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 x 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.
STratifying Resilience and Depression Longitudinally (STRADL)
Progress in understanding the causes of major depressive disorder has been slow. Dividing depression into subtypes, a process called stratification, could ultimately lead to faster progress.
We will stratify or divide individuals with MDD and depressive syndromes into more similar groups of people in UK Biobank.
Our aims are to:
1. Identify and describe specific subtypes of depression
2. Identify the causes underlying different types of depression using GWAS and MRI
3. Test whether resistance to depression (i.e. resilience) to depression can be accurately measured.
4. Identify the mechanisms underlying resilience using genetic and brain imaging data. This research seeks to use the medical, cognitive, imaging and genetic data from UKBiobank to study the mechanisms of common medical conditions and use them as a platform to better diagnosis. These aims are consistent with UK Biobank's. Providing this information will help to identify new drug targets for depression. Stratifying depression into more homogenous categories will provide better 'disease' targets for other research studies because there will be less lumping together of individuals with different causes for their illness within the same broad category of depression. We will test whether these sub-classes of depression and depressive symptom have neurobiological associations in UKbiobank by comparing them with depressed individuals as w whole, as well as controls, using MRI and genetic data.
We will firstly examine the associations of depression with cognition (baseline measures and web-based measures of attention and memory, for example), brain structure, function and connection strength (MRI).
We will examine the association of different depression types with biological intermediates (measurable variables important in the causation of depression) using a technique called polygenic profiling.
We will also compare resilient and non-resilient individuals. We are interested in the full UKbiobank cohort for most analyses - and the subgroup of UKbiobank with genetic and imaging (brain MRI) data for more detailed analysis.
We appreciate the time scale for the availability of genotyping and imaging data.
|Professor Andrew McIntosh
|University of Edinburgh
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