Affective problems and decline in cognitive state in older adults: a systematic review and meta-analysis.

Evidence suggests that affective problems, such as depression and anxiety, increase risk for late-life dementia. However, the extent to which affective problems influence cognitive decline, even many years prior to clinical diagnosis of dementia, is not clear. The present study systematically reviews and synthesises the evidence for the association between affective problems and decline in cognitive state (i.e., decline in non-specific cognitive function) in older adults. An electronic search of PubMed, PsycInfo, Cochrane, and ScienceDirect was conducted to identify studies of the association between depression and anxiety separately and decline in cognitive state. Key inclusion criteria were prospective, longitudinal designs with a minimum follow-up period of 1 year. Data extraction and methodological quality assessment using the STROBE checklist were conducted independently by two raters. A total of 34 studies (n = 71 244) met eligibility criteria, with 32 studies measuring depression (n = 68 793), and five measuring anxiety (n = 4698). A multi-level meta-analysis revealed that depression assessed as a binary predictor (OR 1.36, 95% CI 1.05-1.76, p = 0.02) or a continuous predictor (B = -0.008, 95% CI -0.015 to -0.002, p = 0.012; OR 0.992, 95% CI 0.985-0.998) was significantly associated with decline in cognitive state. The number of anxiety studies was insufficient for meta-analysis, and they are described in a narrative review. Results of the present study improve current understanding of the temporal nature of the association between affective problems and decline in cognitive state. They also suggest that cognitive function may need to be monitored closely in individuals with affective disorders, as these individuals may be at particular risk of greater cognitive decline.

Psychometric precision in phenotype definition is a useful step in molecular genetic investigation of psychiatric disorders.

Affective disorders are highly heritable, but few genetic risk variants have been consistently replicated in molecular genetic association studies. The common method of defining psychiatric phenotypes in molecular genetic research is either a summation of symptom scores or binary threshold score representing the risk of diagnosis. Psychometric latent variable methods can improve the precision of psychiatric phenotypes, especially when the data structure is not straightforward. Using data from the British 1946 birth cohort, we compared summary scores with psychometric modeling based on the General Health Questionnaire (GHQ-28) scale for affective symptoms in an association analysis of 27 candidate genes (249 single-nucleotide polymorphisms (SNPs)). The psychometric method utilized a bi-factor model that partitioned the phenotype variances into five orthogonal latent variable factors, in accordance with the multidimensional data structure of the GHQ-28 involving somatic, social, anxiety and depression domains. Results showed that, compared with the summation approach, the affective symptoms defined by the bi-factor psychometric model had a higher number of associated SNPs of larger effect sizes. These results suggest that psychometrically defined mental health phenotypes can reflect the dimensions of complex phenotypes better than summation scores, and therefore offer a useful approach in genetic association investigations.

Brain derived neurotrophic factor gene (BDNF) and personality traits: the modifying effect of season of birth and sex.

Personality traits are complex phenotypes influenced by interactions of multiple genetic variants of small effect and environmental factors. It has been suggested that the brain derived neurotrophic factor gene (BDNF) is involved in personality traits. Season of birth (SOB) has also been shown to affect personality traits due to its influences on brain development during prenatal and early postnatal periods. The present study aimed to investigate the effects of BDNF on personality traits; and the modifying effects of SOB and sex on associations between BDNF and personality traits. A sample of 1018 young adults (68% women; age range 17-25years) of Caucasian origin from the Russian Federation was assessed on personality traits (Novelty Seeking, Harm Avoidance, Reward Dependence, Persistence, Self-directedness, Cooperativeness, Self-transcendence) with the Temperament and Character Inventory-125 (TCI-125). Associations between personality traits and 12 BDNF SNPs were tested using linear regression models. The present study demonstrated the effect of rs11030102 on Persistence in females only (PFDR=0.043; r(2)=1.3%). There were significant interaction effects between Val66Met (rs6265) and SOB (PFDR=0.048, r(2)=1.4%), and between rs2030323 and SOB (PFDR=0.042, r(2)=1.3%), on Harm Avoidance. Our findings provide evidence for the modifying effect of SOB on the association between BDNF and Harm Avoidance, and for the modifying effect of sex on the association between BDNF and Persistence.

Maternal depression symptoms, unhealthy diet and child emotional-behavioural dysregulation.

