9 ± 2.8 SD years, 58,416 person-years). Positive affect was not associated with incident CVD (CES-D HR: 1.00 per point, 95% CI: 0.98-1.02; HADS HR: 0.98, 95% CI: 0.92-1.05). Stratification by age or sex and assessment of separate CVD outcome did not change results. CONCLUSION In this large, population-based study, there was no association between positive affect and twelve-year incident CVD in older adults who were free of diagnosed CVD at baseline.

Mild cognitive impairment and risk of depression and anxiety: A population-based study

Many people with mild cognitive impairment (MCI) suffer from concomitant depression or anxiety. Whether MCI increases the risk of future depression or anxiety is unknown.