Maaike Verhagen

Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: effects of gender and ethnicity.

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has antidepressant-like effects in animals and may be implicated in the etiology of mood-related phenotypes. However, genetic association studies of the BDNF Val66Met polymorphism (single nucleotide polymorphism rs6265) in major depressive disorder (MDD) have produced inconsistent results. We conducted a meta-analysis of studies comparing the frequency of the BDNF Val66Met-coding variant in depressed cases (MDD) and nondepressed controls. A total of 14 studies involving 2812 cases with DSM-III or -IV defined MDD and 10 843 nondepressed controls met the inclusion criteria. Analyses were stratified either by gender or ethnicity (Asian and Caucasian) because MDD is more prevalent in women and in Caucasians and because BDNF allele frequencies differ by ethnicity. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were provided for allelic analyses (Met versus Val), as well as for genotypic analyses (Met/Met and Val/Met versus Val/Val). In the total sample, the BDNF Val66Met polymorphism was not significantly associated with depression. However, the gender stratified analyses revealed significant effects in both the allelic and genotypic analyses in men (ORMET, 95% CI; 1.27 (1.10–1.47); ORMET/MET, 95% CI; 1.67 (1.19–2.36)). Stratification according to ethnicity did not show significant effects of the Val66Met polymorphism on MDD. Our results suggest that the BDNF Val66Met polymorphism is of greater importance in the development of MDD in men than in women. Future research into gender issues will be of interest.

Loneliness Across the Life Span

Most people have experienced loneliness and have been able to overcome it to reconnect with other people. In the current review, we provide a life-span perspective on one component of the evolutionary theory of loneliness—a component we refer to as the reaffiliation motive (RAM). The RAM represents the motivation to reconnect with others that is triggered by perceived social isolation. Loneliness is often a transient experience because the RAM leads to reconnection, but sometimes this motivation can fail, leading to prolonged loneliness. We review evidence of how aspects of the RAM change across development and how these aspects can fail for different reasons across the life span. We conclude with a discussion of age-appropriate interventions that may help to alleviate prolonged loneliness.

Genome-wide association uncovers shared genetic effects among personality traits and mood states.

Measures of personality and psychological distress are correlated and exhibit genetic covariance. We conducted univariate genome‐wide SNP (∼2.5 million) and gene‐based association analyses of these traits and examined the overlap in results across traits, including a prediction analysis of mood states using genetic polygenic scores for personality. Measures of neuroticism, extraversion, and symptoms of anxiety, depression, and general psychological distress were collected in eight European cohorts (n ranged 546–1,338; maximum total n = 6,268) whose mean age ranged from 55 to 79 years. Meta‐analysis of the cohort results was performed, with follow‐up associations of the top SNPs and genes investigated in independent cohorts (n = 527–6,032). Suggestive association (P = 8 × 10−8) of rs1079196 in the FHIT gene was observed with symptoms of anxiety. Other notable associations (P < 6.09 × 10−6) included SNPs in five genes for neuroticism (LCE3C, POLR3A, LMAN1L, ULK3, SCAMP2), KIAA0802 for extraversion, and NOS1 for general psychological distress. An association between symptoms of depression and rs7582472 (near to MGAT5 and NCKAP5) was replicated in two independent samples, but other replication findings were less consistent. Gene‐based tests identified a significant locus on chromosome 15 (spanning five genes) associated with neuroticism which replicated (P < 0.05) in an independent cohort. Support for common genetic effects among personality and mood (particularly neuroticism and depressive symptoms) was found in terms of SNP association overlap and polygenic score prediction. The variance explained by individual SNPs was very small (up to 1%) confirming that there are no moderate/large effects of common SNPs on personality and related traits.

Loneliness in adolescence: Gene x environment interactions involving the serotonin transporter gene

BACKGROUND Loneliness is assumed to peak in early adolescence and to decrease throughout middle and late adolescence, but longitudinal confirmation of this tendency is lacking. Behavioral genetic studies with twin designs have found a significant genetic component for loneliness in children and adults, but no molecular genetic studies have been conducted to reveal the functional polymorphisms involved. METHODS Associations among the serotonin transporter gene (5-HTTLPR), sex, parental support, and loneliness were examined in a longitudinal study spanning five annual waves (N = 306). RESULTS Using latent growth curve modeling (LGCM), loneliness was found to be highest in early adolescence and slowly declined throughout adolescence. The 5-HTTLPR genotype was related to the development of loneliness, in that short allele carriers remained stable in loneliness over time, whereas adolescents with the long-long genotype decreased in loneliness. Interactions were found between maternal support and 5-HTTLPR genotype, showing that adolescents who perceived little support from their mothers and carried a short allele were at increased risk for developing loneliness. CONCLUSIONS Our study is the first to chart adolescent loneliness longitudinally and to examine the genetic underpinnings of loneliness. Our results contribute to a further understanding of the environmental and genetic basis of loneliness. Replication of our results is needed in both population-based and clinical samples.