BACKGROUND: Maternal depression and unhealthy diet are well-known risk factors for adverse child emotional-behavioural outcomes, but their developmental relationships during the prenatal and postnatal periods are largely uncharted. This study sought to examine the inter-relationships between maternal depression symptoms and unhealthy diet (assessed during pregnancy and postnatal periods) in relation to child emotional-behavioural dysregulation (assessed at the ages of 2, 4 and 7 years). METHOD: In a large prospective birth cohort of 7814 mother-child pairs, path analysis was used to examine the independent and inter-related associations of maternal depression symptoms and unhealthy diet with child dysregulation. RESULTS: Higher prenatal maternal depression symptoms were prospectively associated with higher unhealthy diet, both during pregnancy and the postnatal period, which, in turn, was associated with higher child dysregulation up to the age of 7 years. In addition, during pregnancy, higher maternal depression symptoms and unhealthy diet were each independently associated with higher child dysregulation up to the age of 7 years. These results were robust to other prenatal, perinatal and postnatal confounders (such as parity and birth complications, poverty, maternal education, etc.). CONCLUSIONS: Maternal depression symptoms and unhealthy diet show important developmental associations, but are also independent risk factors for abnormal child development.

Lifetime affect and midlife cognitive function: prospective birth cohort study.

BACKGROUND: Recurrent affective problems are predictive of cognitive impairment, but the timing and directionality, and the nature of the cognitive impairment, are unclear. AIMS: To test prospective associations between life-course affective symptoms and cognitive function in late middle age. METHOD: A total of 1668 men and women were drawn from the Medical Research Council National Survey of Health and Development (the British 1946 birth cohort). Longitudinal affective symptoms spanning age 13-53 years served as predictors; outcomes consisted of self-reported memory problems at 60-64 years and decline in memory and information processing from age 53 to 60-64 years. RESULTS: Regression analyses revealed no clear pattern of association between longitudinal affective symptoms and decline in cognitive test scores, after adjusting for gender, childhood cognitive ability, education and midlife socioeconomic status. In contrast, affective symptoms were strongly, diffusely and independently associated with self-reported memory problems. CONCLUSIONS: Affective symptoms are more clearly associated with self-reported memory problems in late midlife than with objectively measured cognitive performance.

A follow-up case-control association study of tractable (druggable) genes in recurrent major depression.

The High-Throughput Disease-specific target Identification Program (HiTDIP) aimed to study case-control association samples for 18 common diseases. Here we present the results of a follow-up case-control association study of HiTDIP in major depressive disorder (MDD). The HiTDIP in MDD was conducted in a sample of 974 cases of recurrent MDD of white German origin collected at the Max-Planck Institute (MP-GSK) and 968 ethnically matched controls screened for lifetime absence of depression. Six genes were identified as of interest for a follow-up, based on the strength of the association and based on the interest as potential candidate target for developing new treatment for depression: Solute Carrier Family 4 Member 10 (SLC4A10), Dipeptidyl Peptidase IV (DPP4), Dopamine Receptor D3 (DRD3), Zinc Finger Protein 80 (ZNF80), Nitric Oxide Synthase 2A (NOS2A) and Peroxisome Proliferator-Activated Receptor-Gamma, Coactivator 1, Alpha (PPARGC1A). Within the current study, we attempted to follow-up these findings in a sample from the UK, the Depression Case Control (DeCC) sample consisting of 1,196 cases and 842 screened controls, phenotyped using exactly the same methods as the MP-GSK sample. Performing Cochran-Mantel-Haenzel statistics to test for genotypic and/or allelic differences between the DeCC and MP-GSK samples, we found no significant differences, thus being able to combine the two samples for association testing. In the combined sample of 2,170 MDD cases and 1,810 controls, there were positive findings in the Nitric Oxide Synthase 2A (NOS2A) gene both using single SNP analysis and haplotype analysis.

The role of dopamine transporter (SLC6A3) and dopamine D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) gene polymorphisms in personality traits.

Variations in personality traits are caused by interactions between multiple genes of small effect and environmental factors. To date, gender- and ethnicity-specific variations in personality have been established. In the present study, we aimed to test: (1) the effects of four polymorphisms of dopamine system genes: ANKK1/DRD2 Taq1A, DRD2 rs6275, SLC6A3 40-bp VNTR and rs27072, on personality traits; (2) whether these effects differ between men and women and between Russians and Tatars. A sample of 652 healthy individuals (222 men and 430 women) of Caucasian origin (233 Russians and 419 Tatars) from Russia was subjected to personality traits assessment with Eysenck Personality Inventory (EPI) and Temperament and Character Inventory-125 (TCI-125). The associations between each personality trait and polymorphisms were assessed with regression models adjusted for gender and ethnicity. There were significant effects of ANKK1/DRD2 Taq1A on Neuroticism (p=0.016) and of SLC6A3 rs27072 on Persistence (p=0.021) in both genders. The association between ANKK1/DRD2 Taq1A A2/A2-genotype and higher Novelty Seeking and lower Reward Dependence was shown in men only (p for gender interaction=0.018). In women only, there was a significant association between SLC6A3 10R*G-haplotype and higher Persistence (p=0.002). Our findings provide evidence for a modifying effect of gender on the associations between dopamine system genes and approach-related traits (in men) and Persistence (in women).

