@article {Howard134601, author = {David M. Howard and Toni-Kim Clarke and Mark J. Adams and Jonathan D. Hafferty and Eleanor M. Wigmore and Yanni Zeng and Lynsey S. Hall and Jude Gibson and Thibaud S. Boutin and Caroline Hayward and Pippa A. Thomson and David J. Porteous and Blair H. Smith and Alison D. Murray and Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium and Chris S. Haley and Ian J. Deary and Heather C. Whalley and Andrew M. McIntosh}, title = {The stratification of major depressive disorder into genetic subgroups}, elocation-id = {134601}, year = {2017}, doi = {10.1101/134601}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Major depressive disorder (MDD) is a heritable condition (h2 = 37\%)1 and a leading cause of disability worldwide2. MDD is clinically heterogeneous and comorbid with a variety of conditions and it has been hypothesised that this causal heterogeneity may have confounded previous attempts to elucidate its genetic architecture3-5. We applied a relatively new technique, Buhmbox6, to identify the presence of heterogeneous sub-groups within MDD using summary data from genome-wide association studies. We analysed two independent cohorts (ntotal = 31,981) and identified significant evidence (Pcorrected \< 0.05) for 10 sub-groups across both cohorts, including subgroups with a liability for migraine, alcohol consumption and eczema. The most notable subgroups (Pcorrected <= 2.57 {\texttimes} 10-8 in both cohorts) were for blood levels of cholesterol and triglycerides, and blood pressure, indicating subgroups within MDD cases of individuals with a genetic predisposition for anomalous levels of these metabolic traits. Our findings provide strong evidence for novel causal heterogeneity of MDD and identify avenues for both stratification and treatment.}, URL = {https://www.biorxiv.org/content/early/2017/05/05/134601}, eprint = {https://www.biorxiv.org/content/early/2017/05/05/134601.full.pdf}, journal = {bioRxiv} }