Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways

Depression is a polygenic trait that causes extensive periods of disability. Previous genetic studies have identified common risk variants which have progressively increased in number with increasing sample sizes of the respective studies. Here, we conduct a genome-wide association study in 322,580 UK Biobank participants for three depression-related phenotypes: broad depression, probable major depressive disorder (MDD), and International Classification of Diseases (ICD, version 9 or 10)-coded MDD. We identify 17 independent loci that are significantly associated (P < 5 × 10−8) across the three phenotypes. The direction of effect of these loci is consistently replicated in an independent sample, with 14 loci likely representing novel findings. Gene sets are enriched in excitatory neurotransmission, mechanosensory behaviour, post synapse, neuron spine and dendrite functions. Our findings suggest that broad depression is the most tractable UK Biobank phenotype for discovering genes and gene sets that further our understanding of the biological pathways underlying depression

Foot orthoses for the management of low back pain: a qualitative approach capturing the patient’s perspective

Background: The onset of non specific low back pain is associated with heavy lifting, age, female gender, and poor general health, with psychological factors being predictors of it becoming chronic. Additionally, it is thought that altered lower limb biomechanics are a contributory factor, with foot orthoses increasingly being considered as an appropriate intervention by physiotherapists and podiatrists. However, research into the effect of foot orthoses is inconclusive, primarily focusing on the biomechanical effect and not the symptomatic relief from the patient’s perspective. The aim of this study was to explore the breadth of patients’ experiences of being provided with foot orthoses and to evaluate any changes in their back pain following this experience. Method: Following ethical approval, participants (n = 25) with non-specific low back pain associated with altered lower limb biomechanics were provided with customised foot orthoses. At 16 weeks after being provided with the foot orthoses, conversational style interviews were carried out with each patient. An interpretivistic phenomenological approach was adopted for the data collection and analysis. Results: For these participants, foot orthoses appeared to be effective. However, the main influence on this outcome was the consultation process and a patient focussed approach. The consultation was an opportunity for fostering mutual understanding, with verbal and visual explanation reassuring the patient and this influenced the patient’s beliefs, their engagement with the foot orthoses (physical) and their experience of low back pain (psychological). Conclusion: Clinicians need to adopt ‘psychologically informed practice’ in relation to the provision of foot orthoses. Likewise, researchers should consider all the influencing factors found in this study, both in relation to their study protocol and the outcomes they plan to measure. Keywords: Low back pain, Foot orthoses, Qualitative research, Informatio

Network analysis of coronary artery disease risk genes elucidates disease mechanisms and druggable targets

Genome-wide association studies (GWAS) have identified over two hundred chromosomal loci that modulate risk of coronary artery disease (CAD). The genes affected by variants at these loci are largely unknown and an untapped resource to improve our understanding of CAD pathophysiology and identify potential therapeutic targets. Here, we prioritized 68 genes as the most likely causal genes at genome-wide significant loci identified by GWAS of CAD and examined their regulatory roles in 286 metabolic and vascular tissue gene-protein sub-networks ("modules"). The modules and genes within were scored for CAD druggability potential. The scoring enriched for targets of cardiometabolic drugs currently in clinical use and in-depth analysis of the top-scoring modules validated established and revealed novel target tissues, biological processes, and druggable targets. This study provides an unprecedented resource of tissue-defined gene-protein interactions directly affected by genetic variance in CAD risk loci

Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 x 10(-13)) and African ancestries (rs2066702; P = 2.2 x 10(-9)). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.Peer reviewe