The Genetics of Loneliness: Linking Evolutionary Theory to Genome-Wide Genetics, Epigenetics, and Social Science

As a complex trait, loneliness is likely to be influenced by the interplay of numerous genetic and environmental factors. Studies in behavioral genetics indicate that loneliness has a sizable degree of heritability. Candidate-gene and gene-expression studies have pointed to several genes related to neurotransmitters and the immune system. The notion that these genes are related to loneliness is compatible with the basic tenets of the evolutionary theory of loneliness. Research on gene-environment interactions indicates that social-environmental factors (e.g., low social support) may have a more pronounced effect and lead to higher levels of loneliness if individuals carry the sensitive variant of these candidate genes. Currently, there is no extant research on loneliness based on genome-wide association studies, gene-environment-interaction studies, or studies in epigenetics. Such studies would allow researchers to identify networks of genes that contribute to loneliness. The contribution of genetics to loneliness research will become stronger when genome-wide genetics and epigenetics are integrated and used along with well-established methods in psychology to analyze the complex process of gene-environment interplay.

A systematic review of the A118G (Asn40Asp) variant of OPRM1 in relation to smoking initiation, nicotine dependence and smoking cessation

Candidate gene studies on smoking behaviors mainly focused on dopaminergic and serotonergic genes, but genes within the µ-opioid system might also be involved. The A118G variant within the OPRM1 gene has been most often examined in relation to smoking, yielding inconsistent findings. It is largely unknown which of the alleles increases susceptibility for smoking behaviors. The aim of this review was to merge findings of OPRM1 gene studies in relation to smoking behaviors and to elaborate on the underlying biological mechanism of the A118G variant. It appeared that A118 was more likely to increase susceptibility to smoking behaviors than 118G, especially with regard to nicotine dependence, but less with smoking initiation and cessation. The proposed functioning of the OPRM1 gene is further explained.

The dopamine D2 receptor gene, perceived parental support, and adolescent loneliness: longitudinal evidence for gene–environment interactions

BACKGROUND Loneliness is a common problem in adolescence. Earlier research focused on genes within the serotonin and oxytocin systems, but no studies have examined the role of dopamine-related genes in loneliness. In the present study, we focused on the dopamine D2 receptor gene (DRD2). METHODS Associations among the DRD2, sex, parental support, and loneliness were examined in a longitudinal study spanning five annual waves (N = 307). RESULTS Using Latent Growth Curve Modeling, DRD2 genotype was not directly related to loneliness. Interactions were found between parental support and DRD2 genotype, showing that adolescents with the A2A2 genotype who perceived little support from their parents had the highest baseline levels of loneliness. Adolescents with an A1 allele were not susceptible to the rewarding effect of parental support. CONCLUSIONS The present study is the first to examine the role of the DRD2 genotype in loneliness. Our results contribute to a further understanding of the environmental and genetic basis of loneliness in adolescence.

The Oxytocin Receptor Gene (OXTR) in Relation to State Levels of Loneliness in Adolescence: Evidence for Micro-Level Gene-Environment Interactions

Previous research has shown that the rs53576 variant of the oxytocin receptor gene (OXTR) is associated with trait levels of loneliness, but results are inconsistent. The aim of the present study is to examine micro-level effects of the OXTR rs53576 variant on state levels of loneliness in early adolescents. In addition, gene-environment interactions are examined between this OXTR variant and positive and negative perceptions of company. Data were collected in 278 adolescents (58% girls), by means of the Experience Sampling Method (ESM). Sampling periods consisted of six days with nine assessments per day. A relation was found between the OXTR rs53576 variant and state loneliness, in girls only. Girls carrying an A allele had higher levels of state loneliness than girls carrying the GG genotype. In addition, adolescents with an A allele were more affected by negative perceptions of company than GG carriers, on weekend days only. No significant gene-environment interactions were found with positive company. Adolescents carrying an A allele were more susceptible to negative environments during weekend days than GG carriers. Our findings emphasize the importance of operationalizing the phenotype and the environment accurately.

Familiality of depression in the community; associations with gender and phenotype of major depressive disorder

IntroductionAlthough associations between family history and depression have been shown in clinical patients, it is unknown if they also apply to subjects living in the community. The present study considers the relationship between family loading and depression phenotype characteristics in a large community-based sample.MethodIn a Dutch representative population sample of 7,076 individuals, lifetime diagnosis of depression was classified according to severity, course and age of onset. A family loading score of depression (FLSD) was computed by taking the proportion of the first-degree relatives for whom a history of depression was reported.ResultsThere was a strong association between FLSD and lifetime diagnosis of MDD. Severity, recurrence and early onset of depression were the specific phenotypic characteristics associated with familiality. The effects of FLSD and gender were independent.ConclusionAssociations between family history and risk for depression in the community confirm those reported from clinical-based studies using direct interviewing of relatives. A stronger degree of familiality is associated with specific phenotypic characteristics of depression.

Familiality of major depressive disorder and gender differences in comorbidity.

Objective:  Gender differences exist in the prevalence and psychiatric comorbidity of major depressive disorder (MDD). This study investigates whether familiality of MDD contributes to observed gender differences in comorbidity.