Symptoms of depression and anxiety, and change in body mass index from adolescence to adulthood: results from a British birth cohort.

BACKGROUND: Depression and anxiety have been shown to be associated with obesity and underweight, but little is known about how the relationship varies across the life course, from adolescence through adulthood. We aimed to investigate the association between adolescent- and adult-onset affective symptoms and body mass index (BMI) change from age 15 to 53 years. METHOD: We used data from a British birth cohort born in 1946 and followed up ever since. The relationship between affective symptom profiles, distinguishing adolescent-onset and adult-onset symptoms, and BMI change from adolescence to age 53 years was investigated using multilevel models. RESULTS: Women with adolescent-onset symptoms had lower mean BMI at age 15 years, faster rates of increase across adulthood, and higher BMI at age 53 years than those with no symptoms. Men with adolescent-onset symptoms had lower BMI at all ages from 15 to 53 years. The BMI trajectories of men and women with adult-onset symptoms did not differ from those with absence of symptoms at all ages. CONCLUSIONS: The relationship between affective symptoms and change in BMI varies by sex and age at onset of symptoms. Adolescence may be an important period for the development of the association between affective symptoms and weight gain in girls. Intervention to prevent increases in BMI across adult life in women with adolescent-onset symptoms, even if they are not overweight at this age, should be considered.

Association of DISC1 and TSNAX genes and affective disorders in the depression case-control (DeCC) and bipolar affective case-control (BACCS) studies.

The gene known as Disrupted-in-Schizophrenia-1, DISC1, was originally discovered in a large family, in which it also co-segregated with bipolar affective disorder (BD) and with major depressive disorder (MDD). The TSNAX (Translin-associated factor X) gene, located immediately upstream of DISC1, has also been suggested as a candidate gene in relation to psychiatric illness, as one transcript resulting from intergenic splicing encodes a novel TSNAX-DISC1 fusion protein. We explored the TSNAX-DISC1 gene region for an association with BD and MDD in a sample of 1984 patients (1469 MDD, 515 BD) and 1376 ethnically matched controls. Eight single nucleotide polymorphisms (SNPs) within the TSNAX-DISC1 region (rs766288, rs3738401, rs2492367, rs6675281, rs12133766, rs1000731, rs7546310 and rs821597) were investigated using the SNPlex Genotyping System. We found a significant allelic and genotypic association of the TSNAX-DISC1 gene region with BD, whereas a haplotypic association was found for both BD and MDD. Therefore, our results suggest an association between the TSNAX-DISC1 region and both forms of affective disorders, and support the hypothesis that a portion of the genotypic overlap between schizophrenia and affective disorders is attributable to this gene.

NRG1 gene in recurrent major depression: no association in a large-scale case-control association study.

The Neuregulin 1 (NRG1) gene was initially implicated in schizophrenia (SZ) and has recently been associated with bipolar disorder (BPD) in two studies. An association with major depressive disorder (MDD) has not yet been investigated but is warranted in view of the genetic overlap between MDD and BPD. We have performed a large-scale case-control study investigating the association between NRG1 polymorphisms and MDD, genotyping a selection of 14 single nucleotide polymorphisms (SNPs) spanning the NRG1 gene in a sample of 1,398 patients of White European ancestry with a diagnosis of MDD and 1,304 ethnically matched controls from three clinical sites in the UK. We found no single marker or haplotype associations that withstood correction for multiple testing. Our findings do not provide evidence that NRG1 plays a role in MDD or that this gene explains part of the genetic overlap with BPD.

No association with the 5,10-methylenetetrahydrofolate reductase gene and major depressive disorder: results of the depression case control (DeCC) study and a meta-analysis.

Unipolar major depressive disorder (MDD) is a complex disorder thought to result from multiple genes in combination with environmental and developmental components. The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) has been implicated in MDD in a meta-analysis of association studies and is within a linkage region suggested by a recent study of affected sib pairs. A single base mutation in the MTHFR gene (C677T) results in the production of a mildly dysfunctional thermolabile enzyme. The MTHFR 677TT genotype, and to a lesser extent the 677CT genotype, is associated with a significant elevation in the circulating concentrations of homocysteine and a decrease in serum folate concentrations. This may parallel a similar reduction in 5-methyltetrahydrofolate in the CNS, leading to a potential reduction in monoamine neurotransmitter function and an elevated risk of depressive disorder. To test the hypothesis that the MTHFR C677T polymorphism is involved in the predisposition to MDD, we conducted an association study of 1,222 patients with recurrent MDD and 835 control subjects. This allows 99% power to detect an effect of the size reported in the study of Bjelland et al. 2003, however no significant differences in genotype or allele frequencies between depressive patients and controls were observed. This was the case in the sample as a whole, and when females and males were considered separately. Our findings suggest that the MTHFR C677T polymorphism is not involved in the etiology of clinically significant recurrent MDD.