Polygenic and pleiotropic effects on clinical heterogeneity in major depression

Currently, a diagnosis of MD requires that at least five of nine DSM accessory symptoms be present, although patients vary with respect to the particular combination of symptoms endorsed. These nine criteria do not appear to... [ view full abstract ]

Currently, a diagnosis of MD requires that at least five of nine DSM accessory symptoms be present, although patients vary with respect to the particular combination of symptoms endorsed. These nine criteria do not appear to reflect a single underlying genetic factor; instead, concordance among 7,500 adult twin pairs was best explained by three factors representing psychomotor/cognitive, mood, and neurovegetative dimensions of MD (Kendler et al. 2013). In particular, neurovegetative and reversed neurovegetative symptoms—reflecting depression-related changes in weight, appetite, and sleep—seem to implicate energy balance, and despite numerous associations between MD and relevant, comorbid medical conditions (e.g. obesity), there has been limited research on shared liability that addresses heterogeneity in a genetically informed framework. Using detailed clinical information and molecular genetic data from the CONVERGE study of MD in Han Chinese women, along with publicly available genome-wide summary statistics, we consider the evidence in support of widespread pleiotropy between MD and a range of anthropometric traits and metabolic outcomes, and compare the polygenic profiles of MD cases reporting contrasting neurovegetative and reversed neurovegetative symptoms. Subsequent genome-wide association studies (GWAS) employ a ‘case-only’ approach to identify associations between single nucleotide polymorphisms (SNPs) and symptom-based outcomes (e.g. weight gain versus weight loss). In collaboration with independent large-scale European studies, we replicate and perform trans-ancestry fine-mapping of detected loci. Finally, we discuss implications of convergent pleiotropy and comorbidity between psychiatric and metabolic outcomes for genetic studies of multifactorial traits.