Association study of 90 candidate gene polymorphisms in panic disorder

2005

Neuropsychopharmacol

Self Cite

106

The essential role of serotonin (5-hydroxytryptamine (5-HT)) system in the neurobiology and pharmacotherapy of panic disorder (PD) continues to be a topic of intensive interdisciplinary research. Interest in the involvement of 5-HT in PD has been fuelled by clinical studies demonstrating that medications increasing the synaptic availability of 5-HT, such as selective 5-HT re-uptake inhibitors, are effective in the treatment of PD. Rival theories of 5-HT deficiency vs excess have attempted to explain the impact of 5-HT function in PD. In the past decade, knowledge of the role of 5-HT in the neurobiology of PD has expanded dramatically due to much new research including experimental, treatment, brain-imaging, and genetic studies. The current review attempts to summarize the new data and their implications. The challenge and treatment studies generally confirm the specific inhibitory influence of 5-HT on panicogenesis. The brainimaging studies in PD patients demonstrate functional and clinically relevant alterations in various elements of 5-HT system affecting the neurocircuitry of panic. The findings of genetic association studies suggest that certain 5-HT-related genes may contribute to the susceptibility to PD; however, these data are rather limited and inconsistent. It appears that, even if not the primary etiological factor in PD, the 5-HT function conveys important vulnerability, as well as adaptive factors. A better understanding of these processes may be critical in achieving progress in the treatment of patients suffering from PD.

Section: -Ht Receptor Genessupporting

confidence: 71%

Section: -Ht Receptor Genessupporting

confidence: 44%

Section: -Ht Receptor Genesmentioning

confidence: 74%

Section: -Ht Receptor Genesmentioning

confidence: 95%

Section: Tph Genementioning

confidence: 99%

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Serotonin Function in Panic Disorder: Important, But Why?

2005

Neuropsychopharmacol

Self Cite

106

Genetics of Panic Disorder

Encyclopedia of Life Sciences

2013

The molecular genetic research on panic disorder (PD) has grown tremendously in the past decade. To date, several hundreds of candidate genes have been examined in association studies, but most of the results have been negative, inconsistent or awaiting replication. Perhaps most intriguing have been findings involving the genes of biological systems known to be pertinent to anxiety phenotypes, such as serotonin, cholecystokinin and adenosine. An array of other genes related to hormonal, neurotrophic and intracellular systems has also been implicated in disposition to PD. The recent advances in bioinformatics and genotyping technologies, including genome‐wide association and gene expression methods, promise more comprehensive discovery in PD. Preliminary findings point to a number of novel gene targets with still unknown pathogenetic relationship to PD. The progress in clinical and neurobiological concepts of PD may further guide genetic research through the current ambiguity to more definitive findings. Key Concepts: The linkage and candidate gene association studies have so far showed only weak success to identify reliable and replicated evidence for the genetic substrate of PD. The genetic research in PD to date has been mostly restricted to small phenotypically and ethnically diverse datasets with genotyping of limited numbers of SNPs. An improved understanding of neurobiological pathways of PD could contribute to a more effective identification of candidate genes. Novel conceptual and analytic approaches, such as pathways‐based analyses, may help to advance GWA studies in PD. Laboratory panic challenge models may provide clues to genetic predisposition to PD. The understanding of genetic underpinnings of PD will not be of full value without a conceptual integration of the clinical phenomena of PD with psychological models and neurobiological or molecular substrates underlying its development and course. The course of PD may depend on the balance between pathogenetic and compensatory or recovery processes, accompanied by activation or inhibition of relevant genes. PD might exist in many distinct genetic forms, each with a different set of genes, but also in one form with certain genes reflecting broader vulnerability to panicogenesis. The heterogeneity in PD phenotypes, age of onset, subtypes and severity of panic attacks, gender and familial aggregation were not sufficiently accounted for in most of published studies and should be more carefully addressed in further analyses. Other comprehensive genetic approaches, including GWA, the analysis of copy number variants and the study of regulatory small noncoding RNAs, may lead to uncovering new genomic mechanisms of PD.

Genetic Factors and Gene–Environment Interactions

The Wiley Handbook of Anxiety Disorders

2014

Previous genome-wide association studies (GWAS) have identified hundreds of genetic loci to be associated with body mass index (BMI) and risk of obesity. Genetic effects can differ between individuals depending on lifestyle or environmental factors due to gene-environment interactions. In this study, we examine gene-environment interactions in 362,496 unrelated participants with Caucasian ancestry from the UK Biobank resource. A total of 94 BMI-associated SNPs, selected from a previous GWAS on BMI, were used to construct weighted genetic scores for BMI (GS BMI). Linear regression modeling was used to estimate the effect of gene-environment interactions on BMI for 131 lifestyle factors related to: dietary habits, smoking and alcohol consumption, physical activity, socioeconomic status, mental health, sleeping patterns, as well as female-specific factors such as menopause and childbirth. In total, 15 lifestyle factors were observed to interact with GS BMI , of which alcohol intake frequency , usual walking pace, and Townsend deprivation index, a measure of socioeconomic status, were all highly significant (p = 1.45*10 −29 , p = 3.83*10 −26 , p = 4.66*10 −11 , respectively). Interestingly, the frequency of alcohol consumption, rather than the total weekly amount resulted in a significant interaction. The FTO locus was the strongest single locus interacting with any of the lifestyle factors. However, 13 significant interactions were also observed after omitting the FTO locus from the genetic score. Our analyses indicate that many lifestyle factors modify the genetic effects on BMI with some groups of individuals having more than double the effect of the genetic score. However, the underlying causal mechanisms of gene-environmental interactions are difficult to deduce from cross-sectional data alone and controlled experiments are required to fully characterise the causal factors. Author summary Genome-wide association studies (GWAS) have identified hundreds of genes as being associated with body mass index (BMI). How these genetic effects are modulated by lifestyle factors has not been extensively investigated previously. Here we utilise data from PLOS Genetics | https://doi.org/10.1371/journal.pgen.approximately 360,000 participants from the UK Biobank, aged 40-69 years old, to identify interactions between genetic and lifestyle factors in relation to BMI. We investigated 131 lifestyle factors, of which 15 influence the genetic effects on BMI. The most significant factors were those related to physical activity, alcohol consumption, and socioeconomic status. For example, the effect of a genetic score for BMI was almost twice as high in participants who reported never drinking alcohol compared to everyday drinkers. Similarly, the effect of the genetic score for BMI was 2.5 times higher in participants who reported having a slow walking pace compared to participants who reported having a brisk walking pace. Our results show that many lifestyle factors influence the genetic effects, which suggests that changing our lif...